color atlas of neurology

Color Atlas of NeurologyReinhard Rohkamm, M.D.ProfessorNeurological ClinicNordwest-Krankenhaus SanderbuschSande, Germany

172 illustrations by Manfred Güther

Translation revised by Ethan Taub, M.D.

ThiemeStuttgart · New York


Library of Congress Cataloging-in-PublicationData is available from the publisher.

This book is an authorized translation of the2nd German edition published and copyrighted2003 by Georg Thieme Verlag, Stuttgart, Ger-many. Title of the German edition:Taschenatlas Neurologie

Original translator: Suzyon O’Neal Wandrey,Berlin, Germany

Translator/editor: Ethan Taub, M.D., Zürich,Switzerland

Importantnote:Medicine is anever-chang-ing science undergoing continual develop-ment. Research and clinical experience arecontinually expanding our knowledge, inparticular our knowledge of proper treat-ment and drug therapy. Insofar as this bookmentions any dosage or application, read-ers may rest assured that the authors, edi-tors, andpublishers havemade every effortto ensure that such references are in accor-dance with the state of knowledge at thetime of production of the book.Nevertheless, this does not involve, imply,or express any guarantee or responsibilityon the part of the publishers in respect toany dosage instructions and forms of appli-cations stated in the book. Every user is re-quested to examine carefully themanufac-turers‘ leaflets accompanying each drugand to check, if necessary in consultationwith a physician or specialist, whether thedosage schedulesmentioned therein or thecontraindications stated by the manufac-turers differ from the statements made inthe present book. Such examination is par-ticularly important with drugs that areeither rarely used or have been newly re-leased on the market. Every dosageschedule or every form of application usedis entirely at the user’s own risk and re-sponsibility. The authors andpublishers re-quest every user to report to the publishersany discrepancies or inaccuracies noticed.

Some of the product names, patents, and regis-tered designs referred to in this book are in factregistered trademarks or proprietary nameseven though specific reference to this fact is notalwaysmade in the text. Therefore, the appear-ance of a name without designation as pro-prietary is not to be construed as a representa-tion by the publisher that it is in the publicdomain.This book, including all parts thereof, is legallyprotected by copyright. Any use, exploitation,or commercialization outside the narrow limitsset by copyright legislation, without the pub-lisher’s consent, is illegal and liable to prosecu-tion. This applies in particular to photostat re-production, copying, mimeographing, prepara-tion of microfilms, and electronic data pro-cessing and storage.

© 2004 Georg Thieme Verlag,Rüdigerstrasse 14, 70469 Stuttgart, Germanyhttp://www.thieme.deThieme New York, 333 Seventh Avenue,New York, NY 10001 USAhttp://www.thieme.com

Cover design: Cyclus, StuttgartTypesetting by primustype R. Hurler GmbH,NotzingenPrinted in Germany by Grammlich, Pliez-hausen

ISBN 3-13-130931-8 (GTV)ISBN 1-58890-191-2 (TNY) 1 2 3 4 5


PrefaceThe nervous system and the muscles are theseat of many primary diseases and are affectedsecondarily by many others.This pocket atlas is intended as an aid to the de-tection and diagnosis of the symptoms and signsof neurological disease. The text and illustra-tions are printed on facing pages, to facilitatelearning of the points presented in each.The book begins with a summary of the fun-damentals of neuroanatomy in Chapter 1. Chap-ter 2 concerns the functions of the nervous sys-tem and the commonly encountered syndromesin clinical neurology. Individual neurologicaldiseases are discussed in Chapter 3. The clinicalneurological examination is best understoodonce the material of the first three chapters ismastered; it is therefore presented in the lastchapter, Chapter 4.The choice of topics for discussion is directedtoward questions that frequently arise in clinicalpractice. Some of the illustrations have been re-produced from previous works by other authors,because they seemed to us to be optimal solu-tions to the problem of visually depicting a diffi-cult subject. In particular, we would like to paytribute here to the graphic originality of the lateDr. Frank H. Netter.Many people have lent us a hand in the creationof this book. Our colleagues at the SanderbuschNeurological Clinic were always ready to help usface the difficult task of getting the book writtenwhile meeting the constant demands of patientcare. I (R.R.) would particularly like to thank ourOberärzte (Senior Registrars), Drs. Helga Bestand Robert Schumann, for their skillful coopera-

tion and support over several years of work.Thanks are also due to the radiologists, Drs.Benno Wördehoff and Ditmar Schönfeld, forproviding images to be used in the illustrations.This book would never have come aboutwithout the fascination for neurology that wasinstilled in me in all the stages of my clinicaltraining; I look back with special fondness onthe time I spent as a Resident in the Departmentof Neurology at the University of New Mexico(Albuquerque). Above all, I thank the manypatients, past and present, who have entrustedme with their care.Finally, cordial thanks are due to the publishers,Georg Thieme Verlag, for their benevolent andsurefooted assistance throughout the develop-ment of this book, and for the outstanding qual-ity of its production. Among the many membersof the staff to whom we are grateful, we wouldlike to single out Dr. Thomas Scherb, with whomwe were able to develop our initial ideas aboutthe format of the book, as well as Dr. CliffordBergman and Gabriele Kuhn, who saw this edi-tion through to production with assurance, ex-pertise, and the necessary dose of humor.We dedicate this book to our families: Christina,Claire, and Ben (R.R.) and Birgit, Jonas, and Lukas(M.G.).

Reinhard Rohkamm, SandeManfred Güther, BermatingenAutumn 2003


Contents

1 Fundamentals 1

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Meninges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Cerebrospinal Fluid . . . . . . . . . . . . . . . . . . . . . . 8

Blood Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Carotid Arteries . . . . . . . . . . . . . . . . . . . . . . . . . 11Anterior Circulation of the Brain . . . . . . . . . 12Vertebral and Basilar Arteries . . . . . . . . . . . . 14Posterior Circulation of the Brain . . . . . . . . 16Intracranial Veins . . . . . . . . . . . . . . . . . . . . . . . 18Extracranial Veins . . . . . . . . . . . . . . . . . . . . . . . 20Spinal Circulation . . . . . . . . . . . . . . . . . . . . . . . 22

Central Nervous Sysstem . . . . . . . . . . . . . . . . 24Anatomical and Functional Organization . 25Brain Stem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . 28Spine and Spinal Cord . . . . . . . . . . . . . . . . . . . 30

Peripheral Nervous System . . . . . . . . . . . . . . 32Dermatomes and Myotomes . . . . . . . . . . . . . 33Brachial Plexus . . . . . . . . . . . . . . . . . . . . . . . . . 34Nerves of the Upper Limb . . . . . . . . . . . . . . . 35Lumbar Plexus . . . . . . . . . . . . . . . . . . . . . . . . . . 36Nerves of the Lower Limb . . . . . . . . . . . . . . . 37

2 Normal and Abnormal Function of the Nervous System 39

Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . 40Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Motor Control . . . . . . . . . . . . . . . . . . . . . . . . . . 42Motor Execution . . . . . . . . . . . . . . . . . . . . . . . . 44Central Paralysis . . . . . . . . . . . . . . . . . . . . . . . . 46Peripheral Paralysis . . . . . . . . . . . . . . . . . . . . . 50Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Vestibular System . . . . . . . . . . . . . . . . . . . . . . . 56Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Gait Disturbances . . . . . . . . . . . . . . . . . . . . . . . 60Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Chorea, Ballism, Dyskinesia, Myoclonus . . 66Myoclonus, Tics . . . . . . . . . . . . . . . . . . . . . . . . . 68

Brain Stem Syndromes . . . . . . . . . . . . . . . . . . 70Midbrain Syndromes . . . . . . . . . . . . . . . . . . . . 71Pontine Syndromes . . . . . . . . . . . . . . . . . . . . . 72Medullary Syndromes . . . . . . . . . . . . . . . . . . . 73

Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . 74Skull Base Syndromes . . . . . . . . . . . . . . . . . . . 75Smell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Visual pathway . . . . . . . . . . . . . . . . . . . . . . . . . 80Visual Field Defects . . . . . . . . . . . . . . . . . . . . . 82Oculomotor Function . . . . . . . . . . . . . . . . . . . . 84Oculomotor Disturbances . . . . . . . . . . . . . . . . 86Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Pupillomotor Function . . . . . . . . . . . . . . . . . . 90Pupillary Dysfunction . . . . . . . . . . . . . . . . . . . 92Trigeminal Nerve . . . . . . . . . . . . . . . . . . . . . . . 94Facial Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Facial Nerve Lesions . . . . . . . . . . . . . . . . . . . . . 98Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Disturbances of Deglutition . . . . . . . . . . . . . . 102

Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Sensory Disturbances . . . . . . . . . . . . . . . . . . . 106


Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112Normal Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . 113Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 114

Disturbances of Consciousness . . . . . . . . . . . 116Acute Disturbances of Consciousness . . . . . 116Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Comalike Syndromes, Death . . . . . . . . . . . . . 120

Behavioral Manifestations of NeurologicalDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Aphasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Agraphia, Alexia, Acalculia, Apraxia . . . . . . 128Speech Disorders . . . . . . . . . . . . . . . . . . . . . . . 130

Disturbances of Orientation . . . . . . . . . . . . . . 132Disturbances of Memory . . . . . . . . . . . . . . . . 134Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136Pseudo-neurological Disorders . . . . . . . . . . . 138

Autonomic Nervous System (ANS) . . . . . . . . 140Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . . 142Limbic System and Peripheral ANS . . . . . . . 144Heart and Circulation . . . . . . . . . . . . . . . . . . . 148Respiration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . 152Gastrointestinal Function . . . . . . . . . . . . . . . . 154Bladder Function, Sexual Function . . . . . . . 156

Intracranial Pressure . . . . . . . . . . . . . . . . . . . . 158

3 Neurological Syndromes 165

Central Nervous System . . . . . . . . . . . . . . . . . 166Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Epilepsy: Seizure Types . . . . . . . . . . . . . . . . . 192Epilepsy: Classification . . . . . . . . . . . . . . . . . . 196Epilepsy: Pathogenesis and Treatment . . . 198Nonepileptic Seizures . . . . . . . . . . . . . . . . . . . 200Parkinson Disease: Clinical Features . . . . . . 206Parkinson Disease: Pathogenesis . . . . . . . . . 210Parkinson Disease: Treatment . . . . . . . . . . . 212Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . 214CNS Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 222Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266Cerebellar Diseases . . . . . . . . . . . . . . . . . . . . . . 276Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . 282Malformations and DevelopmentalAnomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288Neurodegenerative Diseases . . . . . . . . . . . . . 296Encephalopathies . . . . . . . . . . . . . . . . . . . . . . . 306

Peripheral Nerve and Muscle . . . . . . . . . . . . . 316Peripheral Neuropathies . . . . . . . . . . . . . . . . . 316Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334Neuromuscular Disorders . . . . . . . . . . . . . . . . 346

4 Diagnostic Evaluation 349

Diagnostic Evaluation . . . . . . . . . . . . . . . . . . . 350History and Physical Examination . . . . . . . . 350Neurophysiological and Neuro-psychological Tests . . . . . . . . . . . . . . . . . . . . . . 352

5 Appendix 355

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

Cerebrovascular Ultrasonography,Diagnostic Imaging, and BiopsyProcedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415

Contents


1Fundamentals

! Anatomy

! Physiology


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Neurology is the branch of medicine dealingwith diseases of the central, peripheral, and au-tonomic nervous systems, including the skeletalmusculature.

Central Nervous System (CNS)

! Brain

The forebrain or prosencephalon (supratentorialportion of the brain) comprises the telen-cephalon (the two cerebral hemispheres and themidline structures connecting them) and thediencephalon.The midbrain or mesencephalon lies betweenthe fore brain and the hind brain. It passesthrough the tentorium cerebelli.The hindbrain or rhombencephalon (infraten-torial portion of the brain) comprises the pons,the medulla oblongata (almost always called“medulla” for short), and the cerebellum. Themid brain, pons, and medulla together make upthe brain stem.

! Spinal cord

The spinal cord is approximately 45 cm long inadults. Its upper end is continuous with themedulla; the transition is defined to occur justabove the level of exit of the first pair of cervicalnerves. Its tapering lower end, the conus medul-laris, terminates at the level of the L3 vertebra inneonates, and at the level of the L1–2 interverte-bral disk in adults. Thus, lumbar punctureshould always be performed at or below L3–4.The conus medullaris is continuous at its lowerend with the threadlike filum terminale, com-posed mainly of glial and connective tissue,which, in turn, runs through the lumbar sacamidst the dorsal and ventral roots of the spinalnerves, collectively called the cauda equina(“horse’s tail”), and then attaches to the dorsalsurface of the coccyx. The cervical, thoracic,lumbar, and sacral portions of the spinal cordare defined according to the segmental divisionof the vertebral column and spinal nerves.

Peripheral Nervous System (PNS)

The peripheral nervous system connects thecentral nervous system with the rest of thebody. All motor, sensory and autonomic nervecells and fibers outside the CNS are generally

considered part of the PNS. Specifically, the PNScomprises the ventral (motor) nerve roots, dor-sal (sensory) nerve roots, spinal ganglia, and spi-nal and peripheral nerves, and their endings, aswell as a major portion of the autonomicnervous system (sympathetic trunk). The firsttwo cranial nerves (the olfactory and opticnerves) belong to the CNS, but the remainderbelong to the PNS.Peripheral nerves may be purely motor orsensory but are usually mixed, containing varia-ble fractions of motor, sensory, and autonomicnerve fibers (axons). A peripheral nerve is madeup of multiple bundles of axons, called fascicles,each of which is covered by a connective tissuesheath (perineurium). The connective tissuelying between axons within a fascicle is calledendoneurium, and that between fascicles iscalled epineurium. Fascicles contain myelinatedand unmyelinated axons, endoneurium, andcapillaries. Individual axons are surrounded bysupportive cells called Schwann cells. A singleSchwann cell surrounds several axons of unmy-elinated type. Tight winding of the Schwann cellmembrane around the axon produces the my-elin sheath that covers myelinated axons. TheSchwann cells of a myelinated axon are spaced asmall distance from one another; the intervalsbetween them are called nodes of Ranvier. Thenerve conduction velocity increases with thethickness of the myelin sheath. The specializedcontact zone between a motor nerve fiber andthe muscle it supplies is called the neuromuscu-lar junction or motor end plate. Impulses arisingin the sensory receptors of the skin, fascia,muscles, joints, internal organs, and other partsof the body travel centrally through the sensory(afferent) nerve fibers. These fibers have theircell bodies in the dorsal root ganglia (pseudo-unipolar cells) and reach the spinal cord by wayof the dorsal roots.

Autonomic Nervous System (ANS)

The autonomic nervous system regulates thefunction of the internal organs in response tothe changing internal and external environ-ment. It contains both central (p. 140 ff) and pe-ripheral portions (p. 146ff).

Overview

Overview


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Cerebrum (telencephalon)

Diencephalon Midbrain (mesencephalon)

Pons and cerebellum

Medulla oblongata

Telencephalonmidline structures

Conus medullaris

Filum terminale

Cutaneous receptorsMotor end plate

Ventral root

Dorsal rootSpinal ganglion

Spinal nerve

Mixed peripheral nerve

Sympathetic trunk

Ramus communi-cans

Myelinated nerve

Capillary

UnmyelinatednerveCapillary

Muscle fibers

Fibrocyte

Perineurium of a nerve

fascicle

Epineurium

Schwann cell nucleus

Node of Ranvier

Endoneurium

Central nervous system

Prosencephalon, brain stem

Spinal cord

Peripheral nervous system

Overview

Overview


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The skull (cranium) determines the shape of thehead; it is easily palpated through the thin lay-ers of muscle and connective tissue that cover it.It is of variable thickness, being thicker and stur-dier in areas of greater mechanical stress. Thethinner bone in temporal and orbital portions ofthe cranium provides the so-called bone win-dows through which the basal cerebral arteriescan be examined by ultrasound. Thinner por-tions of the skull are more vulnerable to trau-matic fracture. The only joints in the skull arethose between the auditory ossicles and thetemporomandibular joints linking the skull tothe jaw.

Neurocranium

The neurocranium encloses the brain, labyrinth,andmiddle ear. The outer and inner tables of theskull are connected by cancellous bone andmarrow spaces (diploë). The bones of the roof ofthe cranium (calvaria) of adolescents and adultsare rigidly connected by sutures and cartilage(synchondroses). The coronal suture extendsacross the frontal third of the cranial roof. Thesagittal suture lies in the midline, extendingbackward from the coronal suture and bifurcat-ing over the occiput to form the lambdoid suture.The area of junction of the frontal, parietal, tem-poral, and sphenoid bones is called the pterion;below the pterion lies the bifurcation of themiddle meningeal artery.The inner skull base forms the floor of the cranialcavity, which is divided into anterior, middle,and posterior cranial fossae. The anterior fossalodges the olfactory tracts and the basal surfaceof the frontal lobes; the middle fossa, the basalsurface of the temporal lobes, hypothalamus,and pituitary gland; the posterior fossa, the cere-bellum, pons, and medulla. The anterior andmiddle fossae are demarcated from each otherlaterally by the posterior edge of the (lesser)wing of the sphenoid bone, and medially by thejugum sphenoidale. The middle and posteriorfossae are demarcated from each other laterallyby the upper rim of the petrous pyramid, andmedially by the dorsum sellae.

Scalp

The layers of the scalp are the skin (includingepidermis, dermis, and hair), the subcuticularconnective tissue, the fascial galea aponeurotica,subaponeurotic loose connective tissue, and thecranial periosteum (pericranium). The hair of thescalp grows approximately 1 cm per month. Theconnection between the galea and the peri-cranium is mobile except at the upper rim of theorbits, the zygomatic arches, and the externaloccipital protuberance. Scalp injuries superficialto the galea do not cause large hematomas, andthe skin edges usually remain approximated.Wounds involving the galea may gape; scalpinginjuries are those inwhich the galea is torn awayfrom the periosteum. Subgaleal hemorrhagesspread over the surface of the skull.

Viscerocranium

The viscerocranium comprises the bones of theorbit, nose, and paranasal sinuses. The superiormargin of the orbit is formed by the frontalbone, its inferior margin by the maxilla and zy-gomatic bone. The frontal sinus lies superior tothe roof of the orbit, the maxillary sinus inferiorto its floor. The nasal cavity extends from theanterior openings of the nose (nostrils) to itsposterior openings (choanae) and communi-cates with the paranasal sinuses—maxillary,frontal, sphenoid, and ethmoid. The infraorbitalcanal, which transmits the infraorbital vesselsand nerve, is located in the superior (orbital)wall of the maxillary sinus. The portion of thesphenoid bone covering the sphenoid sinusforms, on its outer surface, the bony margins ofthe optic canals, prechiasmatic sulci, and pitu-itary fossa.

Skull

Skull


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Maxillary sinus

Frontal sinus

Zygomatic bone

Infraorbital margin

Orbit

Supraorbital margin

Dorsum sellaeSuperior marginof petrous bone

Foramen magnum

Lesser wing of sphenoid bone

Crista galli

Cribriformplate

Pituitary fossa(sella turcica)

Mastoid process

Occipito-mastoid

suture

Parieto-mastoid

suture

Squamous suture

Lambdoidsuture

Coronal suture

Temporomandibularjoint

Skull

Inner skull base(yellow = anterior fossa, green = middle fossa, blue = posterior fossa)

Viscerocranium

Sphenoid sinusNasal bone

Glabella

Lower jaw (mandible)

Mental foramen

Infraorbital foramen

Supraorbital foramen

Anterior clinoid process

Scalp

Perpendicular lamina (ethmoid bone, nasal septum)

Vomer

Galea aponeurotica

Upper jaw (maxilla)

Prechiasmatic sulcus

Pterion

Outer and inner table

Diploë

Coronal suture

Skull (cross section)

Jugumsphenoidale

Skull

Skull


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The meninges lie immediately deep to the innersurface of the skull and constitute the mem-branous covering of the brain. The pericraniumof the inner surface of the skull and the duramater are collectively termed the pachymen-inges, while the pia mater and arachnoid mem-brane are the leptomeninges.

Pachymeninges

The pericranium contains the meningeal arter-ies, which supply both the dura mater and thebone marrow of the cranial vault. The per-icranium is fused to the dura mater, exceptwhere they separate to form the dural venoussinuses. The virtual space between the per-icranium and the dura mater—the epiduralspace—may be forced apart by a pathologicalprocess, such as an epidural hematoma. Imme-diately beneath the dura mater, but not fused toit, is the arachnoid membrane; the interveningvirtual space—the subdural space—containscapillaries and transmits bridging veins, which,if injured, can give rise to a subdural hematoma.The falx cerebri separates the two cerebral hemi-spheres and is bordered above and below by thesuperior and inferior sagittal sinuses. It attachesanteriorly to the crista galli, and bifurcates post-eriorly to form the tentorium cerebelli, with thestraight sinus occupying the space between thefalx and the two halves of the tentorium. Themuch smaller falx cerebelli separates the twocerebellar hemispheres; it encloses the occipitalsinus and is attached posteriorly to the occipitalbone.The tentorium cerebelli separates the superioraspect of the cerebellum from the inferioraspect of the occipital lobe. It rises toward themidline, taking the shape of a tent. The openingbetween the two halves of the tentorium,known as the tentorial notch or incisura, istraversed by the midbrain; the medial edge ofthe tentorium is adjacent to the midbrain oneither side. The tentorium attaches posteriorlyto the sulcus of the transverse sinus, laterally tothe superior rim of the pyramid of the temporalbone, and anteriorly to the anterior and poste-rior clinoid processes. The tentorium divides thecranial cavity into the supratentorial and in-fratentorial spaces.The pituitary stalk, or infundibulum, accom-panied by its enveloping arachnoid membrane,

passes through an aperture in the posterior por-tion of the diaphragma sellae (diaphragm of thesella turcica), a horizontal sheet of dura materlying between the anterior and posterior clinoidprocesses. The pituitary gland itself sits in thesella turcica, below the diaphragm.Themeningeal branches of the three divisions ofthe trigeminal nerve (pp. 28 and 94) providesensory innervation to the dura mater of thecranial roof, anterior cranial fossa, and middlecranial fossa. The meningeal branch of the vagusnerve (p. 29), which arises from its superior gan-glion, provides sensory innervation to the duramater of the posterior fossa. Pain can thus be feltin response to noxious stimulation of the duramater, while the cerebral parenchyma is insen-sitive. Some of the cranial nerves, and some ofthe blood vessels that supply the brain, traversethe dura at a distance from their entry into theskull, and thereby possess an intracranial ex-tradural segment, of a characteristic length foreach structure. Thus the rootlets of the trigemi-nal nerve, for instance, can be approached surgi-cally without incising the dura mater.

Pia Mater

The cranial pia mater is closely apposed to thebrain surface and follows all of its gyri and sulci.The cerebral blood vessels enter the brain fromits surface by perforating the pia mater. Exceptfor the capillaries, all such vessels are accom-panied for a short distance by a pial sheath, andthereafter by a glial membrane that separatesthem from the neuropil. The perivascular spaceenclosed by this membrane (Virchow–Robinspace) contains cerebrospinal fluid. The choroidplexus of the cerebral ventricles, which secretesthe cerebrospinal fluid, is formed by an infold-ing of pial blood vessels (tela choroidea) coveredby a layer of ventricular epithelium (ependyma).

Arachnoid Membrane

The dura mater is closely apposed to thearachnoid membrane; the virtual space be-tween them (subdural space) contains capillar-ies and bridging veins. Between the arachnoidmembrane and the pia mater lies the sub-arachnoid space, which is filled with cerebrospi-nal fluid and is spanned by a network of delicatetrabecular fibers.

Meninges

Men

inge

s


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Pacchionian corpuscles

Galea aponeurotica

Diploë

Pericranium and dura mater

Epidural space

Arachnoid membranePia mater

Cerebral arteries

Subarachnoid space

Subduralspace

Superior sagittal sinus


Falx cerebri

Supratentorial compartment

Straight sinus

Falx cerebelli

Tentorium

Infratentorial compartment

Sigmoid sinus

Cranial cavity(dorsal view)

Superior sagittalsinus Falx cerebri

Inferior sagittal sinus

Straight sinus

Tentorial edge

Tentorium of cerebellum

Infratentorial compartment

Diaphragma sellae

Pituitary stalk (infundibulum)

Internal acoustic meatus

Cranial cavity(lateral view)

Scalp, skull, meninges

Virchow-Robin space

Meninges

Men

inge

s


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Cerebral Ventricles and Cisterns

The fluid-filled cerebral ventricles constitute theinner CSF space. Each of the two lateral ventriclescommunicates with the third ventricle throughthe interventricular foramen of Monro (one oneach side). Fluid passes from the third ventriclethrough the cerebral aqueduct (of Sylvius) into thefourth ventricle, and thence through the singlemidline foramen (ofMagendie) andpaired lateralforamina(ofLuschka) into the subarachnoidspace(outerCSFspace).Dilatationsof thesubarachnoidspace are called cisterns. The cerebellomedullarycistern (cisterna magna) lies between the poste-rior surface of the medulla and the undersurfaceofthecerebellum.Thecerebellopontinecisternoc-cupies the cerebellopontine angle. The ambientcistern lies lateral to the cerebral peduncle andcontains theposteriorcerebralandsuperiorcere-bellar arteries, the basal vein, and the trochlearnerve. The interpeduncular cistern lies in themid-linebetweenthecerebralpedunclesandcontainsthe oculomotor nerves, the bifurcation of thebasilarartery,andtheoriginsofthesuperiorcere-bellar and posterior cerebral arteries; anterior toit is the chiasmatic cistern, which surrounds theoptic chiasm and the pituitary stalk. The portionof the subarachnoid space extending from theforamen magnum to the dorsum sellae is collec-tively termed the posterior cistern.

Cerebrospinal Fluid (CSF)

TheCSF, a clearandcolorlessultrafiltrateofbloodplasma, ismainly produced in the choroid plexusof the cerebral ventricles and in the capillaries ofthe brain. It normally contains no red blood cellsand at most 4 white blood cells/µl. Its functionsare both physical (compensation for volumechanges, buffering and equal distribution of in-tracranial pressure despite variation in venousandarterialbloodpressure)andmetabolic (trans-port of nutrients and hormones into the brain,and of waste products out of it). The total CSFvolume in the adult is ca. 150ml, of which ca.30ml is in the spinal subarachnoid space. Some500mlof cerebrospinal fluid is producedperday,corresponding to a flow of ca. 20ml/h. The nor-mal pulsation of CSF reflects brain pulsation dueto changes in cerebral venous and arterialvolume, respiration, andheadmovements. AVal-salva maneuver increases the CSF pressure.

CSF circulation. CSF formed in the choroid plexusflowsthroughtheventricularsystemandthroughthe foramina of Magendie and Luschka into thebasal cisterns. It then circulates further into thespinal subarachnoid space, over the surfaces ofthe cerebellum and cerebrum, eventually reach-ing the sites of CSF absorption. It is mainly ab-sorbed through the arachnoid villi (arachnoidgranulations, pacchionian corpuscles),which aremost abundant along the superior sagittal sinusbut are also found at spinal levels. CSF drainsthrough the arachnoid villi in one direction, fromthe subarachnoid space to the venous compart-ment, by a valve mechanism. This so-called bulkflow isapparentlyachievedwiththeaidofpinocy-totic vacuoles that transport the CSF, and all sub-stances dissolved in it, in ladlelike fashion. At thesame time, CSFdiffuses into thebrain tissueadja-cent to theCSFspaceand is absorbedby thecapil-laries.

The Blood–CSF and Blood–Brain Barriers

These “barriers” are not to be conceived of as im-penetrable; under normal conditions, all plasmaproteins pass into the CSF. The larger the proteinmolecule, however, the longer it takes to reachthe CSF, and the steeper the plasma/CSF concen-tration gradient. The term blood–brain barrier(BBB) is a collective term for all barriers lying be-tween the plasma and the neuropil, one ofwhichis the blood–CSF barrier (BCB). Disease processesoften alter the permeability of the BBB, but veryrarely that of the BCB.Morphologically, the BCB is formed by thechoroid epithelium, while the BBB is formed bythe tight junction (zonula occludens) of capillaryendothelial cells. Up to half of all cerebral capil-laries have a tubular structure, i.e., they have noconnecting interstices. Physiologically, the sys-tem of barriers enables the regulation of theosmolarity of brain tissue and CSF and, thereby,the intracranial pressure and volume. Biochemi-cally, the BCB is permeable towater-soluble sub-stances (e. g., plasma proteins) but not to lipo-soluble substances such as anesthetics, psycho-active drugs, and analgesics. The BBB, on theother hand, is generally permeable to liposolublesubstances (of molecular weight less than 500daltons) but not to water-soluble substances.

Cerebrospinal Fluid

Cerebrospina

lFluid


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Fourth ventricle with lateral recess

CSF circulation

Blood-brain barrier(capillary)

Blood-CSF barrier(vessel of choroid plexus)

Aqueduct

Third ventricle

Interventricular foramen of Monro

Left lateral ventricle with frontal,occipital, and temporal horns

Arachnoid villus

Chiasmatic cistern

Interpeduncular cistern

Ambient cistern

Epidural veins

Arachnoid villus

Spinal nerve root

Cerebellomedullary cistern

Tight junction

Basal membrane

Brain capillary with nonfenestrated endothelium

Tight junction

Processes of astrocytes

Cilia, plexusepithelial cellmembrane

Plexus capillarywith fenestrated

endothelium,erythrocyte

Basal labyrinth (substance transport)

Choroid plexus

Cerebral ventricles

Cerebrospinal Fluid

Cerebrospina

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Blood is pumped from the left ventricle of theheart to the aortic arch and thence to the com-mon carotid arteries and anterior circulation ofthe brain (internal carotid, middle cerebral, andanterior cerebral arteries), and to the subclavianarteries and posterior circulation of the brain(vertebral, basilar, and posterior cerebral arter-ies). The anterior circulation supplies the eyes,basal ganglia, part of the hypothalamus, thefrontal and parietal lobes, and a large portion ofthe temporal lobes, while the posterior circula-tion supplies the brain stem, cerebellum, innerear, occipital lobes, the thalamus, part of the hy-pothalamus, and a smaller portion of the tem-poral lobes.Venous blood from the superficial and deep cere-bral veins (p. 18 ff) drains via the dural venoussinuses into the internal jugular veins andthence into the the superior vena cava and rightatrium. The extracranial and intracranial por-tions of the blood supply of the brain as well asthat of the spinal cord will be detailed further inthe following paragraphs.

Carotid Arteries: Extracranial Portion

The brachiocephalic trunk arises from the aorticarch behind the manubrium of the sternum andbifurcates at the level of the sternoclavicularjoint to form the right subclavian and commoncarotid arteries. The left common carotid artery(usually adjacent to the brachiocephalic trunk)and subclavian artery arise directly from theaortic arch. The common carotid artery on eitherside bifurcates at the level of the thyroid car-tilage to form the internal and external carotidarteries; these arteries lie parallel and adjacentto each other after the bifurcation, with the ex-ternal carotid artery lyingmedial. A dilatation ofthe common carotid artery at its bifurcation iscalled the carotid sinus.The external carotid artery gives off the superiorthyroid, lingual, facial, and maxillary arteriesanteriorly, the ascending pharyngeal artery me-dially, and the occipital and posterior auriculararteries posteriorly. The maxillary and superfi-cial temporal arteries are its terminal branches.The middle meningeal artery is an importantbranch of the maxillary artery.The internal carotid artery gives off no ex-tracranial branches. Its cervical portion runslateral or dorsolateral to the external carotid

artery, then dorsomedially along the wall of thepharynx (parapharyngeal space) in front of thetransverse processes of the first three cervicalvertebrae, and finally curves medially towardthe carotid foramen.

Carotid Arteries: Intracranial Portion

The internal carotid artery (ICA) passes throughthe base of the skull in the carotid canal, whichlies within the petrous part of the temporalbone. It runs upward about 1 cm, then turns an-teromedially and courses toward the petrousapex, where it emerges from the temporal boneto enter the cavernous sinus. Within the sinus,the ICA runs along the lateral surface of the bodyof the sphenoid bone (C5 segment of the ICA),then turns anteriorly and passes lateral to thesella turcica along the lateral wall of the sphe-noid bone (segment C4). It then bends sharplyback on itself under the root of the anteriorclinoid process, so that it points posteriorly(segment C3, carotid bend). After emergingfrom the cavernous sinus, it penetrates the duramater medial to the anterior clinoid process andpasses under the optic nerve (cisternal segment,segment C2). It then ascends in the sub-arachnoid space (segment C1) till it reaches thecircle ofWillis, the site of its terminal bifurcation.Segments C3, C4, and C5 of the ICA constitute itsinfraclinoid segment, segments C1 and C2 its su-praclinoid segment. Segments C2, C3, and C4 to-gether make up the carotid siphon.The ophthalmic artery arises from the carotidbend and runs in the optic canal inferior to theoptic nerve. One of its ocular branches, the cen-tral retinal artery, passes together with the opticnerve to the retina, where it can be seen by oph-thalmoscopy.Medial to the clinoid process, the posterior com-municating artery arises from the posterior wallof the internal carotid artery, passes posteriorlyin proximity to the oculomotor nerve, and thenjoins the posterior cerebral artery.The anterior choroidal artery usually arises fromthe ICA and rarely from the middle cerebralartery. It crosses under the optic tract, passeslaterally to the crus cerebri and lateral genicu-late body, and enters the inferior horn of thelateral ventricle, where it joins the telachoroidea.

Carotid Arteries

Cerebral

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Aortic arch

Brachiocephalic trunk

Subclavian a.

Superior and inferiorvena cava

Vertebral a.

Pulmonary a.

Common carotid a.

Facial a.

Inferior labial a.

Submental a.

External carotid a.

Internal carotid a.

Basilar a.

Bifurcation

Angular a.

Superior labial a.

Ophthalmic a.

Frontal branchof superficialtemporal a.

Thoracic aorta

Pontine arteries

Maxillary a.

Heart and carotid arteries

Internal carotid a.

External carotid a.

Subclavian a.

Left internal carotid artery (anterior view)

Cerebral segment

Cisternal segment

Cavernous seg-ment

Petrous segment

Cervical segment

Anterior clinoidprocess

C 1

Anteriorcerebral a.

Middlecerebral a.

Anteriorchoroidal a.

Posterior communicat-

ing a.

C 3

C 4

C 5

C 2

Ophthalmic a.

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The anterior andmiddle cerebral arteries are theterminal branches of the internal carotid artery.They originate at the ICA bifurcation, located inthe circle of Willis at the level of the anteriorclinoid process, between the optic chiasm andthe temporal pole.

Anterior Cerebral Artery (ACA)

The ACA is the more medial of the two arteriesarising from the ICA bifurcation. It ascendslateral to the anterior clinoid process and pastthe the optic nerve and optic chiasm, giving off asmall branch, the anterior communicatingartery (ACommA), which crosses the midline tojoin the contralateral ACA. The segment of ACAproximal to the origin of the ACommA is its pre-communicating segment (segment A1). The A1segments on either side and the ACommA to-gether form the anterior half of the circle of Wil-lis. Segment A1 gives off an average of eight basalperforating arteries that enter the brain throughthe anterior perforated substance. The recurrentartery of Heubner arises from the ACA near theorigin of the ACommA, either from the distalpart of A1 or from the proximal part of A2.The postcommunicating segment of the ACA (seg-ments A2 to A5) ascends between the frontallobes and runs toward the occiput in the inter-hemispheric fissure, along the corpus callosumand below the free border of the falx cerebri, asthepericallosalartery. SegmentA2,whichusuallygives off the frontopolar artery, ends where theartery turns forward to become apposed to thegenu of the corpus callosum; segment A3 is thefrontally convexarchof thevessel along thegenu.TheA4andA5segmentsrunroughlyhorizontallyover thecallosal surfaceandgiveoff supracallosalbranches that run in a posterior direction.Distribution. The basal perforating arteries aris-ing fromA1supply theventralhypothalamusanda portion of the pituitary stalk. Heubner’s arterysupplies theheadof the caudate nucleus, the ros-tral four-fifths of the putamen, the globus pal-lidus, and the internal capsule. The blood supplyof the inferior portion of the genu of the corpuscallosum, and of the olfactory bulb, tract, andtrigone, is variable.The ACommA gives off a few small branches (an-teromedial central branches) to the hy-pothalamus.

Branches from the postcommunicating segmentof the ACA supply the inferior surface of the fron-tal lobe (frontobasilar artery), the medial andparasagittal surfaces of the frontal lobe (calloso-marginal artery), the paracentral lobule (para-central artery), the medial and parasagittal sur-faces of the parietal lobe (precuneal artery), andthe cortex in the region of the parieto-occipitalsulcus (parieto-occipital artery).

Middle Cerebral Artery (MCA)

The MCA is the more lateral of the two arteriesarising from the ICA bifurcation. Its first seg-ment (M1, sphenoidal segment) follows theanterior clinoid process for a distance of 1 to2 cm. The MCA then turns laterally to enter thedepths of the Sylvian fissure (i.e., the Sylvian cis-tern), where it lies on the surface of the insulaand gives off branches to it (M2, insular seg-ment). It bends back sharply to travel along thesurface of the operculum (M3, opercular seg-ment) and then finally emerges through the Syl-vian fissure onto the lateral convexity of thebrain (M4 and M5, terminal segments).Distribution. Small branches of M1 (thethalamostriate and lenticulostriate arteries)supply the basal ganglia, the claustrum, and theinternal, external, and extreme capsules. M2and M3 branches supply the insula (insular ar-teries), lateral portions of the orbital and infe-rior frontal gyri (frontobasal artery), and thetemporal operculum, including the transversegyrus of Heschl (temporal arteries). M4 and M5branches supply most of the cortex of the lateralcerebral convexity, including portions of thefrontal lobe (arteries of the precentral and tri-angular sulci), the parietal lobe (anterior andposterior parietal arteries), and the temporallobe (arteries of central and postcentral sulci). Inparticular, important cortical areas supplied byM4 and M5 branches include the primary motorand sensory areas (precentral and postcentralgyri) and the language areas of Broca and Wer-nicke.

Anterior Circulation of the Brain

Cerebral

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Anterior cerebral artery(blue: ACA distribution, sections A-E)

Middle cerebral artery(red: MCA distribution)

Horizontal sections A-E

Circle of Willis

AB

CD

E

A 4

A 2

A 3

A 5

Insular arteries

M2 and M3

M 4 M 5

Internal carotid a.

Anterior cerebral a.(peripheral branches)

Anterior choroidal a.

Posterior cerebral a.(central branches) + posterior communicating a.

Posterior cerebral a.(peripheral branches)

Middle cerebral a.(peripheral branches)

Anterior cerebral a.(central branches)

Middle cerebral a.(central branches)

M2 and M3

A2Anterior communicating a.

A1 (precommunicating segment)

Olfactory tract M1


Posterior cerebral a.(precommunicating segment)

Superior cerebellar a.

Posteromedial central arteries

Basilar a.

Oculomotor a.

Optic chiasm,pituitary stalk

recurrent a. ofHeubner

Posterior communicating a.

A

B

C

E

DA. of central sulcus (rolandic a.)

Anterior Circulation of the Brain

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Extracranial Portion

The vertebral artery arises from the arch of thesubclavian artery at a point designated V0. Theprevertebral or V1 segment extends from V0 tothe foramen transversarium of the transverseprocess of C6. The transversarial or V2 segmentpasses vertically through the foramina transver-saria of C6 through C2, accompanied by venousplexuses and sympathetic nerves derived fromthe cervical ganglia. It gives off branches to thecervical nerves, vertebrae and intervertebraljoints, neck muscles, and cervical spinal cord.Often, a prominent branch at the C5 level anas-tomoses with the anterior spinal artery. The V3segment, also called the atlas (C1) loop, runslaterally and then vertically to the foramentransversarium of C1, which it passes through,winds medially along the lateral mass of C1,pierces the posterior atlanto-occipital mem-brane behind the atlanto-occipital joint, andthen enters the dura mater and arachnoid mem-brane at the level of the foramen magnum. Thetwo vertebral arteries are unequal in size inabout 75% of persons, and one of them is ex-tremely narrow (hypoplastic) in about 10%, usu-ally on the right side.

Intracranial Portion

The V4 segment of the vertebral artery lies en-tirely within the subarachnoid space. It termi-nates at the junction of the two vertebral arter-ies to form the basilar artery, at the level of thelower border of the pons. Proximal to the junc-tion, each vertebral artery gives off a mediobasalbranch; these two branches run for ca. 2 cm andthen unite in the midline to form a single ante-rior spinal artery, which descends along theanterior surface of the medulla and spinal cord(see p. 23). The posterior inferior cerebellar artery(PICA), which originates from the V4 segment ata highly variable level, curves around the infe-rior olive and extends dorsally through the rootfilaments of the accessory nerve. It then ascendsbehind the fibers of the hypoglossus and vagusnerves, forms a loop on the posterior wall of thefourth ventricle, and gives off terminal branchesto the inferior surface of the cerebellar hemi-sphere, the tonsils, and the vermis. It providesmost of the blood supply to the dorsolateral

medulla and the posteroinferior surface of thecerebellum. The posterior spinal artery (there isone on each side) arises from either the verte-bral artery or the PICA.The basilar artery runs in the prepontine cisternalong the entire length of the pons and then bi-furcates to form the posterior cerebral arteries.Its inferior portion is closely related to the abdu-cens nerves, its superior portion to the oculo-motor nerves. Its paramedian, short circumfer-ential, and long circumferential branches supplythe pons and the superior and middle cerebellarpeduncles.The anterior inferior cerebellar artery (AICA)arises from the lower third of the basilar artery.It runs laterally and caudally toward the cere-bellopontine angle, passes near the internalacoustic meatus, and reaches the flocculus,where it gives off terminal branches that supplythe anteroinferior portion of the cerebellar cor-tex and part of the cerebellar nuclei. The AICAlies basal to the abducens nerve and ventrome-dial to the facial and auditory nerves in the cere-bellopontine cistern. It often gives rise to a laby-rinthine branch that enters the internal acousticmeatus.The superior cerebellar arteries (SCA) of bothsides originate from the basilar trunk just belowits bifurcation. Each SCA travels through theperimesencephalic cistern dorsal to the oculo-motor nerve, curves around the cerebralpeduncle caudal and medial to the trochlearnerve, and then enters the ambient cistern,where it gives off its terminal branches. The SCAsupplies the upper pons, part of the mid brain,the upper surface of the cerebellar hemispheres,the upper portion of the vermis, and the cere-bellar nuclei.

Vertebral and Basilar Arteries

Cerebral

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V0

V1

V2

V3

V4

Occipital a.

Basilar a.

Posterior cerebral a.

Subclavian a.

Common carotid a.

External carotid a.

Pericallosal a.

Anterior cerebral a.

Caudate nucleus

Internal capsule

Putamen

Thalamus

Middle cerebral a.

Internal carotid a.

PICA

AICA

VIII

Labyrinthine a.

VII


Posteriorcerebral a.


Basilar a., pontine branches

Medial branches

Mediolateral branches Lateral branches


Middle cerebral a.(peripheral + central

branches)



(peripheral +central branches)

Vertebrobasilar system(extracranial; plane of coronal section)

Coronal section

Vertebrobasilar system (intracranial)

Brainstem vessels, territories

(pons)

Basilar a.

IIIIV

V

VI IXX

XI

Vertebral and Basilar Arteries

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Posterior Cerebral Artery (PCA)

The precommunicating segment of the PCA (P1)extends from the basilar bifurcation to theorigin of the posterior communicating artery(PCommA). Its course lies within the inter-peduncular cistern, which is demarcated by theclivus and the two cerebral peduncles. Theoculomotor nerve, after its emergence from thebrain stem, runs between the PCA and the su-perior cerebellar artery. The postcommunicatingsegment (P2) curves laterally and backwardaround the crus cerebri and reaches the poste-rior surface of the midbrain at an intercollicularlevel.The precommunicating and postcommunicat-ing segments are together referred to as the parscircularis of the PCA. (Alternatively, the parscircularis may be divided into three segments—interpeduncular, ambient, and quadrigeminal—named after the cisterns they traverse.)Distal to the pars circularis of the PCA is the parsterminalis, which divides above the tentoriumand caudal to the lateral geniculate body to formits terminal branches, the medial and lateraloccipital arteries.Pars circularis. The precommunicating segmentgives off fine branches (posteromedial centralarteries) that pierce the interpeduncular per-forated substance to supply the anteriorthalamus, the wall of the third ventricle, and theglobus pallidus. The postcommunicating seg-ment gives off fine branches (posterolateral cen-tral arteries) to the cerebral peduncles, the post-erior portion of the thalamus, the colliculi of themid brain, the medial geniculate body, and thepineal body. Further branches supply the poste-rior portion of the thalamus (thalamicbranches), the cerebral peduncle (peduncularbranches), and the lateral geniculate body andchoroid plexus of the third and lateral ventricles(posterior choroidal branches).Pars terminalis. Of the two terminal branches ofthis terminal portion of the PCA, the lateraloccipital artery (together with its temporalbranches) supplies the uncus, the hippocampalgyrus, and the undersurface of the occipitallobe. The medial occipital artery passes underthe splenium of the corpus callosum, giving offbranches that supply it (dorsal branch to thecorpus callosum) as well as the cuneus and pre-

cuneus (parieto-occipital branch), the striatecortex (calcarine branch), and the medial sur-faces of the occipital and temporal lobes (occipi-totemporal and temporal banches), includingthe parasagittal portion of the occipital lobe.

Posterior Circulation of the Brain

Cerebral

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A

B

C

D

E

Middle cerebral a.


Postero-medial central arteries Anterior

choroidal a.

Posterior choroidal

branch

Thalamicbranch

Branch to corpuscallosum

Medial occipital a.

Lateral occipital a. Temporal branch

Basal area of anterior choroidal a.

Calcarine branch

Undersurface of cerebellum(showing arteries)

Postcom-municating segment (P2)

Precommunicatingsegment (P1)

Middle cerebral a.(peripheral branches)


Middle cerebral a.(central branches)


Posterior cerebral a.(peripheral branches)

Posteriorinferiorcerebellar a.


Posterior cerebral a.(central branches)

Oculo-motor n.

Posterior cerebral artery(green = peripheral branches)

Regional arterial blood flow (frontal and coronal planes A-E)

A B C D E

Posterior Circulation of the Brain

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Cerebral Veins

The superficial cerebral veins (cortical veins)carry blood from the outer 1–2 cm of the brainsurface to large drainage channels such as thesuperior and inferior sagittal sinuses, the greatcerebral vein of Galen, the straight sinus, andthe tentorial veins. Thus, the cerebellar veinsdrain blood from the cerebellar surface into thesuperior vermian vein and thence into the greatcerebral vein, straight sinus, and transversesinuses. The deep cerebral veins (central veins)drain blood from the inner regions of the brain(hemispheric white matter, basal ganglia, cor-pus callosum, choroid plexus) and from a fewcortical areas as well.Superficial cerebral veins (cortical veins). Thesuperficial cerebral veins are classified by theirlocation as prefrontal, frontal, parietal, andoccipital. Except for the occipital veins, whichempty into the transverse sinus, these veins alltravel over the cerebral convexity to join the su-perior sagittal sinus. They are termed bridgingveins at their distal end, where they pierce thearachnoid membrane and bridge the sub-arachnoid space to join the sinus. The superficialmiddle cerebral vein (not shown) usually followsthe posterior ramus of the Sylvian fissure andthe fissure itself to the cavernous sinus. The infe-rior cerebral veins drain into the cavernous sinus,superior petrosal sinus, and transverse sinus.The superior cerebral veins drain into the super-ior sagittal sinus.Deep cerebral veins (central veins). The internalcerebral vein arises bilaterally at the level of theinterventricular foramen (of Monro). It traversesthe transverse cerebral fissure to a point just in-ferior to the splenium of the corpus callosum.The venous angle at its junction with the super-ior thalamostriate vein can be seen in a laterallyprojected angiogram. The two internal cerebralveins join under the splenium to form the greatcerebral vein (of Galen), which receives the basalvein (of Rosenthal) and then empties into thestraight sinus at the anterior tentorial edge atthe level of the quadrigeminal plate. The basalvein of Rosenthal is formed by the union of theanterior cerebral vein, the deep middle cerebralvein, and the striate veins. It passes posterome-dial to the optic tract, curves around the cerebralpeduncle, and empties into the internal vein or

the great cerebral vein posterior to the brainstem.Posterior fossa. The anterior, middle, and poste-rior veins of the posterior fossa drain into thegreat cerebral vein, the petrosal vein, and thetentorial and straight sinuses, respectively.

Extracerebral Veins

The extracerebral veins—most prominently, thedural venous sinuses—drain venous blood fromthe brain into the sigmoid sinuses and jugularveins.The diploic veins drain into the extracranialveins of the scalp and the intracranial veins(dural venous sinuses).The emissary veins connect the sinuses, diploicveins, and superficial veins of the skull. Infec-tions sometimes travel along the emissary veinsfrom the extracranial to the intracranial com-partment.The veins of the brain empty into the superiorand inferior groups of dural venous sinuses. Thesinuses of the superior group (the superior andinferior sagittal, straight, and occipital sinuses)join at the confluence of the sinuses (torcularHerophili), which drains into both transversesinuses and thence into the sigmoid sinuses andinternal jugular veins. The sinuses of the inferiorgroup (superior and inferior petrosal sinuses)join at the cavernous sinus, which drains intothe sigmoid sinus and internal jugular vein viathe inferior petrosal sinus, or into the internalvertebral plexus via the basilar plexus.

Intracranial Veins

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Superior cerebral v.,bridging vein

Inferior petrosalsinus

Superior sagittalsinus


Great cerebral v. (Galen)

Great cerebral v.

Sigmoid sinus

Sigmoid sinus

Internal cerebral v.

Basal v. (Rosenthal)

Basal v. (Rosenthal)

Venous angle

Venous angle

Superior cerebral veins, bridging veins

Internal jugular v.

Emissary v.

Transversesinus

Transverse sinus

Confluence of sinuses

Confluence ofsinuses

Straight sinus

Straight sinus

Cavernous sinus

Cavernoussinus


Cerebral veins

Sphenoparietal sinus

Basilar plexus

Ophthalmic v.

Superior petrosal sinusMiddle meningeal v.

Scalp vein

Diploic veins

Petrosal v.Cerebral veins and sinuses

Extracerebral veins


Cerebral vein

Superior cerebral veins, bridging veins


Intracranial Veins

Cerebral

Circulation


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Craniocervical Veins

Anastomotic channels connect the cutaneousveins of the two sides of the head. Venous bloodfrom the facial, temporal, and frontal regionsdrains into the facial and retromandibular veinsand thence into the internal jugular vein. Someblood from the forehead drains via the naso-frontal, angular, and superior ophthalmic veinsinto the cavernous sinus. The occipital vein car-ries blood from the posterior portion of thescalp into the deep cervical vein and thence intothe external jugular vein. Blood from the jugularveins continues to the brachiocephalic vein, su-perior vena cava, and right atrium. The venouschannels in the spinal canal and the transcranialemissary veins play no more than a minor rolein venous drainage. The pterygoid plexus linksthe cavernous sinus, the facial vein, and the in-ternal jugular vein.The numerous anastomoses between the ex-tracranial and intracranial venous systems pro-vide a pathway for the spread of infection fromthe scalp or face to the intracranial compart-ment. For example, periorbital infectionmay ex-tend inward and produce septic thrombosis ofthe cavernous sinus.

Cranial Veins

The facial vein drains the venous blood from theface and anterior portion of the scalp. It beginsat the inner canthus as the angular vein andcommunicates with the cavernous sinus via thesuperior ophthalmic vein. Below the angle ofthe mandible, it merges with the retromandibu-lar vein and branches of the superior thyroidand superior laryngeal veins. It then drains intothe internal jugular vein in the carotid triangle.The veins of the temporal region, external ear,temporomandibular joint, and lateral aspect ofthe face join in front of the ear to form the retro-mandibular vein, which either joins the facialvein or drains directly into the internal jugularvein. Its upper portion gives off a prominentdorsocaudal branch that joins the posteriorauricular vein over the sternocleidomastoidmuscle to communicate with the external jugu-lar vein. Venous blood from the posterior por-tion of the scalp and the mastoid and occipitalemissary veins drains into the occipital vein,

which anastomoses with the occipital venousplexus and finally drains into the external jugu-lar vein.The pterygoid plexus lies between the tem-poralis, medial pterygoid, and lateral pterygoidmuscles and receives blood from deep portionsof the face, the external ear, the parotid gland,and the cavernous sinus, which it carries by wayof the maxillary and retromandibular veins tothe internal jugular vein.

Cervical Veins

The deep cervical vein originates from the occipi-tal vein and suboccipital plexus. It follows thecourse of the deep cervical artery and vertebralartery to arrive at the brachiocephalic vein,which it joins.The vertebral vein, which also originates fromthe occipital vein and suboccipital plexus, en-velops the vertebral artery like a net and accom-panies it through the foramina transversaria ofthe cervical vertebrae, collecting blood alongthe way from the cervical spinal cord, meninges,and deep neck muscles through the vertebralvenous plexus, and finally joining the brachio-cephalic vein.

Extracranial Veins

Cerebral

Circulation


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Extracranial veins

Superficial temporal veins

Supratrochlear v.

Nasofrontal v.

Angular v.

Infraorbital v.

Facial v.

Submental v.

Anteriorjugular v.

Left brachio-cephalic v.

Lymph vessels joining to formthoracic duct

Occipital v.

Suboccipitalvenous plexus

Internal jugular v.

Pterygoid plexus

Retromandibular v.

Deep cervical v.

Externaljugular v.

Transversecervical v.

Suprascapular v.

Subclavian v.

Extracranial Veins

Cerebral

Circulation


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Arteries

Most of the blood supply of the spinal cord issupplied by the segmental spinal arteries, whilerelatively little comes from the vertebral arter-ies via the anterior and posterior spinal arteries.The segmental and spinal arteries are linked bynumerous anastomoses.Segmental arteries. The vertebral, ascendingcervical, and deep cervical arteries give off cer-vical segmental branches; the thoracic andabdominal aorta give off thoracolumbarsegmental branches via the posterior intercostaland lumbar arteries.The segmental arteries give off radicularbranches that enter the intervertebral foramenand supply the anterior and posterior roots andspinal ganglion of the corresponding level. Thespinal cord itself is supplied by unpaired medul-lary arteries that originate from segmental ar-teries. The anatomy of these medullary arteriesis variable; they usually have 5 to 8 larger ven-tral and dorsal branches that join up with theanterior and posterior spinal arteries. Oftenthere is a single large radicular branch on oneside, the great radicular artery (of Adam-kiewicz), that supplies the entire lower two-thirds of the spinal cord. It usually enters thespinal canal in the lower thoracic region on theleft side.Spinal arteries. The spinal arteries run longi-tudinally down the spinal cord and arise fromthe vertebral artery (p. 14). The unpaired ante-rior spinal artery lies in the anterior median fis-sure of the spinal cord and supplies blood to theanterior two-thirds of the cord. The artery’sdiameter steadily increases below the T2 level.The two posterior spinal arteries supply the dor-sal columns and all but the base of the dorsalhorns bilaterally. Numerous anastomoses of thespinal arteries produce a vasocorona around thespinal cord. The depth of the spinal cord is sup-plied by these arteries penetrating it from itsouter surface and by branches of the anteriorspinal artery penetrating it from the anteriormedian fissure (sulcocommissural arteries).

Spinal Veins

Blood from within the spinal cord travelsthrough the intramedullary veins, whose anat-

omy is variable, to the anterior and posterior spi-nal veins, which form a reticulated network inthe pia mater around the circumference of thecord and down its length. The anterior spinalvein drains the anterior two-thirds of the graymatter, while the posterior and lateral spinalveins drain the rest of the spinal cord. These ves-sels empty by way of the radicular veins into theexternal and internal vertebral venous plexuses,groups of valveless veins that extend from thecoccyx to the base of the skull and communicatewith the dural venous sinuses via the suboccipi-tal veins. Venous blood from the cervical spinedrains by way of the vertebral and deep cervicalveins into the superior vena cava; from thethoracic and lumbar spine, by way of the poste-rior intercostal and lumbar veins into the azygosand hemiazygos veins; from the sacrum, by wayof the median and lateral sacral veins into thecommon iliac vein.

Watershed Zones

Because blood can flow either upward ordownward in the anterior and posterior spinalarteries, the tissue at greatest risk of hypoperfu-sion is that located at a border zone between thedistributions of two adjacent supplying arteries(“watershed zone”). Such vulnerable zones arefound in the cervical, upper thoracic, and lowerthoracic regions (ca. C4, T3–T4, and T8–T9).

Spinal Circulation

Spinal

Circulation


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Spinal arteries

Vessels of spinal cord (left: arteries; right: veins)

Posterior spinal a.

Anterior spinal a.

Radicular a.

Vertebral a.

Ascending cervical a.

Aortic arch

Aorta

Great radicular a.(a. of Adamkiewicz)

Lumbar a.

Deep cervical v.

Vertebral v.

Spinal v.

Radicular v.

Inferior jugular v.

Thoracic intercostal a.

Watershed

Subclavian v.

Right brachiocephalic v.

Left brachiocephalic v.

Accessory hemiazygos v.

Azygos v.

Hemiazygos v.

Spinal veins

Watershed

Watershed

Epidural space

Spinal branch

Posterior spinal a.

Anterior spinal a. and v.

Vasocorona

Posterior spinal v.

Sulcocommissural a.

Anterior radicular v.

Spinal ganglia

Posterior externalvertebral venous

plexus

Ventral root

Pia mater

Spinal nerve

Spinal Circulation

Spinal

Circulation


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Cortical Structures

Different areas of the cerebral cortex (neocortex)may be distinguished from one another by theirhistological features and neuroanatomical con-nections. Brodmann’s numbering scheme forcortical areas has been used for many years andwill be introduced in this section.Projection areas. By following the course ofaxons entering and leaving a given cortical area,one may determine the other structures towhich it is connected by afferent and efferentpathways. The primary projection areas arethose that receive most of their sensory im-pulses directly from the thalamic relay nuclei(primary somatosensory cortex; Brodman areas1, 2, 3), the visual (area 17), or the auditory(areas 41, 42) pathways. The primary motor cor-tex (area 4) sends motor impulses directly downthe pyramidal pathway to somatic motor neu-rons within brainstem and the spinal cord. Theprimary projection areas are somatotopicallyorganized and serve the contralateral half of thebody. Proceeding outward along the corticalsurface from the primary projection areas, oneencounters the secondary projection areas(motor, areas 6, 8, 44; sensory, areas 5, 7a, 40;visual, area 18; auditory, area 42), which sub-serve higher functions of coordination and in-formation processing, and the tertiary projectionareas (motor, areas 9, 10, 11; sensory, areas 7b,39; visual, areas 19, 20, 21; auditory, area 22),which are responsible for complex functionssuch as voluntary movement, spatial organiza-tion of sensory input, cognition, memory, lan-guage, and emotion. The two hemispheres areconnected by commissural fibers, which enablebihemispheric coordination of function. Themost important commissural tract is the corpuscallosum; because many tasks are performedprimarily by one of the two hemispheres (cere-bral dominance), interruption of the corpus cal-losum can produce various disconnection syn-dromes. Total callosal transection causes split-brain syndrome, in which the patient cannotname an object felt by the left hand when theeyes are closed, or one seen in the left visualhemifield (tactile and optic anomia), and cannotread words projected into the left visual hemi-field (left hemialexia), write with the left hand(left hemiagraphia), or make pantomimic move-

ments with the left hand (left hemiapraxia).Anterior callosal lesions cause alien hand syn-drome (diagonistic apraxia), in which thepatient cannot coordinate the movements of thetwo hands. Disconnection syndromes are usu-ally not seen in persons with congenital absence(agenesis) of the corpus callosum.Cytoarchitecture. Most of the cerebral cortexconsists of isocortex, which has six distinct cy-toarchitectural layers. The Brodmann classifica-tion of cortical areas is based on distinguishinghistological features of adjacent areas of isocor-tex.Functional areas. The functional organization ofthe cerebral cortex can be studied with varioustechniques: direct electrical stimulation of thecortex during neurosurgical procedures,measurement of cortical electrical cortical activ-ity (electroencephalography and evoked poten-tials), and measurement of regional cerebralblood flow and metabolic activity. Highlyspecialized areas for particular functions arefound in many different parts of the brain. A le-sion in one such area may produce a severefunctional deficit, though partial or total re-covery often occurs because adjacent uninjuredareas may take over some of the function of thelost brain tissue. (The extent to which actualbrain regeneration may aid functional recoveryis currently unclear.) The specific anatomic pat-terns of functional localization in the brain arethe key to understanding much of clinical neu-rology.

Subcortical Structures

The subcortical structures include the basal gan-glia, thalamus, subthalamic nucleus, hy-pothalamus, red nucleus, substantia nigra, cere-bellum, and brain stem, and their nerve path-ways. These structures perform many differentkinds of complex information processing andare anatomically and functionally intercon-nected with the cerebral cortex. Subcortical le-sions may produce symptoms and signs resem-bling those of cortical lesions; special diagnosticstudies may be needed for their precise localiza-tion.

Anatomical and Functional Organization

Anatom

ical

andFu

nction

alOrgan

ization


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Functional areas of cortex(as determined by measurement of regional blood flow)

Brodmann areas (lateral view)

Hemispheric dominance

Subcortical structures(Sections: left, horizontal; right, coronal)

Layers of isocortex

Frontal lobeParietal lobe

Occipital lobe

Temporal lobe

Hand movement

Speech

9

I (Molecular layer)

II (Outer granule cell layer)

III (Middle pyramidal cell layer)

IV (Inner granule cell layer)

V (Large pyramidal cells)

VI (Polymorphic cells)

Thalamus

Red nucleus

Insula

Susbstantianigra

HippocampusFrontal operculum

Lentiform nucleus

Cerebral peduncle

Internal capsule

Caudatenucleus

Left (speech, writing, calculation,abstraction,logical analysis)

Right (stereo-gnosis, spatial

perception,nonverbal

ideation,intuition)

Perception (visual, acoustic,olfactory, somatosensory)

Commis-sural tracts

86

4

5

3

10

11

7b7a

40 19

17

18

374152

22

21

20

38

44

46

45

12

39

43

Anatomical and Functional Organization

Anatom

ical

andFu

nction

alOrgan

ization


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The brain stem consists of the midbrain (mesen-cephalon), pons, and medulla. It contains thenuclei of the cranial nerves and ascending anddescending tracts running to and from the brain,cerebellum, and spinal cord. It also contains au-tonomic centers that regulate cardiovascularfunction, breathing, and eating behavior as wellas acoustic and vestibular relay nuclei. The flowof information along afferent and efferent path-ways is regulated by reflex systems.

Nerve Pathways

All motor (p. 44) and sensory projection systems(p. 104) pass through the brain stem and com-municate with its intrinsic structures at varioussites. The central sympathetic pathway (p. 90)originates in the hypothalamus.

Reticular Formation

The reticular formation (RF) is a network of nu-clei and interconnecting fibers that is anatomi-cally intertwined with the cranial nerve nucleiand other fiber tracts of the brain stem. Differentparts of the reticular formation perform differ-ent functions. The reticular activating system(RAS) provides the anatomical and physiologicalbasis for wakeful consciousness (p. 116). Themedullary RF contains the vital centers control-ling the heartbeat, breathing, and circulation aswell as reflex centers for swallowing and vomit-ing. The pontine RF contains centers for coordi-nation of acoustic, vestibular, respiratory, andcardiovascular processes. The midbrain RF con-tains centers subserving visuospatial orienta-tion and eating behavior (chewing, sucking, lick-ing).

Reflex Systems (pp. 118ff)

Pupillary light reflex. The Edinger–Westphal nu-cleus in the midbrain, which is adjacent to theoculomotor nucleus, provides the efferent armof the reflex loop (p. 90; examination, p. 92.)Vestibulo-ocular reflex (VOR, p. 84). The vestibu-lar nuclei receive their main input from thelabyrinthine semicircular canals and collateralinput from the cerebellar nuclei; their output isconveyed to the extraocular muscles throughthe medial longitudinal fasciculus, and to the

spinal cord through the vestibulospinal tract.Examination: Suppression of visual fixation: thesubject extends his arms and stares at histhumbs while spinning on a swivel chair. Nys-tagmus does not occur in normal subjects.Oculocephalic reflex (doll’s eyes phenomenon):Horizontal or vertical passive rotation of thesubject’s head causes the eyes to rotate in theopposite direction; normally suppressible byawake persons, this reflex is seen in patientswith impaired consciousness but preserved ves-tibular function. Caloric testing: The examinerfirst confirms that the patient’s eardrums are in-tact, then instills cold water in the external audi-tory canal with the head elevated at a 30° angle(which inactivates the ipsilateral horizontalsemicircular canal). This normally causes nys-tagmus in the contralateral direction, i.e., slowipsilateral conjugate deviation of the eyes, fol-lowed by a quick jerk to the other side.Corneal reflex. Afferent arm, CN V/1; efferentarm, CN VII, which innervates the orbicularisoculi muscle. Examination: Touching the corneafrom the side while the subject looks forwardevokes blinking. The reflex can also be assessedby electromyography (EMG).Pharyngeal (gag) reflex. Afferent arm, mainly CNIX, X, and V/2; efferent arm, CN IX and X. The gagreflex may be absent in normal persons. Exami-nation: Touching the soft palate or back of thepharynx evokes pharyngeal muscle contraction.Cough reflex. Afferent arm, CN IX and X; efferentarm, via the solitary tract to the diaphragm andother participating muscle groups. Examination:Tested in intubated patients with endotrachealsuction (tracheal reflex).Masseter (jaw jerk) reflex. Afferent arm, prob-ably CN V/3; efferent arm, CN V. Examination:Tapping the chin evokes jaw closure.Acoustic reflex (p. 68). Afferent arm, projectionsof the cochlear nuclei to the RAS. Examination:Sudden, intense acoustic stimuli evoke a frightreaction including lid closure, startle, turning ofthe head, and increased alertness.

Brain Stem

BrainStem


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Brain stem(ventral; red lines, planes of section)

Corticopontinetract

Corticospinal tractCorticonuclear tract

Corticopontine tract

Medial longitudinal fasciculus

III

Red nucleus

Cerebral peduncle

Reticular formation

Substantia nigra

Medial lemniscus

Central sympathetic tract

IV

Medial lemniscus

Principal sensory nucleus/

Spinal tract ofCN V

Middle cerebellar peduncle

Vestibular nuclei

CN VII and nucleus

VI

X

XII

VIII

Nucleus VI

VII

V

Olive

Pyramidal decussationChoroid plexus

(fourth ventricle)

XI

IX

Lateral ventricle

Cerebralpeduncle

Thalamus

II

Optic -tract

III

Reticular formation IV

Central sympathetic

tract

Reticular formation

V

VIII

VI

VI

VII

Central sympathetic tract

X

Reticularformation

Medial lemniscus

XII

X

Motor nucleus V

A

B

C

D

E

A

B

C

D

E

Brain Stem

BrainStem


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Cranial Nerve Pathways

CranialNerve

Origin/Course (see also pp. 70 ff. and 74 ff)

I Olfactory nerves ! cribriform plate ! olfactory bulb ! olfactory tract ! anterior perforated sub-stance ! lateral olfactory stria (! parahippocampal gyrus) and medial olfactory stria (! limbicsystem)

II Retinal ganglion cells ! optic disk ! optic nerve ! orbit ! optic canal ! optic chiasm ! optictract ! lateral geniculate body (! optic radiation ! occipital lobe) and superior colliculi (! pre-tectal area)

III Midbrain ! interpeduncular fossa ! between superior cerebellar artery and posterior cerebralartery ! tentorial edge ! cavernous sinus ! medial orbital fissure ! oculomotor nerve, superiordivision (levator palpebrae and superior rectus muscles) and inferior division (medial and inferiorrectus and inferior oblique muscles) or parasympathetic fibers ! ciliary ganglion

IV Midbrain ! dorsal brainstem below the inferior colliculi ! around the cerebral peduncle ! lateralwall of the cavernous sinus ! orbital fissure ! superior oblique muscle

V Pons ! ca. 50 root filaments (sensory root = portio major; motor root = portio minor) ! petrousapex ! through the dura mater ! trigeminal ganglion (V/1 ! orbital fissure; V/2 ! foramenrotundum, V/3 + portio minor ! foramen ovale)

VI Posterior margin of pons ! up the clivus ! through the dura mater ! petrous apex ! lateral tointernal carotid artery in the cavernous sinus ! orbital fissure ! lateral rectus muscle

VII Pons (cerebellopontine angle) above the olive ! internal acoustic meatus ! petrous pyramid(canal of facial nerve) ! geniculum of facial nerve (! nervus intermedius/greater petrosal nerve !gustatory fibers) ! medial wall of the tympanic cavity ! stylomastoid foramen ! muscles of fa-cial expression

VIII Lateral to CN VII ! vestibular nerve, cochlear nerve

IX Medulla ! jugular foramen ! between carotid artery and internal jugular vein ! root of thetongue

X Posterolateral sulcus of medulla ! jugular foramen ! internal organs

XI Cranial and spinal roots ! trunk of accessory nerve ! jugular foramen ! muscles

XII Medulla ! hypoglossal canal ! tongue muscles

CN = cranial nerve.

See Table 1, p. 356, for the functions of the cranial nerves.

Cranial Nerves

Cran

ialN

erves


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Cranial nerves at the base of the brain

Optic chiasm

Anterior communicating a.

Optic tract

Oculomotor n.

Basilar a.

Abducens n.

Facial n.,vestibulo-cochlear n.

Accessory n.,spinal root

Olfactory tract

Optic n.

Middle cerebral a.

Trochlear n.

Trigeminal n.

Glossopharyn-geal n., vagus n.

Hypoglossal n.

Cranial nerves at the base of the skull

Glossopharyn-geal n., vagus

n., accessory n.

Facial n.,vestibulo-

cochlear n.

Trochlear n.

Abducens n.

Oculomotor n.

Optic n.

Olfactory bulb and tract

Confluence of sinuses

Transverse sinus

Hypoglossal n.

Trigeminal n.

Pituitary stalk

Cavernous sinus

Cranial Nerves

Cran

ialN

erves


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Spine

The spine (vertebral column) bears the weightof the head, neck, trunk and upper extremities.Its flexibility is greatest in the cervical region,intermediate in the lumbar region, and lowest inthe thoracic region. Its uppermost vertebrae(atlas and axis) articulate with the head, and itslowermost portion, the sacrum (which consistsof 5 vertebrae fused together), articulates withthe pelvis. There are 7 cervical, 12 thoracic (inBritish usage dorsal), and 5 lumbar vertebrae,making a total of 24 above the sacrum. Belowthe sacrum, the coccyx is composed of 3 to 6coccygeal vertebrae.

Intervertebral Disks

Each pair of adjacent vertebrae is separated byan intervertebral disk. From the third decade oflife onward, each disk progressively diminishesin water content, and therefore also in height. Itstensile, fibrous outer ring (annulus fibrosus)connects it with the vertebrae above and belowand is held taut by the pressure in the centralnucleus pulposus, which varies as a function ofthe momentary position of the body. The pres-sure that obtains in the sitting position is doublethe pressure when the patient stands, but thatfound in the recumbent position is only one-third as great. The interior of the disk has nonociceptive innervation, in contrast to the peri-osteum of the vertebral bodies, which is inner-vated by the meningeal branch of the segmentalspinal nerve, as are the intervertebral joint cap-sules, the posterior longitudinal ligament, thedorsal portion of the annulus fibrosus, the duramater, and the blood vessels.

Spinal Canal

The spinal canal is a tube formed by the vertebralforamina of the vertebral bodies stacked one ontop of another; it is bounded anteriorly by thevertebral bodies and posteriorly by the vertebralarches (laminae). Its walls are reinforced by theintervertebral disks and the anterior and poste-rior longitudinal ligaments. It contains the spinalcord and itsmeninges, the surrounding fatty andconnective tissues, blood vessels, and spinalnerve roots. Its normal sagittal diameter ranges

from12 to 22mm in the cervical region and from22 to 25mm in the lumbar region.

Spinal Cord

Like the brain, the spinal cord is intimately en-veloped by the pia mater, which containsnumerous nerves and blood vessels; the piamater merges with the endoneurium of the spi-nal nerve rootlets and also continues below thespinal cord as the filum terminale internum. Theweblike spinal arachnoid membrane containsonly a few capillaries and no nerves. The den-ticulate ligament runs between the pia materand the dura mater and anchors the spinal cordto the dura mater. In lumbar puncture, cere-brospinal fluid is withdrawn from the space be-tween the arachnoid membrane and pia mater(spinal subarachnoid space), which communi-cates with the subarachnoid space of the brain.The spinal dura mater originates at the edge ofthe foramen magnum and descends from it toform a tubular covering around the spinal cord.Its lumen ends at the S1–S2 level, where it con-tinues as the filum terminale externum, whichattaches to the sacrum, thus anchoring the duramater inferiorly. The dura mater forms sleevesaround the anterior and posterior spinal nerveroots which continue distally, together with thearachnoid membrane, to form the epineuriumand perineurium of the spinal nerves. Unlike thecranial dura mater, the spinal dura mater is notdirectly apposed to the periosteum of the sur-rounding bone (i.e., the vertebral canal) but isseparated from it by the epidural space, whichcontains fat, loose connective tissue, and valve-less venous plexuses (p. 22).The root filaments (rootlets) that come togetherto form the ventral and dorsal spinal nerve rootsare arranged in longitudinal rows on the lateralsurface of the spinal cord on both sides. The ven-tral root carries only motor fibers, while the dor-sal root carries only sensory fibers. (This so-called “law of Bell and Magendie” is actually notwholly true; the ventral root is now known tocarry a small number of sensory fibers as well.)The cell bodies of the pseudounipolar sensoryneurons are contained in the dorsal root gan-glion, a swelling on the dorsal root just proximalto its junction with the ventral root to form thesegmental spinal nerve.

Spine and Spinal Cord

Spinean

dSp

inal

Cord


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Spinal cord, spinal canal(thoracic spine, frontal view)

Spinal nerves

Intervertebral disk,annulus fibrosus

Denticulate lig.

Ventral root

Spinal nerve

Posterior branch ( > skin and muscles of back)

Epidural space

Meningealbranch

Posterior longitudinal lig.

Epidural veins

Arachnoid membrane

Costo-vertebral joint

Rib

Pia mater

Dura mater

Vertebral body Coccyx

Subarachnoid space

Spinal ganglion

Root sleeve

Intervertebral foramen

Inter-transverse lig.

C = Cervical nerves (C1-C8, blue)

T = Thoracic nerves (T1-T12, purple)

L = Lumbar nerves (L1-L5, turquoise)

S = Sacral nerves (S1-S5, light green)

Co = Coccygeal nerve (Co1, gray)

2

1

3

4

5

1

23

4

5

Sacrum

12

34

5

6

7

89

10

11

12

1234567

AtlasC 1

C 2C 3C 4C 5C 6C 7

C 8T 1

T 2T 3

T 4T 5T 6

T 7T 8

T 9

T 10

T 11

T 12

L 1

L 2

L 3

L 4

L 5

S 1S 2

S 3S 4S 5

Co 1

Spine and Spinal Cord

Spinean

dSp

inal

Cord


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The precise region of impaired sensation to lighttouch and noxious stimuli is an important cluefor the clinical localization of spinal cord andperipheral nerve lesions. Reflex abnormalitiesand autonomic dysfunction are further ones, asdiscussed below (p. 40, p. 110).

Dermatomes (pp. 34, 36)

A dermatome is defined as the cutaneous areawhose sensory innervation is derived from asingle spinal nerve (i.e., dorsal root). The divi-sion of the skin into dermatomes reflects thesegmental organization of the spinal cord andits associated nerves. Pain dermatomes are nar-rower, and overlap with each other less, thantouch dermatomes (p. 104); thus, the level of aspinal cord lesion causing sensory impairmentis easier to determine by pinprick testing thanby light touch. (The opposite is true of periph-eral nerve lesions.) Radicular pain is pain in thedistribution of a spinal nerve root, i.e., in a der-matome; pseudoradicular pain may occupy abandlike area but cannot be assigned to any par-ticular dermatome. Pseudoradicular pain can becaused by tendomyosis (pain in themuscles thatmove a particular joint), generalized tendomy-opathy or fibromyalgia, facet syndrome (inflam-mation of the intervertebral joints), myelogelo-sis (persistent muscle spasm resulting fromoverexertion), and other conditions. For mne-monic purposes, it is useful to know that the C2dermatome begins in front of the ear and endsat the occipital hairline; the T1 dermatomecomes to the midline of the forearm; the T4 der-matome is at the level of the nipples (which,however, belong to T5); the T10 dermatome in-cludes the navel; the L1 dermatome is in thegroin; and the S1 dermatome is at the outeredge of the foot and heel.

Myotomes

A myotome is defined as the muscular distribu-tion of a single spinal nerve (i.e., ventral root),and is thus the muscular analogue of a cu-taneous dermatome. Many muscles are inner-vated by multiple spinal nerves; only in the par-avertebral musculature of the back (erectorspinae muscle) is the myotomal pattern clearlysegmental (p. 31); the nerve supply here is

through the dorsal branches of the spinalnerves. Knowledge of the myotomes of each spi-nal nerve, and of the segment-indicating muscles(Table 2, p. 357) in particular, enables the clini-cal and electromyographic localization of radic-ular lesions causing motor dysfunction. The seg-ment-indicating muscles are usually innervatedby a single spinal nerve, or by two, though thereis anatomic variation.

Plexuses (pp. 34, 36) and PeripheralNerves (pp. 35, 37)

The ventral branches of spinal nerves supplyingthe limbs join together to form the cervical (C1–C4), brachial (C5–T1), lumbar (T12–L4), andsacral plexuses (L4–S4). The brachial plexusbegins as three trunks, the upper (derived fromthe C5 and C6 roots), middle (C7), and lower (C8,T1). These trunks split into divisions, which re-combine to form the lateral (C5–C7), posterior(C5–C8), and medial (C8 and T1) cords (namedby their relation to the axillary artery). Thecords of the brachial plexus branch into thenerves of the upper limb (p. 35). The nerves ofthe anterior portion of the lower limb arederived from the lumbar plexus, which lies be-hind and within the psoas major muscle (p. 37);those of the posterior portion of the lower limbfrom the sacral plexus. The coccygeal nerve (thelast spinal nerve to emerge from the sacral hia-tus) joins with the S3–S5 nerves to form thecoccygeal plexus, which innervates the coccy-geus and the skin over the coccyx and anus (me-diates the pain of coccygodynia).

Dermatomes andMyotomes

Dermatom

esan

dMyo

tomes


33

Argo light Argo

Peroneus longus m.

Tibialis anterior m.

Quadricepsfemoris m.

Adductors

Thenar muscles

In-teros-sei mm.

Brachio-radialis m.

Biceps brachii m.

Deltoid m.

Pectoralis m.

Gastrocnemius m.

Tibialisposterior

m.

Gluteus maximus m.

Gluteus medius m.

Iliopsoas m.

Hypothe-nar muscles

Diaphragm

Rhomboid mm.

Supraspinatus m.

Infraspinatus m.

Triceps brachii m.

Extensor hallucis longus m.

Dermatomes (left, posterior view; right, anterior view)

Myotomes(left, posterior view; right, anterior view)

T 2T 3

T 1

T 4T 5T 6T 7T 8T 9

T 9T 10

T 10T 11

T 11T 12

T 12

C 2

C 3

C 4C 5

C 6

C 7C 8

L 1L 2

L 3

L 3

L 4

L 4

L 5

L 5 L 5L 4

L 5

L 2L 1

T 8T 7T 6T 5T 4T 3T 2

T 1

C 2

C 3C 4

C 5

C 6

C 8

C 7

S 1S 1

S 1

S 2

S 2

Dermatomes andMyotomes

Dermatom

esan

dMyo

tomes


34

Argo light Argo

C 3

C 4Dia-phragm

Hypoglossal n. (XII)

Ansa cervicalis (from C1 to C3)

Long thoracic n. (C5-C7)

Medialpectoral n.

(C8/T1)

Phrenic n.(C3/C4)

Great auricular n.

Lesser occipital n.

Transversus colli n.

Supraclavicular nn.

Dorsal scapular n. (C3-C5)

Suprascapular n. (C4-C6)

Subclavian n. (C5/C6)

Musculocutaneous n. (C5-C7)

Upper trunk (C5/C6)

Lower trunk (C8/T1)

Medial cord (C8/T1)

Lateral cord (C5-C7)

Posterior cord (C5-C8)

Axillary a.

Medial cutaneous n. of arm

Medial cutaneous n. of forearm

Ulnar n. (C7/8-T1)

Median n.(C5-T1)

Radial n. (C5-T1)

Axillary n. (C5/C6)

Ribs 1 and 2

Deltoid m.

Supra- andinfraspinatusmm.

Bicepsbrachii m.

Brachioradialis m.

Opponens pollicis m.

Flexor carpi radialis m.

Extensor carpi radialis m.

Pronatorteres m.

Triceps brachii m.

Pectoralis major m.

Flexor policisbrevis m.

Interos-sei mm.Abductor

pollicis brevis m.

Flexor carpi ulnarism.

Abductordigiti quinti m.

C 3/C 4

Cervicobrachial plexus (C = cervical vertebra; T = thoracic vertebra)

C 5(Dermatome: blue)

C 6(Dermatome: dark red)

C 7(Dermatome: violet)

C 8(Dermatome: light red)

Middle trunk (C7)

C 1

C 2

C 3

C 4

C 5

C 6

C 7

C 8

T 1

Brachial Plexus

Periph

eral

Nervo

usSystem


35

Argo light Argo

Cervical plexus(C1-C4, cutaneous distribution)

Axillary nerve

Musculocutaneous n.

Radial n.

Median nerve Ulnar nerve

Deltoid m.

C 5C 6

Biceps brachii m.

Coraco-brachialis m.

Brachialis m.

Triceps brachii m.

Brachioradialis m.

Extensorcarpi radialis

longus m.

Extensor carpiulnaris m.

Extensor pollicis longus m.Abductor

pollicislongus m.

Supinator m.

Extensor digitorum communis m.

Branches to extensor digiti quinti,extensor pollicis brevis, and extensorindicis mm.

Pronator teres m.

Cutaneous distribution

Cutaneousdistribution

Flexor carpiradialis m.

Palmaris longus m.

Flexor digitorumsuperficialis m.

Pronatorquadratus m.

Abductor pollicis brevis, flexor pollicisbrevis, and opponenspollicis mm.

Lumbrical mm. 1-3

Flexor carpi ulnaris m.

Flexor digitorum profundus m.Flexor pol-licis brevis m.

Adductor pollicis m.

Dorsal and palmar interosseous mm.

Abductor digiti quinti m.

Flexor brevis and opponensdigiti quinti m.

Lumbrical mm. 3 + 4

C 5

C 5

C 6

C 6

C 7

C 7C 8T 1

C 8C 8C 7C 6

C 5

T 1T 1

Nerves of the Upper Limb

Periph

eral

Nervo

usSystem


36

Argo light Argo

Lumbosacral plexus

L 3 (Dermatome:red; iliopsoas,adductor longus,adductor mag-nus mm. notshown)

L 4 (Dermatome: green)

L 5 (Dermatome: green; gluteusmedius m. not shown)

Psoas major m.Iliohypogastric n.

Ilioinguinal n.

Lateral cutane-ous n. of thigh

Genitofemoral n.

Femoral n.

Lumbosacral trunk (peroneal n.)

Lumbosacral trunk (tibial n.)

Pudendal n. (fromcoccygeal plexus)

Sciatic n. (peronealand tibial n.)

Obturator n.

Vastus lateralis n.

Vastus intermedius m.

Rectus femoris m.

Vastus medialis m.

Sartorius m.

Gracilis m.

Adductor magnus m.

Rectusfemoris m.

Vastus lateralis m.

Vastus medialis m.

Tibialis anterior m.

Extensor hallucis longus m.

Gastrocnemius m. (medial and lateral heads)

Soleus m.

Gluteal n.

Vastusmedialism.

Extensor digitorum brevis m.

Subcostal n.

S 1(Dermatome: yellow; gluteusmaximus not shown)

Obturator n.

T 12

L 1

L 2

L 3

L 4

L 5

S 1S 2S 3S 4S 5

Lumbar Plexus

Periph

eral

Nervo

usSystem


37

Argo light Argo

L 1

L 3

L 4

L 5

Cutaneous innervation of the groin(left, in men; right, in women)

Lateral cutaneous n. of thigh

Femoral nerve(cutaneous distribution)

Sciatic nerve,peroneal nerve(purple: cutaneousdistribution)

Sciatic nerve, tibial nerve

(purple: cutaneousdistribution)

Psoas major m.

Iliacus m.L 2

Iliohypogastric n.

Genitofemoral n.(femoral branch)

Genitofemoral n. (genital branch)

Ilioinguinal n.

Iliacus m.

Pectineus m.

Rectusfemoris m.

Sartorius m.

Vastus medialis m.

Vastus lateralis m.

Biceps femoris m.(short head)

Long peroneal m.

Peroneus brevis m.

Intermediatedorsal cutaneous n.

Semiten-dinosus m.

Semimem-branosus m.

Adductormagnus m.

Gastro-cnemius m.

Flexor digitorumlongus m.

Cutaneous distribution

Inguinal lig.

Anterior cutaneousbranches

Saphenous n.

Saphenous n.

Psoas major m.

Vastus intermedius m.

Sciatic n.

Sciatic n.

Commonperoneal n. Tibial n.

Anterior tibial m.

Extensor digitorum longus m.

Biceps femoris m. (long head)

Femoral nerve

L 2

L 3

L 1L 2L 3L 4

L 4L 4

L 5L 5

S 1

S 1

S 2

S 2S 3

Nerves of the Lower Limb

Periph

eral

Nervo

usSystem


38

Argo light Argo


2Normal and AbnormalFunction of the NervousSystem

! Neural Pathways

! Pathophysiology

! Major Syndromes


40

Reflexes are involuntary and relatively stereo-typed responses to specific stimuli. Afferentnerve fibers conduct the impulses generated byactivated receptors to neurons in the centralnervous system, which fire impulses that arethen transmitted through efferent nerve fibersto the cells, muscles, or organs that carry out thereflex response. The pathway as a whole isknown as the reflex arc. Receptors are found atthe origin of all sensory pathways—in the skin,mucous membranes, muscles, tendons, and pe-riosteum, as well as in the retina, inner ear, ol-factory mucosa, and taste buds. A reflex re-sponse may involve the somatic musculature orthe internal organs. Most reflexes are relativelyindependent of the state of consciousness. Aninterruption of the reflex arc at any pointweakens or abolishes the reflex. Intrinsic reflexesare those whose receptors and effectors are lo-cated in the same organ (e. g., the quadriceps re-flex), while the receptors and effectors of extrin-sic reflexes are in different organs (e. g., theoculovestibular reflex). Reflexes are importantfor normal function (e. g., for postural controland goal-directed movement), and an impairedreflex is an important objective finding in clini-cal neurological examination.

Intrinsic Muscle Reflexes (Phasic StretchReflexes, Tendon Reflexes)

Intrinsic muscle reflexes are triggered by stretchreceptors within the muscle (annulospiral nerveendings of muscle spindles). The impulsesgenerated at the receptors are conveyed via af-ferent fast-twitch Ia fibers to spinal alpha-motorneurons, whose efferent !1 processes excite theagonistic muscle of an opposing muscle pair.The antagonistic muscle is simultaneously in-hibited by spinal interneurons. The resultingmuscle contraction relaxes the muscle spindles,thereby stopping impulse generation at thestretch receptors. The spinal reflex arc is alsounder the influence of higher motor centers.Abnormal reflex responses imply an abnormal-ity of the musculature, the reflex arc, or highermotor centers. The most important reflexes inclinical diagnosis are the biceps (C5–C6), bra-chioradialis (C5–C6), triceps (C7–C8), adductor(L2–L4), quadriceps (L2/3–L4), posterior tibial(L5), and Achilles (S1–S2) reflexes.

Extrinsic Reflexes

Intrinsic muscle reflexes, discussed above, aremonosynaptic, but extrinsic reflexes are polysy-naptic: between their afferent and efferent armslies a chain of spinal interneurons. They may beactivated by stimuli of various types, e. g.,muscle stretch, touch on the skin (abdominal re-flex) or cornea (corneal reflex), mucosal irrita-tion (sneezing), light (eye closure in response toa bright flash), or sound (acoustic reflex). The in-tensity of the response diminishes if thestimulus is repeated (habituation). Because theyare polysynaptic, extrinsic reflexes have a longerlatency (stimulus-to-response interval) than in-trinsic reflexes. Some important extrinsic re-flexes for normal function are the postural andrighting reflexes, feeding reflexes (sucking,swallowing, licking), and autonomic reflexes(p. 110).The flexor reflex is triggered by noxious stimula-tion, e. g., from stepping on a tack. Excitatory in-terneurons activate spinal cord alpha-motorneurons, which, in turn, excite ipsilateral flexormuscles and simultaneously inhibit ipsilateralextensor muscles via inhibitory interneurons.Meanwhile, the contralateral extensors con-tract, and the contralateral flexors relax. The re-sponse does not depend on pain, which is feltonly when sensory areas in the brain have beenactivated, by which time themotor response hasalready occurred. This spinal reflex arc, like thatof the intrinsic muscle reflexes, is under the in-fluence of higher motor centers.Abnormalities of the extrinsic reflexes imply aninterruption of the reflex arc or of the corti-cospinal tracts (which convey impulses fromhigher motor centers). Some clinically impor-tant extrinsic reflexes are the abdominal (T6–T12), cremasteric (L1–L2), bulbocavernosus (S3–S4), and anal wink (S3–S5) reflexes.Reflexes that can be elicited only in the diseasedstate are called pathological reflexes. Pathologi-cal reflexes indicating dysfunction of the py-ramidal (corticospinal) tract include the Babin-ski sign (tonic dorsiflexion of the great toe onstimulation of the lateral sole of the foot), theGordon reflex (same response to squeezing ofthe calf muscles), and the Oppenheim reflex(same response to a downward stroke of the ex-aminer’s thumb on the patient’s shin).

Reflexes

Motor

Func

tion


41

Diminished 1Normal intensity 2Heightened 3Persistent clonus 4

Can only be elicited by maneuvers(e.g., Jendrassik maneuver)

Reflex response(Proprioceptive muscle reflex)

Proprioceptive(intrinsic) musclereflex

Extrinsic muscle reflex

Reflex response Symbol

Extensor muscle Efferent fiber (excitatory)

Flexor muscle

Efferent fiber (inhibitory)

Afferent (Ia) fiber

Afferent (Ia) fiber

Supraspinal control(inhibitory)

Supraspinalcontrol

(inhibitory)

Excitatory synapse

Excitatory synapse

Pseudounipolar nerve cells inspinal ganglion

Afferent fiber

Afferent fiber

Annulospiralending of muscle spindle

Efferent toextensors

Extensor

Extensor muscle

Inhibitory synapse

Inhibitory synapse

Flexor

Flexor muscle

Interneuron

Interneurons

Free ending of afferent fiber (pain,temperature)

Pressure receptor(Vater-Pacini corpuscle)

Efferent to flexors

Fibers to contralateral side ofcommissural cell

Efferent fibers toipsilateral flexors and extensors

Efferent fibers to contralateral extensorsand flexors

+_

Absent, cannot be elicited by maneuvers 0

Reflexes

Motor

Func

tion


42

Themotor system controls the timing, direction,amplitude, and force of movement through thecoordinated opposing actions of agonist and an-tagonist muscles. It also keeps the body in astable position through postural and righting re-flexes. Reflex movements are involuntary, stereo-typed responses to stimuli. Rhythmic movementshave both reflex and voluntary components.Voluntary movements are performed at will.

Reflex Movements

Withdrawing a foot from a noxious stimulus orspreading the armswhen falling are examples ofreflex movements. Intrinsic muscle reflexes regu-late muscle tone and elasticity and are impor-tant for postural control and coordination ofmuscle groups. Specific functions such as jointstabilization or adjustment of contractionstrength are achieved with the aid of inhibitoryspinal interneurons. Extrinsic reflexes includeprotective reflexes (flexor response to noxiousstimulus, corneal reflex) and postural reflexes(extensor reflex, neck reflex).

Rhythmic Movements

Walking, breathing, and riding a bicycle arerhythmic movements. They are subserved bothby spinal reflex arcs and by supraspinal in-fluence from the brain stem, cerebellum, basalganglia, and motor cortex.

Voluntary Movements

Voluntary movements depend on a sequence ofcontractions of numerous different muscles thatis planned to achieve a desired result (motorprogram). Hence different parts of the body areable to carry out similar movements (motorequivalence) more or less skillfully, e. g., simul-taneous rotation of the big toe, foot, lower leg,leg, pelvis and trunk. Voluntary movements in-corporate elements of the basic reflex andrhythmic movement patterns; their smooth ex-ecution depends on afferent feedback from thevisual, vestibular, and proprioceptive systems tomotor centers in the spinal cord, brain stem, andcerebral cortex. Further modulation of volun-tary movements is provided by the cerebellumand basal ganglia, whose neural output reaches

the cortex through thalamic relay nuclei. Finemotor control thus depends on the continuousinteraction of multiple centers responsible forthe planning (efferent copy) and execution ofmovement.Motor cortex (p. 25). Voluntary movements areplanned in the motor areas of the cerebral cor-tex. The primary motor area (area 4) regulatesthe force of muscle contraction and the goal-oriented direction of movement; it mainly con-trols distal muscle groups. The supplementarymotor area (medial area 6) plays an importantrole in complex motor planning. The premotorarea (lateral area 6) receives nerve impulsesfrom the posterior parietal cortex and is con-cerned with the visual and somatosensory con-trol of movement; it mainly controls trunk andproximal limb movement.Cerebellum (p. 54). The cerebellum coordinateslimb and eye movements and plays an impor-tant role in the maintenance of balance and theregulation of muscle tone.Basal ganglia (p. 210). The basal ganglia have aclose anatomic and functional connection to themotor cortex and participate in the coordinationof limb and eye movement.

Motor Control

Motor

Func

tion


43

Areas 5, 7

Areas 3, 1, 2

Area 4

Premotor cortex

Area 8

Supplementary motor cortex

Cerebellum

Cerebellum

Putamen

Globus pallidus

externus

Globus pallidus internus

Subthalamic nucleusSubstantia nigra,pars reticularis

Substantia nigra,pars compacta

Thalamus

Red nucleus,pars magnocel-lularis

Red nucleus,pars parvocel-lularis

Vestibular nuclei

Fastigial nucleus

Globose and emboliform nuclei

Dentate nucleus

Caudate nucleus

Ventral lateralnucleus

Centromedian nucleus

Corticofugal pathways (execution ofmovement)

Cortical motor areas, afferent connections (visual, vestibular, somatosensory)

Motor pathways(cortex, basal ganglia, thalamus,brain stem, cerebellum, spinal cord)

Motor Control

Motor

Func

tion


44

Pyramidal Tract

Each fiber of the pyramidal tract originates inthe first or upper motor neuron, whose cell bodyis located in the primary motor area (area 4),primary sensory areas (areas 1–3), the sup-plementary motor area, or the premotor area(area 6). The fibers descend through the poste-rior portion of the internal capsule through thecerebral peduncle, pons, and medulla, forming asmall bulge (pyramid) on the anterior surface ofthe medulla. Most of the fibers cross the midlinein the decussation of the pyramids and then de-scend through the spinal cord in the lateral cor-ticospinal tract. Among the minority of fibersthat do not cross in the pyramidal decussation,most continue in the ipsilateral anterior corti-cospinal tract, crossing the midline in the ante-rior spinal commissure only once they reach thelevel of their target motor neurons. The py-ramidal tract mainly innervates distal musclegroups in the limbs. In the brain stem, the py-ramidal tract gives off fibers to the motor nucleiof the cranial nerves (corticopontine and corti-cobulbar tracts). Fibers from the frontal eyefields (area 8) reach the nuclei subserving eyemovement (cranial nerves III, IV, VI) through thepyramidal tract. The motor nuclei of cranialnerves III, IV, VI, and VII (lower two-thirds of theface) are innervated only by the contralateralcerebral cortex; thus, unilateral interruption ofthe pyramidal tract causes contralateral paraly-sis of the corresponding muscles. In contrast,the motor nuclei of cranial nerves V (portiominor), VII (frontal branch only), IX, X, XI, andXII receive bilateral cortical innervation, so thatunilateral interruption of the pyramidal tractcauses no paralysis of the correspondingmuscles.

Nonpyramidal Motor Tracts

Other motor tracts lead from the cerebral cortexvia the pons to the cerebellum, and from thecerebral cortex to the striatum (caudate nucleusand putamen), thalamus, substantia nigra, rednucleus, and brain stem reticular formation.These fiber pathways are adjacent to the py-ramidal tract. Fibers arising from the premotorand supplementary motor areas (p. 43) projectipsilaterally and contralaterally to innervate the

muscles of the trunk and proximal portions ofthe limbs that maintain the erect body posture.Because of the bilateral innervation, paresis dueto interruption of these pathways recovers morereadily than distal paresis due to a pyramidal le-sion. Lesions of the pyramidal tract usually in-volve the adjacent nonpyramidal tracts as welland cause spastic paralysis; the rare isolated py-ramidal lesions cause flaccid paralysis (p. 46).Corticopontine fibers. Corticopontine fibersoriginate in the frontal, temporal, parietal, andoccipital cortex and descend in the internal cap-sule near the pyramidal tract. The pontine nu-clei project to the cerebellum (p. 54).Other functionally important tracts. The ru-brospinal tract originates in the red nucleus, de-cussates immediately, forms synapses with in-terneurons in the brain stem, and descends inthe spinal cord to terminate in the anterior horn.Rubrospinal impulses activate flexors and in-hibit extensors, as do impulses conducted in themedullary portion of the reticulospinal tract. Onthe other hand, impulses conducted in the pon-tine portion of the reticulospinal tract and in thevestibulospinal tract activate extensors and in-hibit flexors.

Motor Unit

A motor unit is the functional unit consisting ofa motor neuron and the muscle fibers inner-vated by it. Themotor neurons are located in thebrain stem (motor nuclei of cranial nerves) andspinal cord (anterior horn). The innervation ratiois the mean number of muscle fibers innervatedby a single motor neuron. The action potentialsarising from the cell body of a motor neuron arerelayed along its axon to the neuromuscularsynapses (motor end plates) of the musclefibers. The force of muscle contraction dependson the number of motor units activated and onthe frequency of action potentials. Innervationratios vary from 3 for the extraocular musclesand 100 for the small muscles of the hand to2000 for the gastrocnemius. The smaller the in-nervation ratio, the finer the gradation of force.The muscle fibers of a motor unit do not lie sideby side but are distributed over a region ofmuscle with a cross-sectional diameter of5–11mm.

Motor Execution

Motor

Func

tion


45

Cortical motorareas

Somatotopic organization ofmotor cortex

Cerebellum

Pyramidal tract

Red nucleus

Putamen

Internal capsule

Caudatenucleus (head)

Thalamus

Caudate nucleus (tail)

Oculomotornucleus

Motor nucleus of V

Nucleus VI

Nucleus VII

Nucleus XII

Nuclei IX, X

Nucleus XI

Reticular formation

Vestibular nuclei

Pontocerebellar fibers

Spinocerebellum

Vestibulocerebellum

Pontocerebellum

Anterior corticospinal tract

Lateral corticospinal tract

Ventral root(motor)

Muscle fiber,motor end plateregion

Motor neurons

Pontine nuclei

Pyramidal decussation

Corticonuclear tract

Area 4

Three motor units

Muscle fiber, motor endplate region

Motor Execution

Motor

Func

tion


46

Paralysis Due to Upper Motor Neuron(UMN) Lesions

The clinical features of paralysis due to lesionsof the pyramidal tract (upper motor neuron =UMN) depends on the anatomic site(s) of in-volvement of other efferent or afferent tractsand nuclei.Impairment of fine motor function. Voluntarymovement of paretic limbs requires greater ef-fort than normal and causes greater muscularfatigue. Moreover, rapid alternating movementsare slowed by hypertonia in the opposing ago-nist and antagonist muscles of paretic limbs.There may be synkinesia (involuntary move-ment of paretic limbs associated with othermovements, e. g., yawning), undifferentiated ac-cessory movements (mass movements), or spinalautomatisms (involuntary movements triggeredby somatosensory stimuli).Paralysis. Paralysis of UMN type affects multiple(but not all) muscle groups on one side of thebody. Bilaterally innervated movements (e. g., ofeyes, jaw, pharynx, neck; see p. 44) may be onlymildly paretic, or not at all. Paralysis that is ini-tially total usually improves with time, but re-covery may be accompanied by other motor dis-turbances such as tremor, hemiataxia, hemi-chorea, and hemiballism. Fine motor control isusually more severely impaired than strength.Neurogenic muscular atrophy does not occur inparalysis of UMN type.Spasticity. The defining feature of spasticity is avelocity-dependent increase of muscle tone inresponse to passive stretch. Spasticity is usually,but not always, accompanied by hypertonia. The“clasp-knife phenomenon” (sudden slackeningof muscle tone on rapid passive extension) israre. Spasticity mainly affects the antigravitymuscles (arm flexors and leg extensors).Reflex abnormalities. The intrinsic muscle re-flexes are enhanced (enlargement of reflexzones, clonus) and the extrinsic reflexes arediminished or absent. Pathological reflexes suchas the Babinski reflex can be elicited.

! Cerebral lesions

Monoparesis. Isolated lesions of the primarymotor cortex (area 4) cause flaccid weakness ofthe contralateral face, hand, or leg. Lesions af-fecting adjacent precentral or postcentral areas,

or areas deep to the cortex, cause spasticity andpossibly an associated sensory deficit. It may bedifficult to determine by examination alonewhether monoparesis is of upper or lowermotor neuron type (p. 50). Accessory move-ments of antagonistic muscles are present onlyin paralysis of UMN type.Contralateral hemiparesis. Lesions of the inter-nal capsule cause spastic hemiparesis. Involve-ment of corticopontine fibers causes (central)facial paresis, and impairment of corticobulbarfibers causes dysphonia and dysphagia. Sensorydisturbances are also usually present. Unilaterallesions in the rostral brain stem cause con-tralateral spastic hemiparesis and ipsilateral nu-clear oculomotor nerve palsy (crossed paralysis).For other syndromes caused by brain stem le-sions, see p. 70 ff. A rare isolated lesion of themedullary pyramid (p. 74) can cause con-tralateral flaccid hemiplegia without facial para-lysis, or (at mid-decussational level) con-tralateral arm paresis and ipsilateral leg paresis(Hemiplegia alternans).Ipsilateral paresis. Lesions of the lower medullabelow the pyramidal decussation (p. 74) causeipsilateral paralysis and spasticity (as do lesionsof the lateral corticospinal tract; see p. 45).Quadriparesis. Decortication syndrome (p. 118) iscaused by extensive bilateral lesions involvingboth the cerebral cortex and the underlyingwhite matter, possibly extending into the dien-cephalon; midbrain involvement produces thedecerebration syndrome. Involvement of thepons or medulla causes an initial quadriplegia;in the later course of illness, spinal automatismsmay be seen in response to noxious stimuli.Paraparesis. In rare cases, UMN-type paralysis ofboth lower limbs accompanied by bladder dys-function is caused by bilateral, paramedian, pre-central cortical lesions (parasagittal cortical syn-drome). Focal seizures may occur.

Central Paralysis

Motor

Func

tion


47

Central monoparesis(grasp induces contraction of antagonist muscles)

Peripheralparesis(hand drop)

Pyramidal tract

Right hemiparesis(lesion of internal capsule)

Crossed paresis(left midbrain lesion causing left

oculomotor nerve palsy and right hemiparesis)

Crossed paresis(lesion at the level of the pyramidal decussation

causing paresis of right arm and left leg)

Decerebration

Spastic paraparesis(parasagittal cortical syndrome)

Decortication

Central Paralysis

Motor

Func

tion


48

! Spinal Cord Lesions

The site and extent of a spinal cord lesion canoften be determined by clinical examination(p. 32 ff).Paralysis. Paralysis may be of mixed upper andlower motor neuron type if the lesion affects notonly the long fiber tracts but also the anteriorhorn cells of the spinal cord or their distalprocesses (root entry zone, spinal nerve roots).Reflex abnormalities are found below the levelof the lesion. Central cord lesions cause bothparalysis and a dissociated sensory deficit(p. 106).Posterior cord syndrome. Lesions of the poste-rior columns of the spinal cord impair vibrationand position sense (p. 104 ff). Neck flexion mayinduce a shocklike paresthesia shooting downthe back (Lhermitte’s sign). There may be hyper-sensitivity to touch and noxious stimuli in areasof sensory denervation.Autonomic dysfunction. Spinal cord transectioncauses acute spinal shock, a complete loss of au-tonomic function below the level of the lesion(bladder, bowel, and sexual function; vasomotorregulation; sweating). Injuries at C4 and aboveadditionally cause respiratory paralysis. The spi-nal autonomic reflexes (p. 146 ff) may later re-cover to a variable extent, depending on the siteof the lesion. Slowly progressive lesions of thecaudal portion of the spinal cord (e. g., intrinsictumor) usually come to notice because of uri-nary or sexual dysfunction.Complete transection. Transection causes im-mediate flaccid paraplegia or quadriplegia, an-esthesia and areflexia below the level of trans-ection, bilateral Babinski signs, and spinal shock(see above). The motor and sensory impairmentmay begin to improve within 6 weeks if the spi-nal cord is incompletely transected, ultimatelyleading to a stable chronic myelopathymanifested by spastic paraparesis or quadri-paresis and sensory and autonomic dysfunction.Incomplete transection. Lesions affecting only aportion of the cross-sectional area of the spinalcord cause specific clinical syndromes accordingto their site (pp. 32, 44, 104), of which the bestknown are the posterior column syndrome, theanterior horn syndrome (p. 50), the posteriorhorn syndrome (p. 106), the central cord syn-drome (p. 106), the anterior spinal artery syn-

drome (p. 282), and Brown–Séquard syndrome.In the last-named syndrome, hemisection of thespinal cord causes ipsilateral spastic paresis,vasomotor paresis, anhidrosis, and loss of posi-tion and vibration sense and somatosensorytwo-point discrimination, associated with con-tralateral loss of pain and temperature sensa-tions (the so-called dissociated sensory deficit).Cervical cord lesions. Upper cervical cord lesionsat the level of the foramen magnum (p. 74)cause neck pain radiating down the arms;shoulder and arm weakness that usually beginson one side, then progresses to include the legsand finally the opposite arm and shoulder; atro-phy of the intrinsic muscles of the hand; Lher-mitte’s sign; cranial nerve deficits (CN X, XI, XII);nystagmus; sensory disturbances on the face;and Horner syndrome. Progressive spinal cordinvolvement may ultimately impair respiratoryfunction. Lesions at C1 or below do not causecranial nerve deficits. (C1 root innervates themeninges without dermatome representation.)Lower cervical cord lesions (C5–C8) produce thesigns and symptoms of complete and in-complete transection discussed above, includ-ing segmental sensory and motor deficits. If thelesion involves the spinal sympathetic pathway,Horner syndrome results.Thoracic cord lesions. Transverse cord lesions atT1 can produce Horner syndrome and atrophyof the intrinsic muscles of the hand. Lesions atT2 and below do not affect the upper limbs.Radicular lesions produce segmental pain radi-ating in a band from back to front on one or bothsides. Localized back pain due to spinal cord le-sions is often incorrectly attributed to spinaldegenerative disease until weakness and blad-der dysfunction appear. Lesions of the upperthoracic cord (T1–T5) impair breathing throughinvolvement of the intercostal muscles.Lumbar and sacral cord injuries. Lesions at L1 toL3 cause flaccid paraplegia and bladder dysfunc-tion (automatic bladder, p. 156). Iliopsoas weak-ness may make it difficult or impossible for thepatient to sit. Lesions at L4 to S2 impair hip ex-tension and flexion, knee flexion, and foot andtoe movement. Lesions at S3 and below producethe conus medullaris syndrome: atonic bladder,rectal paralysis, and “saddle” anesthesia of theperianal region and inner thighs. For caudaequina syndrome, see pages 318 and 319.

Central Paralysis

Motor

Func

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49

Segmental muscular atrophy (anterior horn lesion)

Radicularlesion

Extramedullaryintradural lesion

Extradural lesion

Intramedullary lesion

Lhermitte’s sign

Paresthesia, pain(local, radicular radiation)

Sites of spinal lesions

Localization of lesions(left, dermatomes; right,segment-indicating muscles)

Autonomic dysfunction(bladder, bowel,circulatory system,genital organs,sweating)

Gait disturbances(paresis, spinal ataxia)

Babinski sign(pyramidal tract lesion)

Central Paralysis

Motor

Func

tion


50

Signs

Paralysis of peripheral origin can be caused bylesions of the anterior horn (lower motor neu-ron, LMN), nerve root, peripheral nerve, ormotor end plate andmust be distinguished fromweakness due to disease of the muscle itself(myopathy). Apparent weakness can also beproduced by tendon rupture or injury to bonesand joints.Paralysis. Paralysis is accompanied by diminu-tion of muscle tone (flaccidity). The extent ofweakness depends on the type, severity, anddistribution of LMN or myopathic involvement.Reflex abnormalities. The intrinsic muscle re-flexes are diminished or absent to a degree thatmay be disproportionate to the degree of weak-ness: in LMN-type paralysis, loss of reflexes isindependent from the loss of strength; in my-opathy, it parallels the weakness. Extrinsic re-flexes are unaffected unless the effector muscleis atrophic. Pathological reflexes are absent.Muscle atrophy. Muscle atrophy due to an LMNlesion may be disproportionate to the degree ofweakness (either greater or less). Progressiveatrophy of paralyzed muscles begins ca. 3 weeksafter a peripheral nerve injury. The distributionand severity of muscle atrophy in myopathy de-pends on the etiology.Spontaneous movements. Spontaneous move-ments are seen in affected muscles. Fascicula-tions are involuntary, nonrhythmic contractionsof motor units in a relaxed muscle. They are notexclusively caused by anterior horn lesions.Myokymia is rhythmic contraction of musclefibers; if the affected muscle is superficial (e. g.,the orbicularis oculi), waves of muscle contrac-tion are visible under the skin.

Lower Motor Neuron (LMN) Lesions

Anterior horn. Loss of motor neurons in the spi-nal cord paralyzes themotor units to which theybelong. The flaccid segmental weakness maybegin asymmetrically and is accompanied bysevere muscle atrophy. There is no sensory defi-cit. The intrinsic reflexes of the affected musclesare lost at an early stage. The weakness may bemainly proximal (tongue, pharynx, trunkmuscles) or distal (hands, calf muscles) depend-ing on the etiology of anterior horn disease.

Radicular syndrome. A lesion of a single ventralnerve root (caused, for example, by a herniatedintervertebral disk) produces weakness in theassociated myotome. Muscles supplied by mul-tiple nerve roots are only slightly weakened, if atall, but those supplied by a single root may befrankly paralyzed and atrophic (segment-indi-cating muscles, cf. Table 2, p. 357). Involvementof the dorsal root produces pain and paresthesiain the associated dermatome, which may betriggered by straining (sneezing, coughing),movement (walking), or local percussion. Au-tonomic deficits are rare.Peripheral nerve. Paralysis may be caused byplexus lesions (plexopathy) or by lesions of oneor more peripheral nerves (mononeuropathy,polyneuropathy). Depending on the particularsegment(s) of nerve(s) affected, the deficit maybe purely motor, purely sensory, or mixed, witha variable degree of autonomic dysfunction.Motor end plate. Disorders of neuromusculartransmission are typified by exercise-inducedmuscle fatigue and weakness. The degree of in-volvement of specific muscle groups (eyes,pharyngeal muscles, trunk muscles) depends onthe type and severity of the underlying disease.There is no associated sensory deficit. Hy-poreflexia characteristically occurs in Lambert–Eaton syndrome and is found in myastheniagravis to an extent that parallels weakness. Au-tonomic dysfunction occurs in Lambert–Eatonsyndrome and botulism.Myopathy (see p. 52) and musculoskeletal le-sions of the tendons, ligaments, joints, andbones may cause real or apparent weakness andthus enter into the differential diagnosis of LMNlesions. They cause no sensory deficit.Musculoskeletal lesions may restrict movement,particularly when they cause pain, sometimes tothe extent that the muscle becomes atrophicfrom disuse. Severe autonomic dysfunction mayalso occur (p. 110).

Peripheral Paralysis

Motor

Func

tion


51Paresis of finger extensors(supinator syndrome in right hand)

Distal muscular atrophy(here lesion of deep branch ofulnar nerve)

Distal muscular atrophy(here polyneuropathy)

Radicular pain(here due to lumbar disk herniation)

Possible lesion sites

Anterior horn

Mixed peripheralnerve

End plateregion

Purely motornerve

Purely sensory nerve

Muscle

Tendon, bone

Autonomicneurons inlateral horn

Sympatheticchain ganglion

Intervertebraldisk


Motor

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52

Myopathy

Problems such as muscle weakness, fatigue,stiffness, cramps, tension, atrophy, pain, and in-voluntary movement do not necessarily signifydisease of the muscle itself. Myopathy must bedistinguished from neurogenic weakness ofUMN or LMN type. Weakness may accompanysystemic disease because of a generalized cata-bolic state or through a specific disease-relatedimpairment of muscle function. Myopathy maybe either primary or secondary, i.e., the productof another underlying disease. Different types ofmyopathy affect different muscle groups: someare generalized (congenital myopathy), whileothers are mainly either proximal (Duchennetype muscular dystrophy, polymyositis) or distal(myotonic dystrophy, inclusion body myositis),or mainly affect the head and face (mito-chondrial myopathy). Myasthenia gravis, strictlyspeaking a disorder of neuromuscular transmis-sion rather than a form of myopathy, mostprominently affects the orbicularis oculimuscle; weakness increases with exercise.Muscle power is commonly graded according tothe scale proposed by the British Medical Re-search Council (MRC) (1976):

0 No muscle contraction1 Visible or palpable contraction, but no move-

ment2 Movement occurs, but not against gravity3 Movement against gravity4 Movement against gravity and additional re-

sistance5 Normal muscle power

! Muscle Atrophy

Myopathy produces atrophy through the im-paired development, the destruction, and theimpaired regeneration of muscle fibers.Primary (genetic) myopathies include the pro-gressive muscular dystrophies, myotonicmuscular dystrophies, congenital myopathies(e. g., central core disease, nemaline myopathy),and metabolic myopathies (Pompe disease/gly-cogen storage disease type II, Kearns–Sayre syn-drome, carnitine deficiency).Secondary myopathies include myositis, my-opathy due to endocrine disorders (hyperthy-roidism and hypothyroidism, hyperparathyroid-

ism), and chronic toxic myopathies (alcohol,corticosteroids, chloroquine).

! Disorders of Muscle Function

In these disorders, weakness is due to impairedfunction of the muscle fibers. Persistent weak-ness can lead to muscle atrophy. The episodicoccurrence or worsening of muscle weakness istypical.Primary myopathies. Hypokalemia- and hyper-kalemia-related forms of paralysis belong to thisgroup.Myasthenic syndromes. Myasthenia gravis andLambert–Eaton syndrome are characterized byabnormal fatigability of the muscles.Postviral fatigue syndrome. Mildly increasedfatigability of the muscles may persist for weeksafter recovery from a viral illness.

! Muscle Pain and Stiffness

Muscle pain and stiffness restrict movement,causing weakness as a secondary consequence.Muscle pain. Muscle pain (myalgia, p. 346) atrest and on exertion accompanies muscletrauma (muscle rupture, strain, soreness, com-partment syndromes), viral myositis (influenza,Coxsackie virus, herpes simplex virus), fibromy-algia, polymyalgia rheumatica, and musclecramps and spasms of various causes (malig-nant hyperthermia, carnitine palmitoyl-transferase deficiency, phosphorylase defi-ciency/glycogen storage disease type V).Muscle stiffness. Stiffness is prominent in con-genital myotonia, neuromyotonia, and cold-induced paramyotonia.


Motor

Func

tion


53

Motor end plate region

Three primary bundles of muscle fibers

Muscle fascia with epimysium

Artery

Artery

Striated muscle fiber

Muscle pain and stiffness(exercise-induced; here due to ischemia)

Mitochondrion

Myasthenic response(exercise-induced muscleweakness; here in eyes)

External ophthalmoplegia(here mitochondrial myopathy)

Structure of skeletal muscle

Progressive Duchenne muscular dystrophy(proximal leg weakness, patients use arms to raisethemselves to standing position = Gowers’s sign,calf hypertrophy, lumbar hyperlordosis)

Myotonic response(delayed fist opening)


Motor

Func

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54

The functions of the cerebellum include the con-trol of balance, posture, gait, and goal-directedmovement, and the regulation of muscle tone.

Neural Pathways

Afferent connections. The three large white-matter tracts (peduncles) of the cerebellum con-vey afferent input to the cerebellar cortex fromthe cerebral cortex (especially visual areas), pon-tine nuclei, the brain stem nuclei of the trigemi-nal, vestibular, and cochlear nerves, and the spi-nal cord. The superior cerebellar peduncle con-veys ipsilateral proprioceptive input (p. 104)from the anterior spinocerebellar tract of thespinal cord. The middle cerebellar peduncle car-ries fibers of pontine origin (p. 45). The inferiorcerebellar peduncle carries fibers from the vesti-bular nerve and nucleus to the flocculonodularlobe and fastigial nucleus, and from the con-tralateral inferior olive to the cerebellar hemi-spheres (olivocerebellar tract), as well as propri-oceptive input from the posterior spinocerebel-lar tract (derived from muscle spindles anddestined for the anterior and posterior portionsof the paramedian cerebellar cortex) and fibersfrom the brain stem reticular formation.Efferent connections. The cerebellar nuclei(fastigial, globose, emboliform, and dentate;p. 43) project via the (contralateral) superiorcerebellar peduncle to the red nucleus, thalamus,and reticular formation. The thalamus projectsin turn to the premotor and primary motor cor-tex, whose output travels down to the pons,which projects back to the cerebellum, forminga neuroanatomical circuit. Cerebellar output in-fluences (ipsilateral) spinal motor neurons byway of the red nucleus and rubrospinal tract.The inferior cerebellar peduncle projects to thevestibular nuclei and brain stem reticular for-mation (completing the vestibulocerebellarfeedback loop) and influences spinal motor neu-rons by way of the vestibulospinal and reti-culospinal tracts.

Functional Systems

The cerebellum can be thought of as containingthree separate functional components.Vestibulocerebellum (archeocerebellum). Struc-tures: Flocculonodular lobe and lingula. Afferent

connections: From the semicircular canals andmaculae (p. 56), vestibular nucleus, visual sys-tem (lateral geniculate body), superior col-liculus, and striate area to the vermis. Efferentconnections: From the fastigial nucleus to thevestibular nucleus and reticular formation.Functions: Control of balance, axial and proximalmuscle groups, respiratory movements, andhead and eye movements (stabilization of gaze).Effects of lesions: Loss of balance (truncal ataxia,postural ataxia ! gait ataxia), nystagmus onlateral gaze, and absence of visual fixation sup-pression (p. 26) resulting in oscillopsia (station-ary objects seem to move).Spinocerebellum (paleocerebellum). Structures:Parts of the superior vermis (culmen, centrallobule) and inferior vermis (uvula, pyramis),parts of the cerebellar hemispheres (wing ofcentral lobule, quadrangular lobule, parafloc-culus). Afferent connections: The pars intermediareceives the spinocerebellar tracts, projectionsfrom the primary motor and somatosensorycortex, and projections conveying auditory,visual, and vestibular information. Efferent con-nections: From the nucleus interpositus to thereticular formation, red nucleus, and ven-trolateral nucleus of the thalamus, which pro-jects in turn to area 4 of the cortex. Functions:Coordination of distal muscles, muscle tone(postural control), balance, and velocity andamplitude of saccades. Effects of lesions: Gaitataxia ! postural ataxia, muscular hypotonia,dysmetria.Pontocerebellum (neocerebellum). Structures:Most of the cerebellar hemispheres, includingthe declive, folium, and tuber of the vermis. Af-ferent connections: From sensory and motor cor-tical areas, premotor cortex, and parietal lobesvia pontine nuclei and the inferior olive. Efferentconnections: From the dentate nucleus to the rednucleus and the ventrolateral nucleus of thethalamus, and from these structures onward tomotor and premotor cortex. Functions: Coordi-nation, speed, and precision of body movementand speech. Effects of lesions: Delayed initiationand termination of movement, mistiming of ag-onist and antagonist contraction in movementsequences, intention tremor, limb ataxia.

Cerebellum

Motor

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55

Postural and gait ataxia

Structure of cerebellum(overview; median section of vermis right)

Vestibulocerebellum

Spinocerebellum

Pontocerebellum

Reticulospinal tract

Vestibulospinal tract

Vestibular n.

Nodulus

Uvula

Fastigial nucleus

Reticular formation

Vestibularnucleus

Thalamus(ventral lateral nucleus)

Thalamocortical tract

Red nucleus

Reticular formation

Emboliform and globosenuclei

Pyramis

Rubrospinal tract

Reticulospinal tract

Spinocerebellar tract

Vestibulocerebellum

Spinocerebellum

Spinocerebellum

Pontocere-bellum

Culmen

Central lobule

Areas 5 and 7 Area 4

Area 6

Dentatenucleus

Rubrospinal tract

Pontine nuclei

Olive

Thalamus

Hemisphere

Red nucleus

Cerebellum

Motor

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56

Labyrinth

The vestibular apparatus (labyrinth) consists ofthe saccule, the utricle, and three semicircularcanals, each in a plane approximately at rightangles to the others. The labyrinth is filled withfluid (endolymph) and has five receptor organs:the ampullary crests, which lie in a dilatation(ampulla) in front of the utricle at the end ofeach semicircular canal; the saccular macula(macula sacculi), a vertically oriented sensoryfield on the medial wall of the saccule; and theutricular macula (macula utriculi), a horizon-tally oriented sensory field on the floor of theutricle.Semicircular canals. Angular acceleration issensed by the hair cells of the ampullary crestsand the gelatinous bodies (cupulae) suspendedin the endolymph above them. Rotation aboutthe axis of one of the semicircular canals causesits cupula to deflect in the opposite direction,because it is held back by the more slowlymoving endolymph. With persistent rotation ata constant angular velocity (i.e., zero angular ac-celeration), the cupula returns to its neutralposition; but if the rotation should suddenlystop, the cupula is deflected once again, thistime in the direction of the original rotation, be-cause it is carried along by the still moving en-dolymph. The subject feels as if he were rotatingcounter to the original direction of rotation andalso tends to fall in the original direction of rota-tion.Maculae. The otolithic membrane of the saccu-lar and utricular maculae is denser than the sur-rounding endolymph because of the calcitecrystals (otoliths) embedded in it. Linear accel-eration of the head thus causes relative motionof the otolithic membrane and endolymph, re-sulting in activation of the macular receptorcells (hair cells). The resultant forces lead to ac-tivation of the sensory receptors of the maculae.

Neural Pathways

Afferent connections. The semicircular organsproject mainly to the superior and medial vesti-bular nuclei, the macular organs to the inferiorvestibular nuclei. The vestibulocerebellummaintains both afferent and efferent connec-tions with the vestibular nuclei; in particular,the lateral vestibular nucleus receives its major

input from the paramedian region of the cere-bellar cortex. Fibers reach the vestibular nucleusfrom the spinal cord ipsilaterally, and also bi-laterally by way of the fastigial nucleus. Theoculomotor nuclei project to the ipsilateral ves-tibular nuclei through the medial longitudinalfasciculus. The vestibular nuclei are intercon-nected by internuclear and commissural fibers.Efferent connections. The vestibulocerebellumprojects to the ipsilateral nodulus, uvula, andanterior lobe of the vermis, and to the flocculibilaterally. The lateral vestibulospinal tract pro-jects ipsilaterally to the motor neurons of thespinal cord and also gives off fibers to cranialnerves X and XI. Fibers to the motor neurons ofthe contralateral cervical spinal cord decussatein the medial vestibulospinal tract. The mediallongitudinal fasciculus (p. 86) gives off caudalfibers to the motor neurons of the cervical cord,and rostral fibers bilaterally to the nuclei sub-serving eye movement. Other fibers cross themidline to the contralateral thalamus, whichprojects in turn to cortical areas 2 and 3 (pri-mary somatosensory area).

Functional Systems

The vestibular system provides vestibulo-cochlear input to the cerebellum, spinal cord,and oculomotor apparatus to enable the coordi-nation of head, body, and eye movements. It in-fluences extensor muscle tone and reflexes viathe lateral vestibulospinal tract (postural motorsystem). The medial longitudinal fasciculus per-mits simultaneous, integrated control of neckmuscle tone and eye movements. The oculomo-tor system (p. 86) communicates with the vesti-bular nuclei, the cerebellum, and the spinal cordvia the medial longitudinal fasciculus and pon-tine projection fibers; thus the control of eyemovements is coordinated with that of bodymovements. Proprioceptive input concerningjoint position andmuscle tone reaches the vesti-bular system from the cerebellum (p. 54).Thalamocortical connections permit spatialorientation. Phenomena such as nausea, vomit-ing, and sweating arise through interaction withthe hypothalamus, the medullary “vomitingcenter,” and the vagus nerve, while theemotional component of vestibular sensation(pleasure and discomfort) arises through inter-action with the limbic system.

Vestibular System

Motor

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57

Anatomicpathways andfunctionalsystems

Head rotation(above, rotation to right;

below, sudden stop)

Ampulla

Horizontal semicircular canal

Utricular macule

Linear acceleration to side

Deflection of hair cells(effect of gravity)

Vestibular portion of CN VIII

Vestibulocerebellartracts

Vestibular ganglion

Joint afferent fibersCuneate nucleus


Visual information(CN II)

Thalamocortical tracts(to areas 2, 3)

Visual information(area 8)

Spinocerebellar tract

Vestibular apparatus

Visual information(areas 17, 18, 19)

Cerebellum

Neck muscle

Motor neuron

Thalamus

Nucleus of vagus n.

Posterior spinocerebellar tract

Cupula

Ampullary crest

Otoliths

Endolymph

Effect of endolymph pressure on cupula

Cupula

Hair cells with villi

Left Right

Otolithic membrane

Hair cells with villi

Otolithic membrane

Vestibular System

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58

Patients often use the word “dizziness” non-specifically to mean lightheadedness, unsteadi-ness, reeling, staggering, or a feeling of rotation.Dizziness in this broad sense has many possiblecauses. Vertigo, or dizziness in the narrow sense,is the unpleasant illusion that one is moving orthat the external world is moving (so-calledsubjective and objective vertigo, respectively).Pathogenesis. Vertigo arises from a mismatchbetween expected and received sensory input(vestibular, visual, and somatosensory) regard-ing spatial orientation and movement.Cause. Vertigo occurs as a normal response tocertain stimuli (physiological vertigo) or as theresult of diseases (pathological vertigo) affect-ing the labyrinth (peripheral vestibular vertigo),central vestibular system (central vestibularvertigo), or other functional systems (nonvesti-bular vertigo).Symptoms and signs. The manifestations of ver-tigo are the same regardless of etiology. They fallinto the following categories: autonomic (drow-siness, yawning, pallor, sialorrhea, increasedsensitivity to smell, nausea, vomiting), mental(decreased drive, lack of concentration, apathy,sense of impending doom), visual (oscillopsia =illusory movement of stationary objects), andmotor (tendency to fall, staggering and swayinggait).

Physiological Vertigo

Healthy persons may experience vertigo whentraveling by car, boat, or spaceship (kinetosis =motion sickness) or on looking down from amountain or tall building (height vertigo).

Peripheral Vestibular (Labyrinthine)Vertigo (p. 88)

There is usually an acute, severe rotatory vertigodirected away from side of the labyrinthine le-sion, with a tendency to fall toward the side ofthe lesion, horizontal nystagmus away from theside of lesion, nausea, and vomiting. Peripheralvestibular vertigo may depend on position,being triggered, for example, when the patientturns over in bed or stands up (positional ver-tigo), or it may be independent of position (per-sistent vertigo). It may also occur in attacks asepisodic vertigo.

Positional vertigo. Benign, paroxysmal posi-tional vertigo (BPPV) of peripheral origin is usu-ally due todetachedotoliths of theutricularmac-ula floating in the posterior semicircular canal(canalolithiasis). With every bodily movement,the freely floatingotolithsmovewithin the canal,under the effect of gravity. An abnormal cupulardeflection results, starting 1–5 seconds aftermovement and lastingup to30 seconds. TheDix–Hallpikemaneuver is a provocative test for BPPV:the patient is rapidly taken from a sitting to asupine positionwhile the head is kept turned 45°to one side. If nystagmus and vertigo ensue, theyare due to canalolithiasis on the side of the earnearer the ground. The canalith repositioningprocedure (CRP), by which particles can be re-moved from the semicircular canal, involves re-peatedly turning the patient’s head to the op-posite side, then back upright.Episodic and persistent vertigo may be due toviral infection of the vestibular apparatus (vesti-bular neuritis, labyrinthitis) or to Ménière dis-ease, which is characterized by attacks of ro-tatory vertigo, tinnitus, hearing loss, and earpressure. Other causes include labyrinthinefistula and vestibular paroxysm.

Central Vestibular Vertigo(pp. 70 ff and 88)

This type of vertigo is caused by a lesion of thevestibular nuclei, vestibulocerebellum, thala-mus, or vestibular cortex, or their interconnect-ing fibers. Depending on the etiology (e. g.,hemorrhage, ischemia, tumor, malformation, in-fection, multiple sclerosis, “vestibular” epilepsy,basilar migraine), vertigo may be transient orpersistent, acute, episodic, or slowly progres-sive. It may be associated with other neurologi-cal deficits depending on the location and ex-tent of the responsible lesion.

Nonvestibular Vertigo

Episodic or persistent nonvestibular vertigooften manifests itself as staggering, unsteadygait, and loss of balance. The possible causes in-clude disturbances of the oculomotor apparatus,cerebellum, or spinal cord; peripheral neu-ropathy; intoxication; anxiety (phobic attacks ofvertigo); hyperventilation; metabolic disorders;and cardiovascular disease.

Vertigo

Motor

Func

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59

Rotatory vertigo(positional, chronic) Nonvestibular vertigo

(unsteady posture/gait; nondirectionalvertigo)

Benign peripheral paroxysmal positional vertigo

Otolith in posterior semicircular canal

Cupula

Utricle

Semicircularcanal after

repositioning

Vertigo

Motor

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60

Normal Gait

Posture. The assumption of an upright postureand the maintenance of balance (postural re-flexes) are essential for walking upright. Loco-motion requires the unimpaired function of themotor, visual, vestibular, and somatosensorysystems. The elderly cannot stand up as quicklyand tend to walk somewhat unsteadily, withstooped posture and broader steps, leading to anelevated risk of falling.Locomotion. Normally, walking can be initiatedwithout hesitation. The gait cycle (time betweentwo successive contacts of the heel of one footwith the ground = 2 steps) is characterized bythe gait rhythm (number of steps per unit time),the step length (actually the length of an entirecycle, i.e. 2 steps), and the step width (distance

between the lines of movement of the two heels,roughly 5–10 cm). Touchdown is with the heelof the foot. Each leg alternately functions as thesupporting leg (stance phase, roughly 65% of thegait cycle), and as the advancing leg (swingphase, roughly 35% of the gait cycle). During theshifting phase, both feet are briefly in contactwith the ground (double-stance phase, roughly25% of the stance phase). Because the body’scenter of gravity shifts slightly to the side witheach step, the upper body makes small compen-satory movements to maintain balance. Thearms swing alternately and opposite to thedirection of leg movement. Normally, the speedof gait can be changed instantaneously. In oldage, the gait sequence is less energetic and morehesitant, and turns tend to be carried out enbloc.

Gait Disturbances

Description Related Terms Site of Lesion Possible Cause

Antalgic gait Limping gait, leg differ-ence, limp

Foot, leg, pelvis, spinalcolumn

Lumbar root lesion, bone dis-ease, peripheral nerve com-pression

Steppage gait Foot-drop gait Sciatic or peroneal nerve,spinal root L4/5, motorneuron

Polyneuropathy, peronealparesis; lesions of motor neu-ron, sciatic nerve, or L4/5 root

Waddling gait Duchenne gait, Trendelen-burg gait, gluteal gait

Paresis of pelvic girdlemuscles (Duchenne) or ofgluteal abductors (Tren-delenburg)

Myopathy, osteomalacia; le-sions of the hip joint or super-ior gluteal nerve; L5 lesion

Toe-walking Talipes equinus, spasticity Foot deformity, cerebral palsy,Duchenne muscular dystrophy,habit

Spastic gait Paraspastic gait, leg cir-cumduction, spastic-ataxicgait, Wernicke–Mann gait

Pyramidal tract, extrapy-ramidal motor system (su-pratentorial, infratentorial,spinal)

Unilateral or bilateral centralparalysis with spasticity, stiff-man syndrome

Ataxia of gait Gait ataxia, staggeringgait, unsteady gait, ta-betic gait, reeling gait

Peripheral nerves, posteriorcolumn of spinal cord,spinocerebellar tracts, cere-bellum, thalamus, postcen-tral cortex

Polyneuropathy, disease af-fecting posterior columns,tabes dorsalis, cerebellar le-sion, intoxication, progressivesupranuclear palsy

Dystonic gait Choreiform gait Basal ganglia Torsion dystonia, dopa-respon-sive dystonia, kinesiogenicparoxysmal dystonia, Hunting-ton disease

Start delay Hypokinetic rigid gait, gaitapraxia, festinating gait

Frontal lobe, basal ganglia,extensive white matter le-sions

Parkinson disease, frontal lobelesion, normal-pressure hydro-cephalus, Binswanger disease

Psychogenicgait distur-bance

Functional gait distur-bance

Mental illness, malingering

Gait Disturbances

Motor

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61

Gait cycle

Stance phase Swing phase

Right leg supports Right leg advances

Spastic gait(right hemiparesis)

Spastic gait(spastic paraparesis)

Steppage gait

Posture and gait in youth(left) and old age (right)

Psychogenic gait disturbances(histrionic movements)

Knee instability(quadriceps paresis, leg dorsally

angulated)

Hypokinetic-rigid gait(left, Parkinson disease; right, startdelay/gait apraxia)

Ataxic gait

Gait Disturbances

Motor

Func

tion


62

Tremor, the most common movement distur-bance, is an involuntary, rhythmic, oscillatingmovement of nearly constant amplitude. It canoccur wherever movement is subserved by an-tagonisticmuscle pairs. Different types of tremormay be classified by the circumstances in whichthey are activated or inhibited and by their loca-tion, frequency, and amplitude (Table 3, p. 357).Tremor amplitude is the most important deter-minant of disability. Parkinsonian tremor and es-sential tremor are the most common types.Rest tremor occurs in the absence of voluntarymovement and is aggravated by emotional stress(excitement, time pressure) and mental activity(e. g., conversing, reading a newspaper). Thetremor subsides when the limbs are moved, butbegins again when they return to the restingposition. Rest tremor is a typical feature ofparkinsonism.Action tremors occur during voluntary move-ment. Postural tremor occurs during main-tenance of a posture, especially when the armsare held outstretched, and disappears when thelimbs are relaxed and supported. Essentialtremor is a type of postural tremor. Kinetictremor occurs during active voluntary move-ment; it may be worst at the beginning (initialtremor), in the middle (transitory tremor), or atthe end of movement (terminal tremor). Inten-tion tremor, the type that is worst as the move-ment nears its goal, is characteristic of cerebellarand brain stem lesions.Writing tremor and vocaltremor are examples of task-specific tremors.Dystonia-related tremors (e. g., in spasmodictorticollis or writer’s cramp) can be suppressedby a firm grip (antagonistic maneuvers).Frequency. The frequency of tremor in each in-dividual case is relatively invariant and may bemeasured with a stopwatch or by electromyo-graphy. Different types of tremor have charac-teristic frequencies, listed in the table below, butthere is a good deal of overlap, so that differen-tial diagnosis cannot be based on frequencyalone.2.5–5Hz Cerebellar tremor, Holmes tremor3–6Hz Parkinsonian tremor7–9Hz Essential tremor, postural tremor in

parkinsonism7–12Hz Physiological tremor, exaggerated

physiological tremor12–18Hz Orthostatic tremor

Tremor genesis. The tremor of Parkinson diseaseis due to rhythmic neuronal discharges in thebasal ganglia (internal segment of globus pal-lidus, subthalamic nucleus) and thalamus (ven-trolateral nucleus), which are the ultimate resultof degeneration of the dopaminergic cells of thesubstantia nigra that project to the striatum(p. 210). Essential tremor is thought to be due toexcessive oscillation in olivocerebellar circuits,which then reaches themotor cortex by way of athalamic relay. Intention tremor is caused by le-sions of the cerebellar nuclei (dentate, globose,and emboliform nuclei) or their projectionfibers to the contralateral thalamus (ven-trolateral nucleus, p. 54). In any variety oftremor, the abnormal oscillations are relayedfrom the motor cortex through the corticospinaltracts (p. 44) to the spinal anterior horn cells toproduce the characteristic pattern of alternatingcontraction of agonist and antagonist muscles.

Tremor

Motor

Func

tion


63Intention tremor (end tremor)

Rest tremor

Kinetic tremor

Dangling arm

Physiological tremorEssential tremorParkinsonian tremorOrthostatic tremorCerebellar tremorHolmes tremorNeuropathy-related tremorSubstance-induced tremor*Palatal tremorVoice tremorWriting tremorPsychogenic tremor

Tremor types

*Due to coffee, tea, alcohol, medications (stimulants, neuroleptics, antidepressants, anti-

convulsants, cyclosporine A), neurotoxins (heavymetals, insecticides, herbicides, solvents)

Action tremor

Tremor

Motor

Func

tion


64

“Dystonia” is a general term for involuntarymovement disorders involving sustainedmuscle contraction according to a stereotypicpattern, usually resulting in spasmodic ortorsional movement and abnormal posture.Dystonic movements are usually exacerbated byvoluntary activity. They may arise only duringskilled activities such as writing or playing amusical instrument (action dystonia). In-complete relief can be obtained by theavoidance of triggering activities and by the useof antagonistic maneuvers (e. g., placing the fin-gers on the chin, forehead or neck, or yawning,to counteract cervical dystonia). Dystonia maybe classified by its distribution as focal (affectsonly one region of the body), segmental (two ad-jacent regions), multifocal (two or more nonad-jacent regions), generalized, or lateralized(hemidystonia), and by its etiology as either pri-mary (idiopathic) or secondary (symptomatic).Secondary dystonia is usually caused by a dis-order of copper, lipid, or amino acidmetabolism,or by a mitochondrial disorder (p. 306 ff).

Craniocervical Dystonia

Blepharospasm. Spasmodic contraction of theorbicularis oculi muscle causes excessive blink-ing and involuntary eye closure. It can often beaccompanied by ocular foreign-body sensationand be ameliorated by distracting maneuvers,and is worse at rest or in bright light. There maybe involuntary clonic eye closure, tonic narrow-ing of the palpebral fissure, or difficulty openingthe eyes (eye-opening apraxia, p. 128).Blepharospasm may be so severe as to leave thepatient no useful vision.Oromandibular dystonia affects the perioralmuscles and the muscles of mastication. In acondition named Meige syndrome blepharo-spasm is accompanied by dystonia of thetongue, larynx, pharynx, and neck.Cervical dystonia may involve head rotation(torticollis), head tilt to one side (laterocollis), orflexion or extension of the neck (anterocollis,retrocollis), often accompanied by tonicshoulder elevation or head tremor. It may be dif-ficult to distinguish nondystonic from dystonichead tremor; only the latter can be improved byantagonistic maneuvers. Dystonia often causespain, usually in the neck and shoulder.

Arm and Leg Dystonia

These are most often produced by specific, usu-ally complex, activities (task-specific dystonia).Writer’s cramp (graphospasm) and musician’sdystonia (for example, while playing the piano,violin, or wind instruments) are well-known ex-amples. Toe or foot dystonia (“striatial foot”) isseen in patients with Parkinson disease anddopa-responsive dystonia.

Other Types of Dystonia (see also p. 204)

In idiopathic torsion dystonia, focal dystonia ofan arm or leg appears in childhood and slowlybecomes generalized to include a truncal dys-tonia causing abnormal posture (scoliosis, ky-phosis, opisthotonus). In spastic dysphonia, thevoice usually sounds strained and forced, and isinterrupted by constant pauses (adductor type);less commonly, it becomes breathy or whis-pered (abductor type). Dopa-responsive dystonia(Segawa syndrome) arises in childhood andmainly impairs gait (p. 60), to a degree that var-ies over the course of the day. Paroxysmal, auto-somal dominant inherited forms of dystonia arecharacterized by recurrent dystonic attacks ofvariable length (seconds to hours). The attacksmay be either kinesiogenic (provoked by rapidmovements), in which case they usually involvechoreoathetosis, or nonkinesiogenic (provokedby caffeine, alcohol, or fatigue).

Dystonia

Motor

Func

tion


65

BlepharospasmCraniocervical dystonia(Meige syndrome)

Cervical dystonia(torticollis)

Writer’s cramp(= graphospasm)

Multifocal dystonia (axial dystonia, ”Pisa syndrome”)

Dystonia

Motor

Func

tion


66

Chorea

Choreiform movements are irregular, abrupt,and seemingly randomly occurring, and usuallyaffect the distal parts of the limbs. In mildchorea, the hyperkinetic movements may be in-tegrated in voluntary movements, such as strok-ing the hair. More severe cases may involverapidly changing, bizarre body and limb pos-tures. A combination of choreiform and (distal)dystonic movements is termed choreoathetosis.Huntington disease, an autosomal dominant dis-order, is the best-known cause of chorea (p. 300,383). Others include hereditary diseases (e. g.,neuroacanthocytosis, benign hereditary chorea)and neurodegenerative diseases (e. g., Alzheimerdisease, multisystem atrophy). Secondary choreamay be caused by infections (e. g., Sydenham’schorea due to streptococcal infection; herpes en-cephalitis, toxoplasmosis), vascular disease(e. g., lupus erythematosus, stroke), brain tumor,drug therapy (e. g., estrogen, neuroleptic drugs),or old age (senile chorea).

Hemiballism (Ballism)

Ballism consists of violent flinging movementsof the limbs due to involuntary contraction ofthe proximal limb muscles, and usually affectsonly one side of the body (hemiballism). It maybe continuous or occur in attacks lasting severalminutes. The most common cause is an infarc-tion or other destructive lesion of the sub-thalamic nucleus (STN). Diminished neural out-flow from the STN leads to increased activity inthe thalamocortical motor projection (p. 210).

Drug-induced Dyskinesias

Involuntary movements of various kinds may beinduced by numerous drugs, most prominentlyL-dopa and neuroleptic drugs includingphenothiazines, butyrophenones, thioxan-thenes, benzamides, and metoclopramide, all ofwhich affect dopaminergic transmission(p. 210).Acute dystonic reactions (p. 204) involve painfulcraniocervical or generalized dystonia (opistho-tonus, tonic lateral bending and torsion of thetrunk = “Pisa syndrome”) and are treated withanticholinergic agents (e. g., biperidene).

Tardive (i.e., late) dyskinesia is a complication oflong-term administration of the so-called classi-cal neuroleptic agents. It is characterized by ab-normal, stereotyped movements of the mouth,jaw, and tongue (orofacial dyskinesia), some-times accompanied by respiratory disturbances,grunting, and thrusting movements of the trunkand pelvis. The same drugs may induce tardiveakathisia, i.e., motor restlessness with a feelingof inner tension and abnormal sensations in thelegs; this syndrome must be distinguished fromrestless legs syndrome (p. 114) and tics (p. 68).These agents also rarely induce tardivecraniocervical dystonia, myoclonus, and tremor.

Myoclonus

Myoclonus consists of involuntary, brief, sud-den, shocklike muscle contractions producingvisible movement. It has a variety of causes andmay be focal, segmental, multifocal, or general-ized. Its cortical, subcortical, or spinal origin canbe determined by neurophysiological testing.Attacks of myoclonus may be spontaneous ormay be evoked by visual, auditory, or soma-tosensory stimuli (reflex myoclonus) or by vol-untary movement (postural myoclonus, actionmyoclonus).

Chorea, Ballism, Dyskinesia, Myoclonus

Motor

Func

tion


67

Chorea

Hemiballism (left)

Orofacial (buccolingual)dyskinesia

Chorea, Ballism, Dyskinesia, Myoclonus

Motor

Func

tion


68

Physiological myoclonus. Myoclonus of variableintensity may occur normally as a person fallsasleep (sleep myoclonus). Hiccups (singultus) aremyoclonic movements of the diaphragm andnormally cease spontaneously. (Severe, in-tractable hiccups, however, may be produced bylesions of the brain stem.) Normal myoclonicstartle reflexes are to be distinguished from therare startle disorders such as hyperekplexia,stiff-man syndrome, and startle epilepsy. Themyoclonus that occurs in the waking phase aftersyncope is sometimes mistaken for an epilepticseizure.Essential myoclonus is a rare hereditary diseasecharacterized by persistent, very brief, multifo-cal myoclonic movements, accompanied by dys-tonia. The abnormal movements are improvedby small quantities of alcohol.Myoclonic encephalopathies. Multifocal orgeneralized action myoclonus is found in asso-ciation with dementia and tonic-clonic seizuresin various types of progressive myoclonic en-cephalopathy (PME), including Lafora disease,myoclonus epilepsy with ragged red fibers(MERRF syndrome), neuronal lipofuscinosis(Kufs disease) and sialidosis type I/II. Epilepsywithout dementia is found in progressive myo-clonus epilepsy (Unverricht–Lundborg syn-drome) and progressive myoclonic ataxia.Symptomatic myoclonus is associated with manydifferent diseases including Alzheimer disease,corticobasal degeneration, Huntington disease,metabolic disorders (liver disease, lung disease,hypoglycemia, dialysis), encephalitis (Creutz-feldt–Jakob disease, subacute sclerosing panen-cephalitis), and paraneoplastic syndromes (op-soclonus-myoclonus syndrome). It can also bethe result of hypoxic/ischemic brain damage(posthypoxic action myoclonus = Lance–Adamssyndrome).Asterixis consists of brief, irregular flappingmovements of the outstretched arms or handsdue to sudden pauses in the train of afferent im-pulses to muscles (“negative” myoclonus). It isnot specific for any particular disease. In toxic ormetabolic encephalitis, it almost always occurstogether with myoclonus.

Tics

Tics are rapid, irregular, involuntary movements(motor tics) or utterances (vocal tics) that inter-rupt normal voluntary motor activity. They aretriggered by stress, anxiety, and fatigue but mayalso occur at rest; they can be suppressed by avoluntary effort, but tend to re-emerge withgreater intensity once the effort is relaxed. Ticsare often preceded by a feeling of inner tension.They may be transient or chronic.Simple tics. Simple motor tics involve isolatedmovements, e. g., blinking, twitching of abdomi-nal muscles, or shrugging of the shoulders.Simple vocal tics may involve moaning, grunt-ing, hissing, clicking, shouting, throat clearing,sniffing, or coughing.Complex tics. Complex motor tics consist ofstereotyped movements that may resemble vol-untary movements, e. g., handshaking, scratch-ing, kicking, touching, or mimicking anotherperson’s movements (echopraxia). Complexvocal tics may involve obscene language (co-prolalia) or the repetition of another person’swords or sentences (echolalia).Gilles de la Tourette syndrome (often abbre-viated to Tourette syndrome) is a chronic dis-ease in which multiple motor and vocal ticsbegin in adolescence and progress over time.Other features of the disease are personality dis-turbances, obsessive-compulsive phenomena,and an attention deficit.

Myoclonus, Tics

Motor

Func

tion


69Simple motor tic(blinking of right eye, left eye normal)

Myoclonus Asterixis (negative myoclonus)

FocalSegmentalMultifocalGeneralized

Pattern of distribution

CorticalSubcorticalSpinal

Site of possible generators

Myoclonus, Tics

Motor

Func

tion


70

Clinical localization of brain stem lesions de-pends on knowledge of the tiered arrangementof cranial nerve nuclei, the intramedullarycourse of cranial nerve fibers, and their spatialrelationship to tracts passing up and down thebrain stem (see also p. 26). Lesions can be local-ized to the midbrain, pons, or medulla, andfurther classified in terms of their location in across-sectional plane as anterior, posterior, me-dial, or lateral. The “classic” brain stem syn-dromes are rarely seen in actual experience, asthe patterns of damage tend to overlap ratherthan occupy discrete areas of tissue. Brain stemlesions that affect decussating neural pathwaysproximal to their decussation produce crosseddeficits (p. 46); thus, some lesions produce ipsi-lateral cranial nerve palsies and contralateralhemiparesis of the limbs and trunk.

Midbrain Syndromes (Table 4, p. 358)

Lesions of the mid brain may involve its anteriorportion (cerebral peduncle, Weber syndrome);its medial portion (mid brain tegmentum, Bene-dict syndrome), or its dorsal portion (midbraintectum, Parinaud syndrome). Occlusion of thebasilar artery at midbrain level causes “top of thebasilar syndrome”.

Pontine Syndromes(p. 72 and Table 5, p. 359)

The syndromes produced by anterior and poste-rior pontine lesions are summarized in Table 5.

! Paramedian Lesions

Cause. Multiple lacunar infarcts are the mostcommon cause.Symptoms and signs. Unilateral lesions (medi-olateral or mediocentral) cause contralateralparalysis, especially in the distal limb muscles;dysarthria; and unilateral or bilateral ataxia;and, sometimes, contralateral facial and abdu-cens palsies. Bilateral lesions cause pseudobul-bar palsy and bilateral sensorimotor deficits.

! Lateral Pontomedullary Syndrome

Cause. Infarction or hemorrhage in the territoryof the posterior inferior cerebellar artery or ab-errant branch of the vertebral artery.

Lesion. As inWallenberg syndrome (p. 361) withadditional involvement of the facial nerve nu-cleus, vestibular nerve nucleus, and inferiorcerebellar peduncle.Symptoms and signs. As in Wallenberg syn-dromewith additional ipsilateral findings: facialpalsy (nuclear), rotatory vertigo, tinnitus, hear-ing loss, nystagmus, cerebellar ataxia.

Medullary Syndromes(p. 73 and Table 6, p. 361)

Lesions usually involve the medial or the lateralportion of the medulla; the lateral medullarysyndrome is called Wallenberg syndrome andmay be associated with various oculomotor andvisual disturbances (p. 86 ff).Ocular deviation. Vertical deviation (skew devia-tion) in which the ipsilateral eye is lower. Skewdeviation may be accompanied by the ocular tiltreaction: ipsilateral head tilt, marked extorsionof the ipsilateral eye, and mild intorsion of thecontralateral eye.Nystagmus. Positional nystagmus may be hori-zontal, torsional, or mixed. See-saw nystagmus ischaracterized by intorsion and elevation of oneeye and extorsion and depression of the other.Conjugate deviation to the side of the lesion.Abnormal saccades. Ocular dysmetria withoverreaching (hypermetria) when looking to theside of lesion and underreaching (hypometria)when looking to the opposite side. Attemptedvertical eye movements are executed with diag-onal motion.

Brain Stem Syndromes

BrainStem

Synd

romes


71

Anterior lesion

Medial lesion

Dorsal lesion

Brain stem with cranial nerves(at level of midbrain)

Basilar a.



Substantia nigra

Substantia nigra

Medial lemniscus

Red nucleus

Oculomotor n.

Site of lesion

Site of lesion

Site of lesion

Aqueduct

Aqueduct

Fourth ventricle

Cerebellum

CN V, trige-minal ganglion

Motorroot of V

CN III, Edinger-Westphal nucleus

CN III (fibers)

Mesencephalic nucleus of V

Nucleus III

Red nucleus

Cerebral peduncle (corticospinal and corticopontine tracts)

Oculomotor n.

Midbrain Syndromes

BrainStem

Synd

romes


72

Sensory root of V

Motor root of VBasilar a.

Basilar a.

Lateral pontine a.

Medial pontine a.

Medial pontine artery

Aqueduct

Spinothalamic tract

Principal sensorynucleus of VMotor

and spinalnuclei of V

Medial lemniscus

Site of lesion

Site of lesion

VIII

VII

Site of lesion

Pyramidal tract

Pyramidal tract

Medial longitudinalfasciculus

Nucleus VII

Site of lesion

Nucleus VII

Nucleus VI

Nucleus VI

Nucleus VI

NucleusVII

Spinal/main sensorynucleus of V

Motornucleus of V

Proprio-ceptivefibers (VII)

VII/interme-dius n.

VI

Superior salivatorynucleus

VIII

Vestibularnuclei

Cochlear nuclei

Brain stem with cranial nerves(at level of pons)

Midpontine lesion (basis pontis) (section A)

Lesion of upper pontine tegmentum

(section A)

Lesion of lower pontine tegmentum(section B)

Paramedian lesion of lower basis pontis(section B)

A

B

Pontine Syndromes

BrainStem

Synd

romes


73

Olive

Olive

XII

IX (sensory fibers)

X (motor fibers)

X (sensory fibers)

IX (motor fibers)

XI Spinal tract of V

Spinal nucleus of XI

Nucleusambiguus

(motorfibers to CN

IX, X, XI)

Dorsal nucleus of X(parasympathetic

motor fibers)

Inferior salivatory nucleus

Nucleus XII

Nucleus of solitary tract

(taste: VII, IX, X)

Lateral medullary branch

Vertebral a.

Site of lesion

Site of lesion

XII

X

Pyramidal tract

Nucleus ambiguus, central sympathetic tract

Spinaltract and

nucleus ofV

Inferior vestibularnucleus

Lateral spinothalamic tract

Anteriorspinal a.

Posteriorinferior cerebellar a.


Nucleus XII

Lateral lesion

Medial lesion

Brain stem with cranial nerves(at level of medulla)

Medullary Syndromes

BrainStem

Synd

romes


74

The site of a lesion at the base of the skull can often be deduced from the pattern of cranial nerve in-volvement.

Site of Lesion Symptoms CN1 Cause2

Olfactory nerve,bulb, and tract

Anosmia, behavioral changes;may progress to Foster Ken-nedy3 syndrome

I Trauma, mass in anterior cranialfossa (meningioma, glioma,osteoma, abscess)

Medial sphenoidwing4

Ipsilateral anosmia and opticnerve atrophy, contralateralpapilledema

I, II Medial sphenoid wing mening-ioma, mass in anterior cranialfossa

Medial/lateral sphe-noid wing4

Pain in ipsilateral eye, forehead,temple; exophthalmos, diplopia

V/1, III, IV Medial (eye pain) or lateral (tem-poral pain) sphenoid wingmeningioma

Orbital apex, super-ior orbital fissure5

Ipsilateral: incomplete orcomplete external ophthal-moplegia, sensory deficit onforehead; papilledema, visualdisturbances, optic atrophy

II, III, IV,V/1, VI

Tumor (pituitary adenoma,meningioma, metastasis, naso-pharyngeal tumor, lymphoma),granuloma (TB, fungal infection,Tolosa–Hunt syndrome, arteritis),trauma, infraclinoid ICAaneurysm

Cavernous sinus6 Ipsilateral symptoms and signsappear earlier than in orbitalapex syndrome; exophthalmos7,Horner syndrome

III, IV, V/1,VI

Same as in orbital apex syndrome+ cavernous sinus thrombosis,carotid-cavernous fistula

Optic chiasm8 Visual field defects II See p. 80

Petrous apex9 Ipsilateral facial pain (usuallyretro-orbital), hearing loss,sometimes also facial palsy

VI, V/1 (toV/3), VIII,(VII)

Inner ear infection, tumor,trauma

Edge of clivus10 Ipsilateral mydriasis, may pro-gress to complete oculomotorpalsy

III Intracranial hypertension (p. 158)

Cerebellopontineangle

Ipsilateral hearing loss, tinnitus,deviation nystagmus, facialsensory disturbance, peripheralfacial palsy/spasm, abducenspalsy, ataxia, headache

VIII, V/1+2,VII, VI

Acoustic neuroma, meningioma,metastasis

Jugular foramen11 Ipsilateral: pain in region of ton-sils, root of tongue, middle ear;coughing, dysphagia, hoarse-ness, sternocleidomastoid andtrapezius paresis, absence ofgag reflex; sensory deficit inroot of tongue, soft palate,pharynx, larynx

IX, X, XI Metastasis, glomus tumor,trauma, jugular vein thrombosis,abscess

Foramen magnum12 Same as above + ipsilateral glos-soplegia, neck pain, and localspinal symptoms (p. 48)

IX, X, XI, XII Basilar impression, Klippel–Feilsyndrome, local tumor/metastasis

1 CN = cranial nerve (unilateral CN deficits). 2 Only the most common causes are listed; other causes arepossible. 3 (Foster) Kennedy syndrome (Foster is the first name). 4 Sphenoid wing syndrome. 5 Orbital apex syn-drome, superior orbital fissure syndrome. 6 Cavernous sinus syndrome. 7 Patients with carotid-cavernous fistulaehave pulsatile exophthalmos, conjunctival injection, and a systolic bruit that can be heard by auscultation overthe eye and temple. 8 Optic chiasm syndrome. 9 Gradenigo syndrome. 10 Clivus syndrome. 11 Jugular foramensyndrome, Vernet syndrome. 12 Collet–Sicard syndrome; may be accompanied by varying degrees of dysfunctionof CN IX through XII.

Skull Base Syndromes

Cran

ialN

erves


75

Fila olfactoria (CN I)

Tumor

Tumor

Tumor

Tumor

Tumor

Lesser sphenoid wing

III

III

III

IV

V

V

VI

VI

VI

IV

VI

Internal carotid a.

Internalcarotid a.

Internal carotid a.

Trigeminalganglion

Trigeminal ganglion

II

Frontal n.

Frontal n.

Ophthalmic a.

Dorsum sellae

Dorsum sellae

Dorsum sellae,posterior clinoid

process

Cavernous sinus

Cavernous sinus

Pituitary glandand stalk



Optic chiasm

Optic chiasm

IV

VII

VIII

IX

Foramen magnum(posterior margin)

Jugular foramen, petrosal sinus, IX, X, XI

XII in hypoglossal canal

Sphenoid sinus

Pituitary fossa in sella turcica

Mandibular foramen, inferior alveolar n.

Internal acousticmeatus (VII, VIII,labyrinthine a.)

Mandibular branch

Olfactory bulb

Frontal sinus

Nasal cavity

Olfactory tract

Aneurysm

Infratrochlear n.Ciliary ganglion

X

XI (root)

Olfactory nerve syndrome

Jugular foramen, foramen magnum

Sphenoid wing syndrome(Foster-Kennedy syndrome)

Cavernous sinus syndrome

Orbital apex syndrome

Chiasm syndrome(arrows show direction of compression)

Clivus syndrome

Cerebellopontine angle

Skull Base Syndromes

Cran

ialN

erves


76

Olfactory epithelium. The olfactory mucosa oneither side of the nasal cavity occupies an area ofapproximately 2.5 cm2 on the roof of the super-ior nasal concha, extending to the nasal septum.The mucus covering the olfactory epithelium isnecessary for olfactory function, becausemolecules interact with olfactory receptors onlywhen they are dissolved in the mucus. Olfactorycells are bipolar sensory cells with a mean life-span of about 4 weeks. Fine bundles of cilia pro-ject from one end of each olfactory cell into themucus. Olfactory receptors located on the ciliaare composed of specific receptor proteins thatbind particular odorant molecules. Each ol-factory cell produces only one type of receptorprotein; the cells are thus chemotopic, i.e., eachresponds to only one type of olfactory stimulus.Olfactory cells are uniformly distributedthroughout the olfactory mucosa of the nasalconchae.Olfactory pathway. The unmyelinated axons ofall olfactory cells converge in bundles of up to 20fila olfactoria on each side of the nose (thesebundles are the true olfactory nerves), whichpass through the cribriform plate to the ol-factory bulb. Hundreds of olfactory cell axonsconverge on the dendrites of the mitral cells ofthe olfactory bulb, forming the olfactory glomer-uli. Other types of neurons that modulate the ol-factory input (e. g., granular cells) are foundamong the mitral cells. Neural impulses are re-layed through the projection fibers of the ol-factory tract to other areas of the brain includingthe prepiriform cortex, limbic system, thalamus(medial nucleus), hypothalamus, and brain stemreticular formation. This complex intercon-nected network is responsible for the importantrole of smell in eating behavior, affective be-havior, sexual behavior, and reflexes such assalivation. The trigeminal nerve supplies themucous membranes of the nasal, oral, andpharyngeal cavities. Trigeminal receptor cellsare also stimulated by odorant molecules, but ata higher threshold than the olfactory receptorcells.

Olfactory Disturbances (Dysosmia)

Olfactory disturbances can be classified aseither quantitative (anosmia, hyposmia, hyper-osmia) or qualitative (parosmia, cacosmia). Con-

genital olfactory disturbances manifest them-selves as partial anosmia (“olfactory blindness”).The perceived intensity of a persistent odordecreases or disappears with time (olfactoryadaptation). External factors such as an arid en-vironment, cold, or cigarette smoke impair theability to smell; diseases affecting the na-sopharyngeal cavity impair both smell and taste.Odors and emotions are closely linked and caninfluence each other. The perception of smellmay be qualitatively changed (parosmia) be-cause of autonomic (hunger, stress) and hor-monal changes (pregnancy) or disturbancessuch as ozena, depression, traumatic lesions, ornasopharyngeal empyema. Olfactory hallucina-tions can be caused by mediobasal and temporaltumors (focal epilepsy), drug or alcohol with-drawal, and psychiatric illnesses such as schizo-phrenia or depression.Tests of smell. One nostril is held closed, and abottle containing a test substance is held in frontof the other. The patient is then asked to inhaleand report any odor perceived. In this subjectivetest, odor perception per se is more importantthan odor recognition. Odor perception indi-cates that the peripheral part of the olfactorytract is intact; odor recognition indicates thatthe cortical portion of the olfactory pathway isalso intact. More sophisticated tests may be re-quired in some cases. Because there is bilateralinnervation, unilateral lesions proximal to theanterior commissure and cortical lesions maynot cause anosmia.Anosmia/hyposmia. Unilateral anosmia may becaused by a tumor (meningioma). Korsakoff syn-drome can render the patient unable to identifyodors. Viral infections (influenza), heavy smok-ing, and toxic substances can damage the ol-factory epithelium; trauma (disruption of ol-factory nerves, frontal hemorrhage), tumors,meningitis, or radiotherapy may damage the ol-factory pathway. Parkinson disease, multiplesclerosis, Kallmann syndrome (congenitalanosmia with hypogonadism), meningoen-cephalocele, albinism, hepatic cirrhosis, andrenal failure can also cause olfactory distur-bances.

Smell

Cran

ialN

erves


77

Cilia

Olfactory cells

Fila olfactoria, cribriform plate

Mitral cell

Granule cell

Olfactory tract

Anterior commissure

Entorhinal cortex (area 28)

Amygdala

Olfactory mucosa

Olfactorynucleus

To medial nucleus of thalamus

Glomerulus

Hippocampus

Prepiriform cortex

Projection to brain stemreticular formation

via fornix

Fornix

Thalamus

Smell

Olfactory bulb

Smell

Cran

ialN

erves


78

Taste buds. Each taste bud contains 50–150 gu-statory cells. Taste buds are found on the mar-gins and furrows of the different types of gu-statory papillae (fungiform, foliate, and vallate)and are specific for one of the four primarytastes, sweet, sour, salty, and bitter. The lifespanof each gustatory cell is approximately oneweek. Filaments called microvilli projectingfrom the cells’ upper poles are coated with gu-statory receptor molecules. Stimulation of thegustatory cell at its receptors by the specifictaste initiates a molecular transduction process,resulting in depolarization of the cell. Each tastebud responds to multiple qualities of taste, butat different sensitivity thresholds, resulting in acharacteristic taste profile. For example, onepapilla may be more sensitive to “sweet,”another to “sour.” The higher the concentrationof the tasted substance, the greater the numberof gustatory cells that fire action potentials.Complex tastes are encoded in the different pat-terns of receptor stimulation that they evoke.Gustatory pathway. Sensory impulses from thetongue are conveyed to the brain by three path-ways: from the anterior two-thirds of thetongue via the lingual nerve (V/3) to the chordatympani, which arises from the facial nerve(nervus intermedius); from the posterior thirdof the tongue via the glossopharyngeal nerve;and from the epiglottis via the vagus nerve(fibers arising from the inferior ganglion).Sensory impulses from the soft palate travel viathe palatinate nerves to the pterygopalatineganglion and onward through the greaterpetrosal nerve and nervus intermedius. All gu-statory information arrives at the nucleus of thesolitary tract, which projects, through athalamic relay, to the postcentral gyrus. The gu-statory pathway is interconnected with the ol-factory pathway through the hypothalamus andamygdala. It has important interactions with theautonomic nervous system (facial sweating andflushing; salivation) and with affective centers(accounting for like and dislike of particulartastes).

Gustatory Disturbances (Dysgeusia)

When smell is impaired, the patient loses thecapacity for fine differentiation of tastes but isable to distinguish the primary tastes (sweet,

sour, salty, bitter). For example, chocolate pud-ding can be identified as “sweet” but not as“chocolate.” Diminished taste (hypogeusia) ismore common than complete loss of taste(ageusia).Tests of taste. Taste thresholds on each side ofthe tongue are tested with the tongue out-stretched. A test solution is applied to thetongue with a cotton swab for 20 to 30 seconds.The patient is then asked to point to the corre-sponding region of a map divided into “sweet”,“sour”, “salty” and “bitter” zones. The test solu-tions contain glucose (sweet), sodium chloride(salty), citric acid (sour), or quinine (bitter). Themouth is rinsed with water between test solu-tions. The taste zones are not organized in astrict topographic pattern. Electrogustometrycan be used for precise determination of thetaste thresholds but it is time-consuming andrequires a high level of concentration on thepart of the patient.Ageusia/hypogeusia. Dry mouth (Sjögren syn-drome), excessive alcohol consumption, smok-ing, spicy food, chemical burns, medications(e. g., lithium, L-dopa, aspirin, cholestyramine,amitryptiline, vincristine, carbamazepine),radiotherapy, infectious diseases (influenza),and stomatitis (thrush) can damage the tastebuds. Lesions of the chorda tympani producingunilateral gustatory disturbances are seen inpatients with peripheral facial palsy, chronicotitis media, and cholesteatoma. Lesions ofcranial nerves V, IX, or X lead to taste distortion(especially of bitter, sour, and salty) in the poste-rior third of the tongue, in combination withparesthesia (sensation of burning or numbness).Gustatory disturbances may also be caused bydamage to the central gustatory pathway, e. g.,by trauma, brain tumors, carbon monoxide poi-soning, or multiple sclerosis. The sense of tastecan also change because of aging (especiallysweet and sour), pregnancy, diabetes mellitus,hypothyroidism, and vitamin deficiencies (A,B2).

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Chorda tympani

Superior laryngeal n. (X)

Glossopharyngeal n.

Inferior ganglion of IX

Inferior ganglion of X

Nucleusof solitary

tract

Geniculate ganglion (VII)

Salivatory nuclei (inferior

and superior)

Ventral posteromedialnucleus of the thalamus

Insula

Postcentral gyrusHippocampus,amygdala

Jugular foramen

Fibers to muscles of facial expression,

mastication, and deglutition

Lingual n. (V/3)

Fibers to thesalivatorynuclei

Pterygopalatine ganglion

Soft palate, uvula

Greater petrosal n.

Taste

Taste

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Retina. Visible light is electromagnetic radiationat wavelengths of 400–750 nanometers. Thedioptric system (cornea, aqueous humor of theanterior and posterior ocular chambers, pupil,lens, vitreous body) produces a miniature, up-side-down mirror image of the visual field onthe retina. The fovea, located in the center of themacula at the posterior pole of the eyeball, is thearea of sharpest vision in daylight. Blood is sup-plied to the eye by the ophthalmic artery via theciliary arteries (supplies the choroid) and thecentral retinal artery (supplies the retina). Theoptic disk, the central retinal artery thatbranches from it, and the central retinal vein canbe examined by ophthalmoscopy.Visual pathway. The visual pathway begins inthe retina (first three neurons) and continuesthrough the optic nerve to the optic chiasm,from which it continues as the optic tract to thelateral geniculate body. The optic radiationarises at the lateral geniculate body and termi-nates in the primary (area 17) and secondaryvisual areas (areas 18, 19) of the occipital lobe.The fibers of the retinal neuronal network con-verge at the optic disk before continuing via theoptic nerve to the optic chiasm, in which the me-dial (nasal) fibers cross to the opposite side. Theright optic tract thus contains fibers from thetemporal half of the right retina and the nasalhalf of the left retina. The lateral geniculate bodyis the site of the fourth neuron of the optic path-way. Its efferent fibers form the optic radiation,which terminates in the visual cortex (striatecortex) of the occipital lobe. The central fovealarea has the largest cortical representation. Thevisual pathway is interconnected with midbrainnuclei (medial, lateral, and dorsal terminal nu-clei of the pretectal region; superior colliculus),nonvisual cortical areas (somatosensory, pre-motor, and auditory), the cerebellum, and thepulvinar (posterior part of thalamus).Visual field. The monocular visual field is theportion of the external world seen with one eye,and the binocular visual field is that seen by botheyes. The visual fields of the two eyes overlap;the overall visual field therefore consists of acentral zone of clear binocular vision producedby the left and right central foveae, a peripheralbinocular zone, and a monocular zone. Partialdecussation at the optic chiasm brings visual in-formation from the right (left) side of the world

to the left (right) side of the brain. The visualfield is topographically represented at all levelsof the visual pathway from retina to cortex; le-sions at any level of the pathway cause visualfield defects of characteristic types. If the imageson the two retinas are displaced by more than acertain threshold distance, double vision (dipl-opia) results. This is most commonly due to dis-turbances of the extraocular muscles, e. g., para-lysis of one or more of these muscles (p. 86).Stereoscopic vision. Three-dimensional visualperception (stereoscopic vision) is produced bycomparison of the slightly different images inthe two eyes. Stereoscopic vision is very impor-tant for depth perception, though depth can bejudged to some extent, through other cues, withmonocular vision alone.Color vision. Testing of color vision requiresstandard definition of the colors red, blue, andgreen. The visual threshold for various colors,each defined as a specific mixture of the threeprimary colors, is determined with a standard-ized color perception chart. Disturbances of colorvisionmay be due to disturbances of the dioptricsystem, the retina, or the visual pathway. Corti-cal lesions cause various kinds of visual agnosia.Lesions of area 18 may make it impossible forpatients to recognize colors despite intact colorvision (color agnosia), or to recognize familiarobjects (object agnosia) or faces (prosop-agnosia). Patients with lesions of area 19 haveintact vision but cannot recognize or describethe objects that they see. Spatial orientationmay be impaired (visuospatial agnosia), as maythe inability to draw pictures. Persons withvisual agnosia may need to touch objects toidentify them.Limbic system. Connections with the limbic sys-tem (hippocampus, amygdala, parahippocampalgyrus; p. 144) account for the ability of visualinput to evoke an emotional response.

Visual pathway

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Course of the visual pathway

Distribution of fibers along the visual pathway

Projections of the visual pathway

Lateral geniculate body (right)

Optic radiation

(left)

Occipitalcortex (left)

Patient’s right and left visual fields

Retinal imageof object

Cross section ofretrobulbar fibers

Optic n. (cross section)

Left optic tract after chiasmal decussation

Optic tract (posterior third)

Lateral geniculate body

Lateral geniculate body

Area 17(striate cortex)

Area 17 (stri-ate cortex)

Area 18

Area 18

Area 19

Area 19

Optic chiasm

Ophthalmic a.

Optic n.

Centralfovea

Opticdisk(blindspot)

Calcarinesulcus

Monocular visualfield of nasal reti-na (”temporalsickle”)

Binocular portion of visual field

Centralfovea

Retinal fibers

Macular fibers (papillomacular bundle)

Terminal nuclei

Pulvinar

Superior colliculus

Pretectal region

Projections to visual cortex

Fibers of nasal retina(all decussate)

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Examination. The visual fields of both eyesshould always be jointly assessed. The confronta-tion test, in which the examiner “confronts” thepatient’s visual field with his or her own, intact,contralateral visual field, is used to check forvisual field defects. For the test to be performedcorrectly, thepatient and the examinermust firstfixate along the same line. The examiner thenslowly moves a white or red object (at least 1 cmin diameter) from the periphery of the visualfield toward the center in a number of differentdirections, anddetermineswhere thepatient canand cannot see it. Alternatively, the examinermay raise one ormore fingers and ask the patientto count them (a useful test for small children,and for persons whose vision is so poor that itcannot be tested by the first method). The per-ceived brightness (unequal in patients withhemianopsia) of the hand in the nasal and tem-poral portions of the visual field is also deter-mined. The red vision test enables the detectionof a central scotoma as an area in which the redcolor is perceived as less intense. More detailedinformation can be obtained by further oph-thalmological testing (Goldmann perimetry, au-tomatic perimetry).Visual field defect (scotoma). The thin myeli-nated fibers in the center of the optic nerve,which are derived from the papillomacularbundle, are usually the first to be affected byoptic neuropathy (central scotoma). From theoptic chiasm onward, the right and left visualfields are segregated into the left and right sidesof the brain. Unilateral lesions of the retina andoptic nerve cause monocular deficits, while ret-rochiasmatic lesions cause homonymous defects(quadrantanopsia, hemianopsia) that do notcross the vertical meridian, i.e., affect one side ofthe visual field only. Anterior retrochiasmatic le-sions cause incongruent visual field defects,while posterior retrochiasmatic lesions lead tocongruent visual field defects. Temporal lobe le-sions cause mildly incongruent, contralateral,superior homonymous quadrantanopsia. Bitem-poral visual field defects (heteronymous hemi-anopsia) have their origin in the chiasm. Uni-lateral retrochiasmatic lesions cause visual fielddefects but do not impair visual acuity. Organicvisual field defects widen pregressively with thedistance of test objects from the eye, whereaspsychogenic ones are constant (“tubular fields”).Prechiasmatic lesions may affect the retina,papilla (= optic disk), or optic nerve. Transient

episodes of monocular blindness (amaurosisfugax) see p. 372 (table 22a). Acute or subacuteunilateral blindness may be caused by optic orretrobulbar neuritis, papilledema (intracranialmass, pseudotumor cerebri), cranial arteritis,toxic andmetabolic disorders, local tumors, cen-tral retinal artery occlusion, or central retinalvein occlusion.Chiasmatic lesions. Lesions of the optic chiasmusually produce bitemporal visual field defects.Yet, because the medial portion of the chiasmcontains decussating fibers while its lateral por-tions contain uncrossed fibers, the type of visualfield defect produced varies depending on theexact location of the lesion. As a rule, anteriorchiasmatic lesions that also involve the opticnerve cause a central scotoma in the eye on theside of the lesion and a superior temporal visualfield defect (junction scotoma) in the con-tralateral eye. Lateral chiasmatic lesions producenasal hemianopsia of the ipsilateral eye; thosethat impinge on the chiasm from both sides pro-duce binasal defects. Dorsal chiasmatic lesionsproduce bitemporal hemianopic paracentralscotomata. Double vision may be the chief com-plaint of patients with bitemporal scotomata.Retrochiasmatic lesions. Depending on their lo-cation, retrochiasmatic lesions produce differenttypes of homonymous unilateral scotoma: the de-fect may be congruent or incongruent, quadran-tanopsia or hemianopsia. As a rule, temporal le-sions cause contralateral superior quadran-tanopsia, while parietal lesions cause con-tralateral inferior quadrantanopsia. Completehemianopsiamay be caused by a relatively smalllesionof the optic tract or lateral geniculate body,or by amore extensive lesionmore distally alongthe visual pathway. Sparing of the temporalsickle (p. 80) indicates that the lesion is located inthe occipital interhemispheric fissure. Bilateralhomonymous scotoma is caused by bilateral optictract damage. The patient suffers from “tunnelvision” but the central visual field remains intact(sparing ofmacular fibers). Cortical blindness re-fers to subnormal visual acuity due to bilateralretrogeniculate lesions. Bilateral altitudinal ho-monymous hemianopsia (i.e., exclusively aboveor exclusively below the visual equator) is due toextensive bilateral damage to the temporal lobe(superior scotoma) or parietal lobe (inferior sco-toma).

Visual Field Defects

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Confrontation test

Types and localization of visual field defect

Bilateral homonymous

visual field defect

Patient ca. 50 cm fromexaminer

Blind spot

Visual field

Test object

Directions tested

Line of fixation of eye

Macular region

Right visual field

Monocular defect

Binasal homonymous defect

Homonymous hemianopsia

Homonymous hemianop-sia (macular sparing)

Homonymous inferior quadrantanopsia Homonymous superiorquadrantanopsia

Homonymous hemianopic central

visual field defect(occipital pole

lesion)

Sparing of contralat-eral ”sickle” and

macula (lesion ofcalcarine cortex on

medial surface ofhemisphere)

Tunnel vision

Cortical blindness

Inferior altitudinalhemianopsia

Meridian

Left visual field

Bitemporal hemianopsia

Incongruent homonymousquadrantanopsia

”Junction scotoma”

Visual Field Defects

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The visual axes of the eyes are directed straightahead on primary gaze (i.e., 23° inward from themore lateral axes of the orbits). Movements ofthe eyes are mediated by six extraocularmuscles on each side. The lateral and medialrectus muscles are responsible for horizontaleye movements. Vertical eye movements aresubserved by the superior and inferior rectus aswell as superior and inferior oblique muscles.The rectus muscles elevate and depress the eyewhen it is abducted, the oblique muscles whenit is adducted. The twomuscles of each synergis-tic pair (e. g., the left lateral rectus and right me-dial rectus muscles) receive equal degrees of in-nervation (Hering’s law).Vestibulo-ocular reflex (VOR). Impulses arisingin the semicircular canals in response to rapidmovement of the head induce reflex movementof the eyes in such away as to stabilize the visualimage (p. 26). For example stimulation of thehorizontal semicircular canal activates the ipsi-lateral medial rectus and contralateral lateralrectus muscles, while inhibiting the ipsilaterallateral rectus and contralateral medial rectusmuscles. The VOR makes the eyes move in thedirection opposite to the head movements, atthe same angular velocity.Optokinetic reflex. Optokinetic nystagmus(OKN) is triggered by large-scale, moving visualstimuli and serves to stabilize the visual imageduring slow head movement. OKN is character-ized by slow, gliding conjugate movement of theeyes in the direction of an object moving hori-zontally or vertically across the visual field, inalternation with rapid return movements in theopposite direction (saccades). OKN is intact inpsychogenic (pseudo) blindness.Fixation. Fixation is active adjustment of thegaze (with or without the aid of eye movement)to keep a visualized object in focus.Saccades. Saccades are rapid, jerky conjugatemovements of the eyes that serve to adjust orset the point of fixation of an object on the fovea.Saccades may be spontaneous, reflexive (in re-sponse to acoustic, visual, or tactile stimuli), orvoluntary; the rapid phase of nystagmus is asaccade. The speed, direction, and amplitude ofa saccadic movement are determined before it iscarried out and cannot be influenced voluntarilyduring its execution. Shifts of visual fixation bymore than 10° are accompanied by head move-

ments.Slow ocular pursuit. Voluntary ocular pursuitcan occur only when triggered by a movingvisual stimulus (e. g., a passing car). Conversely,fixation of the gaze on a resting object while thehead is moving leads to gliding eye movements.Fixation-independent ocular pursuit also occursduring somnolence and the early stages of sleep(“floating” eye movements).Vergence movements (convergence and diver-gence) are mirror-image movements of the twoeyes toward or away from the midline, evokedby movement of an object toward or away fromthe head in the sagittal plane. They serve tocenter the visual image on both foveae and areaccompanied by an adjustment of the curvatureof the lens (accommodation) to keep the objectin focus.Neural pathways. The medial longitudinalfasciculus (MLF) interconnects the nuclei ofcranial nerves III, IV, and VI. The MLF also con-nects with fibers conveying information to andfrom the cervical musculature, vestibular nuclei,cerebellum, and cerebral cortex and thus medi-ates the coordination of eye movements withmovements of the body and head. Saccades areproduced by two parallel systems: Voluntary eyemovements are subserved by the frontal system,which consists of the frontal eye fields (areas 4,6, 8, 9), the supplementary eye field (area 6), thedorsolateral prefrontal cortex (area 46), and aportion of the parietal cortex (area 7). It projectsto the contralateral paramedian pontine reticu-lar formation (PPRF), which coordinates verticaland horizontal saccades. Vertical and torsionaleye movements are controlled by the rostral in-terstitial nucleus of the MLF and by the intersti-tial nucleus of Cajal. Reflex eye movements are in-itiated in the visual cortex (area 17) and tem-poral lobe (areas 19, 37, 39) and modulated inthe superior colliculus (collicular system). Ver-gence and accommodation are mediated by thepretectal area in the vicinity of the oculomotornucleus.

Oculomotor Function

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Conjugate eye movements(arrows indicate direction of gaze, red = active muscle)

Primary position

Secondary position

Tertiary position

Inferior oblique m. (III)

Superior rectus m. (III)

Lateral rectusm. (VI)

Medial rectus m. (III)

Inferior rectus m. (III)Superior oblique m. (IV)

Visual axis

Orbital axis

Area 46

Areas 4, 6, 8, 9

Area 7

23o

Areas 19, 37, 39

Area 17

Extraocular muscles, cranial nerves and nuclei(anterior view)

Pathway for voluntary eye movement

Pathway for reflex eye movement

Vestibularnuclei

LabyrinthVIII (vestibular n.)

VI

III

IV

Nucleus of DarkschewitschRostral interstitial nucleus of MLF

Interstitialnucleus

Trochlear nucleus

Abducens nucleus

Nucleus prepositus

MLF

Oculomotornucleus

Lateral geniculate

body

Nerve pathways

Pathway for voluntary eye movement

Pathway for reflex eye movement

Vestibular nuclei

Nucleus of Darkschewitsch

Rostral interstitial nucleus of MLF

Nu-clearregion VI

Nu-clearregion III

Trochlear nucleus

MLF

To vestibulo-cerebellum

Vestibulospinaltract

Interstitial nucleusPPRF

Cortical representation

Nucleus prepositus

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Peripheral Oculomotor Disturbances

Weakness of an extraocular muscle results in di-plopia, which is most pronounced in the direc-tion of action of the affected muscle (p. 85). Thecause may be a lesion in the muscle itself, in thecranial nerve that supplies it, or in the cranialnerve nucleus.Examination. The more peripheral of the twoimages seen by the patient is always derivedfrom the affected eye. The impaired eye move-ment may be seen directly by observation ofconjugate eye movements in the nine cardinaldirections of gaze (p. 85). Next, the examiner hasthe patient look in the direction of greatestimage displacement, covers first one eye andthen the other, and asks the patient each timewhich of the two images has disappeared. Themore peripheral image disappears when the af-fected eye is covered. Alternatively, the patientcan be asked to look at a point of light while ared glass is held in front of one eye; if the moreperipheral image is red, then the eye with theglass is the affected eye. Another test is torapidly cover and uncover one eye and then theother while the patient looks in the cardinaldirections of gaze. The greatest ocular deviationand the greatest adjustment of the unaffectedeye (secondary angle of deviation) occur whenthe patient looks in the direction of the pareticmuscle. As a rule, these tests are helpful when asingle muscle is acutely weak; more sophisti-cated ophthalmological tests are needed if theweakness is chronic or affects more than onemuscle.Oculomotor nerve palsy. When a compressivelesion causes complete oculomotor nerve palsy,the patient complains of diplopia (with obliqueimage displacement) only when the ptotic eye-lid is passively elevated. The affected eye isturned downward (action of the intact superioroblique muscle) and outward (intact lateral rec-tus muscle) on primary gaze, and the pupil isfixed, dilated, and irregularly shaped. The in-volved eye can still be abducted (intact CN VI),and looking down causes intorsion (intact CNIV). Incomplete oculomotor nerve palsy becauseof nuclear or myopathic lesions may differen-tially affect the intraocular and extraocularmuscles supplied by CN III and cause differenttypes of diplopia and pupillary disorders (p. 90).

Trochlear nerve palsy. The affected eye pointsupward and toward the nose on primary gaze.Diplopia is worst when the affected eye lookstoward the nose and downward.Abducens nerve palsy. The affected eye deviatestoward the nose on primary gaze. Horizontal di-plopia is worst on looking toward the side of theaffected eye.

Supranuclear and Internuclear Oculomo-tor Disturbances

Internuclear ophthalmoplegia (INO) is charac-terized by inability to adduct one eye, combinedwith nystagmus of the other, abducted eye (dis-sociated nystagmus), on attempted lateral gaze.It is due to a lesion of the medial longitudinalfasciculus (MLF) on the side of the nonadductingeye and at a level between the nuclei of CN IIIand CN VI. Bilateral MLF lesions cause bilateralINO. Both eyes can adduct normally during con-vergence. More rostral lesions lead to conver-gence paresis without nystagmus; more caudallesions lead to paresis of the lateral rectusmuscle. Multiple sclerosis and vascular dis-orders are the most common causes of INO.Unilateral pontine lesions cause ipsilateral gazepalsy (the gaze points away from the side of thelesion) but leave vertical eye movement largelyintact. Co-involvement of the MLF leads to one-and-a-half syndrome (ipsilateral pontine gazepalsy + INO), e. g., paresis of conjugate gaze tothe left and impaired adduction of the left eyeon looking to the right.Supratentorial lesions. Extensive cortical or sub-cortical hemispheric lesions produce con-tralateral gaze palsy (patient gazes toward theside of the lesion). Slow reflex movements of theeyes in all directions are still possible becausethe optokinetic reflex is not affected. In occipitallesions, the optokinetic reflex is absent; volun-tary eye movements are preserved, but the eyescan no longer follow slowly moving objects. Ab-normal, diffuse elevation of activity within ahemisphere (e. g., because of an epilepticseizure) causes contralateral gaze deviation.For further information on horizontal and verti-cal gaze palsy, see page 70.

Oculomotor Disturbances

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Complete right oculomotor palsy(looking straight ahead)

Abducens palsy (looking straight ahead)

Bilateral INO(leftward, rightward, and downward gaze)

Neuroanatomy of internuclear ophthalmoplegia(INO) (shown: left INO on rightward gaze)

Conjugate supranuclear paresis of leftward gaze(right supratentorial lesion or left pontine destructive lesion)

Rightward gaze deviation(irritative lesion: left, supratentorial; right, pontine)

Right trochlear palsy (looking straight ahead)

VI

III

Irritative lesion

Pontine lesion

Supra-tentoriallesion

Irritative lesion

Hypoglossal nucleus

Nucleus praepositushypoglossi(lateral gaze)

MLF

III

VI

IVLesion

Oculomotor Disturbances

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Nystagmus is involuntary rhythmic movementof the eyes consisting of slow movement in onedirection and rapid return movement in theother. The slow component is caused by distur-bances of the motor and stabilizing systems ofthe eye (p. 84) or because of ocular muscle pare-sis; the fast component represents the rapid re-turn movement of pontine generators. Althoughthe slow component is the actual pathologicalcomponent of nystagmus, the direction of nys-tagmus is conventionally said to be that of its fastcomponent, which is easier to detect. The inten-sity of nystagmus increases when the patientgazes in the direction of the fast component.Nystagmus can be further classified according tothe type of movement as pendular, circular, ortorsional (rotatory).Examination. The examiner first observes theeyes on primary gaze, then during horizontaland vertical pursuit (fixation of gaze on a slowlymoving object) and vergence. Nystagmus oflabyrinthine origin is observed best with Frenzelspectacles (preventing visual fixation and givingthe examiner a magnified view of the eyes). Thefollowing features of nystagmus are assessed:positional-dependence, coordination (conjugate,dissociated), direction (horizontal, vertical, ro-tatory, retracting, pendular), amplitude (fine,medium, coarse), and frequency (slow, mod-erate, fast).

Physiological Nystagmus

Physiological nystagmus serves to stabilize thevisual image while the head and body aremoving or when the individual looks at amoving object. The different types include con-genital nystagmus (often X-linked recessive;fixation nystagmus is most pronounced whengazing fixedly on an object; the direction of nys-tagmus is usually horizontal), spasmus nutans(pendular nystagmus beginning in the first yearof life; often accompanied by nodding of thehead and torticollis; disappears spontaneously),end-position nystagmus (occurs during rapidmovement; extreme lateral gaze; usually only afew beats), and optokinetic nystagmus (its ab-sence is pathological; see p. 84).

Pathological Nystagmus

Gaze-evoked nystagmus occurs only in certaindirection(s) of gaze. The main causes are drug

intoxication and brain stem or cerebellar distur-bances. A slower and coarser gaze-paretic nys-tagmus may be seen in association with su-pranuclear or peripheral gaze palsy, beating inthe direction of the paretic gaze. Peripheralpalsy of an eye muscle may cause unilateral nys-tagmus of the affected eye.Spontaneous nystagmus is that which occurswhen the eyes are in the primary position; it isusually caused by vestibular dysfunction and israrely congenital.Peripheral vestibular nystagmus (cf. p. 58) can beseen in patients with benign paroxysmal posi-tional vertigo, vestibular neuritis, Ménière dis-ease, vascular compression of the vestibularnerve, and labyrinthine fistula. Nystagmusdecreases on fixation and increases when fixa-tion is blocked (lid closure, Frenzel spectacles).Most patients exhibit rotatory nystagmus thateither beats continually toward the nonaffectedear, or else begins a short time after a change ofposition (positional nystagmus toward the lowerear, see p. 58).Central vestibular nystagmus (p. 58) is caused bylesions of the brain stem (vestibular nuclei, ves-tibulocerebellum) or of the thalamocortical pro-jections. It is usually accompanied by otherbrain stem or cerebellar signs, does not decreaseon fixation, depends on the direction of gaze,and usually persists. Central positional nystag-mus does not exhibit latency, is not affected bythe rate of positional change, occurs withchanges of position to either side, beats towardthe higher ear, and is not exhaustible, stoppingonly when the patient is returned to the neutralposition. Because positional information fromvestibular, visual, and somatosensory systems isintegrated in the vestibulo-ocular reflex (VOR;see pp. 26, 84), the phenomena associated withnystagmus can be explained as functional dis-turbances in one of the major three spatialplanes of action of the VOR. Lesions cause an im-balance between the neural inputs to the VORconcerning the two sides of the affected plane.Depending on which plane is affected, the re-sulting nystagmusmay be horizontal (horizontalplane; lesion of the vestibular nuclei), vertical(sagittal plane; pontomesencephalic, pon-tomedullary, or floccular lesion), or torsional(coronal plane; pontomesencephalic or pon-tomedullary lesion). Vertical nystagmus (upbeator downbeat) is always due to a central lesion.

Nystagmus

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Direction of nystagmus

Gaze-evoked nystagmus(no nystagmus on primary gaze)

Spontaneous nystagmus Retraction nystagmus(bilateral dorsal midbrainlesion)

Peripheral vestibular nystagmus(no nystagmus on primary gaze)

Skew deviation (vertical disconjugate gaze)Vertical up- and downbeat nystagmus (brain stem lesion)

Central vestibular nystagmus,spatial planes

Horizontal plane = yaw(tendency to fall to ipsilateral side; diminished

response to caloric testing in ipsilateral ear)

Sagittal plane = pitch(tendency to fall forward/backwards;

”elevator” sensation)

Frontal plane = roll(tendency to fall sideways, lateropulsion)

Primary gaze

Primary gaze

Nystagmus

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The colored part of the eye, or iris (Greek “rain-bow”), is the posterior wall of the anterior ocu-lar chamber. Its inner edge forms the margin ofthe pupil. The sphincter pupillae muscle con-tracts the pupil, and the dilator pupillae muscledilates it. The upper eyelid contains twomuscles: the superior tarsal muscle receivessympathetic innervation, and the levator palpe-brae superioris muscle is innervated by theoculomotor nerve.

Nerve Pathways

Parasympathetic fibers. The preganglionicfibers arise in the accessory oculomotor nucleus(Edinger–Westphal nucleus), travel in the oculo-motor nerve along its outer edge, and enter theciliary ganglion. The postganglionic fibers travelto the ciliary and sphincter pupillae muscles inthe short ciliary nerves (of which there are up to20). The parasympathetic fibers and all otherson the outer aspect of CN III receive their bloodsupply from the pial vessels, while fibers in theinterior of the nerve are supplied by the vasanervorum.Sympathetic fibers. The central sympatheticfibers exit from the posterolateral portion of thehypothalamus (first preganglionic neurons),then pass ipsilaterally through the tegmentumof the mid brain and pons and through thelateral medulla to form a synapse onto the sec-ond preganglionic neurons in the intermedi-olateral cell column of the spinal cord (ciliospi-nal center), at levels C8–T2. Most of the fibersexit the spinal cord with the ventral root of T1and join with the sympathetic trunk, which liesadjacent to the pleural dome at this level. Theytravel with the ansa subclavia around the sub-clavian artery and pass through the inferior(stellate) and middle cervical ganglia to the su-perior cervical ganglion, where they form a(third) synapse onto the postganglionic neu-rons. Postganglionic fibers to the pupil travelalong the course of the internal carotid artery(carotid plexus) and the ophthalmic artery, thenin the nasociliary nerve (a branch of CN V) and,finally, the long ciliary nerves, which innervatethe dilator pupillae muscle. Other postgan-glionic fibers of the sympathetic system pass tothe sweat glands, the orbital muscles (bridgingthe inferior orbital fissure), the superior and in-ferior tarsal muscles, and the conjunctival ves-sels. Fibers to the sweat glands arise at the

T3–T4 level and form a synapse with the thirdneuron in the stellate ganglion; thus, nerve rootlesions at C8–T2 do not impair sweating.

Light Reflex

The light reflex regulates the diameter of thepupils according to the amount of light fallingon the eye. Each pupil constricts in response tolight and dilates in the dark. The afferent arm ofthe reflex arc consists of fibers of the optic nervethat decussate in the optic chiasm, then passaround the lateral geniculate body and termi-nate in the mid brain pretectal area, both ipsi-laterally and contralaterally. The parasympa-thetic fibers are the efferent arm. The Edinger–Westphal nuclei of the two sides are connectedto each other by interneurons; thus, impulsesfrom each optic nerve arrive at both Edinger–Westphal nuclei, and light falling on one eyeleads to contraction of both the ipsilateral pupil(direct light reflex) and the contralateral pupil(consensual light reflex). The pupillary diameterin moderate ambient light is normally 3–4mm.Excessive pupillary constriction (!2mm) is re-ferred to as miosis, and excessive dilatation("5mm) as mydriasis. Anisocoria (inequality ofthe diameters of the pupils) often indicates adiseased state (see below); it may be physiologi-cal but, if so, is usually mild.

The Near Response: Convergence,Pupilloconstriction, Accommodation

When a subject watches an approaching object,three things happen: the eyes converge throughthe action of the medial rectus muscles; thepupils constrict; and the curvature of the lensincreases through the action of the ciliarymuscle (accommodation). The near responsemay be initiated voluntarily (by squinting) but ismost often the result of a reflex, whose afferentarm consists of the visual pathway to the visualcortex. The efferent arm for convergence con-sists of descending fibers to the pretectal con-vergence center (Perlia’s nucleus) and onward tothe oculomotor nucleus (nuclear area for themedial rectus muscles); the efferent arm forpupilloconstriction and accommodation is theparasympathetic projection of the Edinger–Westphal nucleus through the oculomotornerve to the sphincter pupillae and ciliarymuscles.

Pupillomotor Function

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91Pupillomotor Function

Pleural dome

Subclavian a.

Ansa subclavia

Inferior cervical(stellate) ganglion

Pretectal area

Ciliospinal center

Middle cervical ganglion

Superior cervical ganglion

Carotid plexus,internal carotid a.

Central sympathetic pathway

Orbicularis oculi m. (VII)

Sweat glands(forehead)

Orbitalis m.

Conjunctival vessels

Dilator muscle

Superiortarsal m.

Lateral geniculatebody

Visual cortex(areas 17, 18, 19)

Perlia’s nucleus

Medial rectus muscle

Edinger-Westphal nuclei

Ciliaryganglion

Oculomotor n.

Pial vessels

Vasa nervorum

Parasympathetic fibers

Sphinctermuscle

Lens

Dilator muscle

Levator palpebrae superioris m. (III)

Zonularfibers

Light reflexAccommodation

Convergence

Pupil

Oculomotor nucleus

Sudoriparous and vaso-motor fibers to skin of

face traveling along theexternal carotid a.

Ciliarymuscle(short ciliary ner-ves)

Pupillomotor Function

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92

Examination. The size and shape of the pupilsare first assessed in diffuse light with thepatient looking at a distant object to prevent thenear response. The room is then darkened andthe direct light reflex of each pupil is tested atvarying light intensities (by varying the distanceof the lamp from the eye). If both pupils con-strict when illuminated, there is no efferentpupillary defect. Next, in the swinging flashlighttest, the examiner indirectly illuminates one eyewith a bright light for ca. 2 seconds, then quicklyswitches the light to the other eye, and backagain, some 5–7 times. The normal finding isthat the two pupils are always of equal diame-ter; an abnormal finding indicates asymmetry ofthe afferent arm of the light reflex on the twosides, e. g., because of an optic nerve lesion(Marcus Gunn pupillary escape phenomenon). Ifeither of these tests is abnormal, or if the pupilsare significantly unequal, the near responseshould be tested and the direct and consensuallight reflexes should be tested separately in eacheye. It is easier to identify which pupil is abnor-mal by observing both phases of the light re-sponse (constriction and dilatation): both areslower in the abnormal pupil. In light–near dis-sociation, the pupils constrict as part of the nearresponse, but not in response to light. Phar-macological pupil testing may be necessary insome cases.

Parasympathetic Denervation(Unilateral Mydriasis)

Oculomotor palsy (p. 86) is accompanied by my-driasis only when the parasympathetic fibers onthemargin of the oculomotor nerve are affected.This is usually not the case in ischemic neu-ropathy of CN III (e. g., in diabetes mellitus), be-cause the marginal fibers receive their bloodsupply from pial vessels (p. 90). A tonic pupil is amydriatic pupil with light–near dissociation.This conditionmay be due to local causes (infec-tion, temporal arteritis) or to systemic diseasessuch as Adie syndrome (+ reduction/absence oftendon reflexes in the legs) and Ross syndrome(+ hyporeflexia + segmental hypohidrosis). Theuse of anticholinergic agents (atropine eye-drops, scopolamine patch) causes iatrogenicmydriasis.

Sympathetic Denervation(Unilateral Miosis)

Horner syndrome is produced by a lesion at anysite along the sympathetic pathway to the eyeand is characterized by unilateral miosis (withsluggish dilatation) and ptosis; anhidrosis (ab-sence of sweating) and enophthalmos are partof the syndrome but are of no practical diagnos-tic value. The affected pupil will fail to dilate inresponse to the instillation of 5% cocaine eye-drops. Preganglionic lesions (i.e., those proximalto the superior cervical ganglion) can be distin-guished from postganglionic lesions by the in-stillation of 5% pholedrine eyedrops (at leastthree days after the cocaine test); the mioticpupil dilates more than the normal pupil if thelesion is preganglionic, symmetrically if it ispostganglionic. Central Horner syndrome (firstpreganglionic neuron) may be due to lesions ofhypothalamus, brain stem, or cervicothoracicspinal cord; the second preganglionic neuronmay be affected by lesions of the brachialplexus, apical thorax, mediastinum, or neck; thepostganglionic neuron may be affected bycarotid dissection or lesions of the skull base.

Supranuclear Lesions

Lesions above the oculomotor nucleus tend tocause bilateral pupillary dysfunction; the mostcommon cause is dorsal compression of themidbrain (Parinaud syndrome; p. 358). Neu-rosyphilis produces Argyll–Robertson pupils—unequal, irregularly miotic pupils with a varia-ble degree of iris atrophy, and light–near disso-ciation.

Coma (see also p. 118)

The cause of coma may be structural, metabolic,or toxic. Pupilloconstriction is produced by opi-ates, alcohol, and barbiturates, pupillary dilata-tion by atropine poisoning (mushrooms, bella-donna), tricyclic antidepressants, botulinumtoxin, cocaine, and other drugs. Focal lesions(clivus, midbrain) may cause unilateral or bi-lateral pupillary areflexia and mydriasis. Uni-lateral miosis is seen in central Horner syn-drome, and bilateral miosis (pinpoint pupils) inacute pontine dysfunction.

Pupillary Dysfunction

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Sympathetic denervation

Spontaneous

Direct light response

Indirect light response

Convergenceresponse

Normal

Amaurosis (right)

Complete rightthird nerve palsy

Pupillotonia

Light-near dissociation

Atropine eye-drops, right eye

Clivus syndrome, intoxications

Parinaud syndrome

Right Left Pupillary dysfunction

Acute pontinelesion, intoxications

Brain stem lesion

Lesion of brachial plexus, thoracic apex,mediastinum; subclavianvenous thrombosis

Spinal lesion (syringomyelia, trauma, tumor)

Carotid dissection

Infiltrating malignant tumor

Cavernous sinus lesion

Hemispheric lesion(infarct, hemorrhage)

Parasym-patheticdener-vation

Amaurosis(right)

Ciliary ganglionitis

Argyll-Robertson pupilsClivus syndrome

Parinaud syndrome

Pupillary Dysfunction

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Peripheral Connections of the TrigeminalGanglion

Ophthalmic nerve (V/1). V/1 gives off a recur-rent branch to the tentorium cerebelli and falxcerebri (tentorial branch) and the lacrimal, fron-tal, and nasociliary nerves, which enter the orbitthrough the superior orbital fissure. The lacri-mal nerve supplies the lacrimal gland, conjunc-tiva, and lateral aspect of the upper eyelid. Thefrontal nerve divides into the supratrochlearnerve, which supplies the inner canthus, and thesupraorbital nerve, which supplies the conjunc-tiva, upper eyelid, skin of the forehead, and fron-tal sinus. Finally, the nasociliary nerve gives offbranches to the skin of the medial canthus,bridge and tip of the nose, the mucous mem-branes of the nasal sinus (anterior ethmoidnerve) and sphenoid sinus, and the ethmoidcells (posterior ethmoid nerve).Maxillary nerve (V/2). Before entering the fora-men rotundum, V/2 gives off amiddle meningealbranch that innervates the duramater of theme-dial cranial fossa and the middle meningealartery. Other branches innervate the skin of thezygomatic region and temple (zygomatic nerve),and of the cheek (infraorbital nerve). The infraor-bital nerve enters the orbit through the inferiororbital fissure, then exits from it again throughthe infraorbital canal; it innervates the cheek andthe maxillary teeth (superior alveolar nerve).Mandibular nerve (V/3). V/3 gives off a mening-eal branch (nervus spinosus) just distal from itsexit from the foramen ovale that reenters thecranial cavity through the foramen spinosum tosupply the dura mater, part of the sphenoidsinus, and the mastoid air cells. In its furthercourse, V/3 gives off the auriculotemporal nerve(supplies the temporomandibular joint, skin ofthe temple in front of the ear, external auditorycanal, eardrum, parotid gland, and anterior sur-face of the auricle), the lingual nerve (tonsils,mucous membranes of the floor of the mouth,gums of the lower front teeth, andmucosa of theanterior two-thirds of the tongue), the inferioralveolar nerve (teeth of the lower jaw and lateralgums), the mental nerve (lower lip, skin of thechin, and gums of front teeth), and the buccalnerve (buccal mucosa).The motor root of CN V contains motor fibersfrom the trigeminal motor nucleus in the pons

and joins the mandibular nerve to innervate themuscles of mastication (temporalis, masseter,and medial and lateral pterygoid muscles),hyoid muscles (anterior belly of the digastricmuscle, mylohyoid muscle), muscles of the softpalate (tensor veli palatini muscle), and tensortympani muscle.

Central Connections of the TrigeminalGanglion

Sensory fibers mediating epicritic sensation ter-minate in the principal sensory nucleus of thetrigeminal nerve, which is located in the pons.Fibers terminating in this nucleus also form theafferent arm of the corneal reflex, whose effer-ent arm is the facial nerve. Fibers mediating pro-topathic sensation terminate in the spinal nu-cleus of the trigeminal nerve, a column of cellsthat extends down themedulla to the upper cer-vical spinal cord. The spinal nucleus is somato-topically organized: its uppermost portion is re-sponsible for perioral sensation, while lowerportions serve progressively more peripheralareas of the face in an “onion-skin” arrange-ment. The caudal portion of the spinal nucleusof the trigeminal nerve also receives fibers fromcranial nerves VII, IX, and X carrying nociceptiveimpulses from the ear, posterior third of thetongue, pharynx, and larynx.Mesencephalic nucleus of trigeminal nerve. Thismidbrain nucleus, too, contains pseudounipolarneurons, whose long dendrites pass through thetrigeminal ganglion without forming a synapseand carry afferent impulses from masticatorymuscle spindles and pressure receptors (for reg-ulation of the force of chewing).Trigeminocortical tracts. Output fibers of thespinal nucleus of the trigeminal nerve decussatein the brain stem and ascend, by way of thetrigeminal lemniscus (adjacent to thespinothalamic tract) and the medial lemniscus,to the ventral posteromedial (VPM) and poste-rior nuclei of the thalamus, where the third neu-ron of the sensory pathway is located. Thesethalamic nuclei project via the internal capsuleto the postcentral gyrus. The supranuclear in-nervation of the motor nucleus of the trigeminalnerve is from the caudal portions of the precen-tral gyrus (bilaterally), by way of the corticonu-clear tract.

Trigeminal Nerve

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95

Cortical projections(postcentral gyrus)

Central innervation patternPeripheral innervation pattern

Motor nucleus of V

Spinal nucleus of V

Muscles ofmastication

Mylohyoid m.,digastric m.

V/1

V/3

V/2 C2

C3

V/1V/2

V/3

Trigeminal ganglion

Trigeminal lemniscus

Thalamus

Lesser occipitaln. (from C2)

Greater occipital n.(from C3)

Mesencephalic nucleus of V

Principal sensory nucleus of V


Trigeminal Nerve

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96

Nerve Pathways

Central motor pathway. The corticonuclear tractoriginates in the precentral cortex (area 8),passes in front of the pyramidal tract in the genuof the internal capsule, then travels in the me-dial portion of the ipsilateral cerebral peduncleto reach the facial nucleus in the lower pons. Thesupranuclear fibers serving the upper facialmuscles (frontalis and corrugator superciliimuscles, upper part of orbicularis oculi muscle,superior auricular muscle) decussate in-completely in the pons, so that these muscleshave bilateral supranuclear innervation; fibersserving the remaining muscles decussatecompletely, so that they have contralateral in-nervation only. The precentral cortex is re-sponsible for the voluntary component of facialexpression, while nonpyramidal motor connec-tions subserve the automatic and emotive com-ponents of facial expression. These anatomicalfacts explain the dissociated functional deficitsthat set supranuclear facial palsies apart fromnuclear or subnuclear palsies, and enable theirfurther differentiation into cortical and subcor-tical types (see below).Peripheral motor pathway. The facial nucleusand its efferent fibers are somatotopically or-ganized. The emerging fibers first run dorsome-dially, then turn anterolaterally to pass aroundthe abducens nucleus (inner genu of facialnerve), and exit the brain stem as the facialnerve in the cerebellopontine angle, near CN VIand VIII. The facial nerve enters the internalacoustic meatus together with the nervus inter-medius and CN VIII, then leaves the meatus toenter the facial canal; it passes between thecochlea and labyrinth, then turns back again(outer genu of facial nerve). After leaving theskull at the stylomastoid foramen, it continuesinside the parotid gland and gives off motorbranches to all muscles of facial expression aswell as the platysma, ear muscles, stapedius, di-gastric (posterior belly), and stylohyoid muscles.Sensory and parasympathetic fibers (nervus in-termedius). Sensory fibers from the geniculateganglion travel to the superior salivatory nu-cleus, nucleus of the tractus solitarius (p. 78),and spinal nucleus of the trigeminal nerve(p. 94). Taste fibers from the anterior two-thirdsof the tongue (lingual nerve) and the soft palate

(greater petrosal nerve) join the chorda tym-pani. Preganglionic parasympathetic fiberstravel in the greater petrosal nerve to the ptery-gopalatine ganglion, from which postganglonicfibers pass to the lacrimal, nasal, and palatineglands; other preganglionic fibers travel in thechorda tympani to the submandibular ganglion,from which postganglionic fibers pass to thesublingual and submandibular glands. Connec-tions via the contralateral medial lemniscus tothe thalamus and postcentral gyrus, and to thehypothalamus, subserve reflex salivation in re-sponse to the smell and taste of food. The facialnerve carries sensory fibers from the externalauditory canal, eardrum, external ear, and mas-toid region (posterior auricular nerve), as well asproprioceptive fibers from the muscles it inner-vates.

Functional Systems

The voluntary component of facial expression ismediated by the precentral cortex, in which theface is somatotopically represented. Only theupper facial muscles have bilateral supranuclearinnervation; thus, a central supranuclear facialpalsy does not affect eye closure or the ability toknit one’s brow. Yet facial palsy that spares theupper face is not necessarily of supranuclearorigin: because the facial nucleus and nerve arealso somatotopically organized, incomplete le-sions of these structures may also produce asimilar appearance. An important and some-times helpful distinguishing feature is that a su-pranuclear palsy may affect facial expression inthe lower face in a dissociated fashion. Supranu-clear facial palsy due to a cortical lesion impairsvoluntary facial expression, but tends to spareemotional expression (laughing, crying); thatdue to a subcortical lesion (e. g., in Parkinson dis-ease or hereditary dystonia) does just the op-posite.The following reflexes are of clinical significance(A = afferent arm, E = efferent arm): orbicularisoculi reflex (blink reflex; A: V/1; E: VII); cornealreflex (A: V/1; E: VII); sucking reflex (A: V/2, V/3,XI; E: V, VII, IX, X, XII), palmomental reflex (A:thenar skin/muscles; E: VII), acoustic blink reflex(A: VIII; E: VII), visual blink reflex (A: II; E: VII),orbicularis oris reflex (snout reflex; A: V/2; E:VII).

Facial Nerve

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97

Submandibular ganglion

Nuclear region

Peripheral tracts

Branches of facial nerve

Motor branches

Motor nucleus of VII

Nucleus abducens

Superior salivatory nucleus

Nucleus of the solitary tract

Peripheral pathway

Peripheralpathway

Lacrimal gland

Submandibular gland

Sublingual gland

Taste fibers

Motor fibers

Motor fibers

Pterygopalatine ganglion

Nervus intermedius

Nucleus of thesolitary tract

Abducensnucleus

Motor nucleus of V

Superior salivatorynucleus

Motornucleus of VII

Spinalnucleus

Chorda tympani

Cervical branch

Posterior auricular n.

Temporal branches

Lingual nerve

Parotid plexus,parotid gland


Inner genu of facial nerve

Otic ganglion

Subman-dibular ganglion

Lingual nerveCervical branch

Posterior auricular n.

Digastric branch

Stylohyoid branch

Marginal mandibularbranch

External genu of facial nerve

Temporal branches

Pterygopalatineganglion

Facial Nerve

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98

Examination. Motor function is assessed at rest(asymmetry of face/skin folds, atrophy, spon-taneous movements, blink rate) and during vol-untary movement (forehead, eyelids and brows,cheeks, mouth region, platysma). Trigeminalnerve dysfunction (V/1) causes unilateral or bi-lateral absence of the blink reflex; facial palsymay impair or abolish the blink response, butlagophthalmos persists, because the extraocularmuscles are unimpaired. Similar logic applies to

other facial nerve reflexes (p. 96). If the patientcomplains of loss of taste, it is tested accordingly(p. 78). Lacrimation can be tested with theSchirmer test, which, however, is positive only iftear flow is minimal or absent. The salivationtest is used to measure the flow of saliva fromthe submandibular and sublingual glands. Thestapedius reflex is tested by measuring the con-traction of the stapedius muscle in response toan acoustic stimulus.

Site of Lesion Clinical Features

Cortex or internal capsule Contralateral central facial palsy (+ pyramidal tract lesion, p. 46). Emotionalcomponent of facial expression is unimpaired

Brainstem, facial nucleus Pontine syndrome (p. 70, 72, 359), myokymia

Cerebellopontine angle Ipsilateral peripheral facial palsy (+V/1–2, VI, VIII; p. 74). Hemifacial spasmipsilateral.

Base of skull, internal acousticmeatus

Peripheral facial palsy (+ other cranial nerve palsies; p. 74)

Geniculate ganglion Peripheral facial palsy, dysgeusia, hyposalivation, diminished lacrimation, earache, hyperacusis (due to absence of stapedius reflex)

Facial canal distal to genicu-late ganglion

Peripheral facial palsy, dysgeusia, hyposalivation (but normal lacrimation),hyperacusis

Proximal to stylomastoid fora-men

Peripheral facial palsy, dysgeusia, hyposalivation, intact stapedius reflex

Stylomastoid foramen Purely motor peripheral facial palsy

Parotid gland, facial region More or less complete, purely motor facial palsy; palsy due to lesions of in-dividual branches of the facial nerve

Facial Nerve Lesions

For signs and symptoms of facial nerve lesions, see Table 7 on p. 362.


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Left peripheral facial palsy

Bilateral peripheral facial palsy

Synkinesia Right hemifacial spasm

Involuntary associated movements

Bilateral absence of lid closure

Lagophthalmos

Paresis at corner of

mouth

Paresis of platysma

Unilateral paresis offrontalis m.

Drooling


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100

Perception of Sound

Sound waves enter the ear through the externalacoustic meatus and travel through the ear canalto the tympanic membrane (eardrum), setting itinto vibration. Vibrations in the 20–16 000Hzrange (most sensitive range, 2000–5000Hz) aretransmitted to the auditory ossicles (malleus,incus, stapes). The base of the stapes vibratesagainst the oval window, creating waves in theperilymph in the vestibular canal (scala vesti-buli) of the cochlea; these waves are then trans-mitted through the connecting passage at thecochlear apex (helicotrema) to the perilymph ofthe tympanic canal (scala tympani). (Oscilla-tions of the round window compensate forvolume changes caused by oscillations of theoval window. Sound waves can also reach thecochlea by direct conduction through the skullbone.) Migrating waves are set in motion alongthe basilar membrane of the cochlear duct; theytravel from the stapes to the helicotrema atdecreasing speed, partly because the basilarmembrane is less tense as it nears the cochlearapex. These waves have their amplitudemaximaat different sites along the basilar membrane,depending on frequency (tonotopicity): there re-sults a frequency-specific excitation of the re-ceptor cells for hearing—the hair cells of theorgan of Corti, which is adjacent to the basilarmembrane as it winds through the cochlea.

Cochlear Nerve

The tonotopicity of the basilar membranecauses each hair cell to be tuned to a specificsound frequency (spectral analysis). Each haircell is connected to an afferent fiber of thecochlear nerve inside the organ of Corti. Thecochlear nerve is formed by the centralprocesses of the bipolar neurons of the cochlearganglion (the first neurons of the auditory path-way); it exits from the petrous bone at the inter-nal acoustic meatus, travels a short distance inthe subarachnoid space, and enters the brainstem in the cerebellopontine angle. Centralauditory processing involves interpretation ofthe pattern and temporal sequence of the actionpotentials carried in the cochlear nerve.

Auditory Pathway

As it ascends from the cochlea to the auditorycortex, the auditory pathway gives off collateralprojections to the cerebellum, the oculomotorand facial nuclei, cervical motor neurons, andthe reticular activating system, which form theafferent arm of the acoustically mediated re-flexes.Axons of the cochlear nerve originating in thecochlear apex and base terminate in the anteriorand posterior cochlear nuclei, respectively.These nuclei contain the second neurons of theauditory pathway. Fibers from the posteriorcochlear nucleus decussate in the floor of thefourth ventricle, then ascend to enter the laterallemniscus and synapse in the inferior colliculus(third neuron). The inferior colliculus projects tothe medial geniculate body (fourth neuron),which, in turn, projects via the acoustic radia-tion to the auditory cortex. The acoustic radia-tion passes below the thalamus and runs in theposterior limb of the internal capsule. Fibersfrom the anterior cochlear nucleus also decus-sate, mainly in the trapezoid body, and synapseonto the next (third) neuron in the olivary nu-cleus or the nucleus of the lateral lemniscus.This branch of the auditory pathway then con-tinues through the lateral lemniscus to the infe-rior colliculus and onward through the acousticradiation to the auditory cortex.The primary auditory cortex (area 41: Heschl’sgyrus, transverse temporal gyri) is located in thetemporal operculum (i.e., the portion of thetemporal lobe overlying the insula and sepa-rated from it by the sylvian cistern). Areas 42and 22make up the secondary auditory cortex, inwhich auditory signals are further processed,recognized, and compared with auditorymemories. The auditory cortex of each side ofthe brain receives information from both ears(contralateral more than ipsilateral); unilaterallesions of the central auditory pathway or audi-tory cortex do not cause clinically relevant hear-ing loss.

Hearing

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101

Migrating wave, spectral analysis,tonotopicity

Auditory cortex

Conduction of Sound; auditory pathway

Cochlea

Acoustic radiation

Cochlear n.

Scala vestibuli

Scala tympani

Tensor tympani m.

Auditory tube (eustachian tube)

Tympanicmembrane

External auditory canal

Cochlea

Vestibular system

Malleus,incus

Stapes

Oval window

Cochlear nerve

Cochlear duct

Posterior cochlear nucleus

Medullary striae

Olivary nuclei

Nucleus of laterallemniscus

Inferior colliculus

Superior colliculus

Medial geniculate body

Anterior cochlearnucleus

Laterallemniscus

Trapezoid body

Areas 41, 42

Frequencybands

Organ of Corti,basilar membrane,

hair cell

Cochlear ganglion

20 000Hz 20 Hz

Cochlear duct

Hearing

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Impairment of swallowing (deglutition) is calleddysphagia; pain on swallowing is called ody-nophagia. Dysphagia or vomiting due to neuro-logical disease often causes aspiration (entranceof solid or liquid food into the airway below thevocal cords). Globus hystericus is a foreign-bodysensation in the swallowing pathway independ-ent of the act of swallowing. Despite its name, itis not always psychogenic; organic causes in-clude Zenker diverticulum and gastroe-sophageal reflux.

Deglutition

Mechanism. The food is ground by the teeth andmoistened with saliva to form chyme, which ismolded by the tongue into an easily swallowedbolus (oral preparatory phase). The tonguepushes the bolus into the oropharynx (oralphase) to initiate the reflex act of swallowing(pharyngeal phase). The lips and jaw close, thesoft palate rises to seal off the nasopharynx, andthe bolus bends the epiglottis backward. Thebolus is pushed further back by the tongue, res-piration briefly ceases, and the raised larynx oc-cludes the airway. The upper esophagealsphincter slackens (cricopharyngeus, inferiorpharyngeal constrictor, smooth muscle of upperportion of esophagus). Pressure from the tongueand pharyngeal peristalsis push the bolus pastthe epiglottis and into the esophagus(esophageal phase). The larynx is lowered, res-piration is reinstated, and esophageal peristalsispropels the bolus into the stomach.Nerve pathways. Fibers of CN V/2, VII, IX, and Xto the nucleus ambiguus and the nucleus of thetractus solitarius (p. 78) make up the afferentarm of the swallowing reflex. The motor swal-lowing center (one on each side) lies adjacent tothese nuclei and is associated with the uppermedullary reticular formation; it coordinatesthe actions of the numerous muscles involved inswallowing. Efferent signals reach thesemuscles through CN V/3, VII, IX, X, and XII.Crossed and uncrossed supranuclear innerva-tion is derived from the cerebral cortex (precen-tral and postcentral gyri, frontoparietal oper-culum, premotor cortex, and anterior insular re-gion). Spinal motor neurons also participate(C1–C4).

Neurological Disturbances of Deglutition(See Table 8 on p. 362)

The disturbance usually manifests itself at thebeginning of the act of swallowing (e. g., a feel-ing of food stuck in the throat, the escape ofliquid or solid food through the nose, choking,coughing). Associated inflammation of theswallowing pathway may cause odynophagia.Chronic dysphagia causes inadequate nutritionand weight loss. Neurogenic dysphagia usuallyimpairs the swallowing of liquids more thansolids; soft, chilled foods (like pudding oryogurt) are often easier to swallow. Sensory dis-turbances in the larynx and trachea, adiminished cough reflex, and muscle weaknessmay cause aspiration, sometimes unremarkedby the patient (silent aspiration). The diagnosticevaluation of dysphagia may require specialtests such as radiocinematography, video endo-scopy, manometry, and pH measurement.

Disturbances of Deglutition

Cran

ialN

erves


103

Nasal breathing(arrow shows path of air)

Act of swallowing(arrow shows path of food)

Nerve pathways (efferent fibers)

Motor cortical areas

IX

X

XII

Constrictor pharyngis m.(not fully depicted)

Motor root of

mandibu-lar n.

Corticobulbar/corticospinal tracts

Palatoglossus, palatopharyngeus,and levator veli palatini mm.

Masseter, tensor veli palatini, andlateral pterygoidmm.

Mm. of tongue

Mm. of face; stylohyoid and digastric mm.

Mm. of pharynx;stylopharyngeus m.

VII

Disturbances of Deglutition

Cran

ialN

erves


104

There are two functionally and anatomically dis-tinct types of somatic sensation and pain. Thespatially and temporally precise perception oflight tactile, noxious, and temperature stimuli iscalled epicritic sensation, and the more diffuseperception of stronger tactile, noxious, andtemperature stimuli is called protopathic sensa-tion. Sensation in the deep tissues (muscles,viscera) is predominantly protopathic.

Receptors

Sensory stimuli affect the nervous system byphysically interacting with receptors. Exterocep-tors respond to external stimuli (mechanical,thermal, optic, acoustic, olfactory, gustatory);interoceptors respond to internal stimuli(stretch, pressure, chemical irritation of internalorgans). A stimulus activates a receptor only if itis sufficiently intense (above threshold). Recep-tors are classified according to their activatingstimuli: mechanoreceptors (pressure, touch;proprioceptive sensations such as joint postion,muscle contraction, muscle stretch; hearing,sense of balance), thermoreceptors (heat, cold),chemoreceptors (pain, smell, itch, taste), andphotoreceptors (light). Cutaneous receptors in-clude both “free” nerve endings and speciallyadapted receptors (e. g., corpuscles of Meissnerand Vater-Pacini). The former type mainly sub-serve pain and temperature sense, the latter tac-tile sensation (touch, pressure, vibration). Inhair-covered skin there are tactile receptorsaround the hair roots.

Nerve Pathways

From the receptor, information is transmitted tothe afferent fibers of the pseudounipolar spinalganglion cells, whose efferent fibers reach thespinal cord by way of the dorsal root. A synapseonto a second neuron in the sensory pathway ismade either immediately, in the posterior hornof the spinal cord (protopathic system), or morerostrally, in the brain stem (epicritic/lemniscalsystem). The highest level of the somatosensorypathway is the contralateral primary soma-tosensory cortex. The somatotopic organizationof the somatosensory pathway is preserved atall levels.Posterior column (epicritic/lemniscal system).

Fibers mediating sensation in the legs are in thefasciculus gracilis (medial), while those for thearms are in the fasciculus cuneatus (lateral).These fibers synapse onto the second sensoryneuron in the corresponding somatosensory nu-clei of the lower medulla (nucleus gracilis, nu-cleus cuneatus), which emit fibers that decus-sate and ascend in the contralateral medial lem-niscus to the thalamus (ventral posterolateralnucleus, VPL). VPL projects to the postcentralgyrus by way of the internal capsule.Anterolateral column (protopathic system).Fibers of the protopathic pathway for somaticsensation (strong pressure, coarse touch) enterthe spinal cord through the dorsal root and thenascend two or more segments before making asynapse in the ipsilateral posterior horn. Fibersoriginating in the posterior horn decussate inthe anterior commissure of the spinal cord andenter the anterior spinothalamic tract, which issomatotopically arranged: fibers for the legs areanterolateral, fibers for the arms are posterome-dial. The anterior spinothalamic tract traversesthe brain stem adjacent to the medial lemniscusand terminates in VPL, which, in turn, projectsto the postcentral gyrus. The protopathic path-way for pain (as well as tickle, itch, and tempera-ture sensation) is organized in similar fashion:Central fibers of the first sensory neuron ascend1 or 2 segments before making a synapse in thesubstantia gelatinosa of the posterior horn.Fibers from the posterior horn decussate andenter the lateral spinothalamic tract, which, likethe anterior spinothalamic tract, projects toVPL; VPL projects in turn to the postcentralgyrus.Spinocerebellar tracts (spinocerebellar system).These tracts mediate proprioception. Fibersoriginating from muscles spindles and tendonorgans make synapses onto the neurons ofClarke’s column within the posterior horn atlevels T1–L2, whose axons form the posteriorspinocerebellar tract (ipsilateral) and the ante-rior spinocerebellar tract (both ipsilateral andcontralateral). These tracts terminate in thespinocerebellum (p. 54).

Sensation

Sensation


105

Areas of innervation (left, nerve roots [dermatomes]); right, cutaneous nerves)

Vibration Touch, pressurePain, temperature

Extensive overlap-ping of adjacent roots

Slight over-lapping of

adjacent cutaneous

nerves

Sensory hairs(touch)

Free nerve endings(pain, temperature)

Vater-Pacini corpuscles (pressure)

Meissner’s corpuscles

Arrector m.

Pseudounipolarnerve cells, spinal ganglion

Deep sensation (proprioception)

Antero-lateralcolumn

Posterior column

Nucleus gracilis (leg),nucleus cuneatus (arm)

Medial lemniscus

Lateral spinothalamic tract

Anterior spinothalamictract

Anterior andposterior spinocerebellartracts

Spino-cerebellartract

Thalamocortical tract

Postcentral gyrus, somatotopy

Ventral postero-lateral nucleus ofthalamus

Cerebellum

Sensation

Sensation


106

Examination. Somatic sensation is tested withthe patient’s eyes closed. The examiner testseach primary modality of superficial sensation(touch, pain, temperature), the patient’s abilityto distinguish different qualities of each modal-ity (sharp/blunt, hot/cold, different intensities,two-point discrimination), and more complexsensory modalities (stereognosis, graphesthe-sia). Next, sensation to pressure and vibrationstimuli are tested, as is acrognosis (posturesense), to evaluate proprioception. Sensory dis-turbances commonly cause disturbances of pos-ture (tests: Romberg test, standing on one leg)or gait (p. 60).

Interpretation of findings. There is a wide rangeof normal findings. Apparent abnormalitiesshould be interpreted in conjunction with find-ings of other types, such as abnormal reflexes orparesis. Sensory dysfunction may involve notonly a diminution or absence of sensation (hy-pesthesia, anesthesia), but also sensations of ab-normal type (paresthesia, such as prickling orformication) or spontaneous pain (dysesthesia,often of burning type). Patients often use thecolloquial term “numbness” to mean hypesthe-sia, anesthesia, or paresthesia; the physicianshould ask specific questions to determine whatis meant.

Localization of Sensory Disturbances

Clinical Features Site of Lesion Possible Causes1

Localized sensory disturbance (not in adermatomal or peripheral nerve distribu-tion)2

Cutaneous nerves/receptors

Skin lesions, scars, lepromatous leprosy(dissociated sensory deficit3 distally in thelimbs, tip of nose, external ear)

Often pain and paresthesia at first, thensensory deficit, in a distribution depend-ing on the site of the lesion

Distal peripheralnerve

Mononeuropathy (compression, tumor),mononeuritis multiplex (involvement ofmultiple peripheral nerves by vasculitis,diabetes mellitus, etc.)

Distal symmetrical sensory disturbances Distal peripheralnerves

Polyneuropathy (diabetes mellitus, alco-hol, drug/toxic, Guillain–Barré syndrome)

Bilateral symmetrical or asymmetricalthigh pain

Peripheral nerves,lumbar plexus

Diabetes mellitus

Multiple sensory and motor deficits in asingle limb

Plexus Trauma, compression, infection, ischemia,tumor, metabolic disturbance

Unilateral or bilateral, monoradicular orpolyradicular deficits

Nerve root Herniated disk, herpes zoster, Guillain–Barré syndrome, tumor, carcinomatousmeningitis, paraneoplastic syndrome

Spinal ataxia, incomplete or completecord transection syndrome (p. 48)

Spinal cord Vascular, tumor, inflammatory/multiplesclerosis, hereditary, metabolic disease,trauma, malformation

Loss of position and vibration sense in theupper limbs and trunk, Lhermitte’s sign

Craniocervical junc-tion

Tumor, basilar impression

Contralateral dissociated or crossedsensory deficit (p. 70 ff)

Brainstem Vascular, tumor, multiple sclerosis

Contralateral paresthesia and sensorydeficits, pain, loss of vibration sense

Thalamus Vascular (p. 170), tumor, multiple sclero-sis

Paresthesia, contralateral sensory deficits(astereognosis, loss of position sense andtwo-point discrimination, inability to lo-calize a stimulus, agraphesthesia)

Postcentral cortex Vascular, tumor, trauma

1 The listing of possible causes is necessarily incomplete. 2 May be factitious or psychogenic.3 Impairment or loss of pain and temperature sensation with preserved touch sensation.

Sensory Disturbances

Sensation


107

Localization of spinal and radicular sensory disturbances

Sensory ataxia

Sensory dissociation, muscularatrophy, scoliosis due to syringomyelia

Radicular sensory disturbances and pain inherpes zoster

Radicular lesion(dorsal root)

Ganglionic lesion (loss of deep sensa-tion leads to markedataxia)

Central cord lesion (sensory dissociation)

Posterior hornlesion (loss of pain

and temperatureperception, refleximpairment with

preserved posterior column

sensation)

Posterior column lesion (loss of positionsense, pallesthesia,graphesthesia, stereoanesthesia,and Lhermitte’ssign in cervicallesions)

Sensory Disturbances

Sensation


108

Pain is an unpleasant sensory and emotional ex-perience associated with actual or potential tissuedamage, or described in terms of such damage(International Association for the Study of Pain).

Pathogenesis

Pain results from the interaction of a noxious(i.e., pain-producing) stimulus with a receptor,and the subsequent transmission and pro-cessing of pain-related signals in the PNS andCNS; the entire process is called nociception.Pain evokes a behavioral response involvingnocifensor activity as well as motor and auto-nomic reflexes.Pain reception. Nociceptors for mechanical,thermal, and chemical stimuli are found in allbody organs except the brain and spinal cord. Byreleasing neuropeptides, the nociceptors canproduce a neurogenic sterile inflammatory re-sponse that enhances nociception (peripheralsensitization).Pain transmission. Nociceptive impulses travelin peripheral nerves to the posterior horn of thespinal cord. Here, the incoming information isprocessed by both pain-specific and nonspecific(wide dynamic range) neurons. Central sensiti-zation processes arising at this level may lowerthe nociceptor threshold and promote thedevelopment of chronic pain (such as phantomlimb pain after amputation). Ascending im-pulses reach the brain through thespinothalamic and spinoreticular tracts as wellas other pathways to a number of different brainregions involved in nociception.Pain processing. The reticular formation regu-lates arousal reactions, autonomic reflexes, andemotional responses to pain. The thalamus re-lays and differentiates nociceptive stimuli. Thehypothalamus mediates autonomic and neu-roendocrine responses. The limbic system(p. 144) mediates emotional and motivation-re-lated aspects of nociception. The somatosensorycortex is mainly responsible for pain differentia-tion and localization. Descending pathways thatoriginate in these CNS areas also modulate noci-ception.Neurotransmitters and neuropeptides are in-volved in nociception on different levels.Various neurotransmitters and neuropeptidesystems play a role in the mechanism of action

of one or more currently used analgesic agents(effective drugs in parantheses): glutamate(memantine); substance P (capsaicin);histamine (antihistamines); serotonin/nor-epinephrine (antidepressants); GABA (baclofen,diazepam); prostaglandins (nonsteroidal anti-inflammatory drugs); enkephalin, endorphin,dynorphin (opiates, opioids).

Types of Pain (See Table 9, p. 363)

Nociceptive pain, the “normal” type of pain, isthat which arises from actual or potential tissuedamage and results from the activation of noci-ceptors and subsequent processing in an intactnervous system. Somatic pain is the variety ofnociceptive pain mediated by somatosensoryafferent fibers; it is usually easily localizable andof sharp, aching, or throbbing quality. Post-operative, traumatic, and local inflammatorypain are often of this variety. Visceral pain isharder to localize (e. g., headache in meningitis,biliary colic, gastritis, mesenteric infarction) andmay be dull, cramplike, piercing, or waxing andwaning. It is mediated peripherally by C fibersand centrally by spinal cord pathways terminat-ing mainly in the limbic system. This may ex-plain the unpleasant and emotionally distress-ing nature of visceral pain. Visceral pain may befelt in its site of origin or may be referred toanother site (e. g., from the diaphragm to theshoulder).Neuropathic pain is that which is caused bydamage to nerve tissue. It is always referred tothe sensory distribution of the affected neuralstructure: e. g., calf pain in S1 radiculopathy,frontal headache in tentorial meningioma, uni-lateral bandlike abdominal pain in schwannomaof a thoracic spinal nerve root. (Note that neu-ropathic pain is not necessarily due to neu-ropathy. The less misleading synonym “neuro-genic pain” is not as widely used.)

Pain

Pain


109

Types of pain

Nociception and thepain pathway

Nociceptive processing

C and Afibers

A fibers (spinothalamic andspinocerebellartracts)

Nociceptor

Ascending pathway

Mechanoreceptor

Descendingpathway

(supraspinalpain modifi-

cation)

Descendingtract (supra-

spinal painmodification)

Nociceptor

Brain stem (periaqueductal gray

substance)

Spinal painmodification

Thalamic projections to cortex,limbic system andhypothalamus

Efferent fibers

Cerebralcortex

Posterior column

Modulatory synapses

Ascending pathway (pain

information)

Reticular formation

Superficial pain Deep pain Neuropathic pain Visceral pain

Skin

Pinprick, pinch

Connective tissue,muscle, bone, joints

Muscle cramps,headache

Nerves, neural tissue Viscera

Neuropathy, neuroma,nerve injury

Biliary colic, ulcer pain,appendicitis

Somatic pain Visceral pain

Pain

Pain

Pain


110

Head’s Zones

Visceral pain is not felt in the internal organwhere it originates, but is rather referred to acutaneous zone (of Head) specific to that organ.This phenomenon is explained by the arrival ofsensory impulses from both the internal organand its related zone of Head at the posteriorhorn at the same level of the spinal cord; thebrain thus (mis)interprets the visceral pain asoriginating in the related cutaneous zone. Thepain may be described as burning, pulling, pres-sure, or soreness, and there may be cutaneoushyperesthesia to light touch. Certain etiologies(e. g., angina pectoris, cholecystitis, gastric ulcer,intestinal disease) can produce ipsilateral my-driasis. In addition to the zones of Head, referredpain may also be felt in muscles and connectivetissue (pressure points, as in Blumberg’s sign orMcBurney’s point). Physicians should beware ofmistaking referred for local pain.

Spinal Autonomic Reflexes

The afferent arm of these reflexes originates inthe internal organs and terminates on the sym-pathetic preganglionic neurons in the interme-diolateral and intermediomedial cell columns ofthe spinal cord at levels T1 through L2 (p. 140).Typical examples are the viscerovisceral reflex(causing meteorism in colic and anuria in myo-cardial infarction), the viscerocutaneous reflex (avisceral stimulus leads to sweating and hyper-emia in the corresponding zone of Head), thecutivisceral reflex (reduction of colic, myogelosis,etc., by warm compresses or massage), thevisceromotor reflex (defensive muscle contrac-tion in response to visceral stimulus), and thevasodilatory axon reflex (dermographism). Anyabnormality of these reflexes may be an impor-tant sign of impaired autonomic function (car-diovascular, gastrointestinal, thermoregulatory,or urogenital), particularly in patients with spi-nal cord disorders.

Complex Regional Pain Syndrome (CRPS)

The International Association for the Study ofPain (IASP) recommends the term CRPS for a setof painful disorders of apparently relatedpathophysiology, which are further classified

into CRPS type I (reflex sympathetic dystrophy;without peripheral nerve injury) and CRPS typeII (causalgia; with peripheral nerve injury).CRPS usually results from a traumatic or otherinjury to a limb, often in conjunction with pro-longed disuse. The pain is persistent and diffuse,and of burning, stabbing, or throbbing quality,often in association with allodynia (pain evokedby a normally nonpainful stimulus) and hyper-pathia (abnormally intense pain evoked by anormally painful stimulus). It is generally not ina radicular or peripheral nerve distribution. Itmay be accompanied by motor disturbances(paresis, disuse of limb), autonomic distur-bances (sweat secretion or circulatory distur-bances), trophic changes (edema, muscle atro-phy, joint swelling, bone destruction), and reac-tive mental changes (depression, anxiety). Thediagnosis of CRPS is based on criteria defined bythe IASP and requires the exclusion of other dis-ease processes such as fracture, vasculitis,thrombosis, radicular lesion, rheumatoid ar-thritis, etc. Its pathogenetic mechanism is un-known.

Pain

Pain


111

Head’s zones

Cutivisceral reflex

Viscerocutaneous reflex

Vasodilatory axon reflex, visceromotor and viscerocutaneous reflexes

Liver, gallbladder

Stomach

Heart

Esophagus

Ilium

Colon

Urinary bladder

Kidney, ureter, testicle

SkinSympathetictrunk

Muscle

Sweat gland

Intestine

Gallbladder

Spinothalamic tract

Posterior horn

Rami communi-

cantes

Pain

Pain


112

Circadian Rhythm

The human sleep–wake cycle has a period of ap-proximately 24 hours, as the term circadian(Latin circa + dies) implies. If all external time in-dicators are removed, the circadian rhythm per-sists but the times of waking and going to sleepbecome later each day. The circadian rhythm isthought to be regulated by the suprachiasmaticnucleus of the hypothalamus (p. 142). Retino-hypothalamic connections tie the circadianrhythm to environmental light conditions. Thereis also a retinal projection to the pineal gland;the melatonin produced there has a rhythm-shifting effect.Not only sleeping and waking but also manyother bodily functions, including cardiovascularand respiratory function, hormone secretion,mitosis rate, intracranial pressure, and atten-tiveness, follow a circadian pattern (chronobi-ology). Circadian variation in performance is im-portant in the workplace and elsewhere. Somediseases are associated with certain times of theday (chronopathology)—certain types of epilep-tic seizures, asthma, cluster headache, gastro-esophageal reflux disease, myocardial infarc-tion, vertricular tachycardia.

Sleep

Sleep is divided into REM sleep, in which rapideye movements occur, and non-REM (NREM)sleep. Polygraphic recordings (EEG, EOG, EMG)can distinguish these two types of sleep and areused to subdivide NREM sleep into four stages,the last two of which constitute deep sleep (seeTable 10, p. 363).Normal sleep occurs in cycles lasting 90–120minutes, of which there are thus four or fiveduring a normal night’s sleep of ca. 8 hours’ du-ration. Sleep cycles are regulated by activatingand deactivating systems (cholinergic REM-onneurons, noradrenergic REM-off neurons) lo-cated mainly in the brain stem. The exact physi-ological significance of sleep is not known. Sleepappears to play a role in regenerative metabolicprocesses, cognitive functions, and memory.

Sleep Profile

The sleep–wake rhythm changes with age.Neonates sleep 16–18 hours a day at irregularintervals. By age 1 year, the sleep pattern stabi-lizes to roughly 12 hours of sleep alternatingwith 12 hours of waking. Adults sleep for 4–10hours nightly, with themedian value ca. 8 hours.As adults age, they tend to take longer and morefrequent naps, sleep less deeply, and lie in bedlonger in the morning. The sleep architecturechanges with age: neonates have 50% REMsleep, but adults only 18%. After age 50, stages 3and 4 account for only about 5% of sleep. Per-sons differ in their sleep–wake patterns (somno-types): there are morning types (“larks”) andnight types (“night owls”); bedtimes vary bytwo or more hours among these individuals.

Normal Sleep

Sleep


113

Circadian rhythm

EEG of sleep stages

Changes in sleep structure with age

Sleep profile (4 sleep cycles)

Shifting in absence ofexternal time indicators

Onset of sleep

REM

Awake

Sleep stages

Time (h)

1

2

0 1 2 3 4 5

24

12

16

10 30 60 802

4

0

8

6 7

3

4

End of sleep

Sleep cycle

Awake

REM sleep

NREM sleep

Amount of sleep/day (h)

Age (years)

50 µ V1s

–WavesAwake

–Waves

–Waves

NREM sleep

Saw-tooth wavesREM sleep

Normal Sleep

Sleep


114

More than 100 sleep disorders have been de-scribed to date. Sleep disorders may involve in-sufficient, interrupted, or absent sleep (in-somnia), or an excessive need for sleep, includ-ing during the day (hypersomnia). They may in-volve respiratory disturbances during sleep(snoring, sleep apnea, asthma), involuntarymovement disorders, parasomnias, pharmaco-logically active substances (medications, illegaldrugs, alcohol, coffee, smoking), or systemic dis-ease.The prerequisite to treatment is an adequate di-agnostic assessment, which begins with the de-termination whether the sleep disorder is pri-mary or secondary (i.e., the result of anotherdisease or condition).

Primary Sleep Disorders (Dyssomnias)

Intrinsic sleep disorders. Psychogenic insomnia ischaracterized by increased mental tension (ina-bility to relax, anxiety, brooding) and excessiveconcern about sleep itself (constant complain-ing about an inability to fall asleep or stayasleep, or about waking up too early). Sleepoften improves in a new environment (e. g., onvacation).Pseudoinsomnia is a subjective feeling of dis-turbed sleep in the absence of objective evi-dence (i.e., normal polysomnography).Restless legs syndrome (RLS) is characterized byascending abnormal sensations in the legs whenthey are at rest (e. g., when the patient watchestelevision, or before falling asleep) accompaniedby an urge to move the legs. It is sometimes pre-sent as a genetic disorder with autosomal domi-nant inheritance. Periodic leg movements duringsleep are repeated, abrupt twitching move-ments of the legs that may persist for minutes tohours. These two movement disorders may ap-pear together or in isolation; both may be eitherprimary or secondary (due to, e. g., uremia,tricyclic antidepressant use, or iron deficiency).Narcolepsy is characterized by daytime som-nolence and frequent, sudden, uncontrollableepisodes of sleep (imperative sleep), which tendto occur in restful situations (e. g., reading, hear-ing a lecture, watching TV, long automobilerides). It may be associated with cataplexy (sud-den, episodic loss of muscle tone without un-consciousness), sleep paralysis (inability to

move or speak when awaking from sleep), andhypnagogic hallucinations (visual or acoustichallucinations while falling asleep). Polysomno-graphy reveals a short sleep latency and an earlyonset of REM sleep. The presence of HLA an-tigens (DR2, DQw1, DQB1*0602) is nonspecific,as is the absence of hypocretin-1 (orexin A) inthe cerebrospinal fluid.Obstructive sleep apnea is characterized by day-time somnolence with frequent dozing, noc-turnal respiratory pauses, and loud snoring. Im-paired concentration, decreased performance,and headaches are also common.Extrinsic sleep disorders. Sleep may be dis-turbed by external factors such as noise, light,mental stress, and medication use.Disturbance of the circadian rhythm. Sleep maybe disturbed by shift work at night or by inter-continental travel (jet lag).Parasomnias. These disorders include confusionon awakening (sleep drunkenness), sleepwalk-ing (somnambulism), nightmares, sleep myo-clonus, bedwetting (enuresis), and nocturnalgrinding of the teeth (bruxism).

Secondary Sleep Disorders

Psychogenic sleep disorders. Depression (ofvarious types) can impair sleep, though para-doxically sleep deprivation can ameliorate de-pression. Depressed persons typically complainof early morning awakening, nocturnal restless-ness, and difficulty in starting the day. Sleep dis-turbances are also common in patients sufferingfrom psychosis, mania, anxiety disorders, alco-holism, and drug abuse.Neurogenic sleep disorders. Sleep can be im-paired by dementia, Parkinson disease, dys-tonia, respiratory disturbances secondary toneuromuscular disease (muscular dystrophy,amyotrophic lateral sclerosis), epilepsy (noc-turnal attacks), and headache syndromes(cluster headaches, migraine). Fatal familial in-somnia is a genetic disorder of autosomal domi-nant inheritance (p. 252).Sleep disorders due to systemic disease. Sleepcan be impaired by pulmonary diseases(asthma, COPD), angina pectoris, nocturia, fibro-myalgia, and chronic fatigue syndrome.

Sleep Disorders

Sleep


115

Psychogenic insomnia

Restless legs syndrome

Narcolepsy

Impaired sleep-wake rhythm Daytime sleepiness

Sleep Disorders

Sleep


116

Consciousness is an active process withmultipleindividual components, including wakefulness,arousal, perception of oneself and the environ-ment, attention, memory, motivation, speech,mood, abstract/logical thinking, and goal-directed action. Psychologists and philosophershave long sought to understand the nature ofconsciousness.Clinical assessment of consciousness tests thepatients’ perception of themselves and their en-vironment, behavior, and responses to externalstimuli. Findings are expressed in terms of threecategories: level of consciousness (state/clarity ofconsciousness, quantitative level of conscious-ness, vigilance, alertness, arousability); contentof consciousness (quality of consciousness,awareness); and wakefulness. Changes in any ofthese categories tend to affect the others as well.Morphologically, the level of consciousness isassociated with the reticular activating system(RAS). This network is found along the entirelength of the brain stem reticular formation(p. 26), from themedulla to the intralaminar nu-clei of the thalamus. The RAS has extensive bi-lateral projections to the cerebral cortex; thecortex also projects back to the RAS. Neurotrans-mission in these systems is predominantly withacetylcholine, monoamines (norepinephrine,dopamine, serotonin), GABA (inhibitory), andglutamate (excitatory).In the normal state of consciousness, the in-dividual is fully conscious, oriented, and awake.All of these categories undergo circadian varia-tion (depending on the time of day, a personmay be fully awake or drowsy, more or less con-centrated, with organized or disorganizedthinking), but normal consciousness with fullwakefulness can always be restored by avigorous stimulus.

Acute Disturbances of Consciousness

Confusion affects the content of consciousness—attention, concentration, thought, memory,spatiotemporal orientation, and perception(lack of recognition). It may also be associatedwith changes in the level of consciousness (fluc-tuation between agitation and somnolence) andin wakefulness (impaired sleep–wake cyclewith nocturnal agitation and daytime som-nolence). Delirium is characterized by visual hal-

lucinations, restlessness, suggestibility, and au-tonomic disturbances (tachycardia, blood pres-sure fluctuations, hyperhidrosis).Somnolence is a mild reduction of the level ofconsciousness (drowsiness, reduced spon-taneous movement, psychomotor sluggishness,and delayed response to verbal stimuli) whilethe patient remains arousable: he or she is easilyawakened by a stimulus, but falls back asleeponce it is removed. The patient responds to nox-ious stimuli with direct and goal-directeddefensive behavior. Orientation and attentionare mildly impaired but improve on stimulation.Stupor is a significant reduction of the level ofconsciousness. These patients require vigorousand repeated stimulation before they open theireyes and look at the examiner. They answerquestions slowly and inadequately, or not at all.They may lie motionless or display restless orstereotyped movements. Confusion reflectsconcomitant impairment of the content of con-sciousness.Disorders of arousal. Wakefulness normally fol-lows a circadian rhythm (p. 112). Sleep apneasyndrome, narcolepsy, and parasomnia are dis-orders of arousal (dyssomnias, p. 114). Hyper-somnia is caused by bilateral paramedianthalamic infarcts, tumors in the third ventricu-lar region, and lesions of the midbrain tegmen-tum (p. 70 ff). The level and content of con-sciousness may also be affected. In patients withbilateral paramedian thalamic infarction, for ex-ample, there may be a sudden onset of confu-sion, followed by somnolence and coma. Afterrecovery from the acute phase, these patientsare apathetic and their memory is impaired(“thalamic dementia”).


Disturban

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Consciou

sness


117

Normal state of consciousness

Apallic syndrome

Disturbance of arousal (hypersomnia)

Acute confusion

Somnolence, stupor

Level of consciousness

Content of consciousness

Sleep-wake phases


Disturban

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Consciou

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Coma (from the Greek for “deep sleep”) is a stateof unconsciousness in which the individual liesmotionless, with eyes closed, and cannot bearoused even by vigorous stimulation. Coma re-flects a loss of the structural or functional inte-grity of the RAS (p. 116) or the areas to which itprojects. Coma may be produced by an exten-sive brain stem lesion or by extensive bi-hemispheric cerebral lesions, as well as by me-tabolic, hypoxic/ischemic, toxic, or endocrinedisturbances. In the syndrome of transtentorialherniation (see p. 162), a large unihemisphericlesion can cause coma by compressing the mid-brain and the diencephalic RAS. Even withoutherniation, however, large unihemispheric le-sions can transiently impair consciousness.

Coma Staging

The degree of impairment of consciousness iscorrelated with the extent of the causative le-sion. The severity and prognosis of coma arejudged from the patient’s response to stimuli.There is no universally accepted grading systemfor coma. Proper documentation involves anexact description of the stimuli given and the re-sponses elicited, rather than isolated items ofinformation such as “somnolent” or “GCS 10.”Coma scales (e. g., the Glasgow Coma Scale) areuseful for the standardization of data for statisti-cal purposes but do not replace a detailed docu-mentation of the state of consciousness.Spontaneous movement. Assessment of motorfunction yields clues to the site of the lesion(p. 44 ff) and the etiology of coma. The examinershould note the pattern of breathing, any utter-ances, yawning, swallowing, coughing, andmovements of the limbs (twitching of the faceor hands may indicate epileptic activity; theremay be myoclonus or flexion/extension move-ments).Stimuli. Lesions of the mid brain or lower dien-cephalon produce the decerebration syndrome(arm/leg extension with adduction and internalrotation of the arms, pronation and flexion ofthe hands), while extensive bilateral lesions athigher levels produce the decortication syn-drome (arm/hand flexion, arm supination, legextension) (p. 47). These pathological flexionand extension movements occur spontaneouslyor in response to external stimuli (verbal stimu-

lation, tickling around the nose, pressure on theknuckles or other bones) whether the cause ofcoma is structural or metabolic. Withdrawal ofthe limb from the stimulus usually means thatthe pyramidal pathway for the affected limb isintact. Stereotyped flexion or extension move-ments are usually seen in patients with severedamage to the pyramidal tract.Brain stem reflexes (p. 26). Structural lesions ofthe brain stem usually impair the function of theinternal and external eye muscles (p. 70 ff),while supratentorial lesions generally do not,unless they secondarily affect the brain stem.Coma in a patient with intact brain stem reflexesis likely to be due to severe bihemispheric dys-function (if no further objective deficit is found,coma may be psychogenic or factitious; seep. 120). Physicians should be aware that comadue to intoxication or drug overdose (p. 92) maybe difficult to distinguish from that due to struc-tural damage by clinical examination alone. Pre-servation of the vestibulo-ocular reflex (VOR)and of the doll’s eyes reflex is compatible witheither a bihemispheric lesion or a toxic or me-tabolic disorder. The VOR induces conjugate eyemovement only if its brain stem pathway is in-tact (from the cervical spinal cord to the oculo-motor nucleus). Nonetheless, the VOR may beabsent in some cases of toxic coma (due to, e. g.,alcohol, barbiturates, phenytoin, pancuronium,or tricyclic antidepressants).Abnormalities of the respiratory pattern (p. 151)are of limited localizing value. Cheyne–Stokesrespiration is characterized by regular waxingand waning of the tidal volume, punctuated byapneic pauses. It has a number of causes, includ-ing bihemispheric lesions and metabolic dis-orders. Slow, shallow respiration usually reflectsa metabolic or toxic disorder. Rapid, deep respi-ration (Kussmaul’s respiration) usually reflects apontine or mid brain lesion, or metabolic acido-sis. Medullary lesions and extensive supraten-torial damage produce ataxic, cluster, or gaspingrespiration.

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Comalike Syndromes

Locked-in syndrome (p. 359) is a “de-efferentedstate” in which the patient is fully conscious butcanmake no spontaneousmovements except lidand vertical eye movements. There may be re-flex extension of the arms and legs in responseto mild stimuli such as repositioning in bed ortracheal suction. Physicians and nurses must re-member that these patients can perceive them-selves and their surroundings fully even thoughthey may be unable to communicate. Possiblecauses include basilar artery occlusion, headtrauma, pontine hemorrhage, central pontinemyelinolysis, and brain stem encephalitis; asimilar clinical picture may be produced by my-asthenia gravis, Guillain–Barré syndrome, or pe-riodic paralysis (see pp. 326, 338).Persistent vegetative state (apallic syndrome) iscaused by extensive injury to the cerebral cor-tex, subcortical white matter, or thalamus. Thepatients are awake but unconscious (loss of cor-tical function). Periods in which the eyes areopen and move spontaneously, in conjugatefashion, seemingly with fixation, alternate witha state resembling sleep (eyes closed, regularbreathing). The patient may blink in response tovisual stimuli (rapid hand movements, light),perhaps creating the impression of consciousperception, but does not obey verbal com-mands. The limbs may be held in a decorticateor decerebrate posture (p. 46). There may benondirected movements of the arms, legs, head,and jaw, as well as utterances, sucking move-ments, and lip-licking. The patient may alsoyawn spontaneously or in response to perioralstimuli. Autonomic disturbances include pro-fuse sweating, tachycardia, urinary and fecal in-continence, and hyperventilation. Optokineticnystagmus is absent, but the vestibulo-ocularreflex can often be elicited. Spontaneous respi-ration is preserved. Swallowing is usuallypossible, but food is kept in the mouth so longthan no effective oral nutrition is possible. Thepersistent vegetative state confers a high mor-tality. When it lasts for more than a year, im-provement is unlikely.Akineticmutism. In this syndrome, the patient isawake but the drive to voluntary movement isseverely impaired and the patient does not speak(mutism). External stimuli evoke no more thanbrief ocular fixation without head movement.

Possible causes include bifrontal lesions, hydro-cephalus, and lesions of the cingulate gyrus or inthe third ventricular region. One should keep inmind that other diseases, among them Guillain–Barré syndrome, amyotrophic lateral sclerosis,periodic paralysis, and myasthenia gravis, canpresent with akinetic mutism or with a similarbut less severe syndrome called abulia (reduceddrive, sluggish voluntary movements, reducedverbal response).Psychogenic disturbances of consciousness arerelatively rare and difficult to diagnose. The lackof arousability can be either an expression of apsychiatricdisease (conversionoracutestress re-action, severe depression, catatonic stupor) or adeliberate fabrication. Clues are sometimesfound in the case history or on neurological ex-amination (e. g., presence of aversive reflexes, ac-tive eye closing, preserved optokinetic and vesti-bulo-ocular nystagmus, catalepsy, stereotypedposture).

Death

Death is medically and legally defined as thetotal and irreversible cessation of all brain func-tion (hence the synonymous term, “braindeath”). Spontaneous respiration (a function ofthe brain stem) is absent, though the heart maycontinue beating and other organs may stillfunction if supportive measures are maintained(ventilation, pressor medications). All organsystems cease to function when these are dis-continued.The clinical determination of death is based onthe following criteria: coma; lack of spon-taneous respiration (apnea test); lack of re-sponse to noxious stimuli (with the possible ex-ception of spinal reflexes); absence of brainstem reflexes (pupillary, corneal, cough, gag,and oculovestibular reflexes). The diagnosis ofdeath requires the exclusion of possibly similar-appearing states such as toxic, metabolic, andendocrine disorders, pharmacological relaxa-tion and sedation, and hypothermia. Majorstructural damage of the brain is present in allcases (though not necessarily demonstrable onall imaging studies). Ancillary diagnostic testing(EEG, Doppler sonography, evoked potentials,perfusion scintigraphy, cerebral angiography,MRI) may support the diagnosis but is generallynot legally required (Table 11, p. 364).

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Apallic syndrome(persistent vegetative state)

Lesion causing apallic syndromeLesion causing locked-in syndrome

Bifrontal lesion (causing akinetic mutism)

Lesion causing death (totalabsence of brain function)

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Personality is the set of physical and psychologi-cal traits that distinguish one individual fromanother. It evolves over time under the influenceof changes in brain function, as well as other in-ternal and external factors. These include neuro-biological factors (heredity, structure and func-tion of the nervous system), physiological fac-tors (endocrine, metabolic), socialization (for-mation of language, thought, emotion, and ac-tion according to societal norms and value sys-tems), individualization (consciousness of one’sown individuality), sexuality, temperament, in-telligence, life experiences, education, economicstatus, and individual will. Changes in personal-ity cause gradual or abrupt changes in behavior.Some neurological diseases produce behavioralchanges; the clinical picture depends mainly onthe location of the disturbance.

Frontal Lobe Lesions

The frontal lobe includes the motor cortex(areas 4, 6, 8, 44), the prefrontal cortex (areas9–12 and 45–47), and the cingulate gyrus(p. 144). It is responsible for the planning, moni-toring, and performance of motor, cognitive,and emotional functions (executive functions).Frontal lobe syndromes may be due to eithercortical or subcortical damage and thus cannotbe reliably localized without neuroimaging. Thetypical syndromes listed here are useful forclassification but do not imply a specific diag-nosis or exact localization of the underlying le-sion.Lateralized syndromes. Left frontal lobe lesions,depending on their location and extent, can pro-duce right hemiparesis or hemiplegia, transcor-tical motor aphasia and diminished verbal out-put (p. 126), buccofacial apraxia (p. 128), and/ordepression or anxiety. Right frontal lobe lesionscan produce left hemiparesis or hemiplegia, lefthemineglect (p. 132), mania, and/or increasedpsychomotor activity.Nonlateralized syndromes. Fronto-orbital lesionsproduce increased drive, memory impairmentwith confabulation, and disorientation. Disinhi-bition and impaired insight into one’s own be-havior may produce abnormal facetiousness(German Witzelsucht), abnormal social behavior(loss of distance, sexual impulsiveness), in-difference, or carelessness.

Lesions of the cingulate gyrus and premotor cor-tex produce syndromes ranging from abulia(loss of drive) to akinetic mutism (p. 120) andgenerally characterized by apathy, loss of inter-est, inertia, loss of initiative, decreased sexualactivity, loss of emotion, and loss of planningability. Urinary and fecal incontinence occur be-cause of the loss of (cortical) perception of theurge to urinate and defecate. Altered voidingfrequency or sudden voiding is the result.These patients are usually impaired in theircapacity for divided attention (the processing ofnew information and adaptation to altered re-quirements, i.e., flexibility) and for directed at-tention (selective attention to a particular thingor task). Their attention span is short, they areeasily distracted, they have difficulty in the ex-ecution of motor sequences, and they tend toperseverate (to persist in a particular activity orthought). Increased distractibility and pro-longed reaction times impair performance inthe workplace and in everyday activities such asdriving.Lesions of pathways. Lesions in pathways con-necting the frontal lobe to other cortical andsubcortical areas (p. 24) can produce frontallobe-type syndromes, as can other diseases in-cluding multisystem atrophy, Parkinson disease,Alzheimer disease, normal-pressure hydro-cephalus, and progressive supranuclear palsy.Lesions of the corpus callosum. See p. 24.

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Abulia Concentration and attentiondeficits

Anxiety, misperceptions

Defensiveness, irritability,psychomotor agitation

Pathological crying and laughing

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Language is a means of transmitting and pro-cessing information, organizing sensory percep-tions, and expressing thoughts, feelings, and in-tentions. The content of language encompassesthe past, present, and future. The developmentof language does not necessarily require speechand audition: deaf-mutes learn to communicatewith sign language. Language is most easily ac-quired in childhood. Linguistic messages aretransmitted and received through speaking andhearing, writing and reading, or (in the case ofsign language) the production and interpreta-tion of gestures. The cerebral language areas arelocated in the left hemisphere in over 90% ofright-handers and in 60% of left-handers; theremaining individuals have bihemispheric or (in1–2%) exclusively right-hemispheric domi-nance for language. The left (dominant) hemi-sphere is responsible for the cognitive pro-cessing of language, while the right (nondomi-nant) hemisphere produces and recognizes theemotional components of language (prosody =emphasis, rhythm, melody). Language is sub-served by subcortical nuclei as well (leftthalamus, left caudate nucleus, associated fiberpathways). Language function depends on thewell-coordinated activity of an extensive neuralnetwork in the left hemisphere. It is simplistic tosuppose that language is understood and pro-duced by means of a unidirectional flow of in-formation through a chain of independentlyoperating brain areas linked together in series.Rather, it has been shown that any particularlinguistic function (such as reading, hearing, orspeaking) relies on the simultaneous activationof multiple, disparate cortical areas. Yet thesimplified model of language outlined below(proposed by Wernicke and further elaboratedby Geschwind) usually suffices for the purposesof clinical diagnosis.Hearing and speaking. Acoustic signals aretransduced in the inner ear into neural impulsesin the cochlear nerve, which ascend through theauditory pathway and its relay stations to theprimary and secondary auditory cortex (p. 100).From here, the information is sent to Wernicke’sarea (the “posterior language area”), consistingof Wernicke’s area proper, in the superior tem-poral gyrus (Brodmann area 22), as well as theangular and supramarginal gyri (areas 39, 40).The angular gyrus processes auditory, visual,

and tactile information, while Wernicke’s areaproper is the center for the understanding oflanguage. It is from here that the arcuatefasciculus arises, the fiber tract that conveys lin-guistic information onward to Broca’s area(areas 44 and 45; the “anterior language area”).Grammatical structures and articulation pro-grams are represented in Broca’s area, whichsends its output to the motor cortex (speech,p. 130). Spoken language is regulated by anauditory feedback circuit in which the uttererhears his or her own words and the cortical lan-guage areas modulate the speech output ac-cordingly.Reading and writing. The visual pathway con-veys visual information to the primary and sec-ondary visual cortex (p. 80), which, in turn, pro-ject to the angular gyrus and Wernicke’s area, inwhich visually acquired words are understood,perhaps after a prior “conversion” to phoneticform. Wernicke’s area then projects via the ar-cuate fasciculus to Broca’s area, as discussedabove; Broca’s area sends its output to themotorcortex (for speech or, perhaps, to the motorhand area for writing). This pathway enables therecognition and comprehension of written lan-guage, as well as reading out loud.Examination. The clinical examination of lan-guage includes spontaneous speech, naming ofobjects, speech comprehension, speech repeti-tion, reading, and writing. The detailed assess-ment of aphasia requires the use of test instru-ments such as the Aachen aphasia test, perhapsin collaboration with neuropsychologists andspeech therapists. Disturbances of speech maybe classified as fluent or nonfluent. Examples ofthe former are paragrammatism (faulty sen-tence structure), meaningless phrases, circum-locution, semantic paraphasia (contextual sub-stitution, e. g., “leg” for “arm”), phonemic para-phasia (substitution of one letter for another,e. g., “tan” for “can”), neologisms (nonexistentwords), and fluent gibberish (jargon). Examplesof the latter are agrammatism (word chainswithout grammatical structure), echolalia (re-petition of heard words), and automatism (re-peating the same word many times). Prosodyand dysarthria (if present; p. 130) are evaluatedduring spontaneous speech. Anomia is the ina-bility to name objects. Patients with aphemiacan read, write, and understand spoken lan-guage but cannot speak.

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Hearing spoken language

Reading written language

Precentral gyrus Angular gyrus

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Aphasia is an acquired disturbance of language.Lesions at various sites produce different typesof aphasia; focal lesions do not cause total loss ofall language functions simultaneously. The sideof cerebral dominance for language can be de-termined by the Wada test (intracarotidamobarbital procedure, IAP), in which amobar-bital is injected first into one internal carotidartery and then into the other, under angio-graphic control, to selectively anesthetize eachhemisphere (this is done, for example, beforecortical resections for epilepsy). Crossedaphasia, i.e., aphasia due to a right hemisphericlesion in a right-handed patient, is rare. Aphasiausually improves markedly within a few weeksof onset and may continue to improve graduallyover the first year, even if the symptoms tem-porarily appear to have stabilized. Improvementbeyond one year is rare and usually minor.Aphasia in bilingual and multilingual persons(usually) affects all of the languages spoken. Theseverity of involvement of each language de-pends on the age at which it was acquired, pre-morbid language ability, and whether the lan-guages were learned simultaneously or sequen-tiallly. Aphasia is most commonly due to strokeor head trauma and may be accompanied byapraxia.Global aphasia involves all aspects of languageand severely impairs spoken communication.The patient cannot speak spontaneously or canonly do so with great effort, producing no morethan fragments ofwords. Speech comprehensionis usually absent; at best, patientsmay recognizea few words, including their own name. Per-severation (persistent repetition of a singleword/subject) and neologisms are prominent,and the ability to repeat heardwords ismarkedlyimpaired. Patients have great difficulty namingobjects, reading, writing, and copying letters orwords. Their ability to name objects, read, andwrite, except for the ability to copy letters of thealphabet or isolated words, is greatly impaired.Language automatism (repetition of gibberish) isa characteristic feature. Site of lesion: Entire dis-tribution of themiddle cerebral artery, includingboth Broca’s and Wernicke’s areas.Broca’s aphasia (also called anterior, motor, orexpressive aphasia) is characterized by the ab-sence or severe impairment of spontaneousspeech, while comprehension is only mildly im-

paired. The patient can speak only with great ef-fort, producing only faltering, nonfluent, garbledwords. Phonemic paraphasic errors are made,and sentences are of simple construction, oftenwith isolated words that are not grammaticallylinked (agrammatism, “telegraphic” speech).Naming, repetition, readingout loud, andwritingare also impaired. Site of lesion: Broca area; maybe due to infarction in the distribution of the pre-rolandic artery (artery of the precentral sulcus).Wernicke’s aphasia (also called posterior,sensory, or receptive aphasia) is characterizedby severe impairment of comprehension. Spon-taneous speech remains fluent and normallypaced, but paragrammatism, paraphasia, andneologisms make the patient’s speech partiallyor totally incomprehensible (word salad, jargonaphasia). Naming, repetition of heard words,reading, and writing are also markedly im-paired. Site of lesion: Wernicke’s area (area 22).May be due to infarction in the distribution ofthe posterior temporal artery.Transcortical aphasia. Heard words can be re-peated, but other linguistic functions are im-paired: spontaneous speech in transcorticalmotor aphasia (syndrome similar to Broca’saphasia), language comprehension in transcor-tical sensory aphasia (syndrome similar to Wer-nicke’s aphasia). Site of lesion: Motor type, leftfrontal lobe bordering on Broca’s area; sensorytype, left temporo-occipital junction dorsal toWernicke’s area. Watershed infarction is themost common cause (p. 172).Amnestic (anomic) aphasia. This type of aphasiais characterized by impaired naming and word-finding. Spontaneous speech is fluent but per-meated with word-finding difficulty and para-phrasing. The ability to repeat, comprehend, andwrite words is essentially normal. Site of lesion:Temporoparietal cortex or subcortical whitematter.Conduction aphasia. Repetition is severely im-paired; fluent, spontaneous speech is inter-rupted by pauses to search for words and byphonemic paraphasia. Language comprehen-sion is only mildly impaired. Site of lesion: Ar-cuate fasciculus or insular region.Subcortical aphasia. Types of aphasia similar tothose described may be produced by subcorticallesions at various sites (thalamus, internal cap-sule, anterior striatum).

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Broca’s aphasia

Wernicke’s aphasia (phonemic paraphasias)

Global aphasia

Transcortical (sensory) aphasia

How did the problem begin?




About one, ... three... days ... sofa ...sleep, uh, wife came... doctor ... uh ... shot ...

Posterior temporal a.

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gyrus

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Facial area in sensory cortexSupramarginalgyrus

Angulargyrus

Middle cerebral a.

It wistullenly towhere show com-mances beside gavethe bename ... we’llhave a mook...

Well, uh, well,like ... umm, so ... like ...

How, how, how ...well, started ... believe to that, tosay ... a start at the beginning ...

Areas 44, 45

Prerolandic branch of middle cerebral a.

Area 22

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Agraphia. Agraphia is the acquired inability towrite. Agraphia may be isolated (due to a lesionlocated in area 6, the superior parietal lobule, orelsewhere) or accompanied by other distur-bances: aphasic agraphia is fluent or nonfluent,depending on the accompanying aphasia;apraxic agraphia is due to a lesion of the domi-nant parietal lobe; spatial agraphia, in which thepatient has difficulty writing on a line and onlywrites on the right side of the paper, is due to alesion of the nondominant parietal lobe; alexiawith agraphia may be seen in the absence ofaphasia. Micrographia (abnormally small hand-writing) is found in Parkinson disease (p. 206)and is not pathogenetically related to agraphia.Various forms of agraphia are common inAlzheimer disease. Examination: The patient isasked to write sentences, long words, or seriesof numbers to dictation, to spell words, and tocopy written words.Alexia. Alexia is the acquired inability to read. Inisolated alexia (alexia without agraphia), thepatient cannot recognize entire words or readthem quickly, but can decipher them letter byletter, and can understand verbally spelledwords. The ability to write is unaffected. The re-sponsible lesion is typically in the left temporo-occipital region with involvement of the visualpathway and of callosal fibers. Anterior alexia(difficulty and errors in reading aloud; impairedability to write, spell, and copy words) is usuallyassociated with Broca’s aphasia. Central alexia(combination of alexia and agraphia) is usuallyaccompanied by right-left disorientation, fingeragnosia, agraphia, and acalculia (Gerstmannsyndrome; lesions of the angular and supra-marginal gyri), or by Wernicke’s aphasia. Otherfeatures include the inability to understandwritten language or to spell, write, or copywords. Examination: The patient is asked to readaloud and to read individual words, letters, andnumbers; the understanding of spelled wordsand instructions is tested.Acalculia. Acalculia is an acquired inability touse numbers or perform simple arithmeticalcalculations. Patients have difficulty countingchange, using a thermometer, or filling out acheck. Lesions of various types may cause acal-culia. Examination: The patient is asked to per-form simple arithmetical calculations and toread numbers.

Apraxia. There are several kinds of apraxia; ingeneral, the term refers to the inability to carryout learned motor tasks or purposeful move-ments. Apraxia is often accompanied byaphasia.Ideomotor apraxia involves the faulty execution(parapraxia) of acquired voluntary and complexmovement sequences; it can be demonstratedmost clearly by asking the patient to performpantomimic gestures. It can involve the face(buccofacial apraxia) or the limbs (limb apraxia).It is due to a lesion in the association fiber path-ways connecting the language, visual, andmotor areas to each other and to the two hemi-spheres (disconnection syndrome). Examination(pantomimic gestures on command): face (openeyes, stick out tongue, lick lips, blow out amatch, pucker, suck on a straw); arms (turn ascrew, cut paper, throw ball, comb hair, brushteeth, snap fingers); legs (kick ball, stamp outcigarette, climb stairs). The patient may performthe movement in incorrect sequence, or maycarry out a movement of the wrong type (e. g.,puffing instead of sucking).Ideational apraxia is impairment of the ability tocarry out complex, learned, goal-directed activi-ties in proper logical sequence. A temporal orparietal lesion may be responsible. Examination:The patient is asked to carry out pantomimicgestures such as opening a letter, making asandwich, or preparing a cup of tea.Apraxia-like syndromes. The following distur-bances are termed “apraxia” even though actualparapraxia is absent: Lid-opening apraxia (p. 64)is difficulty opening the eyes on command. Gaitapraxia is characterized by difficulty initiatinggait and by short steps (p. 160). Dressing apraxiais often seen in patients with nondominantparietal lobe lesions. They cannot dress them-selves and do not know how to position a shirt,shoes, trousers, or other items of clothing to putthem on correctly. An underlying impairment ofspatial orientation is responsible.

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Sites of lesions causing agraphia Topography of lesions in alexia

Sites of lesions causing acalculia

Ideomotor apraxia

Dressing apraxia Lid-opening apraxia

Central alexiaAnterior alexia

Numericalalexia/agraphia,anarithmia

Agraphia, Alexia, Acalculia, Apraxia

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Speech

The neural basis of speech. Speech-relatedmovement programs generated in the premotorcortex (area 6) are modulated by informationfrom the cerebellum and basal ganglia and arerelayed to the motor cortex (inferior portion ofthe precentral gyrus, area 4) for implementa-tion. The motor cortex projects by way of thecorticopontine and corticobulbar tracts to themotor cranial nerve nuclei in the brain stem. CNV (mandibular nerve) controls the muscles thatopen and close the jaw (masseter, temporalis,medial and lateral pterygoid muscles). CN VIIcontrols facial expression and labial articula-tion; CN X and, to a lesser extent, IX controlmotility of the soft palate, pharynx, and larynx;CN XII controls tongue movement. Speech-re-lated impulses to the respiratory muscles travel(among other pathways) from the motor cortexto the spinal anterior horn cells. Connections tothe basal ganglia and cerebellum are importantfor the coordination of speech. Sensory impulsesfrom the skin, mucous membranes, and musclesreturn to the brain through CN V (maxillary andmandibular nerves), IX, and X. These impulsesare processed by a neural network (reticular for-mation, thalamus, precentral cortex) mediatingfeedback control of speech. The central innerva-tion of the speech pathway is predominantly bi-lateral; thus, dysarthria due to unilateral lesionsis usually transient.Voice production (phonation). Voice produc-tion by the larynx (phonation) through the vi-brating vocal folds (cords) yields sound at afundamental frequency with a varying admix-ture of higher-frequency components, whichlend the voice its timbre (musical quality);timbre depends on the resonant cavities abovethe vocal folds (pharynx, oral cavity, nasal cav-ity). The volume of the voice is regulated bystretching and relaxation of the vocal folds andby adjustment of air pressure in the larynx.The air flow necessary for phonation is pro-duced in the respiratory tract (diaphragm,lungs, chest, and trachea). The individual struc-tural characteristics of the larynx, particularlythe length of the vocal folds, determine thepitch of a person’s voice. A whisper is producedwhen the vocal folds are closely apposed anddo not vibrate.

Creation of the sounds of speech (articulation).The sounds of speech are created by changingthe configuration of the physiological resonancespaces and articulation zones. The resonancespaces can be altered bymovement of the velum(which separates the oral and pharyngeal cavi-ties) and tongue (which divides the oral cavity).Each vowel (a, e, i, o, u) is associated with aspecific partitioning of the oral cavity by thetongue. The palate, teeth, and lips are the articu-lation zones with which consonants are pro-duced (g, s, b, etc.).

Dysarthria, Dysphonia

Dysarthria (impaired articulation) and dys-phonia (impaired phonation and resonance) re-sult from a disturbance of the neural controlmechanism for speech (sensory portion, motorportion, or both). Diagnostic assessment re-quires both analysis of the patient’s vocal output(breathing, phonation, resonance, articulation;speed, coordination, and prosody of speech) andthe determination of any associated neurologi-cal findings (e. g. dysphagia, hyperkinesia,cranial nerve deficits). For responsible lesionsand syndromes, see Table 12 (p. 365).

Speech Disorders

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131Neural control of speech (afferent fibers are green)

Motor cortex

Corticobulbarfibers

Basal ganglia

Trigeminal n.(fibers to

muscles of mastication)

Facial n.

Vagus n.

Glossopharyngeal n.

Hypoglossal n.

Cerebellum

Recurrent laryngeal n. (passesaround subclavian a. on right,

around aortic arch on left)

Thalamocortical projections

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Agnosia is defined as a disturbance of recogni-tion in which perception, attention, and generalintelligence are (largely) unimpaired.

Disturbances of Body Image Perception

Autotopagnosia (body-image agnosia) is the ina-bility to correctly orient or perceive differentbody parts; patients cannot obey commands topoint to parts of their own or the examiner’sbody (e. g., foot, hand, nose). The responsible le-sion is usually, though not always, in the tem-poroparietal region (angular and supramarginalgyri). An aphasic patient may appear to have au-totopagnosia because he cannot understandverbal instructions, but aphasia may also coexistwith true autotopagnosia. Finger agnosia is theinability to identify, name, or point to fingers.These patients cannot mimic the examiner’s fin-ger movements or copy finger movements oftheir own contralateral hidden handwith the af-fected hand. Right–left disorientation is the ina-bility to distinguish the right and left sides ofone’s own or another’s body; these patients can-not obey a command to raise their left hand ortouch it to their right ear. This type of disorien-tation can cause dressing apraxia (p. 128) andsimilar problems.Anosognosia is the unawareness or denial of aneurological deficit, such as hemiplegia.Patients may claim that they only want to givethe paralyzed side a rest, or attempt to demon-strate that their condition has improvedwithout realizing that they are moving the limbon the unaffected side. Most such patients haveextensive lesions of the nondominant hemi-sphere. Anosognosia may also accompany visualfield defects due to unilateral or bilateral lesionsof the visual cortex (homonymous hemianopsia,cortical blindness). The most striking exampleof this is Anton syndrome, in which corticallyblind patients act as if they could see, and willeven “describe” details of their surroundings(incorrectly) without hesitation.

Disturbances of Spatial Orientation

A number of different types of agnosia impairthe awareness of one’s position relative to thesurroundings, i.e., spatial orientation. Parieto-occipital lesions are commonly responsible.

Constructional apraxia is characterized by theinability to represent spatial relationships indrawings, or with building blocks. Affectedpatients cannot copy a picture of a bicycle orclock. Everyday activities are impaired by the in-ability to draw diagrams, read (analog) clocks,assemble pieces of equipment or tools, or writewords in the correct order (spatial agraphia).Hemineglect is the inability to consciously per-ceive, react to, or classify stimuli on one side inthe absence of a sensorimotor deficit or exceed-ing what one would expect from the severity ofthe sensorimotor deficit present. Hemineglectmay involve unawareness of one side of thebody (one-sided tooth brushing, shaving, etc.) orof one side of an object (food may be eaten fromonly one side of the plate, eyeglasses may belooked for on only one side of the room). Whenaddressed, the patient always turns to thehealthy side. Neurological examination revealsthat double simultaneous stimulation (touch,finger movement) of homologous body parts(same site, e. g., face or arm) is not felt on the af-fected side (extinction phenomenon). In addition,perception of stimuli on the affected side isquantitatively lower than on the healthy side,there is limb akinesia despite normal strengthon the side of the lesion, and spatial orientationis impaired (e. g., the patient copies only half of aclock-face).

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133Hemispatial neglect (left side)

Hemispatial neglect(left side)

(task was to draw a clockface and set itto “quarter past 12”)

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Memory

Memory involves the acquisition, storage, recall,and reproduction of information. Memory de-pends on intact functioning of the limbic system(p. 144) and areas of the brain that are con-nected to it.Declarative or explicit memory (i.e., memory forfacts and events) can be consciously accessedand depends on intact functioning of themedio-basal portion of the temporal lobe. The durationof information storage may be relatively short(short-term, immediate, and working memory)or long (long-term memory). Verbal (telephonenumber) or visuospatial information (how tofind a street) can be directly recalled from short-term memory. The entorhinal cortex plays a keyrole in these memory functions: all informationfrom cortical regions (frontal, temporal,parietal) travels first to the entorhinal cortexand then, by way of the parahippocampal andperirhinal cortex, to the hippocampus. There isalso a reciprocal projection from the hippocam-pus back to the entorhinal cortex. Long-termmemory stores events of personal history thatoccurred at particular times (episodic memoryfor a conversation, one’s wedding day, last year’sholiday; orbitofrontal cortex) as well as concep-tual, non–time-related knowledge (semanticmemory for the capital of Spain, the number ofcentimeters in a meter, the meaning of the word“stethoscope”; subserved by different corticalregions).Nondeclarative (procedural, implicit) memory, onthe other hand, cannot be consciously accessed.Learned motor programs (riding a bicycle,swimming, playing the piano), problem-solving(rules), recognition of information acquired ear-lier (priming), and conditioned learning (avoid-ing a hot burner on the stove, sitting still inschool) belong to this category. Nondeclarativememory is mediated by the basal ganglia (motorfunction), neocortex (priming), cerebellum(conditioning), striatum (agility), amygdala(emotional responses), and reflex pathways.Examination. Only disturbances of declarativememory (amnesia) can be studied by clinical ex-amination. Short-term memory: the acquisitionof new information is tested by having thepatient repeat a series of numbers or groups ofwords and asking for this information again

5–10 minutes later. The patient’s orientation(name, place of residence/address, time/date)and long-term memory (place of birth, educa-tion, place of employment, family, generalknowledge) are also tested by directedquestioning.

Memory Disorders (Amnesia)

Forgetfulness. Verbal memory does not declineuntil approximately age 60, and even then onlygradually, if at all. Aging is, however, often ac-companied by an evident decline in informationprocessing ability and attention span (benignsenescent forgetfulness). These changes occurnormally, yet to a degree that varies highlyamong individuals, and they are often barelymeasurable. They are far less severe than full-blown dementia, but they may be difficult todistinguish from incipient dementia.Amnesia. Anterograde amnesia is the inability toacquire (declarative) information, for later re-call, from a particular moment onward; retro-grade amnesia is the inability to remember (de-clarative) information acquired before a particu-lar moment (p. 269). Amnestic patients com-monly confabulate (i.e., fill in gaps in memorywith fabricated, often implausible information);they may be disoriented and lack awareness oftheir own memory disorder. For individualsymptoms and their causes, see Table 13(p. 365).

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Explicit memory*

*Model

Temporal cortical representation

Word recollection/recognition(“verbal memory”)

Spatial perception andorientation; recognition of familiar faces (“visuospatial memory”)

Anterior thalamicnuclei

Medial thalamic nuclei

StructureOrbitofrontal cortexEntorhinal areaAmygdalaHippocampusMamillary body/diencephalonRAS

Intralaminarnuclei

Amygdala

Entorhinal region

Orbito-frontal cortex

Septal nuclei Mamillary

body

Reticular activatingsystem (RAS)

Limbic systemInner ringOuter ring (Papez circuit)Medial forebrain bundle

Fornix

Mamillothalamic tract

Basal ganglia

Thalamus

Premotor cortex

Substantia nigra,nigrostriatal projection

Cortical projections to the basal

ganglia

Hippocampus,parahippocampalgyrus

Cerebellarprojections

Thalamocorticalprojection

Function*Activation, drive, long-term memoryVisual memory, recognitionEmotional memorySpatial memory, spatial orientationLong-term memory, insight, flexibilityActivation

Implicit memory*

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Dementia is a newly occurring, persistent, andprogressive loss of cognitive function. Bothshort-term and long-term memory are im-paired, in conjunction with at least one of thefollowing disorders: aphasia, apraxia, agnosia,or impairment of abstract thinking, decision-making ability, visuospatial performance,planned action, or personality. Professional, so-cial and interpersonal relationships deteriorate,and the sufferer finds it increasingly difficult tocope with everyday life without help. The diag-nosis of dementia requires the exclusion of dis-turbances of consciousness (e. g., delirium) andof psychiatric disease (e. g., depression, schizo-phrenia). The differential diagnosis also in-cludes benign senescent forgetfulness (“normalaging,” in which daily functioning is unim-paired) and amnestic disorders. Approximately90% of all cases of dementia are caused byAlzheimer disease (p. 297) or cerebrovasculardisorders; diverse etiologies account for therest. The physician confronted with a case of in-cipient dementia must distinguish primarydementia from that secondary to another dis-ease (Table 14, p. 366). The objective is earlydetermination of the etiology of dementia,especially when these are treatable or rever-sible.Examination. The patient or another informantshould be asked for an account of the duration,type, and extent of problems that arise in every-

day life. The clinical examination is used toascertain the type and severity of cognitive defi-cits and any potential underlying disease. Stand-ardized examining instruments are useful forprecise documentation and differentiation ofthe cognitive deficits. Rapid tests for dementia,such as the Mini-Mental Status Examination,mini-syndrome test, and clock/numbers test,are useful for screening. Function-specific neu-rophysiological tests permit diagnostic assess-ment of individual aspects of cognition includ-ing orientation, attention, concentration,memory, speech, and visual constructive per-formance. Laboratory tests (ESR1, differentialblood count, electrolytes, liver function tests,BUN2, creatinine, glucose, vitamin B12, folic acid,TPHA3, TSH4, and HIV5), EEG, and diagnostic im-aging techniques (CT6, MRI7, SPECT8, and PET9)provide further useful information for classifica-tion and determination of the cause of demen-tia. None of these diagnostic techniques alonecan pinpoint the etiology of dementia; definitivediagnosis practically always requires multipletests and examinations. Diagnostic imaging is ofparticular importance in patients with the sub-acute onset of cognitive impairment or amnesia(!1 month), fluctuation or acute worsening ofsymptoms, papilledema, visual field defects,headaches, a recent head injury, known malig-nancies, epilepsy, a history of stroke, urinary in-continence, or an abnormal gait.

1ESR Erythrocyte sedimentation rate2BUN Blood urea nitrogen3TPHA Treponema pallidum hemagglutination test4TSH Thyroid-stimulating hormone5HIV Human immunodeficiency virus6CT Computerized tomography7MRI Magnetic resonance imaging8SPECT Single photon emission computerized tomography9PET Positron emission tomographyAdditional diagnostic tests to be performed as needed: Coagulation profile, serum protein electrophoresis, serum am-monia, parathyroid hormone, cortisol, rheumatoid factor, antinuclear antibodies, blood alcohol, serum/urine druglevels, copper/ceruloplasmin, lactate/pyruvate, hexosaminidase, CSF tests, molecular genetic analysis.

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Personality change

Loss of social and occupational skills

Loss of cognitive function

Personality change, cognitive impairment

Impairment of other higher cortical functions (abstraction, judgment,arithmetic, aphasia, apraxia,agnosia, attention)

Memory impairment(short- and long-termmemory)

Model drawing

Modeldrawing

Patient’s copy

Patient’s copy

Clock face (patient’s drawing)

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Patients with symptoms and signs that are un-usual, difficult to classify, or resistant to treat-ment are often referred to a neurologist for a de-termination whether the patient’s problem is“organic” or “psychogenic.” Many such patientsmake a diagnostic and therapeutic odyssey fromone medical or paramedical office to another,and have a long list of positive findings to showfor it. In other patients, symptoms and signsmay arise acutely or subacutely, perhaps in re-peated episodes, creating the impression of a se-rious illness. The physician’s primary objectivesmust be (1) to identify the possible physical orpsychosocial causes of the problem, and at thesame time (2) to avoid unnecessary or danger-ous diagnostic tests. A correct diagnosis requirestime, solid knowledge of the relevant anatomyand physiology, and the ability to recognize thepsychosocial dynamics that may have given riseto the patient’s complaints.If detailed neurological examination reveals noabnormality and the symptoms cannot be at-tributed to any neurological disease, the physi-cian should consider potential psychosocialcauses. These may be unconscious (e. g., an innerconflict of which the patient is unaware) or con-scious (e. g., a deliberate attempt to acquire thefinancial benefits and increased attention as-sociated with illness). The underlying causemaybe an unresolved social conflict (familial, pro-fessional, financial) or some other mental dis-order (depression, anxiety, obsessive-compul-sive disorder, personality disorder). Organicdysfunction and objective signs of illness aredisproportionately mild in relation to thepatient’s complaints, unrelated to them, or en-tirely absent.Conversion disorders (previously termed “con-version hysteria”) often present with a single(pseudoneurological) symptom, such as psycho-genic amnesia, stupor, mutism, seizures, paraly-sis, blindness, or sensory loss. It has beentheorized that such symptoms serve to resolveunconscious inner conflicts. The diagnosis maybe particularly difficult to make in patients whosimultaneously suffer from organic neurologicalor psychiatric disease (e. g., hyperventilation inepilepsy, headaches in depression, paralysis inmultiple sclerosis).Somatoform disorders, according to currentpsychiatric terminology, are mental disorders

characterized by “repeated presentation ofphysical symptoms, together with persistent re-quests for medical investigations, in spite of re-peated negative findings and reassurances bydoctors that the symptoms have no physicalbasis” (ICD-10, WHO, 1992). In somatization dis-order, the patient asks for treatment of multiple,recurrent, and frequently changing symptoms,which often affect multiple organ systems (e. g.headaches + bladder dysfunction + leg pains +breathing disorder). In hypochondriacal disorder(previously termed “hypochondriasis”), thepatient is less concerned about the symptomsthemselves, and more preoccupied with thesupposed presence of a serious disease. Thefears persist despite repeated, thorough exami-nation, normal test results, and medical reas-surance. Any mild abnormalities that may hap-pen to be found, e. g. of heartbeat, respiration, orintestinal function, or skin changes, onlyamplify the patient’s anxiety. Persistent soma-toform pain disorder involves complaints of“persistent, severe, and distressing pain, whichcannot be explained fully by a physiologicalprocess or a physical disorder” (ICD-10), thoughan organic cause of pain is often present as well.The physical impairment that the patient at-tributes to pain may actually be due to a lack offulfillment in familial, professional, or social re-lationships. For these patients, dealing with thepain may become the major “purpose in life.”Malingering is not a mental disorder, but ratherthe deliberate, premeditated feigning of illnessto achieve a goal (e. g., feigning of headaches toobtain opiates).Simulated or intentionally induced (factitious)symptoms may serve no clear purpose (neitherthe resolution of an unconscious conflict, norany obvious kind of gain); they may be presentin the simulator (Münchhausen syndrome) or ina child or other person under their care (Münch-hausen-by-proxy). The peregrinating patient(hospital hopper) demands diagnostic tests fromone physician after another, but negative test re-sults can never put the patient’s fears to rest.Patients with Ganser syndrome give approxi-mate or fatuous answers to simple questions,possibly creating the impression of dementia.

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Depression and anxiety (may give rise to pseudoneurological complaints)

Persistent somatoform pain disorder

Factitious gait disturbance Hypochondriacal disorder

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The autonomic nervous system (ANS) is socalled because its functions are normally notsubject to direct voluntary control. It regulateshormonal and immunological processes as wellas the functioning of major organ systems (car-diovascular, respiratory, gastrointestinal, uri-nary, and reproductive systems).

ANS, Central Portion

Central components of the ANS are found in thecerebral cortex (insular, entorhinal, orbitofron-tal, and frontotemporal areas), the hy-pothalamus, the limbic system, the mid brain(periaqueductal gray substance), the medulla(nucleus of the solitary tract, ventrolateral andventromedial areas of the medulla), and the spi-nal cord (various tracts and nuclei, discussed infurther detail below).Afferent connections. Afferent impulses enterthe ANS from spinal tracts (anterolateralfasciculus = spinothalamic + spinocerebellar +spinoreticular tracts), brain stem tracts (arisingin the reticular formation), and corticothalamictracts, and from the circumventricular organs.The latter are small clusters of specialized neu-rons, lying on the surface of the ventricular sys-tem, that sense changes in the chemical com-position of the blood and the cerebrospinal fluid(i.e., on both sides of the blood–CSF barrier).These organs include the organum vasculosumof the lamina terminalis (in the roof of the thirdventricle behind the optic chiasm ! cytokines/fever), the subfornical organ (under the fornicesbetween the foramina of Monro ! angiotensinII/blood pressure and fluid balance), and thearea postrema (rostral to the obex on each sideof the fourth ventricle ! cholecystokinin/gastrointestinal function, food intake).Efferent connections. Projections from the hy-pothalamus and brain stem, particularly fromthe brain stem reticular formation, travel to thelateral horn of the thoracolumbar spinal cord,where they form synapses onto the sympatheticneurons of the spinal cord. The latter, in turn,project preganglionic fibers to the sympatheticganglia (p. 147). The parasympathetic neuronsreceive input from higher centers in similarfashion and project in turn to parasympatheticganglia that are generally located near the endorgans they serve. The hypothalamus regulateshormonal function through its regulator hor-mones as well as efferent neural impulses.

Neurotransmitters. The main excitatory neu-rotransmitter is glutamate, and the main inhibi-tory neurotransmitter is !-aminobutyric acid(GABA). Modulating neurotransmitters includeacetylcholine, amines, neuropeptides, purines,and nitric oxide (NO).

ANS, Peripheral Portion (p. 146)

The sympathetic and parasympathetic com-ponents are both structurally and functionallysegregated.Spinal nuclei. Sympathetic spinal neurons lie inthe lateral horn (intermediolateral and interme-diomedial cell columns) of the thoracolumbarspinal cord (T1–L2) and are collectively termedthe thoracolumbar system. Parasympathetic spi-nal neurons lie in the brain stem (with projec-tions along CN III, VII, IX, X) and the sacral spinalcord (S2–S4), and are collectively termed thecraniosacral system. The intestine has its ownautonomic ganglia, which are located in the my-enteric and submucous plexuses (p. 154).Afferent connections. Afferent impulses to theANS enter the spinal cord via the dorsal roots,and the brain stem via CN III, VII, IX and X.Efferent connections. The projecting fibers ofthe spinal autonomic neurons (preganglionicfibers) exit the spinal cord in the ventral rootsand travel to the paravertebral and prevertebralganglia, where they synapse onto the next neu-ron of the pathway. The sympathetic pregan-glionic fibers (unmyelinated; white ramus com-municans) travel a short distance to the para-vertebral sympathetic chain, and the postgan-glionic fibers (unmyelinated; gray ramus com-municans) travel a relatively long distance to theeffector organs. An exception to this rule is theadrenal medulla: playing, as it were, the role of asympathetic chain ganglion, it receives long pre-ganglionic fibers and then, instead of giving offpostganglionic fibers, secretes epinephrine intothe bloodstream. The parasympathetic pregan-glionic fibers are long; they project to ganglianear the effector organs, which, in turn, give offshort postganglionic processes.Neurotransmitters. Acetylcholine is the neu-rotransmitter in the sympathetic and parasym-pathetic ganglia. The neurotransmitters of thepostganglionic fibers are norepineprhrine (sym-pathetic) and acetylcholine (parasympathetic).Neuromodulators include neuropeptides (sub-stance P, somatostatin, vasoactive intestinal

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Central portionof ANS

Peripheral pathways, enteric nervous system

Effects of catecholamines (epinephrine, norepinephrine)

Sympathetictrunk

Hypothalamus

Mamillothalamic tract

Cortical afferent andefferent fibers

Medial fore brain bundle

Anterior thalamic nucleus

Dorsal longitudinal

fasciculus

Medialthalamicnucleus

Cingulum

III

IV

Reticular formation

VII

X

IX

Area postrema

Control of vasomotor func-tion, breathing,cardiac function,vomiting

Control of breathing, circulation,sucking, licking,chewing

Control of visuo-spatialorientation by ANS

Spinal efferentfibers

Spinal afferent fibers

Organonvasculosumlaminae terminales

Viscero-sensory pathway

Viscerosensory pathway

Myenteric andsubmucousplexuses

Parasympatheticfibers

Autonomicplexus

Postganglionic parasympathetic fibers

Postganglionicsympathetic fibers

Dilatation

Vasoconstriction (skin,viscera) and vasodilata-

tion (muscles, coronary arteries)

Adrenal medulla

Vasoconstriction

Increase inheart rate

Glycogeno-lysis

Lipolysis

Glycogenolysis

Postganglionic parasympathetic fibers

Postganglionic sympathetic fibers

Peripheral portion of ANS

polypeptides, thyrotropin-releasing hormone,cholecystokinin, bombesin, calcitonin-gene-re

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organs. The ensuing effects are sensed by thehypothalamus, thus closing the regulatoryloop.

Hypothalamus

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The hypothalamus lies in the anterior portion ofthe diencephalon, below the thalamus andabove the pituitary gland. It forms part of thewall and floor of the third ventricle. Among itsanatomical components are the preoptic area,infundibulum, tuber cinereum, and mamillarybodies. It is responsible for the control and inte-gration of endocrine function, thermoregulation(p. 152), food intake (p. 154), thirst, cardiovascu-lar function (p. 148), respiration (p. 150), sexualfunction (p. 156), behavior and memory (p. 122ff), and the sleep–wake rhythm (p. 112). Underthe influence of changes in the external and in-ternal environment, and the emotional state ofthe individual, the hypothalamus controls theactivity of the ANS through its neural andhumoral outflow.

Neuroendocrine Control(Table 15, p. 367)

The neuroendocrine control circuits of the hy-pothalamic-pituitary axis regulate the plasmaconcentration of numerous hormones.Adenohypophysis (anterior lobe of pituitarygland). Various regulatory hormones (releasingand inhibiting hormones) are secreted by hy-pothalamic neurons into a local vascular net-work, through which they reach the adenohy-pophysis to regulate the secretion of pituitaryhormones into the systemic circulation. Amongthe pituitary hormones, the glandotropic hor-mones (TSH, ACTH, FSH, LH) induce the releaseof further hormones (effector hormones) fromthe endocrine glands, which, in turn, affect thefunction of the end organs, while the aglan-dotropic pituitary hormones (growth hormone,prolactin) themselves exert a direct effect on theend organs. Finally, the plasma concentration ofthe corresponding effector hormones andaglandotropic pituitary hormones affects thehypothalamic secretion of regulatory hormonesin a negative feedback circuit (closed regulatoryloop).Neurohypophysis (posterior lobe of pituitarygland). A subset of hypothalamic neurons pro-jects axons to the neurohypophysis. The bulb-like endings of these axons store oxytocin andantidiuretic hormone and secrete themdirectly into the bloodstream (neurosecretion).These hormones act directly on their effector


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Hypothalamus and pituitary gland

Fluid balance andblood pressure

Thyroid hormones Corticosteroids

Growth hormonesProlactinGonadotropins

anterior lobe

posterior lobe

Internal carotid a.

Basilar a.Portal venous system

Infundibulum

Medial and lateral preoptic nuclei

Paraventricular nucleus

Posterior hypothalamicnucleus

Dorsomedial nucleus

Ventromedial nucleus

Infundibular nucleus

Supraoptic nucleus

Suprachiasmatic nucleus

Supraoptic nucleus Ventral tegmental area

Optic chiasm

Tuber cinereum

Mamillary body

Preoptic area

Anterior commissure Fornix

Kidney

ADH

Angiotensin II

Renin

Heart

Blood pressure,osmolality

Osmo-receptors

Exogenous/endogenous stimuli

Baro-receptors

Volumereceptors

TRH

TSH

Thyroidgland

T3, T4

Adrenal cortex

ACTH

CRH

Cortisol

GHRH

Growthhormone

Muscle, fat

Bone, cartilage

Somatomedin C

Growth hormone,

somatomedins

Breast

PRL

Dopamine,VIP, TRHLH, FSH

Testosterone,estradiol,

progesterone

GnRH

Liver

Testicle Ovary

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Limbic System

The limbic system consists of a number of sepa-rate structures with complex interconnections.Its function is only partly understood, but it isclear that it plays an important role in memory,emotion, and behavior.

! Structure

The limbic system consists of inner and outerportions, both of which resemble a ring (Latinlimbus). The outer portion extends from rostralstructures (the septal and preoptic areas) in acraniocaudal arch (cingulate gyrus) to the tem-poral lobe, all the way to the temporal pole (hip-pocampus, entorhinal cortex). The inner portionextends from the hypothalamus and mamillarybody via the fornix to the dentate gyrus, hippo-campus, and amygdala.

! Nerve pathways

The neuroanatomical loop, hippocampus ! for-nix ! mammillary body ! mammillothalamictract ! anterior thalamic nucleus ! cingulategyrus ! cingulum ! hippocampus, is called thePapez circuit. Numerous fiber tracts, many ofthem bilateral, connect the limbic system to thethalamus, cortex, olfactory bulb (p. 76), andbrain stem. Themedial forebrain bundle links theseptal and preoptic areas with the hy-pothalamus and midbrain. Fibers from theamygdala pass in the stria terminalis, which oc-cupies the groove between the caudate nucleusand the thalamus, to the septal area and hy-pothalamus. Short fibers from the amygdala alsoproject to the hippocampus. The anterior com-missure connects the two amygdalae, and thecommissure of the fornix connects the two hip-pocampi.

! Functions of the limbic system(Table 16, p. 368)

The limbic system controls emotional processes,such as those involved in anger, motivation, joy,sexuality, sleep, hunger, thirst, fear, aggression,and happiness. These processes are closelylinked with cognition and memory (p. 134). Theamygdala plays a key role in these events(emotional memory), integrating new, incominginformation with the stored contents ofmemory. This integration determines the neural

output of the limbic system, which affects theindividual’s physical state and behavioral re-sponses.

ANS, Peripheral Portion (p. 146 ff)

The peripheral portion of the ANS (p. 140) sub-serves a number of autonomic reflexes (p. 110).Nociceptive, mechanical, and chemical stimuliinteract with their respective receptors to in-duce the generation of afferent impulses, whichthen travel to the spinal autonomic neurons,whose efferent output, as described in previoussections, controls the function of the heart,smooth muscles, and glands. The activity of thespinal sympathetic neurons is subject to su-praspinal regulation by the autonomic centersof the brain. Most organs of the body receiveboth sympathetic and parasympathetic innerva-tion. This double innervation enables synergis-tic coordination of multiple organ systems (e. g.,acceleration of breathing and blood flow duringphysical exercise).

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Inner compartments

Outer compartments

Fornix and hippocampus

Septal areaDentate

gyrus

Left lateral ven-tricle (temporal

horn)Indusium griseum (longitudinalstriae)

Dorsal longitudinal fasciculus

Corpus callosum

Cingulategyrus

Hippocampus

Fornix

Pituitarygland

Preoptic and sep-tal areas

Olfactory bulb

Amygdala


Preoptic and septal areas

Medial thalamic nucleus


Corpus callosum

Medial forebrainbundle

Habenularnuclei

Mamillary body

Cingulum

Monitoring ofinternal environment

Visualinput

Acousticinput

Somatosen-sory input

Taste, smell

Hippo-campal

gyrus

Hippocampus

Stria terminalis

Mamillo-thalamic

tract

Fornix

Amygdala

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Sympathetic End Effect1(Receptor Type2)

Effector Organ Parasympathetic EndEffect1

EyeContraction ! mydriasis (!1) Dilator pupillae m. —Contraction ! lid elevation Tarsal m. —— Sphincter pupillae m. Constriction ! miosis

(light response)— Ciliary m. Contraction ! accommoda-

tion (near response)— Lacrimal gland Secretion

Light mucous secretion (!1) Salivary glands Heavy serous secretion

Thoracic organsRelaxation ("2) Bronchial smooth muscle ConstrictionSecretion:

!

(!1), ! ("2) Bronchial glands !Secretion

!Heart rate ("1) Sinoatrial node

!

Heart rate

!Contractility ("1) Myocardium Slightly

!

contractility

Abdominal organsGlycogenolysis, gluconeogenesis (!1, "2) Liver —Dilatation ("2) Gallbladder, biliary tract Contraction

!

Motility (!2, "2) Intestine !MotilityContraction (!1) Sphincters Relaxation

!

Insulin secretion (!2) Pancreas —

! Renin secretion ("1) Kidney —

! Secretion3 Adrenal medulla —Contraction (!1) Urinary sphincter RelaxationRelaxation ("2) Urinary detrusor ContractionContraction (pregnancy, !1) Uterus Varies (cycle-dependent)Ejaculation (!1) Male genitalia Erection

SkinSecretion: !generalized (cholinergic),localized4

Sweat glands —

Contraction (!1) Arrector muscles of hair —

Blood vesselsVasoconstriction (!1, !2) Cutaneous arteries VasodilatationVasoconstriction (!1), vasodilatation ("2) Arteries of skeletal muscle VasodilatationVasoconstriction (!1) Cerebral arteries VasodilatationVasoconstriction (!1, !2),Vasodilatation ("2)

Coronary arteries Slight vasoconstriction

Vasoconstriction (!1) Abdominal arteries —Vasoconstriction (!1, !2) Veins —

1 The action of the respective organ is listed in this column. 2 These are mainly membrane receptors for epine-phrine and norepinephrine (adrenoceptors). Norepinephrine mainly acts on ! and "1 receptors; epinephrine actson all types of adrenoceptors. Sympathomimetic ! increases sympathetic nervous activity (adrenoceptor agonist);sympatholytic ! reduces sympathetic nervous activity (adrenoceptor antagonist, receptor blocker); parasym-pathomimetic ! muscarinic receptor agonist; indirect parasympathomimetic ! blocks acetylcholinesterase; para-sympatholytic (anticholinergic) ! muscarinic receptor antagonist; antiparasympathotonic ! botulinum toxin. 3 Pre-ganglionic sympathetic fibers; transmitter acetylcholine. 4Palms of hands (adrenergic sweating).

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Sympathetic trunk

III

VII

Chordatym-pani

IX

X

Ciliary ganglionPterygopalatine ganglion

Subman-dibularganglion

Otic ganglion

Parotid gland

Sublingual and submandibular glands

Bronchus

Skin

L1L3

S2

S4


Middle cervical ganglion

Stellate ganglion

Celiac ganglion

Superiormesentericganglion

Inferior mesenteric ganglion

Preganglionic para-sympathetic fibers

Postganglionicsympatheticfibers

Preganglionicsympatheticfibers

T 1

T 12

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Sympathetic efferent impulses cause arterialand venous vasoconstriction, acceleration of theheart rate, activation of the renin–angiotensin–aldosterone system, and secretion of epine-phrine/norepinephrine from the adrenalmedulla. Blood pressure and blood volume rise,and blood is redistributed away from the vascu-lar beds of skin (pallor), intestinal organs, andkidneys in favor of the heart and brain. Con-versely, parasympathetic efferent impulsescause vasodilation and a decrease in heart rate.The normal arterial blood pressure is no higherthan 140mmHg systolic and 90mmHg diastolic.Afferent connections. Baroreceptors (pressuresensors) are located between the media andadventitia of the arterial wall in the carotid sinus(innervated by CN IX), the aortic arch (X), and thebrachiocephalic trunk (X). The impulses theygenerate are conveyed to the nucleus of the soli-tary tract (NST) in the dorsolateral medulla; thepolysynaptic relay proceeds via interneurons tothe anterolateral portion of the caudal medulla(CM), which in turn projects to inhibitory neu-rons in the anterolateral portion of the rostralmedulla (RM). Other fibers from the NST projectto the nucleus ambiguus (NA). Other barorecep-tors, found in the atria and venae cavae neartheir entrance to the heart, sense the volumestatus of the vascular system and generate im-pulses that travel by way of CN X to the NST andhypothalamus. Cerebral ischemia ( !CO2 in extra-cellular fluid and CSF; p. 162) leads to increasedsympathetic activity. Mechanical, nociceptive,metabolic, and respiratory influences also affectthe medullary and hypothalamic centers thatregulate the circulatory system.Efferent connections. Sympathetic impulsestravel from the (inhibitory) RM to the interome-diolateral cell column of the spinal cord, whichprojects to the adrenal medulla and, through arelay in the sympathetic ganglia, to the heart,blood vessels, and kidney. The parasympatheticoutflow of the NST is relayed in the nucleus am-biguus, by way of CN X, to the heart and bloodvessels.Central nervous regulation. The sympatheticand parasympathetic innervation of the circula-tory system act synergistically. Both are ulti-mately controlled by the hypothalamus, whichprojects not only to the intermediolateral cellcolumn (sympathetic), but also to the NST andnucleus ambiguus (parasympathetic). Afferent

impulses from the skeletal muscles, barorecep-tors, and vestibular organs reach the fastigialnucleus of the cerebellum, which has an exci-tatory projection to the NST and an inhibitoryprojection to the RM. Cortical projections tocirculatory control centers enable the car-diovascular system to function as needed in thecourse of voluntary, planned movements.

Syndromes (Table 17, p. 369)

Neurogenic arrhythmias may be of su-praventricular or ventricular origin and arecommonly associated with subarachnoid andintracerebral hemorrhage, head trauma,ischemic stroke, multiple sclerosis, epilepticseizures, brain tumors, carotid sinus syndrome(cardioinhibitory type), glossopharyngealneuralgia and hereditary QT syndrome. Theyalso sometimes occur in the immediate post-operative period after major neurosurgical pro-cedures.Neurogenic ECG abnormalities (ST depression orelevation, T-wave inversion) can occur in thesetting of cerebral hemorrhage or infarction butare often difficult to distinguish from changesdue to myocardial ischemia.Hemodynamic abnormalities. Hypertension:Cerebral hemorrhage, Cushing reflex (accom-panied by bradycardia) in response to elevatedICP, porphyria, Wernicke encephalopathy (ac-companied by arrhythmia), and posterior fossatumors. Hypotension: Head injuries, spinal le-sions (syringomyelia, trauma, myelitis, funicularmyelosis), multisystem atrophy, progressive su-pranuclear palsy, Parkinson disease, peripheralneuropathies (e. g., in diabetes mellitus, amy-loidosis, Guillain–Barré syndrome, or renalfailure). Neurocardiogenic syncope (vasovagalsyncope) is due to pooling of venous blood inthe arms and legs. Underfilling of the left ven-tricle activates baroreceptors, which, in turn,project via CN X to the NST. The ensuing increaseof parasympathetic outflow, if large enough, setsoff a “neurocardiogenic cascade” that leads topresyncope and syncope (p. 200). The charac-teristic features include decreased sympatheticactivity, increased epinephrine secretion fromthe adrenal medulla, and decreased norepine-phrine secretion, resulting in vasodilatation. Hy-perexcitability of the vagus nerve (bradycardia)is also seen.

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Medullary neural control of circulationNA = nucleus ambiguusCM = caudal medullaNST = nucleus of solitary tractRM = rostral medulla

Neural control of circulatory system

Orthostatic test

Rostral andcaudalmedulla

Thoracic spinal cord

Parasympathetic efferent fibers (X)

Preganglionic (sympathetic)fibers

Intermediolateral cell column

NST

NST

NA

X

XNA

RM

Afferent fibers to NST (IX, X)

Sympathetic efferent fibers

Afferent innervation

Efferent-innervation

Vasohypo-thalamic afferent

fibers

Cerebellar outflow

Cortical input

Horizontal position

Upright position

Sympathetic trunk

Effects of standing upright:Sympathetic activityVagal toneRenin-angiotensin systemBlood flow to skin/fat/muscles

Hypothalamic outflowCM

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Respiration ensures an adequate oxygen supplyfor the body’s tissues and maintains acid–basehemostasis.Respiratory movements. Inspiration can beachieved by contraction of the diaphragm (dia-phragmatic respiration) or of the intercostalmuscles (costal respiration). The auxiliary respi-ratory muscles of the shoulder girdle further en-large the chest cavity, if required, for deepbreathing. Expiration is largely passive. Themuscles of the abdominal wall and the latis-simus dorsi muscle serve as auxiliary expiratorymuscles. Other muscles (genioglossus, pharyn-geal constrictor, and laryngeal muscles) keepthe upper airway open during respiration.Afferent connections. Chemoreceptors respond-ing to arterial pH and O2 and CO2 concentrationare found in the carotid glomus (innervated byCN IX), aortic arch (X), andpara-aortic bodies (X).Impulses arising in these chemoreceptors, and inmechanoreceptors in the respiratory muscles(sensory afferent connections ! phrenic nerve,intercostal nerves 2–12, CN IX) and in the lungs(bronchodilatation! pulmonary plexus, sympa-thetic nerve T1–T4), travel to the dorsal respira-tory group of nuclei (DRG) anterior to the nucleusof the solitary tract, fromwhich they are relayed,via interneurons, to the ventral respiratory group(VRG) in the medulla. The DRG also receives af-ferent input from the cardiovascular system,which is thus able to influence respiratory func-tion. Changes in the pH and CO2 concentration ofthe extracellular fluid (ECF) and cerebrospinalfluid (CSF) are also directly sensed by medullarychemoreceptors. Respiration is further in-fluenced by a wide variety of other phenomena,e. g., cold, heat, hormones, reflexes (sneezing,coughing, yawning, swallowing), sleep, mentalstate (anxiety, fear), speaking, singing, laughing,muscle activity (physical work, sports), sexualactivity, and body temperature.Efferent connections. The laryngopharyngealmuscles and bronchoconstrictors are innervatedby CN X. The phrenic nerve (diaphragm, C3–C5)and motor branches of the spinal nerves (inter-costal nerves 2–9/T2–T11 ! intercostal muscles;intercostal nerves 6–12/T6–T12 ! abdominalwall muscles) supply the auxiliary respiratorymuscles.Respiratory rhythm. Rhythmic breathing isachieved by oscillating, alternately inhibitory

and excitatory neural control circuits within theVRG. As inspiration progresses, the inspiratoryneuron groups of the VRG are progressively in-hibited (Hering–Breuer reflex), while the ex-piratory neuron groups are excited. The respira-tory rhythm is influenced by afferent input fromchemoreceptors reflecting changes in the com-position of the blood (decreases in pH and O2

concentration, rise in CO2 concentration !

deeper respiration, ! respiratory rate) or of theECF and CSF (decrease in pH, rise in CO2 concen-tration ! deeper respiration, !respiratory rate).The VRG is influenced by pontine nuclei.


Pathological breathing patterns may be due tometabolic, toxic, or mechanical factors (obstruc-tive sleep apnea) or to a lesion of the nervoussystem (p. 118). Morning headaches, fatigue,daytime somnolence, and impaired concentra-tion may reflect a (nocturnal) breathing dis-order. Neurogenic or myogenic breathing dis-orders often come to medical attention becauseof coughing attacks or food “going down thewrong pipe.” Neurological diseases are oftencomplicated by respiratory dysfunction. Therespiratory parameters (respiratory drive,coughing force, blood gases, vital capacity)should be carefully monitored over time so thatintubation and/or tracheostomy for artificialventilation can be performed as necessary.

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Diaphragm (diaphragmatic respiration)

Costal respiration

Auxiliarymuscles of respiration

Carotid sinus

65*

30

25

15

10

Carotid glomus

IX

Inferior(petrosal)ganglion

Afferentfibers IX

Pulmonary afferent fibers

X

Para-aortic body

Afferentfibers X

Vital capacity

Functional residual capacity

Inspiratorycapacity

Expiratory reserve volume

Tidal volume

Total capacity

Normal respiration

Reduced cough force, accumulation of secretions

Hypoventilation, hypercapnia

Early hypoxia, atelectasis,reduced sighing

Hypoxemia, atelec-tasis + arteriove-

nous shunting

Residual volume

Cheyne-Stokes respiration

Hyperventilation (machine respiration)

Apneusis (pause on full inspiration)

Cluster respiration

Ataxic (Biot) respiration

1 min

Chemoreceptors

Brain stem centers

Pathological respiratory patternsNeuromuscular respiratory disorder, vital capacity*(in ml/kg body weight)

Lung volumes

Respiratory movements

Nucleus ofthe solitary

tract

DRG

Pontine nuclei

VRG

Efferentfibers

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The temperature of the body is a function of heatabsorption, heat production, and heat elimina-tion. Core body temperature normally fluctuatesfrom approximately 36 °C in the morning to37.5 °C in the late afternoon. It can be influencedby the menstrual cycle, pregnancy, and otherhormonal factors, as well as by eating behaviorand digestion, and it varies with age.Neural control. The thermoregulatory centerlies in the preoptic and anterior region of the hy-pothalamus (p. 142). Heat is eliminated throughthe skin (heat radiation, convection, sweating !

cooling by evaporation), respiration (evapora-tion), and blood circulation (heat transport fromthe interior to the surface, cutaneous bloodflow). Heat is produced by metabolic processes(under the influence of thyroid hormones) andby muscle contraction (shivering, voluntarymovement). Thermoreceptors in the skin, spinalcord, medulla, and midbrain generate afferentimpulses that travel to the hypothalamic controlcenter; the cutaneous receptors project to thehypothalamus by way of the spinothalamictract. Thermoreceptors are also present in thehypothalamus itself. The hypothalamus makesextensive connections with other regions of thebrain. Its major efferent pathways relating tothermoregulation (vasomotor and sudoriparouspathways) pass by way of the ipsilateral lateralfuniculus of the spinal cord to the spinal sympa-thetic nuclei (thoracolumbar system). Thesethen give rise to fibers that travel by way of theventral roots to the sympathetic chain ganglia;postganglionic fibers travel with the peripheralnerves to the skin. Sudoriparous fibers are foundonly in the ventral roots of T2/3 to L2/3, yet theyinnervate the skin of the entire body; thus, theirdistribution is not the same as the dermatomaldistribution of sensation. Sudoriparous fibers tothe head travel along the internal and externalcarotid arteries and then join branches of thetrigeminal nerve to arrive at the skin. The neu-rotransmitter for the sympathetic innervation ofthe sweat glands is acetylcholine.Disturbances of body temperature. Central hy-perthermia is an elevation of body temperaturedue to impaired thermoregulation by the cen-tral nervous system. Its mechanism may involveeither excessive heat production, excessive heatabsorption (e. g., in a hot environment), or in-adequate heat elimination. Fevermay be definedas an oral temperature greater than 37.2 °C inthe morning or 37.7 °C in the afternoon (rectal

temperature 0.6 °C higher). Its cause is generallynot an impairment of thermoregulation, butrather a change in the set point for temperatureestablished by the hypothalamic thermoregula-tory center. Such a change can be brought aboutby circulating pyrogenic cytokines (e. g., inter-leukin-1, tumor necrosis factor, interferon-!)that exert an effect on hypothalamic function byinteracting with the circumventricular organs(p. 140). Hypothermia is defined as a coretemperature below 35 °C.

Syndromes

Disturbances of thermoregulatory sweating. Ex-amination: Useful tests include palpation of theskin to appreciate its moisture and temperature,the quantitative sudomotor axon reflex test(QSART), the sympathetic skin response (SSR),iodine–starch test (Minor test), and the ninhy-drin test.Generalized anhidrosis (which confers a risk ofhyperthermia) may be idiopathic or may be dueto lesions in the hypothalamus or in the spinalcord above T3/4 . Monoradicular lesions or cer-vical or lumbosacral polyradicular lesions do notimpair sweating. Lesions of the sympathetictrunk cause segmental anhidrosis. Plexus lesionsand isolated or combined neuropathies produceanhidrosis in the area of a sensory deficit. Le-sions from the level of the stellate ganglion up-ward cause anhidrosis as a component ofHorner syndrome. Sweating of the palms andsoles is not influenced by thermoregulatorymechanisms but rather by the emotional state(fear, nervousness).Central hyperthermia may be due to hy-pothalamic lesions (infarction, hemorrhage,tumor, encephalitis, neurosarcoidosis, trauma),intoxications (anticholinergic agents, salicy-lates, amphetamines, cocaine), acute spinal cordtransection above T3/4, delirium, catatonia,malignant neuroleptic syndrome, malignant hy-perthermia, dehydration, heat stroke, andgeneralized tetanus.Fever. The symptoms include malaise, shivering,feeling cold, chills, nausea, vomiting, and som-nolence. The heart rate and blood pressure rise,thermoregulatory sweating diminishes, and theperipheral blood volume is redistributed to thecore of the body. Simple febrile convulsions inchildrenunder5yearsofagegenerallydonot leadto epilepsy or other neurological complications.

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Neural control

Heat elimination

Innervation of sweat glands

Hypothalamic control center

Afferent pathway(thermo-receptors)

Efferentfibers

Sympathetictrunk

T2

L2

Afferent fibers from internal carotid a.

Postgan-glionic fibers (T2-T4)

Post-ganglionicfibers (T5-T7)

Postganglionic fibers (T8-L3)

Pregan-glionic sudoriparousfibers (T2/3-L2/3)

T5

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The uptake, transport, storage, and digestion offood, the absorption of nutrients, and the elimi-nation of waste matter are under the influenceof both the extrinsic autonomic nervous systemand the intrinsic autonomic nervous system ofthe intestine.The extrinsic system modulates the function ofthe intrinsic enteric system in coordination withthe function of other organs of the body. Brainstem nuclei subserve the gastrointestinal andenterocolic reflexes, while cortical, limbic (hy-pothalamus, amygdala) and cerebellar centers(fastigial nucleus) mediate the perception ofsatiety, the enteral response to hunger andodors, and emotional influences on alimentaryfunction. The parasympathetic innervation (neu-rotransmitter: acetylcholine) of the esophagus,stomach, small intestine, and proximal portionof the large intestine is through the vagus nerve,while that of the distal portion of the large in-testine and anal sphincter is derived from seg-ments S2–S4. Parasympathetic activity stimu-lates intestinal motility (peristalsis) and glandu-lar secretion. Sympathetic innervation (transmit-ter: norepinephrine) is from the superior cervi-cal ganglion to the upper esophagus, from theceliac ganglion to the lower esophagus andstomach, and from the superior and inferiormesenteric ganglia to the colon. Sympatheticactivity inhibits peristalsis, lowers intestinalblood flow, and constricts the sphincters of thegastrointestinal tract (lower esophageal sphinc-ter, pylorus, inner anal sphincter).The intrinsic system (enteric system) consists ofthe myenteric and submucous ganglionic plex-uses (p. 141), which are independent neural net-works of sensory and motor neurons and inter-neurons. The enteric autonomic nervous systemreceives chemical, nociceptive, and mechanicalstimuli, processes this neural input, and pro-duces efferent impulses affecting gastrointesti-nal glandular secretion and smooth-musclecontraction.


Neurological diseases most commonly affectgastrointestinal function by impairing motility,less commonly by impairing resorptive andsecretory processes. The differential diagnosismust include gastrointestinal dysfunction of

nonneurological (often obstructive) origin.Specialized diagnostic testing is usually indi-cated.

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Extrinsic system (afferent fibers not shown)

Intrinsic system

Enteric reflex circuit

Vagus nerve(parasympathetic)

Celiac ganglion


Superior mesenteric ganglion

Inferior mesenteric ganglion

Preganglionicsympatheticfibers

Pelvic splanchnicnerves (parasym-pathetic)

Postganglionic sympathetic fibers

Extrinsic vagal and sympatheticefferent fibers(CNS-controlled)

Smooth muscle cell in intestinal wall

Enteric afferent fibers(stimulus reception)

Interneurons

Enteric motor neurons

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Bladder Function

The urinary bladder stores (continence) andvoids (micturition) the urine produced by thekidneys. Parasympathetic fibers arising in seg-ments S2–S4 (sacral micturition center, detrusornucleus) and traveling through the pelvic plexusactivate the detrusor muscle of the bladder.Sympathetic fibers arising from segments T10–L2 and traveling through the hypogastric plexusinhibit the detrusor (!-adrenergic receptors)and stimulate the vesical neck (trigone, internalsphincter; "-adrenergic receptors). Somaticmotor impulses arising from segments S2–S4(Onuf’s nucleus) travel through the pudendalnerve to the external sphincter and the pelvicfloor muscles. Somatosensory fibers from thebladder travel along the hypogastric and pelvicnerves to spinal levels T10–L2 and S2–S4, con-veying information about the state of bladderstretch (overdistention is painful). The centralnervous system (frontal lobes, basal ganglia)subserves the voluntary inhibition of detrusorcontraction. The pontine micturition center,which triggers the act of micturition, is underthe influence of afferent impulses relating to thestate of bladder stretch; its output passes to so-matic motor neurons in the spinal cord that syn-ergistically innervate the detrusor and externalsphincter muscles.Continence. An intact bladder closure mecha-nism is essential for normal filling (up to500ml). Closure involves contraction of thevesical neck and external sphincter urethrae andpelvic floormuscles, and relaxation of the detru-sor muscle (dome of the bladder).Micturition. Once a urine volume of 150–250mlhas accumulated, stretch receptors generate im-pulses that pass to the pontine micturitioncenter and also produce the sensation of bladderdistention. Micturition begins when the domeof the bladder is stimulated to contract whilethe vesical neck and pelvic floor muscles relax.Contraction of the muscles of the abdominalwall increases the intravesical pressure andfacilitates micturition.Neurogenic bladder dysfunction (Table 20,p. 371). Additional diagnostic tests are per-formed in collaboration with a urologist orgynecologist as deemed necessary on the basisof the case history and neurological findings.

Useful diagnostic aids include laboratory testing(urinalysis and renal function), ultrasound ex-amination (kidney, bladder, pelvis), urodynamictesting, micturition cystourethrography, andneurophysiological studies (evoked potentials,urethroanal/bulbocavernosus reflex).

Sexual Function

The genital organs receive sympathetic (T11–L2), parasympathetic (S2–S4), somatic motor(Onuf’s nucleus), and somatosensory innerva-tion (S2–S4) and are under supraspinal control,mostly through hypothalamic projections to thespinal cord. Hormonal factors also play an im-portant role (p. 142). Neurological disease oftencauses sexual dysfunction (erectile dysfunction,ejaculatory dysfunction) in combination withbladder dysfunction. Isolated sexual dysfunc-tion is more often due to psychological factors(depression, anxiety), diabetes mellitus, en-docrine disorders, and atherosclerosis.

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157Neural control of urinary bladder(EUSM = external urethral sphincter m.)

Spinal reflex arc (sacral micturition center)

Medial prefrontal cortex Basal ganglia

Pudendal n.

Sensory afferent fibers

Reflex arc IV (voluntary and auto-nomic control of EUSM)

Preganglionic sympathetic fibers

Internal urethral

sphincter m.

Sensory pathway

Pyramidal tract

Onuf’s nucleus

Detrusor nucleus

Reflex arc I (voluntary detrusor control)

Pontine micturition center

Sympathetictrunk

Reflex arc II (autonomic detrusor control)

Fibers in superior hypogastric plexus

Sensory afferent fibers

Sensory (afferent) fibers

Sympatheticinnervation(T10-L2)

Sacral micturitioncenter

Fibers in pelvic plexus

Motor efferentfibers (pudendal n.)

Parasympa-thetic fibers

Pelvic ganglion

Ureter

Inferior mesenteric

ganglion

Urinary bladder (dome,

detrusor muscle)

External anal sphincter m.

EUSM

Reflex arc III (autonomicEUSM control)

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The intracranial pressure (ICP) corresponds tothe pressure that the contents of the skull exerton the dura mater.

Intracranial Hypertension

The normal intracranial pressure (ICP) is 60–120mmH2O, which corresponds to 5–15 mmHg. AnICP greater than 30mmHg impairs cerebralblood flow; an ICP greater than 50mmHg formore than30minutes is fatal; an ICPgreater than80mmHg for any length of time can cause braindamage. Intracranial hypertensionmay be eitheracute (developing in hours to days) or chronic(lasting for weeks or months). Its manifestationsareprogressivelymore severe as the ICP rises, butare not specific; thus, the diagnosis cannot bemade from the signs of intracranial hypertensionalone but requires either the demonstration of acausative lesion (e. g., subdural hematoma, en-cephalitis, brain tumor, hydrocephalus) or directmeasurement of the intracranial pressure. Treat-ment is indicated when the ICP persistentlyexceeds 20mmHg, when plateau waves arefound, or when the pulse amplitude rises. In-dividual casesmaymanifest a variety of differentsigns of intracranial hypertension, either in slowor rapid alternation, or all at the same time. Com-pression of the brain stem by a space-occupyinglesion (p. 118) has similar clinical manifesta-tions; thediagnosticdifferentiationofbrain stemcompression from intracranial hypertension iscritical. Lumbar puncture is contraindicated incases of suspected or documented intracranialhypertension, as the resulting increase in the al-ready high craniospinal pressure gradient maylead to brain herniation.

! Clinical Features (Table 21, p. 371)

Headache due to intracranial hypertensionranges in intensity from mild to unbearable.Patients typically report a pressing, bifrontalheadache that is most severe upon awakening inthemorning or after naps in the daytime. It is ex-acerbated by lying flat, coughing, abdominalstraining,orbendingover,andamelioratedbysit-ting or standing. It may wake the patient fromsleep. Often, both mild daytime headaches andmore severe nighttime headaches are present.Nausea due to intracranial hypertension is oftenindependent of movement of the head or of

other abdominal complaints, and its intensity isnot correlated with that of headache. It may bemild or severe.Projectile vomiting may occur without warningor after a brief sensation of nausea upon sittingup or moving the head. Initially, vomitingmainly occurs suddenly, in the morning (on anempty stomach).Eyemovements and vision.Compression of CN IIIor VI causes paresis of extraocular muscles orpupillary dilatation (p. 92). Papilledema often af-fects the eye on the side of the causative lesionfirst, and thengradually theother eyeaswell. Theolder the patient, the less likely that papilledemawill occur as a sign of intracranial hypertension;its absence thus cannot be taken as ruling out in-tracranial hypertension. Early papilledema ischaracterized by hyperemia, blurred papillarymargins, dilated veins, loss of venous pulsations(may be absent normally), and small hemor-rhages around the papilla. Full-blown papil-ledema is characterized by disk elevation, en-gorgedveins, tortuousvessels around thepapilla,and streaky hemorrhages. If intracranial hyper-tensionpersists,chronicpapilledemawilldevelopin weeks or months, characterized by grayish-white optic nerve atrophy and small vessel cali-ber. Acute papilledema generally does not affectthe visual fields or visual acuity (unlike papillitis,which shouldbeconsidered in thedifferential di-agnosis); but physical exertion or head move-mentmaycause transientamblyopicattacks last-ing several seconds (foggy or blurred vision, orblindness). Chronic papilledema, on the otherhand,cancausean impairmentvisualacuity, con-centric visual field defects, and even blindness.Gait disturbances. An unsteady, slow, hesitant,gait with small steps and swaying from sided toside is sometimes seen.Behavioral changes. Impairment of memory, at-tention, concentration, andplanning ability, con-fusion, slowed reactions, andchanges inpersonalhabitsareoftenobservedbyrelativesand friends.

Intracranial Pressure

Intracranial

Pressure


159

Headache

Nausea

Behavioral change

Herniation(decerebration syndrome)

Early papilledema

Papilledema (fully developed)

Chronic papilledema

Optic nerve atrophy

Mild disk elevation (0.5diopters), ill-defined margins

Infarcts (cotton-woolspots)

Dilated vein

Elevated (3-5diopters) andenlarged disk withirregular margins

Disk elevation (5 diopters)

Streaky hemorrhage


Intracranial

Pressure


160

Herniation syndromes (p. 162). Transtentorialherniationcausesan ipsilateraloculomotornervepalsy (ptosis, mydriasis, and secondary ophthal-moplegia), contralateral hemiplegia, and decere-bration syndrome (p. 46). Downward herniationof thecontentsof theposterior fossa into the fora-men magnum causes neck pain and stiffness, ahead tilt, and shoulder paresthesiae. Ifmedullarycompression is also present, respiratory andcirculatorydisorders, cerebellar fits, andobstruc-tivehydrocephalusmaydevelop.Upwardhernia-tion of the contents of the posterior fossa acrossthe tentorial notch causes a decerebration syn-drome in which the ipsilateral pupil is initiallyconstricted and later dilated.Pseudotumor cerebri causes headache (holo-cephalic, bilateral frontal/occipital), visual dis-turbances of varying severity (enlarged blindspot, blurredvision, loss of vision, or diplopia dueto abducens palsy), and bilateral papilledema. CTand MRI scans reveal the absence of an in-tracranialmass (normalventricular size, thicken-ing of optic nerve, “empty sella” = intrasellar ex-pansion of the suprasellar cisterns, with orwithout sellar dilatation). CSF tests are normalexcept for an elevated opening pressure (!250mmH2O). The etiology of pseudotumor cerebri ismultifactorial; it occursmost commonly inobeseyoungwomen. Its differential diagnosis includesintracranial venous or venous sinus thrombosis,drug toxicity (high doses of vitamin A, tetracy-cline, NSAIDs), elevated CSF protein level (spinaltumor, Guillain–Barré syndrome), or endocrinechanges (pregnancy, Addison disease, Cushingsyndrome, hypothyroidism).

Intracranial Hypotension

Spontaneous drainage of cerebrospinal fluid bymeans of lumbar puncture is no longer possiblewhen the CSF pressure is below 20mmH2O(patient is lying flat); when it is below0mmH2O, air is sucked through the LP needleinto the subarachnoid space and travels upwardto the head, where air bubbles can be seen on aCT scan. For causes of low intracranial pressuresee Table 22 (p. 372).

! Symptoms

Severe headache (nuchal, occipital, or frontal) isprovoked by sitting, standing, or walking, and

subsides when the patient lies flat. It is exacer-bated by abdominal straining, coughing, and theValsalva maneuver. Other symptoms includenausea, vomiting, and dizziness. Unilateral orbilateral abducens palsy, tinnitus, ear pressure,or neck stiffness may also occur. Subdural fluidcollections (hematoma due to rupture of thebridging veins, hygroma arising from local CSFcollection due to rupture of the arachnoid mem-brane) are rare. Intracranial hypotension may becaused by a CSF leak; patients may report oc-casional loss of watery fluid from the nose or ear(traces visible on pillows).Normal-pressure hydrocephalus (NPH) is achronic form of communicating hydrocephalusthat reflects an impairment of CSF circulationand resorption, sometimes in the aftermath ofsubarachnoid hemorrhage, head trauma, orchronic meningitis, but often without discerni-ble cause. Symptoms develop over severalweeks or months. Gait disturbances (gaitapraxia, hydrocephalic astasia-abasia) begin asunsteadiness, difficulty climbing stairs, legfatigue, a small-stepped gait, and frequentstumbling and falling, and then typically pro-gress to an inability to stand, sit, or turn over inbed. The associated behavioral changes (p. 132 ff)are variable and may include impaired spatialorientation, reduced psychomotor drive(abulia), mild memory disturbances, or evendementia. Bladder dysfunction such as urge in-continence and polyuria develop as the condi-tion progresses. Patients ultimately lose the per-ception of bladder distension and thus void un-controllably.

Pathogenesis

ICP depends on the volume of nervous tissue,CSF, and blood inside the nondistensible cavityformed by the skull and vertebral canal. An in-crease in the volume of one of these three com-ponents must be offset by a compensatorymechanism (Monro–Kellie doctrine) such as anadjustment of the CSF or (venous) bloodvolume, expansion or the lumbosacral duralsheath, or deformation of the brain. When thecapacity of such mechanisms is exhausted, theICP decompensates. Compliance is defined as thefirst derivative of volume as a function of ICP, i.e.,the ratio of a small, incremental change in


Intracranial

Pressure


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Impaired CSF circulation in thesubarachnoid space

Hydrocephalus

Normal pressurehydrocephalus

Lumbar measurement of CSF pressure

Bladder dysfunction

Gait disturbance

Blockage in the subarachnoid space

Dilated ventricles

Subarachnoid space


Intracranial

Pressure


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Intracranial

Pressure

volume to the change in ICP that it produces.Compliance is thus an index of the ability tocompensate for changes in volume. Decreasedcompliance leads to ICP decompensation.Elastance is the reciprocal of compliance, henceindicating the inability to compensate forchanges in volume.CSF volume. Hydrocephalus is defined as abnor-mal dilatation of the ventricular system. It oc-curs because of disturbances of CSF circulationand/or resorption. Hydrocephalus due to ablockage of the CSF pathway at some pointwithin the ventricular system is called noncom-municating or obstructive hydrocephalus. Hydro-cephalus due to impaired CSF resorption at thearachnoid villi is called communicating ormalre-sorptive hydrocephalus. Acute hydrocephalus ischaracterized by ventricular dilatation withacute intracranial hypertension. Hydrocephaluswith normal ICP and without progression ofventricular dilatation is called arrested, com-pensated or chronic hydrocephalus. So-callednormal-pressure hydrocephalus occupies an in-termediate position between these two condi-tions. External hydrocephalus is a dilatation ofthe subarachnoid space with no more than mildenlargement of the ventricles.

Cerebral Blood Flow

Cerebral blood flow (CBF) is a function of thecerebral perfusion pressure (CPP), which nor-mally ranges from70 to100mmHg, and the cere-bral vascular resistance (CVR): CBF = CPP/CVR.CBF ismaintained at a constant value of approxi-mately 50ml/100 g/min as long as the meanarterial pressure (MAP)1 remains in the relativelywide range from50 to 150mmHg (cerebral auto-regulation). When the patient is lying flat, CPP =MAP – ICP. A rapid rise in the systemic arterialpressure is followedbya slow,delayed rise in ICP;chronic arterial hypertensionusuallydoesnot af-fect the ICP. On the other hand, any elevation ofthe venous pressure (normal central venous pres-sure: 40–120mmH2O) due to Valsalva maneu-vers, hypervolemia, right heart failure, changesinbodyposition, or obstructionof jugular venousdrainage elevates the ICP by a comparableamount. Acidosis (defined as pH ! 7.40), whichmay be due to hypoxia, ischemia, or hypoventila-tion, causes cerebral vasodilatation and in-

creased cerebral blood volume, thereby elevat-ing the ICP. Chronic obstructive pulmonary dis-ease can elevate the ICP by this mechanism. Onthe other hand, alkalosis (e. g., due to hyperventi-lation) reduces the cerebral blood volume andthusalso the ICP. CBFand ICPareelevated in feverand low in hyperthermia.

Intracranial Space-occupying Lesions

Extra-axial or intra-axial compression of braintissue elevates the ICP, calling compensatorymechanisms into play; once these have been ex-hausted, mass displacement of brain tissue oc-curs, possibly resulting in herniation. The dis-tribution of pressure within the cranial cavity isa function of the structure of the brain and thepartitioning of the cavity by dural folds (p. 6).Different herniation syndromes occur depend-ing on the site and extent of the causative le-sion: subfalcine herniation involves movementof the cingulate gyrus under the falx cerebri;transtentorial herniation involves movement ofthe medial portion of the temporal lobe acrossthe tentorial notch; upward posterior fossaherniation involves movement of the brain stemand cerebellum across the tentorial notch; anddownward posterior fossa herniation involvesmovement of the cerebellar tonsils across theforamen magnum.In cerebral edema, accumulation of water andelectrolytes in brain tissue causes an increase inbrain volume. Vasogenic cerebral edema is due toincreased capillary permeability and mainly af-fects white matter; it is caused by brain tumor,abscess, infarction, trauma, hemorrhage, andbacterial meningitis. Cytotoxic cerebral edemaaffects both white and gray matter and is due tofluid accumulation in all cells of the brain (neu-rons, glia, endothelium) because of hypoxia/ischemia or acute hypotonic hyperhydration(water intoxication, dysequilibrium syndrome,inadequate ADH syndrome). Hydrocephalic (in-terstitial) brain edema is found in the walls ofthe cerebral ventricles and results from move-ment of fluid from the ventricles into the adja-cent tissue in the setting of acute hydro-cephalus.1The MAP can be estimated with the following formulas:MAP = [(systolic BP) + (2 ! diastolic BP)] ! 1/3 or, equiv-alently, MAP = diastolic BP + [(BP amplitude) ! 1/3]


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Etiology of hydrocephalus (right: normal state)

Pressure-volume curve(green, compensation; red, decompensation)

Cerebral edema (left, vasogenic; right, cytotoxic)

Subarach-noid space

Venous sinus

Brain

70605040302010

Ventricularsystem

Arteries

Supratentorial mass

Subfalcine herniation

Ventricular compression

Transtentorial herniation

Upwardposterior

fossa her-niation

Infraten-torial mass

Tonsillarherniation

Pontomesencephalic compression,hemorrhagesOpen zonula

occludens(tight junction)

Trans en-dothelialdiffusion

Pinocytotic transport

Astrocyte

Edema of astrocytes/endothelial cells

Obstructive hydrocephalus

Communicating hydrocephalus

Sinus thrombosis

Space-occupying lesion (mass)

ICP (mm Hg)

Compliance = V/ P

PV

Volume

VV

Elastance = P/ V

VV

V

V


Intracranial

Pressure


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3 Neurological Syndromes

! Brain Disorders

! Spinal Disorders

! Peripheral Neuropathies

! Myopathies


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A stroke is an acute focal or global impairment ofbrain function resulting from a pathologicalprocess (e. g. thrombus, embolus, vessel rup-ture) of the blood vessels. Its causes, in order ofdecreasing frequency, are ischemia (80%), spon-taneous intracerebral or intraventricular hemor-rhage (15%), and subarachnoid hemorrhage (5%).The signs and symptoms of stroke are usuallynot specific enough to enable identification ofits etiology without further diagnostic studies.CT, MRI, cerebrovascular ultrasonography, ECG,and laboratory testing are usually needed.

Symptoms and Signs

The clinical manifestations of stroke persist, bydefinition, for more than 24 hours, and are oftenpermanent, though partial recovery is common.The duration of symptoms and signs seems notto be correlated with the etiology of stroke.

Ischemia. A transient ischemic attack (TIA)differs from a stroke (by definition) in that itssymptoms and signs resolve completely within24 hours. The vast majority of TIAs resolvewithin one hour, and only 5% last longer than 12hours. Patients with crescendo TIAs (a rapid suc-cession of TIAs) have a high risk of developing a(completed) stroke, which can cause neurologi-cal deficits that are either minor (minor stroke)or major (disabling stroke, major stroke). A stut-tering, fluctuating, or progressive course ofstroke development (stroke in evolution) is un-common.Hemorrhage. Nontraumatic intracerebral he-morrhages usually cause acute neurologicaldeficits that persist thereafter. If deficits worsenafter the initial hemorrhage, the cause is eitherrecurrent hemorrhage or a complication of theinitial hemorrhage (cerebral edema, electrolyteimbalance, or heart disorder).

Type of Deficit Clinical Manifestations

Weakness(pp. 46 ff, 70)

Acute hemi-, mono-, or quadriparesis/quadriplegia (ca. 80–90%); loss of coordinationand balance; hyperkinesia (during or after stroke), e. g. hemichorea, hemiballism, or(rarely) dystonia

Sensory loss(pp. 70 ff, 106)

Injury of postcentral cortex or subcortical area ! distal sensory (often also motor) defi-cit in contralateral limbs. Paresthesiae and loss of stereognosis, graphesthesia,topesthesia, and acrognosis are prominent

Oculomotor andvisual disturbances(pp. 70, 82 ff)

Conjugate horizontal eye movements, disjugate gaze, nystagmus, diplopia. Visual fielddefects (p. 82), transient monocular blindness (= amaurosis fugax)

Headache (p. 182) May be caused by subarachnoid hemorrhage, temporal arteritis, venous sinus thrombo-sis, arterial dissection, cerebellar hemorrhage, massive intracerebral hemorrhage (rare)

Impairment of con-sciousness (pp. 116,204)

TIA and stroke generally do not impair consciousness (exception: brainstem stroke,massive supratentorial stroke with bilateral cortical dysfunction)

Behavioral changes(p. 122 ff)

Aphasia, confusion (must be distinguished from aphasia), impairment of memory, neg-lect, impaired affect control (compulsive crying and/or laughing), apraxia. Mentalchanges, especially depression and anxiety disorders, are common after stroke

Dysarthria anddysphagia (pp. 102,130)

Severe dysarthria is often accompanied by coughing, difficulty chewing, and dysphasia.Pseudobulbar palsy ! loss of voluntary motor control (e. g., swallowing, speaking,tongue movement) with preservation of involuntary movements (e. g., yawning,coughing, laughing)

Dizziness (p. 58) Cerebellum, brainstem (vertigo, nausea, nystagmus)

Epileptic seizures(p. 192 ff)

Simple partial, complex partial, or generalized tonic-clonic seizures may occur duringor after a stroke

Respiratory disorders(p. 150)

Hiccups (singultus) often occur in stroke, particularly in lateral medullary infarction.Central hyperventilation is associated with a poor prognosis. Bihemispheric lesions maycause Cheyne–Stokes respiration (p. 118)

Minor complications of stroke: Mild unilateral arm paresis, moderate sensory loss, mild dysarthria; these patientscan care for themselves. Major complications: Aphasia, spastic hemiplegia, and hemianopsia; these patientsgenerally need nursing care.

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Time course

Causes of stroke

Stroke(right hemiplegia, aphasia, conjugategaze deviation to left)

TIAProgressive deficit

Territorial infarct(anterior cerebral a., CT)

Territorial infarct(posterior inferior cerebellar a., CT)

Intracerebral hemorrhage(brain stem, CT)

Subarachnoid hemorrhage (CT) Aneurysm(internal carotid a., MRI)

Persistent deficit

Territorial infarct(anterior + middle cerebral a., CT)

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Stroke Syndromes: Carotid ArteryTerritory

! Brachiocephalic Trunk

Brachiocephalic trunk occlusion by emboli fromthe aortic arch has the same clinical manifesta-tions as internal carotid artery (ICA) occlusion.Patients with adequate collateral flow remainasymptomatic.

! Common Carotid Artery (CCA)

CCA occlusion is very rare and, even when it oc-curs, is usually asymptomatic, because of an ade-quate collateral supply. When symptoms dooccur, theyare the sameas thoseof ICAocclusion.

! Internal Carotid Artery (ICA)

Territorial infarcts affect the middle cerebralartery (MCA) more often than the anterior cere-bral artery (ACA). If the ICA is occluded and col-lateral flow via the circle of Willis is inadequate,extensive infarction occurs in the anterior two-thirds of the hemisphere, including the basalganglia. Symptoms include partial or total blind-ness in the ipsilateral eye, impairment of con-sciousness (p. 116), contralateral hemiplegiaand hemisensory deficit, homonymous hemi-anopsia, conjugate gaze deviation to the side ofthe lesion, and partial Horner syndrome. ICA in-farcts in the dominant hemisphere produceglobal aphasia. The occipital lobe can also be af-fected if the posterior cerebral artery (PCA)arises directly from the ICA (so-called fetalorigin of the PCA). Border zone infarcts occur indistal vascular territories with inadequate col-lateral flow. They affect the “watershed” areasbetween the zones of distribution of the majorcerebral arteries in the high parietal and frontalregions, as well as subcortical areas at the inter-face of the lenticulostriate and leptomeningealarterial zones.Ophthalmic artery. Occlusion leads to suddenblindness (“black curtain” phenomenon or cen-tripetal shrinking of the visual field), which isoften only temporary (amaurosis fugax = tran-sient monocular blindness). Thorough diagnosticevaluation is needed, as the same clinical syn-drome can be produced by other ophthalmo-logical diseases (Table 22a, p. 372).Anterior choroidal artery (AChA). Infarction inthe AChA territory, depending on its precise lo-

cation and extent, can produce contralateralmotor, sensory, or mixed deficits, hemiataxia,homonymous quadrantanopsia (both upper andlower), memory impairment, aphasia, andhemineglect.Anterior cerebral artery (ACA). Contralateralhemiparesis is usually more distal than proxi-mal, and more prominent in the lower than inthe upper limb (sometimes only in the lowerlimb). Infarction in the territory of the centralbranches of the ACA (A1 segment, recurrentartery of Heubner) produces brachiofacial hemi-paresis, sometimes accompanied by dystonia.Bilateral ACA infarction (when the arteries ofboth sides share a common origin) and infarc-tions of the cortical branches of the ACA produceabulia (p. 120), Broca aphasia (dominant hemi-sphere), perseveration, grasp reflex, palmomen-tal reflex, paratonic rigidity (gegenhalten), andurinary incontinence. Lesions in the superiorandmedial frontal gyri or the anterior portion ofthe cingulate gyrus cause bladder dysfunction.Disconnection syndromes due to lesions of thecorpus callosum are characterized by ideomotorapraxia, dysgraphia, and tactile anomia of theleft arm.Middle cerebral artery (MCA). Main trunk (M1)occlusion produces contralateral hemiparesis orhemiplegia with a corresponding hemisensorydeficit, homonymous hemianopsia, and globalaphasia (dominant side) or contralateralhemineglect with limb apraxia (nondominantside). Occlusion of the posterior main branchproduces homonymous hemianopsia or quad-rantanopsia as well as Wernicke or globalaphasia (dominant side) or apraxia and dyscal-culia (nondominant side); central main branchocclusion produces contralateral brachiofacialweakness and sensory loss; anterior branch oc-clusion on the dominant side additionally pro-duces Broca aphasia. Occlusion of peripheralbranches produces monoparesis of the face,hand, or arm. Occlusions of the lenticulostriatearteries, depending on their precise location,produce (purely motor) hemiparesis/hemiple-gia, or hemiparesis with ataxia (lacunar infarct,p. 172).

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Visual distur-bance

Anteriorcerebral a.

Middlecerebral a.

Anterior/middlecerebral a. (border zone)

Lenticulostriatearteries (endzone)


Ophthalmic a.(amaurosis fugax)

Internal carotid a.(brachiocephalic trunk,common carotid a.)

Internal carotid a. (branches) Leptomeningeal arterial anastomoses

Anterior cerebral a. Middle cerebral a.

Internal carotid a.(terminal branches)

Internal carotid a. (terminal branches)

Middle/posterior cerebral a.(border zone)

Middlecerebral a.

Basal ganglia

Thalamus

Lenticulo-striate a.

Internalcarotid a.

Anteriorcerebral a.

Terminal branches

Central branches

Terminal branches

A. of central sul-cus (rolandic a.)

Pericallosal a.A. of

angulargyrus

Temporal aa.


Basilar a.

Vertebral a.

Callosomarginal a.

Frontopolar a.

Anteriorcerebrala.


Ophthalmic a.

Internal carotid a.

Central branches

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Stroke Syndromes: VertebrobasilarTerritory

! Subclavian Artery

High-grade subclavian stenosis or occlusionproximal to the origin of the vertebral arterymay cause a reversal of blood flow in the verte-bral artery, which worsens with exertion of theipsilateral arm (subclavian steal). Rapid armfatigue and pain often result; less common arevertigo and other brain stem signs. The arterialblood pressure is measurably different in thetwo arms.

! Vertebral Artery (VA)

VA occlusion produces variable combinations ofsymptoms and signs, including homonymoushemianopsia, dysarthria, dysphagia, unilateralor bilateral limb paralysis with or withoutsensory deficit, ataxia, drop attacks (due tomedullary ischemia), and impairment of con-sciousness. Unilateral VA occlusion (e. g., due todissection) can lead to infarction in the territoryof the posterior inferior cerebellar artery.

! Cerebellar Arteries

Large cerebellar infarcts can cause brain stemcompression and hydrocephalus.Posterior inferior cerebellar artery (PICA). Dor-solateral medullary infarction produces (usuallyincomplete) Wallenberg syndrome (p. 361).Often, only branches to the cerebellum are af-fected (! vertigo, headache, ataxia, nystagmus,lateropulsion).Anterior inferior cerebral artery (AICA). AICA oc-clusion is rare. It produces ipsilateral hearingloss, Horner syndrome, limb ataxia, and disso-ciated facial sensory loss, as well as contralateraldissociated sensory loss on the trunk and limbs(mainly the upper limbs) and nystagmus.Superior cerebellar artery (SCA). SCA occlusioncan produce ipsilateral Horner syndrome, limbataxia, dysdiadochokinesia, and CN VI and VIIpalsy, as well as contralateral hypesthesia andhypalgesia.

! Basilar Artery (BA)

Basilar artery occlusion. Thrombotic occlusionof the BA may be heralded several days in ad-vance by nonspecific symptoms (unsteadiness,dysarthria, headache, mental changes). BA oc-

clusion causes impairment of consciousness(ranging from somnolence to coma), mentalsyndromes (hallucinations, confabulation, psy-choses), quadriparesis, and oculomotor dis-orders (diplopia, vertical or horizontal gazepalsy). Apical BA occlusion (p. 359) is caused bycardiac or arterial emboli. Pontine infarctionsparing the posterior portion of the pons (teg-mentum) produces quadriplegia and mutismwith preservation of sensory function and verti-cal eye movements (locked-in syndrome, pp. 120,359).Paramedian infarction in the BA territory usu-ally affects the pons (pp. 72, 359 ff).Dorsolateral infarction affects the cerebellum,with a corresponding clinical picture. Occlusionof the labyrinthine artery (a branch of the AICA)produces rotatory vertigo, nausea, vomiting andnystagmus.

! Posterior Cerebral Artery (PCA)

PCA occlusion is rare and produces symptomsand signs similar to those of MCA infarction.Unilateral occlusion of a cortical branch pro-duces homonymous hemianopsia with sparingof the macula (supplied by the MCA), while bi-lateral occlusion produces cortical blindnessand, occasionally, Anton syndrome (p. 132). Cen-tral branch occlusion leads to thalamic infarc-tion (p. 106; Dejerine–Roussy syndrome), re-sulting in transient contralateral hemiparesis,spontaneous pain (“thalamic pain”), sensorydeficits, ataxia, abasia, choreoathetosis,“thalamic hand” (flexion of the metacar-pophalangeal joints with hyperextension of theinterphalangeal joints), and homonymoushemianopsia. If branches to the midbrain are af-fected, an ipsilateral CN III palsy results, accom-panied by variable contralateral deficits includ-ing hemiparesis/hemiplegia, (rubral) tremor,ataxia, and nystagmus. Isolated hemihypesthe-sia is associated with thalamic lacunar infarc-tion.

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Medulla (dorsolateral branch)

Cerebellar hemisphere (medial branch)

Posterior inferior cerebellar a.

Craniocervical collaterals(Example: subclavian steal)

Ophthalmica.

Subclavian a.occlusion

Internalcarotid a.

Basilar a.

Vertebral a.

External carotid a.


Capsula internaPutamen

Caudate nucleus


VVII, VIII

External capsule

Basilar a.

Ventricle

Hypothalamus

Thalamus

Anteriorcerebrala.

Internalcapsule

Caudatenucleus

Internal carotid a.

Posterior cerebral a.Putamen


Pericallosal a.

Posterior inferior cerebellar a.

Paramedianpontineinfarct

Dorsolateral infarct

Anterior inferior cerebellar a.

Anteriorcerebral a.

Middlecerebral a.


Basilar a. MRI (sagittal) Posterior cerebral a.

Terminal branches

Central branches

Vertebrobasilar vessels

Vessels of basal ganglia(schematic)

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! Risk Factors

The risk of stroke increases with age and ishigher in men than in women at any age. Majorrisk factors include arterial hypertension(!140mmHg systolic, !90mmHg diastolic),diabetes mellitus, heart disease, cigarette smok-ing, hyperlipoproteinemia (total cholesterol!5.0mmol/l, LDL !3mmol/l, HDL "0.9–1.2mmol/l), elevated plasma fibrinogen, and obes-ity. Symptomatic or asymptomatic carotidartery stenosis, elevated plasma homocysteinelevels, erythrocytosis, anti-phospholipid antibo-dies, alcohol abuse (#60 g of alcohol @ 75 cl ofwine per day in men, #40 g in women). Drugabuse (amphetamines, heroin, cocaine), asedentary lifestyle, and low socioeconomic sta-tus (unemployment, poverty) also increase therisk of stroke.

! Causes

Embolism (ca. 70%) is the most common causeof stroke. Emboli arise from local atheromatouslesions (atheromatous thromboembolism) onthe walls of large arteries (macroangiopathy) ofthe brain or heart (cardiac embolism in atrial fi-brillation, valvular heart disease, ventricularthrombus, and myxoma).Thrombosis (ca. 25%). Occlusion of a small end-artery (microangiopathy, small vessel disease)causes lacunar infarction. The cause is hyaline(lipohyalinosis)orproximal sclerosisofpenetrat-ing arteries (lenticulostriate, thalamoperforatingor pontine arteries, central branches). Causal fac-tors include hypertension, diabetes, and blood–brain barrier disruption leading to deposition ofplasma proteins in the arterial wall. Microan-giopathy-related hemodynamic changes some-times cause hemodynamic infarction.Rare causes (ca. 5%) include hematological dis-eases (e. g., coagulopathy, abnormal blood vis-cosity, anemia, leukemia) and arterial processes(dissection, vasculitis, migraine, fibromusculardysplasia, moyamoya, vasospasm, amyloid an-giopathy, and CADASIL = cerebral autosomaldominant arteriopathy with subcortical infarctsand leukoencephalopathy).

! Infarct Types

Lacunar infarcts (“small deep infarcts”). Lacunesare small ($1.5 cm in diameter), round or oval

infarcts in the subcortical periventricular regionor brain stem. Classic lacunar syndromes in-clude purely motor hemiparesis (internal cap-sule, corona radiata, pons), contralateral purelysensory deficit (thalamus, internal capsule),ataxic hemiparesis (internal capsule, coronaradiata, pons), and dysarthria with clumsinessof one hand (= clumsy hand–dysarthria syn-drome; internal capsule, pons). The presence ofmultiple supratentorial and infratentoriallacunes is termed the lacunar state (“étatlacunaire”) and is clinically characterized bypseudobulbar palsy (p. 367), small-step gait(“marche à petit pas”), urinary incontinence,and affective disorders (compulsive crying). Forleukoaraiosis, see p. 298.Territorial infarcts are those limited to the dis-tribution of the ACA, MCA, or PCA. With the ex-ception of striatocapsular infarcts (internal cap-sule, basal ganglia), these infarcts are predomi-nantly cortical. Embolic territorial infarcts oftenundergo secondary hemorrhage (“hemorrhagicconversion”).End zone infarcts. Low-flow infarction in thesubcortical white matter is due to extracranialhigh-grade vessel stenosis and/or inadequatecollateral flow.Border zone infarcts (p. 168) also result fromhemodynamic disturbances due to microan-giopathy. They are found at the interface (“wa-tershed”) between adjacent vascular territories,and can be either anterior (MCA–ACA ! con-tralateral hemiparesis and hemisensory deficit,mainly in the lower limb and sparing the face,with or without aphasia) or posterior (MCA–PCA ! contralateral hemianopsia and corticalsensory deficit, with or without aphasia).Global cerebral hypoxia/ischemia. The causesinclude cardiac arrest with delayed resuscita-tion, hemorrhagic shock, suffocation, and car-bon monoxide poisoning. Global cerebral hy-poxia/ischemia causes bilateral necrosis of braintissue, particularly in the basal ganglia andwhite matter.

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Thrombus in aortic arch

Intracardiac thrombi(atrium, valves, ventricle)

Intracranial arterial stenosis

Lacunes

Intima

Media

Atherosclerosis (plaque)

Thrombus (source of embolism)

Embolus

Thrombi

Carotid stenosis(hemodynamicdisturbance)

Arterio-arterialthrombo-emboli

Cardio-genic thromboemboli

Carotidstenosis

Thalamus

Basal ganglia

Anterior cerebral a. Middle

cerebral a.

Middle/anterior cerebral a.

Middle/posterior cerebral a.

Sources of thromboembolism

Arterial dissection

Thromboembolism

Subcortical arteriosclerotic encephalopathy

Lacunar state(brain stem)

Territorial infarct(middle cerebral a.)

End zoneinfarcts

Border zoneinfarcts

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Stroke Pathophysiology

Hemodynamic insufficiency. Cerebrovascularautoregulation is normally able to maintain arelatively constant cerebral blood flow (CBF) of50–60ml/100 g brain tissue/min as long as themean arterial pressure (MAP) remains withinthe range of 50–150mmHg (p. 162). The re-gional cerebral blood flow (rCBF) is finely ad-justed according to local metabolic require-ments (coupling of CBF and metabolism). If theMAP falls below 50mmHg, and in certain patho-logical states (e. g., ischemia), autoregulationfails and CBF declines. Vascular stenosis or oc-clusion induces compensatory vasodilatationdownstream, which increases the cerebral bloodvolume and CBF (vascular reserve); the extent oflocal brain injury depends on the availability ofcollateral flow, the duration of hemodynamicinsufficiency, and the vulnerability of the partic-ular brain region affected. Major neurologicaldeficits arise only when CBF falls below thecritical ischemia threshold (ca. 20ml/100 g/min).Hypoperfusion. If adequate CBF is not reestab-lished, clinically evident neurological dysfunc-tion ensues (breakdown of cerebral metabolism! EEG and evoked potential change). Prolonged,severe depression of CBF below the infarctionthreshold of ca. 8–10ml/100 g/min causes pro-gressive and irreversible abolition of all cellularmetabolic processes, accompanied by structuralbreakdown (necrosis). Infarction occurs wherehypoperfusion is most severe; the area of tissuesurrounding the zone of infarction in which theCBF lies between the thresholds for ischemia andinfarction is called the ischemic penumbra. Braintissue in the zone of infarction is irretrievablylost, while that in the ischemic penumbra is atrisk, but potentially recoverable. The longer theischemia lasts, the more likely infarction willoccur; thus, time is brain. The zones of infarctionand ischemia are well demonstrated by recentlydeveloped MRI techniques (DWI, PWI).1,2

Stroke Treatment

Primary prevention involves the therapeuticmodification or elimination of risk factors.

Patients with asymptomatic stenosis are givenantiplatelet therapy (APT) consisting of aspirin,aspirin–dipyridamole combination, or clopido-grel. Endarterectomy may be indicated inasymptomatic high-grade stenosis (!80%4 or!90%3). Anticoagulants may be indicated inpatients with atrial fibrillation without rheu-matic valvular heart disease, depending on theirindividual risk profile (TIAs, age, comorbidities).Acute treatment is based on the existence of a3–6-hour interval between the onset ofischemia and the occurrence of maximum irre-versible tissue damage (treatment window).General treatment measures include the as-surance of adequate cardiorespiratory status(normal blood oxygenation is essential for thesurvival of the ischemic penumbra); because au-toregulation of CBF in the penumbra is im-paired, the systolic BP should be maintainedabove 160mmHg. The serum glucose levelshould not be allowed to exceed 200mg/100ml.Balanced fluid replacement should be provided,and fever, if it occurs, should be treated. Physici-ans should be vigilant in the recognition andtreatment of complications such as aspiration(secondary to dysphagia), deep venous throm-bosis (secondary to immobility of a plegic limb),cardiac arrhythmia, pneumonia, urinary tractinfection, and pressure sores. Rehabilitationmeasures include physical, occupational, andspeech therapy, as well as psychological coun-seling of the patient and family.Special treatment measures: APT (after exclusionof hemorrhage); thrombolysis, treatment ofcerebral edema, surgical decompression inspace-occupying cerebellar or MCA infarcts, andanticonvulsants, as needed.Secondary prevention. APT (TIA, mild stroke,atherothrombotic stroke); oral anticoagulation(cardiac embolism, arterial dissection); en-darterectomy (in symptomatic carotid stenosis!70%4, or !80%3, or after mild strokes). Thepotential utility and indications of carotid an-gioplasty and stenting in the treatment ofcarotid stenosis are currently under intensivestudy.

1Diffusion-weighted imaging (DWI) demonstrates the zone of infarction; the early CT signs of infarction (blurring of in-sular cortex, hypodensity of basal ganglia, cortical swelling) are less reliable.2Perfusion-weighted imaging (PWI) demonstrates the ischemic penumbra and zone of oligemia (tissue at risk).3Data from the European Carotid Surgery Trial (ECST).4Data from the North American Symptomatic Carotid Endarterectomy Trial (NASCET).

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50

40

30

20

10

0

Ischemic cascade

Time course of ischemic lesion development

Decades Years Hours Minutes

Hemodynamic disturbances (asymptomatic)

Metabolic disturbances(asymptomatic)

InfarctPenumbra

Osmolysis

Cell death

(TIA, reversibledeficit)

O2U

pH ,lactic acidosis

VGCC open

Glutamate

(Irreversibledeficit)

CellularCa2+

influxCBV

CBV/CBF

O2

GU

Normal O2U

Free radicals

CBF CBVGU O2O2UVGCC

= ==== =

Cerebral blood flowCerebral blood volumeCerebral glucose utilizationCerebral oxygen extractionCerebral oxygen utilizationVoltage-gated calcium channels

CBF (ml/100g/min)

Arterial occlusion(no perfusion)

Collateral vessel(vascular reserve)

Collateral vessel

Region of infarctionPenumbra

Intact brain tissue

Ischemic threshold

Infarction threshold

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Clinical Features

Spontaneous (i.e., nontraumatic) intracranialhemorrhage may be epidural, subdural (p. 267),subarachnoid, intraparenchymal, or in-traventricular. Its site and extent are readilyseen on CT (somewhat less well on MRI) and de-termine its clinical manifestations.

! Subarachnoid Hemorrhage (SAH)

Symptoms and signs. The typical presentationof aneurysmal rupture (by far the most commoncause of SAH) is with a very severe headache ofabrupt onset (“the worst headache of my life”),often initially accompanied by nausea, vomit-ing, diaphoresis, and impairment of conscious-ness. The neck is stiff, and neck flexion is painful.There may also be focal neurological signs, pho-tophobia, and/or backache. Subarachnoid bloodcan be seen on CT within 24 hours of the hemor-rhage in roughly 90% of cases. If SAH is sus-pected but the CT is negative, a diagnostic lum-bar puncture must be performed.Complications. The initial hemorrhage may ex-tend beyond the subarachnoid space into thebrain parenchyma, the subarachnoid space, and/or the ventricular system. A ruptured saccularaneurysm may rebleed at any time until it isdefinitively treated; the rebleed risk is highest onthe day of onset (day 0), and 40% in the ensuing 4weeks. The greater the amount of blood in thesubarachnoid cisterns, the more likely that va-sospasm anddelayed cerebral ischemiawill occur;the risk is highest between days 4 and 12. Clottedblood blocking the ventricular system or thearachnoid villi can lead to hydrocephalus, of ob-structive or malresorptive type, respectively(p. 162). Other complications include cerebraledema, hyponatremia, neurogenic pulmonaryedema, seizures, and cardiac arrhythmias.

! Intracerebral Hemorrhage

Intraparenchymal hemorrhages of arterialorigin are to be distinguished from secondaryhemorrhages into arterial or venous infarcts.General features. Sudden onset of headache, im-pairment of consciousness, nausea, vomiting,and focal neurological signs, with acute progres-sion over minutes or hours.Hemorrhage into the basal ganglia. Putaminalhemorrhage produces contralateral hemipare-

sis/hemiplegia and hemisensory deficit, conju-gate horizontal gaze deviation, homonymoushemianopsia, and aphasia (dominant side) orhemineglect (nondominant side). Thalamichemorrhage produces similar manifestationsand also vertical gaze palsy, miotic, unreactivepupils, and (sometimes) convergence paresis.The very rare caudate hemorrhages are charac-terized by confusion, disorientation, and con-tralateral hemiparesis. Hemorrhage into thebasal ganglia and internal capsule leads to coma,contralateral hemiplegia, homonymous hemi-anopsia, and aphasia (dominant side).Lobar hemorrhage usually originates at thegray–white matter junction and extends inwardinto the white matter, producing variable clini-cal manifestations. Frontal lobe: Frontal head-ache, abulia, contralateral hemiparesis (armmore than leg). Temporal lobe: Pain around theear, aphasia (dominant side), confusion, upperquadrantanopsia. Parietal lobe: Temporal head-ache, contralateral sensory deficit, aphasia,lower quadrantanopsia. Occipital lobe: Ipsi-lateral periorbital pain, hemianopsia.Cerebellar hemorrhages are usually restricted toone hemisphere. They produce nausea, vomit-ing, severe occipital headache, dizziness, andataxia.Brain stem hemorrhage. Pontine hemorrhage isthe most common type, producing coma, quad-riplegia/decerebration, bilateral miosis (pin-point pupils), “ocular bobbing,” and horizontalgaze palsy. Locked-in syndrome may ensue.General complications. Intraventricular exten-sion of hemorrhage, hydrocephalus, cerebraledema, intracranial hypertension, seizures, andhemodynamic changes (often a dangerouselevation of blood pressure).

! Intraventricular Hemorrhage

Intraventricular hemorrhage only rarely origi-nates in the ventricle itself (choroid plexus). It ismuch more commonly the intraventricular ex-tension of an aneurysmal SAH or other brainhemorrhage.Symptoms and signs. Acute onset of headache,nausea, vomiting, impairment of consciousnessor coma.Complications. Extension of hemorrhage, hy-drocephalus, seizures.

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Subarachnoid hemorrhage (SAH)

Intracranial hemorrhages (mass effect not shown)

Headache of SAH

Retinal hemorrhage in SAH

Hypertensive changes in ocular fundus (grade 3)

Cotton-wool spots

Accumulation of blood in

subarachnoid space

Hemorrhage into basal ganglia/thalamus

Lobar hemorrhage Brain stem hemorrhage

Cerebellarhemorrhage

Intraventricular hemorrhage

Hemorrhage


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Pathogenesis

Subarachnoid hemorrhage (SAH). Roughly 85%of cases of SAH are caused by rupture of a saccu-lar aneurysm at the base of the skull. Another10% are caused by nonaneurysmal lesions(whose nature is not, at present, understood),with bleeding mainly in the perimesencephaliccisterns (p. 8). Other, rare, causes include verte-bral artery dissection, arteriovenous malforma-tion (AVM), cavernoma, hypertension, anti-coagulation, and trauma.Aneurysm. An aneurysm is not a congenital le-sion, but a progressive, localized dilatation of anarterial wall. Saccular aneurysms tend todevelop at branching sites of the internal carotidartery (ICA), the anterior communicating artery,and the proximal middle cerebral artery (MCA).Fusiform aneurysms usually appear as an elon-gated, twisted, and dilated segment (dolichoec-tasis) of the basilar artery or supraclinoid ICA.Most are due to atherosclerosis. Spontaneoushemorrhage is rare; ischemia due to arterio-arterial embolism is more common. The rareseptic-embolic aneurysms (mycotic aneurysms)may be secondary to endocarditis, meningoen-cephalitis, hemodialysis, or intravenous drugadministration. They are located in distal vesselsegments, particularly in the MCA, and maycause SAH, massive hemorrhage, or infarctionwith secondary hemorrhage.Vascular malformations. Arteriovenous malfor-mations (AVMs) are congenital lesions con-sisting of a tangled web of arteries and veinswith pathological arteriovenous shunting. Mostare located near the surface of the cerebralhemispheres. AVMs tend to enlarge over timeand may become calcified. They may cause sub-arachnoid or intracerebral hemorrhage at anyage. They become clinically manifest eitherthrough a hemorrhage or through headache,seizures, or focal neurological signs (aphasia,hemiparesis, hemianopsia).Cavernomas are compact, often calcified, aggre-gations of dilated blood vessels and connectivetissue in the brain and leptomeninges. Theyrarely bleed (ca. 0.5%/year). Some cause seizuresand focal deficits; others are discovered on MRIscans as an incidental finding.Intracerebral hemorrhage. Hypertension is themost common cause; other causes include

aneurysm, AVM, cerebral amyloid angiography,moyamoya, coagulopathy (leukemia, throm-bocytopenia, therapeutic anticoagulation), cere-bral vasculitis, cerebral venous thrombosis, drugabuse (cocaine, heroin), alcohol, metastases,and brain tumors. Massive hypertensive hemor-rhage is thought to be caused by pressure-in-duced rupture of arterioles and micro-aneurysms. The high pressure and a kind ofchain reaction involving multiple micro-aneurysms is thought to explain the size ofthese hemorrhages (despite the small caliber ofthe ruptured vessels). The recurrent, mainly cor-tical, bleeding associated with cerebral amyloidangiopathy is due to the fragility of lepto-meningeal and cortical small vessels in whosewalls amyloid deposits have accumulated.Dural fistula is an abnormal anastomosis be-tween dural arteries and a venous sinus. Hemor-rhage is rare; they may cause pulsating tinnitus,headache, papilledema, and visual disturbances.

TreatmentAneurysmal hemorrhage. Cautious transport,bed rest, analgesia, admission to a neurosurgicalunit, and angiography to establish the diagnosisand define the anatomy of the aneurysm(s). Thetiming of surgical clipping depends on the siteand clinical severity of the hemorrhage, theaneurysm’s configuration, and the age andgeneral medical condition of the patient. In-operable cases can be managed with intravascu-lar neuroradiological techniques (“emboliza-tion”; filling with Guglielmi detachable coils(GDC) is currently favored).Hemorrhage from an AVM may be treated withsurgery, embolization, and/or stereotactic radio-surgery, depending on its site and extent. Caver-nomas that bleed are usually excised.Intracerebral hemorrhage is often treated con-servatively, unless it impairs consciousness orcauses a progressive neurological deficit. Majorcerebellar hemorrhage (rule of thumb: !3 cm)is life-threatening unless treated neurosurgi-cally.


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Vessel wall damage

Cavernoma

Source of hemorrhage(saccular aneurysm)

Lenticulostriate arteries

Internal carotid a.

Vertebral a.

Basilar a.

Posteriorcommuni-cating a.

Middle cerebral a.



Ruptured aneurysm Common aneurysm sites

Microaneurysms

Arteriovenous malformation Cavernoma (MRI)



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Sinus Thrombosis

Symptoms and signs. Aseptic sinus thrombosismost commonly affects the superior sagittalsinus and produces initial headache, vomiting,and focal epileptic seizures, followed by mono-paresis or hemiparesis, papilledema, abulia, andimpairmentofconsciousness.Blockageofvenousoutflowcausescerebral edemaandruptureof thedistended cerebral veins upstream from thethrombosis.Septicsinusthrombosis isheraldedbyfever, chills, andmalaise. Pain, redness, and swel-ling of the eye or ear may develop, in addition tofocal neurological signs. Transverse and sigmoidsinus thromboses are often secondary to ear andmastoid infections,whilecavernoussinusthrom-bosis is often due to infections about the face(orbit, paranasal sinuses, teeth).Etiology. Aseptic sinus thrombosis may occurduringorafterpregnancy,or secondary to theuseof oral contraceptives, deficiencies of protein C,protein S, antithrombin III, or factor V, dehydra-tion, polycythemia vera, leukemia, Behçet dis-ease, trauma, surgical procedures, and malig-nancy. Septic sinus thrombosis often occurs bysecondary spread of infections about the head(sinusitis, otitis media, mastoiditis, facialfuruncle). Identification: CT or MRI angiographygenerally suffices to demonstrate the occludedsinus;conventionalangiographyisrarelyneeded.Treatment. Aseptic thrombosis: anticoagulation.Septic thrombosis (pp. 226, 375): antibiotics andsurgicalmanagement of the source of infection.

Cerebral Vasculitis

Primary vasculitis arises in the cerebral arteriesand veins themselves, while secondary vasculitisis a sequela of another disease (see Causes,below).Symptoms and signs. Cerebral vasculitis pro-duces variable symptoms and signs, includingrecurrent ischemia, intracerebral or sub-arachnoid hemorrhage, persistent headache,focal epilepsy, gradually progressive focal neu-rological signs, dementia, behavioral abnormali-ties, cranial nerve palsies, and meningismus.Vasculitis may also affect vessels of the spinalcord (transverse cord syndrome) and those sup-plying the peripheral nerves (painful mono-neuropathy).Causes. Isolated cerebral angiitis (idiopathic) isdifficult to diagnose because its findings arenonspecific (elevated CSF protein, EEG and MRIabnormalities). Leptomeningeal biopsy may beneeded. Primary or secondary vasculitides ofvarious kinds affect the vessels of the centralnervous system (CNS), peripheral nervous sys-tem (PNS) and/or skeletal muscles to a variableextent (see table).Treatment. Infectious vasculitis is treated withantiviral or antibacterial agents, as needed,while autoimmune vasculitis is treated withcorticosteroids and immune suppressants (cy-clophosphamide, azathioprine).

Syndrome CNS PNS Muscle

Churg–Strauss syndrome ++ +++ +

Wegener granulomatosis ++ ++ +

Behçet disease ++ +/– –

Lymphomatoid granulomatosis ++ +/– –

Syphilis, tuberculosis, herpes zoster, bacterial meningitis,fungal infection

++ +/– +/–

Temporal arteritis + +/– –

Polyarteritis nodosa + +++ +

Takayasu arteritis + – –

Lymphoma + + –

(From Moore and Calabrese, 1994)+++ usual, ++ common, + occasional, +/– rare, – absent

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Superior sagittal sinusConfluence of sinuses Transverse sinus

Sigmoid sinus

Thrombosed segment

Aseptic sinus thrombosis

Perivascular hemorrhage

Capillary

Aorta

Large tomedium-sizedartery

Smallartery Arteriole Venule

CT scan (axial)MRI scan (sagittal)

Vein

Schönlein-Henoch vasculitis and essential cryoglobulinemia

Wegener granulomatosis, Churg-Strauss syndrome

Microscopic polyangiitis

Polyarteritis nodosa, Kawasaki disease

Temporal arteritis, Takayasu arteritis

Cutaneous leukocytoclastic angiitis

Cerebral veins (normal MR angiogram)

Immune vasculitis(gray: regions most commonlyaffected by systemic vasculitis)

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Tension Headache

Tension headache often involves painful cervicalmuscle spasm, may change with the weather,and is frequently ascribed by patients andothers to cervical spinal degenerative disease,visual disturbance, or life stress. It consists of abilateral, prominent nuchal pressure sensationthat progresses over the course of the day.Patients may report feeling as if their head werebeing squeezed in a vise or by a band beingdrawn ever more tightly around it, or as if theirhead were about to explode, though the pain israrely so severe as to impede performance of theusual daily tasks, e. g., at work. It may be accom-panied by malaise, anorexia, lack of concentra-tion, emotional lability, chest pain, and mild hy-persensitivity to light and noise. Unlike mi-graine, it is not aggravated by exertion (e. g.,climbing stairs), nor does it produce vomiting orfocal neurological deficits. It can be episodic(!15 days/month, pain lasting from 30 minutesto 1 week) or chronic ("15 days/month for atleast 6 months). Some patients suffer from per-icranial tenderness (posterior cervical, mastica-tory, and cranial muscles). Isolated attacks ofsudden, stabbing pain (ice-pick headache) mayoccur on one side of the head or neck. Tensionheadache rarely wakes the patient from sleep.Its cause usually cannot be determined, thoughit may be due to disorders of the temporoman-dibular joint or psychosomatic troubles such asstress, depression, anxiety, inadequate sleep, orsubstance abuse. Tension headache combinedwith migraine is termed combination headache.Pathogenesis. It is theorized that diminished ac-tivity of certain neurotransmitters (e. g., endo-genous opioids, serotonin) may lead to abnor-mal nociceptive processing (p. 108) and thusproduce a pathological pain state.

Headache Due to Vascular Processes(Other than Migraine)

The nociceptive innervation of the extracranialand intracranial vessels is of such a nature thatpain arising from them is often projected to asite in the head that is some distance away fromthe responsible lesion. Thus, specific diagnosticstudies are usually needed to pinpoint the loca-tion of the disturbance. The pain may precede

the actual vascular event (arterial dissection,arteriovenous malformation, vasculitis), mayoccur simultaneously with the event (sub-arachnoid hemorrhage, intracerebral hemor-rhage, epidural hematoma, cerebral venousthrombosis, giant cell arteritis, carotidynia,venous outflow obstruction in goiter or medi-astinal processes, pheochromocytoma, pre-eclampsia, malignant hypertension), or may fol-low the event (subdural hematoma, intracere-bral hemorrhage, endarterectomy).

Chronic Daily Headache

Rational treatment is based on the classificationof primary daily headache by clinical charac-teristics (see Table 23, p. 373), and of secondary(symptomatic) headache by etiology.

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Vertebral, basilar, posterior cerebral arteries;transverse/sigmoid sinus

Persistent, variably severe headache

Carotid artery (common, external, internal) Internal carotid a., cavernous sinus


Depression

Referred pain due to cerebrovascular lesions

Tension headache

Anxiety

Stress

Noise

Alcohol

Medications

Transientstabbing pain

Episodic

Chronic

Headache

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Migraine

Migraine is a periodic headache often accom-panied by nausea and sensitivity to light andnoise (photophobia and phonophobia). A typicalattack consists of a prodromal phase of warning(premonitory) symptoms, followed by an aura,the actual headache phase, and a resolutionphase. Attack characteristics often change overtime. Attacks often tend to occur in the morningor evening but may occur at any time. They typi-cally last 4–72 hours.

! Symptoms and Signs

Prodromal phase. The migraine attack may bepreceded by a period of variable prodromal phe-nomena lasting a few hours to two days. Mostpatients complain of sensitivity to smells andnoise, irritability, restlessness, drowsiness,fatigue, lack of concentration, depression, andpolyuria. In children, the chief complaints areabdominal pain and dizziness.Aura. This is the period preceding the focal cere-bral symptoms of the actual migraine headache.Some patients experience attacks without anaura (common migraine), while others have at-tacks with an aura (classic migraine) thatdevelops over 5–20 minutes and usually lastsless than one hour, but may persist as long asone week (prolonged aura). In some cases, theaura is not followed by a headache (“migraineequivalent”). Auras typically involve visual dis-turbances, which can range from undulatinglines (resembling hot air rising), lightningflashes, circles, sparks or flashing lights (phot-opsia), or zig-zag lines (fortification figures, tei-chopsia, scintillating scotoma). The visual im-ages, which may be white or colored, cause gapsin the visual field and usually have scintillatingmargins. Unilateral paresthesiae (tingling orcold sensations) may occur. Emotional changes(anxiety, restlessness, panic, euphoria, grief,aversion) of variable intensity are relativelycommon.Headache phase. Most patients (ca. 60%) com-plain of pulsating, throbbing, or continuous painon one side of the head (hemicrania). Othershave pain in the entire head, particularly behindthe eyes (“as if the eye were being pushed out”),in the nuchal region, or in the temples. Migraineheadache worsens on physical exertion and is

often accompanied by anorexia, malaise,nausea, and vomiting.Resolution phase. This phase is characterized bylistlessness, lack of concentration, and increasedpain sensitivity in the head.

! Pathogenesis

During the interval between attacks, variousdisturbances (genetically determined) may beobserved, e. g., cerebral hypomagnesemia, ele-vated concentration of excitatory amino acids(glutamate, aspartate), and increased reactivityof cranial blood vessels. The cumulative effect ofthese disturbances is a heightened sensitivity tonociceptive stimuli (migraine pain threshold).Impulses from the cortex, thalamus, and hy-pothalamus activate the so-called migrainecenter responsible for the generation of mi-graine attacks, putatively located in the brainstem (serotonergic raphe nuclei, locus ceruleus).The migraine center triggers cortical spreadingdepression (suppression of brain activity acrossthe cortex) accompanied by oligemia, resultingin an aura. Trigeminovascular input frommeningeal vessels is relayed to the brain stem,via projecting fibers to the thalamus and then,by the parasympathetic efferent pathway, backto the meningeal vessels (trigeminal autonomicreflex circuit). Perivascular trigeminal C-fiberendings (trigeminovascular system) are stimu-lated to release vasoactive neuropeptides suchas substrate P, neurokinin A, and calcitoningene-regulated polypeptide (CGRP), causing a(sterile) neurogenic inflammatory response. Va-soconstriction and vascular hyperesthesia withsubsequent vasodilatation spread via trigeminalaxon reflexes. The perception of pain is medi-ated by the pathway from the trigeminal nerveto the nucleus caudalis, thalamus (p. 94) andcortex. Trigeminal impulses also reach auto-nomic centers.

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Prodromal phase Aura

Headache phase

Resolution phase

Triggers

Thalamus

Hypothalamus

Cerebral cortex

Trigeminal nerve

Nucleus caudalis

Pain

Locus ceruleus, raphe nuclei

Spinal tract of trigeminal nerve

Trigeminal lemniscus


Aura (spreading cortical

depression)

Trigeminovascular system

Axon reflexes, neuropeptide release

Vasodilatation, extravasation of plasma (via NO, neuropeptides)

Luminal narrowing

Perivascular trigeminal axons

Dura mater

Platelets (serotoninrelease)

Fortificationspectra

Nausea, vomiting, autonomic disturbances

Migraine attacks

Interval between attacks

Headache

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Trigeminal Neuralgia

Trigeminal neuralgia (tic douloureux) is charac-terized by the sudden onset of excruciating, in-tense stabbing pain (during waking hours).Several brief attacks (!2 minutes each) gener-ally occur in succession. The pain is almost al-ways precipitated by a trigger stimulus or activ-ity (e. g., chewing, speaking, swallowing, touch-ing the face, cold air, tooth brushing, shaving)and is located in the distribution of one or twobranches of the trigeminal nerve, usually V/2and/or V/3. Involvement of V/1, all threebranches, or both sides of the face is uncommon.The attacks may persist for weeks to months ormay spontaneously remit for weeks, or evenyears, before another attack occurs. Trigeminalneuralgia in the V/3 distribution is often mis-taken for odontogenic pain, sometimes result-ing in unnecessary tooth extraction. Typical (id-iopathic) trigeminal neuralgia must be distin-guished from secondary forms of the syndrome(see below).Pathogenesis. Idiopathic trigeminal neuralgia !

much evidence points to microvascular com-pression of the trigeminal nerve root (usually bya branch of the superior cerebellar artery)where it enters the brain stem, leading to thedevelopment of ephapses or suppression of cen-tral inhibitory mechanisms. Symptomatictrigeminal neuralgia ! cerebellopontine angletumors, multiple sclerosis, vascular malforma-tions.

Cluster Headache (CH)

Episodic cluster headache. Attacks of verysevere burning, searing, stabbing, burning,needlelike, or throbbing pain develop over a fewminutes on one side of the head, behind oraround the eye, and may extend to the forehead,temple, ear, mouth, jaw, throat, or nuchal re-gion. If untreated, attacks last ca. 15minutes to 3hours. They are predominantly nocturnal,waking the patient from sleep, but can alsooccur during the day. Attacks come in episodes(clusters) consisting of 1–3 daily bouts of painfor up to 8 weeks. A seasonal pattern of occur-rence may be observed. During a cluster, thepain can be triggered by alcoholic drinks,histamines, or nitrates. Temporal pressure or the

application of heat to the eye may alleviate thepain. Unlike migraine patients, who seek peaceand quiet, these patients characteristically pacerestlessly, and may even strike their aching headwith a fist. The headache may be accompaniedby ipsilateral ocular (watery eyes, conjunctivalinjection, incomplete Horner syndrome, photo-phobia), nasal (nasal congestion, rhinorrhea),and autonomic manifestations (facial flushing,tenderness of temporal artery, nausea, diarrhea,polyuria, fluctuating blood pressure, cardiacarrhythmia). Cluster headache is more commonin men.Chronic cluster headache. Attacks do not occurin clusters, but rather persist for more than oneyear at a time, punctuated by remissions lastingno longer than twoweeks. Chronic cluster head-ache may arise primarily, or else as a confluenceof clusters in what began as episodic clusterheadache.Pathogenesis. One hypothesis attributes CH todilatation of the carotid artery within thecarotid canal, causing compression of the peri-arterial sympathetic plexus. There is also evi-dence suggesting a role for inflammatory dilata-tion of the intracavernous venous plexus. Theresult is abnormal function of the sympatheticand parasympathetic fibers in the region of thecavernous sinus (! autonomic dysfunction, ac-tivation of trigeminovascular system).

Chronic Paroxysmal Hemicrania (CPH)

CPH is a very rare condition characterized by thedaily onset of pain similar to that of clusterheadache. The daily attacks of CPH are muchmore frequent (10–20 times/day) and shorter(5–30 minutes) than those of cluster headache.The pain of CPH typically responds to in-domethacin.

Sinus Headache

The pain of frontal, sphenoid, or ethmoid nasalsinusitis is usually felt in the middle of the fore-head and above the eyes. That of maxillarysinusitis radiates to the upper jaw and zygo-matic region and worsens when the patientbends forward.

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Trigeminal neuralgia

Cluster headache

Sinus headache

Brief paroxysms of pain

Precipitatingfactors (triggers)

May be precipitatedby triggers

Cluster

Increasing pain intensity

Prominent temporal artery

Ptosis, miosis, reddening of eyes

Lacrimation

Rhinorrhea

Frontal sinus

Maxillary sinus

Headache

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Nociceptive Transmission

The brain tissue itself is insensitive to pain. Themajor cranial and proximal intracranial vesselsand dura mater of the supratentorial compart-ment derive nociceptive innervation from theophthalmic nerve (V/1, p. 94), while those of theposterior fossa are innervated by C2 branches.Because nociceptive impulses from the anteriorand middle fossae, the venous sinuses, the falxcerebri, and the upper surface of the tentoriumtravel through V/1, the pain that is experiencedis referred to the ocular and frontoparietal re-gions; similarly, pain arising from the lower sur-face of the tentorium, the posterior cranial fossa,and the upper 2–3 cervical vertebrae (mediatedby C2) is referred to the occipital and nuchal re-gion. Small regions of the dura mater are inner-vated by CN IX and X; pain arising here is, ac-cordingly, referred to the throat or ear. Theseneuroanatomical connections also explain thereferral of pain from the upper cervical region tothe eye (shared trigeminal innervation), andwhy tension and migraine headache can causepain in the neck.

Cervical Syndrome (Upper CervicalSyndrome)

Cervical syndrome typically causes pain in thefrontal, ocular, and nuchal regions. The pain isusually continuous, without any circadian pat-tern, but may be more severe during the day ornight. It may be worsened by active or passivemovement of the head. It is usually due to a le-sion affecting the C2 root and is characterized bymuscle spasm, tenderness, and restricted neckmovement. The diagnosis is based on the typicalclinical findings, and cannot be based solely onradiographic evidence of degenerative diseaseof the cervical spine. For other causes of neckpain, see Table 23 (p. 373). For cervical distortion(whiplash), see p. 272. For Posttraumatic head-ache, see p. 270.

Substance-Induced Headache

Acute headache can be induced by a number ofvasoactive substances. Triggers include alcoholconsumption or withdrawal (“hangover”), caf-feine or nicotine withdrawal, sodium glutamate,

cocaine, marijuana, nitrates, and dihydropyrid-ines (calcium antagonists). The headache is usu-ally a pressing, piercing, or pulsating pain, and istypically bifrontal or frontotemporal. It may beaccompanied by nausea, chest tightness, dizzi-ness, abdominal complaints, lack of concentra-tion, or impairment of consciousness.Rebound headache. Persons suffering from re-current or chronic headache are at risk for theexcessive or uncontrolled use of medications,singly or in combination (analgesics, benzodi-azepines, ergot alkaloids, combined prepara-tions). This may result in daily rebound head-ache, persisting from morning to night andcharacterized by pressurelike or pulsating, uni-lateral or bilateral pain, accompanied bymalaise, nausea, vomiting, phonophobia, andphotophobia. Patients may also complain of lackof concentration, disturbed sleep, blurred orflickering vision, a feeling of cold, and moodswings. These patients change medicationsfrequently and tend to take medication even atthe first sign of mild pain, because they fear a re-currence of severe pain. Eventually, drug toler-ance develops, resulting in persistent headache.The original migraine or tension headache maybe largely masked by the rebound headache.Other drug side effects may include ergotism,gastritis, gastrointestinal ulcers, renal failure,physical dependence, and epileptic seizures(withdrawal seizures).

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Referred pain

Substance-induced headache

Cervical syndrome

Lesser occipital n.

Greater occipital n.

Pain latency

Vagus nerveOphthalmic nerve

Glossopharyngeal n.

Medications

Alcohol

Illegal drugs

Episodic

Chronic

Headache

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Treatment

The proper treatment of headache depends onits cause. Episodic or chronic tension headacheand migraine are by far the most common typesof headache. Structural lesions are a rare causeof headache (!5% of all headaches); such head-aches typically start suddenly, worsen quickly,and represent a new type of pain that thepatient has never had before. If a structural le-sion is suspected, neuroimaging studies shouldbe performed.

! General Treatment Measures

Good patient–physician communication is es-sential for the diagnosis and treatment of head-

ache. The most important clues to differentialdiagnosis are derived from the case history. Themedication history must be obtained, and psy-chological factors must also be considered;headache is often associated with anxiety, e. g.,fear of a brain tumor, of a mental illness, or ofnot having one’s complaints taken seriously.Patients must be instructed how they them-selves can improve their symptoms (behavioralmodification) through lifestyle changes (e. g.,avoidance of alcohol, dietary changes, physicalexercise, adequate sleep) and nonpharmacologi-cal measures (relaxation training, biofeedback,stress management, keeping a pain diary).

! Acute Treatment

Type of Headache General Measures Pharmacotherapy

Episodic tension headache Behavioral therapy, ice packs Peppermint oil to forehead and temples;aspirin, acetaminophen, ibuprofen, ornaproxen

Migraine Rest, ice packs Antiemetic (metoclopramide or domperi-done) + aspirin or acetaminophen; if ineffec-tive, triptans1

Cluster headache Hot compresses Oxygen inhalation; if ineffective, triptan s.c.or ergotamine

Chronic paroxysmalhemicrania

Indomethacin

Trigeminal neuralgia Avoidance of triggers Carbamazepine, gabapentin, phenytoin, ba-clofen, or pimozide2

1 This group includes sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan.2 Patients with primary or secondary resistance to medical treatment should be treated neurosurgically (percu-taneous thermocoagulation or retroganglionic glycerol instillation; microvascular decompression).

! Prophylaxis

Type of Headache General Measures Pharmacotherapy

Episodic or chronic tensionheadache

Behavioral therapy Tricyclic antidepressants (e. g., amitryptiline,doxepin, amitryptiline oxide)

Migraine Behavioral therapy 1st line: Beta-blockers (e. g., metoprolol, pro-pranolol); 2nd line: flunarizine or valproate;3rd line: methysergide or pizotifen

Episodic cluster headache Avoidance of alcohol (duringcluster), nitrates, histamines,and nicotine

Prednisone, ergotamine, verapamil, methy-sergide, or lithium

Chronic cluster headache Lithium, verapamil, or pizotifen

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Hemorrhage2

AbscessHydrocephalusNeoplasiaPseudotumorcerebri

Doppler, MRI; MR angioto-mography, angiographyarterial dissection, venoussinus thrombosis, cerebralinfarction

1 Computed tomography2 Subarachnoid hemorrhage (SAH), intracerebral/intraventricular hemorrhage

MigraineTension headacheSubstance-induced headache (nitrates, glutamate, analgesics)SinusitisCervical syndromeTemporal arteritisAfter lumbar punctureSystemic lupus erythematosus

SinusitisTrigeminal neuralgiaCluster headacheAtypical facial painHerpes zosterChronic paroxysmalhemicrania Oromandibular dysfunc-tion, odontogenicAcute glaucomaOptic neuritisTemporal arteritisThalamic pain

Cluster headacheDiabetic neuropathyLesion in cavernous sinusSupra- or infratentorialmassLesion of brain stem ortrigeminal nerveHerpes zosterTolosa-Hunt syndrome

Lumbar puncturemeningoencephalitis, spinal hemorrhage, lepto-meningeal metastases;pseudotumor cerebri

CT1YES

NO

Normal

Neurological examination

is normal

Neck stiffness

Diagnostic classification(acute or subacute headache)

Diagnostic classification(facial pain)

Neurologic deficits

Headache

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Feature Simple Partial Seizures Complex Partial Seizures

Consciousness Unaffected Impaired

Duration Seconds to minutes Minutes

Symptoms and signs Depend on site of origin; no postictalconfusion

Depend on site of origin; postictalconfusion

Age group Any age Any age

Ictal EEG Contralateral epileptiform discharges;in many cases, no interictal abnormali-ties are detected

Unilateral or bilateral epileptiformdischarges, diffuse or focal

(Adapted from Gram, 1990)

An epileptic seizure (convulsion, fit) is a sign ofbrain dysfunction (p. 198). Seizures generallylast no more than 2 minutes; the postictal periodmay be marked by impairment of consciousnessor focal neurological signs. The type and extentof motor, sensory, autonomic and/or psychologi-cal disturbance during the seizure (seizure sem-iology) reflects the location and extent (local-ized/generalized) of brain dysfunction. Seizureclassification, including the differentiation oftrue epileptic from nonepileptic seizures (pseu-doseizures or psychogenic seizures, p. 202), isessential for effective treatment.

! Partial (Focal) SeizuresFocal or partial seizures reflect paroxysmal dis-charges restricted to a part of the affected hemi-sphere. By definition, simple partial seizures arethose in which consciousness is not impaired,while complex partial seizures (psychomotorseizures) are those in which consciousness isimpaired. A sensory or behavioral disturbancepreceding a focal or generalized seizure withmotor manifestations is called a seizure aura.Some features of partial seizures are listed in thetable below.

The semiology of simple and complex partialseizures depends on their site of origin (focus)and the brain areas to which they spread (seetable, p. 194). They may become secondarilygeneralized, evolving into generalized paroxys-mal attacks or tonic-clonic seizures. The initialsymptoms and signs vary depending on the lo-cation of the epileptic focus.

Epilepsy: Seizure Types

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Normal EEG Focal or generalizeddysrhythmiaand slowing

Ictal and spike waves

Irregular andhigh and sub- wave activity

Extinctionphase

Rhythmic slowing withoccasional spikes

Interictalphase

Prodromalphase

Tonic phase

Clonicphase

Postictal phase

Clonus in right arm

Complex partial seizure

Ictal EEG: Focal activity onleft (frontoprecentral spikewaves)

Ictal EEG: Bilateral frontotemporal activity

(rhythmic waves)

Simple partial seizure

Clonus on right side of face

Oral automatisms (licking, chewing, lip smacking)

Oral automatisms(snorting, throat clearing, chewing)

Partial seizures (focal epilepsy)

Generalized seizures (schematic representation of ictal EEG in grand mal seizure)

1s50 µ V

1s50 µ V


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! Generalized Seizures

Generalized epilepsy reflects paroxysmal dis-charges occurring in both hemispheres. Theseizures may be either convulsive (e. g., general-

ized tonic-clonic seizure ! GTCS) or nonconvul-sive (myoclonic, tonic, or atonic seizures; ab-sence seizures). Generalized seizures areclassified by their clinical features.

Site of focus Seizure type Symptoms and signs

Frontal lobe Simple or complex par-tial seizures with orwithout secondarygeneralization (hypermo-tor frontal lobe seizures)

Adversive head movement and other complex motorphenomena (mainly in legs), e. g., pelvic movements,ambulatory automatisms, swimming movements,fencing posture, staring, laughing, outcries, genitalfumbling, autonomic dysfunction, speech arrest.Mood changes may also occur. Seizures occur severaltimes a day with an abrupt onset. The unvaryingcourse of the seizures may suggest hysteria. Briefpostictal confusion

Temporal lobe Complex partial seizureswith or without second-ary generalization

Ascending epigastric sensations (nausea, heat sensa-tion); olfactory/gustatory hallucinations; compulsivethoughts, feeling of detachment, déjà-vu, jamais-vu;oral and other automatisms (psychomotor attacks);dyspnea, urinary urgency, palpitations; macropsia,micropsia; postictal confusion

Parietal lobe Simple partial seizureswith or without second-ary generalization

Sensory and/or motor phenomena (jacksonianseizures); pain (rare)

Occipital lobe Simple partial seizurewith or without second-ary generalization

Unformed visual hallucinations (sparks, flashes)


Feature Absence Seizure MyoclonicSeizure

Atonic(Astatic)Seizure

Tonic-clonic Seizure

Conscious-ness

Impaired Unaffected Impaired Impaired

Duration A few (!30) seconds 1–5 seconds A few sec-onds

1–3 minutes

Symptomsand signs

Brief absence, vacantgaze and blinking fol-lowed by immediatereturn of mental clar-ity; automatisms (lipsmacking, chewing,fiddling, fumbling)may occur

Sudden, bi-laterally syn-chronousjerks in armsand legs;often occur inseries

Sudden lossof muscletone causingsevere falls

Initial cry (occasionally); falls(loss of muscle tone); respira-tory arrest; cyanosis; tonic,then clonic seizures; muscle re-laxation followed by deepsleep. Tongue biting, urinaryand fecal incontinence

Age group Children and adoles-cents

Children andadolescents

Infants andchildren

Any age

Ictal EEG Bilateral regular3 (2–4) Hz spikewaves

Polyspikewaves, spikewaves, orsharp andslow waves

Polyspikewaves, flat-tening or low-voltage fastactivity

Often obscured by muscle arti-facts



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Absence Tonic seizure(in myoclonic/astatic epilepsy)

Generalized tonic-clonic seizure(Grand mal, tonic phase; transition to clonic phase with forceful, rhythmic convulsions)

Tonic-clonic grand mal seizure (temporal course)

Generalized sharp/slow-wave

activity

Generalized 3 Hzspike-wave activity

Fixed stare, blankfacial expression

Tonic arm position

Eyes open, upward gaze

Leg extension

Mouth open

Body rigid, limbs extended, headback, grimace

Prodromal phase Ictal phase (tonic-clonic)

Extinctionphase

Recovery phase

Respiratory rate

Intravesical pressureBlood pressure (systolic)

Heart rate

EEG

EMG (masseter m.)

EMG (biceps brachii m.)Pupillary diameter

100 µ V 1s 100 µ V 1s


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The etiology and prognosis of epilepsy dependon its clinical type. All forms of epilepsy (e. g.,absence epilepsy of childhood, juvenile myo-clonic epilepsy, temporal lobe epilepsy, frontallobe epilepsy, reflex epilepsy) are characterizedby recurrent paroxysmal attacks; thus classifica-tion cannot be based on a single seizure. Epilep-tic syndromes vary in seizure pattern, cause, ageat onset, precipitating factors, EEG changes, andprognosis (e. g., neonatal convulsions, infantilespasms and salaam seizures = West syndrome,Lennox–Gastaut syndrome, temporal lobeseizures). Seizures triggered by fever, substanceabuse, alcohol, eclampsia, trauma, tumor, sleepdeprivation, or medications are designated asisolated nonrecurring seizures or acute epileptic

reactions. Status epilepticus is a single prolongedseizure or a series of seizures without full re-covery in between. Any type of seizure (convul-sive or nonconvulsive) may appear under theguise of status epilepticus. In grand mal statusepilepticus, patients do not regain consciousnessbetween seizures.Location-related (focal, partial) epilepsy can bedifferentiated from generalized epilepsies andepileptic syndromes on the basis of the seizurepattern. Seizures that cannot be classified be-cause of inadequate data on focal or generalizedseizure development are called unclassifiedepilepsy or epileptic syndrome. Other terms usedin classification refer to seizure etiology (e. g.,idiopathic, cryptogenic, symptomatic).

Type of Epilepsy Features

Location-related Partial (focal) seizures

Generalized Generalized convulsive seizures (GCS)

Idiopathic No known cause other than genetic predisposition. No manifestationsother than epileptic seizures. Characteristic age of onset

Cryptogenic Assumed to reflect a CNS disorder of unidentified type. (Once the causeis identified, epilepsy is classified as symptomatic.)

Symptomatic Due to an identified CNS disorder or lesion

Type of Epilepsy Etiology Epilepsy/Epileptic Syndrome

Location-related(focal, localized,partial)

Idiopathic (charac-teristic age ofonset)

Benign epilepsy of childhood with centrotemporal spikes;epilepsy of childhood with occipital paroxysms

Cryptogenic orsymptomatic

Variable expression depending on cause and location (e. g., tem-poral, frontal, parietal, or occipital lobe epilepsy)

Generalized Idiopathic (charac-teristic age ofonset)

Absence epilepsy of childhood (pyknolepsy); juvenile absenceepilepsy; juvenile myoclonic epilepsy (impulsive petit mal); awak-ening grand mal epilepsy (GTCS); epilepsy with specific triggers(reflex epilepsy)

Cryptogenic orsymptomatic

West syndrome (infantile spasms, salaam seizures); Lennox–Gastaut syndrome; myoclonic-astatic epilepsy; epilepsy withmyoclonic absence

Symptomatic Early myoclonic encephalopathy (unspecific etiology); seizuressecondary to various diseases

Unsure whetherfocal or general-ized

Idiopathic or symp-tomatic

Neonatal convulsions; acquired epileptic aphasia (Landau–Kleffner syndrome)

Variably focal andgeneralized

Symptomatic(situation-relatedseizure)

Febrile convulsions; isolated seizure or isolated status epilepti-cus; acute metabolic or toxic triggers

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Age of onset

Etiology and age of onset

Partial seizure, EEG (right temporoparietal -wave activity)

Generalized seizure, EEG (generalized 3 Hz spike-wave pattern)

Clonus (left)

Absence

Febrile convulsions

Lennox-Gastaut syndrome

Epilepsy with myoclonic-astatic seizures

Benign focal epilepsy of childhood

Epilepsy with spike waves during sleep

PyknolepsyJuvenile absence epilepsy

Impulsive petit mal

Awakening grand mal epilepsy

Benign juvenile focal epilepsyGrand mal epilepsy

Prenatal lesions/disturbances

Metabolic diseases

Congenital anomalies

Encephalitis

Genetic disorders

Head trauma

Brain tumor

Age (years)

Cerebrovascular disorders

Benign neonatal convulsions

1 5

2 3 4 5 10 20 30 50 70

10 15 20

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Causes. Some patients have a genetic predisposi-tion to epilepsy, particularly those with general-ized epilepsies. Some hereditary diseases are as-sociated with epilepsy (e. g., tuberous sclerosis,Sturge–Weber syndrome, mitochondrial en-cephalopathies, sphingolipidoses). Acquiredforms of epilepsy may be focal (possibly withsecondary generalization), bilateral, or diffuse(primary generalized epilepsies). The causes in-clude developmental disorders, pyridoxine defi-ciency, hippocampal sclerosis, brain tumors,head trauma, cerebrovascular disturbances, al-cohol, drug abuse, medications, and CNS infec-tions.Pathophysiology. Seizure activity in the brain isthought to be initiated by a preponderance ofexcitatory over inhibitory postsynaptic poten-tials (EPSP, IPSP), resulting in depolarization ofnerve cell membranes. Such a depolarizationmay appear on the EEG as an interictal spike, aninitial spike component, or an abrupt depolari-zation with superimposed high-frequency ac-tion potentials (paroxysmal depolarization shift,PDS). The synchronous discharges of large num-bers of neurons result in an epileptic seizure.Seizure activity is terminated by activeprocesses such as transmembrane ion transportvia sodium–potassium pumps, adenosine re-lease, and the liberation of endogenous opiates,whose combined effect is membrane hyper-polarization, manifested as slow-wave activityin the EEG. Factors favoring the development ofseizures include changes in the concentration ofelectrolytes (Na+, K+, Ca2+), excitatory aminoacids (glutamic acid), and inhibitory aminoacids (GABA), irregular interneuron connec-tions, and abnormal afferent connections fromsubcortical structures (! diencephalon,thalamus, brain stem). In focal epilepsy, theepileptic focus is surrounded by an “inhibitorymargin”, while the paroxysmal activity of gener-alized epilepsy is spread throughout the brain.General treatment measures. Lifestyle changes(sleep–wake rhythm, avoidance of seizure trig-gers); chronic use of anticonvulsant medication.Patients with partial seizures preceded by longauras may be able to abort their seizures whilestill in the aura phase by various concentrationtechniques (seizure interruption methods).Antiepileptic drugs (AEDs). AEDs work by avariety of mechanisms, e. g., inhibition of vol-

tage-gated sodium channels (carbamazepine,oxcarbazepine, lamotrigine, phenytoin, valproicacid) or thalamic calcium channels (ethosuxi-mide), or interaction with inhibitory GABA re-ceptors (benzodiazepines, phenobarbital,gabapentin, tiagabine, levetiracetam) or exci-tatory glutamate receptors (phenobarbital, fel-bamate, topiramate). Antiepileptic therapy isgenerally started in patients who have had asingle seizure and are thought to be at risk of re-currence, in those with an epileptic syndrome,and in those who have had two or more seizureswithin 6 months. AEDs used to treat focal, un-classified, and symptomatic tonic-clonicseizures include carbamazepine, gabapentin,lamotrigine, oxcarbazepine, topiramate,levetiracetam, phenytoin, phenobarbital, andprimidone; those used to treat generalizedseizures include valproic acid, ethosuximide(absences), primidone, phenobarbital (epilepsyassociated with myoclonic seizures, tonic-clonicseizures), and lamotrigine. Treatment is alwaysbegun with a single drug (monotherapy); if thisineffective, another drug is used instead of or inaddition to the first (combination therapy). An-tiepileptic therapy can be discontinued in somecases if the risk of seizure recurrence is judgedto be low.Other measures. Surgery (indicated in patientswith drug-resistant focal epilepsy and/or re-sectable lesions, such as brain tumors or uni-lateral mesial temporal sclerosis). Vagus nervestimulation by means of an implanted neurocy-bernetic prosthesis (NCP) is a form of treatmentwhose efficacy remains controversial.Prognosis (Table 24, p. 373). Antiepileptic drugsprevent seizure recurrence in roughly 70% ofpatients, reduce the frequency of seizures in25%, and are ineffective in 5% (drug resistance),especially those with Lennox–Gastaut syn-drome, symptomatic myoclonic epilepsy, andcryptogenic syndromes.

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Neurophysiological changes during epileptic seizure(data from animal experiments)

Grand mal (GTCS, clonic phase)

Eyes open

Hypersalivation, tongue biting

Symmetric clonic limb movements

Enuresis, encopresis

Extracellularrecording

Intracellular recording

Initial spike component

Epileptic seizure (GTCS)

InterictalEEG changes

Membrane hyperpolarization

Slow fluctuations Prodromal phase

Interictal spikes

500 ms

Silent periodTonic phase Clonic

phase

Postictalphase

PDS

EEG

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The differentiation of epileptic from nonepilep-tic seizures is of major prognostic and therapeu-tic importance. Nonepileptic seizures may ormay not involve loss of consciousness. Pseudo-seizures resemble epileptic seizures (p. 192 ff),but are of nonepileptic origin. This broad cate-gory includes syncope, psychogenic seizures,and simulated seizures. “Pseudoseizure,” in thenarrower sense, is a synonym for “psychogenicseizure.”Nonepileptic seizures are misdiagnosed asepileptic seizures in nearly 20% of patients,roughly 15% of whom are unnecessarily treatedwith antiepileptic drugs; conversely, some 10%of all epileptic seizures are misdiagnosed asnonepileptic seizures; 20–30% of patients haveboth epileptic and nonepileptic seizures. In caseof doubt, the patient should be referred to a spe-cialist or specialized epilepsy center.

! Syncope

Syncope is defined as a brief loss of conscious-ness, often involving a fall, due to transient cere-bral ischemia or hypoxia (see Table 25, p. 374 forpotential causes). In 45% of cases, the cause canbe determined from the history and physical ex-amination. Important anamnestic clues includetriggers such as excitement or anxiety, precipi-tating situations (blood drawing, prolongedstanding, urination, coughing fits, pain), heartdisease, mental illness (generalized anxiety dis-order, depression, somatization disorders), andmedications. The patient should be evaluatedfor possible blood pressure abnormalities andfor cardiac or neurological disorders (p. 148).EEG yields the diagnosis in only about 2% ofcases. Only rare cases of syncope are due to TIA(p. 166). Syncope clinically resembles an epilep-tic seizure in some ways, but differs in others(see table, below).

Clinical Feature Syncope Epileptic Seizure

Triggers Common No

Time of day Mostly diurnal; does not awakenpatient from sleep

Day or night; awakens patient fromsleep

Skin coloration Pale Cyanotic or normal

Premonitory symptoms Tinnitus, visual blurring or blackout,feeling faint, lightheadedness

None or aura

Type of fall Collapse or fall over stiffly (often back-wards)

Fall over stiffly

Duration Usually ! 30 seconds 1–3 minutes or longer

Abnormal movements(myoclonus)

Frequent, arrhythmic, multifocal togeneralized, last ! 30 seconds

Always generalized, 1–2 minutes

Eyes Open Closed

Urinary incontinence Occasional Common

Postictal confusion Brief or absent Longer-lasting

Tongue-biting Occasional Common

Prolactin, creatine kinase Normal Elevated

Typical EEG changes Absent Common

Focal neurological deficit Absent Occasional

Nonepileptic Seizures

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Warning signs

Vertigo, light-headedness,malaise

Brief reorientation phase

Sweating, yawning, tinnitus, unsteadiness, pallor, visual disturbances(blurred, gray, black)

Fall (by collapsing or falling over stiffly; may cause injury)

Brief unconsciousness (myoclonus possibly accompanied by tonic convulsions)


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! Psychogenic Seizures

Nonorganic, nonepileptic seizures arising frompsychological factors do not involve loss of con-sciousness. They are involuntary and uninten-tional, and thus must be differentiated fromsimulated seizures, which are voluntarily, con-sciously, and intentionally produced events.Psychogenic seizures may resemble frontal lobeseizures (p. 194) and are more common inwomen than men. About 40% of patients withpsychogenic seizures also suffer from trueepileptic seizures. The case history often revealscharacteristic risk factors, which may be bio-graphical (family difficulties, abuse, divorce,sexual assault in childhood), somatic (geneticpredisposition), psychiatric (conflicts, stress,psychosocial gain from illness behavior, mentalillness), or social (poor living and working con-ditions). Patients often meet the psychiatric di-agnostic criteria for a conversion disorder (F44.5according to the ICD-10). Epileptic seizures infamily members, or in the patients themselves,may serve as the prototype for psychogenicseizures.Premonitory signs. Psychogenic seizures can beinduced or terminated by suggestion. They maybe preceded by a restless, anxious, or fearfulstate. They usually occur in the presence ofothers (an “audience”) and do not occur whenthe patient is asleep.Seizure semiology. Psychogenic seizures usuallytake a dramatic course, with a variable ending.Their semiology is usually of a type more likelyto incite sympathy and pity in onlookers thanfear or revulsion. Typical features include anabrupt fall or slow collapse, jerking of the limbs,tonic contraction of the body, writhing (arc decercle), calling out, shouting, rapid twisting ofthe head and body, and forward pelvic thrust-ing; the sequence of movements is usually vari-able. The eyes are usually closed, but sometimeswide open and staring; the patient squeezes theeyes shut when passive opening is attempted.Urinary incontinence or injury (self-mutilation)may also occur. Tongue-bite injuries, if present,are usually at the tip of the tongue (those in trueepileptic fits are usually lateral). The patient isless responsive than normal to external stimuli,including painful stimuli, but not unconscious(squeezes eyelids shut when the eyes are

touched, drops arm to the side when it is heldover the patient’s face and released). Thepatient’s skin is not pale or cyanotic during theictus. Patients who hyperventilate during psy-chogenic seizures may have carpopedal spasms.Psychogenic seizures often last longer thanepileptic seizures.Postictal phase. No focal neurological deficitscan be detected, though there may be a psycho-genic postictal stupor. The serum prolactin levelis not elevated (which, however, does not ruleout a true epileptic seizure). The seizure may beterminated abruptly by suggestion, or by depar-ture of the “audience.” Some patients recall theseizure to some extent, while others emphati-cally deny memory of it.

! Panic Disorder (ICD-10 ! F41.0)

Panic disorder is characterized by sudden, unex-pected and apparently unprovoked attacks ofintense anxiety, which may range in severityfrom a general feeling of restlessness to a mortaldread. The attacks usually last 5–30minutes andmay awaken the patient from sleep. Accom-panying symptoms include feelings of detach-ment from the environment, i.e., depersonaliza-tion (detachment from one’s own body, floatingstate) and derealization (sensation of being in adream or nightmare, feeling of unreality); au-tonomic and other physical symptoms of varia-ble severity, including cardiovascular (tachycar-dia, palpitations, pallor, chest pain or pressure),gastrointestinal (nausea, dry mouth, dysphagia,diarrhea), respiratory (hyperventilation, dysp-nea, smothering sensation), and other manife-stations (tremor, twitching of the limbs, dizzi-ness, paresthesia, mydriasis, urinary urgency,sweating). The differential diagnosis includesepilepsy (aura, simple partial seizures), hyper-thyroidism, hyperventilation syndrome,pheochromocytoma, heart disease, and hy-poglycemia.


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Psychogenic seizure (with arc de cercle)

Panic attack (hyperventilation, psychomotor restlessness)

Eyes closed; patient squeezeseyes shut when examiner

attempts to open them


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! Drop Attacks

Sudden, unprovoked, and unheralded fallswithout loss of consciousness are most commonin patients over 65 years of age. Some 10–15% ofthese drop attacks cause serious injury, particu-larly fractures. The patient may not be able toget up after a fall. The common causes of recur-rent falls in each age group are listed in Table 26(p. 374). Those associated with loss of con-sciousness are described on pages 192 ff and200.

! Hyperventilation Syndrome (Tetany)

The clinical manifestations include paresthesiae(perioral, distal symmetrical or unilateral),generalized weakness, palpitations, tachycardia,dry mouth, dysphagia, dyspnea, yawning, pres-sure sensation in the chest, visual disturbances,tinnitus, dizziness, unsteady gait, muscle stiff-ness, and carpopedal spasms. The patients re-port feelings of restlessness, panic, unreality, orconfusion. Psychological causes include anxiety,hysteria, and inner conflict. Metabolic causes in-clude hypocalcemia (due to hypoparathyroid-ism, vitamin D deficiency, malabsorption, orpancreatitis) and a wide range of other distur-bances including hypercalcemia, hypomag-nesemia, prolonged vomiting, pulmonary em-bolism, salicylate intoxication, acute myocardialinfarction, severe pain, high fever due to sep-ticemia, pneumothorax, stroke, and neurogenicpulmonary edema. Chronic hyperventilation syn-dromes are more common than acute syn-dromes, but also more difficult to diagnose.

! Tonic Spasms

These are unilateral muscular spasms (oftenpainful) that are not accompanied by loss ofconsciousness; they last seconds to minutes,and occur up to 30 or more times a day. They aremost commonly seen in multiple sclerosis, lesscommonly in cerebrovascular disorders. Thesespasms are often triggered by movement. Somepatients have paresthesiae (tingling, burning)contralateral to the affected side before themuscle spasm sets in. The underlying lesionmaybe in the brain stem (pons) or internal capsule.

! Acute Dystonic Reaction

Acute dystonic reactions can occur within a fewhours to one week of starting treatment withdopamine receptor antagonists, e. g., neurolep-tics (benperidol, fluphenazine, haloperidol, tri-flupromazine, perphenazine), antiemetics (me-toclopramide, bromopride), and calcium antag-onists (flunarizine, cinnarizine). Symptoms andsigns: focal or segmental dystonia (p. 64), some-times painful, marked by oculogyric crisis,blepharospasm, pharyngospasm with glos-sospasm and laryngospasm, or oromandibulardystonia with tonic jaw and tongue movements.Generalized reactions are also seen on occasion(p. 66).


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Drop attack

Hyperventilation

Tonic spasms(muscular spasms on left)

Acute dystonic reaction(oculogyric crisis, oromandibular/pharyngeal dystonia)


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The diagnosis of Parkinson disease (PD; some-times termed idiopathic Parkinson disease, todistinguish it from symptomatic forms ofparkinsonism, and from other primary forms) ismainly based on the typical neurological find-ings, their evolution over the course of the dis-ease, and their responsiveness to levodopa (L-dopa). Longitudinal observation may be neces-sary before a definitive diagnosis of PD can begiven. PD is characterized by a number of distur-bances of motor function (cardinal manifesta-tions) and by other accompanying manifestationsof different kinds and variable severity.

Cardinal Manifestations

Bradykinesia, hypokinesia, and akinesia. Motordisturbances include slow initiation of move-ment (akinesia), sluggishness of movement(bradykinesia) and diminished spontaneousmovement (hypokinesia); these terms are oftenused nearly interchangeably, as these distur-bances all tend to occur together. Spontaneousfluctuations of mobility are not uncommon. Themotor disturbances are often more pronouncedon one side of the body, especially in the earlystages of disease. They affect the craniofacialmusculature to produce a masklike facies (hy-pomimia), defective mouth closure, reducedblinking, dysphagia, salivation (drooling), andspeech that is diminished in volume (hypo-phonia), hoarse, poorly enunciated, and mono-tonous in pitch (dysarthrophonia). The patientmay find it hard to initiate speech, or may repeatsyllables; there may be an involuntary accelera-tion of speech toward the end of a sentence(festination). Postural changes include stoopedposture, a mildly flexed and adducted posture ofthe arms, and postural instability. Gait distur-bances appear in the early stages of disease andtypically consist of a small-stepped gait, shuf-fling, and limping, with reduced arm swing. Dif-ficulty initiating gait comes about in the laterstages of disease, along with episodes of “freez-ing”—complete arrest of gait when the patient isconfronted by doorway or a narrow path be-tween pieces of furniture. It becomes difficultfor the patient to stand up from a seated posi-tion, or to turn over in bed. Impairment of finemotor control impairs activities of daily livingsuch as fastening buttons, writing (micro-

graphia), eating with knife and fork, shaving,and hair-combing. It becomes difficult to per-form two activities simultaneously, such aswalking and talking.Tremor. Only about half of all PD patients havetremor early in the course of the disease; therest usually develop it as the disease progresses.It is typically most pronounced in the hands(pill-rolling tremor) and is seen mainly whenthe affected limbs are at rest, improving or dis-appearing with voluntary movement. Itsfrequency is ca. 5 Hz, it is often asymmetrical,and it can be exacerbated by even mild stress(mental calculations, etc.).Rigidity. Elevated muscle tone is felt by thepatient as muscle tension or spasm and by theexaminer as increased resistance to passivemovement across the joints. Examination mayreveal cogwheel rigidity, i.e., repeated, ratchet-like oscillations of resistance to passive move-ment across the wrist, elbow, or other joints,which may be brought out by alternating pas-sive flexion and extension.Postural instability (loss of balance). Propulsionand retropulsion arise in the early stages ofParkinson disease because of generalized im-pairment of the postural reflexes that maintainthe bipedal stance. Related phenomena includeinvoluntary acceleration of the gait (festination),difficulty in stopping walking, gait instability,and frequent falls.

Accompanying Manifestations

! Behavioral Changes

Depression. The range of depressive manifesta-tions includes worry, anxiety, avoidance of so-cial contact, general unhappiness, listlessness,querulousness, brooding, somatoform distur-bances, and (rarely) suicidal ideation.Anxiety. Tension, worry, mental agitation, lackof concentration, and dizziness are relativelycommon complaints.

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Facial expression

Postural change(hypokinesia-left)

Gait impairment (postural instability, propulsion, festination)

Resting tremor

Micrographia

Rigidity (cogwheel phenomenon)

HypomimiaDrooling


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Dementia. Impairment of memory and concen-tration in early PD-associated dementia may bedifficult to distinguish from depressive manife-stations. The side effects of pharmacotherapy(p. 212) must be kept in mind before treatmentis initiated for patients suffering from disorien-tation, confusion, suspiciousness, and otheremotional changes. Impaired memory is usuallynot a major feature of PD; as the disease pro-gresses, about 20% of patients developdecreased flexibility of thought and action, per-severation, and increasing difficulty in planningfuture activities. The development of dementiain PD is correlated with an increase in the num-ber of Lewy bodies (pp. 210).Hallucinations. A state of excessive suspicious-ness, vivid dreams, and increasing anxiety mayevolve into one of severe confusion with visualhallucinations. Frank psychosis (e. g., paranoiddelusions, ideas of reference, or delusionaljealousy) may be due to other causes than PD,particularly an adverse effect of antiparkin-sonian medication. Dementia with Lewy bodies(a syndrome in which the clinical features ofParkinson disease are found together withdementia, fluctuating level of consciousness,visual hallucinations, and frequent falls) isanother possible cause, especially in patientswho are unusually sensitive to low doses of neu-roleptics (! exacerbation of parkinsonism,delirium, malignant neuroleptic syndrome,p. 347).

! Autonomic Dysfunction

Blood pressure changes. Hypotension is a com-mon side effect of antiparkinsonian medications(levodopa, dopamine agonists). Marked ortho-static hypotension, if present, suggests thepossible diagnosis of multisystem atrophy.Constipation may be caused by autonomic dys-function, as a manifestation of the disease, or asa side effect of medication (anticholinergicagents).Bladder disorders. Polyuria, urinary urgency,and urinary incontinence occur mainly at nightand in patients with severe akinesia (who havedifficulty getting to the toilet). PD only rarelycauses severe bladder dysfunction.Sleep disorders. PD commonly causes distur-bances of the sleep–wake cycle, including diffi-culty falling asleep, nocturnal breathing prob-

lems similar to sleep apnea syndrome, andshortening of the sleep cycle. Sleep may also beinterrupted by nocturnal akinesia, which makesit difficult for the patient to turn over in bed.Sexual dysfunction. Spontaneous complaints ofdiminished libido or impotence are rare. In-creased libido is a known side effect of levodopaand dopamine agonists.Hyperhidrosis. Mainly occurs as generalized, ir-regular, sudden episodes of sweating.Seborrhea. Mainly on the forehead, nose, andscalp (greasy face, seborrheic dermatitis).Leg edema is often the result of physical inactiv-ity.

! Sensory Manifestations

Pain in the arm or shoulder, sometimes accom-panied by fatigue and weakness, may be presentfor years before the cardinal manifestationsarise and enable a diagnosis of PD. Back pain andnuchal cramps are frequent secondary effects ofparkinsonian rigidity and abnormal posture.Dystonia may also come to attention because ofthe pain it produces.Dysesthesia. Heat, burning or cold sensationsmay be felt in various parts of the body. For rest-less legs syndrome, see p. 114.

! Other Motor Manifestations

Dystonia. Tonic dorsiflexion of the big toe withextension or flexion of the other toes may occurin the early morning hours or during walking.Dystonia may be drug-induced (e. g., bylevodopa) or due to the disease itself. The differ-ential diagnosis includes dopa-responsive dys-tonia (a disorder of autosomal dominant inheri-tance) andWilson disease (p. 307), two predom-inantly dystonic motor disorders with onset inchildhood and adolescence.Visual disturbances are caused by impairment ofeye movement. Vertical gaze palsy is suggestiveof progressive supranuclear palsy (p. 302). Thereduced blinking rate of PD may lead to a burn-ing sensation on the cornea, or to conjunctivitis.


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Behavioral changes(depression, anxiety, dementia)

Seborrhea

Orthostatichypotension

Constipation

Edema

Urinary dysfunction, impotence

Pain

Dystonia (of foot)

Sleep disorders(increased rigidity at night, ”mental pillow”)

Autonomic dysfunction


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Basal ganglia. The basal ganglia consist of thecaudate nucleus (CN), putamen, globus pallidus(= pallidum; GPe = external segment, GPi = in-ternal segment; putamen + pallidum = lentiformnucleus), claustrum, substantia nigra (SN; SNc =pars compacta, SNr = pars reticularis), and thesubthalamic nucleus (STN). CN + putamen =(dorsal) striatum; nucleus accumbens + portionsof olfactory tubercle + anterior portion of puta-men + CN = limbic (ventral) striatum. Substantianigra (SN): The SNr (ventral portion of SN) con-tains small amounts of dopamine and iron,giving it a reddish color, while the SNc (dorsalportion) contains large quantities of dopamineand melanin, making it black (whence thename, substantia nigra).Connections. The basal ganglia are part of anumber of parallel and largely distinct (segre-gated) neural pathways (circuits). Each circuitoriginates in a cortical area that is specializedfor a specific function (skeletal motor, oculomo-tor, associative-cognitive, or emotional-moti-vational control), passes through several relaystations in the basal ganglia, and travels by wayof the thalamus back to the cerebral cortex. Cor-tical projection fibers enter the basal ganglia atthe striatum (input station) and exit from theGPi and SNr (output station). Input from thethalamus and brain stem also arrives at the stri-atum. Within the basal ganglia, there are twocircuits subservingmotor function, the so-calleddirect and indirect pathways. The direct path-way runs from the putamen to the GPi and SNr,while the indirect pathway takes the followingtrajectory: putamen ! GPe ! STN ! GPi ! SNr.The GPi and SNr project to the thalamus andbrain stem.Neurotransmitters. Glutamate mediates exci-tatory impulses from the cortex, amygdala, andhippocampus to the striatum. Synapses fromSTN fibers onto cells of the GPi and SNr are alsoglutamatergic. Both the excitatory and the inhib-itory projections of the SNc to the basal gangliaare dopaminergic. In the striatum, dopamine actsonneurons bearingD1 andD2 receptors, ofwhichthere are various subtypes (D1 group: d1, d5; D2

group:d2, d3, d4).D1 receptorspredominate in thedirect pathway, D2 receptors in the indirect path-way. Cholinergic interneurons in the striatumform a relay station within the basal ganglia(transmitter: acetylcholine). Medium spiny-type

neurons (MSN) in the striatum have inhibitoryprojections to the GPe, GPi, and SNr (transmit-ters: GABA, substance P/SP, enkephalin/Enk).Other inhibitory GABAergic projections run fromthe GPi to the STN, from the GPi to the thalamus(ventrolateral and ventroanterior nucleus), andfromthe SN to the thalamus. The thalamocorticalprojections are excitatory.Motor function. The direct pathway is activatedby cortical and dopaminergic projections to thestriatum. The projection from the striatum inturn inhibits the GPi, diminishing its inhibitoryoutput to the thalamic nuclei (i.e., causing netthalamic activation). Thalamocortical drive thusfacilitates movement initiated in the cerebralcortex (voluntary movement). In the indirectpathway, the striatum, under the influence of af-ferent cortical and dopaminergic projections,exerts an inhibitory effect on the GPe and STN.The result is a diminished excitatory influenceof the STN on the GPi and SNr, ultimately leadingto facilitation of cortically initiated voluntarymovement and inhibition of involuntary move-ment.

! Pathophysiology

The cause of Parkinson disease is unknown. Itsstructural pathological correlate is a loss of neu-rons in the caudal and anterolateral parts of theSNc, with reactive gliosis and formation of Lewybodies (eosinophilic intracytoplasmic inclusionsin neurons) and Lewy neurites (abnormallyphosphorylated neurofilaments) containing !-synuclein. Loss of pigment in the substantianigra can be seen macroscopically. The mostprominent neurochemical abnormality is a defi-ciency of dopamine in the striatum, whose ex-tent is directly correlated with the severity ofPD. The physiological effect of the lack of (mostlyinhibitory) dopamine neurotransmission in thestriatum is a relative increase in striatal activity,in turn causing functional disinhibition of thesubthalamic nucleus via the indirect pathway.Meanwhile, in the direct pathway, decreasedstriatal inhibition of the GPi enhances the inhib-itory influence of the GPi on the thalamus, lead-ing to reduced activity in the thalamocorticalprojection. These changes in neural activitymanifest themselves in the clinically observableakinesia, rigidity, and postural instability. Fortremor, see p. 62.

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211Functional organization (left, normal; right, Parkinson disease)

Basal ganglia

GPe

Cerebral cortex

Pons

STN

MSN

SNr

GL GL

GL

GL

SNc

GABA,SP

GABA

GABAGABA

GABA,Enk

DA

ACh

Superior colliculus

Lewy body

Melaninpigment

Nucleus accumbens

GPi

Putamen

Neuron

Cerebral peduncle

Direct pathway

Indirect pathway


Ventral lateral nucleus, ventralanterior nucleus

(thalamus)

Neurotransmitters:GL: GlutamateACh: AcetylcholineDA: Dopamine

SN

Rednucleus

CN

Thalamus

Connections:Red: ExcitatoryBlue: InhibitoryGreen: Excitatory and

inhibitory

Thalamus

CNPutamen

GPe

GPi

STN

Direct pathway

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The goal of treatment is improvement of themotor, autonomic, and cognitive symptoms ofthe disease. The treatment generally consists ofmedication along with physical, occupational,and speech therapy. Neurosurgical proceduresare mostly reserved for intractable cases (seebelow). Pharmacotherapy is palliative, not cura-tive. It is begun when the patient has troublecarrying out the activities of daily living and isprescribed, not according to a uniform pattern,but in relation to the needs of the individualpatient.

! Symptomatic Treatment

Dopaminergic agents. Levodopa is actively ab-sorbed in the small intestine and rapidly dis-tributed throughout the body (especially toskeletal muscle). Amino acids compete with thelevodopa transport system at the blood–brainbarrier. A decarboxylase inhibitor that does notpenetrate the blood–brain barrier (benserazideor carbidopa) is administered together withlevodopa to prevent its rapid breakdown in theperipheral circulation. Once it reaches the brain,levodopa is decarboxylated to dopamine, whichis used for neurotransmission in the striatum.After it has been released from the presynapticterminals of dopaminergic neurons in the stri-atum and exerted its effect on the postsynapticterminals, it is broken down by two separateenzyme systems (deamination by monoamineoxidase type B, MAO-B; methylation by cate-chol-O-methyltransferase, COMT). Levodopa ef-fectively reduces akinesia and rigidity, but hasonly a mild effect against tremor. Its long-termuse is often complicated by motor fluctuations,dyskinesia, and psychiatric disturbances.Dopamine agonists (DAs) mimic the function ofdopamine, binding to dopamine receptors. Theirinteraction with D1 and D2 receptors is thoughtto improve motor function, while their interac-tion with D3 receptors is thought to improvecognition, motivation, and emotion. Long-termuse of DAs is less likely to cause unwantedmotorside effects than long-term use of levodopa.Commonly used DAs include bromocriptine(mainly a D2 agonist), lisuride (mainly a D2 ago-nist), and pergolide (a D1, D2, and D3 agonist).Apomorphine, an effective D1 and D2 agonist,can be given by subcutaneous injection, but itseffect lasts only about 1 hour. Other, recently in-

troduced dopamine agonists are ropinirol andpramipexol (D2 and D3), cabergoline (D2), and !-dihydroergocryptine (mainly D2).Selegiline inhibits MAO-B selectively and irre-versibly (! reduced dopamine catabolism ! in-crease in striatal dopamine concentration). En-tacapone increases the bioavailability oflevodopa via peripheral inhibition of COMT.Nondopaminergic agents. Anticholinergic agents(biperidene, bornaprine, metixene, trihexy-phenidyl) act on striatal cholinergic inter-neurons. Budipine can relieve tremor (risk ofventricular tachycardia ! ECG monitoring). Glu-tamate antagonists (amantadine, memantine)counteract increased glutamatergic activity atthe N-methyl-D-aspartate (NMDA) glutamatereceptor in the indirect pathway.

! Transplant Surgery

Current research on intrastriatal transplantationof stem cells (derived from fetal tissue, fromumbilical cord blood, or from bone marrow)seems promising.

! Stereotactic Neurosurgical Procedures, DeepBrain Stimulation (for abbreviations, seep. 210)

These procedures can be used when PD be-comes refractory to medical treatment. Pal-lidotomy (placement of a destructive lesion inthe GPi) derives its rationale from the observedhyperactivity of this structure in PD. Deep brainstimulation requires bilateral placement ofstimulating electrodes in the GPi or STN. High-frequency stimulation by means of a subcu-taneously implanted impulse generator can im-prove rigor, tremor, akinesia, and dyskinesia.

! Genetics of PD

A genetic predisposition for the development ofPD has been postulated. Mutations in the genesfor !-synuclein (AD), parkin (AR), and ubiquitinC-terminal hydrolase L1 (UCHL1; AD) have beenfound in pedigrees affected by the rare auto-somal dominant (AD) and autosomal recessive(AR) familial forms of PD.

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Striatal dopaminergic synapse (schematic)

Speech therapy

Occupational therapy

Physical therapy

Glial cell

MAO-B

Postsynaptic ending

Presynaptic terminal

Transport protein

Phenylalanine

Phenylalaninehydroxylase

Tyrosine

Tyrosinehydroxy-lase

Dopadecar-boxylase

L-Dopa Dopamine

Dopamine vesicle

Dopamine release

3-0-methyldopamine(converted to homo-

vanillic acid)

DOPAC (dihydroxyphenylacetic acid)

Dopamine reabsorption

COMT

D2 receptor

D1 receptor

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Multiple sclerosis (MS) is characterized by mul-tiple symptoms and signs of brain and spinalcord dysfunction that are disseminated in bothtime and space. Its pathological hallmark is in-flammatory demyelination and axonal lesions;its etiology remains unknown at present despitedecades of intensive investigation.A relapse is the appearance of a new neurologi-cal disturbance, or the reappearance of one pre-viously present, lasting at least 24 hours. Allsuch disturbances arising within a one-monthperiod are counted as a single relapse. The re-lapse rate is the number of relapses per year.Clear improvement of neurological function istermed remission.The course of MS varies greatly from one in-dividual to another, but two basic types ofcourse can be identified: relapsing-remitting(66–85%; most common when onset is beforeage 25; well-defined relapses separated by peri-ods of nearly complete recovery with or withoutresidual symptoms; does not progress duringremission) and chronic progressive. The lattercan be divided into three subtypes: primarychronic progressive (9–37%; most commonwhen onset is after age 40; progresses from dis-ease onset onward); secondary progressive (seenin over 50% of cases 6–10 years after onset; ini-tially remitting-relapsing, later chronically pro-gressive; recurrences, mild remissions, andplateau phases may occur); and progressively re-mitting-relapsing (rare; complete remissionmayor may not occur after relapses; symptoms tendto worsen from one relapse to the next).

Clinical Manifestations

The symptoms and signs of MS reflect dysfunc-tion of the particular areas of the nervous sys-tem involved and are not specific for this dis-ease. Typical MS manifestations include paraly-sis, paresthesiae, optic neuritis (retrobulbarneuritis), diplopia, and bladder dysfunction.Paresis, spasticity, fatigability. Upper-motor-neuron type paralysis of the limbs either is pre-sent at onset or develops during the course ofMS. Involvement is often asymmetrical andmainly in the legs, especially in the early stage ofthe disease. Spasticity makes its first appear-ance in the form of extensor spasms; flexorspasms develop later. The latter are often pain-

ful, cause frequent falls, and, if severe and per-sistent, can cause flexion contractures (paraple-gia in flexion). Many patients complain of abnor-mal fatigability.Sensory manifestations. Episodic or continuousparesthesiae (sensations of tingling or numb-ness, tightness of the skin, heat, cold, burning,prickling) are common, particularly in the earlystage of the disease, with or without othermanifestations of neurological dysfunction. Asthe disease progresses, such positive phenom-ena usually recede and are replaced by sensorydeficits affecting all sensory modalities. A con-stant or only slowly rising sensory level(“sensory transverse cord syndrome”) is un-characteristic of MS and should prompt thesearch for a spinal cord lesion of another kind.Many MS patients have Lhermitte’s sign (whichis actually a symptom), an electric or coldlikeparesthesia traveling from the nuchal regiondown the spine, sometimes as far as the legs, onflexion of the neck (p. 49). If no other symptomsor signs are present, other causes should be con-sidered (e. g., a cervical spinal cord tumor).Pain in MS most often appears in the form oftrigeminal neuralgia (p. 186), severe pain in thelimbs (p. 108), tonic spasms (p. 204), or back-aches, sometimes with radiation in a radicularpattern. Other painful phenomena includeflexor spasms due to spasticity, contractures,and dysuria due to urinary tract infection.Visual impairment in MS is usually due to opticneuritis (mostly unilateral), which also producespain in or around the eye. The impairment beginsas blurred or clouded vision and progresses tocause reading impairment and visual field de-fects (central scotoma or diffuse defects).MarcusGunn pupils (p. 92)may be observed. Physical ex-ercise, high ambient temperature,menstruation,or cigarette smoking can aggravate existingvisual problems (Uhthoff’s phenomenon). Opticneuritis, as an isolated finding, is not necessarilythe first manifestation of MS; patients with bi-lateral optic neuritis have a much lower risk ofdeveloping MS than those with the unilateralform.Diplopia is usually due to internuclear oph-thalmoplegia (p. 86). Nystagmus (p. 88).

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Sensory disturbances

Motor disturbances(central paresis, spasticity,

abnormal fatigability)

Central scotoma (optic neuritis)

Dissociated nystagmus(internuclear ophthalmoplegia,patient looking to right)

Temporal papillary atrophy(after optic neuritis)

Test for visual field defects (confrontation test)

Nystagmus of abducting eye

Adductorparalysis

Atrophy

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Incoordination. Intention tremor, dysarthria,truncal ataxia, and oculomotor dysfunction arecommon. Gait unsteadiness due to motor in-coordination is often experienced by the patientas dizziness or lightheadedness. Acute vertigowith nausea, vomiting, and nystagmus can alsooccur.Autonomic dysfunction. Bladder dysfunction(p. 156) frequently develops in the course ofMS, causing problems such as urinary urgency,incomplete voiding, or urinary incontinence.Urinary tract infection is a not infrequent re-sult. Fecal incontinence (p. 154) is rare, but con-stipation is common. Sexual dysfunction (e. g.,erectile dysfunction or loss of libido) is alsocommon and may be aggravated by spasticityor sensory deficits in the genital region. Psy-chological factors such as depression, insecu-rity, and marital conflict often play a role aswell. If its cause is organic, sexual dysfunctionin MS is usually accompanied by bladder dys-function.Behavioral changes. Mental changes (depres-sion, marital conflict, anxiety) and cognitivedeficits of variable severity can occur both as areaction to and as a result of the disease.Paroxysmal phenomena in MS include epilepticseizures, trigeminal neuralgia, attacks of dy-sarthria with ataxia, tonic spasms, episodic dy-sesthesiae, pain, and facial myokymia.

Differential Diagnosis

There is no single clinical test, imaging study, orlaboratory finding that alone establishes the di-agnosis of MS (p. 218; Table 27, p. 375). A metic-ulous differential diagnostic evaluation isneeded in every case.(Cerebral) Vasculitis (p. 180). Systemic lupuserythematosus, Sjögren syndrome, Behçet syn-drome, granulomatous angiitis, polyarteritisnodosa, antiphospholipid syndrome, chronic in-flammatory demyelinating polyradiculoneuro-pathy (CIDP, p. 328).Inflammatory diseases. Neurosarcoidosis, neu-roborreliosis, neurosyphilis, Whipple disease,postinfectious acute disseminated encephalo-myelitis (ADEM), progressive multifocalleukoencephalopathy (PML), subacute scleros-ing panencephalitis (SSPE), HIV infection,HTLV-1 infection.

Neurovascular disorders. Arteriovenous fistulaof spinal dura mater, cavernoma, CADASIL(p. 172).Hereditary/metabolic disorders. Spinocerebel-lar ataxias, adrenoleukodystrophy, endocrinediseases, mitochondrial encephalomyelopathy,vitamin B12 deficiency (funicular myelosis).Tumors of the brain or spinal cord (e. g., lym-phoma, glioma, meningioma).Skull base anomalies. Arnold–Chiari malforma-tion, platybasia.Myelopathy. Cervical myelopathy (spinal steno-sis).Somatoform disturbances in the context ofmental illness.

Prognosis

Favorable prognostic indicators in MS includeonset before age 40, monosymptomatic onset,absence of cerebellar involvement at onset,rapid resolution of the initial symptom(s), a re-lapsing-remitting course, short duration of re-lapses, and long-term preservation of the abilityto walk. A relatively favorable course is also pre-dicted if, after the first 5 years of illness, the MRIreveals no more than a few, small lesionswithout rapid radiological progression and theclinical manifestations of cerebellar disease andcentral paresis are no more than mild. A benigncourse, defined as a low frequency of recur-rences and only mild disability in the first 15years of illness, is seen in 20–30% of patients.The disease takes amalignant course, withmajordisability within 5 years, in fewer than 5% ofpatients. Half of all MS patients have a secondrelapse within 2 years of disease onset.

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Impaired coordination

Behavioral changes

Autonomic dysfunction(urinary/fecal incontinence, sexual

dysfunction)

Paroxysmal symptoms(trigeminal neuralgia)

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Diagnosis

Patients with MS are evaluated by clinical ex-amination, laboratory testing, neuroimaging,and neurophysiological studies. The clinicalmanifestations of MS and the lesions that causethem vary over the course of the disease (dis-semination in time and space). Diagnostic classi-fication is problematic (p. 216) if only one lesionis found (e. g., by MRI), if symptoms and signsare in only one area of the CNS (e. g., spinalcord), or if only one attack has occurred (Table27, p 375).

! Clinical Manifestations

Sensory deficits, upper-motor-neuron paresis,incoordination, visual impairment (field de-fects), nystagmus, internuclear ophthalmople-gia, and/or bladder dysfunction are commonsigns of MS. Complaints of pain, paresthesiae,abnormal fatigability, or episodic disturbancesare often, by their nature, difficult to objectify.Clinical examination may reveal no abnormalitybecause of the episodic nature of the disease it-self.

! Laboratory Tests and Special Studies

Evoked potentials. Visual evoked potential (VEP)studies reliably detect optic nerve lesions, butneuroimaging is better for detecting lesions ofthe optic tract or optic radiation. VEP revealsprolongation of the P100 latency in one eye and/or an abnormally large discrepancy between thelatencies in the two eyes in roughly 40% of MSpatients without known optic neuritis, and in al-most half of those with early optic neuritis. So-matosensory evoked potential (SEP) studies ofthe median or tibial nerve typically reveal pro-longed latencies in MS. Low amplitude ofevoked potentials, on the other hand, often indi-cates a pathological process of another type, e. g.tumor. SEP abnormalities are found in up to 60%of MS patients with predominantly sensorymanifestations. Auditory evoked potential (AEP)studies are less sensitive in MS than VEP or SEP.The most common AEP change is prolongationof latency. AEP studies are helpful for the furtherclassification of vertigo, tinnitus, and hearingloss. Motor evoked potential (MEP) studies re-veal prolonged central conduction times whenCNS lesions involve the pyramidal pathway. The

sensitivity of MEP in MS is approximately thesame as that of SEP. MEP studies can providesupporting evidence for MS in patients withlatent paresis, gait disturbances, abnormal re-flexes, or movement disorders that are difficultto classify.Tests of bladder function. The residual urinevolume can be measured by ultrasound. Itshould not exceed 100ml in patients with a nor-mal bladder capacity of 400–450ml; in general,it should normally be 15–20% of the cys-tomanometrically determined bladder volume.Urodynamic electromyography (EMG) providesmore specific data concerning bladder dysfunc-tion.Neuroimaging. CT may reveal other diseasesthat enter into the differential diagnosis of MS(e. g., brain tumor) but is insufficiently sensitive(ca. 25–50%) to be useful in diagnosing MS it-self. MRI scans reveal the characteristic foci ofdemyelination disseminated in the CNS (MSplaques); contrast enhancement is seen in acutebut not in chronic lesions. The sensitivity of MRIfor MS is greater than 90%, but its specificity isconsiderably lower; thus, the MRI findings alonecannot establish the diagnosis.CSF examination. CSF abnormalities are found inmore than 95% of MS patients. The cell countrarely exceeds 20 cells/mm3. The total proteinconcentration is elevated in ca. 40% of patients,and intrathecal IgG synthesis (IgG index) in ca.90%. Oligoclonal IgG is found in 95% of MSpatients, and antibodies to mumps, measles andherpes zoster in 80%.

Pathogenesis

The early course of MS varies among patients inaccordance with the variable extent of the in-flammatory lesions and disturbances of theblood–brain-barrier. The severity of latemanife-stations is correlated with the number ofplaques. It is hypothesized that MS is caused bya combination of genetic (polygenic) predisposi-tion and exogenous factors (viral or bacterial in-fection?) that induces an inappropriate immuneresponse to one or more CNS autoantigens (seep. 220) that have not yet been identified.

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Clinical findings

Special tests in MS (IEF = isoelectric focusing)

Impaired coordination

Central paresis (right hyperreflexia)

VEP measurement

MRI (T2-weighted imageof cerebral hemispheres)

MRI (T2-weightedimage of cerebellum)

Lumbar puncture IEF in MS IEF in normals

Oligoclonal bands

Serum

CSF

Lesions

Lesions

Ventricle

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Activation. Circulating autoreactive CD4+ T lym-phocytes bear antigen-specific surface receptorsand can cross the blood–brain barrier (BBB)when activated, e. g., by neurotropic viruses,bacterial superantigens, or cytokines. In MS, ac-tivated T lymphocytes react with MBP, PLP,MOG, and MAG. Circulating antibodies tovarious components of myelin can also be de-tected (for abbreviations, see below1).Passage through the BBB. Activated lympho-cytes and myelinotoxic antibodies penetrate theBBB at the venules (perivenous distribution ofinflammation).Antigen presentation and stimulation. In theCNS, antigen-presenting cells (microglia), rec-ognition molecules (MHC class II antigens), andco-stimulatory signals (CD28, B-7.1) trigger therenewed activation and clonal proliferation ofincoming CD4+ T lymphocytes into TH1 and TH2cells. Proinflammatory cytokines elaborated bythe TH1 cells (IL-2, IFN-!, TNF-", LT)2 inducephagocytosis by macrophages and microglia aswell as the synthesis of mediators of inflamma-tion (TNF-", OH–, NO)2 and complement factors.The TH2 cells secrete cytokines (IL-4, IL-5, IL-6)2

that activate B cells (! myelinotoxic autoantibo-dies, complement activation), ultimately caus-ing damage tomyelin. The TH2 cells also produceIL-4 and IL-10, which suppress the TH1 cells.Demyelination. Lesions develop in myelinsheaths (which are extensions of oligoden-droglial cell membranes) and in axons when theinflammatory process outstrips the capacity ofrepair mechanisms.Scar formation. The inflammatory responsesubsides and remyelination of damaged axonsbegins once the autoreactive T cells die (apopto-sis), the BBB is repaired, and local anti-inflam-matory mediators and cells are synthesized.Astroglia form scar tissue that takes the place ofthe dead cells. Axonal damage seems to be the

main cause of permanent neurological deficits,as dystrophic axons apparently cannot be remy-elinated.

Treatment

Relapse is treated with high-dose corti-costeroids, e. g., methylprednisolone, 1 g/day for3–5 days, which produce (unselective) immuno-suppression, reduce BBB penetration by T cells,and lessen TH1 cytokine formation. Plasm-apheresis may be indicated in refractory cases.Drugs that reduce the frequency and intensity ofrelapses. Azathioprine p.o. (immunosuppressionvia reduction of T cell count), interferon beta-1band beta-1a s.c. or i.m. (cytokine modulation, al-teration of T-cell activity), glatiramer acetate s.c.(copolymer-1; blocks/competes at binding sitesfor encephalitogenic peptides on MHC-IImolecules), IgG i. v. (multiple modes of action),and natalizumab (selective adhesion inhibitor).Drugs that delay secondary progression. Inter-feron beta-1b and beta-1a. Mitoxantronesuppresses B cells and decreases the CD4/CD8ratio. Methotrexate and cyclophosphamide(different dosage schedules) delay MS progres-sion mainly by unselective immunosuppressionand reduction of the T-cell count.Slowing of primary progression. No specifictherapy is known at present.Symptomatic therapy/rehabilitation. Medica-tions, physical, occupational, and speech ther-apy, social, psychological, and dietary counsel-ing, and mechanical aids (e. g., walking aids,wheelchair) are provided as needed. Thepossible benefits of oligodendrocyte precursorcell transplantation for remyelination, and ofgrowth factors and immunoglobulins for thepromotion of endogenous remyelination, arecurrently under investigation in both experi-mental and clinical studies.

1MBP, myelin basic protein; MOG, myelin-oligodendro-cyte glycoprotein; MAG, myelin-associated glycoprotein;PLP, proteolipid protein; S100 protein, CNPase, "#-crys-tallin, transaldolase2IL, interleukin; IFN-!, interferon-gamma; TNF-", tumornecrosis factor-alpha; LT, lymphotoxin; OH–: hydroxylradical; NO, nitric oxide3p.o., orally; s.c., subcutaneously; i.m., intramuscularly;i. v., intravenously.

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Cerebral lesion (plaque)

Cerebral cortex

AntigenAntigen peptidesMajor histocompatibility complex

(MHC) protein

Macrophage

T-cell activation

Trimolecular interaction (MHC protein, antigen protein, T-cell receptor)

T-cell receptor

Activated T cell (ad-hering to cell wall)

Crossing the blood-brain barrier (BBB)

AutoreactiveT cell

Astrocyte

Endothelium (BBB)

Oligodendrocyte

Myelinatedaxon

Neuron

Antigen-presenting cell(microglia, astrocyte)

B cell

Antibody

Complement

Complement-activatedcomplexes

Demyelination

T-cell (TH1/TH2) proliferation and activation

Blood vessel

MHC protein-bound peptide(antigen presentation)

MHC/antigen protein complex

White matter

Lesion of myelinsheath/axon

Antigen-presenting cell in CNS (macrophage)

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Syndromes

! Localization

CNS infection may involve the leptomeningesand CSF spaces (meningitis), the ventricular sys-tem (ventriculitis), the gray and white matter ofthe brain (encephalitis), or the spinal cord (my-elitis). A focus of bacterial infection of the brainis called a brain abscess, or cerebritis in the earlystage before a frank abscess is formed. Pus lo-cated between the dura mater and thearachnoid membrane is called a subdural empy-ema, while pus outside the dura is called anepidural abscess.

! Course

The clinical manifestations may be acute(purulent meningitis, CNS listeriosis, herpessimplex encephalitis), subacute (cerebral ab-scess, focal encephalitis, neuroborreliosis, neu-rosyphilis, tuberculous meningitis, actinomyco-sis, nocardiosis, rickettsiosis, neurobrucellosis),or chronic (tuberculous meningitis, neurosy-philis, neuroborreliosis, Whipple encephalitis,Creutzfeldt–Jakob disease). The epidemiologicalpattern of infection may be sporadic, endemic orepidemic, depending on the pathogen.

! Clinical Manifestations

Meningitis and encephalitis rarely occur as en-tirely distinct syndromes; they usually presentin mixed form (meningoencephalitis, en-cephalomyelitis). CSF examination establishesthe diagnosis.These disorders may present in specific ways incertain patient groups. Neonates and childrencommonly manifest failure to thrive, fever orhypothermia, restlessness, breathing disorders,epileptic seizures, and a bulging fontanelle. Theelderly may lack fever but frequently have be-havioral abnormalities, confusion, epilepticseizures, generalized weakness, and impair-ment of consciousness ranging to coma. Im-munodeficient patients commonly have fever,headache, stiff neck, and drowsiness in additionto the manifestations of their primary illness.Meningitic syndrome is characterized by fever,severe, intractable headache and backache, pho-tophobia and phonophobia, nausea, vomiting,impairment of consciousness, stiff neck, and hy-perextended posture, with opisthotonus or neck

pain on flexion. Kernig’s sign (resistance to pas-sive raising of leg with extended knee) andBrudzinski’s sign (involuntary leg flexion on pas-sive flexion of the neck) are signs of meningealinvolvement. Painful neck stiffness is due to(lepto)meningeal irritation by infectiousmeningitis, septicemia, subarachnoid hemor-rhage, neoplastic meningitis, or other causes.Isolated neck stiffness not caused by meningitis(meningism) may be due to cervical disorderssuch as arthrosis, fracture, intervertebral diskherniation, tumor, or extrapyramidal rigidity.Papilledema is usually absent; when present, itindicates intracranial hypertension (p. 158).Encephalitic syndrome is characterized by head-ache and fever, sometimes accompanied byepileptic seizures (often focal), focal signs(cranial nerves deficits, especially of CN III, IV,VI, and VII; aphasia, hemiparesis, hemianopsia,ataxia, choreoathetosis), behavioral changes,and impairment of consciousness (restlessness,irritability, confusion, lethargy, drowsiness,coma). The neurological signs may be precededby limb pain (myalgia, arthralgia), a slight in-crease in body temperature, and malaise. Foracute cerebellitis (! ataxia), see p. 276. Brainstem encephalitis produces ophthalmoplegia, fa-cial paresis, dysarthria, dysphagia, ataxia, andhearing loss.Myelitic syndrome. Myelitis presents withsevere local pain, paraparesis, paresthesiae, orsome combination of these. Incomplete orcomplete paraplegia or quadriplegia (p. 48)develops within a few hours (acute) or days(subacute). The differential diagnosis may bedifficult.

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Osteomyelitis

Epiduralabscess

Meningitis

Subdural empyema, abscess

Encephalitis, focal encephalitis

(cerebritis),abscess

Ventriculitis

Cerebellitis, cerebellar abscess

Brain stem encephalitis

Neck stiffness

Sites of CNS infection

Myelitis, spinal abscess

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Pathogenesis

Pathogens usually reach the CNS by local exten-sion fromanearby infectious focus (e. g. sinusitis,mastoiditis) or by hematogenous spread from adistant focus. The ability of pathogens to spreadby way of the bloodstream depends on theirvirulence and on the immune status of the host.They use special mechanisms to cross or circum-vent the blood–brain barrier (p. 8). Some patho-gens enter theCNSby centripetal travel alongpe-ripheral nerves (herpes simplex virus type I, vari-cella-zoster virus, rabies virus), others by en-docytosis (Neisseria meningitidis), intracellulartransport (Plasmodium falciparum via erythro-cytes, Toxoplasmagondiiviamacrophages), or in-tracellular invasion (Haemophilus influenzae).Those thatenter the subarachnoid spaceprobablydo so by way of the choroid plexus, venoussinuses, or cribriform plate (p. 76). Havingentered the CSF spaces, pathogens trigger an in-flammatory response characterized by the releaseof complement factors and cytokines, the influxof leukocytes and macrophages, and the activa-tion of microglia and astrocytes. Disruption ofthe blood–brain barrier results in an influx offluids and proteins across the vascular en-dothelium and into the CNS, causing vasogeniccerebral edema (p. 162), which is accompaniedby both cytotoxic cellular edema and interstitialedema due to impaired CSF circulation. Cerebraledema causes intracranial hypertension. Theseprocesses, in conjunctionwith vasculitis, impair-ment of vascular autoregulatory mechanisms,and/or fluctuations of systemic blood pressure,lead to the development of ischemic, metabolic,and hypoxic cerebral lesions (focal necrosis,territorial infarction).

Treatment (Table 28, p. 375)

The immune system is generally no longer ableto hold pathogens in check once they havespread to the CNS, as the immune response inthe subarachnoid space and the neural tissue it-self is less effective than elsewhere in the body.Having gained access to the CNS, pathogensmeet with favorable conditions for furtherspread within it.Prophylaxis. The occurrence and spread of CNSinfection can be prevented by mandatory re-

porting (as specified by local law), prevention ofexposure (isolation of sources of infection, disin-fection, sterilization), and prophylaxis in personsat risk (active and passive immunization,chemoprophylaxis).Treatment. Patients with bacterial or viralmeningoencephalitis must be treated at once.The treatment strategy is initially based on theclinical and additional findings. Antimicrobialtherapy is first given empirically in a broad-spectrum combination, then specificallytailored in accordance with the species and drugsensitivity pattern of the pathogen(s) identified.Causative organisms may be found in the CSF,blood, or other bodily fluids (e. g., throat smear,urine or stool samples, bronchial secretions, ga-stric juice, abscess aspirate).

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Hematogenous spread of pulmonaryinfection

Hematogenousspread of

endocarditis

Bacterialendocarditis

Hematogenousspread ofinfection

Otitis media, mastoiditis

Venous sinus

Sinusitis (frontal sinus)

Nasal route ofinfection

(cribriform plate)

Diapedesis of leukocytes (migration

from bloodstream)

Granulocyte

Bacterial invasion

Blood-brain barrierlesion ( increased

permeability)

Macrophage

BloodstreamCSF space(subarachnoid space)

Activated astrocyte

Menin-gococci

Adhesion molecule (adhesion of hematogenous cells)

Endothelial cell

CNSinflammatory response

General inflammatoryresponse

Routes of CNS infection

Hematogenous invasion of CNS

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Bacterial Infections

! Meningitis/Meningoencephalitis

For an overview of the most common patho-gens, cf. Table 29 (p 376). Immune prophylaxis:Vaccines are available against Haemophilus in-fluenzae type B infection (for infants, smallchildren, and children over 6 years of age at in-creased risk), Pneumococcus (children over 2years of age and adults with risk factors suchas immunosuppression or asplenia), andmeningococcus (travel to endemic regions, localoutbreaks). Chemoprophylaxis is indicated forclose contacts of persons infected withHaemophilus influenzae (rifampicin) or menin-gococcus (rifampicin, ciprofloxacin, or ceftri-axone).

! Brain Abscess

Brain abscess begins as local cerebritis and isthen transformed into an encapsulated region ofpurulent necrosis with perifocal edema. Thepathogenic organisms may reach the brain bylocal or hematogenous spread (mastoiditis, otitismedia, sinusitis, osteomyelitis; endocarditis,pneumonia, tooth infection, osteomyelitis,diverticulitis), or by direct inoculation (trauma,neurosurgery). The clinical manifestations in-clude headache, nausea, vomiting, fever, impair-ment of consciousness, and focal or generalizedepileptic seizures, neck stiffness, and focal neu-rological signs. The diagnosis is made by MRIand/or CT (which should include bone windows,as the infection may have originated in bonystructures) and confirmed by culture of thepathogenic organism.

! Bacterial Vasculitis (p. 180)

Arteries. Vessel wall inflammation in associa-tion with sepsis. Bacterial endocarditis causescerebral abscess formation or infarction by wayof infectious thromboembolism (! focal inflam-matory changes in the cerebral parenchyma !

metastatic or embolic focal encephalitis). Thesyndrome is characterized by headache, fever,epileptic seizures, and behavioral changes in ad-dition to focal neurological signs. Meningoen-cephalitis may cause arteritis by direct involve-ment of the vessels. Embolization of infectiousmaterial may lead to the development of septic(“mycotic”) aneurysms.

Veins. Bacterial thrombophlebitis of the cerebralveins or venous sinuses may arise as a complica-tion of meningitis or by local spread of infectionfrom neighboring structures.

! Ventriculitis

Infection of the ventricular system (perhaps inconnection with an intraventricular catheter forinternal or external CSF drainage). The clinicalfindings are often nonspecific (somnolence, im-pairment of concentration and memory).Abdominal complaints (peritonitis) may pre-dominate if the infection has spread down aventriculoperitoneal shunt to the abdomen.Diagnosis: CSF examination and culture.

! Septic Encephalopathy

Bacteremia leads to the release of endotoxins,which, in turn, impair cerebral function. Septicencephalopathy can produce findings sugges-tive of meningoencephalitis such as impairmentof consciousness, epileptic seizures, paresis, andmeningismus, despite the absence of CSF in-flammatory changes and a sterile CSF culture.Diagnosis: EEG changes consistent with the di-agnosis (general changes, triphasic complexes,burst suppression) in the setting of known sys-temic sepsis with sterile CSF. CT and MRI arenormal.

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227Septic encephalopathy

Brain abscess

Bacterial arteritis

Bacterial infections of the spine

Bacterial thrombophlebitis

Ventriculitis

Epidural abscess, osteomyelitisBrain abscess with subduraland epidural extension

Meningitis

Abscess (late stage)

Focal encephalitis (cerebritis)

Septic thrombus, vasculitis

Mycotic aneurysm

Myelitis

Spinalsubduralempyema

Spinal epiduralabscess

Septic superiorsagittal sinus

thrombosis

Subduralempyema

Encephalitis

Orbitalphlegmon

Herpessimplex

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! Lyme Disease (Neuroborreliosis)

Pathogenesis. The spirochete Borrelia burg-dorferi sensu lato (Europe: B. garinii, B. afzelii;North America: B. burgdorferi sensu stricto) istransmitted to man by ticks (Europe: Ixodes ri-cinus; North America: Ixodes pacificus, I. scapu-laris). The probability of infection is low unlessthe infected tick remains attached to the skin forat least 24–48 hours. Only 1–2% of individualsbitten by ticks become infected. The incubationtime ranges from 3–30 days. The disease occursin three stages, as described below.Clinical manifestations. Stage I (localized infec-tion). Up to 90% of all patients develop a pain-less, erythematous macule or papule thatgradually spreads outward from the site of thetick bite in a ringlike or homogeneous fashion(erythema chronicum migrans). This is com-monly accompanied by symptoms due to he-matogenous spread of the pathogen, such asfever, fatigue, arthralgia, myalgia, or other typesof pain, which may be the chief complaint,rather than the skin rash. Regional or general-ized lymphadenopathy (lymphadenosis benignacutis) is a less common presentation. All of thesefindings may resolve spontaneously.Stage II (disseminated infection). Generalizedsymptoms such as fatigue, anorexia, muscle andjoint pain, and headache develop in 10–15% ofpatients within ca. 3–6 weeks, sometimes ac-companied bymild fever and neck stiffness. Car-diac manifestations: Myocarditis or pericarditiswith AV block. Neurological manifestations:Cranial nerve palsies, painful polyradiculitis andlymphocytic meningitis (Bannwarth syndrome,meningopolyneuritis) are commonly seen incombination. One ormore cranial nervesmay beaffected; the most common finding is unilateralor bilateral facial palsy of peripheral type. Neu-roborreliosis-related polyradiculoneuropathy(which may bemistaken for lumbar disk hernia-tion) is characterized by intense pain in a radic-ular distribution, most severe at night, with ac-companying neurological deficits (motor,sensory, and reflex abnormalities, focal muscleatrophy). Borrelia-related meningitis (Lymemeningitis) usually causes alternating headacheand neck pain, but the headache is mild or ab-sent in some cases. It may be worst at certaintimes of day. CSF studies reveal a mononuclear

pleocytosis with a high plasma cell count and anelevated protein concentration, while the glu-cose concentration is normal. Encephalitis oc-curs relatively rarely andmay cause focal neuro-logical deficits as well as behavioral changes(impaired concentration, personality changes,depression). MRI reveals cerebral white-matterlesions, and the CSF findings are consistent withmeningitis. Myelitis, when it occurs, often af-fects the spinal cord at the level of a radicular le-sion.Stage III (persistent infection). The latency fromclinical presentation to the onset of stage III dis-ease varies from 1 to 17 years (chronic Lymeneuroborreliosis). Few patients ever reach thisstage, characterized by neurological deficitssuch as ataxia, cranial nerve palsies, paraparesisor quadriparesis, and bladder dysfunction (Lymeencephalomyelitis). Encephalopathy causing im-pairment of concentration and memory, in-somnia, fatigue, personality changes, and de-pression has also been described. Myositis andcerebral vasculitis may also occur. In stage III ofLyme disease, acrodermatitis chronica atrophi-cans of the extensor surface of the limbs may beseen along with a type of polyneuropathyspecific to Borrelia afzelii.Diagnosis. Many patients have no memory of atick bite. The diagnosis of Lyme disease is basedon the presence of erythema chronicum mi-grans, the immunological confirmation of Bor-relia infection (e. g., by ELISA, indirect immuno-fluorescence assay, Western blot, or specific IgGantibody–CSF-serum index) and/or the identifi-cation of the causative organism (e. g., by cul-ture, histology, or polymerase chain reaction).By definition, the diagnosis also requires thepresence of lymphocytic meningitis (with orwithout cranial nerve involvement or painfulpolyradiculoneuritis), encephalomyelitis, or en-cephalopathy.Treatment. Local symptoms: Antibiotic such asdoxycycline or amoxicillin (p.o.) for 3 weeks.Neuroborreliosis: Ceftriaxone or cefotaxime(i. v.) for 2–3 weeks. A vaccine has been ap-proved for use in the United States, and anotheris being developed for use in Europe.

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Erythema chronicum migrans (ECM)

Facial paresis (bilateral)Radicular pain

Stages of Lyme disease

ECM

Tick Erythema (thigh)

Lagophthalmos

Stage I

Infection

Days...............................Weeks.........................Months......................Years.................

Stage II Stage III

Erythema chronicummigransGeneral symptoms

General symptomsBannwarth syndromeMeningitisEncephalitisCarditisMyelitis

EncephalomyelitisEncephalopathyMyositisCerebral vasculitisAcrodermatitischronica atrophicansPolyneuritis

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! Neurosyphilis

Pathogenesis. Syphilis is caused by the spiro-chete (bacterium) Treponema pallidum (TP) ssp.pallidum and is transmitted by direct exposureto infected lesions, usually on the skin ormucous membranes, during sexual contact.Other routes of transmission, such as the shar-ing of needles by intravenous drug users, aremuch less common. The disease has three clini-cal stages. In the primary and secondary stages,nonspecific tests (VDRL and RPR) and specifictests (TPHA, FTA-ABS, and 19S-(IgM-)FTA-ABStests) yield positive results. Tertiary stage (cur-rently rare): After an asymptomatic period of afew months to years (latent syphilis), organmanifestations develop, such as gummata (skin,bone, kidney, liver) and cardiovascular lesions(aortic aneurysm). The first year of the tertiarystage is designated the early latency period andis characterized by a high likelihood of recur-rence and, thus, recurrent infectivity.Clinical manifestations. TP may invade thenervous system at any stage of syphilis withoutnecessarily producing signs or symptoms.Early meningitis. A variably severe meningiticsyndromemay be accompanied by deficits of CNVIII (sudden hearing loss), VII (facial palsy), or II(visual impairment). Meningopolyradiculitis israre. CSF examination reveals lymphocyticpleocytosis (up to 400 cells/µl) and an elevatedprotein concentration. Meningitis resolvesspontaneously, but late complications mayoccur. Asymptomatic meningitis (CSF changes inthe absence of a meningitic syndrome) occurs in20–30% of all infected persons.Meningovascular neurosyphilis. Fluctuatingsymptoms such as headache, visual distur-bances, and vertigo occur 5–12 years after theinitial infection. Vasculitis (von Heubner angiitis)causes stroke, particularly in the territory of themiddle cerebral artery, andmay also affect smallperforating vessels as well as cranial nerves(VIII, VII, V). Hydrocephalus, personalitychanges, epileptic seizures, and spinal cordsigns (paraparesis, bladder dysfunction, anteriorcord syndrome) round out the kaleidoscopicclinical picture. Gummata are rarely seen. CTand MRI findings suggest the diagnosis, and CSFexamination reveals a mononuclear pleocytosis(up to 100 cells/µl), elevated protein concentra-

tion, elevated oligoclonal IgG, and VDRL positiv-ity (up to 80%).Progressive paralysis. Chronic meningoen-cephalitis with progressive paralysis occurs10–25 years after the initial infection. The “pre-paralytic” stage, characterized by personalitychanges and mild impairment of concentrationand memory, later evolves into the “paralytic”stage, characterized by more severe cognitivechanges, dysarthria, dysphasia, tremor (mimictremor), apraxia, gait impairment, urinary in-continence, and abnormal pupillary reflexes(roughly 25% of patients have Argyll–Robertsonpupils, p. 92). The CSF findings resemble those ofmeningovascular syphilis.Tabes dorsalis. This late meningovascular com-plication (25–30 years after the initial infection)produces ocular manifestations (Argyll–Robert-son pupils, strabismus, papillary atrophy), pain(lightning pains = lancinating pain mainly in thelegs; colicky abdominal pain), gait impairment(due to loss of acrognosis and proprioception),and autonomic dysfunction (impotence, urinarydysfunction). Joint deformities (Charcot joints) inthe lower limbs are occasionally seen. The CSFcell count is relatively low, as in meningovascu-lar syphilis.Antibiotic therapy. The efficacy of treatment de-pends on the stage of disease in which it is insti-tuted (the earlier, the better). Penicillin is theagent of choice.

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Early meningitis (cranial nerve dysfunction)

Development of symptoms of neurosyphilis (no fixed time course)

Ocular symptoms (progressive paralysis, tabes dorsalis)

Progressive paralysis (behavioral changes)

Tabes dorsalis (lancinating pain)

Abducenspalsy

Primarystage

Earlymeningitis Meningovascular

neurosyphilis

Progressive paralysis

Tabes dorsalis

Secondary stage

Infection

Tertiary stage

Peripheral facial palsy

......Weeks.............Months........................Years.....................................................

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! Tuberculous Meningitis

Pathogenesis. Mycobacterium tuberculosistransmission in man is usually by transfer ofdroplets from and to the respiratory tract (rarelyorally or through skin lesions). The pathogenreplicates in the lungs (primary infection), eitherin the lung tissue itself or within alveolar mac-rophages. Macrophages can only destroytubercle bacilli after they have been activated byT cells; the course of the infection thus dependson the state of the immune system, i.e., on theability of activated macrophages to hold thebacilli in check. The stage of primary infectionlasts 2–4 weeks, is not necessarily symptomatic(if it is, then with nonspecific symptoms such asfever, anorexia, and lethargy), and cannot be de-tected by immune tests performed on the skin.The inflammatory process may also involve theregional (hilar) lymph nodes (primary complex).Calcified foci in the primary complex are easilyseen on plain radiographs of the chest. Thebacilli may remain dormant for years or may bereactivated when the patient’s immunedefenses are lowered by HIV infection, alco-holism, diabetes mellitus, corticosteroid ther-apy, or other factors (reactivated tuberculosis).Spread from the primary focus to other organs(organ tuberculosis) can occur during primaryinfection in immunocompromised patients, butonly after reactivation in other patients. Thebacilli presumably reach the CNS by hemato-genous dissemination; local extension to theCNS from tuberculous bone (spinal cord, base ofskull) is rare.Symptoms and signs. The type and focus of CNSinvolvement (neurotuberculosis) vary, depend-ing mainly on the age and immune status of thehost.Tuberculous meningoecephalitis. The prodro-mal stage lasts 2–3 weeks and is characterizedby behavioral changes (apathy, depression, irri-tability, confusion, delirium, lack of concentra-tion), anorexia, weight loss, malaise, nausea,and fever. Headache and neck stiffness reflectmeningeal involvement. Finally, cerebral involve-mentmanifests itself in focal signs (deficits of CNII, III, VI, VII, and VIII; aphasia, apraxia, centralparesis, focal epileptic seizures, SIADH) and/orgeneral signs (signs of intracranial hypertension,hydrocephalus). The focal signs are caused by

leptomeningeal adhesions, cerebral ischemiadue to vasculitis, or mass lesions (tuberculoma).Chronic meningitis most likely reflects inade-quate treatment, or resistance of the pathogen,rather than being a distinct form of the disease.Diagnosis: CSF examination for initial diagnosisand monitoring of disease course. The diagnosisof tuberculous meningitis can only be con-firmed by detection of mycobacteria in the CSFwith directmicroscopic visualization, culture, ormolecular biological techniques. As the progno-sis of untreated tuberculous meningitis is poor,treatment for presumed disease should be in-itiated as soon as the diagnosis is suspectedfrom the clinical examination and CSF findings;the latter typically include high concentrationsof protein (several grams/liter) and lactate, a lowglucose concentration (!50% of blood glucose),a high cell count (over several hundred), and amixed pleocytosis (lymphocytes, monocytes,granulocytes).Tuberculoma is a tumorlike mass with a caseousor calcified core surrounded by granulationtissue (giant cells, lymphocytes). Tuberculomasmay be solitary or multiple and are to be differ-entiated from tuberculous abscesses, which arefull of mycobacteria and lack the surroundinggranulation tissue. Diagnosis: CT or MRI.Spinal tuberculosis. Transverse spinal cord syn-drome can arise because of tuberculous myelo-meningoradiculitis, epidural tuberculous ab-scess associated with tuberculous spondylitis/discitis, or tuberculoma. Diagnosis: MRI.Antibiotic treatment. One treatment protocolspecifies a combination of isoniazid (with vi-tamin B6), rifampicin (initially i. v., then p.o.),and pyrazinamide (p.o.). After 3 months, pyrazi-namide is discontinued, and treatment withisoniazid and rifampicin is continued for afurther 6–9 months. The treatment for HIV-positive patients includes up to five different an-tibiotics.

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Prodromal phase

Focal disturbances(patient looking to right)

Caseating meningitis (basal exudate)

Tuberculoma in brain stem

Leptomeningealcontrast enhance-

ment in MRI

Ischemic lesion(tuberculous arteritis)

Tuberculous spondylitis, gibbus deformity

Leptomeninges fullof exudate; cranial

nerves barely visible

Spinal cord compression

Abducens palsy

Hydrocephalus

II

V

VI

III

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Viral Infections

! Viral Meningoencephalitis

Aseptic meningitis is characterized by amening-itic syndrome (p. 222) that arises acutely andtakes a benign course over the ensuing 1 or 2weeks, in the absence of signs of generalized orlocal infection (otitis media, craniospinal ab-scess, sinusitis). CSF findings: A mild granulo-cytic pleocytosis is seen in the first 48 hours andis then transformed into a mild lymphomono-cytic pleocytosis which can persist as long as 2months after the clinical findings have re-gressed. The CSF protein and lactate concentra-tions are normal or only slightly elevated, whilethe CSF glucose concentration is normal ormildly decreased. The term “viral meningitis” isoften used synonymously with aseptic mening-itis, though, strictly speaking, the clinical pic-ture of aseptic meningitis can also be producedby fungal, parasitic, or even bacterial infection(e. g., mycobacteria, mycoplasma, Brucella,spirochetes, Listeria, rickettsiae, incompletelytreated bacterial meningitis). Aseptic meningitismay be postinfectious (HIV, rubella, measles,zoster) or postvaccinial or a sequela of sarcoido-sis, Behçet disease, Vogt–Koyanagi–Harada syn-drome, Mollaret meningitis, connective tissue dis-eases, and other, noninflammatory disorders(meningeal carcinomatosis, contrast agents,medications, subarachnoid hemorrhage, leadpoisoning).

Viral meningitis. Frontal or retro-orbital head-ache, fever, and low-grade neck stiffness usuallybegin acutely and last for 1–2 weeks. The CSFfindings are those of aseptic meningitis, de-scribed above; the IgG index or oligoclonal IgGmay be elevated.Viral encephalitis. The meninges are usually in-volved concomitantly (meningoencephalitis).Acute encephalitis mainly affects the gray mat-ter and perivascular areas of the brain. Be-havioral changes, psychomotor agitation, andfocal epileptic seizures may be the leadingsymptoms (p. 192). The CSF findings are gener-ally as listed above for aseptic meningitis,though pleocytosis may be absent at first. Dif-fuse and focal EEG changes are usually seen. CTand MRI often reveal pathological changes.Acute demyelinating encephalomyelitis (ADEM)predominantly affects perivenous regions andthe cerebral white matter (leukoencephalitis).The disease takes a variable course (a mono-phasic course with complete resolution isamong the possibilities). ADEM can occurduring or after a bout of infectious disease(measles, chickenpox, rubella, influenza) orafter a vaccination (smallpox, measles, mumps,polio). Both encephalitic and myelitic syn-dromes can occur (spastic paraparesis or quad-riparesis). The white-matter lesions are demon-strated best by MRI, less well by CT.

Summer, Early Spring Autumn, Winter Winter, Spring All Year Round

Arboviruses, ente-roviruses

Lymphocytic chorio-meningitis virus

Mumps HIV, herpes simplexvirus, cytomegalovirus

Pathogens. Their seasonal peak frequency isshown in the following table.

The viral pathogens that most commonly causemeningitis differ from those most commonlycausing encephalitis and myelitis (cf. Table 30,p. 376).Identification of pathogen: Serologic tests orisolation of the virus from throat smears(poliovirus, coxsackievirus, mumps virus; ade-

novirus, HSV type 1), stool samples (coxsack-ievirus, polio virus), CSF (coxsackievirus,mumps, adenovirus, arbovirus, rabies, VZV,LCMV, HSV type 2), blood (arbovirus, EBV, LCMV,CMV, HSV type 2), urine (mumps, CMV), or saliva(mumps, rabies).

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Personality change(perseveration, apraxia, aphasia)

Clonus

Confusion(hallucinations, psychomotor hyperactivity,

loss of coordination, fluctuating level ofconsciousness)

Focal signs(partial epileptic seizure) Extrapyramidal motor

dysfunction(tonic upward gaze deviation)

Loss of drive (anxiety, apathy, mutism)

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! Herpes Simplex Virus Infection

Pathogenesis. Herpes simplex virus type 1 (HSV-1) is usually transmitted in childhood throughlesions of the oral mucosa (gingival stomatitis,pharyngitis). The virus travels centripetally byway of nerve processes toward the sensory gan-glia (e. g., the trigeminal ganglion), where it re-mains dormant for a variable period of timeuntil reactivated by a trigger such as ultravioletradiation, dental procedures, immunosuppres-sion, or a febrile illness. It then travels centrifu-gally, again over nerve processes, back to the pe-riphery, producing blisterlike vesicles (herpeslabialis). HSV-1 also causes eye infection (kera-toconjunctivitis), as well as (meningo)encephal-itis when it spreads via CN I and leptomeningealfibers of CN V. There is no association betweenherpes labialis and HSV-1 encephalitis. Herpessimplex virus type 2 (HSV-2) reaches the lum-bosacral ganglia by axonal transport from a siteof (asymptomatic) urogenital infection. Its reac-tivation causes genital herpes. In adults, HSV-2infection can cause (aseptic) meningitis and, oc-casionally, polyradiculitis or myelitis. HSV-2virus can be transmitted to the newborn duringthe birth process, causing encephalitis. HSV-1encephalitis is very rare in neonates, and HSV-2encephalitis is very rare in adults.Symptoms and signs. Herpes simplex encephali-tis (HSE) in adults begins with local inflamma-tion of the caudal andmedial parts of the frontaland temporal lobes. Uncharacteristic prodromalsigns such as fever, headache, nausea, anorexia,and lethargy last a few days at the most. Focalsymptoms including olfactory and gustatoryhallucinations, aphasia, and behavioral distur-bances (confusion, psychosis) then appear,along with focal or complex partial seizureswith secondary generalization. There is usuallyrepeated seizure activity, but status epilepticusis rare. Intracranial hypertension causes impair-ment of consciousness or coma within a fewhours. In neonates, the inflammation spreadsthroughout the CNS.The diagnosis of HSE can be difficult, especiallyat first. The clinical findings include neck stiff-ness, hemiparesis, and mental disturbances. CSFexamination reveals a lymphomonocyticpleocytosis (granulocytes may predominate ini-tially) with an elevated protein concentration;

low glucose and high lactate concentrations areonly rarely found. Xanthochromia and erythro-cytes may be present (hemorrhagic necrotizingencephalitis). In the first 3 weeks, the virus canalmost always be detected in the CSF by poly-merase chain reaction; brain biopsy is onlyrarely needed for identification of the viralpathogen. Lumbar puncture carries a risk if in-tracranial hypertension is present (p. 162). EEGreveals periodic high-voltage sharp waves and2–3Hz slow wave complexes as a focal or dif-fuse finding in one or both temporal lobes. In theacute stage of HSE, CT is normal or reveals onlymild temporobasal hypointensity without con-trast enhancement. Hemorrhage may appear asa hyperdense area. Sharply defined areas of hy-podensity appear on CT only in the later stagesof HSE. T2-weighted MRI, however, already re-veals inflammatory lesions in early HSE. Thus,MRI is used for early diagnosis, CT for the moni-toring of encephalitic foci and cerebral edemaover the course of the disease.Meningitis. The clinical manifestations are thoseof aseptic meningitis (p. 234).Myelitis. Low back pain, fever, sensory deficitwith spinal level, flaccid or spastic paraparesis,bladder and bowel dysfunction. These mani-festations usually regress within 2 weeks.Radiculitis. Inflammation of the lumbosacralnerve roots produces a sensory deficit and blad-der and bowel dysfunction.Virustatic agents. HSV infection of the CNS istreated with acyclovir 10mg/kg (i. v.) q8h for14–21 days. Particularly in HSE, it is importantto begin treatment as soon as possible.

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1s 50 µ V

Prodromal signs, behavioral changes

Route of HSV-1 infection (in encephalitis)

EEG

MRI(contrast-enhanced T1-weighted image)

Space-occupying

lesion (herpessimplex

encephalitis of left

temporal lobe)

Viral invasion (olfactory epithelial cell)Migration of virus(olfactory bulb)

Olfactory epithelium

HSV-1

Periodic slow-wave complexes, left temporal

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! Varicella-Zoster Virus Infection

Pathogenesis. In children, primary infectionwith varicella-zoster virus (VZV) usually causeschickenpox (varicella). The portals of entry forinfection by droplets or mucus are the conjunc-tiva, oropharynx, and upper respiratory tract.The virions replicate locally, then enter cells ofthe reticulohistiocytic system by hematogenousand lymphatic spread (primary viremia). There,they replicate again and disseminate (secondaryviremia). VZV infection is followed by immunity.VZV travels by centripetal axonal transportthrough the sensory nerve fibers of the skin andmucous membranes to the spinal and cranialganglia and may remain latent there for years(ganglionic latency phase). The thoracic andtrigeminal nerve ganglia are most commonly af-fected, but those of CN VII, IX, and X can also beinvolved. Spontaneous viral reactivation in theganglia (ganglionitis) is most common in theelderly, diabetics, and immunocompromisedpersons (HIV, lymphoma, radiotherapy,chemotherapy, etc.). The reactivated virustravels over the axons centrifugally to the der-matome corresponding to its ganglion of origin,producing the typical dermatomal rash ofherpes zoster. It may also spread to the CNS viathe spinal dorsal roots (radiculitis), causingherpes zoster myelitis or meningoencephalitis.VZV attacks cerebral blood vessels by way of ax-onal transport from the trigeminal ganglion.Postherpetic neuralgia is thought to be due todisordered nociceptive processing in both pe-ripheral and central structures.Symptoms and signs. Chickenpox: After an in-cubation period of 14–21 days, crops of itchy ef-florescent lesions appear, which progressthrough the sequence macule, papule, vesicle,scab within a few hours. The scabs detach in 1–2weeks. Immunocompromised patients candevelop severe hemorrhagic myelitis, pneu-monia, encephalitis, or hepatitis. Acute cerebelli-tis in children causes appendicular, postural, andgait ataxia, less commonly dysarthria and nys-tagmus. CSF examination reveals mild pleocyto-sis and elevation of the protein concentration, oris normal, and the MRI is usually normal. VZVcerebellitis resolves slowly in most cases.Herpes zoster begins with general symptoms(lethargy, fever) followed by pain, itching, burn-

ing or tingling in the affected dermatome(s),which are most commonly thoracic orcraniocervical (special forms: herpes zoster oph-thalmicus, oticus, and occipitocollaris). Within afew days, groups of distended vesicles contain-ing clear fluid appear on an erythematous basewithin the affected dermatome. The contents ofthe vesicles become turbid and yellowish in 2–3days. The rash dries, becomes encrusted, andheals in another 5–10 days. The pain and dy-sesthesia of herpes zoster generally last nolonger than 4 weeks. They may also occurwithout a rash (herpes zoster sine herpete).Complications. Elderly and immunocom-promised persons are at increased risk for com-plications. Pain that persists more than 4 weeksafter the cutaneous manifestations have healedis called postherpetic neuralgia and is most com-mon in the cranial and thoracic dermatomes.Cranial nerve involvement may cause unilateralor bilateral ocular complications (ophthal-moplegia, keratoconjunctivitis, visual impair-ment) or Ramsay–Hunt syndrome (facial palsy,hearing loss, tinnitus, vertigo). Other cranialnerves (IX, X, XII) are rarely affected. Furthercomplications include Guillain–Barré syn-drome, myelitis, segmental muscular paresis/atrophy, myositis, meningitis, ventriculitis, en-cephalitis, autonomic disturbances (anhidrosis,complex regional pain syndrome), generalizedherpes zoster, and vasculitis (ICA and itsbranches, basilar artery). The viral pathogen isdetected in CSF with the polymerase chain reac-tion.Virustatic therapy. Acyclovir: 5mg/kg i. v. q8h or800mg p.o. 5 times daily; brivudine: 125mg p.o.4 times daily; famcyclovir: 250mg p.o. 3 timesdialy; or valacyclovir: 1 g p.o. 3 times daily.Treatment is continued for 5–7 days. Theseagents are only effective during the viral replica-tion phase. Intrathecal administration ofmethylprednisolone is effective in postherpeticneuralgia.

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Acute cerebellarataxiaPostinfectiousencephalomyelitisMyelitisGuillain-Barré syndromeReye syndromeVasculitis (infarct)

Postherpetic neuralgiaCranial nerve palsySegmental paresisAseptic meningitisMeningoencephalitisMyelitisVasculitis (infarct)

Varicella(different stages of efflorescence)

Intraneuronal virus (spinal ganglion)

Herpes zoster(“shingles”; dermatome T6/7, left)

Portals of entry

Possible complications of VZV infection

Vesicle

Scab formation

Macule

PapuleViremia

Centripetal axonaltransport

Spread via spinal dorsal root

Group of vesicles on reddened base

(Adapted from Johnson, 1998)

Ganglionic latency phase

Reactivation

Varicella Zoster

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! Human Immunodeficiency Virus (HIV)Infection

Pathogenesis.HIV type 1 (HIV-1) is foundworld-wide, HIV-2 mainly in western Africa and onlyrarely in Europe, America, and India. HIV is trans-mitted by sexual contact, by exposure to con-taminated blood or blood products, or frommother to neonate (vertical transmission). It isnot transmitted through nonsexual contactduring normal daily activities, by contaminatedfood orwater, or by insect bites. In industrializedcountries, the mean incubation period for HIV is9–12 years, and the mean survival time after theonset of acquired immunodeficiency syndrome(AIDS) is 1–3 years. In primary infection (trans-mitted throughmucosal lesions, etc.), the free orcell-bound organisms enter primary target cellsin thehematopoietic system (T cells, B cells,mac-rophages, dendritic cells), CNS (macrophages,microglia, astrocytes, neurons), skin (fibro-blasts), or gastrointestinal tract (goblet cells).After replicating in the primary target cells, thevirions spread to regional lymph nodes, CD4+ Tcells, and macrophages, where they replicaterapidly, leading to amarkedviremiawithdissem-inationofHIV toother target cells throughout thebody. About 7–14 days after this viremic phase,the immune system gains partial control overviral replication, and seroconversion occurs. Thesubsequent period of clinical latency is charac-terized by a steady rate of viral replication, elimi-nation of HIV by the immune system, and the ab-sence ofmajor clinical manifestations for severalyears. Eventually, the immune system fails tokeep up with the replicating virus, various im-mune functions become impaired, and the CD4+

T-lymphocyte count declines sharply. The risingviral load correlates with the progression of HIVinfection to AIDS. In the nervous system, HIV ini-tially appears in theCSF, but is later foundmainlyin macrophages and microglia.Symptoms and signs. Neurological manifesta-tions can occur at any stage of HIV infection, butusually appear only in the late stages of AIDS.One-half to two-thirds of all HIV-positive in-dividuals develop neurological disturbances as aprimary or secondary complication of HIV infec-tion or of a concomitant disease.Primary HIV infection. Early manifestations atthe time of seroconversion are rare; these in-

clude acute reversible encephalitis or asepticmeningitis (p. 234), cranial nerve deficits (espe-cially facial nerve palsy), radiculitis, or myelitis.Neurological signs are usually late manifesta-tions of HIV infection. HIV encephalopathy pro-gresses over several months and is character-ized by lethargy, headache, increasing socialwithdrawal, insomnia, forgetfulness, lack ofconcentration, and apathy. Advanced AIDS is ac-companied by bradyphrenia, impaired ocularpursuit, dysarthrophonia, incoordination, myo-clonus, rigidity, and postural tremor. Inconti-nence and central paresis develop in the finalstages of the disease. CT of the brain revealsgeneralized atrophy, and MRI reveals multifocalor diffuse white-matter lesions. The CSF exami-nation may be normal or reveal a low-gradepleocytosis and an elevated protein concentra-tion. EEG reveals increased slow-wave activity.Other neurological manifestations include HIVmyelopathy (vacuolar myelopathy), distal sym-metrical polyradiculoneuropathies, mononeuritismultiplex, and polymyositis.Secondary complications of HIV infection in-clude opportunistic CNS infections (toxoplasmo-sis, cryptococcal meningitis, aspergillosis, pro-gressive multifocal leukoencephalopathy, cy-tomegalovirus encephalitis, herpes simplex en-cephalitis, herpes zoster, tuberculosis, syphilis),tumors (primary CNS lymphoma), stroke (infarc-tion, hemorrhage), and metabolic disturbances(iatrogenic or secondary to vitamin deficiency).Virustatic treatment. Antiretroviral combina-tion therapy (HAART: highly active antiretrovi-ral therapy).

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Primaryinfection

Spread in regionallymph node

HIV replication(lymph node)

Viremia, dissemination

HIV replication cycle in host cell

Course of HIV infection (number of CD4+ lymphocytes and HIV)

CNS toxoplasmosis (axialT2-weighted MRI scan)

Nonintegrated DNA

Cellular DNA

HIV-1

Co-receptor

rT*

Primary infection (Weeks) (Years)

Early manifestation, viremia, disseminationCD4+ T cells/ml)

HIV-1 RNAcopies/ml plasma)

Death1000

500

100

3 1 5 106 9 12

107

106

105

104

103

102

Adsorption(virus gp120 + CD4+ receptor)

Viral penetration

Genomic RNA

mRNA, translation

Protein synthesis, processing of gp160, envelope, capsid

Release of virions

Integrated proviral DNA

Pathogenesis of HIV infection (*rT = reverse transcriptase)

Construction of virions

Transcription of viral genome

Mucosal lesion

Chromosomal integration

Clinical latency

Opportunisticdiseases

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! Poliomyelitis

Pathogenesis. There are three types ofpoliovirus: type 1 (ca. 85% of all infections), type2 and type 3. Like other enteroviruses (e. g., cox-sackievirus, echovirus, and hepatitis-A virus),they are transmitted via the fecal–oral and oral–oral routes, and poor sanitary conditions favortheir spread. Having entered the body, the vir-ions infiltrate epithelial cells, where they repli-cate, and then spread to the lymphatic tissues ofthe nasopharynx (tonsils) and intestinal wall(Peyer’s patches). A second replication phase(6–8 days) is followed by hematogenous dis-semination (viremia), with nonspecific symp-toms. Polioviruses reach the CNS via the blood-stream and can produce signs of poliomyelitis10–14 days after infection. The virus is presentin the saliva for 3–4 days and in the feces for 3–4weeks. The infected individual becomes im-mune only to the specific type of poliovirus thatcaused the infection. The viral pathogen can bedetected in throat smears and feces by serologyor by the polymerase chain reaction.Symptoms and signs. 90–95% of all poliovirusinfections remain asymptomatic (occult im-munization). Roughly 5–10% of infected personsdevelop abortive poliomyelitis, while only 1–2%go on to develop major spinal, bulbar, or en-cephalitic disease.Minor poliomyelitis (abortive type) has non-specific manifestations including fever, head-ache, sore throat, limb pain, lethargy, andgastrointestinal disturbances (nausea, anorexia,diarrhea, constipation), which resolve in 4 daysat most, without CNS involvement.Major poliomyelitis (preparalytic and paralytictypes). Either immediately or after a latency pe-riod of 2–3 days, fever rises and organ manife-stations appear, with a meningitic syndrome(preparalytic stage) that may be followed byparalysis in the later course of the disease (para-lytic stage). The meningitis of the preparalyticstage exhibits typical features of asepticmeningitis as well as marked generalized weak-ness and apathy. It resolves in about one-half ofcases; in the other half, increasing myalgia andstiffness herald the onset of the paralytic stage.The spinal form (most common) causes flaccidparesis (usually with asymmetrical proximalweakness) and areflexia, mainly in the lower

limbs. The paresis may worsen over 3–5 days;its severity is highly variable. Some patientsdevelop paresthesiae without sensory loss orautonomic dysfunction (urinary retention, hy-pohidrosis, constipation). Muscle atrophydevelops within a week of the onset of paralysis.Bulbar poliomyelitis develops in some 10% ofpatients (in isolated form, or concurrently withspinal poliomyelitis), involving CN VII, IX, and Xto produce dysphagia and dysphonia. Involve-ment of the brain stem reticular formationcauses hemodynamic fluctuations, respiratoryinsufficiency or paralysis, and gastric atony. Theencephalitic form is very rare; it may be accom-panied by autonomic dysfunction (p. 222).Postpolio syndrome. Newly arising manifesta-tions in a patient who recovered from poliomy-elitis at least 10 years earlier with stable neuro-logical deficits in the intervening time. Postpoliosyndrome is characterized by general symptoms(abnormal fatigability, intolerance to cold, cya-nosis of the affected limbs, etc.), arthralgias, andincreasing neuromuscular deficits (exacerbationof earlier weakness, weakness of previously un-affected muscles, new atrophy), sometimes ac-companied by dysphagia, respiratory insuffi-ciency, and sleep apnea.Prevention. Subcutaneous immunization withinactivated polioviruses (e. g., Salk vaccine), fol-lowed by a first booster in 6–8 weeks and a sec-ond booster in 8–12 months.

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Route of infection

Paresis and muscular atrophy

Oral transmissionof poliovirus

Replication intonsils

Viremia

Neuronal involvement(organ manifestation)

Acute poliomyelitis

Complete recovery (no muscular atrophy)

Incomplete recovery (muscular atrophy)

Neurogenicmuscle lesion

Increasing muscular atrophy

Postpolio syndrome

Motor neuron

Latency phase (10-15 years) with stable deficit

New muscular atrophy

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! Progressive Multifocal Leukoencephalopathy(PML)

Pathogenesis. The causative organism, JC virus,is a ubiquitous papovavirus that usually staysdormant within the body. It is reactivated inpersons with impaired cellular immunity andspreads through the bloodstream to the CNS,where it induces multiple white-matter lesions.Symptoms and signs. PML appears as a compli-cation of cancer (chronic lymphatic leukemia,Hodgkin lymphoma), tuberculosis, sarcoidosis,immune suppression, and AIDS, producing vari-able symptoms and signs. The major manifesta-tions in patients without AIDS are visual distur-bances (visual field defects, cortical blindness),hemiparesis, and neuropsychological distur-bances (impairment of memory and cognitivefunctions, dysphasia, behavioral abnormalities).The major manifestations of PML as a complica-tion of AIDS are (from most to least frequent):central paresis, cognitive impairment, visualdisturbances, gait impairment, ataxia, dys-arthria, dysphasia, and headache. PML usuallyprogresses rapidly, causing death in 4–6months. The definitive diagnosis is by histologi-cal examination of brain tissue obtained by bi-opsy or necropsy. CT reveals asymmetrically dis-tributed, hypodense white-matter lesionswithout mass effect or contrast enhancement;these lesions are hyperintense on T2-weightedMRI, which also demonstrates involvement ofthe subcortical white matter (“U fibers”). TheCSF findings are usually normal, but oligoclonalbands may be found in AIDS patients.Virustatic therapy. There is as yet no validatedtreatment regimen.

! Cytomegalovirus (CMV) Infection

Pathogenesis. CMV, a member of the her-pesvirus family, is transmitted through respira-tory droplets, sexual intercourse, and contactwith contaminated blood, blood products, ortransplanted organs. It is widely distributedthroughout the world, with a regional and age-dependent prevalence of up to 100%. CMV vir-ions are thought to replicate initially inoropharyngeal epithelial cells (salivary glands)and then disseminate to the organs of the body,including the nervous system, through thebloodstream. The virus remains dormant in

monocytes and lymphocytes as long as the im-mune system keeps it in check. Reactivation ofthe virus is almost always asymptomatic inhealthy individuals, but severe generalized dis-ease can develop in persons with immune com-promise due to AIDS, organ transplantation, im-munosuppressant drugs, or a primary malig-nancy.Symptoms and signs. The primary infection isusually clinically silent. Intrauterine fetal infec-tion leads to generalized fetopathies in fewerthan 5% of neonates. In immunocompromisedpatients, particularly those with AIDS, (reacti-vated) CMV infection presents a variable combi-nation of manifestations, including retinitis(partial or total loss of vision), pneumonia, andenteritis (colitis, esophagitis, proctitis). The neu-rological manifestations of CMV infection aremanifold. PNS involvement is reflected as Guil-lain–Barré syndrome or lumbosacral poly-radiculopathy (subacute paraparesis with orwithout back pain or radicular pain). CNS in-volvement produces encephalitis, meningitis,ventriculitis (inflammatory changes in theependyma) and/or myelitis. Symptoms andsigns may be absent, minor, or progressivelysevere, as in HIV-related encephalopathy. CMVvasculitis may lead to ischemic stroke. The diag-nosis usually cannot be made from the clinicalfindings alone (except in the case of CMV retini-tis). MRI reveals periventricular contrast en-hancement in CMV vasculitis; other MRI and CTfindings are nonspecific. There may be CSFpleocytosis with an elevated protein concentra-tion. The diagnosis can be established by cultureor identification by polymerase chain reactionof CMV in tissue, CSF, or urine, or by serologicaldetection of CMV-specific antibodies.Virustatic therapy. Gancyclovir, foscarnet, orcidofovir are given for initial treatment and sec-ondary prophylaxis.

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Progressive multifocal leukoencephalopathy

Cytomegalovirus (CMV) infection

Dysarthria, dysphasia, cognitiveimpairment, behavioral changes

Foci of demyelination seen onMRI (no mass effect or contrast

enhancement)

CMV ventriculitis onMRI (ependymal contrast enhancement)

Cotton-wool spotsnear optic disk

Microangiopathy

CMV retinitis

Hemorrhage

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! Rabies

Pathogenesis. Rabies virus is a rhabdovirus thatis mainly transmitted by the bite of a rabid ani-mal. The reservoirs of infection are wild animalsin Europe and America (foxes, wild boar, deer,martens, raccoons, badgers, bats; sylvatic rabies)and dogs in Asia (urban rabies). The virus repli-cates in muscles cells near the site of entry andthen spreads via muscle spindles and motor endplates to the peripheral nerves, as far as the spi-nal ganglia and spinal motor neurons, wheresecondary replication takes place. It sub-sequently spreads to the CNS and other organs(salivary glands, cornea, kidneys, lungs) by wayof the fiber pathways of the autonomic nervoussystem. The limbic system (p. 144) is usuallyalso involved. The mean incubation time is 2–3months (range: 1 week to 1 year). Proof that thebiting animal was rabid is essential for diagno-sis, as rabies is otherwise very difficult to diag-nose until its late clinical manifestations appear.The virus can be isolated from the patient’ssputum, urine or CSF in the first week after in-fection.Symptoms and signs. The course of rabies can bedivided into three stages. The prodromal stage(2–4 days) is characterized by paresthesia, hy-peresthesia, and pain at the site of the bite andthe entire ipsilateral side of the body. Thepatient suffers from nausea, malaise, fever, andheadache and, within a few days, also fromanxiety, irritability, insomnia, motor hyperactiv-ity, and depression.Hyperexcitability stage. In the ensuing days, thepatient typically develops increasing restless-ness, incoherent speech, and painful spasms ofthe limbs and muscles of deglutition, reflectinginvolvement of the midbrain tegmentum. Hy-drophobia, as this stage of the disease is called, ischaracterized by painful laryngospasms, respi-ratory muscle spasms, and opisthotonus, withtonic-clonic spasms throughout the body thatare initially triggered by attempts to drink butlater even by the mere sight of water, unex-pected noises, breezes, or bright light. Theremay be alternating periods of extreme agitation(screaming, spitting, and/or scratching fits) andrelative calm. The patient dies within a few daysif untreated, or else progresses to the next stageafter a brief clinical improvement.

Paralytic stage (paralytic rabies). The patient’smood and hydrophobic manifestations improve,but spinal involvement produces an ascendingflaccid paralysis with myalgia and fascicula-tions. Weakness may appear in all limbs at once,or else in an initially asymmetrical pattern,beginning in the bitten limb and then spreading.In some cases, the clinical picture is dominatedby cranial nerve palsies (oculomotor distur-bances, dysphagia, drooling, dysarthrophonia)and autonomic dysfunction (cardiac arrhyth-mia, pulmonary edema, diabetes insipidus, hy-perhidrosis).Rabies prophylaxis. Preexposure prophylaxis:Vaccination of persons at risk (veterinarians,laboratory personnel, travelers to endemicareas).Local wound treatment: Thorough washing ofthe bite wound with soap and water.Postexposure prophylaxis: Vaccination and rabiesimmunoglobulin.

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Route of rabies virus transmission

Rabies virus (bullet-shaped)

Motor end plate

Sympathetictrunk

Animal bite Excitation stage (hydrophobia)

Excitation stage (spasms, opisthotonus)

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Opportunistic Fungal Infections

CNS mycosis is sometimes found in otherwisehealthy persons but mainly occurs as a com-ponent of an opportunistic systemic mycosis inpersons with immune compromise due to AIDS,organ transplantation, severe burns, malignantdiseases, diabetes mellitus, connective tissuediseases, chemotherapy, or chronic corti-costeroid therapy. Certain types of mycosis(blastomycosis, coccidioidmycosis, histoplas-mosis) are endemic to certain regions of theworld (North America, South America, Africa).

! Cryptococcus neoformans (Cryptococcosis)

Cryptococcus, a yeastlike fungus with a polysac-charide capsule, is a common cause of CNS my-cosis. It is mainly transmitted by inhalation ofdust contaminated with the feces of pet birdsand pigeons. Local pulmonary infection is fol-lowed by hematogenous spread to the CNS. Inthe presence of a competent immune system(particularly cell-mediated immunity), the pul-monary infection usually remains asympto-matic and self-limited. Immune-compromisedpersons, however, may develop meningoen-cephalitis with or without prior signs of pulmo-nary cryptococcosis. Its manifestations are het-erogeneous and usually progressive. Signs ofsubacute or chronic meningitis are accom-panied by cranial nerve deficits (III, IV, VI), en-cephalitic syndrome, and/or signs of intracranialhypertension. Diagnosis: MRI reveals granulo-matous cystic lesions with surrounding edema.Lung infiltrates may be seen. The nonspecificCSF changes include a variable (usually mild)lymphomonocytic pleocytosis as well as ele-vated protein, low glucose, and elevated lactateconcentrations. An india ink histological pre-paration reveals the pathogen with a surround-ing halo (carbon particles cannot penetrate itspolysaccharide capsule). Identification of patho-gen: demonstration of antigen in CSF andserum; tests for anticryptococcal antibody yieldvariable results. Treatment: initially, amphoteri-cin B + flucytosine; subsequently, fluconazole or(if fluconazole is not tolerated) itraconazole.

! Candida (Candidiasis)

Candida albicans is a constituent of the normalbody flora. In persons with impaired cell-medi-

ated immunity, Candida can infect theoropharynx (thrush) and then spread to theupper respiratory tract, esophagus, and in-testine. CNS infection comes about by hemato-genous spread (candida sepsis), resulting inmeningitis or meningoencephalitis. Ocularchanges: Candida endophthalmitis. Diagnosis:Candida abscesses can be seen on CT or MRI. TheCSF changes included pleocytosis (severalhundred cells/µl) and elevated concentrations ofprotein and lactate. Pathogen identification: Mi-croscopy, culture, or detection of specific an-tigens or antibodies. Local treatment: Amphoter-icin B or fluconazole. Systemic tratment: Am-photericin B + flucytosine.

! Aspergillus (Aspergillosis)

The mold Aspergillus fumigatus is commonlyfound in cellulose-containing materials such assilage grain, wood, paper, potting soil, andfoliage. Inhaled spores produce local inflamma-tion in the airways, sinuses, and lungs. Or-ganisms reach the CNS by hematogenous spreador by direct extension (e. g., from osteomyelitisof the skull base, otitis, or mastoiditis), causingencephalitis, dural granulomas, or multiple ab-scesses. Diagnosis: CT and MRI reveal multiple,sometimes hemorrhagic lesions. The CSF find-ings include granulocytic pleocytosis andmarkedly elevated protein, decreased glucose,and elevated lactate concentration. Pathogenidentification: Culture; if negative, then lung orbrain biopsy. Treatment: Amphotericin B + flucy-tosine or itraconazole.

! Mucor, Absidia, Rhizopus (Mucormycosis)

Inhaled spores of these molds enter the na-sopharynx, bronchi, and lungs, where theymainly infect blood vessels. Rhinocerebral mu-cormycosis is a rare complication of diabetic ke-toacidosis, lymphoproliferative disorders, anddrug abuse; infection spreads from the para-nasal sinuses via blood vessels to the retro-orbi-tal tissues (causing retro-orbital edema, exoph-thalmos, and ophthalmoplegia) and to the brain(causing infarction with secondary hemor-rhage). Diagnosis: CT, MRI; associated findingson ENT examination. Pathogen identification: Bi-opsy, smears. Treatment: Surgical excision of in-fected tissue if possible; amphotericin B.

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Candidiasis of tongue (thrush)

Pigeon feces

Ink-stained CSFspecimen

Bright polysaccharide capsule,sprouting of daughter cells

Cerebral aspergillosis (multiple hemorrhagic, necrotic foci)

Aspergillus fumigatus(hyphal filaments)

Bloody nasal discharge

Erythema, periorbital edema,exophthalmos, ptosis

Facial nerve palsy

Candida albicans(yeast form)

Candida

Cryptococcosis

Aspergillosis

Rhinocerebral mucormycosis

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Protozoan and Helminthic Infections

! Toxoplasma gondii (Toxoplasmosis)

This protozoan goes through three stages ofdevelopment. Tachyzoites (endozoites; acutestage) are crescent-shaped, rapidly replicatingforms that circulate in the bloodstream and arespread from one individual to another throughcontaminated blood or blood products. Thesedevelop into bradyzoites (cystozoites; latentstage), which aggregate to form tissue cysts(e. g., in muscle) containing several thousand or-ganisms each. Oocysts are found only in the in-testinal mucosa of the definitive host (domesticcat). Infectious sporozoites (sporulated oocysts)appear 2–4 days after the oocysts are eliminatedin cat feces. Reuptake of the organism by thedefinitive host, or infection of an intermediatehost (human, pig, sheep), occurs by ingestion ofsporozoites from contaminated feces, or by con-sumption of rawmeat containing tissue cysts. Inthe intermediate host, the sporozoites developinto tachyzoites, which then become brady-zoites and tissue cysts. Placental transmission(congenital toxoplasmosis ! hydrocephalus, in-tracellular calcium deposits, chorioretinitis) oc-curs only if the mother is initially infectedduring pregnancy. In immunocompetent per-sons, acute toxoplasmosis is usually asympto-matic, and only occasionally causes symptomssuch as lymphadenopathy, fatigue, low-gradefever, arthralgia, and headache. IgG antibodiescan be detected in latent toxoplasmosis (brady-zoite stage). In immunodeficient persons(p. 240), however, latent toxoplasmosis usuallybecomes symptomatic on reactivation. The cen-tral nervous system is most commonly affected(mainly encephalitis; myelitis is rare); other or-gans that may be affected include the eyes(chorioretinitis, iridocyclitis), heart, liver,spleen, PNS (neuritis) and muscles (myositis).Diagnosis: EEG (slowing, focal signs), CT/MRI(solitary or multiple ring-enhancing abscesses),CSF (lymphomonocytic pleocytosis, mildly ele-vated protein concentration). Treatment: py-rimethamine/sulfadiazine or clindamycin/folinic acid.

! Taenia solium (Neurocysticercosis)

Ingestion of the tapeworm Taenia solium in rawor undercooked pork leads to a usually asymp-

tomatic infection of the human gut. Tapewormsegments that contain eggs (proglottids) areeliminated in the feces of pigs (the intermediatehost) or humans with intestinal infection andthen reingested by humans (or pigs) under poorhygienic conditions. The oval-shaped larvaepass through the intestinal wall and travel tomultiple organs (including the eyes, skin,muscles, lung, and heart) by hematogenous,lymphatic, or direct spread. The CNS is often in-volved, though manifestations such as epilepticseizures, intracranial hypertension, behavioralchanges (dementia, disorientation), hemipare-sis, aphasia, and ataxia are uncommon. Spinalcysts are rare. Diagnosis: CT (solitary or multiplehypodense cysts with or without contrast en-hancement, calcification and/or hydro-cephalus), MRI (demonstration of cysts and sur-rounding edema), CSF examination (low-gradelymphocytic pleocytosis, occasionaleosinophilia). Treatment: Praziquantel or alben-dazole; neurosurgical excision of intraventricu-lar cysts; ventricular shunting in patients withhydrocephalus.

! Plasmodium falciparum (Cerebral Malaria)

This protozoan is most commonly transmittedby the bite of the female anopheles mosquito.Primary asexual reproduction of the organismstakes place in the hepatic parenchyma (pre-erythrocytic schizogony). The organisms then in-vade red blood cells and develop further insidethem (intraerythrocytic development). The re-peated liberation of merozoites causes recur-rent episodes of fever. P. falciparum preferen-tially colonizes the capillaries of the brain, heart,liver, and kidneys. Pathogen identification: Bloodculture. Treatment: See current topical literaturefor recommendations.

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Toxoplasmosis

Cerebral cysticercosis

Cerebral malaria

Sporulated oocysts

Oral transmission(sporulated oocysts,cysts in meat)

Endo-zoites

Hematogenous/lymphaticspread

Placental transmission

Infected porcine muscle(hydatid)

Contaminated raw pork

Cerebral cyst with mass effect(potential complications:meningitis, calcification,

obstructive hydrocephalus)Scolex (head of tapeworm)

Proglot-tids

Tapeworm

Intestinalinfection

Worm eggs

Intermediatehost

Contam-inated vegetables

Endemic regions formalaria (current distribution may differ)

Female anopheles mosquito

Multiplepetechiae in

cerebralmalaria

Immunodeficiency

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Transmissible SpongiformEncephalopathies

The transmissible spongiform encephalopathies(TSEs) are characterized by spongiform histo-logical changes in the brain (vacuoles in neuronsand neuropil), transmissibility to humans byway of infected tissue or contaminated surgicalinstruments, and, in some cases, a genetic deter-mination. TSEs are transmitted by nucleic acid-free proteinaceous particles called prions andare associated with mutations in prion protein(PrP); they are therefore referred to as prion dis-eases.Normal cellular prion protein (PrPc) is synthe-sized intracellularly, transported to the cellmembrane, and returned to the cell interior byendocytosis. Part of the PrPc is then brokendown by proteases, and another fraction istransported back to the cell surface. The physio-logical function of PrPc is still unknown. It isfound in all mammalian species and is espe-cially abundant in neurons. PRNP, the gene re-sponsible for the expression of PrPc in man, isfound on the short arm of chromosome 20. PRNPmutations yield the mutated form of PrP (!PrP)that causes the genetic spongiform en-cephalopathies. Another mutated form of PrP(PrPsc) causes the infectious spongiform en-cephalopathies. PrPsc induces the conversion ofPrPc to PrPsc in the following manner: PrPsc ent-ers the cell and binds with PrPc to yield a hetero-dimer. The resulting conformational change inthe PrPc molecule ("-helical structure) and itsinteraction with a still unidentified cellular pro-tein (protein X) transform it into PrPsc (#-sheetstructure). Protein X is thought to supply theenergy needed for protein folding, or at least tolower the activation energy for it. PrPsc cannotbe formed in cells lacking PrPc. Mutated PrPsc

presumably reaches the CNS by axonal transportor in lymphatic cells; these forms of transporthave been demonstrated in forms of spongiformencephalopathies that affect domestic animals,e. g., scrapie (in sheep) and bovine spongiformencephalopathy (BSE). !PrP and PrPsc cannot bebroken down intracellularly and therefore accu-mulate within the cells. Partial proteolysis ofthese proteins yields a protease-resistantmolecule (PrP 27–30) that polymerizes to formamyloid, which, in turn, induces further neu-

ropathological changes. PrP and amyloid havebeen found in certain myopathies (such as in-clusion body myositis, p. 344); others involve anaccumulation of PrP (PrP overexpression my-opathy).

! Creutzfeldt–Jakob Disease (CJD)

CJD is a very rare disease, arising in ca. 1 personper 106 per year. It usually affects older adults(peak incidence around age 60). 85–90% ofcases are sporadic (due to a spontaneous genemutation or conformational change of PrPc toPrPsc); 5–15% are familial (usually autosomaldominant); and very rare cases are iatrogenic(transmitted by contaminated neurosurgical in-struments or implants, growth hormone, anddural and corneal grafts). It usually progressesrapidly to death within 4–12 months of onset,though the survival time in individual cases var-ies from a few weeks to several years. Earlymanifestations are not typically seen, but mayinclude fatigability, vertigo, cognitive impair-ment, anxiety, insomnia, hallucinations, in-creasing apathy, and depression. The principalfinding is a rapidly progressive dementia as-sociated with myoclonus, increased startle re-sponse, motor disturbances (rigidity, muscleatrophy, fasciculations, cerebellar ataxia), andvisual disturbances. Late manifestations includeakinetic mutism, severe myoclonus, epilepticseizures, and autonomic dysfunction. A newvariant of CJD has recently arisen in the UnitedKingdom; unlike the typical form, it tends to af-fect younger patients, produces mainly be-havioral changes in its early stages, and is as-sociated with longer survival (though it, too, isfatal). It is thought to be caused by the con-sumption of beef from cattle infected with BSE.Diagnosis: EEG (1 Hz periodic biphasic ortriphasic sharp-wave complexes), CT (corticalatrophy), T2/proton-weighted MRI (bilateral hy-perintensity in basal ganglia in ca. 80%), CSF ex-amination (elevation of neuron-specific enolase,S100# or tau protein concentration; presence ofprotein 14–3-3).

! Gerstmann–Sträussler–Scheinker Disease(GSS) and Fatal Familial Insomnia (FFI)

See pp. 114 and 280.

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Normal PrPc synthesisHereditary

prion disease

Creutzfeldt-Jakob disease (CJD)

Infectious priondisease

Normal PrP conformation

Accumulation of PrP amyloid in neuron

Spongiform dystrophy of graymatter

PRNP(nucleus)

PrPc synthesis

PrPc trans-ported tocell surface

Reab-sorbed,trans-ported back to cellsurface

Breakdown by cellular proteases (lysosomes)

InfectiousPrPsc

Protease resistance of PrPsc accumulation of PrPsc,storage of amyloid

Conversion ofPrPc to PrPsc

PRNP mutation

Heterodimer formation

Mutatedprion

protein( PrP)

Spontaneousconversion of

PrP zu PrPsc

Continuous sharp wave complexes (CJD)

Dementia, ataxia,

myoclonus,visual

disturbances,behavioral

changes

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Symptoms and Signs

The clinical manifestations of a brain tumormayrange from a virtually asymptomatic state to aconstellation of symptoms and signs that isspecific for a particular type and location of le-sion. The only way to rule out a brain tumor forcertain is by neuroimaging (CT or MRI).

! Nonspecific Manifestations

Tumors whose manifestations are mainly non-specific include astrocytoma, oligodendro-glioma, cerebral metastasis, ependymoma,meningioma, neoplastic meningitis, and pri-mary CNS lymphoma.Behavioral changes. Patients may complain ofeasy fatigability or exhaustion, while their rela-tives or co-workers may notice lack of concen-tration, forgetfulness, loss of initiative, cognitiveimpairment, indifference, negligent task per-formance, indecisiveness, slovenliness, andgeneral slowing of movement. Such manifesta-tions are often mistaken for signs of depressionor stress. Apathy, obtundation, and somnolenceworsen as the disease progresses. There mayalso be increasing confusion, disorientation, anddementia.Headache. More than half of patients with braintumors suffer from headache, and many head-ache patients fear that they might have a braintumor. If headache is the sole symptom, theneurological examination is normal, and theheadache can be securely classified as belongingto one of the primary types (p. 182 ff), then abrain tumor is very unlikely. Neuroimaging isindicated in patients with longstanding head-ache who report a change in their symptoms.The clinical features of headache do not differ-entiate benign from malignant tumors.Nausea, vertigo, and malaise are frequent,though often vague, complaints. The patientfeels unsteady or simply “different.” Vomiting(sometimes on an empty stomach) is less com-mon and not necessarily accompanied bynausea; there may be spontaneous, projectilevomiting.Epileptic seizures. Focal or generalized seizuresarising in adulthood should prompt evaluationfor a possible brain tumor.Focal neurological signs usually become promi-nent only in advanced stages of the disease but

may be present earlier in milder form. Hemi-paresis, aphasia, apraxia, ataxia, cranial nervepalsies, or incontinence may occur dependingon the type and location of the tumor.Intracranial hypertension (elevated ICP) (p. 158)may arise without marked focal neurologicaldysfunction because of a medulloblastoma,ependymoma of the fourth ventricle, cerebellarhemangioblastoma, colloid cyst of the 3rd ven-tricle, craniopharyngioma, or glioblastoma (e. g.of the frontal lobe or corpus callosum). Cervicaltumors very rarely cause intracranial hyperten-sion. Papilledema, if present, is not necessarilydue to a brain tumor, nor does its absence ruleone out. Papilledema does not impair vision inits acute phase.

! Specific Manifestations

Some tumors produce symptoms and signs thatare specific for their histological type, location,or both. These tumors include craniopharyn-gioma, olfactory groove meningioma, pituitarytumors, cerebellopontine angle tumors, pontineglioma, chondrosarcoma, chordoma, glomustumors, skull base tumors, and tumors of theforamen magnum. In general, these specificmanifestations are typically found when thetumor is relatively small and are gradually over-shadowed by nonspecific manifestations (de-scribed above) as it grows.

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Behavioral changes

Incontinence, focal neurological signs

Vertigo, unsteady gait

Headache Nausea, vomiting

Early papilledema(irregular margins, disk elevation, reduced venous pulsation)

Advanced papilledema

Fully developedpapilledema

Peripapillaryhemorrhage

Hemorrhage

Blurring of disk margins

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Benign Brain Tumors

! Astrocytoma (WHO grades I and II)

Astrocytomas arise from blastomatous astro-cytes. They are classified as benign (WHO gradeI) or semibenign (WHO grade II) according totheir histological features (p. 377).Pilocytic astrocytoma (WHO grade I) is a slowlygrowing tumor that mainly occurs in childrenand young adults and usually arises in the cere-bellum, optic nerve, optic chiasm, hy-pothalamus, or pons. It is not uncommonlyfound in the setting of neurofibromatosis I.There may be a relatively long history of head-ache, abnormal gait, visual impairment, dia-betes insipidus, precocious puberty, or cranialnerve palsies before the tumor is discovered.Low-grade astrocytoma (WHO grade II). Fibril-lary astrocytoma is more common than thegemistocytic and protoplasmic types. Thesetumors most commonly arise in the frontal andtemporal lobes and often undergo malignanttransformation to grades III and IV over thecourse of several years. They may be calcified.They may produce epileptic seizures and be-havioral changes.Oligodendroglioma (WHO grade II) usually ap-pears in the 4th or 5th decade of life. It tends toarise at or near the cortical surface of the frontaland temporal lobes and may extend locally toinvolve the leptomeninges. Oligodendrogliomasare often partially calcified. Tumors of mixedhistology (oligodendrocytoma plus astrocy-toma) are called oligoastrocytomas.Pleomorphic xanthoastrocytoma (WHO gradeII) is a rare tumor that mainly arises in the tem-poral lobes of children and young adults and isassociated with epileptic seizures in most cases.It can progress to a grade III tumor.

! Meningioma (WHO grade I)

Meningiomas are slowly growing, usuallybenign, dural-based extraaxial tumors that arethought to arise from arachnoid cells. Twelvehistological subtypes have been identified.Meningiomas tend to recur if they are not totallyresected. They may involve not only the duramater but also the adjacent bone (manifestingusually as hyperostosis, more rarely as thinning)and may infiltrate or occlude the cerebralvenous sinuses. They can occur anywhere in the

CNS but are most often found in supratentorial(falx, parasagittal region, sphenoid wing, cere-bral convexities), infratentorial (tentorium, cere-bellopontine angle, craniocervical junction),and spinal locations. Multiple or intraventricularmeningioma is less common. Extracranialmeningiomas rarely arise in the orbit, skin, ornasal sinuses. Familial meningioma is seen inhereditary disorders such as type II neurofibro-matosis.

! Choroid Plexus Papilloma (WHO grade I)

This rare tumor most commonly arises in the(left) lateral ventricle in children and in the 4thventricle in adults. Signs of intracranial hyper-tension, due to obstruction of CSF flow, are themost common clinical presentation and mayarise acutely.

! Hemangioblastoma (WHO grade I)

These solid or cystic tumors usually arise in thecerebellum (from the vermis more often thanthe hemispheres) and produce vertigo, head-ache, truncal ataxia, and gait ataxia. Obstructivehydrocephalus may occur as an early manifesta-tion. 10% of cases are in patients with von Hip-pel–Lindau disease (p. 294).

! Ependymoma (WHO grades I–II)

Ependymomas most commonly arise in child-ren, adolescents, and young adults. They mayarise in the ventricular system (usually in thefourth ventricle) or outside it; they may be cys-tic or calcified. Subependymoma of the fourthventricle (WHO grade I) may appear in middleage or later. Spinal ependymomas may arise inany portion of the spinal cord.

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Common sites of meningioma

Convexity meningioma causingbone destruction

Supratentorial sites

Supraten-torial sites

Infratentorialsite

Plexus papilloma(3rd ventricle)

Ependymoma (craniocervical

junction, extraventricular site)

Cystic hemangioblastoma(cerebellum)

Hemangioblastoma (von Hippel-Lindau

syndrome)

MRI (sagittal T1-weighted image)

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Tumors in Specific Locations

! Supratentorial Region

Colloid cyst of 3rd ventricle. These cysts filledwith gelatinous fluid are found in proximity tothe interventricular foramen (of Monro). Smallcolloid cysts may remain asymptomatic, butlarge ones cause acute or chronic obstructive hy-drocephalus (p. 162). Sudden obstruction of theforamen causes acute intracranial hypertension,sometimes with loss of consciousness. Sympto-matic colloid cysts can be surgically removedwith stereotactic, neuroendoscopic, or opentechniques.Craniopharyngioma (WHO grade I). Adamanti-nomatous craniopharyngioma is suprasellartumor of children and adolescents that has bothcystic and calcified components. It producesvisual field defects, hormonal deficits (growthretardation, thyroid and adrenocortical insuffi-ciency, diabetes insipidus), and hydrocephalus.Large tumors can cause behavioral changes andepileptic seizures. Papillary craniopharyngiomais a tumor of adults that usually involves the 3rdventricle.Pituitary adenomas (WHO grade I). Adenomassmaller than 10mm, called microadenomas, areusually hormone-secreting, while those largerthan 10mm, called macroadenomas, are oftennon–hormone-secreting. In addition to possiblehormone secretion, these tumors have intrasel-lar (hypothyroidism, adrenocortical hormonedeficiency, amenorrhea reflecting anteriorpituitary insufficiency, and, rarely, diabetes in-sipidus), suprasellar (chiasmatic lesions, p. 82,hypothalamic compression, hydrocephalus),and parasellar manifestations (headache, defi-cits of CN III–VI, encirclement of the ICA bytumor, diabetes insipidus), which gradually pro-gress as the tumor enlarges. Hemorrhage or in-farction of a pituitary tumor can cause acutepituitary failure (cf. Sheehan’s postpartumnecrosis of the pituitary gland). Prolactinomas(prolactin-secreting tumors) elevate the serumprolactin concentration above 200 µg/l, in dis-tinction to the less pronounced secondary hy-perprolactinemia (usually !200 µg/l) as-sociated with as pregnancy, parasellar tumors,dopamine antagonists (neuroleptics, metoclo-pramide, reserpine), and epileptic seizures. Pro-lactinomas can cause secondary amenorrhea,

galactorrhea, and hirsutism in women, andheadache, impotence, and galactorrhea (rarely)in men. Growth hormone-secreting tumors causegigantism in adolescents and acromegaly inadults. Headache, impotence, polyneuropathy,diabetes mellitus, organ changes (goiter), andhypertension are additional features. ACTH-secreting tumors cause Cushing disease.Tumors of the pineal region. The most commontumor of the pineal region is germinoma (WHOgrade III), followed by pineocytoma (WHO gradeI) and pineoblastoma (WHO grade IV). The clini-cal manifestations include Parinaud syndrome(p. 358), hydrocephalus, and signs of metastaticdissemination in the subarachnoid space(p. 262).

! Infratentorial Region

Acoustic neuroma (WHO grade I) is commonlyso called, though it is in fact a schwannoma ofthe vestibular portion of CN VIII. Early manife-stations include hearing impairment (rarelysudden hearing loss), tinnitus, and vertigo.Larger tumors cause cranial nerve palsies (V, VII,IX, X), cerebellar ataxia, and sometimes hydro-cephalus. Bilateral acoustic neuroma is seen inneurofibromatosis II.Chordoma arises from the clivus and, as itgrows, destroys the surrounding bone tissue andcompresses the brain stem, causing cranialnerve palsies (III, V, VI, IX, X, XII), pituitary dys-function, visual field defects, and headache.Paragangliomas. This group of tumors includespheochromocytoma (arising from the adrenalmedulla), sympathetic paraganglioma (arisingfrom neuroendocrine cells of the sympatheticsystem), and parasympathetic ganglioma or che-modetectoma (arising from parasympatheticallyinnervated chemoreceptor cells). The last-named is a highly vascularized tumor that maygrow invasively. It arises from the glomus body.

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Colloid cystCystic craniopharyngioma

Pituitary adenoma

Pineal tumor

Acoustic neuroma

Chordoma

Clivus

Inferior petrosal sinus

Dorsum sellae

MRI (axial T1-weighted image)

Sphenoid sinus

InfundibulumOptic chiasm

Pons

Bone destruction

Retrosellarspread

III

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Malignant Tumors

! Anaplastic Astrocytoma (WHO grade III)and Glioblastoma (WHO grade IV)

These infiltrative, rapidly growing tumors usu-ally arise in adults between the ages of 40 and65. They usually involve the cerebral hemi-spheres, but are sometimes found in infraten-torial locations (brain stem, cerebellum, spinalcord). They are occasionally multicentric or dif-fuse (gliomatosis cerebri is extremely rare). Infil-trative growth across the corpus callosum to theopposite side of the head is not uncommon(“butterfly glioma”). These tumors are oftenseveral centimeters in diameter by the time ofdiagnosis. Even relatively small tumors can pro-duce considerable cerebral edema. Metastasesoutside the CNS (bone, lymph nodes) are rare.CT and MRI reveal ringlike or garlandlike con-trast around a hypointense center.

! Primary Cerebral Lymphoma(WHO grade IV)

These tumors are usually non-Hodgkin lym-phomas of the B-cell type and are only rarely ofthe T-cell type. They are commonly associatedwith congenital or acquired immune deficiency(Wiskott–Aldrich syndrome; immune suppres-sion for organ transplantation, AIDS) and canarise in any part of the CNS (80% supratentorial,20% infratentorial). Headache, cranial nerve pal-sies, polyradiculoneuropathy, meningismus,and ataxia suggest (primary) leptomeningeal in-volvement. Ocular manifestations: Infiltration ofthe uvea and vitreous body (visual disturbances;slit-lamp examination). Moreover, lymphomasmay occur as solitary or multiple tumors or mayspread diffusely through CNS tissue (per-iventricular zone, deep white matter). They pro-duce local symptoms and also such generalsymptoms as psychosis, dementia, and anorexia.CT reveals them as hyperdense lesions sur-rounded by edema, usually with homogeneouscontrast absorption and with little or no masseffect. MRI is more sensitive for lymphoma thanCT; it reveals the extent of surrounding edemaand is especially useful for the detection of spi-nal, leptomeningeal, and multilocular involve-ment. CSF examination reveals malignant cells inthe early stages of the disease; the CSF proteinconcentration is not necessarily elevated. Biop-

sies and/or CSF serology for diagnosis should beperformed before treatment is initiated, be-cause some of the drugs used, particularly corti-costeroids, can make the disease more difficultto diagnose.

! Anaplastic Oligodendroglioma(WHO grade III)

This rare form of oligodendroglioma respondswell to chemotherapy with procarbazine, CCNU,and vincristine (PCV). As histological confirma-tion of cellular anaplasia (the defining criterionfor grade III) can be difficult, the diagnosis mustsometimes be based on the clinical and radio-logical findings. There may be leptomeningealdissemination or meningeal gliomatosis.

! Anaplastic Ependymoma (WHO grade III)

These tumors may have subarachnoid and(rarely) extraneural metastases, e. g., to the liver,lungs and ovaries.

! Primitive Neuroectodermal Tumor(PNET; WHO grade IV)

A PNET is a highly malignant embryonal tumorof the CNS that mainly arises in children. PNETsarising in the cerebellum, called medulloblas-tomas, are most commonly found in the vermis;they tend to metastasize to the leptomeningesand subarachnoid space (drop metastasis). Theprimary tumor and its metastases are best seenon MRI; they may appear in CT scans as areas ofhyperdensity.

! Primary Cerebral Sarcoma (WHO grade IV)

The very rare tumors in this group, includingmeningeal sarcoma, fibrosarcoma, chondrosar-coma, rhabdomyosarcoma, and malignantfibrous histiocytoma, all tend to recur locallyand only rarely metastasize.

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Topographic distribution of anaplastic astrocytoma and glioblastoma

Multifocal primarycerebral lymphoma

Non-Hodgkin lymphoma (dorsalbrain stem region)

MRI (contrast-enhanced, sagittal T1-weighted image)

Anaplastic oligodendroglioma

Anaplastic ependymoma

Primitive neuroectodermaltumor (medulloblastoma)

Focal calcification

3rd ventricle

4th ventricle

11%

31%

32%

7%

10%

5%

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Metastatic Disease

Metastases spread to the nervous systemthrough the bloodstream (cerebral, spinal, andleptomeningeal metastases), lymphatic vessels(metastases to the PNS), and cerebrospinal fluid(so-called drop metastases in the spinal sub-arachnoid space). Aside from direct metastaticinvolvement, the nervous system can also be af-fected by local tumor infiltration (e. g., of thebrachial plexus by a Pancoast tumor), by exter-nal compression (e. g., of the spinal cord by avertebral tumor, or of a peripheral nerve by atumor-infiltrated lymph node), or by perineuralinfiltration (e. g. melanoma or salivary glandcarcinoma). Only a small fraction of proliferat-ing tumor cells are capable of metastasizing;thus, the biological behavior and drug responseof metastasizing cells may differ from that of theprimary tumor. Angiogenesis is essential fortumor growth and metastasis. Local invasion ofsurrounding tissue by the primary tumor makesit possible for tumor cells to break off andmetastasize by way of the lymphatic vessels,veins, and arteries. Metastatic cells often settlein a vascular bed just downstream from the siteof the primary tumor, thus (depending on its lo-cation) in the lungs, liver, or vertebral bodies.The nervous system may become involvedthereafter in a second phase of metastasis (cas-cade hypothesis), or else directly, in which casethe metastasizing cells must have passedthrough the intervening capillary bed withoutsettling in it. Metastases may also bypass thelungs through a patent foramen ovale (paradoxi-cal embolism).

! Intracranial Metastases

Of all intracranial metastases, 85% are supraten-torial, 15% infratentorial. The primary process inmen is usually a tumor of the lung, gastrointesti-nal tract, or urogenital system, in women atumor of the breast, lung, or gastrointestinaltract. Prostate, uterine, and gastrointestinaltumors metastasize preferentially to the cere-bellum. The clinical manifestations of in-tracranial metastases are usually due to theirlocal mass effect and surrounding cerebraledema. Brain metastases of melanoma, chorio-carcinoma, and testicular cancer tend to pro-duce hemorrhages. Metastases to the calvaria

are usually asymptomatic. Skull base me-tastases cause pain and cranial nerve deficits.Dural-based metastases may compress or infil-trate the adjacent brain tissue, or exude fluidcontaining malignant cells into the subduralspace. Pituitary metastases (mainly of breastcancer) cause endocrine dysfunction and cranialnerve deficits.

! Spinal Metastases

The clinical manifestations of vertebralmetastases, including vertebral or radicularpain, paraparesis/paraplegia, and gait ataxia, aremainly due to epidural mass effect. The bonemarrow itself being insensitive to pain, painarises only when the tumor compresses the pe-riosteum, paravertebral soft tissue, nerve roots,or spinal cord. Spinal instability and pathologi-cal fractures cause additional pain. Pain in thespine may be the first sign of spinal metastasis.Subarachnoid and intramedullary metastasesare rare (!5%).

! Leptomeningeal Metastases (NeoplasticMeningeosis, “Carcinomatous Meningitis”)

Seeding of the meninges may be diffuse or mul-tifocal. Meningeal metastases may spread intothe adjacent brain or spinal cord tissue, cranialnerves, or spinal nerves. Cerebral leptomening-eal involvement produces headache, gait ataxia,memory impairment, epileptic seizures, andcranial nerve deficits (e. g., facial nerve palsy,hearing loss, vertigo, diplopia, and loss of vi-sion). Spinal involvement produces neck or backpain, radicular pain, paresthesia, paraparesis,and atony of the bowel and bladder.

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Spinal metastases

Spinal metastasis frombronchial carcinoma

MRI (contrast-enhanced, sagittalT1-weighted imageof thoracic spine)

Cranial metastasis

Leptomeningeal metastasis

Intradural/leptomeningeal metastasis

Vertebral body metastasis causing secondary spinal cordcompression

Epidural metastasis

Metastatic compression of vessel (radicular a.)

Radicularmetastasis

Development of neoplasm distant from CNSMalignant cells

infiltrating veins andlymph vessels

Malignant cells

Invasion ofright heartby malignantcells

Invasion of lungvia pulmonary a.

Systemic spread of

malignant cells

Cerebralmetastases

Pulmonary metastases

Systemic spread ofmalignant cells (via foramen ovale)

Patent foramen ovale

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Classification and Treatment

As the treatment and prognosis of brain tumorsdepend on their histological type and degree ofmalignancy, the first step of management istissue diagnosis (see Table 31, p. 377). The sub-sequent clinical course may differ from that pre-dicted by the histological grade because of“sampling error” (i.e., biopsy of an unrepresen-tative portion of the tumor). Other factors in-fluencing prognosis include age, the complete-ness of surgical resection, the preoperative andpostoperative neurological findings, tumor pro-gression, and the site of the tumor.

! Incidence (adapted from Lantos et al., 1997)

The most common primary intracranial tumorsin patients under 20 years of age are medullo-blastoma, pilocytic astrocytoma, ependymoma,and astrocytoma (WHO grade II); from age 20 toage 45, astrocytoma (WHO grade II), oligoden-droglioma, acoustic neuroma (schwannoma),and ependymoma; over age 45, glioblastoma,meningioma, acoustic neuroma, and oligoden-droglioma. The overall incidence of pituitarytumors (including pituitary metastases),craniopharyngioma, and intracranial lymphomaand sarcoma is low.

! Severity (Table 32, p. 378)

The Karnofsky scale (Karnofsky et al., 1951) is acommonly used measure of neurological disa-bility, e. g., due to a brain tumor. Its use permits astandardized assessment of clinical course.

! Treatment

The initial treatment is often neurosurgical,with the objective of removing the tumor ascompletely as possible without causing a severeor permanent neurological deficit. The resectioncan often be no more than subtotal because ofthe proximity of the tumor to eloquent brainareas or the lack of a distinct boundary betweenthe tumor and the surrounding tissue. The over-all treatment plan is usually a combination ofdifferent treatment modalities, chosen withconsideration of the patient’s general conditionand the location, extent, and degree of malignityof the tumor.Symptomatic treatment. Edema: The an-tiedematous action of glucocorticosteroids

takes effect several hours after they are admin-istered; thus, acute intracranial hypertensionmust be treated with an intravenously givenosmotic agent (20% mannitol). Glycerol can begiven orally to lower the corticosteroid dose inchronic therapy. Antiepileptic drugs (e. g., pheny-toin or carbamazepine) are indicated if thepatient has already had one or more seizures, orelse prophylactically in patients with rapidlygrowing tumors and in the acute postoperativesetting. Pain often requires treatment (head-ache, painful neoplastic meningeosis, painfullocal tumor invasion; cf. WHO staged treatmentscheme for cancer-related pain). Restlessness:treatment of cerebral edema, psychotropicdrugs (levomepromazine, melperone, chlor-prothixene). Antithrombotic prophylaxis: Subcu-taneous heparin.Grade I tumors. Some benign tumors, such asthose discovered incidentally, can simply be ob-served—for example, with MRI scans repeatedevery 6 months—but most should be surgicallyresected, as a total resection is usually curative.Residual tumor after surgery can often betreated radiosurgically (if indicated by the histo-logical diagnosis). Pituitary tumors andcraniopharyngiomas can cause endocrine dis-turbances. Meningiomas and craniopharyn-giomas rarely recur after (total) resection.Grade II tumors. Five-year survival rate is50–80%. Complete surgical resection of grade IItumors can be curative. As these tumors growslowly, they are often less aggressively resectedthan malignant tumors, so as not to produce aneurological deficit (partial resection, later re-section of regrown tumor if necessary). Obser-vation with serial MRI rather than surgical re-section may be an appropriate option in somepatients after the diagnosis has been estab-lished by stereotactic biopsy; surgery and/orradiotherapy will be needed later in case ofclinical or radiological progression. Chemother-apy is indicated for unresectable (or no longerresectable) tumors, or after failure of radiother-apyGrade III tumors. Patients with grade III tumorssurvive a median of 2 years from the time of di-agnosis with the best current treatment involv-ing multiple modalities (surgery, radiotherapy,chemotherapy). Many patients, however, liveconsiderably longer. There are still inadequate

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data on the potential efficacy of chemotherapyagainst malignant forms of meningioma, plexuspapilloma, pineocytoma, schwannoma, heman-giopericytoma, and pituitary adenoma.Grade IV tumors. Patients with grade IV tumorssurvive a median of ca. 10 months from diagno-sis even with the best current multimodalitytreatment (surgery, radiotherapy, chemother-apy). The 5-year survival rate of patients withglioblastoma is no more than 5%. PNET (includ-ing medulloblastoma) and primary cerebrallymphoma have median survival times of a fewyears.Cerebral metastases: Solitary, surgically acces-sible metastases are resected as long as there isno acute progression of the underlying malig-nant disease, or for tissue diagnosis if the pri-mary tumor is of unknown type. Solitarymetastases of diameter less than 3 cm can alsobe treated with local radiotherapy, in one of twoforms: interstitial radiotherapy with surgicallyimplanted radioactive material (brachytherapy),or stereotactic radiosurgery. The latter is aclosed technique, requiring no incision, employ-ing multiple radioactive cobalt sources (as in theGamma Knife and X-Knife) or a linear accelera-tor. Solitary or multiple brain metastases in thesetting of progressive primary disease aregenerally treated with whole-brain irradiation.Chemotherapy is indicated for tumors of known

responsiveness to chemotherapy in patientswhose general condition is satisfactory. Meta-static small-cell lung cancer, primary CNS lym-phoma, and germ cell tumors are treated withradiotherapy or chemotherapy rather thansurgery.Spinal metastases: Resection and radiotherapyfor localized tumors; radiotherapy alone for dif-fuse metastatic disease.Leptomeningeal metastases: Chemotherapy (sys-temic, intrathecal, or intraventricular); irradia-tion of neuraxis.

! Aftercare

Follow-up examinations are scheduled atshorter or longer intervals depending on thedegree of malignity of the neoplasm and on theoutcome of initial management (usually involv-ing some combination of surgery, radiotherapy,and chemotherapy), with adjustment for in-dividual factors and for any complications thatmay be encountered in the further course of thedisease. A single CT or MRI scan 3 months post-operatively may suffice for the patient with acompletely resected, benign tumor, whilepatients with malignant tumors should be fol-lowed up by examination every 6 weeks andneuroimaging every 3 months, at least initially.Later visits can be less frequent if the tumordoes not recur.

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Traumatic Brain Injury (TBI)

The outcome of traumatic brain injury dependson the type and extent of the acute (primary) in-jury and its secondary and late sequelae.Direct/indirect history. A history of the precipi-tating event and of the patient’s condition at thescene should be obtained from the patient (ifpossible), or from an eyewitness, or both. Vomit-ing or an epileptic seizure in the acute aftermathof the event should be noted. Also important arethe past medical history, current medications(particularly anticoagulants), and any history ofalcoholism or drug abuse.Physical examination. General: Open wounds,fractures, bruises, bleeding or clear dischargefrom the nose or ear. Neurological: Respiration,circulation, pupils, motor function, other focalsigns.Diagnostic studies. Laboratory: Blood count,coagulation, electrolytes, blood glucose, urea,creatinine, serumosmolality, blood alcohol, druglevels in urine, pregnancy testing if indicated.Essential radiological studies:Head CTwith brainand bone windows is mandatory in all cases un-

less the neurological examination is completelynormal. A cervical spine series from C1 to C7 isneeded to rule out associated cervical injury.Plain films of the skull are generally unneces-sary if CT is performed.Additional studies, as indicated: Cranial or spinalMRI or MR angiography, EEG, Doppler ultra-sonography, evoked potentials.In multiorgan trauma: Blood should be typedand cross-matched and several units should bekept ready for transfusion as needed. Physicalexamination and ancillary studies for any frac-tures, abdominal bleeding, pulmonary injury.

! Primary Injury

The primary injury affects different parts of theskull and brain depending on the precipitatingevent. The traumatic lesion may be focal (hema-toma, contusion, infarct, localized edema) ordiffuse (hypoxic injury, subarachnoid hemor-rhage, generalized edema). The worse the in-jury, the more severe the impairment of con-sciousness (pp. 116 ff). The clinical assessmentof impairment of consciousness is described onpp. 378 f (Tables 33 and 34).

Region Type of Injury

Scalp Cephalhematoma (neonates), laceration, scalping injury

Skull " Fracture mechanism: Bending fracture (caused by blows to the head, etc.), burst frac-ture (caused by broad skull compression)

" Fracture type: Linear fracture (fissure, fissured fracture, separation of cranial sutures),impression fracture, fracture with multiple fragments, puncture fracture, growingskull fracture (in children only)

" Fracture site: Convexity (calvaria), base of skull" Basilar skull fracture: Frontobasal (bilateral periorbital hematoma (“raccoon sign”),

bleeding from nose/mouth, CSF rhinorrhea) or laterobasal (hearing loss, eardrum le-sion, bleeding from the ear canal, CSF otorrhea, facial nerve palsy)

" Facial skull fracture: LeFort I–III midface fracture; orbital base fracture

Dura mater Open head trauma1, CSF leak, pneumocephalus, pneumatocele

Blood vessels Acute epidural, subdural, subarachnoid or intraparenchymal hemorrhage; carotid–cavernous sinus fistula; arterial dissection

Brain2 " Contusion" Diffuse axonal injury (clinical features: coma, autonomic dysfunction, decortication

or decerebration, no focal lesion on CT or MRI)" Penetrating (open or closed3) injury, or perforating (open) injury" Brainstem injury

1 Wound with open dura and exposure of brain (definition). 2 Excluding cranial nerve lesions. 3 Without duralpenetration (definition).

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Brain herniation,edema

Gunshotwound, hema-toma along trajectory

Retroauricular ecchymosis(due to basilar skull fracture)

Lacerations

Head injuries

Traumatic intracranial hematoma

Classification of head trauma (HT) by Glasgow Coma Scale (GCS)

Mild HT

GCS:13-15

ModerateHT

GCS:9-12

SevereHT

GCS:3-8

(Duration of unconsciousness)

Innerdural layer

Hemorrhagic contusion

Outerdural layer

Subdural hematomaInner and outer dural layer

Head trauma (schematic)

Depressed skull fracture, hematoma,dural opening

Cranial impression

1 h

24 h

Epidural hematoma

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! Secondary Sequelae of TBI

For overview of late complications of head trauma, see p. 379 (Table 35).

! Prognosis

Head trauma causes physical impairment and behavioral abnormalities whose severity is correlatedwith that of the initial injury.

Type of Sequela Location/Syndrome Special Features

Neurological

" Hematoma ! Epidural ! Lucid interval1, immediate uncon-sciousness, or progressive deterioration ofconsciousness

! Subdural ! May be asymptomatic at first, withprogressive decline of consciousness

! Subarachnoid ! Meningism

! Intraparenchymal ! Intracranial hypertension, !focal signs;often a severe injury

" Intracranialhypertension

" Cerebral edema, hydrocephalus,massive hematoma

" See p. 162. Risk of herniation

" Ischemia " Vasospasm, arterial dissection, fatembolism

" Acute focal signs

" Epileptic seizure " Focal or generalized " Common in focal injury

" Infection " CSF leak, open head injury " Recurrent meningitis, encephalitis,empyema, abscess, ventriculitis

" Amnesia " Anterograde/retrograde " See p. 134

General

" Hypotension,hypoxia, anemia

" Shock, respiratory failure " Multiple trauma, pneumothorax orhemothorax, pericardial tamponade,blood loss, coagulopathy

" Fever,meningitis

" Infection " Pneumonia, sepsis, CSF leak

" Fluid imbalance " Hypothalamic lesion " Diabetes insipidus2, SIADH3

1 Patient immediately loses consciousness ! awakens and appears normal for a few hours ! again loses con-sciousness. 2 Polyuria, polydipsia, nocturia, serum osmolality !295mOsm/kg,

!

urine osmolality. 3 Syndrome ofinappropriate secretion of ADH: euvolemia, serum osmolality " 275mOsm/kg, excessively concentrated urine(urine osmolality !100mOsm/kg), !urinary sodium despite normal salt/water intake; absence of adrenal, thy-roid, pituitary and renal dysfunction.

Severity1 Prognosis

Mild Posttraumatic syndrome resolves within 1 year in 85–90% of patients. The re-maining 10–15% develop a chronic posttraumatic syndrome

Moderate The symptoms and signs resolve more slowly and less completely than those ofmild head injury. The prognosis appears to be worse for focal than for diffuse in-juries. Reliable data on the long-term prognosis are not available

Severe Age-dependent mortality ranges from 30% to 80%. Younger patients have a bet-ter prognosis than older patients. Late behavioral changes (impairment ofmemory and concentration, abnormal affect, personality changes)

1 For severity of head trauma, cf. pp. 378 f, Tables 33 and 34.

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Cerebral complications of trauma

Posttraumatic neurological changes

Time course of memory disturbances(closed head injury)

CSF leak

Frontal brain atrophy

Cystic postcon-tusional defect

Brain atrophy, normal pressure hydrocephalus (ventricular dilatation)

Infection, abscess (penetrating injury)

Frontal sinus, fracture

CSF leak from nose

CSF leak (nasopharyngeal space)

Basilar skull fracture,

sphenoid sinus

Bilateral chronic subduralhematoma

Pneumocephalus(air in intracranialcavity)

Infarct (posterior cerebral artery)

Postcontu-sional lesion

Frontal brain atrophy

Retrogradeamnesia

Unconscious-ness or coma

Trauma Anterogradeamnesia

Normalization of memory

function

Normalmemory

(Time)

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! Posttraumatic Headache

Posttraumatic headache may be acute (!8weeks after head trauma) or chronic ("8weeks). The duration and intensity of the head-ache are not correlated with the severity of theprecipitating head trauma. It can be focal or dif-fuse, continuous or episodic. It often worsenswith physical exertion, mental stress, and ten-sion and improves with rest and stressavoidance. Its type and extent are highly varia-ble. If the headache gradually increases in sever-ity, or if a new neurological deficit arises, furtherstudies should be performed to exclude a lateposttraumatic complication, such as chronicsubdural hematoma (p. 379).

! Pathogenesis of Traumatic Brain Injury

Direct blunt or penetrating injuries of the headand acceleration/deceleration injuries can dam-age the scalp, skull, meninges, cerebral vascula-ture, ventricular system, and brain parenchyma.The term primary injury refers to the initial me-chanical damage to these tissues. Traumatizedbrain tissue is more sensitive to physiologicalchanges than nontraumatized tissue. Secondaryinjury is caused by cellular dysfunction due tofocal or global changes in cerebral blood flowandmetabolism. Mechanisms involved in secondaryinjury include disruption of the blood–brain bar-rier, hypoxia, neurochemical changes (increasedconcentrations of acetylcholine, norepinephrine,dopamine, epinephrine, magnesium, calcium,and excitatory amino acids such as glutamate),cytotoxic processes (production of free radicalsand of calcium-activated proteases and lipases),and inflammatory responses (edema, influx ofleukocytes and macrophages, cytokine release).Epidural hematoma. Bleeding into the epiduralspace (pp. 6, 267) due to detachment of theouter dural sheath from the skull and rupture ofa meningeal artery (usually the middle mening-eal artery, torn by a linear fracture of the tem-poral bone). Epidural hematoma is lessfrequently of venous origin (usually due to tear-ing of a venous sinus by a skull fracture).Subdural hematoma. Bleeding into the subduralspace (pp. 6, 176, 267) because of disruption oflarger bridging veins; often accompanied byfocal contusion of the underlying brain.Frequently located in the temporal region.

Intracerebral hematoma. Bleeding into thetissue of the brain (intraparenchymal hema-toma) under the site of impact, on the oppositeside (contre-coup), or in the ventricular system(intraventricular hemorrhage) (pp. 176, 267).Subarachnoid hemorrhage. Rupture of pial ves-sels.

! Treatment

At the scene of the accident. The scene shouldbe secured to prevent further injury to the in-jured person, bystanders, or rescuers. First aid:Evaluation and clearing of the airway; car-diopulmonary resuscitation (CPR) if necessary.Immobilization of the cervical spine with a hardcollar. Recognition and treatment of hemody-namic instability (keep systolic blood pressureabove 120mmHg), fluid administration asneeded (“small volume resuscitation” with hy-peroncotic-hypertonic solutions’). Dressing ofwounds, sedation if necessary to reduce agita-tion, elevation of the upper body to 30°. Docu-mentation: Time and nature of accident, generaland neurological findings, drugs given. Trans-port: Cardiorespiratory monitoring.In the hospital. Systematic assessment andtreatment by organ system, with documenta-tion of all measures taken. Cardiorespiratorymonitoring: monitoring of blood gases andblood pressure (cerebral perfusion pressure"60–70mmHg, p. 162). Respiratory system:Supplementary oxygen, intubation, and ventila-tion as needed. Cardiovascular system: Centralvenous access, administration of fluids andpressors as needed. Treatment of fever or hyper-thermia. Administration of anticonvulsants asneeded. Evaluation of tetanus vaccination sta-tus. Immediate neurosurgical consultation re-garding the possible need for surgery. Treatmentof intracranial hypertension: Sedatives, analges-ics; if ICP (p. 162) is above 20–25mmHg,osmotherapy with 20% mannitol, bolus of0.35mg/kg over 10–15 minutes, repeated every4–8 hours as needed; barbiturate coma(thiopental); decompressive bifrontalcraniectomy may be indicated in refractorycerebral edema.

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Ensure that airways are free and unobstructed Check cardiopulmonary function

Stable lateral position: Patient is unconscious but breathing spontaneously

Supine position: Patient is unconscious, notbreathing (cardiopulmonary resuscitation),

and may have spinal injury. Elevate upperbody if there is a head injury

Traumatic brain injury

Blood-brain barrier lesion

Hypoxia

Neurochemical changes

Cytotoxic processes

Inflammatory response

Pathogenesis of traumatic brain injury

First-aid measures at scene of accident

Posttraumatic headache

Hemorrhagic contusion

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Spinal Trauma

Spinal injury can involve the vertebrae, liga-ments, intervertebral disks, blood vessels,muscles, nerve roots, and spinal cord. The spinalcord and spinal nerve roots may be directly in-jured (e. g. by gunshot or stab wounds) or sec-ondarily affected by compression (bone frag-ments), hyperextension (spinal instability), andvascular lesions (ischemia, hemorrhage). Diag-nosis: Bone injuries can be identified by radio-graphy and/or CT; spinal cord lesions (hemor-rhage, contusion, edema, transection) and soft-tissue lesions (hematoma, edema, arterial dis-section) are best seen on MRI.Cervical spine distortion (whiplash injury). In-direct spinal trauma (head-on or rear-end colli-sion) leads to sudden passive retroflexion andsubsequent anteflexion of the neck. The forcesacting on the spine (acceleration, deceleration,rotation, traction) can produce both cervicalspine injuries (spinal cord, nerve roots, retro-pharyngeal space, bones, ligaments, joints, in-tervertebral disks, blood vessels) and cranial in-juries (brain, eyes, temporomandibular joint).There may be an interval of 4–48 hours untilsymptoms develop, rarely longer (asympto-matic period). Symptoms and signs: Pain in thehead, neck, and shoulders, neck stiffness, andvertigo may be accompanied by forgetfulness,poor concentration, insomnia, and lethargy. Thesymptoms usually resolve within 3–12 monthsbut persist for longer periods in 15–20% ofpatients, for unknown reasons. Severity classifi-cation: Grade I = no neurological deficit or radio-logical abnormality, grade II = neurological defi-cit without radiological abnormality, grade III =neurological deficit and radiological abnormal-ity.Vertebral fracture. It must be determinedwhether the fracture is stable or unstable; if it isunstable, any movement can cause (further)damage to the spinal cord and nerve roots. Thus,all patients who may have vertebral fracturesmust be transported in a stabilized supine posi-tion, with the head in a neutral position (e. g., ona vacuum mattress). Repositioning the patientmanually with the “collar splint grip,” “paddlegrip,” or “bridge grip” should be avoided ifpossible. In the assessment of stability, it is use-ful to consider the spinal column and interverte-

bral disks as composed of three columns. In-volvement of only one column = stable injury;two columns = potentially unstable; threecolumns = unstable. For details, see p. 380 (Table36).Trauma to nerve roots and brachial plexus.Nerve root lesions usually involve the ventralroots, and thus usually produce a motor ratherthan sensory deficit. Nerve root avulsion may besuspected on the basis of (multi)radicular find-ings and/or Horner syndrome and can be con-firmed by myelography (empty root sleeves,bulging of the subarachnoid space) or MRI.Downward or backward traction on theshoulder and arm (as in a motorcycle accident)can produce severe brachial plexus injuries ac-companied by nerve root avulsion. Brachialplexus lesions can also be caused by improperpatient positioning during general anesthesia,intense supraclavicular pressure (backpack par-alysis), or local trauma (stab or gunshot wound,bone fragments, contusion, avulsion). These in-juries more commonly affect the upper portionof the brachial plexus (pp. 34, 321).

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Whiplash injury of cervical spine(traumatic cervical distortion)

Three-column model of spinal stability

Spinal injuries

Normal cervical spine

Anteriorcolumn

Middle column

Posterior column

Burst fracture

Ruptured ligament

Fracture in poste-rior column

Spinal cordcompression

Vertebralluxation

Spinal cord contusion

Gunshotwound

Syringomyelia(posttraumatic)

Anterior longitudinalligament

Posterior longitudinalligament

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Spinal Cord Trauma

Open spinal cord trauma, by definition, involvespenetration of the dura mater by a stab wound,gunshot wound, bone fragment, or severely dis-located vertebra. Closed spinal cord trauma(with dura intact) is the indirect effect of a non-penetrating injury. The result may be a completeor incomplete spinal cord transection syndrome(p. 48; Table 37, p. 380).Acute stage (spinal shock). The acute manifesta-tions of spinal cord transection syndrome are

seen below the level of the injury and includethe total loss of voluntary and reflexmotor func-tion (flaccid paraplegia or quadriplegia,areflexia) and sensation, and autonomic dysfunc-tion (urinary retention ! overflow incontinence,intestinal atony ! paralytic bowel obstruction,anhidrosis ! hyperthermia, cardiovascular dys-function ! orthostatic hypotension, cardiacarrhythmia, paroxysmal hypertension). Patientsare usually stable enough to begin rehabilitationin 3–6 weeks (rehabilitation stage, see below).For acute treatment, see p. 380 (Table 38).

Rehabilitation stage. The neurological deficits depend on the level of the lesion.

Chronic stage—late sequelae. Persistence ofneurological deficits; assorted complications in-cluding venous thrombosis, pulmonary em-bolism, respiratory insufficiency, bowel obstruc-

tion, urinary tract infections, sexual dysfunc-tion, cardiovascular disturbances, spasticity,chronic pain, bed sores, heterotopic ossification,and syringomyelia.

Level1 Motor Deficit Sensory Deficit2 Autonomic Deficit3

C1–C34 Quadriplegia, neck muscleparesis, spasticity, respira-tory paralysis

Sensory level at back ofhead/edge of lower jaw; painin back of head, neck, andshoulders

Voluntary control of bladder,bowel, and sexual functionreplaced by reflex control;Horner syndrome

C4–C5 Quadriplegia, diaphragmaticbreathing

Sensory level at clavicle/shoulder

Same as above

C6–C85 Quadriplegia, spasticity, flac-cid arm paresis, diaphrag-matic breathing

Sensory level at upper chestwall/back; arms involved,shoulders spared

Same as above

T1–T5 Paraplegia, diminished respi-ratory volume

Sensory loss from inner sur-face of lower arm, upperchest wall, back regiondownward

Voluntary control of bladder,bowel, and sexual functionreplaced by reflex control

T5–T10 Paraplegia, spasticity Sensory level on chest walland back corresponding tolevel of spinal cord injury

Same as above

T11–L3 Flaccid paraplegia Sensory loss from groin/ven-tral thigh downward, de-pending on level of injury

Same as above

L4–S26 Distal flaccid paraplegia Sensory loss at shin/dorsumof foot/posterior thighdownward, depending onlevel of injury

Flaccid paralysis of bladderand bowel, loss of erectilefunction

S3–S57 No motor deficit Sensory loss in perianal re-gion and inner thigh

Flaccid paralysis of bladderand bowel, loss of erectilefunction

1 Spinal cord level (not the same as vertebral level). 2 See p. 32 ff. 3 Disturbance of bladder, bowel, rectal, anderectile function, sweating, and blood pressure regulation; p. 140 ff. 4 High cervical cord lesion. 5 Low cervicalcord lesion. 6 Epiconus. 7 Conus medullaris.

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Segment-indicating muscles

Topography of spinal cord lesions

Cervical cord lesion

Thoracic cord lesion

123456781

1

2

2

3

3

4

4

5

5

6789

101112

Lumbar cord lesion

Lesion of conus/cauda equina

Tricepsbrachii m.(C7-C8)

Latissimus dorsi m. (C6-C8)

Trapeziusm. (C2-C4)

Pectoralis major m. (C7-T1)

Diaphragm (C3-C5)

Deltoid m.(C4-C6)

Biceps brachiim. (C5-C6)

Brachioradialism. (C5-C6)

Abductorpollicis brevis m.(C8-T1)

Adductormagnus m.(L2-L4) Quadriceps

m. (L2-L4)

Gastrocnemius m. (L5-S1)

Tibialis anteriorm. (L4-L5)

Flexor digi-torum pro-fundus m.(C8-T1)

Interossei(C8-T1)

Extensor hallucis longusm. (L5-S1)

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! Signs of Cerebellar Dysfunction

Loss of coordination and balance. Ataxia is un-coordinated, irregular, and poorly articulatedmovement (dyssynergy). The typical patientsways while sitting (truncal ataxia) or standing(postural ataxia), undershoots or overshoots anintended target of movement (dysmetria = hy-pometria or hypermetria), andwalks with quick,irregular steps in an unsteady, swaying, broad-based gait reminiscent of alcohol intoxication(gait ataxia, p. 54). Pointing tests are used to de-tect dysmetria, incoordination, and tremor thatis worst as a movement approaches its target(intention tremor); the finger–nose, finger–fin-ger, and heel–knee–shin tests should be carriedout with the eyes open and closed. Bárány’spointing test: The patient is asked to close his orher eyes, touch the doctor’s finger with his orher own index finger, then lower and raise thestill outstretched arm and touch the doctor’s fin-ger again; the patient’s finger deviates laterallyfrom the target, and the direction of deviation istoward the side of the lesion. Unsteadiness ofstance of cerebellar origin, which may be sosevere as to make standing impossible (astasia),is not influenced by opening or closing the eyes(Romberg sign) and differs in this respect fromspinal (sensory) ataxia. Stepping in place for30–60 seconds with the eyes closed causes thebody to turn to the side of the lesion. Patientswith mild ataxia find it difficult or impossible towalk a straight line (abasia; detected by heel-to-toe walking, tandem gait). The patient may beunable to perform rapid alternating movements(dysdiadochokinesia). The handwriting is en-larged (macrographia), coarse, and shaky, andthe patient’s drawing of parallel lines or a spiralis unsatisfactory.Dysarthria. The patient’s speech (p. 130) is slow,unclear (babbling, slurred), and monotonous(dysarthrophonia), and possibly also discontinu-ous (choppy, faltering, or scanning speech).There is poor coordination of breathing with theflow of speech, resulting in a sudden transitionfrom soft to loud speech (explosive speech).Oculomotor disturbances. Gaze-evoked nystag-mus is a frequent finding in cerebellar disease.Voluntary saccades are too short or too long(ocular dysmetria) and are therefore followed byafterbeats. Slow pursuit movements are jerky

(saccadic). Patients are frequently unable tosuppress the vestibulo-ocular reflex (p. 26), i.e.,the normal visual suppression of nystagmus isimpaired. The result is impaired visual fixationon turning of the head.Muscle tone. Decreased muscle tone is mainlyfound in patients with acute unilateral lesions ofthe cerebellum. The examiner can detect it bypassively swinging or shaking the patient’slimbs, or by testing for the rebound phenome-non. The patient is asked to extend the armswith the eyes closed (posture test) and the ex-aminer lightly taps on one wrist, causing deflec-tion of the arm. The rebound movement under-shoots or overshoots the original arm position.Alternatively, the patient can be asked to flexthe elbow against resistance. When the ex-aminer suddenly releases the resistance, the af-fected arm rebounds unchecked.

! Topography of Cerebellar Lesions

Lesions of the cerebellum and its afferent andefferent connections (p. 54) produce charac-teristic signs of cerebellar disease. Expanding le-sions may go on to produce further, extracere-bellar deficits (e. g., cranial nerve palsies, hemi-paresis, sensory loss).

! Special Diagnostic Studies

The diagnostic studies to be obtained depend onthe clinical findings (to be described below) andmay include imaging studies (MRI, CT), neu-rophysiological studies (nerve conduction stu-dies, electromyography), ECG, pathological stu-dies (of tissue, blood, CSF, bone marrow, muscle,or nerve biopsy specimens), and/or ophthalmo-logical consultation (optic nerve atrophy, Kay-ser–Fleischer ring, tapetoretinal degeneration).

! Idiopathic Cerebellar Ataxia (IDCA)

This group of disorders includes various formsof nonfamilial cerebellar ataxia of unknowncause with onset in adulthood (generally age 25years or older). IDCA occurs as an isolated dis-turbance or as a component of multiple systematrophy (MSA; p. 302).

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Finger-finger test(intention tremor)

Saccades; gaze-evoked and rebound nystagmus

Dysdiadochokinesis

Rebound phenomenon

Postural test for positionsense

Gait ataxia with “tandem” gait

Dysmetria (hypermetria)

Test for gaze-evoked nystagmus

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Acquired Cerebellar Syndromes

Onset Etiology Symptoms and Signs

Acute (minutes tohours)

! Infection1 ! Viral infection: varicella-zoster virus, Epstein–Barr virus,rubella, mumps, influenza, parainfluenza, echovirus,coxsackievirus, cytomegalovirus, FSME, herpes simplex virus.Children are more commonly affected than adults. Specialtype: opsoclonus-ataxia syndrome2.

! Abscess! Miller Fisher syndrome (ataxia, ophthalmoplegia, areflexia;

p. 395)

! Vascular ! Brainstem signs (pp. 70 ff., 170) predominate! Infarcts can be differentiated from hemorrhages by imaging

studies! Early treatment, often neurosurgical, may be needed to pre-

vent rapid development of life-threatening complications(p. 174 f)

! Toxic ! Alcohol, barbiturates, phenytoin, lithium

Subacute(days to weeks)

! Tumor3 ! Occipital pain (radiating to forehead, nuchal region, andshoulders), recurrent vomiting, stiff neck, vertigo, truncalataxia; obstructive hydrocephalus

! Paraneoplastic4 ! Cerebellar dysfunction may appear months or years beforethe tumor is discovered. Anti-Purkinje-cell antibodies are pre-sent in the serum and CSF of patients with neuron loss

! Toxic ! Alcohol! Medications (anticonvulsants, e. g., phenytoin; lithium, 5-

fluorouracil, cytosine arabinoside)! Heavy metals (mercury, thallium, lead)! Solvents (toluene, carbon tetrachloride)

! Other ! Hypoxia, heat stroke, hyperthermia

Chronic (months toyears)

! Infection ! Progressive rubella panencephalitis (very rare complication ofcongenital rubella infection in boys; onset at age 8 to 19years; characterized by ataxia, dementia, spasticity, and dys-arthria)

! Creutzfeldt–Jakob disease (p. 252)

! Vascular ! Meningeal siderosis causes ataxia and partial or completehearing loss (leptomeningeal deposition of hemosiderin inchronic subarachnoid hemorrhage ! vascular malformations,oligodendroglioma, ependymoma of the cauda equina, post-operative occurrence)

! Metabolic ! Hypothyroidism, malabsorption syndrome (vitamin E defi-ciency), thiamin deficiency (acute ! Wernicke encephalo-pathy)

! Refsum disease5 ( !serum phytanic acid level, p. 332)! Wilson disease5 (ataxia, tremor, dysarthrophonia, dysphagia,

dystonia, behavioral disturbances, p. 307)

Intermittent ! Metabolic5 ! Hereditary metabolic disorders in neonates, children, and ju-veniles (see also pp. 306 f, 386 f)

! Disorders of amino acid metabolism (hyperammonemia,Hartnup syndrome, maple syrup urine disease)

! Storage diseases (metachromatic leukodystrophy, neuronalceroid lipofuscinosis, sialidosis, GM2 gangliosidosis)

1 Partial listing; numerous infections can cause ataxia as part of the syndrome of encephalomyelitis. 2 High-frequency bursts of saccades in all directions of gaze without an intersaccadic interval. 3 See p. 254 ff; cerebellarastrocytoma, medulloblastoma, ependymoma, hemangioblastoma (von Hippel–Lindau disease), meningioma ofthe cerebellopontine angle, metastases (lung cancer, breast cancer, melanoma). 4 Antibodies (p. 388) against Hu,Yo, TR, CV2, Ma1, CRD1, CRD2, Ma2, and mGluR1. 5 Genetic; listed here for differential diagnostic purposes.

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Alcoholic cerebellardegeneration

Cerebellar atrophy

Hyperthermia-related cerebellar dysfunction

Vascular cerebellar lesion

Cerebellar infections

Paraneoplastic and hypoxic cerebellar syndromes

Malabsorptive and metabolic cerebellar syndromes

Lesion of cerebellar cortex

Drug-induced cerebellar syndromes

Normalcortex

Cortical atrophy

Purkinje celllesions

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Syndrome Symptoms and Signs CL/Gene Product

Autosomal domi-nant cerebellarataxia (ADCA);spinocerebellarataxia (SCA)1

! ADCA1: Ataxia, ophthalmoplegia, pyramidal/extrapyramidal distur-bances (p. 44); SCA15, SCA25, SCA32,5, SCA4, SCA85, SCA12, SCA13,SCA17

! ADCA2: Ataxia, retinopathy, SCA75

! ADCA3: Predominant cerebellar ataxia; SCA5, SCA65, SCA10, SCA11,SCA125, SCA14, SCA15, SCA16

SCA1: 6p23/ataxin1SCA2: 12q24/ataxin2SCA3: 14q24.3-q31/MJD1 proteinSCA4: 16q22.1SCA5: 11p11-q11SCA6: 19p13/!-1Acalcium channelSCA7: 3p21.1-p12

Episodic ataxia(EA)3

! EA1: Episodes of ataxia lasting seconds to minutes, 1 to 10 times daily;provoked by abrupt changes of position, emotional or physical stress,and caloric vestibular stimulation; myokymia in face and hands be-tween attacks; continuous spontaneous activity in resting EMG

! 12p135/potassiumchannel (pointmutation)

! EA2: Episodes of ataxia lasting minutes to hours (rarely days) of varia-ble frequency (daily to yearly); headache, tinnitus, vertigo, ataxia,nausea, vomiting, nystagmus; induced by same stimuli as EA1; ataxia,nystagmus, and head tremor between attacks

! 19p135/voltage-gated calciumchannel4 (pointmutation)

Gerstmann–Sträussler–Scheinker syn-drome (p. 252)

Onset between the ages 40 and 50 years; presents with cerebellar ataxia;dysarthrophonia, dementia, nystagmus, rigor, visual disturbances, andhearing loss develop in the course of the disease

20pter-p12/P102L

Fatal familial in-somnia (p. 252)

Progressive insomnia, autonomic dysfunction (arterial hypertension,tachycardia, hyperthermia, hyperhidrosis), myoclonus, tremor, ataxia

20pter-p12/D178N

1 Definitive identification of the SCA types listed is possible only with molecular genetics tests (examples in right column,see OMIM for details). 2 Machado–Joseph disease (MJD). 3 Other forms: EA3 and EA4. 4 Other mutations of this gene areassociated with SCA6 and familial hemiplegic migraine. 5 A direct genetic test is available.

Hereditary Cerebellar Syndromes

" Autosomal Recessive Cerebellar Syndromes (partial listing)

" Autosomal Dominant Cerebellar Syndromes (partial listing)

Syndrome Symptoms and Signs CL1/Gene Product

Friedreich ataxia2,7 Usual manifestations:! Progressive limb/gait ataxia! Age of onset !30 years! Areflexia in legs! Neurophysiological evidence of sensory neuropathy

Variable manifestations:! Dysarthria, distal muscular atrophy/paresis (ca. 50%), pes cavus (ca.

50%), scoliosis, optic nerve atrophy (ca. 25%), nystagmus (ca. 20%),oculomotor disturbances (p. 276), hearing loss (ca. 10%), cardiomy-opathy (ca. 65%), diabetes mellitus (ca. 10%)

9q13, 9p23-p11/frataxinMutation: ExtendedGAA-trinucleotiderepeat

Ataxia with vitaminE deficiency7(serum:

!

vitaminE, !cholesterol/triglycerides)

! Onset in childhood or adulthood! Gait ataxia! Dysarthria! Other symptoms similar to those of Friedreich ataxia

8q13.1-q13.3/!-to-copherol transferprotein

Abetalipoprotein-emia3,7 (p. 300)

! Steatorrhea, other symptoms similar to those of Friedreich ataxia 4q24/triglyceridetransfer protein

Ataxia-telangiec-tasia4,7

! Ataxia first seen when child learns to walk! Choreoathetosis! Oculomotor disturbances5! Oculocutaneous telangiectases! Immunodeficiency (frequent infections)! Increased risk of malignant tumors! Elevated serum !-fetoprotein

11q22.3/phosphatidyl-inositol-3’-kinase and rad36

1 Chromosome location (CL). 2 Classic form. 3 Bassen–Kornzweig syndrome; vitamin A and E deficiency, low cholesterol/triglyceride levels, acanthocytosis. 4 Louis-Bar syndrome. 5 Oculomotor apraxia. 6 DNA repair kinase/cell cycle control;ataxia-telangiectasia-mutated (ATM) gene. 7 A direct gene test is available.

For mitochondrial syndromes with ataxia, see p. 403.

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Lipid

Mitochondria

Myofibrils

Friedreich ataxia (FA)

Scoliosis in FA

Spinal degeneration in FA

Pes cavus/clawfoot

Ocular telangiectasia

Acanthocyte (crenated erythrocyte)in abetalipoproteinemia

Distal muscular atrophy

Mitochondrial encephalomyopathy

Ataxia and loss ofposition sensedue to posteriorcolumn lesion

Paresis due topyramidal

tract lesion

Ataxia due to lesion ofposterior andanterior spinocerebellartracts

Cardiomyopathy in FA(ECG shows repolarization

disturbances and left axis deviation)

I aVR V1 V4

V5

V6

V2

V3

aVL

aVF

II

III

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The clinical differential diagnosis of my-elopathies is based on the level of the spinalcord lesion, the particular structures affected,and the temporal course of the disorder (p. 48,Table 39, p. 381).

Acute Myelopathies

Symptoms and signs develop within minutes,hours, or days.

! Spinal Cord Trauma(See p. 274)

! Myelitis

Viral myelitis (p. 234 ff). Enteroviruses(poliovirus, coxsackievirus, echovirus), herpeszoster virus, varicella zoster virus, FSME, rabies,HTLV-1, HIV, Epstein–Barr virus, cytome-galovirus, herpes simplex virus, postvaccinialmyelitis.Nonviral myelitis (p. 222 ff). Mycoplasma, neu-roborreliosis, abscess (epidural, intramedul-lary), tuberculosis, parasites (echinococcosis,cysticercosis, schistosomiasis), fungi, neurosy-philis, sarcoidosis, postinfectious myelitis, mul-tiple sclerosis/neuromyelitis optica (Devic syn-drome), acute necrotizing myelitis, connectivetissue disease (vasculitis), paraneoplastic myeli-tis, subacute myelo-optic neuropathy (SMON),arachnoiditis (after surgical procedures, myelo-graphy, or intrathecal drug administration).

! Vascular Syndromes (p. 22)

Anterior spinal artery syndrome. Segmentalparesthesia and pain radiating in a bandlike dis-tribution may precede the development ofmotor signs by minutes to hours. A flaccid para-paresis or quadriparesis (corticospinal tract,anterior horn) then ensues, along with a disso-ciated sensory loss from the level of the lesiondownward (spinothalamic tract ! impairedpain and temperature sensation, with intactperception of vibration and position) and uri-nary and fecal incontinence. Often only some ofthese signs are present.Posterior spinal artery syndrome is rare and dif-ficult to diagnose. It is characterized by pain inthe spine, paresthesiae in the legs, a loss of posi-tion and vibration sense below the level of thelesion, and global anesthesia with segmental

loss of deep tendon reflexes at the level of the le-sion. Larger lesions cause paresis and sphincterdysfunction.Sulcocommissural artery syndrome. Segmentalpain at the level of the lesion, followed by flaccidparesis of ipsilateral arm/leg; loss of propriocep-tion, position sense, and touch perception withcontralateral dissociated sensory loss (Brown–Séquard syndrome). Sphincter dysfunction israre.Complete spinal infarction. Acute spinal cordtransection syndrome with flaccid paraplegia orquadriplegia, sphincter dysfunction, and totalsensory loss below the level of the lesion. Au-tonomic dysfunction may also occur (e. g., va-sodilatation, pulmonary edema, intestinalatony, disordered thermoregulation). The causeis often an acute occlusion of the great radicularartery (of Adamkiewicz).Central spinal infarction. Acute paraplegia,sensory loss, and sphincter paralysis.Claudication of spinal cord. Physical exercise(running, long walks) induces paresthesiae orparaparesis that resolves with rest and does notoccur when the patient is lying down.Cause: Exercise-related ischemia of the spinalcord due to a dural arteriovenous fistula or high-grade aortic stenosis (see also p. 284).Dural/perimedullary arteriovenous (AV) fistulais an abnormal communication (shunt) betweenan artery and vein between the two layers of thedural mater. An arterial branch of a spinal arteryfeeds directly into a superficial spinal vein,which therefore contains arterial rather thanvenous blood, flowing in the opposite directionto normal. Paroxysmal stabbing pain and/or epi-sodes of slowly progressing paraparesis andsensory loss separated by periods of remissionoccur in the early stage of the disorder, whichusually affects men between the ages of 40 and60. If the suspected diagnosis cannot be con-firmed by MRI scans (because of low shuntvolume), myelography may be helpful (! di-lated veins in the subarachnoid space).Spinal hemorrhage can occur in epidural, sub-dural, subarachnoid, and intramedullary loca-tions (intramedullary hemorrhage = hematomy-elia). Possible causes: intradural/intramedullaryAV malformation, cavernoma, tumor, aneurysm,trauma, lumbar puncture, and coagulopathy.

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Vascular spinal cordlesion

Infarct (anterior spinal a.)

Anterior spinal a.

Anterior radicular a.

Great radicular a. (a. ofAdamkiewicz)

Posterior spinal a.

Vertebral a.

Aorta

Subclavian a.

Spondylitis (thoracic vertebra)

Intraspinal (epidural)spread of infection

Destruction of vertebral body

Fractured vertebral archand dislocated vertebralbody

Spinal arteries(green: common infarct sites)

Thoracic dural AV fistula(T2-weighted MRI scan, lateral view of

thoracic spine)

Trauma

Infarct (left sulco-commissural a.)

Anterior spinal a.Radicular aa.

Engorged dorsalmedullary veins

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Subacute and Chronic Myelopathies

Spinal cord syndromes (p. 282) may be subacuteor chronic depending on their cause. The

complete clinical picture may develop over daysto weeks (subacute) or months to years(chronic). For myelopathies due to developmen-tal disorders, see p. 288 ff.

! Mass Lesions

Syndrome Symptoms and Signs Causes Diagnosis/Treatment1

Cervicalmyelopathy

Progressive paraparesis orquadriparesis, spasticity, Lher-mitte’s sign, reduced mobilityof cervical spine; cervicalradiculopathy may also occur

Spinal cord compres-sion2 by cervical spinelesions3

MRI, CT, myelography; evokedpotentials, EMG for radicular le-sions, plain radiograph of cervi-cal spine.Treatment: Surgery for progres-sive impairment or severe ste-nosis; otherwise, symptomatictreatment

Lumbar spinalstenosis4(intermittentclaudication)

Early: Paresthesiae (sensation ofheaviness) occur upon standingor walking (especially downstairs) and disappear with rest.Late: Only partial improvementof paresthesiae with rest; re-duced walking range

Compression of caudaequina by lumbarspine lesions5

Diagnostic testing as above.Treatment: Surgery for severelydecreased walking range orpersistent symptoms; other-wise, analgesics and physi-otherapy (to strengthen trunkmuscles)

Syringo-myelia6

Pain, central cord deficits,kyphoscoliosis

Anomalous develop-ment of neuralgroove, obstruction ofCSF flow, trauma,tumor

Diagnostic testing as above.Treatment: Surgery for progres-sive symptoms, especially pain7

Neoplasm Pain, sensory loss, segmental/radicular paresis, Lhermitte’ssign (cervical), incomplete orcomplete spinal cord transec-tion syndrome

Intramedullary:Ependymoma, gliomaExtramedullary:Meningioma, neurofi-broma, vascular mal-formationExtradural: Metastasis,sarcoma

Diagnostic testing as above.Treatment: Surgery; radiother-apy if indicated; symptom con-trol with corticosteroids andanalgesics

1 Principles of diagnosis and treatment. 2 Symptoms arise when sagittal diameter of spinal canal is in the rangeof 7–12mm (normal 17–18mm). 3 Primary spinal canal stenosis, disk protrusion/herniation, spinal degenerativedisease (spondylosis, osteochondrosis), hyperextension of cervical spine (trauma, chiropractic maneuvers, dentalprocedures) in patient with cervical stenosis, Paget disease, or ossification of the posterior longitudinal ligament.4 Not a myelopathy (the cauda equina is affected); mentioned here for differential diagnostic reasons. 5 Primaryspinal canal stenosis, intervertebral disk protrusion/herniation, degenerative changes in spinal column. 6 Syrin-gobulbia ! pain (V), caudal cranial nerve lesions (VIII–XII), nystagmus. 7 Suboccipital decompression in Chiarimalformation (p. 292), shunt ! syringotomy.

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Spinal claudication

Syringomyelia (kyphoscoliosis)

Sites of spinal neoplasms

Narrowing of lumbar spinalcanal, spondylarthrosis

Inter-vertebral

disk

Calcifiedvessel

Narrowing of cervical spinal canal by osteophytes(contrast-enhanced, midline sagittal T1-weighted MRI image)

Vascular lesionof spinal cord

Cavitation of cervical spinalcord (T1-weight-

ed sagittal MRIscan)

Radicular

Leptomeningeal, radicular

Intramedullary

Extradural compression(vertebral body metastasis)

Extramedullary,intradural/leptomeningeal

Extradural

Dura

Leptomeninx

Cervical myelopathy

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! Non-Mass Lesions

Myelitis. See p. 282 for a listing of various infec-tious myelitides.Subacute combined degeneration (SCD) appearsin middle to old age, causing tingling and burn-ing dysesthesiae in the limbs, gait unsteadiness,and abnormal fatigability. There may also bevisual disturbances and depressive or psychoticsymptoms accompanied by weight loss, glos-sopyrosis, and abdominal complaints. The neu-rological examination reveals a loss of positionsensation (! spinal ataxia), spastic paraparesis,variable abnormalities of the deep tendon re-flexes, and autonomic dysfunction (bladder,bowel, sexual dysfunction). Megalocytic anemiais usually present. The cause is vitamin B12 defi-ciency, whichmay, in turn, be due tomalabsorp-tion, cachexia, or various medications. Folic aciddeficiency produces a similar syndrome. Thepatient should be treated with parenteral cy-anocobalamin or hydroxocobalamin as soon aspossible. Neurological deficits can arise even if

the hematocrit and red blood cell count are nor-mal.Toxic myelopathy. Most patients initially pre-sent with polyneuropathy, developing clinicallyapparent myelopathy only in the later stages ofdisease. Common causes include solvent abuse(“glue sniffing”), a high dietary intake of grosspeas (lathyrism; p. 304), and consumption ofcooking oil adulterated with lubricant oil (tri-orthocresyl phosphate poisoning).Hereditary. The clinically and geneticallyheterogeneous forms of familial spastic paraple-gia (FSP; spinal paralysis = SPG, p. 384) becomesymptomatic either in the first decade of life orbetween the ages of 10 and 40. Progressive cen-tral paraparesis with spasticity arises either inisolation (uncomplicated SPG) or accompaniedby variable neurological deficits (complicatedSPG). Both types can be transmitted in an auto-somal dominant, autosomal recessive, or X-linked inheritance pattern. Spinal muscular atro-phy, see p. 304. Adrenomyeloneuropathy, seep. 384.

Diagnostic Studies in Myelopathy1

Treatment of Myelopathies (partial listing)

Method Information Provided

Evoked potentials SEP2: conduction delay. MEP3: prolongation of CMT4

Plain radiograph Anomalies of spinal column or craniocervical junction, degenerative changes, fractures,lytic lesions, spondylolisthesis

CT Same as above, tumor, 3-D reconstruction

MRI Tumor, myelitis, vascular myelopathy, (MR) myelography

Bone scan Vertebral body lesions (trauma, neoplasm, inflammation, degeneration)

CSF analysis Inflammatory, hemorrhagic (vascular), or neoplastic changes

Myelography5 Position-dependent changes (dynamic spondylolisthesis), spinal stenosis, arachnoiditis,nerve root avulsion

Spinal angiography Arteriovenous fistula/malformation, location of source of hemorrhage

1 Urodynamic tests are used to evaluate bladder dysfunction (p. 156). 2 Somatosensory EP. 3 Motor EP. 4 Centralmotor conduction time (CMT). 5 Used when CT/MRI findings are ambiguous, in an emergency if CT and MRI arenot available, or if position-dependent changes must be evaluated.

Cause Treatment Measures

Myelitis HSV/VZV1: acyclovir. Bacterial infection: antibiotics. Unknown pathogen: corticosteroids

Neoplasm2 Surgical resection of tumor and stabilization of spinal column; radiotherapy; corti-costeroids; chemotherapy; hormonal therapy

Vascular lesion AV malformation: Embolization, surgery. Ischemia/hematomyelia: symptomatic treat-ment, physiotherapy

1 HSV/VZV: herpes simplex virus/varicella-zoster virus. 2 Treatment depends on type and extent of neoplasm.

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Subacute coombined degeneration, vitamin B12 deficiency

Toxic myeloneuropathy

Glossopyrosis/glossodynia (smooth red tongue)

Perlèche (angular cheilosis)

Spinal (sensory) ataxia(Romberg sign)

Nut of cycad tree(associated withamyotrophic lateralsclerosis + parkinso-nian dementia complex, WesternPacific)

Neurogenic muscular atrophy

Familial spastic spinal paralysis

Megaloblastic anemia(anisocytosis/poikolocytosis)

Hypersegmentedgranulocyte

Pale yellow complexion, yellowish sclerae

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Hereditary Diseases

Phenotype. The manner in which a hereditarydisease expresses itself at a given moment indevelopment (phenotype) is the product of boththe individual’s genetic makeup (genotype) andthe environment in which development hastaken place.Inheritance. The human genome consists of 22pairs of chromosomes (autosomes) and 2 sexchromosomes (either XX or XY). Individuals in-herithalfof theirchromosomesfromeachparent.The chromosomes aremade of DNA and bear thegenes, sequencesofnucleotidebasepairs thaten-code the proteins of the body. Stretches of DNAthat encode proteins are called exons; there arealso intervening noncoding sequences, called in-trons. The inheritance pattern of hereditary dis-eases can be monogenic—the disease is due to adefect in a single (autosomal or X-chromosomal)gene, and is transmitted in a recessive or domi-nant manner in accordance with Mendel’s laws;polygenic—the disease is due to defects in multi-ple genes; ormultifactorial—the cause of diseaseis not exclusively genetic, and exogenous factorsalong with genetic factors determine its pheno-type. Mitochondrial disorders are transmittedexclusively by maternal inheritance, as mito-chondrial DNA is nonchromosomal and is in-herited exclusively from the mother.Mutation. Alleles are different forms of a gene. Agenemutation is a change in theDNAsequence ofa gene and may involve a change in a single basepair (pointmutation), the lossofoneormorebasepairs (deletion), the insertionof oneormorebasepairs, or unstable trinucleotide repeats. There arealsogenomemutations,which involvea change inthe number of chromosomes, such as trisomy 21(thecauseofDownsyndrome), aswell aschromo-some mutations, in which the chromosomalstructure is altered.Mutations canoccur either inthe germ cells (germ-line mutation) or in thedifferentiated cells of the body (somatic muta-tion). Somatic mutations cause cancer, autoim-mune diseases, and congenital anomalies.Diagnosis. Thediagnosis of hereditary diseases isby family history. Many monogenic diseases canbe diagnosed by direct genotypic analysis (DNAsequencing). Indirect genotypic analysis, with in-vestigationof theaffectedandnonaffectedmem-bers of a single pedigree, is used in the diagnosisof disorders for which a gene locus is known butthe responsiblemutation(s) has not yet been de-termined.

Malformations and DevelopmentalAnomalies (Table 40, p. 381)

Malformation.Amalformation is a structural ab-normality of an organ or part of the body in an in-dividual whose body tissues are otherwise nor-mal. Malformations arise during prenataldevelopment because of primary absence or ab-normality of the primordial tissue destined todevelop into a particular part of the body (“an-lage”). Dysplasia is malformation due toanomalous organization or function of tissuesand tissue components; disorders involving dys-plasia include tuberous sclerosis, neurofibroma-tosis,migrationdisorders, andvariousneoplasticdiseases.Developmental anomaly. Disruption of thegrowthofanorganorbodypartafternormal (pri-mary) primordial development can cause a sec-ondary developmental anomaly. Mechanical in-fluences during development can cause ananomalous position and shape (deformity) of anorgan or body part.

! Infantile Cerebral Palsy (CP) (p. 291)

Infantile cerebral palsy (cerebral movement dis-order) is a manifest, but not necessarily unvary-ing, motor and postural disorder caused by non-progressivedamagetothebrainbefore,during,orafter birth. The underlying brain damage is usu-ally of multifactorial origin. Prenatal causes in-clude chromosomal defects, infection, hypoxia,or blood group intolerance; perinatal causes in-cludehypoxia, cerebral hemorrhage, birth injury,adverse drug effects, and kernicterus; postnatalcauses include meningoencephalitis, stroke,brain tumor, metabolic disturbances, andtrauma.Symptoms and signs. Paucity of spontaneousmovement, abnormalpatternsofmovement, anddelayed development of standing and walkingare noted just after birth and as the childdevelops. Cerebral palsy frequently involves cen-tral paresis (hemiparesis, paraparesis, or quadri-paresis), spasticity, ataxia, and choreoathetosis(p. 66). There may also be mental retardation,epileptic seizures, behavioral disturbances (rest-lessness, impulsiveness, lack of concentration,impaired affect control), and impairment of vi-sion, hearing, and speech. The motor distur-bances produce deformities of the bones andjoints (talipes equinus, contracture, scoliosis, hipdislocation).

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Genotype

DNA double helix (genetic information)

Phenotype

Relationship between genotype and phenotype

Modes of inheritance (examples)

Chromosome Chromosomeregion

Gene

RNA polymerase

Messenger RNA

Triplet (codon)

Transcription

Translation(transfer RNA)

Amino acid

Protein

Symboles

Male Female Affected Carrier X-chromosomalcarrier

Autosomal recessive inheritance Autosomal dominant inheritance

X-linked recessive inheritance

Maternal (mitochondrial) inheritance

RD RD RR

RD RR

RR

DR DR RR

RRDD RD DD RR RD RR DR DR

DR D D

DD D R

DR

DDRR

D

DD

D DR R

RR DR DR RR

D = Dominant alleleR = Recessive alleleRR/DD = HomozygoteRD/DR = Heterozygote


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Treatment. Physical, occupational, and speechtherapy and perception training should bestarted as soon as possible. Botulinum toxin canbe useful in the treatment of spasticity at certainsites (dynamic talipes equinus, leg adductors,arm flexors). Other measures: Orthopedic care,seeing and hearing aids, developmental sup-port.

! Hydrocephalus

Hydrocephalus is dilatation of the cerebral ven-tricles (p. 8) due to obstruction of CSF outflow(p. 162). Common etiologies include aqueductalstenosis, Dandy–Walker and Chiari malforma-tions, infection (toxoplasmosis, bacterial ven-triculitis), hemorrhage, and obstructing tumors(colloid cyst of the third ventricle, midlinetumors).Symptoms and signs. If the cranial sutures havenot yet fused, congenital obstructive hydro-cephalus produces an enlarged head (macro-cephaly) with a protruding forehead, the resultof chronic intracranial hypertension. The headcircumference should be measured regularly, asit is a more useful indicator of congenital hydro-cephalus than the clinical signs of intracranialhypertension (p. 158), which are often not verypronounced in infants and may be masked byirritability, failure to thrive, crying, and psycho-motor developmental delay. These signs includedistended veins visible through the patient’sthin scalp; bulging of the fontanelles, and verti-cal gaze palsy (the lower lid covers the open eyeto the pupil, the upper lid reveals a portion ofthe sclera ! “sunsetting”). Signs of intracranialhypertension are the most useful indicators ofhydrocephalus once the cranial sutures havefused. A chronic form of hydrocephalus to bedifferentiated from NPH (p. 160) has been de-scribed as long-standing overt ven-triculomegaly in adults (LOVA hydrocephalus);symptoms include macrocephaly, headache,lightheadedness, gait disturbances, and bladderdysfunction.Treatment. Acute hydrocephalus: There is alimited role for medical treatment (e. g., withcarbonic anhydrase inhibitors and osmodiureticagents); neurosurgical treatment is generallyneeded for CSF drainage (external drainage orsurgical shunt) and/or the resection of an ob-structing lesion.

! Porencephaly

Porencephaly (from Greek poros, “opening”), theformation of a cyst or cavity in the brain, is usu-ally due to infarction, hemorrhage, trauma, orinfection. Porencephaly in the strict sense of theterm involves a communication with theventricular system. Porencephalic cysts are onlyrarely associated with intracranial hyperten-sion. Large ones reflect extensive loss of braintissue; the extreme case is termed hydranen-cephaly. Porencephaly may be asymptomatic ormay be associated with focal signs (paresis,epileptic seizures).

! Arachnoid Cysts

An arachnoid cyst is a developmental anomalyof the leptomeninges (p. 6), usually supraten-torial, and located either within the lepto-meningeal membranes or between thearachnoid and pia mater. Some arachnoid cystscommunicate with the subarachnoid space.Many are asymptomatic, even when large. Inrare cases, they can obstruct the CSF pathways(midline or infratentorial arachnoid cysts) orcause new or progressive signs and symptomsbecause of intracystic hemorrhage, cyst expan-sion (perhaps by a one-way valve mechanism),or cyst rupture. Symptomatic arachnoid cystsare treated neurosurgically by shunting,fenestration, or excision.

! Agenesis of the Corpus Callosum

Hypoplasia or agenesis of the corpus callosumoccurs as an isolated finding or in combinationwith other anomalies (Chiari malformation, het-erotopy, chromosomal anomaly, Aicardi syn-drome ! infantile spasms, micro-ophthalmia,chorioretinopathy, costovertebral anomalies).Isolated agenesis of the corpus callosummay beasymptomatic and is occasionally found in-cidentally on CT or MRI scans. Cystic deformitiesof the septum pellucidum (cavum septi pel-lucidi, cavum vergae) may obstruct the flow ofCSF and cause intracranial hypertension.


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CT scan (axial view)

MRI scan (coronal T1-weighted )

MRI scan (coronal T1-weighted )

Hydrocephalus

Porencephaly

Arachnoid cyst

Choreoathetosis

Posturalabnormali-ties, spasticity

Adduction position,skeletal deformity

Lateral ventricle(anterior horn)

Abnormalpostureof foot


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! Anomalies of the Craniocervical Junction

! Spinal Dysraphism (Neural Tube Defects)

Syndrome Symptoms and Signs Causes Diagnosis/Treatment

Platybasia Usually asymptomatic Flattening of the skull base Plain radiograph1/None

Occipitalization ofC1

Usually asymptomatic; possiblesigns of medullary dysfunction

Synostosis of C1 with theocciput

Plain radiograph, CT, MRI/Surgical decompression ifsymptomatic

Basilar impression Occipitocervical pain; reducedneck flexibility. Long-term: im-pairment of gait, urinary reten-tion, dysarthria, dysphagia, ver-tigo, nausea

Underdevelopment of theoccipital bone causing“elevation” of cervicalspine2

Plain radiograph, CT, MRI/Usually symptomatic;medullary symptoms !neurosurgical treatment

Klippel–Feil syn-drome3

Short neck, abnormal head pos-ture, high shoulders, headache,radicular symptoms in arm;possible spinal cord compression

Fused cervical vertebrae Same as above/Treatment depends onsigns and symptoms

1 Angle between root of nose and clivus ! 145°. 2 Congenital (Chiari malformation), acquired (Paget disease, osteomala-cia). 3 Additional malformations such as syringomyelia, spina bifida, cleft palate, or syndactyly may be present.

Syndrome Symptoms and Signs Causes Diagnosis/Treatment

Anencephaly Absence of cranial vault; cerebralaplasia; normally developedviscerocranium

Nonclosure of anterior por-tion of neural tube

Prenatal ultrasound screen-ing/Termination of preg-nancy

Encephalocele Protrusion of brain tissuethrough a midline skull defect1

Inhibition malformation(incomplete closure ofneural tube)

Measurement of !-feto-protein2, prenatal ultra-sound screening/Folic acid-vitamin B12 administrationduring pregnancy; surgicalrepair if indicated

Dandy–Walker mal-formation

Hydrocephalus, hypoplasia/agenesis of vermis; cystic dilata-tion of 4th ventricle; variabledegree of facial dysmorphism

Abnormality of embryonaldevelopment

CT, MRI/Shunt

Chiari malformation3 Lower cranial nerve and brain-stem dysfunction (dysphagia, res-piratory dysfunction); head, neckand shoulder pain; abnormalhead posture, vertigo, downbeatnystagmus, hydrocephalus (typeII)

Abnormality of earlyembryonal development(weeks 5–6 of gestation)

CT, MRI/Suboccipitaldecompression; shunt pro-cedure for hydrocephalus;early surgery for myelo-meningocele

Spina bifida4 Spina bifida occulta: Dermal sinus,lumbar hypertrichosis, lum-bosacral fistula, leg pain, gait dis-turbance, foot deformities, blad-der dysfunction (enuresis inchildren)Other forms: Sensorimotor para-plegia at birth; bladder/boweldysfunction, foot deformities; hy-drocephalus may occur

Inhibition malformation(incomplete closure ofneural tube)

!!-Fetoprotein2, prenatalultrasound screening, plainX-ray, CT, MRI/Folic acidadministration duringpregnancy; surgical treat-ment, physiotherapy, or-thopedic therapy

Tethered cordsyndrome

Same as above, with varyingseverity. Low-lying conus medul-laris, fixed filum terminale

Traction on spinal cord andcauda equina

MRI/Surgery for symptomsand signs reflecting dys-function of the spinal cordand/or cauda equina

1 Meningocele: Only the meninges protrude through the skull defect. Meningoencephalocele: Meninges + brain. Meningoen-cephalocystocele: meninges + brain + ventricular system. 2 In maternal serum; also in amniotic fluid in open defects. 3 TypeI: unilateral or bilateral cerebellar tonsillar herniation with or without caudal displacement of medulla; hydrocephalus, syrin-gomyelia (p. 284); there may be an accompanying anomaly of the skull base. Type II: same as type I + caudal displacementof medulla, parts of cerebellum, and fourth ventricle, with myelomeningocele. Type III: same as type II + occipital en-cephalocele. 4 Rachischisis = fissure of vertebral column, incomplete closure of neural tube; spina bifida occulta = in-complete vertebral arch (lamina) with normal position of spinal cord and meninges; meningocele = the arachnoid liesdirectly under the skin, not covered by the missing dura and bone; myelomeningocele = prolapse of spinal cord (or caudaequina) and arachnoid through the dural and bony defect; diastematomyelia = split spinal cord, with two halves separatedby connective tissue or a bone spur.


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Lines for assessment of platybasiaand basilar impression

Klippel-Feil syndrome

Chiari malformation (type II)

Tethered cord syndrome(sagittal T1-weighted MRI scan)

Spina bifida(left, spina bifida occulta; middle, meningocele;right, meningomyelocele)

Chiari malformation type I(sagittal T1-weighted MRI scan)

Elongation ofcerebellar tonsil

Adhesion of filum

terminale

Abnormally lowconus medullaris

Hairy patch

Dura Dura

Arachnoid Subarachnoid space

Spinal cord

Pons

Short neck, abnormal

neck posture

Hard palate

Dens

Palato-occipital(Chamberlain’s)line

Basal (McGregor’s) line

Angle between root of nose and clivus(enlarged in platybasia)

Medulla oblongata

Displacement of cervical cord

Basilar impression: Dens > 5 mm over Chamberlain’sline and > 7 mm over McGregor’s line

Foramen magnum(anterior and posterior margins)


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The Phakomatoses

The phakomatoses (neurocutaneous diseases)are a group of congenital diseases in whichpathological changes are found in both the cen-tral nervous system and the skin. Neurofibroma-tosis, tuberous sclerosis, and von Hippel–Lindaudisease are transmitted in an autosomal domi-nant inheritance pattern with high penetranceand variable phenotypic expression. These dis-orders are generally characterized by the forma-tion of benign nodules (hamartoma); malignanttumors (e. g., hamartoblastomas) are rare.

! Neurofibromatosis (NF; von RecklinghausenDisease)

The genetic locus for neurofibromatosis type 1(NF1), the “classical” form of the disease, is onchromosome 17q11.2; that for NF type 2 (NF2) ison 22q12.2.Symptoms and signs. The characteristic lesionsof NF1 are found in the skin (early stage: café-au-lait spots, axillary/inguinal freckling; laterstages: neurofibromas/plexiform neurofibro-mas), eyes (Lisch nodules = whitish hamartomasof the iris, optic glioma), and bone (cysts, patho-logical fractures, skull defects, scoliosis). Theremay also be syringomyelia, hydrocephalus,epileptic seizures, precocious puberty, orpheochromocytoma. The hallmark of NF2 is bi-lateral acoustic neuroma with progressive bi-lateral hearing loss. Cutaneous manifestationsare rare; other nervous system tumors (neurofi-broma, meningioma, schwannoma, glioma) aremore common. Subcapsular cataract is a typicalfeature of NF2 in children.Treatment. Symptomatic tumors are resected.

! Tuberous Sclerosis (TSC; Bourneville–PringleDisease)

The clinical syndrome of tuberous sclerosis isproduced by a mutation at either one of twoknown loci (TSC1: 9q34, TSC2: 16p13.3). TSC1and TSC2 are clinically identical.Symptoms and signs. Epileptic seizures (infantilespasms and salaam seizures = West syndrome;focal, generalized) are found in association withskin changes (early: hypomelanotic linear spotsreadily visible under UV light; late signs: ade-noma sebaceum, subungual angiofibroma, thickand leathery skin in the lumbar region), ocular

changes (retinal hamartoma), and tumors (car-diac rhabdomyoma, renal angiomyolipoma,cysts). There may be marked mental retardationand behavioral abnormalities (vocal and motorstereotypy, psychomotor restlessness). CT andMRI reveal periventricular calcification, corticallesions, and tumors.Treatment. Symptomatic (anticonvulsants).

! Von Hippel–Lindau Disease

Gene locus. 3p25-p26.Symptoms and signs. Cystic cerebellar heman-gioblastoma causes headache, vertigo, andataxia, and possibly hydrocephalus by compres-sion of the 4th ventricle. Hemangioma may alsooccur in the spinal cord. Further lesions areoften present in the eyes (retinal angiomatosis !

retinal detachment), kidneys (cysts, carcinoma),adrenal glands (pheochromocytoma), pancreas(multiple cysts), and epididymis (cystadenoma).Treatment. Regular screening of each poten-tially involved organ system is carried out sothat tumors can be resected and vascular com-plications prevented as early as possible.

! Cutaneous Angiomatoses with CNS Involve-ment

Sturge–Weber disease (encephalofacial angio-matosis). A unilateral or bilateral port winestain (nevus flammeus) is present at birth andmay be either localized (characteristically in theupper eyelid and forehead, in which case in-volvement of the brain is likely) or widespread(entire head or body). Not all cutaneous heman-giomas are accompanied by cerebral involve-ment.Hereditary hemorrhagic telangiectasia (HHT;Osler–Weber–Rendu disease). Known geneticloci: 9q34.1 (HHT1) and 12q11–14 (HHT2).Telangiectases (vascular anomalies) of the skin,mucous membranes, gastrointestinal tract, uro-genital tract, and CNS cause recurrent bleeding(nosebleed, gastrointestinal hemorrhage, hema-turia, hemoptysis, cerebral hemorrhage, ane-mia). Arteriovenous shunting in the lung maycause cyanosis and polycythemia.


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Neurofibroma

Tuberous sclerosis

von Hippel-Lindau syndrome(sagittal MRI scan)

Ataxia-telangiectasia

Sturge-Weber syndrome

Lisch nodules Bilateral acoustic neuroma (axial

T1-weighted MRI scan)

Adenoma sebaceum

Periventricular calcifica-tion (axial CT scan)

Telangiectasis

Hemangioblastoma ofthe cervical spinal cord

Hemangioma of upper eyelid


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Throughout the industrialized world, the popu-lation is becoming older. It is predicted that thepercentage of persons over age 65 will risefurther, while that of persons under age 15 willfall.

Aging

Aging is a biological process with a characteris-tic temporal course. Senescence refers to thephysical changes associated with aging. It is stillunclear whether human aging is specificallygenetically predetermined or, alternatively, re-flects cumulative damage incurred over time.The cellular correlates of aging include an in-crease in spontaneous chromosomal mutations,altered protein conformations, impairment ofcell metabolism by the accumulation of freeoxygen radicals, a decline of mitochondrialfunction with an increase in apoptosis (geneti-cally programmed cell death), and diminishedactivity of regenerative processes. It is not yetknownwhether these processes are the cause orthe effect of aging.The current average natural lifespan, barringpremature death from disease or externalcauses, is approximately 85 years. Themaximumhuman lifespan (to date, at least) is approxi-mately 120 years. Life expectancy is the averagestatistically predicted lifespan of a given popu-lation at a given point in time. Human life ex-pectancy has risen considerably in the course ofhistory, particularly in the 20th century. The ac-tive life expectancy, or the expected time duringwhich the individual can function independ-ently with regard to meals, dressing, personalhygiene, shopping, and finances, is of practicalsignificance. About 35% of persons over 85 arenot fully independent, and about 20% neednursing-home care.

Aging and Disease

Aging decreases physiological reserve, i.e., theability to compensate for the effects of harmfulinfluences, be they endogenous (e. g., diabetesmellitus, heart failure, thyroid dysfunction) orexogenous (e. g., trauma, infection, side effectsof medication). Diseases therefore tend to affectthe elderly with shorter latency and greaterseverity. Age-related changes promote the

development of diseases such as Alzheimer dis-ease or stroke, as well as accidents such as falls.Brain tumors (p. 254), particularly metastases,glioma, meningioma, acoustic neuroma, andprimary cerebral lymphoma, are more commonin older patients. Aging is neither a disease nor acause of disease, but it increases the chance ofbecoming ill. The physician must distinguishchanges due to disease from those of normalaging (see Table 41, p. 382).

Aging and Degenerative Changes

Structural changes in the brain due to agingrather than disease are referred to as involution.Gross changes include diminished brain volume,gyral atrophy, ventriculomegaly, leukoaraiosis(p. 298), parasagittal leptomeningeal fibrosis,and ventricular expansion, while microscopicchanges include neuron and axon loss, gliosis,and the presence within neurons of lipofuscin,neuromelanin, granulovacuolar degeneration,microtubular neurofibrillary tangles (NFTs),senile plaques, Lafora bodies, and Lewy bodies.The term abiotrophy refers to the genetically de-termined, age-dependent occurrence ofdegenerative changes such as these. Degenera-tive diseases, on the other hand, are character-ized by an abnormal accentuation of these andother morphological changes, producing typicalconstellations of functional disturbances (dis-ease-specific clinical syndromes). They developslowly, progressively, sometimes asymmetri-cally, and with variable intervals of relativelystable disease manifestations. Some are familial.

Alzheimer Disease (AD)

Alzheimer disease (in its sporadic form) is themost common cause of dementia in old age(p. 136). It progresses steadily or stepwise andusually leads to death in 8–10 years (range, 1–25years). Risk factors for AD include old age, familyhistory of AD, female sex, elevated plasma ho-mocysteine concentration, and the presence ofthe allele Apo E!4. Nonsteroidal anti-inflam-matory drugs appear to lower the risk of AD. Fa-milial AD is rare; it is transmitted in an auto-somal dominant inheritance pattern.

Neurodegenerative Diseases

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Early stage. Memory impairment developsgradually and almost imperceptibly, barelydiffering at first from that of benign senile for-getfulness (p. 136). Ultimately, however, thecognitive deficits of AD produce noticeablechanges of behavior, e. g., when the patient isworking, shopping, running errands, or takingcare of finances, or operating such devices as atelephone, stove, television, or computer. Thepatient may be aware of these deficits and be-come additionally anxious and depressed be-cause of them. The distinction between AD withdepressive features and primary depressionwith secondary cognitive changes (pseudo-dementia) has major implications for treatment(Table 42, p. 383).Intermediate stage. The patient is too confusedand disoriented to carry out previous occu-pational and social activities (p. 132) and needshelp and supervision in almost all activities, butmay still be able to perform habitual dailyroutines, carry on a simple conversation, andabide by the basic rules of etiquette. Aphasia(e. g., impaired comprehension of speech,word-finding difficulty, cf. p. 126) and apraxia(p. 128) are often present. The patient cannotdo simple arithmetic or tell time. Visual ag-nosia is rare at this stage.Late stage. The increasing cognitive impair-ment and loss of reasoning and judgment makeit impossible for the patients to plan their ac-tivities. The patient’s aimless wandering, un-directed motor activity, and inability to recog-nize people—even close relatives and friends—complicate the caregiver’s job, along withchanges in the patient’s circadian rhythm (quietor apathetic by day, restless by night), impul-sive behavior (packing suitcases or runningaway), delusions, hallucinations, paranoid sus-picion of close relatives and friends, aggressivebehavior, and neglect of personal hygiene.Patients with advanced AD need help with thesimplest activities of daily living (eating, dress-ing, going to the toilet). They may become in-continent of urine and stool, bedridden,akinetic, and mute. Pathological reflexes (suck-ing and grasping) can be elicited. Auditory andtactile stimuli may trigger epileptic seizuresand myoclonus (for differentiation from

Creutzfeldt–Jakob disease, see p. 252). Death iscaused by secondary complications such aspneumonia and heart failure.

! Pathogenesis

PET and SPECT studies in early AD reveal bi-lateral metabolic disturbances in the parie-totemporal cortex and decreased neu-rotransmitter activity in cortical cholinergicfibers (acetylcholine, choline acetyltransferase,nicotinic acetylcholine receptors ! nucleusbasalis, medial septal region), serotonergicfibers (raphe nuclei), and noradrenergic fibers(locus coeruleus). There is probably a reductionof cortical glutamatergic activity (excitatory)with a preponderance of GABAergic activity (in-hibitory). Neuropathology: Changes such as neu-ronal death, neuritic (senile) plaques (NPs), andintraneuronal neurofibrillary tangles (NFTs) areseen mainly in the entorhinal cortex, hippocam-pus, temporal cortex, primary/secondary visualcortex, and nucleus basalis. NPs consist of a cen-tral core containing amyloid-A", apolipoproteinE (Apo E), #1-antichymotrypsin, synuclein, andother proteins, surrounded by dead neurons, ac-tivated glial cells, macrophages, and other in-flammatory cells. NFTs consist of paired helicalfilaments (PHFs) composed of tau proteins,which are normally an important stabilizingcomponent of the microtubular (neurofibrillary)cytoskeleton. Increased phosphorylation of tauproteins leads to the formation of NFTs. Amy-loid-A" (normal function unknown) is formedby proteolysis of the transmembrane amyloidprecursor protein (APP), to which neurotrophicand neuroprotective properties have beenascribed. A point mutation in APP on chromo-some 21q has been implicated in familial AD;patients over 40 years of age with Down syn-drome (trisomy 21) also have neuropathologicalchanges similar to those of AD. Accumulation ofamyloid-A" in arterial walls is the basic abnor-mality in amyloid angiopathy (p. 178). The genefor Apo E (a lipoprotein involved in cholesteroltransport) is found on chromosome 19q and hasthree alleles, designated !2, !3, and !4; !4 isstrongly associated with both sporadic and fa-milial AD. Other familial forms of AD have beentraced to mutations of the presenilin-1 gene(PS1 ! 14q24.3 ! protein S182) and the pre-senilin-2 gene (PS2 ! 1q31-42 ! STM2 protein).


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These genes encode cytoplasmic neuronal pro-teins whose function is as yet unknown.

! Treatment

There is no specific treatment for AD. Sympto-matic, social, and psychiatric measures andfamily assistance are the mainstays of treat-ment. Acetylcholinesterase inhibitors(donepezil, galantamine, rivastigmine, tacrine)or N-methyl-D-aspartate (NMDA) inhibitors(memantine) can improve cognitive function inthe early stages of disease. A proposed protec-tive effect of estrogen therapy in post-menopausal women has not been confirmed.

Pick Disease, Frontotemporal Dementia(FTD)

Pick disease causes behavioral changes (e. g., re-duced interpersonal distance, apathy, abulia,obsessive-compulsive symptoms, amnesticaphasia, increased appetite) and impairment ofsemantic memory. CT and MRI mainly revealasymmetric frontotemporal atrophy. Neu-ropathology: Neuron loss, gliosis, and variablysevere “ballooning” of neurons (Pick cells).There are no neuritic plaques. The disease is fa-milial in 40% of cases; familial Pick disease istransmitted in an autosomal dominant inheri-tance pattern and is due to a mutation on chro-mosome 17 (FTDP-17) that causes changes in tauprotein (! FTD with parkinsonian manifesta-tions).

Vascular Dementia (Table 14, p. 367)

Cerebrovascular disturbances can producedementia in a variety of ways. The main risk fac-tors for cerebrovascular dementia are old age,arterial hypertension, diabetes mellitus, andgeneralized atherosclerosis. After AD, cere-brovascular disturbance are the second mostcommon cause of dementia.Multi-infarct dementia. Multiple small infarcts(lacunes) or large bilateral infarcts may produceany of a variety of focal neurological, behavioral,and cognitive disturbances, depending on theirlocation and extent. These disturbances usuallyprogress in stepwise fashion. CADASIL (p. 172) isa rare cerebrovascular disorder that predisposesto multi-infarct dementia.

Subcortical arteriosclerotic encephalopathy(SAE) is characterized by rarefaction of thewhite matter (leukoaraiosis) due to microan-giopathy. Neuropathology: Histological exami-nation reveals demyelination and reactive glio-sis in the white matter, along with changes inthe walls of small arteries (hyalinosis, fibrinoidnecrosis, hypertrophy). These vascular changesare the cause of chronic ischemic and secondarymetabolic damage in areas of white matter sup-plied by terminal branches. Behavioral changes(attention deficit, loss of cognitive flexibility,abulia, disorientation), gait disturbances, pseu-dobulbar palsy, urinary incontinence, and otherneurological deficits develop slowly and con-tinuously (not in stepwise fashion, as in multi-infarct dementia).Strategic infarct dementia. Dementia can beproduced by a localized infarct in a particular,“strategic” areas of the brain (e. g., limbic sys-tem, thalamus, cortical association areas).Leukoaraiosis is characterized by white-matterlesions (WMLs) that are hypodense on CT andhyperintense on T2-weightedMRI. The extent ofWMLs is correlated with the clinical severity ofthe disease: there may be mild or moderatecognitive impairment (cognitive slowing,memory loss) or severe dementia. WMLs are notalways due to a cerebrovascular disturbance andare present in a variety of conditions other thanchronic arterial hypertension (e. g., AD, multiplesclerosis, PML, Creutzfeldt–Jakob disease,ADEM, trauma, radiation therapy, chemother-apy, vitamin B12 deficiency, hypoxic-ischemicencephalopathy, CADASIL, central amyloid an-giopathy).


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Progressive course of AD

Pick disease (coronary MRI scan)

Vascular dementia(axial T2-weighted MRI scan)

Pathogenesis of Alzheimer disease (AD)(left, coronal MRI scan; middle, brain histopathology; right, schematic view)

Aging and Alzheimer disease(*the longer the arrow, the stronger the effect)

Predominantly corticalatrophy (MRI)

NFT

OnsetIntermediate stage Late

stage

NP

NPBlood-brain barrier lesion

( CSF markers like protein)

Apo E expression,inflammatory cell

NFT ( protein)

NPs ( protein, -amyloid,ubiquitin, presenilin andother proteins)

Temporal atrophy

Dementia syndrome

White-matterlesion

Effect of AD-associatedgenes*

Age (years)

Neuron

Astrocyte, Apo E

Presenilin-1

APP, Presenilin-2

Apo E

100

90

80

70

60

50

40

30

20

10

Othergenes

Effect of metabolic

changes (e.g., oxidative processes)


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Huntington Disease (HD)

The first symptoms of HD typically appear be-tween the ages of 35 and 45 years. HD appearingbefore age 20 (the Westphal variant of HD) ischaracterized by akinesia, bradykinesia, epilep-tic seizures, action tremor, and myoclonus.Onset before age 10 or after age 70 is rare. HDpatients require total nursing care 10–15 yearsafter the onset of this inexorably progressive,and ultimately fatal degenerative disease.


Early stage. In cases of earlier onset, akinesiaand cognitive impairment tend to be moreprominent than choreiform movements, while,in cases of later onset, the reverse is true. Be-havioral changes such as depression, suicidaltendencies, paranoia, querulousness, irritability,impulsiveness, emotional outbursts, aggressivebehavior, poor hygiene, loss of initiative, and in-appropriate sexual behavior impair familial andsocial relationships and may even lead to crimi-nal charges. Other changes include cognitiveslowing, diminished tolerance for stress, andimpairment of memory and concentration. Thepatient becomes obviously unable to performhis or her usual tasks at work or at home. Chorea(p. 66; Table 43, p. 383) may initially bemisdiag-nosed as “nervous” agitation or fidgeting. Evensevere chorea disappears during sleep. Choreamay be accompanied by akinesia, dystonia, anddecreased voluntary motor control. Thepatient’s gait is impaired by poor balance andloss of postural motor control. Oculomotor dis-turbances are also common.Intermediate stage. Progressive dementia(p. 136) is accompanied by loss of drive, general-ized choreiform, dystonic, and bradykineticmovements, and frequent falls.Late stage. Many patients become cachectic,with muscular atrophy (! interosseous musclesof hands) and weight loss despite an adequatecaloric intake. Chorea is largely replaced byakinesia in late HD. General motor control isgreatly impaired. Urinary incontinence is not un-common. These patients need full nursing care.

! Pathogenesis (for abbreviations, see p. 211)

HD is characterized by generalized cerebralatrophy, especially of the dorsal striatum

(p. 210), and, neurochemically, by amarked defi-ciency of GABA and of glutamate decarboxylase(an enzyme involved in GABA synthesis). HD istransmitted in an autosomal dominant patternwith complete penetrance, that is, all personsbearing the gene eventually develop the disease.The gene for HD (IT15) is on the end of the shortarm of chromosome 4 (4p16.3), which containsCAG repeats (the trinucleotide sequence CAGcodes for glutamine; cf. p. 288). Healthy subjectshave 11–34 CAG repeats at this locus, while per-sons with HD have more than 40. Paternal in-heritance is associated with anticipation (in-creasingly early onset in subsequent genera-tions), but maternal inheritance is not. The geneproduct is referred to as huntingtin. Thepathophysiological mechanism of HD remainsobscure; increased glutamatergic transmissionat NMDA receptors is thought to produce neu-rodegenerative changes (excitotoxicity). There isnow a direct gene test that can be performed ona peripheral blood sample to detect HD beforethe onset of symptoms. It may only be per-formed with the informed consent of a patientabove the legal age of majority, after the poten-tial social and psychiatric implications of a posi-tive result have been explained.

Neuroacanthocytosis

Acanthocytes (crenated erythrocytes withthorny processes) make up more than 3% of allerythrocytes in fresh blood smears obtainedfrom patients with the following neurologicaldiseases: abetalipoproteinemia (Bassen–Korn-zweig syndrome, p. 280, 307;

!

cholesterol andtriglycerides), McLeod syndrome (X-linked re-cessive myopathy; absence of Kell precursorprotein), and neuroacanthocytosis (normal lipo-protein concentrations). The mode of inheri-tance of neuroacanthocytosis is unknown. Itsmajor features, orofacial dyskinesia (tongue-biting and lip-biting) and chorea, usually appearbetween the ages of 20 and 30 years.


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Behavioral changes

Chromosome 4Stimulation of glutamate

receptors

Acanthocytosis

Putamen

GPi

4p 16.3

Increased influx of Ca2+

Glutamatesynapse

Glutamatevesicle

NMDA receptor

Receptorbindingsite

AcanthocytesNormal erythrocytes

Activity of thalamocorticalprojection (hyperkinesia)

CNVentral lateral

nucleus of thalamus

Thalamus

Activity (direct striatonigral system)

STN

GL GL

GL

GL

DA

GABAGABA

GABA

GABA

ACh

GPe

Huntington disease (HD)

Chorea

Dementia

Nursing dependence

Normal functions Functional disturbances inHuntington disease


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Atypical Parkinsonian Syndromes

Roughly 80% of patients with parkinsonismsuffer from idiopathic Parkinson disease (p. 206ff), while the rest have either symptomaticparkinsonism (Table 44, p. 383) or atypicalparkinsonism (AP) due to one of the neu-rodegenerative “Parkinson-plus” syndromes.The more common AP syndromes are multiplesystem atrophy, progressive supranuclear palsy,and corticobasal degeneration. An unequivocaldifferentiation of these disorders from oneanother, and from idiopathic Parkinson disease,may not be possible at the onset of symptoms,or even later in the course of the disease.

! Multiple System Atrophy (MSA)

MSA is a gradually progressive, sporadic, nonfa-milial disease of adults marked by autonomicand cerebellar dysfunction of variable severity,accompanied by parkinsonian manifestationsthat respond poorly to levodopa. The term MSAcovers the earlier-described disorders olivopon-tocerebellar atrophy (OPCA), idiopathic ortho-static hypotension (IOH), Shy–Drager syndrome,and striatonigral degeneration (SND). The onsetof symptoms is usually between the ages of 45and 70. Autonomic dysfunction is manifested byurinary incontinence (p. 156; abnormal EMG ofurethral/anal sphincter ! increased polyphasicrate) and orthostatic hypotension (p. 148), andsometimes by hypertension while the patient islying down. Cerebellar dysfunction ismanifested by gait ataxia, frequent falls, dys-arthria, and oculomotor disturbances. Theparkinsonian manifestations include akinesia,rigidity, postural instability (p. 206), andfrequent falling, but there is no resting tremor.

! Progressive Supranuclear Palsy (PSP)

PSP (Steele–Richardson–Olszewski syndrome)is a progressive, nonfamilial disease that usuallyappears around the age of 40. Its major featuresare unsteady gait, postural instability, frequentfalls (often backward), axial dystonia, rigidity,akinesia, behavioral changes (bradyphrenia,irritability, social withdrawal, abnormal fatiga-bility, uncontrollable laughing and crying), andpseudobulbar palsy (p. 166). Paralysis of volun-tary conjugate upward gaze may be present atonset, but paralysis of downward gaze is more

common. Passive (reflex) vertical eye move-ments (doll’s eye sign) are still present, i.e., thevestibulo-ocular reflex remains intact (p. 26).The fully developed clinical picture of PSP (ab-normally erect posture, retrocollis, wide-openeyes, elevated forehead muscles, dysarthria, dy-sphagia, and frontal brain syndrome, p. 122) ispractically pathognomonic, but its manifesta-tions in the early phase can be very difficult todistinguish from those of other neurodegenera-tive diseases. The symptoms and signs of PSP re-spond poorly to levodopa, if at all.

! Corticobasal Degeneration (CBD)

CBD is a progressive neurodegenerative diseasethat most often occurs in adults over the age of60. Its major features are akinesia, rigidity, limbapraxia (p. 128), and cortical sensory deficits(astereognosis, graphanesthesia). There is a lossof motor control, so that the patient’s hands(limbs) appear to move spontaneously withoutthe patient’s guiding them (alien hand/limb phe-nomenon). Gait instability is an early sign and islater accompanied by dysarthria, dysphagia,myoclonus, dystonic arm posture (wrist andelbow flexion, shoulder adduction), action/pos-tural tremor, supranuclear oculomotor distur-bances (p. 86), blepharospasm, and cognitiveimpairment. Levodopa is unhelpful.

! Dementia with Lewy Bodies (DLB), DiffuseLewy Body Disease

DLB is characterized at first by an akinetic-rigidparkinsonian syndrome (p. 208), which is lateraccompanied by fluctuating behavioral changes(attention deficit, disorientation, impairment ofconsciousness, visual hallucinations) andfrequent falling for no apparent reason. Patientsare hypersensitive to neuroleptics and benzodi-azepines. An abundance of Lewy bodies (p. 211)can be observed, particularly in cortical neu-rons.


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Multiple system atrophy

Vertical gaze palsy(progressive supranuclear palsy)

Corticobasal degeneration

Asymmetrical parkinsonism,akinesia/rigidity, early postu-ral/gait instability ( falls)

Autonomic dysfunction (orthostatic hypotension, urinary incontinence, impotence, anhidrosis)

Ataxia, dysarthria, dysphonia

Doll’s eyes phenomenonon vertical head movement

Limb apraxia, dystonic arm position

Myoclonus


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Motor Neuron Diseases

These diseases involve a degeneration of thecerebral and/or spinal motor neurons (p. 44).They present with a wide variety of neurologicalsyndromes of varying temporal course.

! Upper Motor Neuron Diseases(p. 46; Table 45, p. 384)

Hereditary. Familial spastic spinal paralysis(p. 286), adrenomyeloneuropathy, spinocerebel-lar ataxia type 3 (p. 280).Acquired. Lathyrism (central spastic paraparesisdue to a neurotoxin in the pulse Lathyrus sativus(grass pea), a dietary staple in certain poor dis-tricts in India); konzo (= cassavaism, a toxic re-action to flour made of insufficiently processedcassava, seen in certain parts of Africa); tropicalspastic paraparesis (HTLV1-associated my-elopathy = HAM).

! Lower Motor Neuron Diseases(p. 50; Table 46, p. 385)

Most cases of spinal muscular atrophy arehereditary. Their clinical features vary accordingto the age of onset. Acquired forms are rare.

! Diseases Affecting Both the Upper and theLower Motor Neuron

Hereditary. Amyotrophic lateral sclerosis (ALS)is familial in 5–10% of cases. Familial ALS withonset in childhood and adolescence (juvenileALS) is transmitted either as an autosomal reces-sive trait (ALS2:2q33;ALS5:15q15.1!21.1) or asan autosomal dominant trait (9q34 linkage).Adult-onset familial ALS is transmitted as an au-tosomal dominant trait (ALS1:21q22.1;ALS3:18q21) associated with a mutation of thegene for superoxide dismutase 1 (SOD1). SOD1plays a role in converting cytotoxic oxygen radi-cals to hydrogen peroxide. It remains unknownhow the SOD1 defect causes motor neuron dis-ease. Autosomal dominant inheritance has alsobeen found for ALS plus frontotemporal demen-tia (9q21–22). ALS together with parkinsonismand dementia occurs among the Chamorropeople of Guam.Acquired. Sporadic ALS usually becomes ap-parent between the ages 50 and 70 (Table 47,p. 386). The presentation is typically with asym-metric weakness of the limbs, either proximal

(difficulty raising the arms or standing up from asitting position) or distal (frequent falls; diffi-culty grasping, turning a key in a lock), or elsewith bulbar dysfunction (dysarthria). Thesedeficits are often accompanied by leg crampsand continuous, marked fasciculation in theproximal limb muscles. As the disease pro-gresses, weakness, muscular atrophy, dyspha-gia, and dysarthria become increasingly severe.Respiratory weakness leads to respiratory in-sufficiency. Spasticity, hyperreflexia, pseudo-bulbar palsy, emotional lability, and Babinski re-flex (inconsistent) are caused by dysfunction ofthe first motor neuron; muscular atrophy andfasciculation are caused by dysfunction of thesecond motor neuron; and dysarthria, dyspha-gia, and weakness are caused by both. About10% of patients have paresthesiae, and somehave pain in later stages of the disease. Bladder,rectal, and sexual dysfunction, impairment ofsweating, and bed sores are not part of the clini-cal picture of ALS. The disease progressesrapidly and usually causes death in 3–5 years.

! Treatment

There is currently no effective primary treat-ment for motor neuron diseases. Treatment canbe provided for the palliation of various diseasemanifestations, e. g., dysarthria (speech therapy,communication aids), dysphagia (swallowingtraining, percutaneous endoscopic gastrostomy,surgery), and drooling (medication to decreasesalivary flow). Antispasmodic agents can beused to treat spasticity and muscle spasms, andpsychiatric medications to treat emotional labil-ity. Physical and occupational therapy are pro-vided, including breathing exercises, contrac-ture prophylaxis, and measures to increase mo-bility. Further measures include orthoses,breathing training (aspiration prophylaxis,secretolysis, ventilator for home use, tra-cheotomy), and psychosocial support. Riluzole(a glutamate antagonist) has been found to pro-long survival in ALS.


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First motor neuron lesion(spastic paraparesis)

Second motor neuron lesion

Lesion of both first and second motor neurons

Flaccid quadriparesis (floppy infant; Werdnig-Hoffmann

disease)

Localized atrophy(shoulder, scapula)

Proximal muscle atrophy(Kugelberg-Welander disease)

Calf hypertrophy

Paresis, muscular atrophy, fasciculation

Emotional lability

Tongue muscle atrophy, dysarthria, dysphagia


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The term encephalopathy refers to a focal orgeneralized disturbance of brain function ofnoninfectious origin. Depending on their eti-ology, encephalopathies may be reversible, per-sistent, or progressive. Their clinical manifesta-tions are diverse, depending on the particularfunctional system(s) of the brain that they af-fect.

Hereditary Metabolic Encephalopathies

These disorders frequently cause severe cogni-tive impairment. Most of them have an auto-somal recessive inheritance pattern; a few areX-linked recessive. The underlying primary

enzyme defect (enzymopathy) may be a mono-genic, polygenic, or mitochondrial genetic trait,or a multifactorial disorder (see p. 288). Allhereditary metabolic encephalopathies arecharacterized by chronic progression, recurrentimpairment of consciousness, spasticity, cere-bellar ataxia, extrapyramidal syndromes, andpsychomotor developmental delay. The follow-ing tables contain a partial listing of hereditarymetabolic encephalopathies (Lyon et al., 1996);for such disorders affecting neonates and in-fants, see p. 386 f. Some of the diseases listedmay appear earlier or later than the typical ageof onset indicated.

! Metabolic Encephalopathies of Infancy (up to age 2 years)

Syndrome Defect/Enzyme Defect Symptoms and Signs

Phenylketonuria Phenylalanine hydroxylasedeficiency

Psychomotor retardation, hyperactivity,movement disorders, stereotypic move-ments

Hartnup disease Impaired renal/intestinal trans-port of neutral amino acids

Reddish, scaly changes of exposed skin,emotional lability, episodic cerebellarataxia

Gaucher disease (type III, sub-acute neuropathic form)

See p. 387 Generalized seizures, ataxia, myoclonus,progressive mental decline, supranuclearoculomotor disturbances, splenomegaly

Niemann–Pick disease (type C) Exact defect not known Mental retardation, seizures, ataxia, dys-arthria, vertical gaze palsy

Metachromatic leukodystro-phy

Arylsulfatase A deficiency Progressive gait impairment, spasticity,progressive dementia, dysarthria, blind-ness, cerebellar ataxia, polyneuropathy

Leigh disease1 No consistent defect2 Respiratory disturbances, gaze palsy,ataxia, decreased muscle tone, retinitispigmentosa, seizures

1 Subacute necrotizing encephalomyelopathy. 2 Known defects include mitochondrial respiratory chain defects(complexes IV and V) and protein synthesis defects. The clinical features are heterogeneous. MRI scans showmultiple, bilaterally symmetric lesions with sparing of the mamillary bodies. CSF lactate concentration increased.Muscle biopsy reveals no ragged red fibers.

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Abetalipoproteinemia See pp. 280, 300 Gait impairment, ataxia, dysarthria, poly-neuropathy, night blindness

Progressive myoclonusepilepsy1 with Laforabodies2

Lysosomes Epileptic seizures, myoclonus, dementia, cerebel-lar ataxia, epileptic visual phenomena

Wilson disease (dystonictype)

Copper transport protein3 Dysfunction/cirrhosis of liver, behavioral changes,facio-oropharyngeal rigidity (dysarthria, dyspha-gia), parkinsonism, tremor, dystonia, Kayser–Fleischer ring (p. 309)

Neuronal ceroid lipofusci-nosis (Spielmeyer–Vogtsyndrome)

Storage of lipid pigment inlysosomes

Visual impairment, dysarthria, dementia, epilep-tic seizures, myoclonus, parkinsonism

Panthothenate kinase-associated degeneration8

Accumulation of iron pig-ment in substantia nigraand globus pallidus4

Gait impairment, dystonia, dysarthria, behavioralchanges, dementia, retinal depigmentation

Adrenoleukodystrophy5 Peroxisomes (p. 386) Behavioral changes/dementia, gait impairment,cortical blindness, spastic quadriparesis, deafness,primary adrenocortical insufficiency

Homocystinuria6 Cystathionine !-synthase7 Dementia/behavioral changes, osteoporosis,ectopia lentis

Fabry disease6 "-Galactosidase A( !glycosphingolipids)

Attacks of pain in digits and abdomen; diffuseangiokeratomas; cataract

Mitochondrial syndromes See p. 402 See p. 402

1Other forms (p. 68) include Unverricht–Lundborg syndrome, myoclonus epilepsy with ragged red fibers (MERFF,p. 402), late forms of other lysosome defects (e. g., sialidosis type I, GM2-gangliosidosis). 2 Cytoplasmic inclusion bo-dies containing glycoprotein mucopolysaccharides in the brain, muscles, skin, and liver (also called Lafora disease).3 Autosomal recessive trait, mutation at 13q14.3;

!

serum ceruloplasmin, !hepatic copper, free serum copper,and urinary copper levels,

!

rate of incorporation of 64Cu in ceruloplasmin, MRI signal changes (striatum, dentatenucleus, thalamus). 4MRI shows bilaterally symmetric hypointensity of globus pallidus with central zone of hyper-intensity (“tiger eye” sign). 5 Adrenomyeloneuropathy, p. 384. 6 Increased risk of stroke. 7Most common form.8 Formerly called Hallervorden-Spatz disease.


Metachromatic leuko-dystrophy

Arylsulfatase-A deficiency Behavioral changes, gait impairment, dementia

Krabbe disease See p. 387 Gait impairment, spastic quadriparesis, poly-neuropathy, optic nerve atrophy

Adrenoleukodystrophy Peroxisomes Adult form extremely rare

Neuronal ceroid lipofusci-nosis (Kufs disease)

Storage of lipid pigment inlysosomes

Type A: Epilepsy, myoclonus, dementia, ataxiaType B: Behavioral changes/dementia, facial dys-kinesia, movement disorders

GM1 gangliosidosis See p. 387 Progressive dysarthria and dystonia

GM2 gangliosidosis1 See p. 387 Chronic progression (p. 387)

Wilson disease (pseudo-sclerotic type)2

See above Postural/intention tremor (beginning in one arm),behavioral changes, dysarthria, dysphagia, mask-like facies, parkinsonism

Gaucher disease type 3 See p. 387 Supranuclear ophthalmoplegia, epileptic seizures,myoclonus, splenomegaly

Niemann–Pick disease(type C)

See p. 387 Cerebellar ataxia, intention tremor, dysarthria,supranuclear vertical gaze palsy

Mitochondrial syndromes See p. 402 See p. 402

1 Tay–Sachs disease. 2 Westphal–Strümpell disease.

! Metabolic Encephalopathies of Childhood and Adolescence (ages 3–18 years)

! Metabolic Encephalopathies of Adulthood

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Acquired Metabolic Encephalopathies

Hypoxic–ischemic encephalopathy. An acutelack of oxygen (Pao2 !40mmHg), severe hy-potension (!70mmHg systolic), or a combina-tion of the two causes loss of consciousnesswithin minutes. The most important causes ofhypoxic and ischemic states are an inadequatepumping function of the heart (as in myocardialinfarction, shock, and cardiac arrhythmia), suf-focation, carbon monoxide poisoning, respira-tory muscle paralysis (as in spinal trauma, Guil-lain–Barré syndrome, and myasthenia), and in-adequate ventilation (as in opiate intoxication).Permanent damage usually does not occur if thepartial pressure of oxygen and the blood pres-sure can be brought back to normal in 3–5minutes. Longer periods of hypoxia andischemia are rarely tolerated (except under con-ditions of hypothermia or barbiturate intoxica-tion); brain damage usually ensues, and may bepermanent. Persistent coma (p. 118) with absentbrain stem reflexes (pp. 26, 118) once the circu-lation is restored indicates a poor prognosis; theprobable outcome is then a persistent vegeta-tive state or death (p. 120). Patients who regainconsciousness may develop various postanoxicsyndromes, e. g., dementia, visual agnosia,parkinsonism with personality changes,choreoathetosis, cerebellar ataxia, intention oraction myoclonus (Lance–Adams syndrome),and Korsakoff syndrome. Delayed postanoxicsyndrome occurs 1–4 weeks after the initial re-covery from anoxia and is characterized by be-havioral changes (apathy, confusion, restless-ness) that may either regress or worsen, per-haps to coma. These changes may be accom-panied by gait impairment and parkinsonism.Hypercapnia ( !PaCO2) due to chronic hypoventi-lation (as in emphysema, fibrosing alveolitis, orcentral hypoventilation) causes headache, be-havioral disturbances, impairment of conscious-ness (p. 116 ff), asterixis (p. 68), fasciculations,and bilateral papilledema.Hypoglycemia. If the blood glucose concentra-tion acutely falls below 40mg/dl, behavioralchanges occur (restlessness, hunger, sweating,anxiety, confusion). Any further decrease leadsto unconsciousness (grand mal seizure, dilatedpupils, pale skin, shallow breathing, bradycar-dia, decreased muscle tone). Glucose must be

given intravenously to prevent severe braindamage. Subacute hypoglycemia producesslowed thinking, attention deficits, and hy-pothermia. Chronic hypoglycemia produces be-havioral changes and ataxia (p. 324); it is rarelyseen (e. g., in pancreatic islet cell tumors).Hyperglycemia (p. 324). Diabetic ketoacidosis ischaracterized by dehydration, headache,fatigue, abdominal pain, Kussmaul respiration(deep, rhythmic breathing at a normal or in-creased rate). Blood glucose " 350mg/dl (

!

pH,!

pCO2,

!

HCO3–). In hyperosmolar non-

ketotic hyperglycemia, the blood glucose con-centration is "600mg/dl and there is little or noketoacidosis. The persons at greatest risk areelderly patients being treated with corti-costeroids and/or hyperosmolar agents to re-duce edema around a brain tumor.Hepatic/portosystemic encephalopathy occursby an unknown pathogenetic mechanism inpatients with severe liver failure (hepatic en-cephalopathy) and/or intrahepatic or extrahe-patic venous shunts (portosystemic en-cephalopathy). Venous shunts can developspontaneously (e. g., hepatic cirrhosis) or becreated surgically (portocaval anastomosis,transjugular intrahepatic stent). Clinical features(see Table 50, p. 387): Behavioral changes, varia-ble neurological signs (increased or decreasedreflexes, Babinski reflex, rigidity, decreasedmuscle tone, asterixis, dysarthrophonia, tremor,hepatic coma), and EEG changes (generalizedsymmetric delta/triphasic waves). The diagnosisis based on the clinical findings, the exclusion ofother causes of encephalopathy (such as intox-ication, sepsis, meningoencephalitis, and elec-trolyte disorders), and an elevated arterialserum ammonia concentration.Repeated episodes of hepatic coma may lead tochronic encephalopathy (head tremor, asterixis,choreoathetosis, ataxia, behavioral changes);this can be prevented by timely liver transplan-tation.

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Hypoxic-ischemic encephalopathy(apallic syndrome; axial CT scan)

Hepatic encephalopathy

EEG changes in hypoglycemia

Normal EEG

Slow waves Coma Seizure Loss of brainfunction

Decrease in blood sugar level

Hepatic cirrhosis (ascites, gynecomastia, absence of chest and axillary hair)

Palmar erythema

Cutaneous and scleral jaundice

Asterixis

Somnolence, stupor

NormalEEG

Declining liver function

Coma Loss of brain function

Kayser-Fleischer ring(Wilson disease)

Brain atrophy

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Disorders of fluid and electrolyte balance. Theregulation of water balance (osmoregulation) isreflected in the serum sodium concentration,[Na+]. The hypothalamus, which containsosmoreceptors (p. 142), controls thirst and thesecretion of ADH; these in turn determine fluidintake and urine osmolality. Sodium salts ac-count for more than 95% of the plasma osmolal-ity (moles of osmotically active particles per kgof water). Hyperhydration causes a decrease inplasma osmolality (

!

[Na+]). The ensuing inhibi-tion of thirst and of ADH secretion leads to a re-duction of oral fluid intake and to the produc-tion of dilute urine (

!

urinary [Na+]), restoringthe normally hydrated state. Dehydration in-duces the opposite changes, again resulting inrestoration of the normally hydrated state.The regulation of sodium balance (volume regu-lation) maintains adequate tissue perfusion(p. 148). Volume receptors in the carotid sinusand atria of the heart are the afferent arm of thereflex pathway controlling renal sodium excre-tion, whose efferent arms are the sympatheticsystem, the renin–angiotensin–aldosterone sys-tem (RAAS), and natriuretic peptides. Hy-povolemia and hypervolemia usually involvecombined abnormalities of water and sodiumbalance.In neurological disorders (head trauma, menin-goencephalitis, brain tumor, subarachnoidhemorrhage, acute porphyria), the syndrome ofinappropriate ADH secretion (SIADH) is charac-terized by water retention (volume expansion),abnormally concentrated urine, and hy-ponatremia. The more rapidly hyponatremiadevelops, the more severe its clinical signs (e. g.,confusion, seizures, impairment of conscious-ness). SIADH is to be distinguished from centralsalt-wasting syndrome, which is characterizedby hypovolemia and dehydration.Too rapid correction of hyponatremia causesmost cases of central pontine myelinolysis (othercauses are serum hyperosmolality and mal-nutrition). In this syndrome (p. 315), a patientwith a major systemic illness (e. g., postopera-tive state, alcoholism) develops quadriplegia,pseudobulbar palsy, and locked-in syndrome(p. 120) over the course of a few days. A lesssevere form of central pontine myelinolysis ischaracterized by confusion, dysarthria, and gazepalsies.

Calcium/magnesium. Hypercalcemia causesnonspecific symptoms along with apathy, pro-gressive weakness, and impairment of con-sciousness (or even coma). Hypocalcemia ischaracterized by increased neuromuscular exci-tability (muscle spasms, laryngospasm, tetany,Chvostek’s and Trousseau’s signs), irritability,hallucinations, depression, and epilepticseizures. Hypomagnesemia has similar clinicalfeatures.Uremic encephalopathy arises in patients withrenal failure and is characterized by behavioralchanges (apathy, cognitive impairment, atten-tion deficit, confusion, hallucinations), head-ache, dysarthria, and hyperkinesia (myoclonus,choreoathetosis, tremor, asterixis). Severeuremia can produce coma. The differential diag-nosis of uremic encephalopathy includes cere-bral complications of the primary disease, suchas intracranial hemorrhage, drug intoxicationbecause of impaired catabolism, and hyperten-sive encephalopathy. A similar neurological syn-drome can arise during or after hemodialysis orperitoneal dialysis (dysequilibrium syndrome).Dialysis encephalopathy (dialysis dementia; nowrare) is probably due to aluminum poisoning asa complication of chronic hemodialysis. Itsmanifestations include dysarthria with stutter-ing and stammering, myoclonus, epilepticseizures, and behavioral changes (p. 122 ff).Endocrine encephalopathy is characterized byagitation with hallucinations and delirium,anxiety, apathy, depression or euphoria, irrita-bility, insomnia, impairment of memory andconcentration, psychomotor slowing, and im-pairment of consciousness. It may be produced(in varying degrees of severity) by Cushing dis-ease, high-dose corticosteroid therapy, Addisondisease, hyperthyroidism or hypothyroidism,and hyperparathyroidism or hypoparathyroid-ism.

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Water loss (dehydration) ( [Na+] (hypertonicdisturbances)

Decrease in thirst, ADH,urinary [Na+], hematocrit,and total protein; increasein blood pressure and central venous pressure;edema, dyspnea

Water balance (mOsm/kg water; 1 “pseudohyponatremia” in association withhyperglycemia, hyperlipidemia, and hyperproteinemia)

Causes 2

Diabetes insipidus, hypothalamic dysfunction, hyperhidrosis, dysphagia, Cushing syndrome, hyperaldosteronism

Symptome and signs

Syndromes

Coma, epileptic seizure,lethargy, confusion, irritability

Hypernatremia(hypertonic)

Normonatremia(isotonic)

Vomiting, diarrhea, burns, diuretics, Addison disease, SIADH, polydipsia, hyperglycemia, mannitol

Headache, nausea, vomiting,impairment of consciousness,confusion, epileptic seizure, coma

Hyponatremia(hypotonic)

Sodium balance (mmol/L;2 examples, some with combined deficits)

EuhydrationIsotonic [Na+] (isotonic disturbances)

Water retention (hyperhydration)[Na+] (hypotonic disturbances)1

155

150

145

140

135

130

125

120

160

305

300

295

290

285

280

275

Dialysis for uremia Hypothyroidism, goiter

Marked endocrine orbitopathy(in Graves disease)

Increase in thirst, ADH, urinary[Na+], hematocrit, and totalprotein; decrease in bloodpressure and central venouspressure; tachycardia

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Encephalopathy due to sepsis, multiple organfailure, or burns may arise within a few hours,manifesting itself as impaired concentration,disorientation, confusion, and psychomotor agi-tation in addition to the already severe systemicdisturbances. In severe cases, there may bedelirium, stupor or coma. Focal neurologicalsigns are absent; meningismus may be present,and CSF studies do not show signs of menin-goencephalitis. There are nonspecific EEGchanges (generalized delta and theta wave ac-tivity). The pathogenesis of these syndromes isunclear. Their prognosis is poor if the underlyingdisease does not respond rapidly to treatment.Paraneoplastic encephalopathy occurs as a com-plication of neoplasms outside the centralnervous system. It can only be diagnosed afterthe exclusion of local tumor invasion ormetastasis, complications of tumor treatment,or other complications of the primary disease.For paraneoplastic encephalopathy, see Table 51,p. 388; for paraneoplastic disorders affectingthe PNS, neuromuscular junction, and muscle,see p. 406.Wernicke–Korsakoff syndrome. Wernicke en-cephalopathy is characterized by gaze-evokednystagmus or dissociated nystagmus, ophthal-moplegia (abducens palsy, conjugate gaze palsyor, rarely, miosis), postural and gait ataxia, andimpairment of consciousness (p. 116; apathy, in-difference, somnolence). Korsakoff syndrome ischaracterized by confabulatory amnesia(p. 134), disorientation, and decreased cognitiveflexibility. Most patients have a combination ofthese two syndromes, which is then called Wer-nicke–Korsakoff syndrome. Polyneuropathy, au-tonomic dysfunction (orthostatic hypotension,tachycardia, exercise dyspnea), and anosmiamay also be present. These syndromes arecaused by a deficiency of thiamin (vitamin B1)due to alcoholism or malnutrition (malignanttumors, gastroenterologic disease, thiamin-freeparenteral nutrition). This, in turn, causes dys-function of thiamin-dependent enzymes (in-crease in transketolase, pyruvate decarboxylase,!-ketoglutarate dehydrogenase, and serum py-ruvate and lactate; decrease in transketolase ac-tivity in erythrocytes). MRI reveals lesions inparaventricular areas (thalamus, hypothalamus,mamillary bodies) and periaqueductal areas(mid brain, motor nucleus of X, vestibular nu-

clei, superior cerebellar vermis). Treatment: Im-mediate intravenous infusion of thiamin (50–100mg) in glucose solution. Note: glucose infu-sion without thiamin in a patient with latent orunrecognized thiamin deficiency may provokeor exacerbate Wernicke encephalopathy.

Encephalopathies Due to SubstanceAbuse

Alcohol. Acute alcohol intoxication (drunken-ness, inebriation) may be mild (blood alcohol0.1–1.5‰ ! dysarthria, incoordination, disinhi-bition, increased self-confidence, uncritical self-assessment), moderate (blood alcohol 1.5–2.5‰! ataxia, nystagmus, explosive reactions, ag-gressiveness, euphoria, suggestibility), or severe(blood alcohol !2.5‰ ! loss of judgment,severe ataxia, impairment of consciousness, au-tonomic symptoms such as hypothermia, hy-potension, or respiratory arrest). Concomitantintoxication with other substances (sedatives,hypnotics, illicit drugs) is not uncommon. Thepossibility of a traumatic brain injury (subduralor epidural hematoma, intracerebral hemor-rhage) must also be considered. Pathological in-toxication after the intake of relatively smallquantities of alcohol is a rare disorder character-ized by intense outbursts of emotion and de-structive behavior, followed by deep sleep. Thepatient has no memory of these events.Alcohol withdrawal syndrome. Reduction of al-cohol intake or total abstinence from alcoholafter chronic alcohol abuse causes acute auton-omic disturbances (sweating, tachycardia, in-somnia, nausea, vomiting), tremor, impairmentof concentration, and behavioral changes. Thisinitial stage of predelirium is followed by a stageof delirium (delirium tremens), in which all ofthe disturbances listed worsen and are accom-panied by visual hallucinations. Epilepticseizures may occur. The course of delirium tre-mens can be complicated by systemic diseasesthat are themselves complications of alcoholism(hepatic and pancreatic disease, pneumonia,sepsis, electrolyte imbalances). Auditory alco-holic hallucinosis without autonomic symptomsor disorientation is an unusual form of alcoholwithdrawal syndrome.

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Microemboli in a patient with bacteremia (Staphylococcus aureus)

Chronic alcoholism Alcohol withdrawal syndromeAlcoholism

Wernicke encephalopathy (ophthalmoplegia)Sepsis

Acute alcohol intoxication (uncritical self-assessment, disinhibition)

Decline of general healthLoss of appetite, weight lossGastrointestinal disturbancesBehavioral changesWernicke-Korsakoff syndromeBrain atrophyHead traumaPolyneuropathyMyopathy

Epileptic seizuresPredelirium/deliriumAlcoholic hallucinosis

Additional intoxication with

hypnotics orother substances

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Late complications of alcoholism. Various dis-orders are associated with chronic alcoholabuse, though alcohol abuse may not be theironly causative factor. Brain atrophy is often seenin CT or MRI scans and seems to be reversible byabstinence. In alcoholic dementia, brain atrophyis accompanied by cognitive impairment; mostcases are probably due to Wernicke–Korsakoffsyndrome (p. 312). Cerebellar atrophy predomi-nantly affects the anterosuperior vermis (! pos-tural and gait ataxia). Central pontine myelinoly-

sis (p. 310) and tobacco–alcohol amblyopia (bi-lateral impairment of visual acuity and visualdefects, probably due to a combined deficiencyof vitamins B1, B6, and B12) are other late compli-cations of alcoholism. Fetal alcohol syndrome(congenital malformations, hyperactivity, atten-tion deficit, impaired fine motor control) is seenin the children of alcoholic mothers.Substance abuse. Neurological signs of sub-stance abuse are described in the table below.

Iatrogenic Encephalopathies

Neurological side effects of diagnostic studiesand therapies must be kept in mind in the clini-cal decision-making process (risk/benefit analy-

sis) and must be considered in the differentialdiagnosis of encephalopathy. Such side effectsare easily mistaken for neurological dysfunctionof another etiology. Examples are listed in Table52 (p. 389).

Substance Pupils Motor Dysfunction Reflexes3 Behavior/Consciousness

Cocaine1,2 Dilated Chorea, tremor, dys-tonia, myoclonus, brux-ism

! Anxiety, agitation, insomnia, psy-chosis/hypervigilance !lethargy, coma

Am-phetamines1,2

Dilated Chorea, bruxism,muscle spasms, tremor

! Euphoria, hyperactivity, dys-phoria, hallucinations, confusion/hypervigilance

MDMA1,2,4 Dilated Tremor, rigidity ! Anxiety, hyperactivity, psychosis/coma5

Opiates1,6 Pinpoint Hypokinesia, parkin-sonism

!

Euphoria/somnolence ! coma,respiratory depression

LSD7 Dilated, slug-gish

Tremor ! Euphoria, panic, depression, hal-lucinations, illusions

Phencyclidine(PCP)

Miotic; nystag-mus

Ataxia, tremor,increased muscle tone

! Euphoria, dysphoria, psychosis,aggressiveness, hallucinations/coma (rare)

1 Epileptic seizures may occur. 2 Cerebral infarction or hemorrhage may occur. 3

!

: weak; !: brisk or increased.4 Methylenedioxymethamphetamine = “ecstasy.” 5 Causes: dehydration, hyponatremia, cerebral edema, car-diovascular complications, hyperthermia, rhabdomyolysis. 6 Myelopathy, polyneuropathy, Guillain–Barré syn-drome, and rhabdomyolysis may occur in chronic heroin users. 7 D-lysergic acid diethylamide.

Encephalopathies

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ervo

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315

Inhalation of industrial or household chemicals(“sniffing”)

Signal attenuation(pons)

Central pontine myelinolysis(sagittal/axial T1-weighted MRI images)

Iatrogenic encephalopathy

Drugs (behavioral changes)

Encephalopathies caused by industrial toxins

Ethylene oxide (gas sterilization)Lead (children)Industrial wasteOrganic solvents (hydrocarbons, ketones,esters, alcohols)Organic tin compounds (wood care products,silicone rubber, thermal insulators)PesticidesMercuryThallium (rat poison)

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Neuropathy Syndromes

Disturbances of the peripheral nervous systemmay be subdivided into those affecting neuronalcell bodies (neuronopathy) and those affectingperipheral nerve processes (peripheral neu-ropathy). Neuronopathies include anterior horncell syndromes (motor neuron lesions; p. 50)and sensory neuron syndromes (sensory neu-ronopathy, ganglionopathy; pp. 2, 107, 390).Motor neuron diseases are described on p. 304.Peripheral neuropathy is characterized by dam-age to myelin sheaths (myelinopathy) and/oraxons (axonopathy). Neuropathies may affect asingle nerve (mononeuropathy), multiple iso-lated nerves (mononeuropathy multiplex), allperipheral nerves generally (polyneuropathy),or all peripheral nerves generally with accen-tuation of one or a few (focal polyneuropathy).Polyneuropathy may be accompanied by auton-omic dysfunction (p. 140). The terms poly-neuropathy (PNP) and peripheral neuropathyare often used synonymously. Radiculopathies(nerve root lesions) are classified as either mon-oradiculopathies or polyradiculopathies, de-pending on whether a single or multiple rootsare involved.


Peripheral neuropathy causes sensory, motor,and/or autonomic dysfunction. Its etiological di-agnosis is based on the pattern and timing ofclinical manifestations (Table 53, p. 390).Sensory dysfunction (p. 106) is often the firstsign of neuropathy. Sensory deficits have dis-tinctive patterns of distribution: they may bepredominantly proximal or distal, symmetrical(stocking/glove distribution) or asymmetrical(multiple mononeuropathy), or restricted to in-dividual nerves (cranial nerves, single nerves ofthe trunk or limbs; p. 32 f). Disordered sensoryprocessing (p. 108 f) can produce hyperalgesia(more pain than normal upon noxious stimula-tion), hyperesthesia (increased tactile sensationwith lowering of threshold), paresthesia (spon-taneous or provoked abnormal sensation), dys-esthesia (spontaneous or provoked, abnormal,painful sensation), or allodynia (pain resultingfrom nonnoxious stimuli). Damage to rapidlyconducting, thickly myelinated A-! fibers causesparesthesiae such as tingling, prickling (“pins

and needles”), formication, and sensations oftension, pressure, and swelling. Damage toslowly conducting, thinly myelinated A-" and Cfibers (small fiber neuropathy) causes hypalgesiaor analgesia with thermal hypesthesia or an-esthesia, abnormal thermal sensations (cold,heat), and pain (burning, cutting, or dull, pullingpain).Motor dysfunction (p. 50). Weakness usually ap-pears first in distal muscles. In very slowly pro-gressive neuropathies, muscles may becomeatrophic before they become weak, but weak-ness is usually the initial symptom, accom-panied by hyporeflexia or areflexia. The cranialnerves can be affected. Hyperactivity in motorA-# fibers produces muscle spasms, fascicula-tions, and/or myokymia.Autonomic dysfunction (p. 146 f) can bemanifest as vasomotor disturbances (syncope),cardiac arrhythmias (tachycardia, bradycardia,fixed heart rate), urinary and gastrointestinaldysfunction (urinary retention, diarrhea, consti-pation, gastroparesis), sexual dysfunction (im-potence, retrograde ejaculation), hyperhidrosisor hypohidrosis, pupillary dysfunction, andtrophic lesions (skin ulcers, bone and jointchanges).

! Etiology (Table 54, p. 390)

Polyneuropathies can be hereditary or acquired(see Table 54).

! Diagnosis (Table 55, p. 391)

The diagnosis of a neuropathy is based on thecharacteristic clinical findings and patient his-tory. Additional diagnostic studies not indicatedon the basis of the patient history and clinicalfindings may produce not only unjustified costsbut also confounding data, leading occasionallyto misdiagnosis. Studies to be performed as in-dicated include neurophysiological tests (nerveconduction studies, electromyography), labora-tory tests (blood, CSF), tissue biopsy (nerve,skin, muscle), and genetic tests.

Peripheral Neuropathies

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NeuronopathyRadiculopathyAxonopathyMyelinopathyDisorder of neuromuscularconductionMyopathy

Peripheral nerve lesions

Distribution of sensory deficit (examples)

Hereditary neuropathies Acquired neuropathies

Cutaneous receptors

Afferent myelinatednerve

Spinal/peripheral nerve

Unmyelinated (autonomic) nerve

Autonomic ganglion

Motor end plate

Spinal ganglion

Efferent myelinated nerve

Motor neuron

Spinal cord

Distal symmetrical Asymmetrical Proximal symmetrical

Mono-neurop-athy

Multiplemononeurop-

athies

Endogenous disorders

Exogenous noxae

Mees lines (in patient with nephrot-

ic syndrome)


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Radicular Lesions


Patients usually complain mainly of positivesensory symptoms (tingling, burning, intensepain), which, like the accompanying sensorydeficit (mainly hypalgesia, see p. 104 f), are in adermatomal distribution (p. 32 ff). Weakness, ifany, is found mainly in muscles that are largelyor entirely innervated by a single nerve root(pp. 32, 50); loss of the segmental deep tendonreflex (p. 40) is, however, a typical early finding.Monoradiculopathy does not cause any evidentautonomic dysfunction in the limbs. Lumbarmonoradiculopathy is frequently caused bylumbar disk herniation with secondary rootcompression; typical findings in such cases in-clude exacerbation of radicular pain by cough-ing, straining at stool, sneezing, or vibration (!the patient adopts an antalgic posture), as wellas Lasègue’s sign (radicular pain on passive rais-ing of the leg with extended knee) and Bragard’ssign (radicular pain on dorsiflexion of the footwith the leg raised and extended). Bladder,bowel, and sexual dysfunctionmay be caused bya lesion affecting multiple roots of the caudaequina (p. 48), or by processes affecting the spi-nal cord (pp. 48, 282) or sacral plexus (seebelow).Pseudoradicular syndromes (including so-calledmyofascial syndrome, tendomyalgia, myotendi-nosis) are characterized by limb pain, localizedmuscle tenderness, and muscle guarding anddisuse, without radicular findings.

! Causes

See Table 56, p. 392, and p. 320.

Plexopathy (p. 321)

For clinical purposes the brachial plexus (p. 34)located behind the clavicle may be divided intosupraclavicular and infraclavicular regions. Thesupraclavicular plexus consists of the primary(ventral and dorsal) roots, mixed spinal nerves,five anterior primary rami, and three trunks; theinfraclavicular plexus is composed of the threecords and the terminal nerves. Lesions affectingthe supraclavicular plexus can either be pregan-glionic (intradural, inside the spinal canal) or in-fraganglionic (extradural, extraforaminal, out-


side the spinal canal). Supraclavicular plex-opathies are more common than infraclavicularones.


Brachial plexus. Lesions affecting the entirebrachial plexus cause anesthesia and flaccid par-alysis of the entire upper limb, with muscleatrophy. Lesions of the upper brachial plexus(C5–C6) cause weakness of shoulder abductionand external rotation, elbow flexion, and supi-nation, with preservation of hand movement(Erb palsy). The limb hangs straight down withthe hand pronated. A sensory deficit may befound on the lateral aspect of the arm and fore-arm. Lesions of the lower brachial plexus (C8–T1)mainly cause weakness of the hand muscles(Klumpke–Dejerine palsy); atrophy of the in-trinsic muscles produces a claw hand deformity.A sensory deficit is found on the ulnar aspect ofthe forearm and in the hand. Concomitant in-volvement of the cervical sympathetic pathwayproduces Horner syndrome. Erb palsy is morelikely to recover spontaneously than Klumpke–Dejerine palsy.Lumbosacral plexus. Lesions of the lumbarplexus (L1–L4) cause weakness of hip flexionand knee extension (as in a femoral nerve le-sion) as well as thigh adduction and external ro-tation. A sensory deficit is found in the affecteddermatomes (p. 36). Lesions of the sacral plexus(L5–S3) cause weakness of the gluteal muscles,hamstrings, and plantar and dorsiflexors of thefoot and toes. A sensory deficit is found on thedorsal aspect of the thigh, calf, and foot. Lesionsof the lumbar sympathetic trunk cause leg painand an abnormally warm foot with diminishedsweating on the sole.

! Causes

See Table 57, p. 393.

Mononeuropathies (p. 322 f)

Lesions affecting a single nerve tend to occur atcertain favored sites and are usually of mechani-cal origin (compression, hyperextension, trans-ection) (Table 58, p. 394).

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Segmental distribution (radicular n.)

Lumbar intervertebral disk herniation (axial CT)

Cauda equina syndrome (TSR) Radicular syndromes

Dorsal branch

Intercostal n.

Sympathetictrunk

Anterior cutaneous branch

Lateral herniation Mediolateral herniation

Medial herniation Lateral herniation(extraforaminal)

C5 (BR)C6 (BR) C7 (TR)

L3 (QR) L4 (QR) L5 (TPR) S1 (TSR)

C8 (Trömner reflex)

Deltoid m.

Biceps brachii and bra-chioradialis mm.

Dermatome

Dermatome

Dermatome

Dermatome

Dermatome

Dermatome

Pectoralis major m.

Triceps brachii m.

Pronatorteres m.

Hypothenar

Quadri-cepsfemoris m.

Extensorhallucis longus m.

Triceps surae m.,peronei

Pain, paresthesiae

Bladder and boweldysfunction, impotence

BRTRQRTPR

TSR

====

=

Biceps reflexTriceps reflexQuadriceps reflexTibialis posteriorreflexTriceps suraereflex


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Articularfacet

Transverse process

Vertebral body

Root of pedicle Spondylolysis

Spondyl-olisthesis

Vertebral compres-sion fracture

Carpal tunnel syndrome

Spondylolysis (oblique view lumbar spine)

Epicondylitis, pronatorteres syndrome

Tendinopathy,rotator cuff tear,frozen shoulder

Thoracic outletsyndrome (cervical rib,fibrous band) Pancoast

tumor

Vertebraldegenerativechanges

Schwan-noma/neuro-

fibroma

Dumbbell schwannoma, widened foramen

Sagittal MRI scan(thoracic spine)

Intradural extramedul-lary tumor

Metastases

LungBreast

ProstateKidney

Thyroid gland

Extraduraltumor

Dissecting aortic aneurysm

Paraspinal tumor(lymphoma)

Spondylitis, abscess

Axial CT scan (thoracic spine)

Leptomeningeal metastases(lumbar myelography)

Multiple filling defects

Axial MRI scan(thoracic spine)


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Brachial plexus neuropathies

Lumbosacral plexus lesions

Upper brachial plexus paresis

Lower brachial plexus paresis

C5 der-matome

Dermatome C6

Dermatome T1

Neuralgic amyotrophy

Radiation-induced lesion

*P/A of shoulderabductors andexternal rotators, arm flexors

Weaknessand atrophymainly in leftshouldergirdle

Horner syndrome(left)

Dermatomes C7, C8; clawhand

*P/A: flexor digitorum superficialis m., intrinsichand muscles

Palm turned backward

Lymphedema, paresis, pain, sensory and trophic disturbances

Mastectomy

Spinal root

Trunks of brachial plexus (supraclavicular)

Cords of brachial plexus (infraclavicular)

Subclavian a., axillary a.

Lumbar plexus lesion (left)

Anhidrosis (lumbarsympathetic lesion,ninhydrin test)

*P/A of hip flexors,knee extensors,thigh adductorsand external rotators

Sacral plexuslesion

*P/A of hip abductors/extensors, knee flexors, calf and foot muscles

Trendelenburgsign

Lumbar plexus

Sacral plexusCoccygeal plexus

* P/A: Paresis/atrophy


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Mononeuropathies in shoulder/arm region

Axillary nerve

Long thoracic nerve

Radial nerve

Median nerve Ulnar nerve

Sensory distribution(autonomouszone darker) Paresis/atro-

phy of deltoid m.

Winged scapula (serratus anterior m. paresis)

Pronators,flexors offorearm

Sensory distribution(autonomous zone

darker)

Sensory distribution(autonomous zonedarker)

Sensory distribution

(autonomouszone darker)

Extensors of armand forearm Hand drop

Supinatorsyndrome

Carpal tunnel syndrome in right hand

Thenar atrophy

Monkey hand

Wrist flexors, finger flexors IV/V, finger adductors and abductors

Clawhand


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CompressionMononeuropathies in lumbosacral region

N. tibialis

Sensory distribu-tion (autonomouszone darker)

Compression(head of fibula)

Sciatic n.

Knee flexors(ischiocruralmuscles)

Foot/toeextensors

Sensory distribution(autonomous zone

darker)

Adductormuscles

Hip extensors/abductors(Trendelenburg sign)

Weakness ofdorsiflexion

Hip flexors, kneeextensors

Lateral cutaneousnerve of thigh

Sensory distribution (autonomous zone darker)

Peroneal nerve

Femoral nerve

Obturator nerve

Paresis of knee extension(proximal femoral lesion)

Superior and inferior gluteal nn.

Sensory distribu-tion (autono-mous zone darker)

Flexors of footand toe

Tibial nerve


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Diabetic Neuropathies

! Diabetes Mellitus

Diabetes mellitus (DM) is a syndrome of im-paired carbohydrate metabolism due to insulindeficiency. In Type 1 DM (about 10% of cases),the insulin-secreting pancreatic cells are de-stroyed by an autoimmune process; Type 2 DM(the remaining 90%) is a nonautoimmune dis-order typified by insulin resistance and abnor-mally low insulin secretion, usually in conjunc-tion with obesity. Sequelae of DM include arteri-osclerosis, microangiopathy, retinopathy, ne-phropathy, and peripheral neuropathy. The fast-ing blood glucose concentration is elevated(!126mg/dl), or else the blood glucose concen-tration is elevated after a standardized oral glu-cose load. An integrated index of elevated bloodglucose concentration over time can be obtainedby measuring the concentration of glycosylatedhemoglobins (HBA1, HBA1C ! 4–6 weeks) andproteins (fructosamine ! 8–14 days).

! Syndromes

Pathogenesis. Distal symmetric polyneuro-pathy, a form of diabetic polyneuropathy (DPN),is due to generalized peripheral nerve damage.It is a complication of continuous hypergly-cemia and the related metabolic changes (!polyols, phospholipids, fatty acids, oxidativeradicals, lack of nerve growth factors). Normali-zation of the blood glucose concentration bymedical treatment can prevent DPN (at leastpartially) but, long-standing severe DPN, onceestablished, cannot be completely reversed byeuglycemia. Pathological examination revealsextensive axon loss, which is thought to be dueeither to the chronic hyperglycemia itself or tothe resulting (perhaps inflammatory) micro-vascular changes. Repeated episodes of hypogly-cemia (p. 308) can also cause neuropathy.Symptoms and signs. DPN produces both nega-tive neurological signs (sensory loss, sensoryataxia, thermanesthesia, hypalgesia, autonomicdysfunction, paresis) and positive neurologicalsigns (paresthesia, dysesthesia, pain). Themanifestations of DPN are classified in Table 59(p. 395). They may be present in varying combi-nations.Diagnosis. DPN is diagnosed in diabetic patientswith distal, symmetric, sensorimotor poly-

neuropathy of the lower limbs, after the exclu-sion of other causes (e. g., diabetic lumbosacralor radicular lesions (! Table 59), other neu-ropathies or primary illnesses); it is usually ac-companied by diabetic retinopathy or ne-phropathy of comparable severity. Other neu-ropathic syndromes found in diabetes (somesymmetric, some asymmetric) require the use ofspecialized tests for their differential diagnosis(p. 391).Treatment. The main objective of treatment isnormoglycemia. Pain (p. 108) due to diabeticneuropathy usually responds to tricyclic antide-pressants (amitryptiline, clomipramine), anti-convulsants (carbamazepine, gabapentin,lamotrigine), antiarrhythmics (lidocaine, mex-iletine), capsaicin (administered locally as a0.075% cream), or transdermal clonidine. Auton-omic dysfunction of various types is treatedsymptomatically. Other factors that may worsenthe neuropathy should be avoided (alcohol, vi-tamin deficiency, medication side effects). Thecomplications of DPN (diabetic foot ulcer, infec-tion, weakness, falls) may require specific treat-ment.

Uremic Neuropathy

Uremic neuropathy is a distal, symmetrical, sen-sorimotor, axonal peripheral neuropathy thatmainly affects the legs. Paresthesiae and a “rest-less legs” sensation are typical. Uremic neu-ropathy may complicate renal failure of any eti-ology and is treated by therapy of the underly-ing disease.


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Diabetes mellitus

Diabetic polyneuropathy

Proximal diabetic neuropathy (left)

External oculomotor nerve palsy (right)

Abdominal wall paresis (right) Quadriceps paresis (left)

Amyotrophy,pain

Distal symmetricalsensorimotor neuropathy

Generalizedautonomicdysfunction

Paresthesia(tingling)

Dysesthesia (stabbing/burning pain)

Neuropathic ulcer


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Inflammatory Polyneuropathies

! Guillain–Barré Syndrome

The term Guillain–Barré syndrome (GBS) coversa group of monophasic, acute, inflammatorypolyneuropathies of autoimmune pathogenesis(Table 60, p. 395). Their onset is 1–4 weeks aftera respiratory or gastrointestinal infection intwo-thirds of all cases. The causative organismoften cannot be identified. GBS is known to beassociated with certain viruses (cytome-galovirus, Epstein–Barr virus, varicella-zostervirus, HIV ! lymphocytic pleocytosis in CSF),bacteria (Campylobacter jejuni, Mycoplasmapneumoniae), and vaccines (rabies).Pathogenesis. The organisms causing the pre-ceding infection are thought to induce T-cell au-toreactivity; after a latency period of days toweeks, antigen-specific T and B cells are acti-vated. The target antigen is still unknown. IgGantibodies of various types, produced by the Bcells, can be detected in serum in varying con-centrations. These antibodies may block im-pulse conduction (! acute paralysis) or activatecomplement and macrophages (! myelin le-sions). TH1 lymphocytes release proinflam-matory cytokines (IFN-!, TNF-"; p. 220) thatstimulate macrophages (! peripheral nerve le-sions). Once the inflammatory response hassubsided, regenerative processes (axonalgrowth and remyelination) begin.Symptoms and signs. GBS classically presentswith an acute ascending and often rapidly pro-gressive symmetrical weakness, areflexia, andrelatively mild sensory abnormalities (paresthe-siae). Pain is not uncommon, especially at onset;it is often in the back, of shocklike, tingling,aching, or myalgic quality, and may be misat-tributed to a herniated disk, “the flu,” or “rheu-matism.” Cranial nerve deficits (VII, often bi-lateral; III, IV, VI, IX, X) are almost always pre-sent. So, too, are respiratory weakness and au-tonomic disturbances (bradycardia or tachycar-dia, hypotension or hypertension, abnormalitiesof fluid and electrolyte balance), all of whichfrequently cause complications. The suddenonset of disease with severe, ascending weak-ness is often a terrifying experience for patientsand their families.The clinical features and course of GBS arehighly variable. Predictors of an unfavorable

outcome include age over 60 years, progressionto quadriplegia within one week, the need formechanical ventilation, and a reduction of theamplitude of motor evoked potentials to lessthan 20% of normal. The manifestations of lesscommon forms of GBS are listed on p. 395.Diagnosis (Table 61, p. 396). GBS is diagnosedfrom its typical clinical features. Neurophysio-logical findings are used to support the diagno-sis, rule out alternative diagnoses, and docu-ment the type and extent of peripheral nervedamage. CSF studies are mainly useful for theexclusion of alternative diagnoses. It may be dif-ficult to determine which specific type of GBS ispresent.Treatment. Complications of GBS aremainly dueto autonomic dysfunction, respiratory insuffi-ciency, and immobility (! deep venous throm-bosis, pulmonary embolism, compression neu-ropathies, pressure sores, contractures).Patients should thus be closely monitored in anintensive care unit, especially in the acutephase. They and their relatives should be offeredclear and ample information about the disease,as well as psychological counseling. GBS may betreated by intravenous gammaglobulin therapyor plasmapheresis.


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Bilateral peripheral complete facial palsy, dysphagia, beginning respiratory insufficiency

Respiratory insufficiency,dysphagia, facial palsy in

regression

Intended gaze direction

Nerve biopsy (sural n.,semithin cross section)

Initially dispersedand prolonged

Normalization (week 2)

Normal findings(week 8)

External ophthalmoplegia

Distal symmetricalmuscle atrophy

Demyelination Hypomyelinated fibers

Proliferation of connective tissue

Incomplete bilateral peripheral facial palsy

Miller Fisher syndrome(left: sensory action potentials ofsural nerve)

Guillain-Barré syndrome

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)


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! Chronic Inflammatory DemyelinatingPolyradiculoneuropathy (CIDP)

CIDP differs from GBS in that it is of subacuteonset (slow progression over 2 months or more)and responds readily to immune suppression(corticosteroids, azathioprine, cyclophos-phamide; dose titrated to response) in combina-tion with immunoglobulins or plasmapheresis.Its course is usually progressive or relapsingrather than monophasic. It is less commonlypreceded by systemic infection than GBS butotherwise has very similar clinical features. Painmay accompany or precede an exacerbation ofthe illness. Neurophysiological studies revealevidence of demyelination. The CSF protein con-centration is markedly elevated, and sural nervebiopsy reveals chronic demyelination and remy-elination with rare inflammatory infiltrates.

! Multifocal Motor Neuropathy (MMN)

MMN is characterized by progressive asym-metrical weakness, which usually begins in theupper limbs. The underlying lesion is usually inisolated peripheral nerves (most often radial,median, ulnar, and common peroneal). Musclespasms and fasciculations are common. Sensoryloss, if any, is mild, andmuscle atrophy ismild orabsent even if weakness is marked. The reflexesmay be absent, diminished, or (rarely) brisk.Nerve conduction studies reveal a motor con-duction block. There may be an elevated serumconcentration of IgM antibodies to GM1. Re-peated intravenous administration of immuno-globulin or cyclophosphamide is an effectivetreatment. The differential diagnosis includesamyotrophic lateral sclerosis, distal spinalmuscular atrophy (p. 385), and CIDP.

! Paraproteinemic Polyneuropathies

These disorders are most commonly due to non-malignant monoclonal gammopathies, usuallyof IgM type, rarely IgG or IgA, though there isprogression to plasmocytoma or Waldenströmmacroglobulinemia in some 20% of cases. Themain features ofmonoclonal gammopathy of un-determined significance (MGUS) include: k-type,M protein !25 g/l, Bence Jones proteinuria(rare), no skeletal or organ involvement, normalblood smear. The clinical manifestations are ofslowly progressive, distal, symmetrical, sen-

sorimotor polyneuropathy, which is sometimespainful. Serum antibodies to myelin-associatedglycoprotein (MAG) may be present, and the CSFprotein concentration may be elevated. Thetreatment is by immune suppression, but theideal type of agent, timing, and dosage have notyet been determined. POEMS syndrome (PNP +organomegaly + endocrinopathy + M protein +skin changes; Crow–Fukase syndrome) is a raresystemic manifestation of osteosclerotic my-eloma.

! Neuropathy of Infectious Origin

Leprosy, HIV infection, herpes zoster infection,borreliosis, tetanus, botulism, diphtheria, orother infectious diseases may cause neuropathy.Leprosy is the most common cause of peripheralneuropathy around the world. Its pathogenic or-ganism (Mycobacterium leprae) attacks periph-eral nerves in the cooler parts of the body, suchas the skin, nose, anterior portion of the eye, andtestes. There is segmental thickening of periph-eral nerves (elbow, wrist, ankle). Areas of skinbecome depigmented and anhidrotic, with dis-sociated sensory loss. There are different typesof leprosy, each of which is associated with acharacteristic type of neuropathy.

! Neuralgic Amyotrophy

This disorder involves acute, usually nocturnalattacks of severe pain in the shoulder for severaldays or weeks, followed by weakness andmuscle atrophy. Sensory deficits are rare (axil-lary nerve distribution). The symptoms usuallyresolve spontaneously.

! Vasculitic Neuropathy

Peripheral neuropathy due to connective tissuedisease is usually multifocal, rarely symmetric(p. 180). Early treatment by immune suppres-sion improves the outcome. Various connectivetissue diseases can produce an isolated sensorytrigeminal neuropathy.


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Multifocal motor neuropathy

Neuralgic amyotrophy

Vasculitic neuropathyLeprosy

Paraproteinemic polyneuropathy(MGUS; distal symmetrical neuropathy)

Predominantly distal paresis,muscular atrophy and cramps

distal sym-metrical PNP

IgM deposits (immunohisto-chemistry, sural n., cross section)

Increased distance between myelin lamellae (electronmicroscopy, nerve cross section)

Pain, muscle atrophy

Painfulmononeuritis

Vasculitic ulcer, neuropathy

Neurotrophic ulcer (malum perforans)

Mycobacterium leprae

Cutaneous nerve branches

Dimorphic leprosy

Defective

Lepromatous leprosyTuberculoid leprosy

Intact

Pathogen entersSchwann cells

Cellulardefense?


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Peripheral Nerve Injuries

Peripheral nerves can be temporarily or per-manently damaged by pressure, transection,crushes, blows, or traction.

! Pathogenesis

Local nerve compression displaces the axoplasmlaterally from the site of compression. Thiscauses invagination and subsequent demyeli-nation at the nodes of Ranvier, so that saltatoryimpulse conduction is blocked. Compressionpreferentially impairs conduction in large-cali-ber fibers. Crushing of a nerve destroys the axo-plasm but not the basal lamina. Schwann cellsand axon processes regenerate in the damaged

region and distally along the intact envelopingstructures until they reach the effector muscle.Nerve transection is followed by axonal andSchwann cell proliferation, which may lead tothe formation of a neuroma at the proximalnerve stump. Suturing the proximal and distalstumps together enables the regeneratingfibers to enter the distal enveloping structuresand regenerate further, but the function of thenerve is usually not fully restored to its originalstate.

! Treatment

Type of Lesion Selected Causes/Features Classification1/Prognosis

Local conduction block, with nor-mal conduction distal to the le-sion

Local demyelination due to com-pressionConduction blockade withoutEMG evidence of degeneration

NeurapraxiaResolution within a few weeks inmost cases

Damage to axon and myelinsheath with preservation of en-veloping structures (Schwann cellbasal membrane and en-doneurium); wallerian degenera-tion distal to the lesion

Crushing of nerveRegeneration occurs from proxi-mal to distal along the envelopingstructures, taking weeks, months,or years, depending on whetherthe damage is partial or com-plete2

AxonotmesisEMG evidence of reinnervation isseen first in muscle groups proxi-mal to the lesion, and later in dis-tal groups

Damage to axon, myelin sheath,and enveloping structures; wal-lerian degeneration distal to thelesion

Excessive traction, open incisionwoundAxon regeneration greatly limited;anomalous regeneration and neu-roma development are common

NeurotmesisFull recovery is unusual

1 Seddon (1943). 2 Axons regenerate at 1–2mm/day proximally, more slowly distally.

Type of Lesion Treatment

Nerve root avulsion Surgery (e. g., tenodesis, tendon-muscle transfer), treatment of painBrachial plexus injury " Open ! primary nerve suture

" Closed ! surgical exploration if there is no reinnervation in 3–5 months; iffunction fails to improve, other surgical procedures for restoration of functioncan be considered

Neurapraxia oraxonotmesis(nontransecting injury)

" Diagnosed from clinical findings, EMG, and nerve conduction studies at pre-sentation and 3 weeks later; treated with physical therapy

" Clinical and neurophysiological re-assessment every 2–5 months" Clinical and neurophysiological improvement ! further physical therapy" No clinical or neurophysiological improvement ! corrective surgery 2–3

weeks after local injury (e. g., gunshot wound) or 4–5 months after extensiveinjury (e. g., traction injury)

Neurotmesis(nerve transection)

" Primary suture of nerve cut by knife, glass, etc." Secondary suture 2–4 weeks after crushing injury and/or destruction of

epineurium


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Spinal cord with peripheral nerve

Neurapraxia (nerve compression)

Axonotmesis (crushing injury) Neurotmesis (nerve transection)

Epineurium

Peripheralnerve

Perineurium

Nerve fibers

Sympathetic trunk ganglion

Ventral root

Dorsal root

Pia materArach-noid

Dura mater

Dura mater

Subarachnoidspace

Local compression

Normal nerve, muscle

Displacementof myelin

Demyelination(segmental)

Remyeli-nation

Wallerian degeneration

Proliferation of Schwann cells

Tactile body

Destroyedimpulse-conducting structures

Sensory fibers Neuroma

Muscular atrophyMuscular atrophy

Nerve fiber group


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Nonmetabolic Hereditary Neuropathies(Tables 62 and 63, p. 396 f)

For neuropathies associated with systemic dis-ease, see p. 280.

! Hereditary Motor–Sensory Neuropathy(HMSN)

These are the most common among the heredi-tary neuropathies, all of which are rare.HMSN type I is characterized by high pedalarches (pes cavus), hammer toes (digitus mal-leus), distal weakness and atrophy, loss of vibra-tion sense with preservation of position sense,areflexia, and unsteady gait (p. 60; frequentstumbling, steppage gait). Some peripheralnerves are palpably thickened in half of thecases (e. g., the greater auricular, ulnar, or com-mon peroneal nerve), and tremor is present inone-third. The clinical picture is highly variable.The type I phenotype is produced by threedifferent genotypes: CMT1 (autosomal domi-nant), CMT4 (autosomal recessive), and CMTX(X-linked).HMSN type II. CMT2A and B resemble HMSNtype I but begin later, with only rare areflexiaand no palpable thickening of peripheral nerves.CMT2C is characterized by vocal cord paralysis(hoarseness, inspiratory stridor), proximal anddistal weakness, distal muscle atrophy, andareflexia.HMSN type III. This rare polyneuropathy(eponym: Dejerine–Sottas disease) becomesmanifest at birth or in childhood with general-ized weakness, areflexia, and palpable nervethickening. Hearing loss, skeletal deformity, andsensory deficits (!ataxia) ensue as the diseaseprogresses.

! Hereditary Neuropathy with Pressure Palsies(HNPP)

HNPP is characterized by recurrent, transientepisodes of weakness and sensory loss afterrelatively mild compression of a peripheralnerve (ulnar, peroneal, radial, or median nerve).There may be evidence of a generalized poly-neuropathy or a painless plexopathy. The“sausagelike” pathological changes seen onsural nerve biopsy are the origin of the alterna-tive name, tomaculous neuropathy (from Latintomaculum, “sausage”).

Metabolic Hereditary Neuropathies

Other members of this class are listed in the sec-tion on metabolic diseases (p. 306 ff).

! Porphyria

Among the known porphyrias, four hepatictypes are associated with encephalopathy andperipheral neuropathy: variegate porphyria,acute intermittent porphyria, hereditary copro-porphyria, and !-aminolevulinic acid dehydrasedeficiency (autosomal recessive; the others areautosomal dominant). The porphyrias arehereditary enzymopathies affecting the biosyn-thesis of heme. Severe peripheral neuropathy isseen during attacks of acute porphyria, whichare most often precipitated by medications andhormonal influences (also fasting, alcohol, andinfection). The manifestations of porphyria in-clude colicky abdominal pain, pain in the limbs,paresthesiae, tachycardia, and variable degreesof weakness. Encephalopathy is manifest asconfusion, lack of concentration, somnolence,psychosis, hallucinations and/or epilepticseizures. The diagnosis of porphyria is based onthe demonstration of porphyrin metabolites inthe urine and feces.

! Neuropathy Due to Hereditary Disordersof Lipid Metabolism

Polyneuropathy occurs in metachromaticleukodystrophy (p. 306), Krabbe disease(p. 307), abetalipoproteinemia (p. 300), adreno-myeloneuropathy (p. 384), Tangier disease (ton-sillar hypertrophy, hepatosplenomegaly, lowserum cholesterol, serumHDL deficiency), Fabrydisease (punctate red angiokeratoma on but-tocks and in the genital and periumbilical areas,retinovascular changes, corneal deposits, ne-phropathy, painful neuropathy; glycosphin-golipid deposition due to "-galactosidase defi-ciency), and Refsum disease. The last is an auto-somal recessive disorder of phytanic acid me-tabolism in which phytanic acid accumulationleads to tapetoretinal degeneration, night blind-ness, and a distal, symmetric polyneuropathywith peripheral nerve thickening. The CSF pro-tein concentration is markedly elevated, but theCSF cell count is normal. The serum phytanicacid concentration is elevated.


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HMSN type I

Hereditary sensory neuropathy type I

Porphyric attack(acute intermittent porphyria)

Metachromatic leukodystrophy

(axial T1-weighted MRI scan)

HNPP

Amyloid neuropathy

Distal muscleparesis andatrophy

Thickened nerve

Dorsiflexor weakness, pes cavus

Radial nerve pressure palsy

Peroneal nerve pressure palsy

Foot ulcer/mutilation

Amyloid deposits(sural nerve, Congored staining)

Green birefringence (polarized light)

Darkening of urine ( -aminolevulinicacid, porphobilinogen)

Demyelination ofwhite matter


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Myopathic Syndromes

Myopathies are diseases of muscle. Many differ-ent hereditary and acquired diseases attackmuscle, sometimes in combination with otherorgans. The diagnosis and classification of themyopathies have been transformed in recentyears by the introduction of molecular biologi-cal tests for the hereditary myopathies, but theirtreatment remains problematic. The manage-ment of the hereditary myopathies currentlyconsists mainly of genetic counseling and theattempt to provide an accurate prognosis.

! Symptoms and Signs (Table 64, p. 397)Weakness (p. 52) is the most common sign ofmyopathy; it may be of acute, rapidly progres-sive, or gradual onset, fluctuating, or exercise-induced. It may be local (restricted to themuscles of the eye, face, tongue, larynx,pharynx, neck, arms, legs, or trunk), proximal, ordistal, asymmetric or symmetric. Myalgia,muscle stiffness, and muscle spasms are less com-mon. There may be muscle atrophy or hypertro-phy, often in a typical distribution, whose sever-ity depends on the type of myopathy. Skeletaldeformity and/or abnormal posture may be aprimary component of the disease or a con-sequence of weakness. Other features includeacute paralysis, myoglobulinemia, cardiacarrhythmia, and visual disturbances.

! Causes

For a list of causes of hereditary and acquiredmyopathies, see Tables 65 and 66, p. 398.

! Diagnosis (Table 67, p. 399)

The myopathies are diagnosed primarily by his-tory and physical examination (p. 52). Phar-macological tests are used for the differential di-agnosis of myasthenia. Neurophysiological stu-dies are used to rule out neuropathy (p. 391), todetermine the specific type of acute musclechange, or to identify disturbances of muscularimpulse generation and conduction. Variouslaboratory tests are helpful in myopathies due tobiochemical abnormalities; imaging studies ofmuscle aid in the differential diagnosis of atro-phy and hypertrophy. Muscle biopsy is oftenneeded for a definitive diagnosis. Molecular bio-logical studies are used in the diagnosis ofhereditary myopathies.

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Structures involvedin neuromusculardisturbances

Signs of myopathy

Muscle fiber

Blood vessel

Bloodvessel

Neuromuscular synapse(motor end plate)

Connective tissue

Myelinatednerve fiber Nerve fiber bundle

Spinal nerve

Thinly myelinated nerve fibers

Sympathetictrunk

Weakness in pelvic girdle andthigh (Gowers’ sign)

Lack of head and trunk control(congenital myopathy)

Myotonic reaction (adduction ofthumb on thenar percussion)

Weakness in shoulder girdle and upper arm Weakness of facial muscles with myopathic facies (ptosis, attenuated

facial expression, looks tired)


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Muscular Dystrophies

The muscular dystrophies—myopathies charac-terized by progressive degeneration of muscle—are mostly hereditary.

! Pathogenesis (Table 65, p. 398)

Dystrophinopathies are X-linked recessive dis-orders due to mutations of the gene encodingdystrophin, a protein found in the cell mem-brane (sarcolemma) of muscle fibers. Such mu-tations cause a deficiency, alteration, or absenceof dystrophin. The functional features of dystro-phin are not fully understood; it is thought tohave a membrane-stabilizing effect. Some formsof limb girdle dystrophy (e. g., sarcogly-canopathy) are due to mutation of genes encod-ing dystrophin-associated glycoproteins, whileothers are due tomutation of genes encoding in-tracellular enzymes such as calpain-3. Emery–Dreifuss muscular dystrophy is due to a mutationof the gene for emerin, a nuclearmembrane pro-tein whose exact function is unknown.


Muscular dystrophies may be characterized byatrophy, hypertrophy, or pseudohypertrophyand are further classified by their mode of in-heritance, age of onset, and distribution. Otherfeatures such as myocardial involvement, con-tractures, skeletal deformity, endocrine dys-function, and ocular manifestations may pointto one or another specific type of muscular dys-trophy. Each type has a characteristic course(Table 68, p. 400).

! Diagnosis

The history and physical examination aresupplemented by additional diagnostic studiesincluding ECG, creatine kinase fractionation(CK-MM), EMG, and DNA studies. If DNA analy-sis fails to reveal a mutation, immunohisto-chemical techniques, immune blotting, or thepolymerase chain reaction can be used to detectabnormalities of dystrophin and sarcoglycan(e. g., in muscle biopsy samples) and therebydistinguish between Duchenne and Beckermuscular dystrophy, or between dystro-phinopathies and other forms of muscular dys-trophy. DNA tests are used for the identificationof asymptomatic female carriers (in whom

muscle biopsy is hardly ever necessary), and forprenatal diagnosis.

! Treatment

The goal of treatment is to prevent contractureand skeletal deformity and to keep the patientable to sit and walk for as long as possible. Thepatient’s diet should be monitored to preventobesity. The most important general measuresare genetic counseling, social services, psychi-atric counseling, and educating the patient onthe special risks associated with general an-esthesia. The type of schooling and employmentmust be appropriately suited to the patient’s in-dividual abilities and prognosis. Physical ther-apy includes measures to prevent contractures,as well as breathing exercises (deep breathing,positional drainage, measures to counteract in-creased inspiratory resistance). Patients withalveolar hypoventilation may need intermittentventilation with continuous positive airwaypressure (CPAP) at night. Orthoses may be help-ful, depending on the extent of weakness (nightsplints to prevent talipes equinus, seat cushions,peroneal springs, orthopedic corsets, leg or-thoses). Home aids may be needed as weaknessprogresses (padding, eating aids, toilet/bathingaids, stair-lift, mechanized wheelchair, speciallyadapted automobile). Surgery may be needed tocorrect scoliosis, prevent contracture about thehip joint (iliotibial tract release), and correctwinging of the scapula (scapulopexy/scapulode-sis) and other deformities and contractures. In-tracardiac conduction abnormalities (e. g., inEmery–Dreifuss muscular dystrophy) requiretimely pacemaker implantation. Heart trans-plantation may be needed when severe cardio-myopathy arises in conjunction with certaintypes of muscular dystrophy (Becker, Emery–Dreifuss; Table 68, p. 400).

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Pathogenesis

DystrophinCalpain-3

Sarcotubular system

Sarcolemma

Sarcolemma

Mitochondria

Nuclear envelope

Emerin

F-Actin

Syntrophins

Laminin-2

Dystroglycan complex

Sarcoglycancomplex

Extracellular matrix,basal lamina

Sarcoplasm

Duchenne-type MD

Calfhyper-trophy

Calfhyper-trophy

Hyper-lordosis

Proximalmuscle

weakness

Proximalmuscle

weakness

Proximalmuscleweakness

Becker dystrophyLimb girdle MD

Proximalmuscleweaknessand atrophy

Facioscapulohumeral MD

Myopathic facies with weak-

ness (shoulder girdle, dorsiflexion)and winged scapula

Weakness of lidclosure (no

ptosis)

Weakness of mouth closure

Emery-Dreifuss dystrophy

Flexion contracture,focal atrophy

ShortenedAchilles tendon

Mild weakness

Cardiac arrhythmias,respiratory insufficiency

MD: Muscular dystrophy

Merosin

Dystrobrevin

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The Myotonias (Table 69, p. 401)

! Pathogenesis

Point mutations in ion channel genes causechannel defects that render the muscle cellmembrane electrically unstable (Table 65,p. 398), leading to involuntary muscle contrac-tion.


The transient, involuntary muscle contractionsare perceived as stiffness. Depolarizing musclerelaxants used in surgery can trigger severe my-otonia in susceptible patients. Acute, general-ized myotonia can also be induced by tocolyticagents such as fenoterol.

! Diagnosis

Myotonia is diagnosed from the observation ofinvoluntary muscle contraction after voluntarymuscle contraction (action myotonia) or percus-sion (percussion myotonia), along with thecharacteristic EMG findings. Specific forms ofmyotonia are diagnosed by their mode of inheri-tance and clinical features, and moleculargenetic analysis. The serum creatine kinase con-centration is usually not elevated, and there isusually no muscle atrophy, except in myotonicdystrophy. Muscle hypertrophy is present inmyotonia congenita. Myotonic cataract is foundin myotonic dystrophy and proximal myotonicmyopathy; slit-lamp examination is indicated inpatients with these disorders.

! Treatment

Membrane-stabilizing drugs such as mexiletinealleviate myotonia; cardiac side effects may beproblematic, particularly in myotonic dystrophy.Cold exposure should be avoided.

Episodic Paralyses (Table 69, p. 401)

! Pathogenesis

Hyperkalemic and normokalemic paralysis,potassium-aggravated myotonia (PAM = myo-tonia fluctuans), and paramyotonia congenitaare due to sodium channel dysfunction, whilehypokalemic paralysis is due to calcium channeldysfunction.


In hypokalemic and hyperkalemic myotonia,there are irregularly occurring episodes of flac-cid paresis of variable duration and severity,with no symptoms in between. The anal andurethral sphincters are not affected. In paramyo-tonia congenita, muscle stiffness increases onexertion (paradoxical myotonia) and is followedby weakness. Cold exposure worsens the stiff-ness.

! Diagnosis

The diagnosis can usually bemade from the per-sonal and family history, abnormal serumpotassium concentration, and molecular geneticfindings (mutation of the gene for a membraneion channel). If the diagnosis remains in ques-tion, provocative tests can be performed be-tween attacks. The induction of paralytic attacksby administration of glucose and insulin indi-cates hypokalemic paralysis, while their induc-tion by potassium administration and exercise(e. g. on a bicycle ergometer) indicates hyperka-lemic paralysis. The diagnosis of paramyotoniacongenita is based on the characteristic clinicalfeatures (paradoxical myotonia, exacerbation bycold exposure), autosomal dominant inheri-tance, and demonstration of the causative pointmutation of the sodium channel gene.

! Treatment

Acute attacks. Milder episodes of weakness inhypokalemic disorders need no treatment, whilemore severe episodes can be treated with oralpotassium administration. Milder episodes ofweakness in hyperkalemic disorders also needno treatment; more severe episodes may re-quire calcium gluconate i. v., or salbutamol byinhaler.Prophylaxis. Hypokalemic paralysis: Low-salt,low-carbohydrate diet, avoidance of strenuousexercise; oral acetazolamide or spironolactone.Hyperkalemic paralysis: high-carbohydrate diet;avoidance of strenuous exercise and cold; oralhydrochlorothiazide or acetazolamide.

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Ion channels for maintenance of transmembrane potential

Paramyotonia congenita Myotonic dystrophy

Myotonia congenita(generalized muscular

hypertrophy)

Extracellular matrix

Intracellular matrix

Cell membrane

Calcium channelUnselective channel

Potassium channel

Chloride channel

Sodium channel

Action myotonia (delayedhand opening after grasping)

Percussion myotonia(adduction of thumb on

thenar percussion)

Cold exposuremyotonia(delayed eyeopening, facialrigidity)

Lingual percussion myotonia

Myopathic facies, weakness of lid closure, atro-phy of anterior neck muscles,

myotonic cataract

Predominantlydistal muscular atrophy

K+ Cl-

Cl- Na+ Ca2+

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Congenital Myopathies

The typical pathological findings on muscle bi-opsy distinguish this group of disorders bothfrom the congenital muscular dystrophies andfrom muscle changes secondary to peripheralneuropathy. Some congenital myopathies havedistinctive clinical features. Proximal flaccidweakness is usually present at birth (floppybaby); skeletal deformities may also be seen(e. g., high palate, hip luxation, pes cavus, chestdeformities). Many congenital myopathies pro-gress slowly, causing little or no disability; theCK and EMG may be only mildly abnormal, ornot at all. Some types can be diagnosed bygenetic analysis (Table 70, p. 402).

Metabolic Myopathies

In most metabolic myopathies (Table 71, p. 402f), exercise induces myalgia, weakness, andmuscle cramps, and myoglobinuria. Progressiveproximal weakness is seen in myopathy due toacid-maltase deficiency (glycogen storage dis-ease type II), debrancher deficiency (glycogenstorage disease type III), or primary myopathiccarnitine deficiency.Mitochondrial myopathies. Pyruvate and fattyacids are the most important substrates for mi-tochondrial ATP synthesis, which occurs by oxi-dative phosphorylation, a function of the respi-ratory chain enzymes (found on the inner mito-chondrial membrane). !-oxidation occurs in themitochondrial matrix. The respiratory chainenzymes are encoded by both mitochondrialand nuclear DNA (mtDNA, nDNA).The mitochondrial myopathies are a hetero-geneous group of disorders whose common fea-ture is dysfunction of the respiratory chain, !-oxidation, or both. These disorders have varyingclinical and biochemical features (Table 71,p. 402 f); their inheritance is either maternal orsporadic; non-heritable cases also occurthroughmtDNAmutations. These disordersmayaffect multiple organ systems, e. g.:! Muscle (reduced endurance, pain, cramps,

myoglobinuria)! CNS (seizures, headache, behavioral abnor-

malities)! Eye (ptosis, external ophthalmoplegia, tape-

toretinal degeneration)

! Ear (hearing loss)! Heart (arrhythmia, heart failure)! Gastrointestinal system (diarrhea, vomiting)! Endocrine system (diabetes mellitus, hy-

pothyroidism)! ANS (impotence, sweating)The diagnosis is based on the clinical features,laboratory tests (elevated lactate concentrationat rest in serum, sometimes also in CSF, withsustained increase after exercise), muscle bi-opsy (ragged red fibers, sometimes with cy-tochrome-c oxidase deficiency), and molecularstudies (mtDNA analysis of muscle, platelets,leukocytes). There is no etiological treatment forthemitochondrial myopathies at present; a low-fat, carbohydrate-rich diet is recommended indisorders with defective !-oxidation, and carni-tine supplementation in those with systemiccarnitine deficiency. Coenzyme Q10, vitamin K3,vitamin C, and/or thioctic acid supplements arerecommended in disorders with impaired respi-ratory chain function.

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Congenital myopathies

Mitochondrial myopathies

Nemaline myopathy

Central coredisease

Hypacusis

Optic neuropathy,external ophthalmo-

plegia, retinopathy

Cardiac arrhythmias, cardiomyopathyMuscular weakness,neuromy-opathy

Epileptic seizures, myoclonus, ataxia,dementia, migraine,infarction

Mitochondrialaccumulation(ragged redfiber; crosssection ofmuscle fiber)

Paracrystalline mitochondrial inclusions (electron microscopy)

Tapetoretinaldegeneration

(CPEO)

Occipital infarcts (MELAS syndrome, axial

CT scan)

Centronuclearmyopathy

General-ized muscleweakness,skeletalanom-alies

Generalized mus-cle weakness, skeletal anomaliesPredom-

inantly proximal muscle weakness

Centrally located nuclei(centronuclear

myopathy; cross section of muscle fiber)

High palate

Respiratory chain defect due to faulty communication between nuclear and mitochondrial DNA

nDNA

ATP

mtDNA

Nuclear-codedsubunits of

respiratory chainDefective mitochon-drial sub-units

Respiratory chain defect

Faulty communication ( deletion/point mutation of mtDNA)

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Myasthenic Syndromes

! Myasthenia Gravis (MG)

Pathogenesis. The exercise-induced weaknessthat typifies MG is due to impaired transmissionat the neuromuscular junction, which is, in turn,due to an underlying molecular lesion affectingthe nicotinic acetylcholine receptor (AChR) inthe postsynaptic membrane of the muscle cell.Circulating IgG autoantibodies to this receptorimpair its function, speed its breakdown, and in-duce complement-mediated damage to themuscle cell membrane. Recently the anti-MuSK(receptor tyrosine kinase) antibody has been de-tected in about half of patients who are serone-gative for AChR antibodies. The thymus plays animportant role in this autoimmune disorder (itis normally a site of maturation and removal ofautoreactive T lymphocytes). MG is usually ac-quired late in life; there are also rare congenitaland familial forms.Symptoms and signs. MG is characterized byasymmetric weakness and fatigability of skeletalmuscle that worsens on exertion and improvesat rest. Weakness often appears first in the ex-traocular muscles and remains limited to themin some 15% of cases (ocular myasthenia), butprogresses to other muscles in the rest (general-ized myasthenia). The facial and pharyngealmuscles may be affected, resulting in a blank fa-cial expression, dysarthria, difficulty in chewingand swallowing, poor muscular control of thehead, and rhinorrhea. Respiratory weaknessleads to impairment of coughing and an in-creased risk of aspiration. It may become diffi-cult or impossible for the patient stand up, re-main standing, or walk, and total disability mayensue. Myasthenia can be aggravated by certainmedications (Table 72, p. 403), infections,emotional stress, electrolyte imbalances, hor-monal changes, and bright light (eyes), and isoften found in association with hyperthyroid-ism, thyroiditis, rheumatoid arthritis, and con-nective tissue disease. Myasthenic or cholinergiccrises can be life-threatening (Table 73, p. 404).Diagnosis. The diagnosis is based on the charac-teristic history and clinical findings, supportedby further tests that are listed in Table 74(p. 404).Treatment. Ocular MG is treated symptomati-cally with an acetylcholinesterase (AChE) inhibi-

tor, such as pyridostigmine bromide; if the re-sponse is insufficient, corticosteroids orazathioprine can be added. Generalized MG istreated initially with AChE inhibitors and, if theresponse is insufficient, with corticosteroids,azathioprine, intravenous gammaglobulin, orplasmapheresis; once the patient’s conditionhas stabilized, thymectomy is performed.Further treatment depends on the degree of im-provement achieved by these measures. Themortality of MG with optimal management isless than 1%. Most patients can lead a normallife but need lifelong immunosuppression.Specific measures are needed to manage respi-ratory crises, thymoma, and pregnancy inpatients with MG, and for the treatment ofneonatal, congenital, and hereditary forms ofMG.

! Lambert–Eaton Myasthenic Syndrome(LEMS)

LEMS is caused by autoantibodies directedmainly against voltage-gated calcium channelsin the presynaptic terminal of the neuromuscu-lar junction; diminished release of acetylcholinefrom the presynaptic terminal is the result.LEMS is often a paraneoplastic manifestation ofbronchial carcinoma, sometimes appearingbefore the tumor becomes clinically evident. Itis characterized by proximal (leg) weakness thatimproves transiently with exercise but worsensshortly afterward. There are also autonomicsymptoms (dry mouth) and hyporeflexia. EMGreveals a diminished amplitude of the sum-mated muscle action potential, which increaseson high-frequency serial stimulation. The treat-ment is with 3,4-diaminopyridine (which in-creases acetylcholine release) and AChE inhibi-tors. Immune suppression and chemotherapy ofthe underlying malignancy can also improveLEMS.

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Neuromuscular synapse–Pathogenesis

Myasthenia gravis

Repetitive nerve stimulation

Exercise-induced muscle weakness Normal muscle strength (afteredrophonium chloride)

Repeated low-frequency stimulation (3 Hz, trapezius m., MG)

Repeated high-frequency stimulation(20 Hz, abductor digiti quinti m., LEMS)

Amplitude reduction (decrementfrom 1st to 5th stimulus)

*ACh = acetylcholine

Low starting amplitude

Increase in amplitude (increment > 3.5 times higher than baseline)

Normal

MG

LEMS

Axon terminal

Mitochon-drion

Synaptic vesicle containing ACh*

Release of ACh

Basement membrane

Muscle AChR

Ptosis

AChR autoantibodybinding

Complement-mediated AChR lysis

Loss of AChR (ACh-effect diminished)

Calcium channel autoantibodies(reduced ACh release)

Intravenous edrophonium chlorideFaciopharyngeal

weakness

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Myositis

The myositides (inflammatory myopathies) area heterogeneous group of disorders, causingthree distinct clinical syndromes: polymyositis(PM), dermatomyositis (DM), and inclusionbody myositis (IBM).

! Pathogenesis

Most myositides found in the temperate zonesare autoimmune diseases of unknown cause,characterized histologically by muscle inflam-mation and fibrosis and loss of muscle fibers. InPM, cytotoxic CD8+ T cells penetrate and damagemuscle fibers (! intramuscular cellular infil-trates). CD8+ T cell activation is induced by ab-normal expression of class I HLA antigens on thesurface of the muscle fibers, which are normallyHLA-negative. DM is thought to be largely due toantibodies against blood vessels within muscle,which activate the complement system (mem-brane attack complex). Vascular endothelialdamage ultimately leads to ischemia and deathof muscle tissue (! perifascicular atrophy). In-flammatory T cells and macrophages migrateinto muscle and cause further damage. IBM is ofunknown pathogenesis. Infectious myositis maybe due to bacteria, viruses, parasites, or fungi.

! Syndromes

Polymyositis (PM) begins with weakness of theproximal muscles of the lower limbs, whichthen progresses and slowly spreads to the upperlimbs. The deltoid and neck flexor muscles arecommonly involved. Dysphagia may be present.The involved muscles eventually becomeatrophic. In overlap syndrome, myositis appearstogether with another autoimmune disease,e. g., progressive systemic sclerosis, systemiclupus erythematosus, rheumatoid arthritis, pol-yarteritis nodosa, polymyalgia rheumatica, orSjögren syndrome. Myalgia is often the majorsymptoms in patients with PM, as also inpatients with hypereosinophilia syndrome(Churg–Strauss syndrome) or eosinophilicfasciitis (Shulman disease).Dermatomyositis (DM) progresses more rapidlythan PM and is distinguished from it mainly bythe bluish-red or purple (heliotrope) rash foundon exposed areas of the skin (eyelids, cheeks,neck, chest, knuckles, and extensor surfaces of

the limbs). Small hemorrhages and telangiec-tasias are found in the nailbeds; affected child-ren may have subcutaneous calcium deposits.Cancer accompanies DM six times morefrequently than PM; DM is also associated withscleroderma and mixed connective tissue dis-ease.Inclusion body myositis (IBM) is characterizedby distal (sometimes asymmetric) weaknessand muscle atrophy, mainly in the lower limbs(plantar flexors), with early loss of the quadri-ceps reflexes. There are both sporadic andhereditary forms of IBM (see also p. 252).

! Diagnosis

The myositides are diagnosed by history andphysical examination, elevated serum concen-tration of sarcoplasmic enzymes (particularlyCK-MM), and characteristic findings on EMGand muscle biopsy. Muscle atrophy can also beassessed with various imaging techniques (CT,MRI, ultrasonography). The presence of antibo-dies in association with a connective tissue dis-ease may be relevant to the diagnosis (p. 180).

! Treatment

PM and DM are treated by immune suppression,e. g., with corticosteroids, azathioprine, or in-travenous gammaglobulin (ivig). Physical ther-apy is begun once the patient’s condition hasstabilized. IBM may respond to intravenous im-munoglobulin therapy.

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Dermatomyositis (DM)

Inclusion body myositis (IBM) Butterfly rash (lupus erythematosus)

Polymyositis (PM)

Lymphomonocytic infiltrate in muscle,vessel (PM, cross section of muscle fiber)

Perifascicular atrophy(DM; cross section of

muscle fiber)

Ischemic lesion of muscle fiber

Proximal muscle weakness and atrophy

Proximal muscle weak-ness

Facial erythema

Telangiectasis,hemorrhage

(nailbed)

Erythema in joint region (extensor side)

Cervical muscleweakness

Lid edema

Distal muscle atrophy

Bleeding

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Muscle Pain (Myalgia)

Myalgia is an aching, cramping, or piercing painin muscle. It is triggered by stimulation of noci-ceptors (p. 108). Pressure or traction on amusclecauses myalgia that subsides once the mechani-cal stimulus is removed, while inflammatoryand other lesions in muscle cause persistent andgradually increasing myalgia. Muscle ischemiaand/or metabolic dysfunction are reflected bymyalgia occurring only during muscle activity.Myalgia includes allodynia, which is defined as

pain induced by normally nonpainful stimuliand is explained by the sensitization of nocicep-tors by pain-related substances such as brady-kinin, serotonin, and prostaglandin. A “charley-horse” is a type of myalgia that normally begins8–24 hours after muscle overuse (simultaneousstretching and contraction) and lasts 5–7 days. Itis caused by an inflammatory reaction to musclefiber damage. Myalgia can be triggered by dis-orders whose primary pathology lies anywherein the nervous system (peripheral nerve, spinalcord, brain).

! Causes of Myalgia

Type of Myalgia Selected Causes

Localized myalgia" Hematoma " Trauma, coagulopathy" Myositis " Infectious: Streptococcal infection, trichinosis, influenza, epidemic pleurodynia. Non-

infectious: Nodular focal myositis, eosinophilic fasciitis, sarcoidosis, myositis ossifi-cans

" Ischemic " Arteriosclerosis (intermittent claudication), embolism" Toxic-metabolic " Acute alcoholic myopathy, metabolic myopathy (pp. 402, 405)" Overactivity " Stiff-man syndrome, neurogenic myotonia, tetanus, strychnine poisoning, amyo-

trophic lateral sclerosis, tetany" Exercise-

induced" Metabolic myopathy, arteriosclerosis, physical exertion

" Parkinsonian " Rigidity" Muscle spasm " Polyneuropathy, metabolic disorder (electrolyte imbalance, uremia, thyroid dysfunc-

tion)" Pain at rest " Restless legs syndrome, painful legs and moving toes syndrome

Generalized myalgia" Myositis " Polymyositis/dermatomyositis (p. 344)" Toxic-metabolic " Hypothyroidism, medications2, mitochondrial myopathy (pp. 340, 402, 405)" Other " Polymyalgia rheumatica, amyloidosis, osteomalacia, Guillain–Barré syndrome,

porphyria, hypothyroidism, corticosteroid withdrawal, fibromyalgia

(Adapted from Layzer, 1994)1 E.g., emetine, lovastatin, and !-aminocaproic acid.

Rhabdomyolysis

Local or generalized damage to skeletal musclecan cause myoglobinuria and an elevated serumconcentration of creatine kinase, usually accom-panied by the acute onset of proximal or diffuseweakness, with myalgia, muscle swelling, andgeneral manifestations including nausea, vomit-ing, headache, and sometimes fever. The urinemay be discolored at the onset of symptoms orseveral hours later. Rhabdomyolysis can becaused by certain types of myopathy (e. g., poly-myositis, central core disease, metabolic my-opathies; pp. 402, 405), by muscle strain ortrauma (long-distance walking or running, heat

stroke, delirium tremens, status epilepticus), bytoxic substances (see below), and by infectiousdisease (bacterial sepsis, influenza, coxsack-ievirus or echovirus infection).

Malignant Hyperthermia (MH)

This life-threatening disorder of skeletal musclefunction is characterized by hyperthermia,muscle rigidity, hyperhidrosis, tachycardia, cya-nosis, lactic acidosis, hyperkalemia, massiveelevation of the serum creatine kinase concen-tration, and myoglobinuria. It is induced by an-esthetic agents such as halothane and succinyl-choline. The predisposition to MH is inherited as

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an autosomal dominant trait (gene loci: 19q13.1,17q11–24, 7q12.1, 5p, 3q13.1, 1q32). The creatinekinase level may be chronically elevated in sus-ceptible individuals, who can be identified withan in vitro contracture test performed inspecialized laboratories. Persons suffering fromcentral core disease, multicore disease, andKing–Denborough syndrome (dwarfism,skeletal anomalies, ptosis, high palate) are alsoat risk for MH. Treatment: dantrolene.Malignant neuroleptic syndrome clinically re-semblesMH; unlikeMH, however, it is usually ofsubacute onset (days to weeks), it is not heredi-tary, and it is triggered by psychotropic drugs(haloperidol, phenothiazines, lithium). Malig-nant neuroleptic syndrome can also be inducedby abrupt withdrawal of dopaminergic agents inpatients with Parkinson disease.

Toxic Neuromuscular Syndromes

The muscle fiber lesions regress if the re-sponsible substance is eliminated in timelyfashion (Table 75, p. 405).

Myopathy in Endocrine Disorders

Hyperthyroidism or hypothyroidism, hyper-parathyroidism, Cushing syndrome, steroid my-opathy, and acromegaly all cause proximalweakness, while Addison disease and primaryhyperaldosteronism usually cause generalizedweakness. Timely correction of the endocrinedisorder or withdrawal of steroid drugs is usu-ally followed by improvement.

Critical Illness Polyneuropathy (CIP)and Critical Illness Myopathy (CIM)

Sepsis is the most common cause not only of en-cephalopathy (see p. 312) but also of CIP andCIM. CIP is an acute, reversible, mainly axonalpolyneuropathy. It causes distal, symmetricweakness with prominent involvement of themuscles of respiration, resulting in prolongedventilator dependence and delayed mobiliza-tion. CIM causes generalized weakness. Theclinical differentiation of CIM and CIP is difficultand often requires muscle biopsy.

Paraneoplastic Syndromes(Table 76, p. 406)

Distant neoplasms can affect not only the CNS(see p. 388) but also the PNS and skeletalmuscle. Remarkably, paraneoplastic syndromessometimes appear months or years before theunderlying malignancy becomes clinicallymanifest. Paraneoplastic neuromuscular syn-dromes typically present with marked weak-ness of subacute onset (i.e., developing overseveral days or weeks).

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4 Diagnostic Evaluation

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A detailed description of diagnostic evaluationprocedures can be found in the textbooks listedon p. 409. The goals of history-taking, physicalexamination, and additional testing (if neces-sary) are:! Data collection (manifestations of disease)! Localization of the lesion! Provision of an etiological diagnosis

" Data Collection

The diagnostic process begins with the historyand physical examination. The history providesinformation about the patient’s experience ofillness, the temporal course of symptomdevelopment, and potentially relevant familial,social, occupational, and hereditary factors. Aninaccurate or incomplete history is a frequentcause of misdiagnosis.History. The physician engages the patient in astructured conversation about the manifesta-tions of the illness. The physician must remem-ber that the patient is the “expert” in this sit-uation, as the patient alone knows what istroubling him (though perhaps helpful infor-mation can also be obtained from a close rela-tive or friend). The physician aims to obtain ac-curate information on the nature, location, du-ration, and intensity of the symptoms bylistening patiently and asking directed ques-tions in an atmosphere of openness and trust.Questionnaires, computer programs, and ancil-lary personnel cannot be used for primary his-tory-taking, as they do not enable the con-struction of a trusting physician–patient rela-tionship (though they may provide useful addi-tional information at a later stage). Some im-portant elements of the case history are as fol-lows.! Nature of symptoms. The physician must

ascertain, by detailed questioning if neces-sary, that he understands the patient’s com-plaints in the same sense that the patientmeans to convey. “Blurred vision” may meandiplopia, “dizziness” may mean gait ataxia,“headache” may mean hemicrania, “numb-ness” may mean paresthesia—but patientsmay use all of these terms with other mean-ings as well.

! Severity of symptoms. Quality and intensity ofsymptoms, activities with which they inter-fere.

! Onset of symptoms. When, where, and overwhat interval of time did the symptomsarise?

! Time course of symptoms. How did theydevelop? Are they constant or variable? Arethere any exacerbating or alleviating factors?

! Accompanying symptoms, if present.! Past history of similar symptoms.! Previous illnesses and their outcome.! Social, occupational, and family history.! Medications, smoking, alcohol abuse, sub-

stance abuse, toxic exposures.! Previous diagnostic studies and treatment.! Information from third partiesmay be needed

for patients with aphasia, confusion, demen-tia, or impairment of consciousness.

Physical examination. The general and neuro-logical physical examination may yield impor-tant clues to the disease process, but only if theexaminer has the requisite knowledge of theunderlying principles of (neuro-)anatomy,(neuro-)physiology, and (neuro-)pathology. Theexamination is guided by the case history, i.e.,the patient’s complaints and general physicalcondition determine what the examiner looksfor in the examination. The unselective,“shotgun” application of every possible tech-nique of neurological examination in everypatient is not only a waste of time and money;it generally only creates confusion rather thanclarifying the search for the diagnosis. The neu-rological examination of small children,patients with personality changes or mental ill-ness, and unconscious patients poses specialchallenges.Important elements of the neurological exami-nation include:! Inspection. Dress, appearance, posture,

movements, speech, gestures, facial expres-sion.

! Mental Status. Orientation (to person, place,and time), attention, concentration, memory,thought processes, language function, levelof consciousness.

! Cranial nerves. Olfaction, pupils, visual fields,eyegrounds, eye movements, facial move-ment, facial sensation, hearing, tonguemovements, swallowing, speaking, reflexes.

! Motor function. Muscular atrophy/hypertro-phy, spontaneous movements, coordination,paresis, tremor, dystonia, muscle tone.

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! Reflexes (p. 40).! Sensory function. The findings of sensory

testing are heavily influenced by the patient’s“sensitivity” and ability to cooperate. Vaguesensory abnormalities without other neuro-logical deficits are difficult to classify; theirinterpretation requires a good knowledge ofthe underlying neuroanatomy (pp. 32 ff,106 f).

! Posture, station, and gait. The observation andtesting of posture, station, and gait providesimportant information about a possiblemotor deficit (p. 42 ff).

! Autonomic function. The patient is ques-tioned about bladder function, bowel move-ment/control, sexual function, blood pres-sure, cardiac function, and sweating, and isexamined as needed.

" Localization of the Lesion

The findings of the history and physical exami-nation findings are then related to dysfunctionof a particular neuroanatomical structure(s)(p. 2 ff) or neurophysiological process (p. 40 ff);the site of the patient’s problem is thus localized(topical diagnosis).

" Provision of an Etiological Diagnosis

Once the site of the problem is localized, it mustbe determined whether it is due to a structurallesion (e. g., hemorrhage, nerve compression, orinfection) or a functional disturbance (e. g.,

epileptic seizure, migraine, or Parkinson dis-ease). The line between structural andfunctional pathology is not perfectly defined, asthere is constant interaction between these twolevels; at the same time, considerations of eti-ology and pathogenesis also influence data in-terpretation. The diagnostic process ideally endsin the diagnosis of a specific disease entity(nosological diagnosis).

Additional Diagnostic Studies

The clinical diagnosis may be considered firmlyestablished by the history and physical exami-nation alone in many cases, e. g., migraine orParkinson disease. Additional diagnostic studiesare merely confirmatory and are generally notneeded unless doubt arises as to the diagnosis,e. g., if an epileptic seizure or new type of head-ache should appear.Additional studies are needed, however, if thereis no otherway to decide among several diagnos-tic possibilities remaining after thorough his-tory-taking and physical examination. The num-ber and type of studies neededdiffer fromcase tocase. Studies that are costly or fraught with non-negligible risk should never be ordered except toanswer a clearly stated diagnostic question. Thepotential benefits of a proposed study must al-ways be weighed against its risks and cost.

" Laboratory Tests

Table 77, p. 407

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" Neurophysiological Tests

" Neuropsychological Tests

Comprehensive testing of cognitive function,behavior, and affective processes, perhaps incollaboration with a neuropsychologist, is re-quired when the history and physical examina-

Test/Purpose Risks Comments

Electroencephalography: To assess elec-trical activity of the brain1

Surface electrodes: noneNeedle electrodes: infec-tion

Sphenoid, subdural or depth re-cording3 for special questions relevantto the (preoperative) diagnostic eval-uation of epilepsy

Induction of seizures byprovocative methods2

Evoked potentials (EPs):! VEPs4: Study of optic nerve, optic

chiasm and optic tract! None ! Used mainly to diagnose prechias-

matic lesions! AEPs5: Study of peripheral and cen-

tral segments of the auditory path-way6

! None ! Used mainly for diagnosis of multi-ple sclerosis, tumors of the poste-rior cranial fossa, brain stem le-sions causing coma or brain death,and intraoperative monitoring

! SEPs7: Study of somatosensory sys-tems8

! None ! Used to assess proximal peripheralnerve lesions (plexus, roots) andspinal cord or parietal lobe lesions

! MEPs9: Study of corticospinalmotor pathway

! May induce epilepticseizures. Contraindica-tions: cardiacpacemakers, metalprostheses in the targetarea, pregnancy, un-stable fractures

! Pyramidal tract lesions, motor neu-ron lesions, root compression,plexus lesions, stimulation of deepnerves, differential diagnosis ofpsychogenic paresis

Electromyography: Study of electricalactivity in muscle

Contraindication:coagulopathy. Risk of in-jury in special studies11

Provides information on motor unitdisorders in patients with peripheralnerve lesions or myopathies. Not dis-ease-specific. Disposable needlesshould be used to prevent spread ofinfectious disease10

Electroneurography: Measurement ofmotor and sensory conduction veloci-ties.

Needle recordings con-traindicated in patientswith coagulopathy

Localization (proximal, distal, conduc-tion block) and classification (axonal,demyelinating) of peripheral nerve le-sions12

Electro-oculography: To record andassess eye movements and/or nystag-mus

Caloric testing with watercontraindicated in patientswith perforated eardrums

Diagnosis and localization of periph-eral and central vestibular lesions.Differentiation of saccades

1 For assessment of epilepsy, localized pathology (neoplasm, trauma, meningoencephalitis, infarct) or general-ized pathology (intoxication, hypoxia, metabolic encephalopathy, Creutzfeldt–Jakob disease, coma, brain death),for sleep analysis (polysomnography), or to monitor the course of such conditions. 2 Photostimulation, hyperven-tilation, sleep, sleep withdrawal. 3 For diagnostic assessment before epilepsy surgery, in specialized centers.4 Visual EPs. 5 Acoustic EPs. 6 Peripheral nerve and cochlear lesions are mainly studied audiometrically, and pe-ripheral and central disorders by electro-oculography or posturography. 7 Somatosensory EPs. 8 Functionalassessment of sensory pathways (p. 104) by tibial, median, ulnar, and trigeminal nerve stimulation. 9 Motor EPs.10 Particularly Creutzfeldt–Jakob disease, hepatitis, AIDS. 11 Examples: Pneumothorax in study of the serratusanterior m., perforation of the rectal wall in study of the anal sphincter. 12 F-wave measurement for localizationof proximal nerve damage, H-reflex in S1 syndrome.

tion suggest the possibility of mental illness orof mental dysfunction due to neurological dis-ease. Objectives: Accurate detection and effec-tive monitoring, prognostication, identificationof etiology, and treatment of mental disorders(p. 122 ff).

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Aspect To Be Tested Questions/Tests

! Attention (p. 116) ! Awake, somnolent, stuporous, comatose? Arousability, attentionspan, perception

! Orientation ! Personal data (name, age, date/place of birth), orientation (“whereare we?”, place of residence); time (day of the week, date, month,year); situation (reason for consultation, nature of symptoms)

! Memory, recall ! The patient should be able to name the months of the year back-ward, spell a word backward, repeat random series of numbers be-tween 1 and 9. Can the patient recall 3 objects mentioned 3minutes ago, recall figures, name famous people? Tests of generalknowledge

! Serial subtraction ! Serial subtraction of 3s (or 7s), starting from 100! Frontal lobe function ! Perseveration1; hand sequence test2; proverb interpretation! Language (pp. 124, 128) ! Following commands, naming, repetition, writing, reading aloud,

simple arithmetic! Praxis ! See p. 128! Spatial orientation, visual percep-

tion! See p. 132. Naming of colors and objects

(After Schnider, 1997)1 Drawing of simple figures (Luria’s loops). 2 Command sequence: “Make a fist—open the hand to the side—openthe hand flat.”

" Cerebrovascular Ultrasonography

Ultrasound can be used to assess the ex-tracranial and intracranial arteries. The trans-mitter emits ultrasonic waves in two modes,continuous wave (CW; cross-sectional data, butno depth information) and pulse wave (PW;flow information at different levels). The re-flected waves are recorded (echo impulse sig-nal) and analyzed (frequency spectrum analysis,color coding). The flow velocity of blood parti-cles can be determined according to the Dopplerprinciple. As the flow velocity is correlated withthe diameter of a blood vessel, its measurementreveals whether a vessel is stenotic. In directvessel recordings, CW Doppler can be used todetermine the direction of flow and the pre-sence or absence of stenosis or occlusion. In du-plex sonography, the PW Doppler and ultra-sound images (echo impulse) are combined forsimultaneous demonstration of blood flow(color-coded flow image) and tissue structures(tissue image). This permits visualization and

quantitation of stenosis, dissection, extracranialvasculitis, and vascular anomalies. TranscranialDoppler (TCD) and duplex sonography are usedto study the intracranial arteries, e. g., for steno-sis, occlusion, collateral flow, vasospasm (aftersubarachnoid hemorrhage), shunting (arteri-ovenous malformation or fistula), and hemody-namic reserve.

" Neuroimaging

The neuroradiologist can demonstrate struc-tural changes associated with neurological dis-ease with a number of different imaging tech-niques. When a patient is sent for a neuroimag-ing study, the reason for ordering the study andthe question(s) to be answered by it must beclearly stated. Interventional procedures in theneuroradiology suite are mainly performed totreat vascular lesions (embolization of an arteri-ovenous malformation, fistula, or aneurysm;thrombolysis; angioplasty; devascularization ofneoplasms; stent implantation).

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Imaging Study Indication/Objective1

Conventional radiography2Skull, spine

Metallic foreign bodies, air-filled cavities, fractures, skull defects, bonyanomalies, osteolysis, spinal degenerative disease

Computed tomography (CT)Head, spine, spinal canal, CT-guideddiagnostic interventions, 3-D recon-struction

Assessment of skeleton (anomalies, fractures, osteolysis, degenerativechanges, spinal canal stenosis), metastases, trauma, intracranialhemorrhage, cerebral ischemia, hydrocephalus, calcification, inter-vertebral disk disease, contrast studies3 (brain, spinal canal, CT angio-graphy)

Magnetic resonance imaging (MRI)4! Head, spine, spinal canal ! Tumors (brain, spine, spinal cord), infection (encephalitis, myelitis,

abscess, AIDS, multiple sclerosis), structural anomalies of the brain(epilepsy), leukodystrophy, MR angiography (aneurysm, vascularmalformation), ischemia of the brain or spinal cord, spinal trauma,hydrocephalus, myelopathy, intervertebral disk disease

! Skeletal muscle ! Muscular atrophy, myositisAngiography3,5Cerebral, spinal; preinterventional orpreoperative study6

High-grade arterial stenosis, aneurysm, arteriovenous malformation/fistula, sinus thrombosis, vasculitis

Myelography3,7 Largely replaced by CT and, especially, MRI. Used to clarify special di-agnostic questions in spinal lesions

Diagnostic nuclear medicine! Skeletal scintigraphy (“bone

scan”)! Tumor metastasis, spondylodiscitis

! CSF scintigraphy ! Intradural catheter function test, CSF leak! Emission tomography8 ! Cerebral perfusion, cerebral metabolic disorders, degenerative dis-

eases, diagnosis of epilepsy

1 Examples. 2 Plain radiographs, X-ray tomography. 3 Risks: allergy (! intolerance), latent hyperthyroidism (!thyrotoxicosis), thyroid carcinoma (! radioiodine therapy cannot be performed for a long time afterward), renalfailure, left heart failure (! pulmonary edema), plasmacytoma (! renal failure). 4 Gadolinium contrast agent canbe used to show blood–brain barrier lesions (e. g., acute multiple sclerosis plaques). T1-weighted scans: CSF/edema dark (hypointense), diploe/fat light (hyperintense), white matter light; gray matter dark. T2-weightedscans: CSF/edema light, scalp dark, diploe/fat light, muscle dark, white matter dark; gray matter light. Contrain-dications: Cardiac pacemaker, mobile ferromagnetic material. 5 Contraindicated in patients with coagulopathy. 6Endovascular or surgical therapy. 7 Rare complications: generalized epileptic seizures, meningitis, post–lumbarpuncture headache; acute transverse cord syndrome possible in patients with spinal tumors. Coagulopathy is acontraindication. 8 SPECT = single-photon emission computed tomography, PET = positron emission tomography.

" Tissue Biopsy

In certain cases, the provision of a definitive di-agnosis requires biopsy of nerve (usually thesural nerve, p. 391), muscle (a moderately af-fected muscle in myopathy, p. 399), or blood

vessels (e. g., the temporal artery in suspectedtemporal arteritis). These biopsies can usuallybe carried out under local anesthesia. Spinaltumors can be biopsied under CT or MRIguidance, and brain tumors and abscesses canbe biopsied with stereotactic technique.

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! Supplementary tables

! Detailed information

! Outlines

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Table 1 Cranial nerves (p. 28)

Pathway Cranial Nerve (CN)/Nucleus Functions

Somatosensory(afferent)

II Retina VisionIII Proprioceptors of extraocular mm.1 Proprioception2

IV Proprioceptors of extraocular mm. ProprioceptionV Semilunar ganglion, proprioceptors

of masticatory, tensor veli palatini,and tensor tympani muscles

Sensation in face, nose, nasal cavity, oralcavity; proprioception, dura mater (pp. 6,94)

VI Proprioceptors of extraocular mm. ProprioceptionVII Geniculate ganglion External ear, parts of auditory canal, outer

surface of eardrum (sensation)VIII Vestibular ganglion; spiral ganglion Balance/equilibrium; hearingIX Superior ganglion Middle ear, auditory tube (sensation)X Superior ganglion External auditory canal/dura mater of

posterior fossa (p. 5)

Visceral (afferent) I Olfactory cells of nasal mucosa SmellVII Geniculate ganglion Taste on anterior 2/3 of tongue (chorda

tympani), taste on inferior surface of softpalate (greater petrosal n.)

IX Inferior and superior ganglia Taste/sensation on posterior 1/3 oftongue, pharyngeal mucosa, tonsils, audi-tory tube (sensation)

X Inferior ganglion Abdominal cavity (sensation), epiglottis(taste)

Motor (efferent) III Oculomotor nucleus3 Extraocular mm. (except those suppliedby CN IV, VI), raise eyelid (levator palpe-brae superioris m.)

IV Trochlear nucleus Oblique eye movements (superior obliquem.)

V Motor nucleus of trigeminal n. Mastication,4 tensing of palate5 and tym-panic membrane6

VI Abducens nucleus Lateral eye movements (lateral rectus m.)VII Facial nucleus Facial muscles, platysma, stylohyoid and

digastric musclesIX Nucleus ambiguus Pharyngeal mm., stylopharyngeus m.X Nucleus ambiguus Swallowing (pharyngeal mm.), speech

(superior laryngeal nerve)XI Nucleus ambiguus, motor cells of

anterior horn of cervical spinal cordMuscles of pharynx and larynx, sternoclei-domastoid m.7 trapezius m.8

XII Hypoglossal nucleus Muscles of tongue

Visceral (efferent) III Parasympathetic, Edinger–Westphalnucleus

Pupillary constriction (sphincter pupillaem.), accommodation (ciliary m.)

VII Parasympathetic, superior salivatorynucleus

Secretion of mucus, tears, and saliva (sub-lingual and submandibular glands)

IX Parasympathetic, inferior salivatorynucleus

Secretion of saliva (parotid gland)

X Parasympathetic, dorsal nucleus ofvagus nerve

Lungs, heart, intestine to left colonicflexure (motor); glandular secretion (res-piratory tract, intestine)

1 Eye muscles. 2 See p. 104. 3 Nucleus. 4 Masseter, temporalis, lateral pterygoid, and medial pterygoid muscles.5 Tensor veli palatini m. 6 Tensor tympani m. 7 Shoulder elevation, scapular fixation, accompanying movementsof cervical spine. 8 Neck flexion and extension, head rotation.

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Table 2 Segment-indicating muscles (p. 32)

Segment Segment-indicating Muscle(s)

C4 Diaphragm

C5 Rhomboids, supraspinatus, infraspinatus, deltoid

C6 Biceps brachii, brachioradialis

C7 Triceps brachii, extensor carpi radialis, pectoralis major, flexor carpi radialis, pronatorteres

C8 Abductor pollicis brevis, abductor digiti quinti, flexor carpi ulnaris, flexor pollicis brevis

L3 Quadriceps femoris, iliopsoas; adductor longus, brevis et magnus

L4 Quadriceps femoris (vastus medialis m.)

L5 Extensor hallucis longus, tibialis anterior, tibialis posterior, gluteus medius

S1 Gastrocnemius, gluteus maximus

Tables 3 Types of tremor (p. 62)

Type Features

Physiological tremor (PT) Normal. Discrete, usually asymptomatic tremor of unclear significance.Isometric tremor may occur, e. g., when holding a heavy object.

Exaggerated PT, toxic or drug-induced tremor

Amplitude !PT, frequency = PT. Absent at rest. Mainly PosT.1 Stress(anxiety, fatigue, excitement, cold). Metabolic disturbances (hyperthyroidism,hypoglycemia, pheochromocytoma). Drugs/toxins (alcohol or drug with-drawal; mercury, manganese, lithium, valproic acid, cyclosporine A, amio-darone, flunarizine, cinnarizine, tricyclic antidepressants, neuroleptics ! tar-dive tremor)

Essential tremor (ET) Classical ET: PosT !KT 2. Approx. 60% autosomal dominant, rest sporadic.Hands !head !voice ! trunk. Often improved by alcohol.Orthostatic tremor: Occurs only when standing ! unsteadiness, hard tostand still.Task-specific tremor

Parkinsonian tremor RT 3 See p. 206. Postural and kinetic tremor may also be present.

Cerebellar tremor IT4 reflecting cerebellar dysfunction. Postural tremor and head/trunk tremormay be seen when the patient is standing (alcohol intoxication).

Holmes tremor (rubral, mid-brain tremor, myorhythmia)

RT + PosT + IT, mainly proximal, disabling. Associated with lesions of nigro-striatal and cerebello-thalamic pathways (multiple sclerosis, infarct)

(Poly-)neuropathic tremor RT, PosT, or IT, predominantly either proximal or distal. 3–10 Hz5

Palatal tremor Symptomatic (medullary lesion due to encephalitis, multiple sclerosis, brainstem infarct) or essential; clicking noise in ear

Psychogenic tremor Migrates from one part of the body to another. Accompanied by musclecontraction (co-contraction)

1 PosT = postural tremor. 2 KT = kinetic tremor. 3 RT = resting tremor. 4 IT = intention tremor. 5 Occurs inhereditary sensorimotor neuropathy type I, chronic demyelinating polyradiculitis, paraproteinemic neuropathy,diabetic neuropathy, and uremic neuropathy.

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Table 4 Midbrain syndromes (p. 71)

Anterior Midbrain Lesions (Peduncle, Weber Syndrome)

Cause. Infarct. Less commonly caused by hemorrhage, tumor (germinoma, teratoma, pineocytoma, pineoblas-toma, astrocytoma, tentorial edge meningioma, lymphoma), or multiple sclerosis.

Structure Affected Symptoms and Signs

Intramesencephalic fibers ofoculomotor n.

Ipsilateral oculomotor paralysis + parasympathetic dysfunction (pupil dilatedand unreactive to light)

Pyramidal tract Contralateral central paralysis + face (! supranuclear facial palsy) + spastic-ity. Dysarthria (supranuclear hypoglossal palsy)

Substantia nigra Rigidity (rare)

Medial Midbrain Lesions (Tegmentum, Benedikt Syndrome)

Cause. Same as in anterior lesions.


Intramesencephalic fibers ofoculomotor n.

Ipsilateral oculomotor paralysis + parasympathetic dysfunction (see above )

Medial lemniscus Contralateral impairment of touch, position, and vibration sense

Red nucleus Contralateral tremor (myorhythmia ! red nucleus syndrome, Holmestremor)

Substantia nigra Rigidity (variable)

Superior cerebellar peduncle Contralateral ataxia (! Claude syndrome)

Dorsal Midbrain Lesions (Tectum, Parinaud Syndrome)

Cause. Tumor of third ventricle, infarct, arteriovenous malformation, multiple sclerosis, large aneurysm ofposterior fossa, trauma, shuntmalfunction, metabolic diseases (Wilson disease, Niemann–Pick disease), infec-tious diseases (Whipple disease, AIDS)


Oculomotor nuclei Pathological lid retraction (Collier’s sign) due to overactivity of levatorpalpebrae superioris m. Over the course of the disease, accommodation isimpaired; the pupils become moderately dilated and unreactive to light, butthey do constrict on convergence (light-near dissociation)

Medial longitudinal fasciculus Supranuclear palsy of upward conjugate gaze (vertical gaze palsy ! theeyes move upward on passive vertical deflection of the head, but not volun-tarily). Convergence nystagmus with retraction of the eyeball on upwardgaze (retraction-convergence nystagmus)

Trochlear nucleus Trochlear nerve palsy

Aqueduct (compressed) Hydrocephalus (headache, papilledema)

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Table 4 Midbrain syndromes (continued)

Top of the Basilar Artery Syndrome

Cause. Large aneurysm of the basilar tip, thromboembolism in the upper basilar territory, vasculitis, complica-tion of angiography. (Central paralysis is not found.)

Site of Lesion Symptoms and Signs

Midbrain Unilateral or bilateral vertical gaze palsy; impaired convergence; retractionnystagmus. Sudden oscillations (sensation of movement of surroundingswhen walking or when moving head). Collier’s sign. Strabismus with di-plopia. Pupils may be constricted and responsive or dilated and unrespon-sive to light.

Thalamus, parts of temporaland occipital lobes

Visual field defects (homonymous hemianopsia, cortical blindness). Variablefeatures: Somnolence, peduncular hallucinations (dreamlike scenic halluci-nations), memory impairment, disorientation, psychomotor hyperactivity

Table 5 Pontine syndromes (p. 72)

Anterior Pontine Lesions (Ventral Pons)

Cause. Basilar artery thrombosis, hemorrhage, central pontine myelinolysis, brain stem encephalitis,tumors, trauma. Arterial hypertension (lacunar infarct).

! Mid Ventral Pons

Structures Affected Symptoms and Signs

Pyramidal tract Contralateral central paralysis sparing the face

Intrapontine fibers of trigemi-nal nerve

Ipsilateral facial hypesthesia, peripheral-type weakness of muscles of mas-tication

Middle cerebellar peduncle Ipsilateral ataxia

! Lacunar Syndromes1


Pyramidal tract Contralateral central paralysis, sometimes more pronounced in legs, with orwithout facial involvement

Middle cerebellar peduncle Ipsilateral ataxia, which may be accompanied by dysarthria and dysphagia,depending on the site of the lesion (dysarthria—clumsy hand syndrome)

1Similar syndromes can also occur in patients with supratentorial lacunas (internal capsule, thalamocortical path-ways).

! Locked-in Syndrome (p. 120)


Ventral pons (corticobulbar and corti-cospinal tracts) bilaterally, abducens nu-cleus, pontine paramedian reticular for-mation, fibers of trigeminal nerve

Quadriplegia, aphonia, inability to swallow, horizontal gaze palsy(including absence of caloric response), absence of corneal re-flex (risk of corneal ulceration)

Eyelid and vertical eye movements (supranuclear oculomotor tracts), sensation, wakefulness (reticular ascendingsystem), and spontaneous breathing remain intact.

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Table 5 Pontine syndromes (continued)

Dorsal Pontine Lesions (Pontine Tegmentum)

Cause. Same as in lesions of ventral pons.

! Oral (Superior) Pontine Tegmentum (Raymond–Céstan Syndrome)


Trigeminal nucleus/fibers Ipsilateral facial hypesthesia, peripheral paralysis of muscles of mastication

Superior cerebellar peduncle Ipsilateral ataxia, intention tremor

Medial lemniscus Contralateral impairment of touch, position, and vibration sense

Spinothalamic tract Contralateral loss of pain and temperature sensation

Paramedian pontine reticularformation (PPRF, “pontinegaze center”)

Ipsilateral loss of conjugate movement (loss of optokinetic and vestibularnystagmus ! PPRF lesion with intact vestibulo-ocular reflex (VOR, p. 84))


! Caudal Pontine Tegmentum



Nucleus/fibers of the facial n. Ipsilateral (nuclear = peripheral) facial palsy (! Millard–Gubler syndrome)

Fibers of abducens nerve Ipsilateral abducens paralysis (! Foville syndrome, eyes drift “away fromthe lesion”; loss of VOR)

Central sympathetic pathway Ipsilateral Horner syndrome

PPRF Loss of ipsilateral conjugate movement

Medial and lateral lemniscus Contralateral impairment of touch, position, and vibration sense

Lateral spinothalamic tract Contralateral impairment of pain and temperature sensation

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Table 6 Medullary syndromes (p. 73)

Medial Medullary Lesions

Cause. Occlusion of the anterior spinal artery or vertebral artery.


Hypoglossal n. nucleus/fibers Ipsilateral peripheral (nuclear) hypoglossal paralysis

Pyramidal tract Contralateral central paralysis sparing the face (flaccid, in isolated pyramidaltract lesions)

Medial lemniscus Contralateral impairment of touch, position, and vibration sense (pain andtemperature sensation intact)

Medial longitudinal fasciculus Upbeat nystagmus

Lateral Medullary Lesions (Dorsolateral Medullary Syndrome, Wallenberg Syndrome)

Cause. Occlusion of posterior inferior cerebellar artery (PICA) or vertebral artery. Less common causes: tumor,metastases, hemorrhage due to vascular malformations, multiple sclerosis, vertebral artery dissection (afterchiropractic maneuvers), trauma, gunshot wounds, cocaine intoxication.

Site of Lesion Symptoms and Signs

Spinal nucleus of trigeminalnerve

Ipsilateral analgesia/thermanesthesia of the face and absence of corneal re-flex with or without facial pain

Cochlear nucleus Ipsilateral hearing loss

Nucleus ambiguus Ipsilateral paralysis of the pharynx and larynx (hoarseness, paralysis of thesoft palate), dysarthria, and dysphagia. Tongue movement remains intact

Solitary nucleus Ageusia (impaired sense of taste)

Dorsal nucleus of vagus n. Tachycardia and dyspnea

Inferior vestibular nucleus Nystagmus away from the side of the lesion, tendency to fall toward theside of the lesion, nausea and vomiting

Central tegmental tract Ipsilateral myorhythmia of the soft palate and pharynx

Central sympathetic pathway Ipsilateral Horner syndrome

Reticular formation Singultus

Inferior cerebellar peduncle Ipsilateral ataxia and intention tremor

Anterior spinocerebellar tract Ipsilateral hypotonia

Lateral spinothalamic tract Contralateral loss of pain and temperature sensation with sparing of touch,position, and vibration sense (sensory dissociation)

Involvement of the lower pons produces diplopia. Occipital pain in Wallenberg syndrome is most commonly dueto vertebral artery dissection.

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Table 7 Syndromes affecting the facial muscles (p. 98)

Syndrome Etiology

Hypomimia or amimia Basal ganglia dysfunction (p. 206), depression

Blepharospasm, Meige syndrome, lid-openingapraxia, oromandibular dystonia, tics (p. 64 ff.)

Basal ganglia dysfunction

Melkersson–Rosenthal syndrome (recurrent swellingof face/lips, peripheral facial palsy, and fissuredtongue)

Unknown

Heerfordt syndrome (fever, uveitis, parotitis, periph-eral facial palsy)

Occasional manifestation of sarcoidosis, lymphoma.Cryptogenic

Bilateral peripheral facial paralysis Neuroborreliosis, Guillain–Barré syndrome, Fishersyndrome, botulism

Möbius syndrome Congenital bilateral facial palsy and cranial nerve in-volvement (bilateral: VI; unilateral: XII, IV, VIII, IX)

Synkinesis (involuntary co-movement of facialmuscles, e. g., narrowing of palpebral fissure whenthe lips are pursed); hemifacial spasm

Faulty regeneration of CN VII after facial palsy. Nerveroot compression and segmental demyelination inhemifacial spasm

Pseudobulbar palsy Multiple bilateral supratentorial or pontine vascularlesions

Myopathic facies Myopathic disorders (myotonic dystrophy, my-asthenia, facial-scapular-humeral muscular dystrophy)

Gustatory sweating (Frey syndrome) or lacrimation(“crocodile tears”)

Faulty regeneration of the auriculotemporal/facialnerve

Progressive facial hemiatrophy Unknown

Table 8 Neurological Causes of Dysphagia (p. 102)

Symptoms and Signs Site of Lesion Cause

Oral phase impaired and swallow-ing reflex delayed (slightly) be-cause of paralysis

SupratentorialUnilateral

Cerebral infarct, tumor or hemorrhage

Delayed swallowing reflex, aspira-tion (especially of fluids), pro-longed oral phase (pseudobulbarpalsy, akinesia, dysarthria, dys-phonia, salivation, oromandibulardystonia)

SupratentorialBilateral

Vascular lesions (single or multiple infarcts, hemor-rhage), trauma, tumor, multiple sclerosis, encephali-tis, parkinsonism, multiple system atrophy, Alzheimerdisease, Creutzfeldt–Jakob disease, hydrocephalus,dystonia (toxic/drug-induced), chorea, intoxication,cerebral palsy

Loss of swallowing reflex, im-paired pharyngeal phase, impairedcough reflex (bulbar palsy, dy-sarthria, respiratory disturbances),risk of aspiration

Brain stem,cerebellum

Vascular lesions, multiple sclerosis, tumor, trauma,amyotrophic lateral sclerosis, syringobulbia, poliomy-elitis, Arnold–Chiari malformation, central pontinemyelinolysis, listerial meningitis, spinobulbar muscu-lar atrophy, spinocerebellar degeneration

Weakness of muscles of mastica-tion, impaired oral phase, im-paired lip closure, nasal drip; im-paired pharyngeal phase (dy-sarthria) may occur: depending onwhich nerve/muscle is affected

Cranial nerves Facial paralysis, Guillain–Barré syndrome, diabeticneuropathy, amyloidosis, base of skull syndrome(p. 74)

Same as above (generalized my-opathy, dysphonia)

Neuromuscular Myasthenia, amyotrophic lateral sclerosis, Lambert–Eaton syndrome, botulism, polymyositis/dermatomy-ositis, scleroderma, hyperthyroidism, oculopharyn-geal muscular dystrophy, myotonic dystrophy, facial–scapular-humeral muscular dystrophy, nemaline my-opathy, inclusion-body myositis

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Table 9 Classification of pain1,2 (p. 108)

Type Clinical Features Etiology (examples)

Nociceptive pain (somatic,p. 110)3

Paresthesia, allodynia,4 loss of sensa-tion, readily localizable

Meralgia paresthetica, carpal tunnelsyndrome, skin lesion

Neuropathic pain, neural-gia (pp. 186, 318 ff.)

Severe pain in nerve distribution,paresthesiae, allodynia, sensory loss,pain on nerve pressure, readily localiz-able

Mononeuritis, polyneuropathy,trauma, nerve compression, trigemi-nal neuralgia, neuroma

Radicular pain (p. 319 f) Same as above + aggravated bystretching (e. g., Lasègue sign) ormovement

Herniated intervertebral disk, poly-radiculitis, leptomeningealmetastases, neurofibroma/schwan-noma

Referred pain See p. 110 See p. 110

Deafferentation pain,anesthesia dolorosa

Pain in an anesthetic or analgesicnerve territory

Plexus lesion, radicular lesion, trigemi-nal nerve lesion

Phantom limb pain Pain felt in an amputated limb Limb amputation

Central pain Burning, piercing pain in the region ofa neurological deficit; imprecisely lo-calizable; frequently accompanied bysensory dissociation, dysesthesia,paresthesia; triggered by stimuli

Cerebral infarct, hemorrhage, ortumor (cortex, thalamus, white mat-ter, internal capsule), brain stem, spi-nal cord; syrinx, trauma, multiplesclerosis (brain stem, spinal cord)

Chronic pain(“pain disease”)

Pain that lasts !6 months, impairssocial contacts, emotional state, andphysical activity

Sensitization of nociceptors? Transsy-naptic neuropeptide induction (calci-tonin gene-related peptide = CGRP,substance P = SP, neurokinin A =NKA)?

Psychogenic pain Discrepancy between symptoms andorgan findings and/or syndromeclassification

Mental illness

1 Selected types. 2 Features may overlap. 3 = nociceptor pain. 4 Pain evoked by a normally nonpainful stimulus.

Table 10 Sleep Characteristics Observed in Sleep Studies (p. 112)

Stage EEG1 EOG2 EMG3

Awake ! activity (8–13 Hz) Blinks, saccades High muscle tone, move-ment artifact

NREM stage 1 Increasing q activity(2–7 Hz), vertex waves4

Slow eye movements5 Slight decrease in muscletone

NREM stage 2 q activity, sleep spindles,6K-complexes7

No eye movement untilstage 4, EEG artifact

Further decrease in muscletone until stage 4

NREM stage 3 Groups of high-amplitude "waves (0.5–2 Hz, amplitude! 0.75 µV)

NREM stage 4 Groups of high-amplitude "waves

REM sleep q activity, saw-tooth waves8may be observed

Conjugate, rapid eye move-ments (episodic)

Low to medium muscletone

(Berger, 1992)

1 Electroencephalogram (EEG). 2 Electro-oculogram (EOG). 3 Electromyogram (EMG). 4 Steep parasagittal wavesof not more than 200 µV. 5 Slow eye movements (SEM). 6 Fusiform 11.5–14 Hz waves lasting 0.5–1.5 secondsand occurring 3–8 times/second. 7 Biphasic, initially negative " waves appearing spontaneously or in response toacoustic stimuli. 8 Grouped, regular q activity with a saw-toothed appearance.

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Table 11 Diagnostic criteria for death (“brain death”) (recommendations of the Scientific Advisory Council of theFederal Chamber of Physicians (Germany), 1998, p. 120)

Prerequisites Acute, severe brain damage (either primary or secondary)Exclusion of other causes1

Clinical criteria ComaAbsent light reflex, moderately to maximally dilated pupils2Absent oculocephalic reflex3Absent corneal reflex3Absent response to painful stimulation in trigeminal distributionAbsent pharyngeal and tracheal reflexes3Absence of spontaneous breathing4

Proof of irreversiblebrain damage

Required time of observation5

Supratentorial primary brain damageAdults and children over 2 years of age ! at least 12 hoursChildren under 2 years of age ! at least 24 hours6Neonates ! at least 72 hours6Infratentorial primary brain damageSame as supratentorial damage, but with at least 1 additional examination6

Secondary brain damageAdults and children over 2 years of age ! at least 72 hours

Supplementary criteria7Isoelectric EEGAbsence of evoked potentials8Absence of cerebral blood flow

1 Intoxication, pharmacological sedation, neuromuscular blockade, primary hypothermia, circulatory shock orcoma secondary to endocrine, metabolic or infectious disease. 2 Not due to mydriatic agents. 3 See p. 26. 4 Asshown by apnea test. 5 The clinical findings at the beginning and end of the observation period must be identi-cal. 6 At least one of the following supplementary criteria must be observed twice: isoelectric EEG, loss of earlyacoustic evoked potentials, demonstration of absent cerebral blood flow (by Doppler ultrasound or perfusionscintigram); standardized examination procedures must be strictly followed. 7 Once the prerequisites and clinicalcriteria have been met, the diagnosis of brain death can be made as soon as one of the supplementary criteriahas been met. 8 Early auditory, somatosensory cerebral or high cervical components of evoked potentials.

Table 11a Apnea test

Steps Measures/Objective Parameters To Be Measured

Prerequisites Body core temperature !36.5 °C1

Systolic blood pressure !90mmHg2

Positive fluid balance for more than 6 hours

Preparation Oxygenation: Inspiratory O2 concentration 100% PO2 !200 ( to 400) mmHg(54 kPa)3

Tidal volume: 10ml/kg body weight pCO2 "40mmHg (5.3 kPa)

Procedure4 Disconnect ventilator ! administer 100% O2 at rateof 6 to 8 l/min via thin catheter (tip at carina)

Monitor heart rate, blood pres-sure, SpO2, respiratory rate; ob-serve for chest or abdominalmovement; check ABG every 2–3minutes

Termination If no respiratory activity/movement is observed in 8minutes5

pCO2 !60mmHg (8 kPa) or pCO2rises by more than 20mmHg6

(2.7 kPa)

(Wijdicks, 2001)

1 Because hypothermia impairs CO2 production and O2 release from oxyhemoglobin. 2 Raise with 5% albuminsolution or increase intravenous dopamine when administered, if necessary. 3 Arterial blood gas (ABG) analysis.4 If blood pressure #90mmHg, O2 saturation #80%, and there is severe cardiac arrhythmia, stop the apnea testand put patient back on ventilator. 5 Reconnect ventilator, ventilate at 10/min. 6 If pCO2 baseline value of"40mmHg cannot be achieved (e. g., in patient with pulmonary disease).

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Table 12 Sites and manifestations of lesions causing dysarthria (p. 130)

Site of Lesion Manifestations Causes1

Periphery2 Slurred speech (impaired labial/lingual articulation,rhinolalia = “speaking through nose,” unclear differ-entiation of vowels and consonants), dyspnea, whis-pering (recurrent laryngeal nerve paralysis), hoarse-ness (laryngitis, vocal cord polyp, extubation)

Facial nerve palsy, myasthenia,amyotrophic lateral sclerosis,diphtheria, Guillain–Barré syn-drome, syringobulbia, tumor

Cerebellum/brain stem(pp. 54, 70)

Ataxic dysarthria (clipped, scanning speech), articula-tion problems. Hoarse, deep voice (vagus nerve le-sion)

See p. 278 f, multiple sclerosis, in-farction

Basal ganglia(nonpyramidaldysarthria)

Hypophonia (p. 206, monotonous, soft, slurred).Spasmodic dysphonia (p. 64). Hyperkinetic speech(p. 66; explosive, loud, uncoordinated, clippedspeech)

Parkinsonism, dystonia, chorea,tic, myoclonus

White matter/cortex

Monotonous, slow, hoarse, pressured speech. Deep,variable pitch. Poor articulation

Bilateral white-matter lesions(pseudobulbar palsy, lacunar in-farcts, multiple sclerosis), uni-lateral infarct

Diffuse Slurred, effortful, slow speech Intoxication, metabolic distur-bances

1 Examples; see also p. 64. 2 Pontine (bulbar paralysis), nuclear (2nd motor neuron), peripheral nerve or musclelesion.

Table 13 Types and causes of amnesia (amnesia, p. 134)

Type of Amnesia Manifestations Causes1/Site of Lesion

Transient globalamnesia2

Acute onset, limited duration. Patient repeatsquestions (e. g., “What am I doing here?”), ishelpless, anxious; can perform everyday activi-ties. Anterograde/retrograde amnesia

Ischemia (venous)? Migraine? Re-solves completely or nearly so

Acute transientamnesia

Anterograde/retrograde amnesia; manifestationsof underlying disease

Complex partial seizures (focalepilepsy). Posttraumatic phenom-enon

Acute persistentamnesia

Anterograde/retrograde amnesia; manifestationsof underlying disease

Bilateral infarction (hippocampus,thalamus, anterior cerebralartery). Trauma (orbitofrontal,mediobasal, diencephalic). Hy-poxia (cardiopulmonary arrest,carbon monoxide poisoning)

Subacute per-sistent amnesia

Many patients are initially confused, with antero-grade/retrograde amnesia; manifestations of un-derlying disease

Wernicke–Korsakoff syndrome.Herpes simplex encephalitis.Basilar meningitis (tuberculosis,sarcoidosis, fungi)

Chronic progres-sive amnesia

Anterograde amnesia; retrograde amnesiadevelops in the course of the condition; manife-stations of underlying disease

Tumor (3rd ventricle, temporallobe). Paraneoplastic “limbic” en-cephalitis (lung cancer). Alzheimerdisease. Pick disease

1 Examples. 2 Also called amnestic episode.

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Table 14 Classification of dementia (p. 136)

Cause Diagnostic criteria1

Alzheimer disease (p. 297 f) Mainly temporal and parietal lobe degeneration. Rarely hereditary (au-tosomal dominant). No focal neurological deficit. CSF: increasedacetylcholine, A!-amyloid, and " protein levels. Cognitive deficits: An-terograde amnesia, amnestic aphasia, acalculia, impaired visuospatialperformance. Behavioral changes: Hardly any at first; later anosognosiaor dissimulation, paranoia, disturbance of sleep–wake cycle.

Vascular dementia (p. 298) Subcortical vascular demyelination due to multiple infarcts, lacunes,vasculitis or CADASIL. Fluctuating course. Focal neurological signs:Hemiparesis, aphasia, apraxia, gait impairment, bladder dysfunction,Babinski sign. Pseudobulbar palsy (bilateral lesion of the corticobulbartracts ! dysarthrophonia or anarthria, dysphagia, lingual/facial paraly-sis, loss of emotional control with outbursts of laughing or crying).Cognitive deficits: Memory deficit (“forgetting to remember”), frontalbrain dysfunction (p. 122). Behavioral changes: Sluggishness, reduceddrive, disturbance of sleep–wake cycle

Depression Psychomotor slowing, reduced drive, and anxiety suggest dementia,which is not, in fact, present (pseudodementia). See Table 42, p. 383

Alcohol Korsakoff syndrome: Disorientation/amnesia, confabulation

Hydrocephalus Normal pressure hydrocephalus (p. 160)

Metabolic/endocrine disorders Wilson disease, hypothyroidism, hypopituitarism, hepatic/uremic en-cephalopathy, hypoglycemia, vitamin B12 deficiency, Wernicke en-cephalopathy, pellagra, hypoxia, hypoparathyroidism or hyperparathy-roidism, adrenocortical insufficiency, Cushing syndrome, acute inter-mittent porphyria (p. 332)

Tumor See p. 254 ff

Degenerative diseases Parkinson disease (p. 206 ff), atypical parkinsonism (p. 302), Hunting-ton disease (p. 300), frontotemporal dementia (p. 298), hereditaryataxia (p. 280), motor neuron disease (p. 304), multiple sclerosis

Infectious diseases (p. 222 ff) HIV and other viral encephalitides, prion diseases, neurosyphilis,Whipple disease, brain abscess, neurosarcoidosis, subacute sclerosingpanencephalitis

Trauma Chronic subdural hematoma, posttraumatic phenomenon, punch-drunk syndrome (dementia pugilistica)

Toxic Drugs, substance abuse, heavy metal poisoning, organic toxins

1 Mainly early manifestations are listed; these usually worsen and are accompanied by other manifestations asthe disease progresses.

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Table 15 The hypothalamic-pituitary regulatory axis (p. 142)

ControlledVariable(s)

Hormones Stimulus Effect Comments

Water balance andblood pressure

ADH

!

BP1

! Plasmaosmolality

Renal water reabsorptionand arterial vasoconstric-tion (at higher ADHlevels)

!

ADH: Diabetes in-sipidus; !ADH: ectopicproduction, SIADH(p. 310)

Triiodothyronine(T3), thyroxine (T4)

TRH, TSH

!

/ !T3/T4 TRH2 increase/decrease !TSH3

!TSH (basal) usuallyfound in primary hypothy-roidism;

!

TSH usuallyfound in hyperthyroidism

Cortisol CRH,ACTH4

!

/ ! Cortisol CRH5 increase/decrease !ACTH: Cushing syn-drome;

!

ACTH: second-ary adrenocortical insuffi-ciency

Testosterone (man) GnRH,LH, FSH6

!

/ ! Te-stosterone

GnRH7 increase/decrease

!

Testosterone: Decreasein muscle mass, loss of li-bido, hypospermia, im-potence

Estradiol, pro-gesterone(woman)

GnRH,LH, FSH

!

/ !

Estradiol,pro-gesterone

GnRH increase/decrease

!

LH/FSH: menstrual dis-turbances, breast/uterineatrophy, osteoporosis,atherosclerosis

Prolactin (PRL) PRL ! PRL!

PRL

!Dopamine8!

VIP9, TRH

!PRL: galactorrhea,amenorrhea, headaches

Growth(somatomedins)

GHRH,GH10

Variousstimuli

GHRH11

Somatostatin12Somatomedins mediatethe effect of GH. !GH:acromegaly;

!

GH: dwar-fism (children), weightgain, muscle atrophy

Endogenous opioidpeptides

!-endorphin(pituitarygland)

Variousstimuli

Analgesia, food intake,thermoregulation, learn-ing, memory

1 Blood pressure. 2 Thyrotropin-releasing hormone. 3 Thyroid-stimulating hormone of the anterior pituitary =thyrotropin. 4 Adrenocorticotropic hormone of the anterior pituitary = corticotropin. 5 Corticotropin-releasinghormone. 6 LH = luteinizing hormone, FSH = follicle-stimulating hormone (both anterior pituitary hormones);both are called gonadotropins. 7 Gonadotropin-releasing hormone. 8 Released from the hypothalamus; inhibitsprolactin release via pituitary D2 receptors. 9 Vasoactive intestinal peptide (anterior pituitary). 10 GH = humangrowth hormone. 11 Growth hormone-releasing hormone (stimulatory). 12 Released from hypothalamus (inhibi-tory).

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Table 16 Limbic syndromes (p. 144)

Syndrome Symptoms and Signs Site of Lesion1

Delirium, acute confusionalstate

Disturbances of consciousness, attention,perception, memory, sleep–wake cycle,and cognition. Visual hallucinations. Fluc-tuating motor hypoactivity and hyperac-tivity. Affective disturbances (anxiety, de-pression, irritability, euphoria, helpless-ness)

Bilateral mediobasal temporallobe (hippocampus, amyg-dala), hypothalamus

Pathological laughing andcrying

Uncontrollable emotional outbreaks. Seenin central paralysis (pseudobulbar palsy,amyotrophic lateral sclerosis, multiplesclerosis) and focal epilepsy (gelasticseizures). Stroke prodrome

Internal capsule, basal ganglia,thalamus, corticonuclear tract

Aggressive, violent behavior;fits of rage

Aggression with minimal or no provoca-tion, seen in focal epilepsy, head trauma,hypoxic encephalopathy, brain tumor,herpes simplex encephalitis, rabies, cere-bral infarction or hemorrhage, hypogly-cemia, intoxication (drugs, alcohol)

Mediobasal temporal lobe(amygdala)

Indifference, apathy, akineticmutism

Usually due to a primary illness such asAlzheimer or Pick disease, herpes simplexor AIDS encephalitis, hypoxic en-cephalopathy, cerebral infarction orhemorrhage

Bilateral septal area, cingulategyrus

Memory deficit, transitoryglobal amnesia (p. 134, Table13)

Korsakoff syndrome: impairment of short-term memory and sense of time. Othercognitive functions and consciousness areunimpaired

Both mamillary bodies,mediobasal temporal lobe

Disturbed sexuality Hypersexual behavior: after head traumaor stroke, or as a side effect of dopamin-ergic antiparkinsonian medication.Diminished libido: depression, medica-tions

Septal area, hypothalamus

1 The specified lesions do not always produce these syndromes, and the location and extent of the causative le-sion is often not known with certainty.

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Table 17 Tests for autonomic circulatory dysfunction (p. 148)

Dizziness, syncope, lack of concentration, forgetfulness or tinnitus should not be attributed to circula-tory dysfunction unless thorough diagnostic evaluation reveals a circulatory cause (see p. 166 ff).

Test Method Normal Findings

Tests of sympathetic function

Schellong test (orthostasistest)

Measure heart rate and blood pressureonce per minute for 10 minutes with thepatient supine, then 5 minutes with thepatient erect (tilt table if necessary)

Heart rate rises by no morethan 20 beats/min; systolicblood pressure drops no morethan 10mmHg, diastolic nomore than 5mmHg

Valsalva maneuver (VM) The patient inspires deeply and tries toexhale against resistance (up to40mmHg) for 10–15 seconds. The bloodpressure is measured before, during andafter the VM, or continuously

During VM, the blood pressuredoes not drop below 50% ofinitial value; after VM, theblood pressure reboundsabove the initial value (+ reflexbradycardia)

Hand grip test Isometric muscle contraction (hand grip)30% of maximal force for 3 minutes

Diastolic blood pressure!15mmHg

Tests of parasympathetic func-tion

Schellong test with 30/15quotient

Continuous ECG recording Quotient of R-R interval of30th and 15th heart beat afterstanding up is !1

Respiratory sinus arrhythmia(respiratory test)

ECG recorded with patient supine andbreathing maximally deeply at 6/min for atotal of 8 cycles. Repeat after a period ofrest

The quotient of the longest(expiration) and shortest R-Rintervals is normally !1.2(age-dependent)

VM with ECG Continuous ECG recording Quotient of longest and short-est R-R interval is !1 (age-de-pendent)

Carotid sinus massage1 Perform unilateral carotid sinus massagefor 10–20 seconds while continuouslymonitoring blood pressure and ECG withemergency resuscitation equipment ready

Reflex decrease in heart rateand blood pressure

(Low, 1997)

1 Contraindicated in carotid stenosis. Risk of cardiac arrest and ischemic stroke.

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Table 18 Respiratory disturbances in neurological disease (p. 150)

Hypoventilation

Site of lesion Causes

Brain stem, upper cervical spinal cord Tumor, infarction, hemorrhage, meningoencephalitis (Lis-teria, poliomyelitis), trauma, multiple sclerosis, intoxica-tion, parkinsonism (rigidity of respiratory muscles)

Motor anterior horn cell Amyotrophic lateral sclerosis, tetanus, poliomyelitis, post-polio syndrome

Peripheral nerve Guillain–Barré syndrome, phrenic nerve lesion

Neuromuscular Myasthenia gravis, botulism, Lambert–Eaton syndrome,muscular dystrophy, polymyositis, acid maltase deficiency,electrolyte imbalance (Na

!

, K

!

, Ca !, phosphate

!

, Mg !)

Hyperventilation

Possible metabolic changes

Ca2+

!

! carpopedal spasm, paresthesiae,tetany; Phosphate

!

! weakness;pH !! dizziness, visual disturbances, syncope,seizures

Pneumonia, pulmonary embolism, asthma, acidosis (dia-betic, renal, lactate !), meningoencephalitis, brain tumor,fever, sepsis, salicylates, anxiety, pain, psychogenic

Table 19 Neurological causes of gastrointestinal dysfunction (p. 154)

GI Syndrome1 Manifestations Causes2

Dysphagia See p. 102 Table 8

Gastroparesis Delayed gastric emptying !nausea, vomiting, anorexia, bloat-ing

Diabetes mellitus, amyloidosis, paraneoplastic syn-drome, dermatomyositis, Duchenne-type musculardystrophy

Intestinalpseudo-obstruction

Impaired intestinal motility !nausea, vomiting, bloating,weight loss, impairment ofperistalsis

Parkinson disease, multiple sclerosis, transverse spi-nal cord syndrome, Guillain–Barré syndrome, dia-betes mellitus, botulism, amyloidosis, paraneoplasticsyndrome, drugs (tricyclic antidepressants, codeine,morphine, clonidine, phenothiazines, anticholiner-gics, vincristine), Hirschsprung disease

Constipation3 Highly variable. Infrequent hardstools, straining, bloating, sensa-tion of incomplete defecation,pain, flatulence, belching

Lack of exercise, dysphagia, poor nutrition, trans-verse spinal cord syndrome, head trauma, brain stemlesions, Parkinson disease, multiple system atrophy,multiple sclerosis, diabetes mellitus, porphyria, drugs(morphine, codeine, tricyclic antidepressants)

Diarrhea4 !Defecation rate, liquid stools,tenesmus

Diabetes mellitus, amyloidosis, HIV infection, drugs,Whipple disease

Vomiting5 Gagging, yawning, nausea, hyper-salivation, pale skin, outbreaks ofsweating, apathy, low blood pres-sure, tachycardia

Intracranial hypertension (p. 158), vertigo (p. 58), mi-graine, infectious and neoplastic meningitis, drugs(digitalis, opiates, chemotherapeutic agents), intox-ication

Anal inconti-nence

Complete or partial loss of controlof defecation

Diabetes mellitus, multiple sclerosis, spinal cord le-sions, lesion of the conus medullaris or cauda equina,dementia, frontal lobe lesions (tumor, infarction)

1 Gastrointestinal syndrome. 2 Neurological diseases often associated with gastrointestinal syndromes or neuro-genic causes of such syndromes. 3 Normal frequency of defecation is ca. 3 times a week (variable). 4. Upperlimit of normal frequency of defecation, ca. 3 times/day. In diarrhea, the stool weight is !200 g/day. In pseudodi-arrhea, the defecation rate in increased but the stool weight is not. Diarrhea must be differentiated from anal in-continence. 5 Vomiting is regulated by a “vomiting center” in the reticular formation, which lies between theolive and solitary tract. Input: Chemoreceptors of the area postrema (p. 140), vestibular system, cortex, limbicsystem, gastrointestinal and somatosensory afferents. Output: Phrenic nerve (diaphragm), spinal nerve roots (res-piratory and abdominal musculature), vagus nerve (larynx, pharynx, esophagus, stomach).

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Table 20 Neurogenic bladder dysfunction (p. 156)

Site of Neuro-logical Lesion

Neurological Condition Type of Bladder Dysfunction

Supratentorial Stroke (frontal cortex, motorpathway)

Frequency !, urge !1, urge incontinence2, detrusorhyperreflexia

Parkinson disease Detrusor hyperreflexia, bladder hypocontractility

Frontal brain tumor Frequency !, urge !, urge incontinence

Dementia Usually a late manifestation: frequency !, urge incon-tinence

Supratentorialand infraten-torial

Multiple sclerosis3 (variable distur-bances depending on site ofplaques)

Frequency !, urge !, imperative urinary urge, urgeincontinence, detrusor hyperreflexia, DSD4

Amyotrophic lateral sclerosis Frequency !, urge incontinence, detrusor hyper-reflexia

Multiple system atrophy Nocturia, frequency !, urge incontinence, impairmentof voluntary voiding

Spinal cord5 Trauma, tumor, ischemia, myelitis,multiple sclerosis, cervical my-elopathy, spinal arteriovenousfistula

Lesion above S2 (“reflex bladder”) ! hyperreflexia,residual urine, DSDLesion of sacral micturition center (“autonomic blad-der”) ! residual urine, detrusor areflexia, impairedbladder reflex

Cauda equina,peripheralnerves

Autonomic neuropathy (e. g., dia-betes mellitus, paraneoplastic syn-drome, Guillain–Barré syndrome,drugs, toxins), trauma, lumbarcanal stenosis, myelodysplasia,tumor, herpes zoster, arachnoid-itis, disk herniation

Residual urine, detrusor areflexia, impaired bladderreflex, impaired filling sensation, frequency

!

1 Pollakisuria. 2 Urge incontinence ! involuntary passage of urine on strong (imperative) urinary urge. 3 Urinarytract infections are frequent. 4 Detrusor-sphincter dyssynergy. 5 Spinal shock with detrusor areflexia (bladderatony, “shock bladder”) and residual urine formation (overflow incontinence). Overdistention of the bladder canlead to a sharp rise in blood pressure accompanied by headache, dizziness, and hyperhidrosis above the level ofthe spinal lesion.

Table 21 Causes of intracranial hypertension (p. 158)

Pathogenetic Mechanism Causes

Mass lesion Hematoma (epidural, subdural, intracerebral), brain tumor/metastasis, brain abscess

CSF outflow obstruction Hydrocephalus

Increased brain volume Pseudotumor cerebri, infarct, global hypoxia or ischemia,hepatic encephalopathy, acute hyponatremia

Increased brain volume and increasedintravascular blood volume

Head trauma, meningitis, encephalitis, eclampsia, hyper-tensive encephalopathy, venous sinus thrombosis

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Table 22 Causes of intracranial hypotension (p. 160)

PathogeneticMechanism

Findings Causes

Impaired spinalCSF circulation1

Absence of pressure rise inQueckenstedt test

Tumor, arachnoiditis, herniated intervertebral disk

CSF leak Spinal dural defect, rhinor-rhea, otorrhea

Prior LP2, trauma, neurosurgical procedures, tumor,osteomyelitis

Dehydration Thirst, dry skin, fatigue,low blood pressure, light-headedness or uncon-sciousness

Isotonic, hypotonic: Vomiting, diarrhea, diuretics. Hyper-tonic: Thirst, profuse sweating, mannitol administration

Spontaneous Low ICP Spinal CSF fistula (?)

1 In a complete blockade, the pressure decreases sharply when small volumes of fluid are removed. In that case,there is a risk of aggravation of spinal compression syndrome due to incarceration.2 Lumbar puncture.

Table 22a Causes of transient monocular blindness (amaurosis fugax, p. 168)

Site and Type of Lesion Cause

Retinal vessels—embolic Atheroembolic/thromboembolic (e. g., internal carotid artery dissection/stenosis),cardioembolic (right–left shunt, e. g., in patent foramen ovale, thrombus in atrialfibrillation, mitral valve defect, acute myocardial infarction, endocarditis, artificialheart valve)

Retinal vessels—ischemic Low perfusion pressure (orthostatic hypotension, arteriovenous shunt, intracranialhypertension, glaucoma); high perfusion resistance (migraine, glaucoma, malig-nant arterial hypertension, increased blood viscosity, retinal venous thrombosis,vasospasm)

Retina Retinal detachment, paraneoplastic (p. 388), chorioretinitis, blow to eye

Orbit/eyeball Tumor, subluxation of lens, vitreous body hemorrhage

Optic nerve Vascular (ischemia, arteritis [p. 180], malignant arterial hypertension), papil-ledema, retrobulbar neuritis (Uhthoff sign, p. 216)

Unknown Blowing the nose, malaria, pregnancy, hypersensitivity to cold, interleukin-2,acute stabbing pain, sinus lavage

(Gautier, 1993; Warlow et al., 2001)

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Table 23 Causes of chronic daily headache (p. 182)

Type of Headache Symptoms and Signs/Syndromes

Primary headache

Chronic tensionheadache

See p. 182

Migraine Mild to severe, often unilateral pain (transformed migraine). Additional migraine at-tacks (p. 184)

Atypical facial pain Unilateral or bilateral pain, often predominantly felt in the nasolabial or palatal region,often very severe. Unresponsive to a wide variety of medical and surgical therapies.Normal findings on a wide variety of diagnostic tests (“diagnosis of exclusion”)

Secondary headache Posttraumatic, drug-induced, vascular (p. 182), intracranial mass, hydrocephalus, sinusi-tis, parkinsonism, cervical dystonia, myoarthropathy of the masticatory apparatus,1mental illness (depression, schizophrenia, hypochondria), cervical spine lesions(degenerative lesions, fractures, Klippel–Feil syndrome), Down syndrome, basilar im-pression, osteoporosis, skull metastasis, spondylitis, rheumatoid arthritis, lesions of cer-vical spinal cord/meningismus (tumor, hemorrhage, syringomyelia, cervical myelopathy,von Hippel–Lindau syndrome, meningitis, carcinomatous meningitis, intracranial hypo-tension)

1 Temporomandibular joint dysfunction, oromandibular dysfunction.

Table 24 Prognostic factors in epilepsy (p. 198)

Favorable Prognostic Factors Unfavorable Prognostic Factors

One seizure type Multiple seizure types

No interictal neurological deficit Interictal neurological deficit

Older age of onset Younger age of onset

Seizures secondary to a treatable disease Spontaneous seizures

Individual seizures of short duration Status epilepticus

Frequent seizures Infrequent seizures

Good response to anticonvulsants Poor response to anticonvulsants

(Neville, 1997)

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Table 25 Causes of syncope (p. 200)

Cause Underlying Condition/Trigger

Cardiac Arrhythmia (bradyrhythmia, tachyrhythmia, or reflex arrhythmia), heart disease (e. g.,cardiomyopathy, myxoma, mitral stenosis, congenital malformation, pulmonary em-bolism)

Hemodynamic Hypovolemia, hypotension (vasovagal as an emotional reaction to pain, anxiety, suddenshock, sight of blood; hypotension from prolonged standing, heat, exhaustion, alcohol;multiple system atrophy; polyneuropathies, e. g., amyloid, hereditary, toxic; polyradicu-lar neuropathies/Guillain–Barré syndrome; antihypertensive agents, nitrates, otherdrugs; postural orthostatic tachycardia syndrome = POTS; paraplegia above T6)

Cerebrovascular Subclavian steal syndrome, basilar migraine, Takayasu disease

Metabolic Hypoglycemia, hyperventilation, anemia, anoxia, postprandial (older individuals)

Miscellaneous Coughing fit (cough syncope = tussive syncope = laryngeal syncope), micturition (mic-turition syncope), defecation, prolonged laughing (“laughing fit”, geloplegia), glos-sopharyngeal neuralgia, affect-induced respiratory convulsion in childhood (breath-holding spells), pop concerts (teenage females), lying in supine position during preg-nancy (supine syndrome)

(Bruni, 1996; Lempert, 1997)

Table 26 Causes of sudden falling without loss of consciousness (p. 204)

Type of Fall/Pathogenesis Cause Features

Drop attack TIA1 in vertebrobasilar territory Usually accompanied by dizziness,diplopia, ataxia, or paresthesias

TIA in anterior cerebral arteryterritory

Seen when the two anterior cere-bral arteries arise from a commontrunk

Colloid cyst of 3rd ventricle Position-dependent headache

Posterior fossa tumor Sudden fall after flexion of neck

Parkinsonism Parkinson disease, multiplesystem atrophy

See p. 206 f

Muscle weakness Myopathy, Guillain–Barré syn-drome, polyneuropathy, spinallesions

See p. 50 f

Spinal or cerebellar ataxia, gaitapraxia

Funicular myelosis, cerebellarlesions, metabolic encephalo-pathies, hydrocephalus, lacunarstate, cervical myelopathy, multi-ple sclerosis

See specific diseases

Cryptogenic Unknown Occurs in women over 40 whilewalking

Vestibular disorder Ménière disease (vestibular dropattack ! Tumarkin otolithic crisis);occasionally due to otitis media,toxic or traumatic causes

Dizziness, nausea, nystagmus, tin-nitus. Vestibular drop attacks mayoccur in isolation

Cataplexy Loss of muscle tone triggered byemotional stimuli (fright, laughter,anger)

Alone or with narcolepsy

1 Transient ischemic attack.

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Table 27 Diagnostic criteria for multiple sclerosis (pp. 216, 218)

Manifestations Additional Information Needed for Diagnosis

Two or more episodes; objective eviden-ce1 of 2 or more lesions

None

Two or more episodes; objective evidenceof 1 lesion

Disseminated lesions (MRI2) or two or more MS-typical lesions(MRI and positive CSF tests3) or relapse4

One episode; objective evidence of 2 ormore lesions

Dissemination of lesions over time (MRI5) or relapse

One episode; objective evidence of 1 le-sion (monosymptomatic syndrome)

Disseminated lesions (MRI2) or two or more MS-typical lesions(MRI + positive CSF findings3) + dissemination of lesions overtime (MRI5) or relapse

Gradual worsening of neurologicalmanifestations suggestive of MS

Positive CSF findings3 + disseminated lesions6 or pathologicalVEP + 4–8 cerebral lesions7 + dissemination of lesions over time(MRI5) or continuous progression for 1 year

(McDonald et al., 2001)

1 MRI, CSF, visual evoked potentials (VEP). 2 For special criteria, see McDonald et al., 2001. 3 Oligoclonal im-munoglobulin, elevated IgG index. 4 Topographic-anatomic classification differs from that of previous episodes.5 Follow-up examination after an interval of at least 3 months; for special criteria, see McDonald et al., 2001.6 Nine or more cerebral lesions or two or more spinal lesions or 4–8 cerebral lesions + 1 spinal lesion. 7 Inpatients with fewer than 4 cerebral lesions, at least 1 additional spinal lesion must be observed by MRI.

Table 28 Therapeutic guidelines for meningoencephalitis (p. 224)

Clinical Features Additional Findings Treatment1

Previously healthy patient Gram-positive cocci in CSF Vancomycin + cephalosporin

Gram-negative cocci in CSF Penicillin G

Gram-positive bacilli in CSF Ampicillin or penicillin G +aminoglycoside3

Gram-negative bacilli in CSF Cephalosporin2 + aminoglycoside3

Previously healthy patient Negative CSF Gram stain5 Bacterial infection suspected:cephalosporin2. Age !50 years +ampicillinViral infection suspected: influenzaA, amantadine or rimantadine;herpes simplex (p. 236); cytome-galovirus (p. 244); poliovirus(p. 242); HIV (p. 241); varicellazoster (p. 239)

Septic focus (e. g., mastoiditis),neurosurgery, head trauma

Supportive evidence from imagingstudy, e. g., CT with bone windows

Vancomycin + cephalosporin2

Immune deficiency/immunosup-pressant therapy4

(possible) Brain stem signs, Gram-negative bacilli in CSF

Ampicillin + ceftazidime

Nosocomial infection (possible) Gram-negative bacilli inCSF

Cephalosporin2 + e. g., oxacillin orfosfomycin + aminoglycoside3

Focal neurological signs Temporal lobe process demon-strated by EEG, CT and/or MRI

Acyclovir (p. 236)

Spinal and radicular pain Spinal epidural abscess confirmedby imaging study (MRI, myelogra-phy, or CT)

Cephalosporin2 + (e. g.) oxacillinor fosfomycin + aminoglycoside3.Surgery

Neonate ("3 months of age) Negative CSF Gram stain Ampicillin + cephalosporin2

1 Drugs recommended by Quagliarello and Scheld (1997). 2 E.g., cefotaxime or ceftriaxone. 3 Gentamycin or to-bramycin. 4 Predisposes to tubercular, fungal, and other opportunistic infections (pp. 233, 245 f). 5 Aseptic/viralmeningitis, p. 234.

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Table 29 Bacteria commonly causing meningitis and meningoencephalitis (p. 226)

Pathogen Portal of Entry/Focus Clinical Features

Pneumococcus (S. pneumoniae/Gram+ extracellular diplococ-cus) ! adults1

Nasal and pharyngeal mucosa,head trauma, neurosurgicalprocedures, external CSFdrainage

Meningitis may be accompanied orpreceded by sinusitis, otitis media orpneumonia. Posttraumatic meningitismay occur several years after trauma; re-current meningitis (CSF leak? Im-munodeficiency?). Course may be hyper-acute (nonpurulent meningitis2), acute orsubacute (days to weeks). Epilepticseizures. Risk of brain abscess, subduralempyema or cerebral vasculitis

Meningococcus (N. meningitid-is3/Gram– intracellular diplo-coccus) ! children and ado-lescents4

Nasopharynx Hyperacute course with sepsis,adrenocortical insufficiency and consump-tion coagulopathy (Waterhouse–Frider-ichsen syndrome). Petechial or confluentcutaneous hemorrhages. Myocarditis/peri-carditis

Haemophilus influenzae (Gram–

bacillus) ! children and ado-lescents

Nasal and pharyngeal mucosa Usually type B. May be accompanied orpreceded by sinusitis, otitis media, orpneumonia

Listeria (L. monocytogenes/Gram+/organism difficult toidentify) ! neonates5, adults!50 years of age

Gastrointestinal tract (con-taminated food, e. g., dairyproducts or salads)

Focal neurological deficits, particularlybrain stem encephalitis (rhombencephali-tis), are commonly seen.Predisposing factors: pregnancy, old age,alcoholism, immune suppression, primarymalignancy. CSF findings are extremelyvariable (“mixed cell picture”)

Staphylococcus (S. aureus/Gram+) ! neonates and adultsEnterobacter (Gram–/bacilli)! neonates

Endocarditis, head trauma, ex-ternal CSF drainage, lumbarpuncture, urinary tract,spondylodiskitis

In association with sepsis, i. v. drug use,alcoholism, diabetes mellitus, primarymalignancy

M. tuberculosis (acid-fast bacil-lus)

Extracerebral organ tuberculo-sis

See p. 232

Gram+ = Gram-positive; Gram– = Gram-negative.1 Age !18 years. 2 Very rapidly progressive meningitis, low cell count and high total protein and lactate levels inCSF, and CSF smear culture containing large quantities of bacteria. 3 Group A, Central Africa, South America;Group B, Europe; Group C, North America; type may change. 4 Age 3 months to 18 years. 5 Age "3 months.

Table 30 Viruses causing CNS infection (p. 234)

Common Occasional Rare

Meningitis

Enteroviruses1,3, arboviruses2,3,HIV5, HSV type 24

HSV type 14, LCMV3, mumpsvirus3

Adenoviruses4, CMV4, Epstein–Barr virus(EBV)4, influenza virus A+B3, measlesvirus3, parainfluenza virus3, rubella virus3,varicella-zoster virus (VZV)4

Encephalitis, myelitis

Arboviruses, enteroviruses,HSV type 1, mumps virus

CMV, EBV, HIV, measles virus3,VZV

Adenoviruses, influenza A, LCMV, parain-fluenza virus, rabies virus3, rubella virus,HTLV-I5,6

1 Poliovirus 1–3, coxsackievirus (B5, A9, B3, B4, B1, B6), echovirus (7, 9, 11 30, 4, 6, 18, 2, 3, 12, 22), enterovirus(70, 71). 2 Arthropod-borne viruses, including alphaviruses, flaviviruses, pestiviruses, bunyaviruses, and or-biviruses. 3 RNA virus. 4 DNA virus. 5 Retrovirus. 6 Human T-cell lymphotropic virus type I causes myelitis.

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Table 31 Grades of malignancy of brain tumors (p. 264)

Tumor Grade I(benign)

Grade II(semi-benign)

Grade III(malig-nant)

Grade IV(malig-nant)

Neuroepithelial tumorsAstrocytoma! Fibrillary, protoplasmic, gemistocytic astrocytoma +++ ++! Anaplastic astrocytoma +++! Glioblastoma ( = glioblastoma multiforme) +++! Pilocytic astrocytoma +++ +! Pleomorphic xanthoastrocytoma +++ ++

Oligodendroglioma! Oligodendroglioma +++! Anaplastic oligodendroglioma +++

Ependymoma! Ependymoma (cellular, papillary, epithelial) ++ +++ ++! Anaplastic ependymoma +++

Mixed glioma! Oligoastrocytoma +++! Anaplastic oligoastrocytoma +++

Choroid plexus tumors! Plexus papilloma +++! Plexus carcinoma +++ ++

Neuronal/mixed neuronal-glial tumors! Gangliocytoma +++! Ganglioglioma +++! Anaplastic ganglioglioma +++

Pineal tumors! Pineocytoma +++ ++! Pineoblastoma (PNET) +++

Embryonal tumors! Primitive neuroectodermal tumor (PNET), see p. 260 +++! Neuroblastoma +++

Cranial nerve tumors! Schwannoma +++

Meningeal tumors! Meningioma +++! Anaplastic meningioma +++

Blood vessel tumors! Hemangiopericytoma +++ ++! Glomus tumor +++

Lymphoma! Primary CNS lymphoma ++ +++

Germ cell tumors! Germinoma +++

Intra- and suprasellar tumors! Pituitary adenoma +++ +! Craniopharyngioma +++

Metastatic tumors +++

(Kleihues et al., 1993 and Krauseneck, 1997)

+++, Common; ++, Rare; +, Very rare.

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Table 32 Karnofsky performance scale for quantification of disability (p. 264)

General Condition % Comments

Patient can perform normal daily activities andwork without impairment

100 Normal; no complaints; no evidence of disease

No specific treatment required 90 Able to carry on normal activity; minor impair-ment

80 Normal activity with effort; some impairment isclearly evident

Patient cannot work; can meet most personalneeds, but needs some degree of assistance; canbe cared for at home

70 Cares for self; cannot perform normal activitiesor work

60 Needs occasional assistance, but can meet mostpersonal needs

50 Needs considerable assistance and frequentmedical care

Patient cannot care for self; needs to be cared forin a hospital, nursing home, or at home by anurse/family members. Disease may progressrapidly

40 Disabled; requires special care and assistance;home nursing care still possible

30 Severely disabled; hospitalization indicated al-though death not imminent

20 Gravely ill; hospitalization necessary10 Moribund

Table 33 Glasgow coma scale (p. 266)

I II IIIEye Opening Score Best Verbal Response Score Best Motor Response (arms) Score

Obeys commands 6

Oriented 5 Selectively avoids painful stimuli 5

Spontaneous 4 Confused 4 Withdraws limb from painfulstimuli

4

To speech 3 Single words 3 Flexes limb in response to painfulstimuli

3

To pain 2 Meaningless utterances 2 Extends limb in response to pain-ful stimuli

2

No response 1 No response 1 No response 1

(Teasdale, 1995)

The scores in columns I, II, and III are summed to yield the overall value.GCS 13–15 = mild head trauma; GCS 9–12 = moderate head trauma; GCS 3–8 = severe head trauma.

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Table 34 Criteria for assessment of head trauma (p. 266)

Severity (GCS)1 Risk ofSecondaryInjury2

Symptoms and Signs 3

Mild (13–15) Low Impairment of consciousness lasting !1 hourAsymptomatic (or, at most: headache, dizziness, bruises, and lacera-tions)

Moderate (9–12) Moderate Impairment of consciousness at time of accident or thereafter, last-ing between 1 and 24 hoursIncreasingly severe headacheAlcohol/drug intoxicationNo reliable description of accident. Multiple trauma, severe facial injur-ies, basilar skull fracture, suspicion of depressed skull fracture or openhead injury. Posttraumatic ! epileptic seizure, vomiting, amnesiaAge !2 years (except in minor accidents), possibility of child abuse

Severe (3–8) High Impairment of consciousness lasting !24 hours + brain stem syn-drome orImpairment of consciousness lasting "24 hours orPosttraumatic psychosis lasting "24 hoursImpairment of consciousness not due to alcohol/substance abuse/medi-cations, and not a postictal or metabolic phenomenonFocal neurological signsDepressed skull fracture, open head injury

(White and Likavec, 1992)1 Glasgow Coma Scale. 2 Patients with one or more manifestations from the list at right belong to the corre-sponding risk group. 3 Criteria for assessment of severity are in bold type.

Table 35 Late complications of head trauma (p. 268)

Complications Clinical Features Remarks

Posttraumatic syn-drome

Headache, nausea, vertigo, orthostatichypotension, depressed mood, irritability,fatigue, insomnia, impaired concentration

Usually follows mild head trauma; maycause significant psychosocial impairment

Chronic subduralhematoma (SDH)

Headache, behavioral change, focal signs Usually follows mild trauma (predisposingfactors: old age, brain atrophy, alco-holism)

Subdural hygroma Same as in chronic SDH Symptoms may improve when the patientis lying down and worsen on standing

CSF leak Drainage of CSF from the nose or ear; riskof recurrent meningitis, brain abscess

CSF rhinorrhea worsens on head flexion.CSF otorrhea indicates a laterobasal skullfracture

Hydrocephalus Headache, behavioral change, urinary in-continence

Normal pressure hydrocephalus, venoussinus thrombosis

Epilepsy Focal/generalized seizures May arise years after head trauma

Encephalopathy Behavioral changes See p. 122 ff. Types include septic en-cephalopathy, punch-drunk en-cephalopathy (p. 302, Table 44)

Critical illness neu-ropathy and my-opathy

Prolonged ventilator dependence, weak-ness

Associated with sepsis and multiple organfailure

Heterotopic ossifi-cation (myositisossificans)

Restricted mobility of joints, pain Due to muscle trauma

Complications ofimmobility

Bed sores, peripheral nerve lesion, jointmalposition

Ensure proper positioning and frequentchanges of position (especially of para-lyzed limbs)

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Table 36 Spinal fractures (p. 272)

Fracture/Dislocation Pathogenesis Stability1

Cervical spine

! Atlantoaxial dislocation ! Dislocation between C1 and C2 ! Unstable! Jefferson’s fracture2 ! Axial trauma ! Unstable! Dens fracture ! Hyperflexion ! Unstable3! Bilateral axis arch fracture4 ! Hyperflexion and distraction ! Unstable! Dislocation fracture of C3–7 ! Hyperflexion ! Unstable! Lateral compression fracture ! Flexion and axial compression ! Stable

Thoracic spine, lumbar spine

! Compression fracture Fall (back, buttocks, extended legs),direct trauma. These fractures may bepathological (osteoporosis, myeloma,metastasis)

! Stable

! Burst fracture ! Stable! Dislocation fracture ! Unstable

(Ogilvy and Heros, 1993; Sartor 2001)

1 At the time of injury. 2 Fracture of the ring of C1 due to compression between the occiput and C2. 3 May beoverlooked if the dens is not displaced; sometimes stable. 4 Hangman’s fracture.

Table 37 Classification of traumatic transverse spinal cord syndrome (p. 274)

Loss of Function Category Features

Complete A No sensory or motor function, including in S4–5

Incomplete B No motor function. Sensory function intact below level of lesion,including in S4–5

Incomplete C There is motor function below level of lesion; most segment-in-dicating muscles have strength !3

Incomplete D There is motor function below level of lesion; most segment-in-dicating muscles have strength "3

None E Normal motor and sensory function

(American Spinal Cord Injury Association Impairment Scale; Ditunno et al., 1994)

Table 38 Treatment of spinal trauma (p. 274)

Result of Trauma Treatment Measures

Neck sprain/whiplash in-jury

Analgesics, application of heat/cold, immobilization (as brief as possible). Early in-itiation of active exercise therapy. Measures to prevent chronification

Fracture Stable ! conservative (extension/fixation). Unstable ! surgery

Arterial dissection Anticoagulation

Spinal cord trauma Methylprednisolone (i. v.) within 8 hours of trauma (bolus of 30mg/kg over 15min, then 5.4mg/kg/h for 23 hours). Monitor respiratory and cardiovascular func-tion, bladder/bowel function; thrombosis prophylaxis, pain therapy, carefulpatient positioning and pressure sore prevention. Transfer to specialized centerfor rehabilitation of paraplegic patients (as indicated)

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Table 39 Clinical manifestations of spinal cord lesions (p. 282)

Features Site of Lesion Clinical Manifestations

Spinal cord transection(p. 48)

! Cervical spinal cord ! Quadriplegia! Thoracic spinal cord ! Paraplegia! Lumbar/sacral spinal

cord! Paraplegia/conus syndrome with paralysis of blad-

der/rectum and saddle anesthesia

Lesion affecting a por-tion of the spinal cord(pp. 32, 50)

! Anterior root ! Flaccid paralysis, muscle atrophy, hyporeflexia (!segment-indicating muscles, see Table 2, p. 357)

! Posterior root ! Localized/radicular/referred pain, sensory deficit incorresponding dermatome

! Incomplete transversecord syndrome

! Brown–Séquard syndrome, posterior column syn-drome, anterior horn syndrome, posterior hornsyndrome, central cord syndrome, anterior spinalsyndrome

! Complete transversecord syndrome

! See p. 48

Temporal course ! Acute ! Spinal shock! Chronic ! Spasticity, sensory and autonomic dysfunction

Table 40 Malformations and developmental anomalies (p. 288)

Feature Syndrome1 Comments2

Macrocephaly (ab-normally largehead)

Hydrocephalus (p. 290), hydranencephaly, megalencephaly(massively enlarged brain)

4th week/2nd to 4th month

Craniostenosis(premature ossifi-cation of cranialsutures, p. 4)

Turricephaly (! lambdoid and coronal suture; oxycephaly),scaphocephaly (! sagittal suture; dolichocephaly, “longhead”), brachycephaly (! coronal suture; “short head”)

Before 4th year of life

Migration disorder(defective migra-tion of neuroblastsinto cortex)

Schizencephaly (presence of cysts or cavities in the brain),agyria (lissencephaly3, few or no convolutions), pachygyria(broad, plump convolutions), heterotopia/dystopia (ectopicgray matter)

2nd to 5th month

Microcephaly (ab-normally smallhead)

Micrencephaly (abnormally small brain) 5th week (primary),peri- or postnatal (sec-ondary)

Dysraphism (neuraltube defect)

See p. 292 3rd to 4th week/4th to 7th week

Chromosomalanomaly

Down syndrome (trisomy 21, mongolism), Patau syndrome(trisomy 13), Edwards syndrome (trisomy 18), cri-du-chatsyndrome (deletion, short arm of chromosome 5), Klinefeltersyndrome (XXY), Turner syndrome (XO), fragile-X syndrome

Genome mutation

Phakomatosis See p. 294

Prenatal or peri-natal infection

Rubella, cytomegalovirus, congenital neurosyphilis, HIV/AIDS, toxoplasmosis

Mental retardation A component of many syndromes (e. g., microcephaly, hy-drocephalus, Down syndrome, perinatal or prenatal infec-tion)

Cerebral lesion Ulegyria (postanoxic corticomedullary scarring), poren-cephaly (p. 290), hemiatrophy, infantile cerebral palsy(p. 288 f)

Prenatal, perinatal orpostnatal

1 (Selected). 2 The times specified refer to the gestational and neonatal ages, respectively. 3 There are twoforms of lissencephaly: type 1, Miller–Dicker syndrome (craniofacial deformity), and type 2 (pronounced hetero-topia with Fukuyama muscular dystrophy).

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Table 41 Age-related changes (p. 296)

Change Sequelae Elevated risk1 of

!

Accommodation Presbyopia

Miosis

!

Light/convergence reaction

Cataract Glare,

!

visual acuity Blindness

!

Hearing (inner ear) Presbycusis Deafness

!

Sense of smell/taste Impaired sense of smell/taste

! Body fat ! volume of distribution for fat-soluble drugs2 Obesity

!

Total body water,!

Thirst

!

volume of distribution for water-soluble drugs2 Dehydration, hydro-penia

Arteries Atherosclerosis, impairment of cerebral autoregula-tion and blood-brain barrier, decrease in cerebralblood flow, reduced tolerance of brain tissue toischemia and metabolic changes

Stroke3, leukoaraiosis4,subcortical arterios-clerotic encephalo-pathy (p. 172), cerebralamyloid angiopathy5,atrial fibrillation, myo-cardial infarction

Motor function

!

Mobility,!

reactivity,

!

coordination,

!

fine motorcontrol, muscle atrophy (especially thenar, dorsal in-terosseous, and anterior tibial muscles),!

muscle force, ! leg muscle tone, hypokinesis ofarms, gait impairment (p. 60)

Falls (p. 204), osteo-porosis, fear of falling/inactivity (avoidance ofsocial contact, isola-tion)

Reflexes!

Reflex movements (p. 42), palmomental reflex,snout reflex, grasp reflex

Falls

Sensation Pallhypesthesia in toe/knuckle region,

!

positionsense

Polyneuropathy, ataxia,falls

Brain atrophy Senile forgetfulness6 (impairment of episodicmemory, p. 134)

Alzheimer disease,leukoaraiosis4

!

Cerebral dopamine syn-thesis

Stooped posture Parkinsonism

!Cerebral norepinephrine Depression

!

Non-REM stage 4(p. 112)

Early awakening, insomnia Sleep apnea syndrome

(Resnick, 1998)

1 Risk of developing condition in old age. 2 Increased risk of drug side effects. 3 Especially due to border zoneinfarction, subdural hematoma (after relatively minor trauma). 4 Rarefaction of white matter seen as bilateral,usually symmetrical hypodensity on CT and as hyperintensity on T2-weighted MRI (FLAIR = fluid-attenuated inver-sion recovery sequence). 5 Increased risk of spontaneous intracranial hemorrhage (p. 176). 6 Benign senescentforgetfulness, age-associated memory impairment (AAMI).

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Table 42 Criteria for differentiation between dementia and depression (p. 297)

Dementia Depression

Patients seem indifferent to memory impairment;semantic paraphasia

Patients describe memory impairment precisely andin detail

Tests reveal cognitive deficit Tests reveal minimal or no cognitive deficit

Depressive manifestations develop slowly (second-ary)

Depressive manifestations prominent on presenta-tion (brooding, anxiety, early awakening, loss of ap-petite, self-doubt)

Rare past history of depression Frequent past history of depression

Table 43 Criteria for differentiation between different types of hyperkinesia (p. 300)

Syndrome Features

Chorea (p. 66) Overshooting, spontaneous, abrupt, alternating, irregular movements. Promi-nence varies from restlessness with little gesticulation, fidgety hand movementsand hesitant, dance-like gait impairment to continuous, flowing, violent, disablinghyperkinesias

Dystonia (p. 64) Involuntary, continuous and stereotyped muscle contractions that lead to rotat-ing movements and abnormal posture

Athetosis (p. 66) Localized peripheral dystonic movements

Ballismus (p. 66) Violent, mainly proximal flinging movements of the limbs

Tics (p. 68) Repetitive, stereotyped, localized twitches that can be voluntarily suppressed, butwith a build-up of inner tension

Myoclonus (p. 68) Brief, sudden, shocklike muscle twitches occurring repetitively in the samemuscle group(s)

(Harper, 1996)

Table 44 Symptomatic forms of parkinsonism (p. 302)

Cause Examples

Infectious disease Encephalitis lethargica1 (von Economo postencephalitic parkinsonism), measles,tick-borne encephalitis, poliomyelitis, cytomegalovirus, influenza A, herpes sim-plex

Intoxication MPTP2, manganese (miners, industrial workers), carbon monoxide, methanol

Drugs3 Neuroleptics (phenothiazines4, butyrophenones5, thioxanthenes6, benzamide7),reserpine, calcium channel blockers (cinnarizine, flunarizine)

Other diseases8 Multiple brain infarcts/subcortical arteriosclerotic encephalopathy9, punch-drunkencephalopathy (dementia pugilistica), normal pressure hydrocephalus (p. 160),brain tumor (frontal), subdural hematoma, calcification of basal ganglia10, neu-roleptic malignant syndrome11

1 In the aftermath of the influenza pandemic that followed the First World War (now only of historical interest).2 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MPTP is converted into MPP+, which accumulates in dopaminer-gic neurons and interferes with electron transfer in the mitochondrial respiratory chain, leading to an accumula-tion of free radicals and neuronal death. An outbreak of MPTP-induced parkinsonism occurred in California in theearly 1980s, when this substance appeared as a contaminant of opiate drugs synthesized in clandestine laborato-ries for illegal use. 3 Parkinsonoid. 4 Fluphenazine, levomepromazine, perazine, perphenazine, promazine, triflu-promazine, etc. 5 Benperidol, fluspirilene (diphenylbutylpiperidine), haloperidol, etc. 6 Chlorprothixene, clopen-thixol, fluanxol. 7 Metoclopramide. 8 Includes the terms pseudoparkinsonism, hypokinetic-rigid syndrome, andhypertonic-hyperkinetic syndrome. 9 Lower-body parkinsonism. 10 Autosomal recessive (Fahr disease), associatedwith hypoparathyroidism and pseudohypoparathyroidism. 11 Parkinsonian hyperthermia syndrome: rigidity, hy-perthermia, impairment of consciousness; induced by neuroleptic drugs or by the use or withdrawal of levodopaor other dopaminergic agonists.

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Table 45 Diseases affecting the first (upper) motor neuron (p. 304)

Syndrome Features

Hereditary

Familial spastic paraple-gia (SPG, p. 286)

Uncomplicated SPG1,2: SPG26 (X/Xq22/PLP = proteolipid protein), SPG3A (AD/14q11.2–24.3/atlastin), SPG46 (AD/2p22-p21/spastin), SPG5A (AR/8p12-q13/?),SPG6 (AD/15q11.1/?), SPG76 (AR/16q24.3/paraplegin), SPG8/AD/8q23–24/?),SPG10 (AD/12q13/?), SPG11 (AR/15q13–15/?), SPG12 (AD/19q13/?), SPG13 (AD/2q24–34/?)Complicated SPG3: SPG16 (X/Xq28/L1-CAM = L1 cell adhesion molecule), SPG26

(X/Xq22/PLP), SPG76 (AR/16q24.3/paraplegin), SPG9 (AD/10q23.3–24.1/?), SPG14(AR/3q27–28/?), SPG16 (X/Xq11.2/?)

Adrenomyelo-neuropathy4

X-linked recessive, onset usually after age 20. Progressive spastic paraparesis,polyneuropathy, urinary incontinence, sometimes hypocortisolism. A similarsyndrome develops in 20% of all female heterozygotes (carriers)

Spinocerebellar ataxiatype 3

See p. 280

Acquired

Primary lateral sclerosis Onset usually after age 50. Slowly progressive symmetrical paraspasticity withoutmarked weakness, dysarthria. More common in men than in women

Lathyrism (p. 304) Onset usually before age 50. Subacute or chronic development of gait distur-bances (tip-toe/scissors gait, dorsal tilting of trunk), leg cramps, paresthesiae, uri-nary retention

Tropical spastic para-paresis (TSP)5

Onset: Slow up to age 60. Back pain, dysesthesiae, spastic paraparesis, urinary re-tention, impotence

1 Abbreviations: AD = autosomal dominant, AR = autosomal recessive, X = X-chromosome/gene locus/gene pro-duct (? = unknown). 2 Isolated progressive spastic paraparesis. 3 As in uncomplicated SPG with additionalmanifestations including cerebellar ataxia, dystonia, optic neuropathy, tapetoretinal degeneration, muscle atro-phy, dysarthria, deafness, sensory neuropathy, ichthyosis, dementia. 4 Impaired !-oxidation of very long chainfatty acids (VLCFA; C24–26) due to defective peroxisomal transport ! accumulation of VLFCA in nervous system,adrenal cortex, plasma. 5 HTLV-I-associated myelopathy (= HAM, human T-cell/lymphotropic virus type I);Jamaica, Japan, Caribbean. 6 Molecular genetic tests are available.

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Table 46 Diseases affecting the second (lower) motor neuron (p. 304)

Syndrome1 Features

Hereditary

Proximal2 (SMA)3 SMA I4: onset !3 months. AR. Flaccid quadriparesis5. Triangular mouth shape,paradoxical respiratory movements, impaired sucking ability, unable to sitSMA II: onset !5 years. AR. The children learn to sit independently, but never tostand/walk. Scoliosis, joint contracturesSMA III6; SMA IIIa: onset 3 years. AR. Delayed motor development. Children learnto stand/walkSMA IIIb: onset 3–30 years. AR. Development normal. Calf (pseudo)hypertrophy.Absence of bulbar muscle involvement. CK7 sometimes elevatedSMA IV: onset "30 years. AR

Nonproximal8 SMA Distal SMA9: forms with different ages of onset (infantile, juvenile, adult). Usuallyslow course, sometimes stabilizing after a few years, sometimes progressive. Maybe accompanied by myoclonus, deafness, dysphonia, dysarthria, and/or ataxia.Scapuloperoneal muscular atrophy10: Onset: Adolescence or adulthood. Weakness! foot dorsiflexors, shoulder girdle, armProgressive bulbar palsy11: Onset in adulthood12. Progressive weakness of bulbarmuscles. Muscular atrophy and respiratory muscle involvement develop as thedisease progresses

Spinobulbar muscularatrophy (Kennedy type)

Onset: 20–70 years. Gynecomastia, gradual progression of muscular atrophy (legs"arms, proximal "distal, asymmetrical; dysarthria, dysphagia, tongue atrophy).Slight elevation of CK. Gene locus Xq12

Acquired

Acute viral infection Poliomyelitis (p. 242), other enteroviruses (e. g., echovirus, coxsackievirus, enter-ovirus type 70/71 ! acute hemorrhagic conjunctivitis), mumps virus

Postpolio syndrome See p. 242

Lymphoma Accompanies Hodgkin and non-Hodgkin lymphomas. Elevation of CSF protein,oligoclonal IgG in CSF

Radiation-induced Develops months to years after irradiation of para-aortic lymph nodes (testiculartumors, uterine carcinoma). May progress rapidly

(Tandan, 1996; Rudnik-Schöneborn, Mortier and Zerres, 1998)

AR = autosomal recessive, AD = autosomal dominant; XR = X-linked recessive.1 Selected syndromes. 2 Proximal muscle involvement. 3 SMA = spinal muscular atrophy; gene locus for SMA I toIII: 5q12.2–q13.3. 4 AR; infantile SMA, Werdnig–Hoffmann disease. 5 Floppy baby syndrome, froglike posture insupine position; lack of head control. 6 AR "AD; juvenile SMA; Kugelberg–Welander disease. 7 Creatine kinase(CK). 8 Distal or localized (monomelic segmental SMA) muscle groups, symmetrical or asymmetrical involve-ment. 9 AR "AD. 10 AD ! Onset age 30–50 years, slowly progressive; AR ! onset !5 years; may progressslowly. 11 AD/AR. 12 Fazio–Londe type with onset at age 2–13 years, rapidly progressive

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Table 47 Diseases affecting both the first (upper) and the second (lower) motor neurons (p. 304)

Diagnostic Categories1

Definite ALS2 Evidence of first + second motor neuron lesion in 3 regions of the body3

Probable ALS Evidence of first + second motor neuron lesion in 2 regions of the body

Possible ALS Evidence of first + second motor neuron lesion in 1 region of the body or evi-dence of first motor neuron lesion in 2 to 3 regions of the body

Suspected ALS Evidence of second motor neuron lesion in 2 to 3 regions of the body

Diagnostic features Progressive symptoms of a first (p. 46) and second motor neuron lesion (p. 50).Fasciculation in more than one region of the body. Neurogenic EMG findings, nor-mal nerve conduction velocity/absence of motor conduction block. Absence ofsensory deficits, sphincter dysfunction, visual disturbances, autonomic dysfunc-tion, parkinsonism, and Alzheimer, Pick or Huntington disease

Syndromes with manife-stations similar to thoseof ALS

Cervical radicular syndromes, cervical myelopathy, monoclonal gammopathy.Multifocal motor neuropathy (GM1 antibodies). Lymphoma; paraneoplastic syn-drome; hyperthyroidism, hyperparathyroidism; diabetic amyotrophy; postpoliosyndrome; hexosamidinase A deficiency. Radiation-induced lesion. Toxicity (lead,mercury, manganese). Myopathy (inclusion body myositis, polymyositis, musculardystrophy). Spinal muscular atrophy. Creutzfeldt–Jakob disease

1 According to Leigh and Ray-Chaudhuri (1994). 2 ALS = amyotrophic lateral sclerosis. 3 Brain stem, proximal/dis-tal arm, chest, proximal/distal leg.

Table 48 Neonatal metabolic encephalopathies (from birth to 28 days, p. 306)


Galactosemia Galactose-1-phosphateuridyltransferase1

Milk intolerance, apathy, jaundice, anemia, cata-ract, psychomotor retardation

Nonketonic hyperglycine-mia

Defective conversion ofglycine to serine

Hypotonia, dyspnea, myoclonus, generalizedseizures

Hyperammonemia Urea cycle2 Crisislike episodes of vomiting, sucking weakness,somnolence, coma, seizures, hyperpnea, hyper-pyrexia

Maple syrup urine disease Defective breakdown ofbranched-chain aminoacids

Hypotonia, seizures, coma, ketoacidosis

Zellweger syndrome Peroxisomes3 Hypotonia, sucking weakness, nystagmus,seizures, craniofacial dysmorphism

1 Multiple types ! high galactose-1-phosphate levels. 2 Defects of all six enzymes of the urea cycle are known.Adult onset is rare. Hyperammonemia in defects of carbamoyl-phosphate synthetase, ornithine carbamoyl-transferase, argininosuccinic acid synthetase (citrullinemia), argininosuccinase. Arginase defect leads to argine-mia. 3 Cytoplasmic organelles that mediate fatty acid oxidation, biliary acid and cholesterol synthesis, pipecolicand phytanic acid metabolism, and plasmalogen (myelin) synthesis. Other peroxisomal syndromes: neonataladrenoleukodystrophy, infantile Refsum disease, hyperpipecolatemia.

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Table 49 Metabolic encephalopathies of infancy (first year of life, p. 306)


Tay–Sachs disease1 Hexosaminidase A (! ac-cumulation of gangliosideGM2)

Abnormal acoustic startle reaction, delayeddevelopment. Begins with muscular hypotonia,followed by spasticity, seizures, blindness,dementia, and optic nerve atrophy2

Gaucher disease3 (type II,acute neuropathic)

Glucocerebrosidase (!lipid storage)

Loss of motor control, apathy, dysphagia, retro-flexion of the head, strabismus, splenomegaly

Niemann–Pick disease4(type A)

Sphingomyelinase defi-ciency (sphingomyelinstorage ! Niemann–Pickcells)

Enlargement of spleen, liver and lymph nodes;pulmonary infiltrates, spasticity, muscular axialhypotonia, blindness, nystagmus, macular cherryred spot

GM1 gangliosidosis !-Galactosidase Craniofacial dysmorphism. Initial flaccid paralysisthat later becomes spastic; loss of visual acuity,nystagmus, strabismus, hepatomegaly

Krabbe disease (globoidcell leukodystrophy)

!-Galactocerebrosidase(galactocerebroside !)

General muscular hypertonia, vomiting, opistho-tonus, spasticity, blindness, deafness

Pelizaeus–Merzbacherdisease5

Proteolipid protein synthe-sis

Nystagmus, ataxia, psychomotor retardation,choreoathetosis

1 GM2 gangliosidosis. 2 Cherry red spot in optic fundus is found in over 90% of cases. 3 Glucocerebrosidase;three known subtypes ! type 1: nonneuropathic (juvenile) form with hematological changes and bone fractures;type 3: see p. 307. 4 Different types (A, B, C) exist. Type B does not produce neurological symptoms. 5 Othersudanophil (orthochromatic) forms of leukodystrophy are known.

Table 50 Stages of hepatic/portosystemic encephalopathy (p. 308)

Stage Behavior1 Motor function EEG2

I Attention deficit, impairedconcentration, euphoria or de-pression, dysarthria, insomnia

Handwriting illegible, asterixis+/–

Usually normal to q waves

II Sleepy, marked behavioralchanges (confusion, disorien-tation, apraxia)

Asterixis Pathological (" waves)

III Severely confused, somnolentto soporific

Asterixis Pathological ("/triphasicwaves)

IV Coma Presence (stage IVa) or ab-sence (stage IVb) of motor re-sponses to pain

Pathological (triphasic/arrhythmic "/sub-" waves)

(Adams and Foley, 1952)1 Earlier stages are assessed with psychometric methods, e. g., number connection test (time required forpatient to connect 25 numbered circles in numerical order), ability to draw a five-pointed star. 2 Nonspecificchanges; actual findings may differ.

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Table 51 Paraneoplastic syndromes of the CNS (p. 312)

Site Syndrome ! Timecourse

Symptoms andSigns

Common Tumors Lesions/Antibodies

Cerebrum Photoreceptor/retinaldegeneration !weeks to months

Progressive blindnesswithout pain

Small-cell lung cancer Loss of photorecep-tors/anti-CAR1

Limbic encephalitis !weeks to months

Restlessness, confu-sion, memory impair-ment

Small-cell lung cancer Neuronal loss, peri-vascular and mening-eal lymphocytic infil-trates ! medial tem-poral lobe, limbic sys-tem/ANNA-12

Cerebel-lum, brainstem

Brain stem encephali-tis ! days to weeks

Dysphagia, dys-arthria, nystagmus,diplopia, ataxia, dizzi-ness

Small-cell lung cancer Neuronal loss, inflam-matory infiltrates inthe brain stem

Subacute cerebellardegeneration !weeks to months

Cerebellar ataxia,dysarthria, nystag-mus, diplopia, ver-tigo

Small-cell lungcancer, carcinoma ofovary/breast, Hodg-kin disease

Death of Purkinjecells/APCA3

Opsoclonus-myo-clonus ! weeks

Abrupt, irregular eyeand muscle move-ments, cerebellarataxia, encephalo-pathy

Neuroblastoma(children); breastcancer/lung cancer(adults)

Neuronal loss in den-tate nucleus(adults)/ANNA-24

Spinalcord

Necrotizing my-elopathy ! hours,days to weeks

Flaccid para-/ quadri-paresis, bladder/bowel dysfunction,segmental sensoryloss

Small-cell lungcancer, lymphoma

Necrosis of white andgray matter of spinalcord

Stiff man syndrome5! days to weeks

Painful muscularrigidity initially trig-gered by emotional,acoustic and/or tac-tile stimuli; auton-omic dysfunction

Small-cell lungcancer, Hodgkin lym-phoma, breastcancer, pharyngealcarcinoma

Transitory high-cervi-cal lesions may beseen in MRI scans/anti-GAD6

(Brown, 1998)

1 CAR = cancer-associated retinopathy. 2 ANNA-1 = antineural nuclear antibody type 1 = anti-Hu. 3 APCA = anti-Purkinje cell cytoplasmic antibody = anti-Yo. 4 ANNA-2 = antineural nuclear antibody type 2 = anti-Ri. 5 Manife-stations variable (e. g., axial or distal muscle may be more prominent); attributed to diminished supraspinal inhi-bition of motor neurons, leading to continuous contraction of agonists and antagonists. 6 Anti-GAD = glutamicacid decarboxylase antibodies; antibodies directed against amphiphysin (terminal synaptic protein) have alsobeen found.

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Table 52 Iatrogenic encephalopathies (p. 314)

Substance Adverse Effects1

Neuroleptics Drug-induced parkinsonism (p. 383, Table 44), early/late dyskinesia (p. 66),akathisia2, low seizure threshold

Antidepressants Somnolence, increased drive, confusion, akathisia, low seizure threshold, tremor,serotonin syndrome3

Aspirin4 Tinnitus, dizziness

Baclofen Fatigue, depression, headaches, low seizure threshold

Levodopa, dopamineagonists

Confusion, hallucinations, psychosis, insomnia, hyperkinesia

Corticosteroids, ACTH Depression, increased drive, mania, insomnia, headaches, dizziness, sweating, lowseizure threshold, tremor

Antibiotics Aminoglycosides: Tinnitus, hearing impairment. Quinolone derivatives: Insomnia,hallucinations, headaches, low seizure threshold, dizziness, somnolence, tinnitus.Tetracyclines: Pseudotumor cerebri (children), abducens paralysis (adults)

Glycosides Visual disturbances, somnolence, hallucinations, seizures, delirium

Calcium antagonists Fatigue, insomnia, headaches, depression. Flunarizine/cinnarizine: Drug-inducedparkinsonism

Coumarins Intracranial hemorrhage (2–12%/year)

Radiotherapy5 Acute (!1 week): Headaches, nausea, somnolence, fever. Subacute: (2–16 weeks):Somnolence, focal neurological deficits, leukoencephalopathy, brain stem syn-drome (rare). Late ("4 months): radiation necrosis6, leukoencephalopathy,dementia, secondary tumor

Chemotherapy7 Acute: Insomnia, confusion, restlessness, stupor, generalized seizures, myoclonus.Late: Apathy, dementia, insomnia, incontinence, gait impairment, ataxia

(Biller, 1998; Diener and Kastrup, 1998; Keime-Guibert et al., 1998)

1 Common adverse effects. 2 Inability to sit still with tormenting sensations in the legs that improve briefly whenthe patient moves about. 3 Characterized by confusion, fever, restlessness, myoclonus, diaphoresis, tremor, diar-rhea, and ataxia; usually due to drug interactions, e. g., fluoxetine + sertraline, serotonin reuptake inhibitor +tryptophan, MAO inhibitors, carbamazepine, lithium, or clomipramine. 4 Acetylsalicylic acid (ASA). 5 Syndromesalso occur in combination with chemotherapy. 6 One to two years after percutaneous radiotherapy, ca. 6 monthsafter interstitial radiotherapy. Focal neurological deficits. 7 Methotrexate (high-dose i. v., intrathecal) cisplatin,vincristine, asparaginase, procarbazine, 5-fluorouracil, cytosine arabinoside, nitrosourea compounds (high-dose),ifosfamide, tamoxifen, etoposide (high-dose).

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Table 53 Neuropathy syndromes (p. 316)

Syndrome Causes

Predominantly sym-metrical motor deficits

Amyotrophic lateral sclerosis (ALS), multifocal motor neuropathy, Guillain–Barrésyndrome, CIDP1, acute porphyria, hereditary sensorimotor neuropathy

Predominantly asym-metrical or focal motordeficits

Neuronopathy: ALS, poliomyelitis, spinal muscular atrophyRadicular lesion: Root compression (herniated intervertebral disk, tumor), herpeszoster, carcinomatous meningitis, diabetes mellitusPlexus lesion: Neuralgic amyotrophy of shoulder, tumor infiltration, diabetes melli-tus, tomaculous neuropathy, compression (positional)Multiple mononeuropathy: Vasculitis, diabetes mellitus, multifocal motor neu-ropathy, neuroborreliosis, sarcoidosis, HIV, tomaculous neuropathy, leprosy, neu-rofibromatosis, cryoglobulinemia, HNPP (p. 332), neoplastic infiltrationMononeuropathy: Compartment syndrome (median n., ulnar n.), compression(anterior interosseous n., peroneal n.), lead poisoning, diabetes mellitus

Predominantly auton-omic disturbances

Diabetes mellitus, amyloidosis, Guillain–Barré syndrome, vincristine, porphyria,HIV, idiopathic pandysautonomia, botulism, paraneoplastic neuropathy

Predominant pain Diabetes mellitus, vasculitis, Guillain–Barré syndrome, uremia, amyloidosis, ar-senic, thallium, HIV, Fabry disease, cryptogenic neuropathy

Predominantly sensorydisturbances

Diabetes mellitus, alcohol, ethambutol, vitamin B12 deficiency, folic acid defi-ciency, overdosage of vitamin B6, paraneoplastic, metronidazole, phenytoin, thali-domide, leprosy, cytostatic agents (e. g., vincristine, vinblastine, vindesine,cisplatin, paclitaxel), amyloidosis (dissociated sensory loss), hereditary sensoryneuropathy, monoclonal gammopathy, tabes dorsalis, Friedreich ataxia (p. 280)

Ganglioneuropathy2(ataxia)

Paraneoplastic, Sjögren syndrome, cisplatin, vitamin B6 intoxication, HIV, id-iopathic sensory neuronopathy

(Barohn, 1998)

1 Chronic inflammatory demyelinating polyneuropathy. 2 Asymmetrical proprioceptive loss without paralysis.

Table 54 Acquired and hereditary neuropathies (p. 316)

Cause Examples

Acquired! Metabolic disorder ! Diabetes mellitus, uremia, hypothyroidism, acromegaly! Dietary deficiency ! Vitamin deficiency (B1 = beriberi, B6, B12, E), malabsorption! Immune-mediated ! Guillain–Barré syndrome, Fisher syndrome, chronic inflammatory demyelinat-

ing polyneuropathy (CIDP), multifocal motor neuropathy, pandysautonomia,neuralgic amyotrophy of shoulder1, vasculitis, connective tissue disease,plasmocytoma, benign monoclonal gammopathy, Churg–Strauss syndrome,cryoglobulinemia, rheumatoid arthritis

! Infection ! Herpes zoster, leprosy, Lyme disease, HIV, neurosyphilis, diphtheria, typhus,paratyphus

! Drugs ! Carbimazole, cisplatin, cytarabine, enalapril, ethambutol, etoposide, gentami-cin, gold, imipramine, indomethacin, INH, paclitaxel, phenytoin, procarbazine,suramine, thalidomide, vinca alkaloids, vitamin B6

! Toxins (environmen-tal, industrial)2,drugs2

! Alcohol, arsenic, benzene, lead, heroin, hexachlorophene, pentachlorophenol,polychlorinated biphenyls, mercury, carbon tetrachloride, thallium, triarylo-phosphate

! Neoplasm ! Paraneoplastic: Lung, stomach, or breast cancer; Hodgkin disease, leukemia. In-filtration: Hodgkin disease, leukemia, carcinomatous meningitis, polycythemia

! Mechanical ! Compression, trauma, distortion! Unknown ! Critical illness polyneuropathy

Hereditary See pp. 332 and 396 f

(Barohn, 1998)

1 Causes not confirmed. 2 A large number of substances can lead to polyneuropathy (PNP). Only some of themare listed.

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Table 55 Additional diagnostic studies for neuropathies (p. 316)

Method Information/Parameters

Neurography Motor neuron lesion: Normal (consider conduction block)Ganglionopathy: MSAP1 normal to

!

, SNAP2 normal to

!

, (dermatomal) SEP3

!

Radiculopathy: H reflex: Lateral inequality/absence4; F waves: some prolonged;(dermatomal) SEP

!

Axonal lesion: Motor NCV5: Normal; MSAP

!

, SNAP

!

Demyelination: DML6 !, NCV:

!

or local conduction block (localize by inching);MSAP

!

/dispersed; F waves: Prolongation or absence; SNAP: normal/dispersed inmotor neuropathy,

!

in sensory neuropathy

Needle electro-myography

Motor neuron lesion: Fibrillation, positive waves, fasciculation. Amplitude, poly-phasia rate, MAP7 duration !

Ganglionopathy: MAP: Low-grade neurogenic changes may be observedRadiculopathy: Pathological spontaneous activity in paravertebral muscles/seg-ment-indicating muscles (p. 357); MAP8: neurogenic changesAxonal lesion: Pathological spontaneous activity (fibrillation, fasciculation); MAP:neurogenic changesDemyelination: Absence of pathological spontaneous activity, maximum innerva-tion with thinning pattern

Laboratory tests9 Standard tests: Erythrocyte sedimentation rate, differential blood count, bloodglucose (diurnal profile), C-reactive protein, calcium, sodium potassium, alkalinephosphatase, SGOT10, SGPT11, CK12, !-GT13, electrophoresis, rheumatoid factors,vitamin B12/ folic acid, Borrelia/HIV antibodies, basal TSH14, triglycerides,cholesterol, urine status, blood cultureSpecial tests: CSF, homocysteine, hemoglobin A1C, syphilis serology, parathyroidhormone, antinuclear antibodies (e. g., Sm, RNP, Ro SS-A, La SS-B, Scl-70, Jo-1,Pm-Scl), antineuronal antibodies (ANNA-1, anti-Hu), myelin-associated glyco-protein (MAG), ganglioside antibodies (GM1, GD1a, GD1b, GQ1b), heavy metals(blood, urine), porphyrins, cryoglobulins, serum phytanic acid, very long chainfatty acids (VLCFA, C24–26), molecular genetic testing

Sural nerve biopsy15 Vasculitis, amyloid neuropathy, neuropathy with sarcoidosis, leprosy, chronic neu-ropathy (HMSN III/metachromatic leukodystrophy, with or without other forms ofhereditary neuropathy ! p. 332; chronic inflammatory neuropathy, polyglucosanbody neuropathy), tumor (neurofibroma/schwannoma, neoplastic infiltration; par-aneoplastic neuropathy), neuropathy with monoclonal gammopathy, if applicable

Diagnostic imaging Guided by clinical findings (spinal, radicular, plexus, distal peripheral lesions?),plain radiographs, ultrasound, CT, MRI, myelography, skeletal scintigraphy and/orangiography

!= elevated, prolonged;

!

= diminished, absent1 Summated muscle action potential (evoked). 2 Amplitude of sensory nerve action potential. 3 Somatosensoryevoked action potential amplitude reduced or absent. 4 For technical reasons, can only be determined for S1.5 Nerve conduction velocity. 6 Distal motor latency. 7 Muscle action potential. 8 After 2 weeks, at earliest. 9 Par-tial list. 10 Serum glutamic–oxaloacetic transaminase. 11 Serum glutamate–pyruvate transaminase. 12 Creatinekinase. 13 !-Glutamyl transpepsidase. 14 Thyrotropin. 15 Muscle biopsy may also be helpful in some cases.

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Table 56 Causes of radicular syndromes (p. 318)

Cause Comments

Degenerative changes! Intervertebral disk hernia-

tion! Symptoms usually resolve with conservative treatment1

! Spondylosis deformans ! Torus-, buckle- or spur-shaped spondylophytes form due to degenerativechanges in the intervertebral disks

! Spinal canal stenosis ! See p. 284! Spondylolisthesis ! Slippage of a vertebra with respect to the next lower vertebra because

of bilateral spondylolysis2

Trauma See p. 272

Neoplasm Primary spinal tumor (p. 284), metastatic tumor/neoplastic meningeosis(p. 262)

Infection/inflammation See p. 222 ff. herpes zoster, borreliosis, epidural abscess, spondylitis, sar-coidosis, arachnopathy

Vascular See p. 282

Metabolic Diabetes mellitus (p. 324; Table 59, p. 395)

Inflammatory rheumatic Ankylosing spondylitis, rheumatoid arthritis

Malformation See p. 288 ff

Iatrogenic Injection, lumbar puncture, surgery

Radiotherapy Radiation-induced amyotrophy (cauda equina)3

Pseudoradicular syndrome4,nonradicular pain

! Arm: Carpal tunnel syndrome, stiff shoulder, humeroscapular periar-thropathy, syringomyelia

! Leg: Facet syndrome, sacroiliac joint syndrome, coccygodynia, coxarthro-sis, heterotopic ossification

! General: Polyradiculitis, connective tissue diseases, rheumatoid diseases,malformations, myopathy/muscle trauma, strain, arthropathy, en-dometriosis, osteomyelitis, osteoporosis, arterial dissection, prostatitis,cystitis, Paget disease, somatization disorder

(Mumenthaler et al., 1998)

1 Absolute indications for surgery: Massive lumbar disk herniation with sphincter dysfunction, cervical diskherniation with spinal cord compression, severe weakness. Relative indications: Persistent radicular pain, frequentrecurrence of radicular symptoms. 2 Defect in the pars interarticularis of the vertebral arch. 3 Development offollowing manifestations months to years after radiotherapy (para-aortic irradiation): malignant testicular tumor,lymphoma; progressive flaccid paraparesis without major sensory loss. 4 To be considered in the differential diag-nosis.

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Table 57 Causes of plexus lesions (p. 318)

Cause Comments

Neoplasm ! Upper limb: neurofibroma/schwannoma, metastatic tumor, breast/lung cancer (Pan-coast tumor)

! Lower limb: urogenital tumors, cancer of the rectum, lymphoma

Vascular ! Lower limb: psoas hematoma due to anticoagulation, hemophilia, aneurysm

Metabolic ! Lower limb: diabetes mellitus (p. 395, Table 59)

Inflammatory ! Upper limb: neuralgic shoulder amyotrophy (p. 328)! Lower limb: neuropathy of lumbosacral plexus, vasculitis

Trauma ! Upper limb: stab or gunshot wound, strain, contusion (trauma, birth), cervical nerveroot avulsion (p. 272)

! Lower limb: pelvic fracture, sacral fracture

Compression ! Upper limb: carrying heavy loads (backpack paralysis), thoracic outlet syndrome (T1–C8)1, costoclavicular syndrome, hyperadduction syndrome

Infection ! Lower limb: psoas abscess

Iatrogenic ! Upper limb: positioning, retraction (heart surgery), plexus anesthesia! Lower limb: hip surgery, vascular surgery, hysterectomy, adverse positioning

Pregnancy ! Lower limb: end of pregnancy, delivery

Radiotherapy ! Upper limb: brachial plexus paralysis months to years after radiotherapy! Lower limb: due to radiotherapy of neoplasms in pelvic region

1 Thoracic outlet compression may be caused by a cervical rib, fibrous band or narrow scalene gap.

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Table 58 Common sites of mononeuropathy (pp. 318 and 312 f)

Nerve Lesion ! Syndrome Cause1

Axillary nerve Abduction paralysis, deltoid atrophy Dislocation of shoulder

Long thoracicnerve

Winging of scapula; no sensory deficit, weakness ofarm elevation

Compression (“backpack” paraly-sis), neuralgic shoulder amyo-trophy, postinfectious

Radial nerve ! UA2 ! hand drop with sensory

!

in radial back ofhand; prominent between 1st and 2nd finger

! Compression3/fracture of shaftof humerus

! PFA4 ! supinator syndrome5 ! Fractured head of radius

Median nerve ! UA ! monkey hand6 ! Compression, fracture! PFA ! pronator teres syndrome, anterior interos-

seous syndrome8! Strain, compression, fracture

! DLA9 ! carpal tunnel syndrome, brachialgia, noc-turnal paresthesia10

! Compression, arteriovenousfistula/uremia, rheumatoidarthritis, pregnancy, diabetesmellitus, hypothyroidism,monoclonal gammopathy

Ulnar nerve ! UA ! clawhand ! Supracondylar process! PFA ! clawhand ! Trauma, compression, arthro-

sis, habitual! DLA ! different types of paralysis ! Compression, habitual

Lateral femoralcutaneousnerve

! Meralgia paresthetica12 ! Compression

Femoral nerve ! Proximal lesion ! paralysis of knee extensors ! Psoas hematoma/abscess! Intrapelvic lesion ! additional paralysis of hip

flexors (gait disturbance)! Surgery (hip surgery, hyster-

ectomy), trauma

Sciatic nerve ! Peroneal + tibial (partial) lesion ! Trauma, hip surgery, intra-gluteal injection

Common per-oneal nerve

! Lesion at head of fibula ! paralysis of dorsiflexorsof foot (step gait)

! Compression, fracture, sprain,compartment syndrome

Tibial nerve ! Popliteal lesion ! paralysis of all flexor muscles(foot, toes), sensory loss on back of calf and soleof foot; pain, absence of ankle jerk reflex

! Fracture, compression

! Lesion of lower leg ! clawed toes; preservation ofreflex

! Compression

! Tarsal tunnel syndrome13, pain.! Calf, ankle, sole of foot. Clawed toes

! Compression, trauma

1 Selection. 2 Lesion at level of upper arm. 3 “Park bench paralysis”, tourniquet (ischemia). 4 Lesion at level ofelbow, proximal forearm. 5 Deep branch lesion: Pain on extensor surface of forearm, no sensory deficit, paralysisof long finger/thumb extensors with preservation of (radial) lifting of hand. 6 Paralysis of radial hand/finger flex-ors, pronators, thenar atrophy; sensory

!

in first 31/2 fingers, trophic disturbances. 7 Pain on outer surface offorearm. 8 Lesion: anterior interosseous n.; no sensory deficit; flexor weakness in distal segments of thumb,index and middle finger. 9 Lesion of distal forearm, wrist. 10 Painful nocturnal/morning paresthesia (in arm) withsensory loss, thenar atrophy, and paralysis as the condition progresses. 11 Overextension of finger at metacar-pophalangeal joint, flexion of middle and distal phalanges, sensory deficit in ulnar 11/2 fingers. 12 Paresthesiae,pain in outer surface of thigh. 13 Lesion behind medial malleolus.

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Table 59 Diabetic polyneuropathy syndromes (p. 324)

Syndrome Features

Symmetric distribution! Diabetic polyneuropathy (DPN)1 ! Distal, primarily sensory, with or without pain. NCV2

!

and/or res-piration-dependent change in heart rate (p. 370)

!. Areflexia3, pall-

hypesthesia or pallanesthesia in toes, either initially or over time.Progression: increased sensory loss, impairment of position sense(sensory ataxia), paresthesiae, trophic changes, and paralysis. Au-tonomic dysfunction

! Diabetic pandysautonomia ! Cardiovascular4, gastrointestinal5, urogenital6, and skin7 changes.Usually associated with DPN, but isolated occurrence is possible

! Small-fiber polyneuropathy (PNP)with weight loss

! Painful (burning, dull dragging pain, more prominent at night). Au-tonomic dysfunction. Relatively mild impairment of somatic sensa-tion, vibration and position sense, muscle strength and reflexes

! Hypoglycemic PNP ! Seen in insulinoma. May also be caused by recurrent hypoglycemia

Asymmetric distribution! Lumbosacral radicular neu-

ropathy/plexus neuropathy8,9! Rarely symmetrical. Intense pain radiating from low back to upper

thigh. Weakness and atrophy of muscles innervated by the femoralnerve. Loss of quadriceps reflex. Minimal sensory loss

! Thoracolumbarradiculoneuropathy9

! Segmental beltlike pain distribution, sensory deficit, abdominalwall paralysis

! Compression syndromes ! Carpal tunnel syndrome (Table 58), ulnar lesion at level of elbow! Cranial mononeuropathy9,10 ! III ! acute, painful11 ophthalmoplegia, usually without pupillary in-

volvement. VII ! acute, often painful paralysis of the peripheraltype

(Taylor and Dyck, 1999)

1 Cannot be clinically distinguished from uremic neuropathy. 2 Nerve conduction velocity (sensory/motor).3 Mainly the gastrocnemius reflex. 4 Resting tachycardia, fixed heart rate. 5 Gastroparesis, diarrhea, constipation,biliary stasis, fecal incontinence. 6 Urinary retention, erectile dysfunction, retrograde ejaculation. 7 Hypohidrosis,hyperkeratosis. 8 Also referred to as proximal diabetic neuropathy, diabetic amyotrophy, and femoral neuropathy.9 Indicative of favorable prognosis (partial or complete remission). 10 Local infection (rhinocerebral mucormyco-sis, p. 246, otitis externa circumscripta) can cause cranial nerve deficits in patients with diabetes mellitus. 11 Peri-orbital, retro-orbital, frontotemporal, hemispheric.

Table 60 Clinical spectrum of Guillain–Barré syndrome (p. 326)

Syndrome Features1

Acute inflammatory demyelinating poly-radiculoneuropathy (AIDP)2

Perivenous lymphocytic infiltrates and demyelination.IgM/IgG antibodies3 against GM1

Acute motor-sensory axonal neuropathy (AMSAN)4 Pronounced paralysis, early muscular atrophy. Axonaldegeneration. IgG antibodies directed against GM1

Acute motor-axonal neuropathy (AMAN)4 Pure motor neuropathy with axonal degeneration.IgG antibodies directed against GM1, GD1a, GD1b

Miller Fisher syndrome (MFS) Diplopia (usually external ophthalmoplegia), ataxia,areflexia. IgG antibodies to GQ1b

5

(Hahn, 1998)

1 The most common manifestations are listed. Other motor, sensory, or autonomic disturbances may also occur.2 The most common form in Europe, North America, and Australia. 3 Ganglioside antibodies. 4 Commonly occurin North China, Japan, and Mexico; rarely in Western countries. 5 Detected in over 95% of all patients; correlatedwith the course of the disease.

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Table 61 Diagnostic criteria: Guillain–Barré syndrome (GBS) (p. 326)

Necessary1 Supportive1 Doubtful1 Exclusion 1

! Progressive paralysisin more than onelimb

! Hyporeflexia orareflexia

! Progression lastingdays to 4 weeks

! Symmetry (relative) ofinvolvement

! Mild sensory distur-bances

! Cranial nerve involve-ment, especially VII

! Resolution 2–4 weeksafter end of progres-sion

! Autonomic dysfunc-tion

! Initial absence offever

! CSF protein !2

! Typical neurophysio-logical findings3

! Markedly asymmetri-cal involvement

! Initial or persistentbladder/bowel dys-function

! Granulocytes in CSF;cell count !50mononuclear cells/mm3

! Sharply localizedsensory loss in thetrunk region

! Diagnosis of my-asthenia, botulism,poliomyelitis, toxicneuropathy

! Porphyria! Recent diphtheria! Isolated sensory dis-

turbances withoutparalysis

(Asbury and Cornblath, 1990)

1 “Necessary” = prerequisite for diagnosis of GBS; “supportive” = supports the diagnosis; “doubtful” = GBS un-likely; “exclusion” = excludes the diagnosis of GBS. 2 May be normal initially, then rise in the course of the dis-ease to several g/l; blood–brain barrier dysfunction; cell count " 10 mononuclear cells/mm3. 3 Early phase: Partialconduction block with reduced amplitude of evoked motor response potentials (proximal stimulation), loss of re-flex and F-wave responses due to a proximal lesion; EMG recordings show reduced number of activatable motorunits. Later stages: Variably reduced motor response potential; EMG shows mild to marked denervation (the lessmarked, the better the prognosis).

Table 62 Genetic features of hereditary polyneuro-pathy (p. 332)

Syndrome Mode of Inheritance1/Gene Locus

HMSN type ICMT1A2 AD/17p11.2–123

CMT1B AD/1q22–234

CMT1C AD/?CMT4A AR/8qCMT4B AR/11q23CMT4C AR/5qCMTX1 XD/Xq13.15

CMTX2 XR/Xp22.2CMTX4 XR/Xq26

HMSN type IICMT2A AD/1p36CMT2B AD/3q13–22CMT2C AD/?CMT2D AD/7p14

HMSN type IIICMT3A AD/17p11.2–123

CMT3B AD/1q22–234

CMT3C AD/8qHNPP AD/17p11.2–123

(Mendell, 1998; Schaumburg et al., 1992; Schöls,1998)

1 AD = autosomal dominant, AR = autosomal reces-sive, XR = X-linked recessive; XD = X-linked dominant.2 CMT = Charcot–Marie–Tooth. 3 Gene: PMP22 (PMP= peripheral myelin protein). 4 Gene: P0 (point muta-tion). 5 Gene: connexin 32 (point mutation).

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Table 63 Features of rare nonmetabolic neuropathies (p. 332)

Syndrome Inheritance/Gene Locus

Clinical Features/NCV1

Giant axon neuropathy(GAN)

AR/16q24.1 PNP syndrome, fair, frizzy hair, gait impairment, NCVslightly

!

HSN2 type I AD/9q22.1–22.3 Sensory and autonomic neuropathy, reflexes

!

, sensoryloss in feet, restless legs, perforating foot ulcers, hearingloss, lancinating pain in limbs, deforming arthropathy,normal motor NLV

FAP3 AD Autonomic PNP (! autonomic dysfunction), dissociatedsensory loss, pain, trophic disturbances, vitreous opacity,cardiomyopathy, nephropathy, hepatopathy

1 Nerve conduction velocity. 2 Hereditary sensory neuropathy. 3 Familial amyloid polyneuropathy (PNP). Thereare different subtypes with variable serum protein changes (transthyretin, apolipoprotein A1, gelsolin) that giverise to extracellular amyloid (AF) deposits. Liver transplantation can be performed to remove the amyloid precur-sors and bring about degeneration of the amyloid deposits.

Table 64 Myopathy syndromes (p. 334)

Features Potential causes

Acute generalizedweakness

Myasthenia gravis, botulism, periodic paralysis1, polymyositis/dermatomyositis, acuterhabdomyolysis, critical illness myopathy, toxic or drug-induced myopathy2, hypermag-nesemia

Subacute orchronic, mainly pro-ximal weakness

Myasthenia gravis, Lambert–Eaton syndrome, muscular dystrophy, congenital myopathy,polymyositis/dermatomyositis, metabolic myopathy, mitochondriopathy, electrolyte im-balance, endocrine disorder3, toxic or drug-induced myopathy

Subacute orchronic, mainly dis-tal weakness

Inclusion body myositis, myotonic dystrophy, facioscapulohumeral muscular dystrophy,nemaline myopathy, central core disease, scapuloperoneal syndrome, Welander myo-pathy4, oculopharyngodistal myopathy

Periodic weakness Myasthenia gravis, Lambert–Eaton syndrome, dyskalemic paralysis, paramyotonia con-genita, neuromyotonia, Conn syndrome, thyrotoxicosis

Asymmetric or lo-calized weakness

Facioscapulohumeral muscular dystrophy, myasthenia gravis, ischemic muscular necro-sis, local myositis, muscle rupture/trauma

Multiple system in-volvement

Mitochondriopathy, critical illness myopathy, myotonic dystrophy, proximal myotonicmyopathy, dermatomyositis

Dysphagia Myasthenia gravis, polymyositis, myotonic dystrophy, oculopharyngeal muscular dystro-phy, inclusion body myositis, mitochondriopathy

Myalgia Viral/bacterial/parasitic/granulomatous/interstitial myositis, dermatomyositis/ polymyosi-tis, vasculitis, eosinophilic fasciitis, polymyalgia rheumatica, fibromyalgia. Alcohol,drugs, hypothyroidism. Metabolic myopathies. Muscle strain. Neuromyotonia. Stiff-mansyndrome

Muscle cramps Idiopathic, exercise-induced, pregnancy, uremia, hypothyroidism, electrolyte imbalance

Muscle hypertrophy Muscular dystrophy (Duchenne/Becker: calves, deltoid), myotonia congenita, amyloido-sis, cysticercosis, acromegaly, glycogen storage disease type II (Pompe)

Cardiomyopathy Duchenne/Becker muscular dystrophy, Emery–Dreifuss muscular dystrophy, myotonicdystrophy, centronuclear myopathy, nemaline myopathy, glycogen storage diseasetype II

CK-emia5 Physical stress, muscle trauma (fall, injection, epileptic seizure), toxins/drugs (alcohol),hypothyroidism, female carrier of trait (Duchenne/Becker muscular dystrophy), incipientmyopathy (muscular dystrophy, myositis, glycogen storage disease), hereditary

1 Hypokalemic or hyperkalemic form. 2 Table 66. 3 Hypothyroidism or hyperthyroidism, acromegaly, Cushing dis-ease, hyperparathyroidism, Conn syndrome, Cushing syndrome. 4 Myopathia distalis tarda hereditaria. 5 Eleva-tion of creatine kinase (CK) levels in serum without clinical evidence of myopathy; risk of malignant hyperthermia(related to general anesthesia, see p. 346).

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Table 65 Some hereditary myopathies (p. 334)

Type Myopathy Inh.1 Gene locus Gene product

Dystrophinopathy Duchenne MD2 XR3 Xp21.2 DystrophinBecker MD XR Xp21.2 Dystrophin

Sarcoglycanopathy LGMD2D4 AR5 17q21 !-Sarcoglycan6

LGMD2E AR 4q12 "-SarcoglycanLGMD2C AR 13q12 #-SarcoglycanLGMD2F AR 5q33 $-Sarcoglycan

Other LGMDs LGMD2A AR 15q15.1–21.1 Calpain-3LGMD2B AR 2p13.3–13.1 DysferlinLGMD1A AD 5q31 MyotilinLGMD1B AD 1q11–21 Lamin A/CLGMD1C AD 3p25 Caveolin-3

Other MDs Facioscapulohumeral MD AD 4q35 ?Oculopharyngeal MD AD 14q11.2-q13 PABP27

Myotonic MD8 AD 19q13 DMPK9

Emery–Dreifuss MD XR Xq28 Emerin

Channel diseasesChloride channel Thomsen MC10 AD 7q35 Chloride channel

Becker MC AR 7q35 Chloride channelSodium channel Hyperkalemic PP11 AD 17q23.1–25.3 Sodium channel

Paramyotonia congenita AD 17q23.1–25.3 Sodium channelPAM12 AD 17q23.1–25.3 Sodium channel

Calcium channel Hypokalemic PP13 AD 1q32 Calcium channel14Malignant hyperthermia AD 1q31–32 Calcium channel14Malignant hyperthermia AD 19q13.1 Calcium channel15Central core disease AD 19q13.1 Calcium channel15

Mitochondriopathies Mitochondrial myopathy16 Mitochondrial DNA17

(Gene loci as specified by OMIM)

1 Mode of inheritance. 2 Muscular dystrophy. 3 X-linked recessive. 4 LGMD = limb girdle muscular dystrophy.5 Autosomal recessive. 6 Adhalin-7-poly(A) binding protein-2. 7 Poly(A) binding protein-2. 8 Unstable trinu-cleotide repeat (CTG). 9 Myotonin-protein kinase. 10 Myotonia congenita. 11. Hyperkalemic periodic paralysis.12. Potassium-sensitive myotonia (myotonia fluctuans). 13. Hypokalemic periodic paralysis. 14. Dihydropyridinereceptor. 15. Ryanodine receptor. 16 Mainly systemic diseases, usually maternally inherited or sporadic. 17. Nu-clear DNA mutations are rare.

Table 66 Some acquired myopathies (p. 334)

Type Myopathy

Neuromuscular end platedysfunction

Myasthenia gravis, Lambert–Eaton syndrome, botulism

Endocrine myopathy Hyperthyroidism, hypothyroidism, Cushing syndrome, acromegaly, Conn syn-drome, primary hyperparathyroidism

Inflammatory myopathy Polymyositis, dermatomyositis, myositis with vasculitis, Churg–Strauss syndrome,granulomatous myositis, inclusion body myositis, myositis induced by pathogens(e. g., bacteria, viruses, parasites)

Toxic/drug-inducedmyopathy1

Alcohol, corticosteroids, lovastatin, simvastatin, cocaine, emetin, diazocholesterol

1 Rarely caused by other drugs or toxins (not listed).

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Table 67 Additional diagnostic studies for myopathy (p. 334)

Method Information Supplied/Parameters

Pharmacological tests Edrophonium chloride (p. 404)In vitro testing for malignant hyperthermia.

Neurography/Stimulationelectromyography

Used to exclude peripheral neuropathy (p. 404). Serial stimulation: Evidence ofneuromuscular conduction disturbances

Needle electromyo-graphy1

! Muscular dystrophy: Possible findings include fibrillation, positive waves, pseu-domyotonic discharges. Brief, low-amplitude MAPs, polyphasia rate !, rapidand dense interference pattern

! Myositis: Fibrillation, positive waves, pseudomyotonic discharges. Polyphasiarate !, narrow and low-amplitude MAPs

! Myotonia/paramyotonia: Myotonic discharges, MAPs resembling those ofmuscular dystrophy

Laboratory tests ! Creatine kinase2: !10 000 in acute rhabdomyolysis, myositis, toxic myopathy,Duchenne/Becker muscular dystrophy (early stage)

! 4000–10 000 in Duchenne/Becker type muscular dystrophy (later stages), my-ositis

! 1000–4000 in muscular dystrophies, hypokalemic or hypothyroid myopathy,congenital myopathy, female carrier (muscular dystrophy)

! "1000 in spinal muscular atrophy, amyotrophic lateral sclerosis, inclusionbody myositis, chronic/infectious myositis

! Myoglobin: Severe muscle degeneration ! myoglobinuria3! Serum lactate/pyruvate (venous): Elevated at rest or after light physical exercise

! mitochondriopathies, respiratory chain defects. Absence of rise in disordersof glycolysis and glycogenolysis4

! Molecular genetics: Depends on results of immunohistochemistry (dystrophies)and biochemical muscle analysis (mitochondriopathies). Used to supplementclinical findings if necessary (channel diseases)

! Other tests5: Erythrocyte sedimentation rate, hepatitis antigen, ANCA6 (vasculi-tis). Eosinophilia (eosinophil fasciitis, Churg–Strauss syndrome). Sarcoplasmicenzymes incl. SGOT, SGPT, lactate dehydrogenase, aldolase, !-GT (elevated inPROMM7). Basal TSH. Rheumatoid factor (myositis). Antibodies: AChR8 (my-asthenia), Jo-1 (myositis, antisynthetase syndrome), Pm-Scl (myositis with sys-temic sclerosis), SS-A (Ro) (myositis with Sjögren syndrome), U1RNP (mixedconnective tissue disease)

Diagnostic imaging Ultrasound, CT/MRI: Distribution of atrophy, fat and connective tissue. Supportiveevidence when selecting site of biopsy. Localization of local muscle changes(tumor, hemorrhage, pyomyositis/ossification ! scintigraphy)

Muscle biopsy Mainly used for definitive proof of an inflammatory, vasculitic or metabolic my-opathy. Also used for clarification of diseases not clearly classifiable as “myo-genic” or “neurogenic.” Sporadic cases of muscular dystrophy

1 For abbreviations, see p. 391. 2 U/l of CK-MM; selected examples. 3 Alcohol, barbiturates, acute myositis,malignant hyperthermia, carnitine palmitoyl transferase deficiency, glycogen storage disease type V/VII, posttrau-matic, postictal, idiopathic. 4 Determined by stress testing (ischemia ! risk of rhabdomyolysis). 5 Selected ex-amples, see also p. 391. 6 Antineutrophil antibodies. 7 Proximal myotonic myopathy. 8 Acetylcholine receptor.9 Specimens taken from muscle moderately affected by disease process. Two specimens are deep-frozen in anisopentane–nitrogen mixture (for histochemistry, immunohistochemistry; biochemical diagnosis, etc.). One speci-men is fixed in glutaraldehyde for electron-microscopic study.

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Table 68 Clinical features of selected muscular dystrophies1 (p. 336)

Criteria DuchenneMD2

Becker MD Limb girdleMD

Facioscapulo-humeral MD

Myotonic MD

Mean age atonset (years)

2 12 Adolescence/adulthood

Adolescence/adulthood

Adolescence/adulthood

Sex3 M M M/F M/F M/F

Site of onset Pelvic girdle Pelvic girdle Pelvic girdle(often)

Face, shouldergirdle

Head, shouldergirdle, arms,dorsiflexors offoot

Facial muscleinvolvement

No No No Yes Yes (cataract)

(Pseudo) Hy-pertrophy

Calf, deltoid,gluteal muscles

Calf muscles Calf muscles(rarely)

None None

Cardiac involve-ment

Common Rare Occasional None Common(pacemaker)

Inheritance X-linked reces-sive

X-linked reces-sive

Usually auto-somal recessive

Autosomaldominant

Autosomaldominant

CK level4 50 (to 300)times higherthan normal

20 (to 200)times higherthan normal

!10 timeshigher thannormal

Normal to 4times higherthan normal

Normal to 3times higherthan normal

Dystrophin Absent Deficient Normal Normal Normal

Myotonia No No No No Yes

Prognosis Age (years)3–6, gait dis-turbance; 5–6,hypertrophy;6–11, increas-ing weaknessand contrac-tures; deathoften at age15–30

Slow progres-sion. Unable towalk by ca. age20. Mean ageat death, 42years (range,23–89)

Mainly slow.Life span usu-ally onlyslightlydecreased

Slow progres-sion. Ability towalk is pre-served. Normallife span

Ability to walkis preserved.Life span short-ened only insevere cases

1 Very rare syndromes (prevalence !1/106) such as Emery–Dreifuss MD, oculopharyngeal MD, distal myopathies,proximal myotonic MD, and congenital MD are not listed here. 2 MD = muscular dystrophy. 3 M = male; F =female. 4 CK = creatine kinase.

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Table 69 Myotonia and periodic paralysis (p. 338)

Criterion Hyperka-lemic par-alysis

Paramyo-tonia con-genita

Myotoniafluctuans

MyotoniacongenitaThomsen

MyotoniacongenitaBecker

Proximalmyotonicmyo-pathy1

Myotonicdystrophy

Periodicparalysis

Yes Yes No No Yes No No

Cold-in-duced par-alysis

No Yes No No No No No

Potassium-inducedparalysis

Yes Some-times

No No No No No

Paradoxi-cal myo-tonia2

Some-times

Yes No No No No No

Additionalorgan in-volve-ment3

No No No No No Yes Yes

Inheri-tance

AD4 AD AD AD AR5 AD AD

Defect Sodiumchannel

Sodiumchannel

Sodiumchannel

Chloridechannel

Chloridechannel

? Proteinkinase

Features Durationof para-lytic at-tacks var-ies (!4hours)

Attacks ofmusclestiffnessand weak-ness canlast up to1 day

Myotoniaof variableseverity

General-ized myo-tonia, noweakness

Myotoniamoreseverethan inThomsentype. Tran-sientweakness

Proximalmuscleweakness,cataract,musclepain, mildmuscularatrophy

Weakness,especiallyofcraniocer-vicalmuscles,less pro-nouncedin limbs(mainlydistal).Cataract.Defectivecardiacimpulseconduc-tion

(Ptacek et al., 1993)

1 Unlike in myotonic dystrophy, there is no cytosine–thymine–guanine (CTG) repeat. 2 In this case, myotoniagenerally subsides after repeated voluntary muscle contraction (“warm-up”), whereas it increases in paradoxicalmyotonia. 3 I.e., extramuscular involvement. 4 Autosomal dominant. 5 Autosomal recessive.

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Table 70 Selected forms of congenital myopathy (p. 340)

Myopathy Gene Locus/Gene Comments

Central core disease AD1: 19q13.1/Ryanodinereceptor

Neonatal hypotonia. Slow progression. Atten-tuated muscles, skeletal anomalies2, hyporeflexiaor areflexia; exercise-induced muscle stiffness;risk of malignant hyperthermia

Nemaline myopathy(NEM1)

AD: 1q22–23/Tropomyosin-3 Neonatal hypotonia; nonprogressive; high palate

Nemaline myopathy(NEM2)

AR3/2q22/Nebulin Delayed motor development. Attenuatedmuscles, thin extremities; dysplasia4. Respiratorydisturbances (paretic diaphragm muscles), recur-rent pneumonia, dysphagia, dysarthria; hy-poreflexia or areflexia

Centronuclear (my-otubular) myopathy

XR5: Xq28/Myotubularin Neonatal hypotonia, facial muscle weakness, ex-ternal ophthalmoplegia, hyporeflexia, respiratorydisturbances, dysphagia, high palate

1 Autosomal dominant. 2 Congenital hip dislocation, chest deformity, kyphoscoliosis, pes cavus. 3 Autosomal re-cessive. 4 Elongated and oval face, open mouth, micrognathia, high palate, kyphosis, hyperlordosis, pes cavus,cardiomyopathy, heart failure. 5 X-linked recessive; autosomal recessive and autosomal dominant inheritance arealso found, with less severe manifestations.

Table 71 Metabolic myopathies (p. 340)

Myopathy/Gene Locus Defect/Inheritance Features

Carbohydrate metabolism! Acid maltase deficiency1 (type

II, Pompe)/17q25.2–25.3! 1,4-Glucosidase/! Autosomal recessive

! Slowly progressive proximalmyopathy, respiratory distur-bances (nocturnal hypoventila-tion)

! Muscle phosphorylase deficien-cy1 (type V, McArdle)/11q13

! Myophosphorylase/! Autosomal recessive

! Exercise-induced muscle painand stiffness, contractures thatsubside at rest, rhabdomyolysis

! Phosphofructokinase deficiency(type VII, Tarui)/12q13.3

! Phosphofructokinase/! Autosomal recessive

! Similar to McArdle type

Fat metabolism! Carnitine deficiency my-

opathy/?! Carnitine/Autosomal recessive? ! Symmetrical, proximal, slowly

progressive myopathy, CK !

! CPT-I deficiency2/11q13 ! CPT I/Autosomal recessive ! Exercise and cold-inducedmuscle pain and weakness,rhabdomyolysis, hypoglycemia,hyperammonemia

! CPT-II deficiency/1p32 ! CPT II/Autosomal recessive ! Exercise/fasting-inducedmuscle pain, rhabdomyolysis

(continued next page)

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Table 71 Metabolic myopathies (p. 340) (continued)

Myopathy/Gene Locus Defect/Inheritance Features

Mitochondria! CPEO3 ! mtDNA deletion in ca. 50% of

cases! Ptosis, external ophthalmople-

gia, tapetoretinal degenera-tion, cardiac arrhythmias, pro-ximal myopathy

! KSS4 ! mtDNA deletion/! duplication

! Onset before 13th year of life,ataxia, hearing impairment,

!CSF protein, endocrine distur-bances, otherwise identical toCPEO

! MERRF5 ! mtDNA point mutation ! Myoclonus, ataxia, seizures! MELAS6 ! mtDNA point mutation ! Episodic vomiting, focal

seizures, dwarfism, proximalmuscle weakness

! LHON7 ! mtDNA point mutation ! Acute/subacute bilateral loss ofvision, eye pain

! MILS8 ! mtDNA point mutation9 ! Developmental delay, ataxia,dystonia, visual disturbances,respiratory disturbances10

1 Adult type. 2 Carnitine palmitoyl transferase; defect located on outer mitochondrial membrane in type I, andon inner membrane in type II. 3 Chronic progressive external ophthalmoplegia. 4 Kearns–Sayre syndrome; car-diac pacemaker implantation may be necessary in patients with cardiac arrhythmias. 5 Myoclonus epilepsy withragged red fibers. 6 Myopathy, encephalopathy, lactic acidosis, and “strokelike episodes”. 7 Hereditary hepatic-optic neuropathy. 8 Maternally inherited Leigh syndrome. 9 Autosomal recessive and sporadic forms are alsofound. 10 T2-weighted MRI reveals bilateral symmetric lesions (brain stem, periaqueductal region, cerebellum,basal ganglia)

Table 72 Drugs that can aggravate myasthenia gravis (p. 342)

Drugs That Can Aggravate Myasthenia Gravis Alternatives

Antibiotics: tetracyclines, aminoglycosides, polymy-xins, gyrase inhibitors, penicillins

Cephalosporins, chloramphenicol

Psychoactive drugs: benzodiazepines, barbiturates,tricyclic antidepressants, chlorpromazine,haloperidol, droperidol, lithium

Promethazine, thioridazine. Chlordiazepoxide, ma-protiline, mianserin or carbamazepine can be used atlow doses and with careful monitoring

Anticonvulsants: phenytoin, ethosuximide, barbitu-rates

Carbamazepine

Cardiovascular agents: Quinidine, ajmaline, procain-amide, lidocaine, ganglioplegics, nifedipine, !-block-ers1

Digitalis, reserpine, methyldopa, tocainide, verapamil(low-dose)

Miscellaneous: ACTH, corticosteroids2, D-penicil-lamine, morphine and derivatives, magnesium,general anesthesia (muscle relaxants)

Aspirin, gold, indometacin, acetaminophen, di-clofenac, local/regional anesthesia, spinal anesthesia,inhalant anesthetics/deeper general anesthesia

(Selected drugs from McNamara and Guay, 1997)

1 Mask symptoms of myasthenia. 2 High starting dose.

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Table 73 Myasthenia-related crises (p. 342)

Syndrome Symptoms and Signs Precipitating Factors

Myasthenic crisis Restlessness, anxiety, confusion, respira-tory weakness, weak cough, dysphagia,dysarthria, mydriasis, ptosis, tachycardia,pallor

Infectious diseases, surgical interventions,anesthesia, drugs, psychosocial stress, im-paired drug uptake (vomiting, diarrhea),disease progression, previously unde-tected myasthenia (and previously men-tioned factors)

Cholinergic crisis Restless, anxiety, confusion, respiratoryweakness, weak cough, dysphagia, dy-sarthria, miosis, bradycardia, skin redden-ing, muscle fasciculation/spasms, saliva-tion, tenesmus, diarrhea

Overdosage (relative) of AChE inhibitors;acetylcholine poisoning

Table 74 Ancillary tests in myasthenia gravis (p. 342)

Test Objective Interpretation of Results

Edrophonium chloride test1 (Ten-silon, Camsilon)

Increase in muscle strength (withimprovement of ptosis, eye move-ments, speech, and swallowing)

Marked improvement (beginning30 seconds after administrationand lasting roughly 5 minutes) !unequivocal response. Sensitivityfor OMG2: ca. 86%, for GMG3: ca.95%

Electromyography (EMG)4 Documentation of impaired neu-romuscular conduction (decre-ment in amplitude seen with se-rial stimulation; jitter may be ob-served in single-fiber EMG)

A decrement of 10% or more ispathological. Sensitivity of serialstimulation in OMG: ca. 34%; inGMG: up to 77%. Prior muscle ex-ercise ! more pronounced decre-ment. Sensitivity of single-fiberEMG: ca. 92%

Serum acetylcholine receptor anti-body titer

Documentation of presence ofacetylcholine receptor antibodies

Sensitivity: 50% in OMG, ca. 90%in GMG. False-positive results mayoccur in Lambert–Eaton syn-drome, rarely in amyotrophiclateral sclerosis

Diagnostic imaging5 Measurement of thymus Thymic enlargement due to thy-moma or hyperplasia

(Phillips and Melnick, 1990)

1 Short-term inhibition of cholinesterase, given intravenously for diagnostic purposes. 2 Ocular myastheniagravis. 3 Generalized myasthenia gravis. 4 Example: Repeated stimulation of accessory nerve (3/sec for 3 sec-onds) and recording of activity in trapezius muscle. 5 CT (contrast-enhanced) or MRI (younger patients, betterdifferentiation of thymic hyperplasia).

Appendix

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Table 75 Toxic myopathies (p. 347)

Syndrome Substances (selected)

Muscle weakness with or without pain; rhabdomyo-lysis may occur

Alcohol, chloroquine, cimetidine, clofibrate, cocaine,colchicine, ciclosporin, disulfiram, emetine, er-gotamine, gemfibrozil, induced hypokalemia (diuret-ics, licorice), imipramine, isoniazide, lithium,lovastatin, meprobamate, niacin, pentazocine, thy-roid hormones, vincristine, zidovudine

Myalgia Alcohol, allopurinol, cimetidine, clofibrate, clonidine,dihydroergotamine, ergotamine, methyldopa, suc-cinylcholine, vincristine, zidovudine

Polymyositis, pseudo-lupus erythematosus Bezafibrate, chlorpromazine, cimetidine, clofibrate,D-penicillamine, etofibrate, etofyllin clofibrate, fenofi-brate, gold, hydralazine, isoniazide, L-tryptophan,penicillin, phenytoin, procainamide, tetracyclines,zidovudine

Myotonia Ciclosporin, 20,25-diazocholesterol, diuretics, D-peni-cillamine, fenoterol, pindolol, propranolol

Local muscle lesions (pain, swelling, local muscularatrophy)

Heroin, insulin, meperidine, pentazocine

Appendix

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Table 76 Neuromuscular paraneoplastic syndromes (pp. 347, 388)

Site of Lesion Syndrome !Manifestation

Symptoms andSigns

CommonTumors

Lesions/Antibodies

Motor neuron Subacute muscularatrophy (hands,bulbar muscles) !weeks to months

Asymmetrical para-lysis, muscle atro-phy (p. 304)

Small-cell lungcancer, lymphoma,renal cell carci-noma

Motor neurons/Anti-Hu1

Spinal posteriorroot, ganglion

Subacute sensoryneuronopathy !weeks to months

Marked sensoryloss, areflexia,ataxia, paresthe-siae, pain

Small-cell lungcancer, other lungtumors

Spinal ganglia

Proximal peripheralnerve

! Acute poly-radiculopathy !hours to days

! Ascending sen-sorimotor defi-cits2

! Hodgkin disease Segmental demy-elination, neuritis

! Chronic poly-radiculopathy3! weeks tomonths

! Chronic pro-gressive/recur-rent sensorimo-tor deficits

! Small-cell lungcancer, lym-phoma, my-eloma

Distal peripheralnerve

! Paraproteinemicpolyneuropathy! weeks tomonths

! See p. 328 ! Plasmacytoma ! Segmental de-myelination

! Sensorimotorpolyneuropathy! weeks tomonths

! Distal sym-metrical poly-neuropathy

! Small-cell lungcancer, othercancers

! Mainly axonallesions

! Neuromyotonia ! Muscle stiff-ness, cramps

! Thymoma, lungcancer

! Distal motornerve/Anti-VGPC4

End-plate region ! Lambert–Eatonsyndrome !weeks tomonths

! See p. 342 ! Small-cell lungcancer; breast,prostate orstomach cancer

! See p. 343/Anti-VGCC anti-bodies5

! Myastheniagravis ! weeksto months

! See p. 342 ! Thymoma ! See p. 343/Skeletal muscleantibodies

Skeletal muscle ! Polymyositis/dermatomyosi-tis ! months toyears

! See p. 344 ! Various cancers(breast, lung orovarian cancer,lymphoma)

! Myonecrosis,lymphomono-cytic infiltrates

! Rhabdomyolysis! days toweeks

! Rapidly progres-sive paralysis,dysphagia

! Various cancers ! Myonecrosis,rare inflam-matory infil-trates

(Brown, 1998)

1 In small-cell lung cancer. 2 Similar to Guillain–Barré syndrome (p. 326). 3 Similar to CIDP (p. 328). 4 VGPC =voltage-gated potassium channel; EMG shows high-frequency discharges (150–300 Hz). 5 VGCC = voltage-gatedcalcium channel.

Appendix

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Appendix

Table 77 Laboratory tests (p. 351)

Test/Objective Risks Comments

Antiepileptic drugs! Verify drug compliance! Assess for drug resistance! Avoid underdosage or over-

dosage! Assess for drug interactions

! Laboratory error! Misuse of measured values

(the physician should beguided by the clinical objectiveof a seizure-free state, ratherthan by “therapeutic levels”)

Time of sample collection is deter-mined by the pharmacokinetics ofthe antiepileptic drug in question

Lumbar puncture! Measure CSF pressure! Obtain CSF sample for analysis! Intrathecal drug administration! Diagnosis (contrast agent1,

radioactive substances2)

! Increased intracranial pressure3! Intraspinal mass4! Postpuncture headache! Intraspinal hemorrhage

(coagulopathy)! Meningitis! Discitis

Suboccipital or lateral cervicalpuncture is very rarely indicated(e. g. if a CSF sample is required,but cannot be obtained by lumbarpuncture, or for myelographyabove a spinal lesion). Myelogra-phy and MRI have renderedQueckenstedt’s test5 obsolete

1 For myelography. 2 For scintigraphy. 3 Risk of transtentorial/cerebellar herniation. 4 Risk of acute spinal decom-pensation with paraplegia. 5 Compression of jugular vein to test for patency of subarachnoid space, which maybe blocked, for example, by a spinal tumor.

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References

Suggested Reading

Aminoff, M. J. (ed.): Neurology and general medi-cine. Churchill Livingstone, New York, Edin-burgh, London, Philadelphia, 2001.

Berg, B. O. (ed.): Principles of child neurology.McGraw–Hill, New York, 1996.

Bernstein, M., M. S. Berger: Neuro-oncology.Thieme Medical Publishers, New York, 2000.

Bradley, W. G., R. B. Daroff, G. M. Fenichel, C. D.Marsden (eds.): Neurology in clinical practice(Volumes 1 and 2). Butterworth–Heinemann,Boston, Oxford, Singapore, Melbourne, Toronto,Munich, Tokyo, New Delhi, 2000.

Brazis, P. W., J. C. Masdeu, J. Biller: Localization inclinical neurology. Little, Brown and Company,Boston, 1996.

Brooke, M. H.: A clinician’s view of neuromusculardiseases. Williams & Wilkins, Baltimore, 1986.

Compston, A., G. Ebers, H. Lassmann, I. McDonald,B. Matthews, H. Wekerle: McAlpine’s multiplesclerosis. Churchill Livingstone, Edinburgh, Lon-don, Melbourne, New York, 1998.

Dyck, P. J., P. K. Thomas, J. W. Griffin, P. A. Low, J. F.Poduslo (eds.): Peripheral neuropathy (Volumes1 and 2). W. B.Saunders, Philadelphia, 1993.

Engel, A. G., C. Franzini-Armstrong (eds.): My-ology. McGraw-Hill, New York, 1994.

Engel, J., T. A. Pedley (eds.): Epilepsy: a compre-hensive textbook. Lippincott-Raven, Philadel-phia, New York, 1998.

Graham, D. I., P. L. Lantos (eds.): Greenfields’s neu-ropathology (Volumes 1 and 2). Arnold, London,Sydney, Auckland, 2002.

Haerer, A. F.: DeJongs’s The neurologic examina-tion. J.B. Lippincott, Philadelphia, New York,London, Hagerstown, 1992.

Hardman, J. G., L. E. Limbird, A. G. Gilman (eds.):Goodman & Gilman’s The pharmacological basisof therapeutics. McGraw, Hill, New York, 2001.

Hirsch, M. C., T. Kramer: Neuroanatomy. Springer-Verlag, Berlin, Heidelberg, New York, 1999.

Kandel, E. R., J. H. Schwartz, T. M. Jessell: Principlesof neural science. McGraw-Hill, New York, 2000.

Katirji, B., H. J. Kaminski, D. C. Preston, R. L. Ruff, B.E. Shapiro: Neuromuscular disorders in clinicalpractice. Butterworth-Heinemann, Boston, Ox-ford, Auckland, Johannesburg, Melbourne, NewDehli, 2002.

Low, P. A.: Clinical autonomic disorders. Lip-pincott-Raven, Philadelphia, New York, 1997.

Lyon, G., R. D. Adams, E. H. Kolodny: Neurology ofhereditary metabolic diseases of children.McGraw-Hill, New York 1996.

Polman, C. H., A. J. Thompson, T. J. Murray, W. I.McDonald: Multiple sclerosis: the guide totreatment and management, 5th edition.Demos Medical Publishing, New York, 2001.

Rosenberg, R. N., S. B. Prusiner, S. DiMauro, R. L.Barchi, E. Nestler: The molecular and geneticbasis of neurologic and psychiatric disease. But-terworth-Heinemann, Boston, 2003.

Sadock, B. J.,V.A. Sadock: Kaplan and Sadocks’sSynposis of psychiatry. Lippincott Williams &Wilkins, Baltimore, 2002.

Shapiro, C. M.: ABC of sleep disorders. BMJ Pub-lishing Group, London, 1993.

Spillane, J. D., J. A. Spillane: An atlas of clinicalneurology. Oxford University Press, Oxford,1982.

Swaiman, K. F., S. Ashword: Pediatric neurology.Mosby, St. Louis, 1999.

Van Allen, M. W., R. L. Rodnitzky: Pictorial manualof neurological tests. Year Book Medical Pub-lishers, Chicago, London, 1981.

Victor, M., A. H. Ropper: Adams & Victor’s Prin-ciples of neurology. McGraw-Hill, New York,2002.

Warlow, C. P., M. S. Dennis, J. van Gijn, G. J. Hankey,P. A. G. Sandercock, J. M. Bamford, J. M. War-dlaw: Stroke—a practical guide to management.Blackwell Science Ltd., Oxford, 2001.

Watts, R. L., W. C. Koller: Movement disorders:neurologic principles and practice. McGraw-Hill, New York, 1997.

Wiebers, D. O., A. J. D. Dale, E. Kokmen, J. W. Swan-son (eds.): Mayo Clinic examinations in neu-rology. Mosby, St. Louis, 1998.

References

(numbers in brackets refer to appropriate pages)

Ackerman, M. J., D. E. Clapham: Ion channels—basic science and clinical disease. N. Engl. J.Med. 1997;336:1575–1585. [339]

Adams, R. D., J. M. Foley: The neurological dis-orders associated with liver disease. Proc. Assoc.Res. Nerv. Ment. Dis. 1952;32:198–237. [387]

Referenc

es


410

Asbury, A. K., D. R. Cornblath: Assessment of cur-rent diagnostic criteria for Guillain Barré syn-drome. Ann. Neurol. 1990;27(Suppl.):S21–S24.[396]

Bain, P. G.: The management of tremor. J.Neu-rol.Neurosurg.Psychiatry 2002;72(Suppl.1):13–19. [62]

Barohn, R. J.: Approach to peripheral neuropathyand neuronopathy. Semin. Neurol. 1998;18:7–18. [390]

Behin, A., K. Hoang-Xuan, A. F. Carpentier, J.-Y.Delattre: Primary brain tumours in adults. Lan-cet 2003;361:323–331. [264f]

Berger, M. (ed.): Handbuch des normalen undgestörten Schlafs. Springer-Verlag, Berlin,Heidelberg, 1992. [113, 363]

Biller, J. (ed.): Iatrogenic neurology. Butterworth-Heinemann, Boston, 1998. [314, 389]

Bogousslavsky, J., L. Caplan (eds.): Stroke syn-dromes. Cambridge University Press, Cam-bridge, 1995. [166 ff]

Brandt, T.: Vertigo: its multisensory syndromes.Springer-Verlag, London, 1991. [89]

Brott, T., J. Bogousslavsky: Treatment of acuteischemic stroke. N. Engl. J. Med. 2000;343:710–722. [174]

Brown, R. H.: Paraneoplastic neurologic syn-dromes. In: Fauci, A. S., E. Braunwald, K. J. Issel-bacher, J. D. Wilson, J. B. Martin, D. L. Kasper, S. L.Hauser, D. L. Longo (eds.): Harrison’s Principlesof internal medicine. McGraw-Hill, New York,St. Louis, San Francisco, Colorado Springs, Auck-land, 1998. Chapter 103. [388, 406]

Bruni, J.: Episodic impairment of consciousness.In: Bradley, W. G., R. B. Daroff, G. M. Fenichel, C.D. Marsden (eds.): Neurology in clinical prac-tice. Butterworth-Heinemann, Boston, Oxford,Singapore, Melbourne, Toronto, Munich, Tokyo,New Delhi, 1996. 11–21. [200]

Compston, A., A. Coles: Multiple sclerosis. Lancet2002;359:1221–1231. [214f]

Compston, A., G. Ebers, H. Lassmann, I. McDonald,B. Matthews, H. Wekerle (eds.): McAlpine’sMultiple sclerosis. Churchill Livingstone, Edin-burgh, London, Melbourne, New York, 1998.[220]

Conrad, B., A. O. Ceballos-Baumann (eds.): Be-wegungsstörungen in der Neurologie. GeorgThieme Verlag, Stuttgart, New York, 1996.[64,68]

Deuschl, G.: New treatment options for tremors.N. Engl. J. Med. 2000;342:505–507. [62, 357]

Dichgans, J., T. Klockgether: Krankheiten desKleinhirns. In: Kunze, K. (eds.): Praxis der Neu-rologie. Georg Thieme Verlag, Stuttgart, NewYork, 1999. 411–443. [55]

Diener, H. C., O. Kastrup: Nebenwirkungen medi-kamentöser Therapie in der Neurologie. In:Brandt, T., J. Dichgans, H. C. Diener (eds.): Ther-apie und Verlauf neurologischer Erkrankungen.W. Kohlhammer, Stuttgart, Berlin, Köln, 1998.1275–1289. [389]

Ditunno, J. F., W. Young, W. H. Donovan, G.Creasey: The international standards booklet forneurological and functional classification of spi-nal cord injuries. Paraplegia 1994;32:70–80.[380]

Donnan,G.A., S.M. Davis, B.R. Chambers, P.C. Gates:Surgery for prevention of stroke. Lancet1998;351:1372–1373. [174]

Dubowitz, V.: Atlas der Muskelerkrankungen imKindesalter. Hippokrates Verlag, Stuttgart, 1991.[53, 305, 335, 339, 341, 345]

Duus, P.: Neurologisch-topische Diagnostik. GeorgThieme Verlag, Stuttgart, New York, 1995. [57,79,85, 87, 111, 358–361]

Dyck, P. J., P. K. Thomas (eds.): Diabetic neu-ropathy. W. B. Saunders, Philadelphia, London,Toronto, Montreal, Sydney, Tokyo, 1999. [325]

Ebe, M., I. Homma: Leitfaden für die EEG-Praxis.Gustav Fischer Verlag, Stuttgart, Jena, New York,1992. [309]

Elble, R. J.: Origins of tremor. Lancet 2000;355:1113–1114. [62]

Fauci, A. S., H. C. Lane: Human immunodeficiencyvirus (HIV) disease: AIDS and related disorders.In: Fauci, A. S., E. Braunwald, E. M. Isselbacher, J.D. Wilson, J. B. Martin, D. L. Kasper, S. L. Hauser,D. L. Longo (eds.): Harrison’s Principles of inter-nal medicine. McGraw-Hill, New York, St. Louis,San Francisco, Colorado Springs, Auckland,1998. Chapter 308. [241]

Ferro, J. M.: Cardioembolic stroke: an update. Lan-cet Neurology 2003;2:177–188. [172]

Fischbach, G. D., G. M. McKhann: Cell therapy forParkinson’s disease. N. Engl. J. Med.2001;344:763–765. [212]

Fishman, R. A.: Cerebrospinal fluid in diseases ofthe nervous system. W. B. Saunders, Philadel-phia, London, Toronto, Montreal, Sydney, Tokyo,1992. [9, 163]

Fleetwood, I. G., G. K. Steinberg: Arteriovenousmalformations. Lancet 2000;359:863–873.[178]

Frick, H., H. Leonhardt, D. Starck: AllgemeineAnatomie—Spezielle Anatomie I. Georg ThiemeVerlag, Stuttgart, New York, 1992. [141]

Frisoni, G. B.: Structural imaging in the clinical di-agnosis of Alzheimer’s disease: problems andtools. J.Neurol.Neurosurg.Psychiatry 2001;70:711–718. [297]

References

Referenc

es


411

Gautier, J. C.: Amaurosis Fugax. N. Engl. J. Med.1993;329:426–428. [168]

Goadsby, P. J., R. B. Lipton, M. D. Ferrari: Migraine—current understanding and treatment. N. Engl. J.Med. 2002;346:257–270. [184]

Glaser, J.S. (ed.): Neuro-ophthalmology. J. B. Lip-pincott, Philadelphia, 1990. [81, 159]

Gram, L.: Epileptic seizures and syndromes. Lan-cet 1990;336:161–163. [192, 194]

Grumme, T., W. Kluge, K. Kretzschmar, A. Roesler:Zerebrale und spinale Computertomographie.Blackwell Wissenschafts-Verlag, Berlin, Wien,1998. [269]

Hacke, W., M. Hennerici, H. J. Gelmers, G. Krämer:Cerebral ischemia. Springer-Verlag, Berlin,Heidelberg, New York, 1991. [171]

Hahn, A. F.: Guillain Barré syndrome. Lancet.1998;352:635–641. [395]

Hakim, A. M.: Ischemic penumbra. Neurology1998;51(Suppl. 3):S44–S46. [175]

Hardman, J. G., L. E. Limbird, P. B. Molinoff, R. W.Ruddon, A. G. Gilman (eds.): Goodman & Gil-man’s The pharmacological basis of therapeu-tics. McGraw-Hill, New York 1996. [199]

Harms, L.: Tuberkulöse Meningitis. In: Henkes, H.,H. W. Kölmel (eds.): Die entzündlichen Er-krankungen des Zentralnervensystems.ecomed, Landsberg/Lech, 1993. II-10/1–II-10/66. [233]

Harper, P. S. (eds.): Huntington’s disease. W. B.Saunders, London, Philadelphia, Toronto, Syd-ney, Tokyo, 1996. [383]

Hartje, W., K. Poeck: Klinische Neuropsychologie.Georg Thieme Verlag, Stuttgart, New York, 1997.[124, 126, 128, 132]

Henkes, H., H.W. Kölmel (eds.): Die entzündlichenErkrankungen des Zentralnervensystems.ecomed, Landsberg/Lech, 1993. [233, 249,251]

Hichman, S. J., A. J. Lindahl: Minerva. BMJ1999;318:408. [267]

Hoppenfeld, S.: Orthopädische Neurologie. Ferdi-nand Enke Verlag, Stuttgart, 1980. [320]

Huber, A., D. Kömpf (eds.): Klinische Neurooph-thalmologie. Georg Thieme Verlag, Stuttgart,New York, 1998. [83]

Huber, G., M. Voges: Andere Mißbildungen undEntwicklungsstörungen. In: Sartor, K. (eds.):Neuroradiologie. Georg Thieme Verlag, Stutt-gart, New York, 1996. 48–53. [48–53]

Huber, P.: Zerebrale Angiographie für Klinik undPraxis. Georg Thieme Verlag, Stuttgart, NewYork, 1979. [11–19, 169, 171]

Hudson, L. D., C. M. Lee: Neuromuscular sequelaeof critical illness. N. Engl. J. Med. 2003;348:745–747. [347]

International Statistical Classification of Diseasesand Related Health Problems (ICD-10). 1989 Re-vision, World Health Organization, Geneva,1992.

Inzitari, D., M. Eliasziw, P. Gates, B. L. Sharpe, R. K.T. Chan, H. E. Meldrum, H. J. M. Barnett, theNorth American Symptomatic Carotid En-darterectomy Trial Collaborators: The causesand risk of stroke in patients with asympto-matic internal-carotid-artery stenosis. N. Engl. J.Med. 2000;342:1693–1701. [174]

Jankovic, J.: Extrapyramidal disorders. In: Wyn-gaarden, J. B., L. H. South, J. C. Bennett (eds.):Cecil Textbook of medicine. W. B. Saunders,Philadelphia, London, Toronto, Montreal, Syd-ney, Tokyo, 1991. 2129–2130. [211, 301]

Jankovic, J.: Tourette’s Syndrome. N. Engl. J. Med.2001;345:1184–1192. [68]

Jeffcoate, W. J., K. G. Harding: Diabetic foot ulcers.Lancet 2003;1–7. [324]

Jerusalem, F., S. Zierz: Muskelerkrankungen:Klinik—Therapie—Pathologie. Georg ThiemeVerlag, Stuttgart, New York, 1991. [397]

Johns, D. R.: Mitochondrial DNA and disease. N.Engl. J. Med. 1995;333:638–644. [341]

Johnson, R. T.: Viral infections of the nervous sys-tem. Lippincott-Raven, Philadelphia, New York,1998. [234, 239, 253]

Kahle, W.: Nervensystem und Sinnesorgane.Georg Thieme Verlag, Stuttgart, 1979. [7, 9,34–37, 55, 57, 71ff, 81, 95, 97]

Kandel, E. R., J. H. Schwartz, T. M. Jessell (eds.):Principles of neural science. Prentice-Hall Inter-national, London, 1991. [43, 77, 85, 147, 301]

Kapoor, W. N.: Syncope. N. Engl. J. Med..2000;343:1856–1862. [200]

Karnofsky, D. A., J. H. Burchenal, G. C. Armistead, C.M. Southam, J. L. Bernstein, L. F. Craver, C. P.Rhoads: Triethylene melamine in the treatmentof neoplastic diseases. Arch. Intern. Med.1951;87:477–516. [264, 378]

Kaye, A. H., E. R. Laws Jr. (eds.): Brain tumors.Churchill Livingstone, Edinburgh, Hongkong,London, Madrid, Melbourne, New York, Tokyo,1995. [257–261]

Keime-Guibert, F., M. Napolitano, J.-Y. Delattre:Neurological complications of radiotherapy andchemotherapy. J. Neurol. 1998;245:695–708.[389]

Kleihues, P., P. C. Burger, B. W. Scheithauer: Thenew WHO classification of brain tumors. BrainPathol. 1993;3:255–268. [377]

Kolb, B., I. Q. Whishaw: Neuropsychologie. Spek-trum Akademischer Verlag, Heidelberg, Berlin,New York, 1996. [123, 125]

References

Referenc

es


412

Krauseneck, P.: Neoplasien. In: Jörg, J. (eds.): Neu-rologische Therapie. Springer-Verlag, Berlin,Heidelberg, 1997. 242–293. [264f, 377]

Kretschmann, H.-J., W. Weinrich: Klinische Neu-roanatomie und kranielle Bilddiagnostik: Com-putertomographie und Magnetresonanztomo-graphie. Georg Thieme Verlag, Stuttgart, NewYork, 1991. [13, 17, 169]

Krstic, R. V.: Die Gewebe des Menschen und derSäugetiere. Springer-Verlag, Berlin, Heidelberg,New York, 1978. [3, 317, 331, 335, 337]

Kuhlenbäumer, G., P. Young, G. Hünermund, B.Ringelstein, F. Stögbauer: Clinical features andmolecular genetics of hereditary peripheralneuropathies. J.Neurol. 2002;249:1629–1650.[332]

Lance, J. W.: Mechanism and management ofheadache. Butterworth-Heinemann, Oxford,1993. [183,189]

Lantos, P. L., S. R. Vandenberg, P. Kleihues: Tumorsof the nervous system. In: Graham, D., P. L. Lan-tos: Greenfield’s Neuropathology. Arnold, Lon-don, Sydney, Auckland, 1997, 583–879. [264]

Layzer, R. B.: Muscle pain, cramps, and fatigue. In:Engel, A. G., C. Franzini-Armstrong (eds.): My-ology. McGraw-Hill, New York, St. Louis, SanFrancisco, Colorado Springs, Auckland, 1994.1754–1768. [346]

Leigh, P. N., K. Ray-Chaudhuri: Motor neuron dis-ease. J. Neurol. Neurosurg. Psychiatry1994;57:886–896. [386]

Lempert, Th.: Synkopen—Phänomenologie undDifferenzierung von epileptischen Anfällen.Nervenarzt 1997;68:620–624. [200, 374]

Levin, H. S., A. L. Benton, R. G. Grossman: Neurobe-havioral consequences of closed head injury.Oxford University Press, New York, 1982. [269]

Louis, E. D.: Essential tremor. N. Engl. J. Med.2001;345:887–891. [62]

Low, P. A. (eds.): Clinical autonomic disorders. Lip-pincott-Raven, Philadelphia, New York, 1997.[149, 151, 153, 155, 157, 370]

Lücking, C. H., C.-W. Wallesch: Phänomenologieund Klinik der Bewußtseinsstörungen. In: Hopf,H. C., K. Poeck, H. Schliack (eds.): Neurologie inPraxis und Klinik. Georg Thieme Verlag, Stutt-gart, New York, 1992. 2.1–2.18. [116, 119]

Ludin, H.-P., W. Tackmann (eds.): Poly-neuropathien. Georg Thieme Verlag, Stuttgart,New York, 1984. [317]

Lyon, G., R. D. Adams, E. H. Kolodny: Neurology ofhereditary metabolic diseases of children.McGraw-Hill, New York 1996. [304]

Mann, D. M. A.: Molecular biology’s impact on ourunderstanding of ageing. BMJ 1997;315:1078–1081. [299]

Martin, J. B.: Molecular basis of the neu-rodegenerative disorders. N. Engl. J. Med.1999;340:1970–1980. [288]

Masuhr, K. F., M. Neumann: Neurologie. Hippok-rates, Stuttgart, 1996. [293]

Matthes, A., H. Schneble: Epilepsien. GeorgThieme Verlag, Stuttgart, New York, 1992. [193,195, 197, 199]

McDonald, W. I., A. Compston, G. Edan, D. Good-kin, H.-P. Hartung, F. D. Lublin, H. F. McFarland,D. W. Paty, C. H. Polman, S. C. Reingold, M. Sand-berg-Wollheim, W. Sibley, A. Thompson, S. vander Noort, B. Y. Weinshenker, J. S. Wolinsky:Recommended diagnostic criteria for multiplesclerosis: guidelines from the InternationalPanel on the Diagnosis of Multiple Sclerosis.Ann.Neurol. 2001;50:121–127. [375]

McNamara, A. M., D. R. P. Guay: Update on drugsthat may cause or exacerbatemyasthenia gravis.Consult. Pharm. 1997;12:155–164. [403]

Medical Research Council: Aids to the examina-tion of the peripheral nervous system. HMSO,London, 1976. [52]

Mendell, J. R.: Charcot–Marie–Tooth neuropathiesand related disorders. Semin. Neurol.1998;18:41–47. [396]

Montagna, P., P. Gambetti, P. Cortelli, A. Lugaresi:Familial and sporadic fatal insomnia. LancetNeurology 2003;2:167–176. [114, 252, 280]

Moore, P. M., L. H. Calabrese: Neurologic manife-stations of systemic vasculitides. Semin. Neurol.1994;14:300–306. [180]

Moore, P. M., B. Richardson: Neurology of thevasculitides and connective tissue diseases. J.Neurol. Neurosurg. Psychiatry 1998;65:10–22.[180, 181]

Mumenthaler, M., H. Mattle: Neurologie. GeorgThieme Verlag, Stuttgart, New York, 1997. [93,173]

Mumenthaler, M.: Neurologische Differentialdiag-nostik. Georg Thieme Verlag, Stuttgart, NewYork, 1997. [61, 131, 374]

Mumenthaler, M., H. Schliack, M. Stöhr (eds.): Lä-sionen peripherer Nerven und radikuläre Syn-drome. Georg Thieme Verlag, Stuttgart, NewYork, 1998. [33–37, 47, 153, 318–323, 357, 392]

Netter, F. H.: Farbatlanten der Medizin. Band 6:Nervensystem II—Klinische Neurologie. GeorgThieme Verlag, Stuttgart, New York, 1989. [101,155, 167, 209, 239]

Neville, B. G. R.: Epilepsy in childhood. BMJ1997;315:924–930. [373]

Nieuwenhuys, R., J. Voogd, C. Van Huijzen: DasZentralnervensystem des Menschen. Springer-Verlag, Berlin, Heidelberg, New York, 1991. [3,15, 17, 23, 27, 31, 81, 141, 143, 145, 171, 211, 283]

References

Referenc

es


413

Noseworthy, J. H., C. Lucchinetti, M. Rodriguez, B.G. Weinshenker: Multiple sclerosis. N. Engl. J.Med. 2000;343:938–952. [214]

Ogilvy, C. S., R. C. Heros: Spinal cord compression.In: Ropper, A. H. (ed.): Neurological and neuro-surgical intensive care. Raven Press, New York,1993. 437–451. [380]

Online Medelian Inheritance in Man (OMIM):National Center for Biotechnology Information.http://www3.ncbi.nlm.nih.gov/omim [280,398]

Pallis, C., D. H. Harley: ABC of brainstem death.BMJ Publishing Group, London, 1996. [121]

Parsons, M.: A colour atlas of clinical neurology.Wolfe Publishing, London, 1993. [207, 237]

Patten, J.: Neurological differential diagnosis.Springer-Verlag, Berlin, Heidelberg, New York,1996. [83, 91, 215]

Paty, D. W., D. L. Arnold: The lesions of multiplesclerosis. N. Engl. J. Med. 2002;346:199–200.[218]

Perkin, G. D., F. H. Hochberg, D. C. Miller: Atlas ofclinical neurology. Wolfe Publishing, London,1993. [67, 233]

Phillips, L. H., P. A. Melnick: Diagnosis of my-asthenia gravis in the 1990s. Semin. Neurol.1990;10:62–69. [404]

Platzer,W.: Pernkopf Anatomie. Urban & Schwar-zenberg, München, Wien, Baltimore, 1987. [5,21, 75]

Plum, F., J. B. Posner: The diagnosis of stupor andcoma. F. A. Davis Co., Philadelphia, 1980. [119,151]

Poeck, K., W. Hacke: Neurologie. Springer-Verlag,Berlin, Heidelberg, New York, 1998. [127]

Posner, J. B.: Neurologic complications of cancer. F.A. Davis, Philadelphia, 1995. [263, 285]

Prange, H., A. Bitsch (eds.): Infektionskrankheitendes Zentralnervensystems. WissenschaftlicheVerlagsgesellschaft, Stuttgart, 2001. [224–232]

Prusiner, S. B.: Neurodegenerative diseases andprions. N. Engl. J. Med. 2001;344:1516–1526.[252]

Ptacek, L. J., K. J. Johnson, R. C. Griggs: Genetics andphysiology of the myotonic disorders. N. Engl. J.Med. 1993;328:482–489. [401]

Quagliarello, V. J., W. M. Scheld: Bacterial mening-itis: pathogenesis, pathophysiology, and pro-gress. N. Engl. J. Med. 1992;327:864–872. [225]

Quagliarello, V. J., W. M. Scheld: Treatment ofbacterial meningitis. N. Engl. J. Med. 1997;336:708–716. [375]

Qureshi, A. I., S. Tuhrim, J. P. Broderick, H. H. Batjer,H. Hondo, D. F. Hanley: Spontaneous intracere-bral hemorrhage. N. Engl. J. Med.2001;344:1450–1460. [176, 178]

Remmel, K. S., R. Bunyan, R. A. Brumback, G. G.Gascon, W. H. Olson: Handbook of symptom-oriented neurology. Mosby, St. Louis, 2002. [47,277]

Resnick, N. M.: Geriatric medicine. In: Fauci, A. S.,E. Braunwald, E. M. Isselbacher, J. D. Wilson, J. B.Martin, D. L. Kasper, S. L. Hauser, D. L. Longo(eds.): Harrison’s Principles of internal medi-cine. McGraw-Hill, New York, St. Louis, SanFrancisco, Colorado Springs, Auckland, 1998.Chapter 9. [382]

Ricker, K.: Miller-Fisher-Syndrom. Pers. Mit-teilung, 1985. [327]

Ropper, A. H. (ed.): Neurological and neurosurgi-cal intensive care. Raven Press, New York, 1993.[151, 163]

Ropper, A. H.: Miller Fisher syndrome and otheracute variants of Guillain Barré syndrome.Baillière’s Clin. Neurol. 1994;3:95–106. [326,328]

Rosenberg, R. N. (ed.): Atlas of clinical neurology.Butterworth-Heinemann, Boston, 1998. [287]

Rowland, L. P., N. A. Shneider: Amyotrophic lateralsclerosis. N. Engl. J. Med. 2001;344:1688–1700.[304]

Rudnik-Schöneborn, S., W. Mortier, K. Zerres: Spi-nale Muskelatrophien. In: Rieß, O., L. Schöls(eds.): Neurogenetik. Springer-Verlag, Berlin,Heidelberg, New York, 1998. 294–308. [385]

Sacco, R. L.: Extracranial carotid stenosis. N. Engl. J.Med. 2001;345:1113–1118. [168ff]

Sadler, T. W.: Medizinische Embryologie. GeorgThieme Verlag, Stuttgart, New York, 1998. [293]

Sartor, K. (eds.): Neuroradiologie. Georg ThiemeVerlag, Stuttgart, New York, 2001. [380]

Schaumburg, H. H., A. R. Berger, P. K. Thomas: Dis-orders of peripheral nerves. F. A. Davis, Philadel-phia, 1992. [331, 396]

Scientific Advisory Council of the Federal Cham-ber of Physicians (Germany): Richtlinien zurFeststellung des Hirntodes. Dt. Ärztebl.1998;30:49–56. [364]

Schmidt, D.: Epilepsien und epileptische Anfälle.Georg Thieme Verlag, Stuttgart, New York, 1993.[197]

Schmidt, R. F., G. Thews (eds.): Physiologie desMenschen. Springer-Verlag, Berlin, Heidelberg,New York, 1995. [101, 105, 109, 141, 149, 151]

Schnider, A.: Verhaltensneurologie. Georg ThiemeVerlag, Stuttgart, New York, 1997. [25, 129, 133,135, 353]

Schöls, L.: Erkrankungen des peripheren Ner-vensystems. In: Rieß, O., L. Schöls (eds.): Neuro-genetik. Springer-Verlag, Berlin, Heidelberg,New York, 1998. 315–332. [396]

References

Referenc

es


414

Seddon,H.J.: Three types of nerve injury. Brain.1943;66:237–288. [330]

Skoog, I., J. Marcusson, K. Blennow: It’s gettingbetter all the time. Lancet. 1998;352(Suppl.IV):4. [299]

Speckmann, E.-J., C. E. Elger: Introduction to theneurophysiological basis of the EEG and DCpotentials. In: Niedermeyer, E., F. Lopes da Silva(eds.): Electroencephalography—basic prin-ciples, clinical applications, and related fields.Williams & Wilkins, Baltimore, 1993. 15–26.[198]

Stefan, H.: Epilepsien—Diagnose und Behandlung.VCH, Weinheim, 1991. [195]

Stöhr, M.: latrogene Nervenläsionen. GeorgThieme Verlag, Stuttgart, New York, 1996. [321,323]

Tandan, R.: Disorders of the upper and lowermotor neurons. In: Bradley, W. G., R. B. Daroff, G.M. Fenichel, C. D. Marsden (eds.): Neurology inclinical practice. Butterworth-Heinemann, Bos-ton, Oxford, Singapore, Melbourne, Toronto,Munich, Tokyo, New Delhi, 1996. 1823–1852.[385]

Taylor, B. V., P. J. Dyck: Classification of the diabeticneuropathies. In: Dyck, P. J., P. K. Thomas (eds.):

Diabetic neuropathy. W. B. Saunders, Philadel-phia, 1999. 407–414. [395]

Teasdale, G. M.: Head injury. J. Neurol. Neurosurg.Psychiatry 1995;58:526–539. [267]

The Deep-Brain Stimulation for Parkinson’s Dis-ease Study Group: Deep-brain stimulation ofthe subthalamic nucleus or the pars interna ofthe globus pallidus in Parkinson’s disease. N.Engl. J. Med. 2001:345:956–963. [212]

Toole, J. F., A. N. Patel: Cerebrovascular disorders.McGraw-Hill, New York, 1974. [169]

Victor,M., A. H. Ropper: Adams & Victor’s prin-ciples of neurology. McGraw-Hill, New York,2002. [60, 163]

Warlow, C. P., M. S. Dennis, J. van Gijn, G. J. Hankey,P. A. G. Sandercock, J. M. Bamford, J. M. War-dlaw: Stroke—a practical guide to management.Blackwell Science Ltd., Oxford, 2001. [166 ff]

White, R. J., M. A. Likavec: The diagnosis and initialmanagement of head injury. N. Engl. J. Med.1992;327:1507–1511. [270, 379]

Wijdicks, E. F. M.: Brain death. Lippincott Williams& Wilkins, Philadelphia 2001. [120, 365]

Zimmermann, M., H. O. Handwerker: Schmerz—Konzepte und ärztliches Handeln. Springer-Ver-lag, Berlin, Heidelberg, 1984. [109]

References

Referenc

es


415

Inde

x

Index

A

Aachen aphasia test 124Abasia 276Abetalipoproteinemia 280, 281,300, 307, 332

Abiotrophy 296Abscessbrain 222, 226, 227diagnosis 226pathogenesis 226

candida 248epidural 222tuberculous 232

Absidia 248Abulia 122, 123Acalculia 128, 129Acanthocytes 300, 301Acetazolamide 338Acetylcholine 140, 152, 210Acetylcholine receptor anti-body titer 404

Acetylcholinesterase inhibitors298, 342

Acid maltase deficiency 340,402

Acidosis 162Acoustic meatus, external 100Acoustic neuroma 258, 259,294

Acquired immunodeficiencysyndrome (AIDS) 240cytomegalovirus and 244progressive multifocalleukoencephalopathy and244

Acrodermatitis chronicaatrophicans 228

ACTH-secreting tumors 258Acute demyelinating ence-phalomyelitis (ADEM) 234

Acute dystonic reactions 66,204, 205

Acute inflammatory demyeli-nating polyradiculo-neuropathy (AIDP) 395

Acute motor-axonal neuro-pathy (AMAN) 395

Acute motor-sensory axonalneuropathy (AMSAN) 395

Acyclovir 236, 238

Adaptation, olfactory 76Adenohypophysis 142Adenoma, pituitary 258, 259,377

Adie syndrome 92Adrenal medulla 140Adrenoleukodystrophy 307Adrenomyeloneuropathy 332,384

Ageusia 78Aging 296, 382degenerative changes 296disease and 296

Agnosia 132body-image 132finger 132

Agrammatism 124, 126Agraphia 128, 129alexia with 128aphasic 128apraxic 128isolated 128spatial 128, 132

Agyria 381AIDS see Acquired immuno-deficiency syndrome

Akathisia 66Akinesia 206, 208Huntington disease 300

Akinetic mutism 120, 122,368

Albendazole 250Alcoholintoxication 312, 313withdrawal syndrome 312,313

Alcoholism 312, 313, 366fetal alcohol syndrome 314late complications 314

Alexia 128agraphia and 128anterior 128central 128isolated 128

Alien hand syndrome 24, 302Alkalosis 162Alleles 288Allodynia 316, 346Alzheimer disease (AD) 136,296–298, 299, 366

agraphia 128pathogenesis 297–298risk factors 296symptoms and signs 297treatment 298see also Dementia

Amaurosis fugax 82, 168, 372Amblyopia, tobacco–alcohol314

Amimia 362Amnesia 134, 268, 365, 368anterograde 134examination 134retrograde 134

Amoxicillin 228Amphetamine abuse 314Amphotericin B 248Ampullary crests 56Amygdala 144Amyloid precursor protein(APP) 297

Amyloid-Aß 297Amyotrophic lateral sclerosis(ALS) 304, 386adult-onset 304bladder dysfunction and 371juvenile 304sporadic 304

Amyotrophy, neuralgic 321,328, 329

Anal incontinence 370Anencephaly 292Anesthesia 106Aneurysm 178, 179fusiform 178rupture 176, 178, 179

treatment 178saccular 178septic-embolic 178, 226

Angiitiscerebral 180von Heubner 230

Angiography 354Angiomatosiscutaneous 294encephalofacial 294

Angiopathy, amyloid 178Anhidrosis, generalized 152Anisocoria 90Annulus fibrosus 30


416

Inde

x

Anomia 124Anosmia 76partial 76

Anosognosia 132Anterocollis 64Antibiotics 224adverse effects 389myasthenia gravis aggrava-

tion 403see also specific drugs and in-fections

Anticholinergic agents 212Anticipation 300Anticoagulants, stroke man-agement 174

Anticonvulsants 198myasthenia gravis aggrava-

tion 403Antidepressants, adverse ef-fects 389

Antiemetics, acute dystonicreaction 204

Antiepileptic drugs (AEDs)198, 264laboratory tests 407myasthenia gravis aggrava-

tion 403Antimicrobial therapy see An-tibiotics

Antioxidants, neuroprotectivetherapy 212

Antiplatelet therapy, stroke174

Anton syndrome 132Anxiety, Parkinson disease and206

Apallic syndrome 117, 120, 121Aphasia 124, 126–127

Alzheimer disease and 297amnestic (anomic) 126Broca’s 126, 127conduction 126crossed 126global 126, 127subcortical 126test of 124transcortical 126, 127motor 126sensory 126

Wernicke’s 126, 127Aphemia 124Apnea test 364Apo E gene 297Apomorphine 212Apraxia 128, 129

Alzheimer disease and 297buccofacial 128

constructional 132dressing 128, 129, 132gait 128, 374ideational 128ideomotor 128, 129lid-opening 128, 129, 362limb 128

Apraxia-like syndromes 128Aqueduct, cerebral (of Sylvius)8

Arboviruses 376Arch, aortic 148, 150Archeocerebellum 54AreaBroca’s 124postrema 140Wernicke’s 124

Argyll–Robertson pupils 92,230

Arousal disorders 116, 117Arrhythmias, neurogenic 148Arteriovenous malformations(AVMs) 178, 179hemorrhage treatment 178

Arteritis 226, 227Takayasu 180temporal 180see also Vasculitis

Artery(ies)age-related changes 382basilar 14–15occlusion 170, 171

callosomarginal 12carotid 10–12

common 10occlusion 168

external 10internal 10–12

infarction 168, 169occlusion 168

centralposterolateral 16posteromedial 16

cerebellarinfarction 170inferior

anterior 14, 170posterior 14, 170, 171

occlusion 170superior 14, 170

cerebralanterior 12, 13infarction 168, 169

middle 12, 13occlusion 168, 169

posterior 16–17occlusion 170, 171

pars circularis 16pars terminalis 16

choroidal, anterior 10infarction 168

communicatinganterior 12posterior 10, 16

frontobasal 12frontobasilar 12frontopolar 12insular 12lenticulostriate 12

occlusion 168medullary 22meningeal 6

middle 10occipitallateral 16medial 16

ophthalmic 10occlusion 168

paracentral 12parietal

anterior 12posterior 12

parieto-occipital 12pericallosal 12precuneal 12radicular, great (of Adam-

kiewicz) 22occlusion 282

recurrent, of Heubner 12retinal, central 10segmental 22spinal 22, 23, 283

anterior 14, 22syndrome of 282

posterior 14, 22syndrome of 282

subclavianocclusion 170subclavian steal 170

sulcocommissural arterysyndrome 282

temporal 12thalmostriate 12vertebral 14–15extracranial 14intracranial 14occlusion 170

Arthralgia, postpolio syndrome242

Articulation 130dysarthria 130

Aspergillus fumigatus (aspergil-losis) 248, 249

Aspiration 102

Index


417

Inde

x

Aspirin, adverse effects 389Astasia 276Asterixis 68, 69Astrocytoma 256, 377anaplastic 260, 261, 377low-grade 256pilocytic 256, 377

Ataxia 107, 276, 374autosomal dominant cere-

bellar (ADCA) 280episodic (EA) 280Friedreich (FA) 280, 281gait 276, 277idiopathic cerebellar (IDCA)

276postural 276spinal (sensory) 276, 374spinocerebellar (SCA) 280,

384truncal 276

Ataxia-telangiectasia 280, 295Athetosis 383Atlas 30Atrophyage-related 382cerebellar 279

alcoholism and 314cerebral

alcoholism and 314Huntington disease 300

muscular 49–52, 107, 281,287, 334, 406peripheral neuropathy and

316poliomyelitis and 242, 243spinal (SMA) 385spinobulbar 385

olivopontocerebellar 302optic nerve 158, 159temporal papillary 215

Attack(s)drop 204, 205, 374panic 202, 203transient ischemic (TIA) 166crescendo 166

Attentiondeficits 122, 123

directed attention 122divided attention 122

evaluation 353Auditory evoked potentials(AEP) 218, 352

Auditory pathway 100, 101Auramigraine 184, 185seizure 192

Automatism 124, 126

Autonomic dysfunction 48,371diabetic neuropathy 324multiple sclerosis 216, 217neurosyphilis 230Parkinson disease 208, 209peripheral neuropathies 316,

390Autonomic nervous system(ANS) 2, 140–141central portion 140, 141

afferent connections 140efferent connections 140neurotransmitters 140

enteric 154peripheral portion 140–141,144–146afferent connections 140efferent connections 140neurotransmitters 140–141

spinal nuclei 140Autotopagnosia 132Axis 30Axonopathy 316Axonotmesis 330, 331Axons 2Azathioprine 180, 220, 342,344

B

Babinski sign 40, 49Baclofen, adverse effects 389Bacterial infections 226–233

brain abscess 226, 227Lyme disease 228–229meningitis/meningo-

encephalitis 226, 376neurosyphilis 230–231septic encephalopathy 226vasculitis 226ventriculitis 226, 227see also specific infections

Ballism 66, 383Bannwarth syndrome 228Bárány’s pointing test 276Baroreceptors 148Basilar impression 292, 293Bassen–Kornzweig syndrome

300Becker muscular dystrophy

336, 337, 400Behavioral changes 122–123,

368brain tumors 254, 255Huntington disease 300

intracranial hypertension158, 159

multiple sclerosis 216, 217normal-pressure hydro-

cephalus 160Parkinson disease 206–209stroke 166

Behçet disease 180, 234Benedict syndrome 70, 358Benperidol 204Benzodiazepines 198Biopsy 354, 399sural nerve 391

“Black-curtain” phenomenon168

Bladder dysfunction 156, 371multiple sclerosis 216, 217,

218normal-pressure hydro-

cephalus and 160, 161Parkinson disease 208

Bladder function 156, 157tests of 218residual urine volume 218urodynamic electro-myography 218

Blepharospasm 64, 65, 362Blindness, transient monocular168, 372

Blink reflex 96, 98Blood pressure 143, 148, 367

Parkinson disease and 208see also Hypertension; Hy-potension

Blood–brain barrier 8–10disruption of 224multiple sclerosis and 220passage of pathogens 224

Blood–CSF barrier 8–10Body(ies)

geniculate, lateral 80inclusion 52, 252, 344, 345Lafora 307Lewy 208, 210, 302para-aortic 150

Body image perception distur-bances 132

Body temperature see Thermo-regulation

Body-image agnosia 132Bone windows 4Borrelia burgdorferi 228–229Bourneville–Pringle disease

294, 295Bovine spongiform ence-

phalopathy (BSE) 252Brachycephaly 381

Index


418

Inde

x

Bradykinesia 206Huntington disease 300

Bragard’s sign 318Brain 2

abscess 222, 226, 227diagnosis 226pathogenesis 226

blood–brain barrier 8–10degenerative changes 296,

382fore brain 2hind brain 2mid brain 2, 26syndromes 70, 71, 358–

359traumatic brain injury (TBI)266–271complications 269, 270evaluation 266pathogenesis 270, 271primary injury 266, 270prognosis 268secondary sequelae 268,

270treatment 270hospital 270scene of accident 270,

271types of 266

see also Brain tumorsBrain death 120Brain stem 2, 3, 24, 26–27

encephalitis 222hemorrhage 176syndromes 70–71

Brain tumors 254–265ACTH-secreting 258aging and 296benign 256–257bladder dysfunction and 371classification 264grades of malignancy 377growth hormone-secreting258

incidence 264infratentorial region 258malignant 260–261metastatic disease 262–263

treatment 265severity 264, 377supratentorial region 258symptoms and signs 254–255

behavioral changes 254,255

epileptic seizures 254focal neurological signs

254, 255

headache 254, 255intracranial hypertension

254nausea, vertigo and

malaise 254, 255treatment 264–265aftercare 265grade I tumors 264grade II tumors 264grade III tumors 264–265grade IV tumors 265metastases 265symptomatic treatment 264

see also specific tumorsBreathing 150, 151

disorders 150, 151Brivudine 238Broca’s

aphasia 126, 127area 124

Bromocriptine 212Bromopride 204Brown–Séquard syndrome 48Brudzinski’s sign 222Bruxism 114Bundle, medial fore brain 144Bupidine 212Burns 312Burst fracture 380

C

Cabergoline 212Calcium antagonists

acute dystonic reaction 204adverse effects 389

Calcium balance 310Calcium channel dysfunction

338, 398Caloric testing 26Calvaria 4metastases 262

Canalear 100infraorbital 4semicircular 56spinal 30, 31vestibular 100

Canalolithiasis 58Candida albicans (candidosis)

248, 249Capsule, internal, hemorrhage176

Carbamazepine 198, 264Carcinoma

choroid plexus 377meningitis and 262

Cardiomyopathy 397Carnitine deficiency 340, 402Carnitine palmitoyl transferase

(CPT) deficiency 402Carpal tunnel syndrome 322Cataplexy 374Cataract 382myotonic 338

Cauda equina 2syndrome 319

Causalgia 110Cavernoma 178, 179Cefotaxime 228Ceftriaxone 226, 228Central core disease 402Central nervous system (CNS) 2infections 222–225

clinical manifestations 222course of 222localization 222, 223opportunistic infections

240pathogenesis 224, 225prophylaxis 224treatment 224see also specific infections

see also Brain; Spinal cordCentral pontine myelinolysis

310, 315alcoholism and 314

Central salt-wasting syndrome310

Cerebellitis, acute 238Cerebellum 2, 24, 42, 54–55

diseases 276–281acquired 278–279atrophy 279

alcoholism and 314diagnostic studies 276hereditary 280–281

autosomal dominant280

autosomal recessive 280signs of dysfunction 276topography of lesions 276see also specific diseases

hemorrhage 176Cerebral blood flow (CBF) 162hemodynamic insufficiency174

hypoperfusion 174Cerebral cortex 24–25Brodmann classification 24,

25cytoarchitecture 24functional areas 24ischemia 148

Index


419

Inde

x

motor 42primary 42lesions 46

supplementary 42premotor area 42projection areas 24

Cerebral palsy, infantile 288–291, 381causes 288symptoms and signs 288treatment 290

Cerebral perfusion pressure(CPP) 162

Cerebral vascular resistance(CVR) 162

Cerebral ventricles 8, 9Cerebritis 222, 226Cerebrospinal fluid (CSF) 8–9

blood–CSF barrier 8–10circulation 8, 9impaired 160, 161, 372

intracranial hypotension and160

leak 269, 372, 379lymphoma and 260multiple sclerosis and 218pressure measurement 161viral meningoencephalitisand 234

volume 162Cervical syndrome 188, 189

upper 188Charcot joints 230Chemodetectoma 258Chemoreceptors 104, 150, 151Chemotherapy 264–265

adverse effects 389Cheyne–Stokes respiration 118Chiari malformation 292, 293Chiasm, optic 80lesions 82

Chickenpox 238symptoms and signs 238

Chloride channel disease 398Chlorprothixene 264Cholinergic crisis 404Chondrosarcoma 260Chorda tympani lesions 78Chordoma 258, 259Chorea 66–67, 300, 383secondary 66Sydenham’s 66

Choreoathetosis 66Chromosomal anomalies 381Chronic inflammatory demy-

elinating polyradiculo-neuropathy (CIDP) 327, 328

Chronic paroxysmalhemicrania (CPH) 186, 190

Chronobiology 112Chronopathology 112Churg–Strauss syndrome 180,

344Cidofovir 244Cingulate gyrus lesions 122Cinnarizine 204Ciprofloxacin 226Circadian rhythm 112, 113

disturbances 114Circle of Willis 10, 12, 13Circulation 148–149

anterior 10central nervous regulation148

cerebrospinal fluid 8, 9impaired 160, 161, 372

posterior 10Cistern(s) 8

ambient 8cerebellomedullary (cisternamagna) 8

cerebellopontine 8chiasmatic 8interpeduncular 8posterior 8

Claudication, spinal 282, 284,285

Clindamycin/folinic acid 250Clock/numbers test 136, 137Cluster headache see HeadacheCocaine abuse 314Cochlea 100, 101Cognitive impairment

Alzheimer disease 297Huntington disease 300

Colon 154Column

Clarke’s 104vertebral 30

Coma 92, 118–119pupillary dilatation 92pupilloconstriction 92staging 118–119, 267

brain stem reflexes 118Glasgow coma scale 378respiratory pattern abnor-

malities 118spontaneous movement 118stimuli 118

Comalike syndromes 120–121akinetic mutism 120, 122,

368locked-in syndrome 120,121, 170, 359

persistent vegetative state120

Commissure, anterior 144Complex regional pain syn-

drome (CRPS) 110Compliance 162Compressionfracture 380nerve injuries 330

Computed tomography (CT)354brain tumors 260, 265head trauma and 266multiple sclerosis 218

Confabulation 134Confusion 116, 117, 368

Alzheimer disease 297Connective tissue diseases 234Consciousness 116–117

acute disturbances 116–117arousal disorders 116, 117confusion 116, 117somnolence 116, 117stupor 116, 117

assessment of 116content of 116head trauma and 266, 267

assessment 379level of 116normal state of 116, 117psychogenic disturbances120

stroke and 166see also Coma

Constipation 370Parkinson disease 208

Continence 156see also Incontinence

Conus medullaris 2Conversion disorders 138Convulsions, neonatal 196

see also SeizuresCoordination dysfunction 276multiple sclerosis 216, 217

Corneal reflex 26, 96Corpus callosum 24

agenesis 290Cortex

auditory 100, 101primary 100secondary 100

entorhinal 144premotor, lesions 122somatosensory 108see also Cerebral cortex

Corticobasal degeneration(CBD) 302, 303

Index


420

Inde

x

Corticosteroids 143, 264, 342,344adverse effects 389multiple sclerosis treatment

220Cortisol 367Cough reflex 26Coumarins, adverse effects

389Craniocervical junction

anomalies 292Craniopharyngioma 258, 259,

377adamantinomatous 258papillary 258treatment 264

Craniostenosis 381Cranium 4roof 4see also Skull

Creatine kinase elevation 397Creutzfeldt–Jakob disease

(CJD) 252, 253Crisis

cholinergic 404myasthenic 404

Critical illness myopathy (CIM)347, 379

Critical illness polyneuropathy(CIP) 347, 379

Crow–Fukase syndrome 328Cryptococcus neoformans

(cryptococcosis) 248, 249Cupulae 56Cyanocobalamin 286Cyclophosphamide 180, 220,

328Cyst

arachnoid 290, 291colloid 258, 259porencephalic 290

Cysticercosis 250, 251Cytokines 220Cytomegalovirus (CMV) 244–

245pathogenesis 244symptoms and signs 244

D

Dandy–Walker malformation292

Dantrolene 347Death 120–121, 364Debrancher deficiency 340Decerebration syndrome 46,

47, 118, 158, 159

Decortication syndrome 46, 47,118

Deep brain stimulation 212Deficiency

acid maltase 340, 402carnitine 340, 402carnitine palmitoyl trans-ferase (CPT) 402

debrancher 340folic acid 286muscle phosphorylase 402phosphofructokinase 402vitamin B1 312vitamin B12 286, 287vitamin E 280

Degeneration 382corticobasal (CBD) 302, 303panthothenate kinase-

associated 307striatonigral (SND) 302subacute combined (SCD)

286, 287Degenerative changes 296

radicular syndromes and392

see also Neurodegenerativediseases

Deglutition 102, 103disturbances 102, 103mechanism 102nerve pathways 102, 103

Dehydration 372Dejerine–Sottas disease 332Delirium 116, 368

tremens 312Dementia 136–137

alcoholic 314, 366bladder dysfunction and 371classification 366diagnosis 136

differential 383dialysis 310examination 136frontotemporal (FTD) 298,

299Parkinson disease and 208thalamic 116vascular 298, 299, 366multi-infarct 298strategic infarct 298

with Lewy bodies 208, 302see also Alzheimer disease

Demyelination 220Dens fracture 380Depersonalization 202Depression 366

cortical spreading 184

differential diagnosis 383Parkinson disease and 206

Derealization 202Dermatomes 32–36Dermatomyositis 344, 345,

406Developmental anomalies 288,

381Diabetes mellitus 324, 325Diabetic

ketoacidosis 308neuropathy 324, 325, 395

diagnosis 324symptoms and signs 324treatment 324

pandysautonomia 395Dialysis encephalopathy 310,

311Diaphragma sellae 6Diarrhea 370Diencephalon 2Diffuse Lewy body disease

(DLB) 302Diploë 4Diplopia 86

multiple sclerosis 214Disconnection syndrome 24, 128Disequilibrium syndrome 310Disk(s)

intervertebral 30herniation 318, 319, 392

optic 80Dislocation

atlantoaxial 380fracture 380

Disorientation 132–133right–left 132

“Doll’s eye” phenomenon 26,302, 303coma and 118

Dopamine 210age-related changes 382Parkinson disease and 210

Dopamine agonists 208, 212adverse effects 389

Dopaminergic agents 212Doxycycline 228Drooling 206, 207Drop attacks 204, 205, 374Drop metastasis 260, 262Duchenne muscular dystrophy52, 53, 336, 337, 400

Duplex sonography 353Dura mater 6

fistula 178, 282, 283injuries 266spinal 30

Index


421

Inde

x

Dysarthria 124, 130, 166, 276,365

Dysarthrophonia 206, 276Dysdiadochokinesia 276, 277Dysesthesia 106, 316

Parkinson disease and 208Dysgeusia 78Dyskinesia(s)

drug-induced 66orofacial 66, 67tardive 66

Dysmetria 276, 277ocular 276

Dysosmia 76Dysphagia 102, 166, 370, 397

causes 362Dysphonia 130Dysplasia 288Dysraphism, spinal 292, 293,

381Dyssomnia 114, 116Dyssynergy 276Dystonia 64–65, 383

action 6acute dystonic reactions 66,204, 205

arm 64cervical 64, 65classification 64craniocervical 64, 65dopa-responsive 64idiopathic torsion 64leg 64multifocal 65oromandibular 64, 362Parkinson disease 208, 209paroxysmal, autosomal

dominant 64spastic 64task-specific 64

Dystrophinopathy 336, 398Dystrophy

limb-girdle 336, 337, 400myotonic 52, 338, 339, 400,

401reflex sympathetic 110see also Muscular dystro-phies

E

Ecchymosis, retroauricular 267ECG abnormalities, neurogenic148

Echolalia 124Edema

cerebral 162, 163, 224

cytotoxic 162hydrocephalic 162–163treatment 264vasogenic 162

leg, Parkinson disease and208

Edinger–Westphal nucleus 26,90

Edrophonium chloride test404

Ejaculatory dysfunction 156Elastance 162Electro-oculography 352Electroencephalography 352Electrogustometry 78Electrolyte balance disorders

310, 311Electromyography (EMG) 352

myasthenia gravis 404needle 391, 399stimulation 399urodynamic 218

Electroneurography 352Embolism 172, 173

infectious 226paradoxical 262

Emery–Dreifuss muscular dys-trophy 336, 337

Empyema, subdural 222Encephalitis 222

brain stem 222clinical manifestations 222hemorrhagic necrotizing 236Lyme disease and 228toxoplasmosis and 250viral 234, 376herpes simplex 236

Encephalocele 292Encephalomyelitis 222

acute demyelinating (ADEM)234

Lyme 228Encephalopathy 306–315

burns and 312chronic 308dialysis 310, 311endocrine 310, 311hepatic 308, 309, 387HIV 240hypoxic–ischemic 308, 309iatrogenic 314, 315, 389Lyme disease and 228metabolic 386–387

acquired 308–312hereditary 306–307infancy 387neonatal 386

mitochondrial 281multiple organ failure and

312paraneoplastic 312portosystemic 308, 387progressive myoclonic 68septic 226, 227, 312, 313

diagnosis 226spongiform 252–253

bovine (BSE) 252Creutzfeldt–Jakob disease

(CJD) 252, 253genetic 252infectious 252

subcortical arteriosclerotic(SAE) 298

substance abuse and 312,313

trauma and 379uremic 310, 311Wernicke 312, 313

Endarterectomy 174Endocarditis, bacterial 226Endocrine

encephalopathy 310, 311myopathy 347, 398

Endolymph 56Endoneurium 2Endophthalmitis, candida 248Entacapone 212Enteroviruses 376Enuresis 114Eosinophilic fasciitis 344Ependyma 6spinal 256

Ependymoma 256, 257, 377anaplastic 260, 377

Epiduralabscess 222hematoma 268, 270space 6, 30

Epilepsy 192–199acquired 198acute epileptic reactions 196age of onset 197causes 198, 379classification 196–197epileptic syndromes 196generalized 194, 196genetic predisposition 198location-related 196myoclonus

progressive, with Laforabodies 307

with ragged red fibers(MERRF) 403

pathophysiology 198, 199

Index


422

Inde

x

Epilepsyprognosis 198, 373seizure types 192–195, 373

generalized 193, 194–195,197

grand mal 194, 195, 199partial (focal) 192–194,197

status epilepticus 196grand mal 196

treatment 198antiepileptic drugs 198

unclassified 196see also Seizures

Epineurium 2, 30Episodic

ataxia (EA) 280headache

cluster 186, 190tension 182, 190

memory 134paralysis 338, 339, 401vertigo 58

Epithelium, olfactory 76Erb palsy 318Erectile dysfunction 156Erythema chronicum migrans

228, 229Esophagus 154Essential tremor 62, 357Estradiol 367Ethosuximide 198Evoked potentials 352

auditory (AEP) 218, 352motor (MEP) 218, 352somatosensory (SEP) 218,

352visual (VEP) 218, 219, 352

Examination 350–351see also specific conditions

Excitotoxicity 300Executive functions 122Exons 288Expiration 150Exteroceptors 104Extinction phenomenon 132Eye movements 84, 85

convergence 90intracranial hypertension

and 158reflex 84vergence movements 84voluntary 84

F

Fabry disease 307, 332Factitious symptoms 138, 139Falling 374Falx

cerebelli 6cerebri 6

Famcyclovir 238Familial spastic paraplegia

(FSP) 286, 287, 384Fascicles 2Fasciculations 50Fasciculus

arcuate 124cuneatus (lateral) 104gracilis (medial) 104longitudinal, medial 56, 84

Fasciitis, eosinophilic 344Fatal familial insomnia 114,

280Fatigue, multiple sclerosis 214Felbamate 198Festination 206Fetal alcohol syndrome 314Fever 152, 268Fiber(s)

commissural 24corticopontine 44parasympathetic 90, 140,154, 156

preganglionic 140sudoriparous 152sympathetic 90, 140, 154,156

taste 96“U fibers” 244

Fibromyalgia 52Fibrosarcoma 260Fila olfactoria 76Filum terminale 2

externum 30internum 30

Finger agnosia 132Finger–finger test 276, 277Finger–nose test 276First aid 270, 271Fistula, dural 178, 282, 283Fits see SeizuresFluconazole 248Flucytosine 248Fluid balance 143, 268, 367

disorders 310Flunarizine 204Fluphenazine 204Folic acid deficiency 286Foramen(ina)

interventricular, of Monroe8, 258

of Luschka 8of Magendie 8vertebral 30

Forgetfulness 134benign senescent 134, 136see also Memory

Fornix 144, 145Foscarnet 244Fossa, cranial 4

anterior 4middle 4posterior 4, 18

Fovea 80Fractureskull 266vertebral 272, 380atlantoaxial dislocation

380bilateral axis arch 380burst 380compression 380dens 380dislocation 380Jefferson’s 380stability 272, 273

Frey syndrome 362Friedreich ataxia 280, 281Fronto-orbital lesions 122Fungal infections 180, 248–249

aspergillosis 248, 249candidosis 248, 249cryptococcosis 248, 249mucormycosis 248, 249

G

Gabapentin 198Gag reflex 26Gait 60

antalgic 60apraxia 128, 374ataxia 60, 61, 276–277cycle 60, 61disturbances 49, 60–61factitious 139intracranial hypertension158

neurosyphilis 230normal-pressure hydro-

cephalus 160, 161Parkinson disease 206, 207

dystonic 60, 61spastic 60, 61steppage 60, 61waddling 60

Index


423

Inde

x

Galactosemia 386Galea aponeurotica 4Gamma-aminobutyric acid

(GABA) 140, 300Gancyclovir 244Gangliocytoma 377Ganglioglioma 377

anaplastic 377Ganglioma, parasympathetic

258Ganglion(a)

basal 24, 42, 210, 211connections 210, 211hemorrhage 176Parkinson disease and 210,

211dorsal root 2spinal 2trigeminalcentral connections 94, 95peripheral connections 94,

95varicella-zoster and 238

Ganglioneuropathy 390Ganglionitis 238Gangliosidosis

GM1 307, 387GM2 307

Ganser syndrome 138Gastrointestinal function 154–155neurological causes of dys-

function 370Gastroparesis 370Gaucher disease 306, 307,

387Gaze deviation

contralateral 86skew 70, 89

Gaze palsy 88contralateral 86ipsilateral 86Parkinson disease 208progressive supranuclear

palsy 303Genetic predisposition

epilepsy 198Parkinson disease 213spongiform ence-

phalopathies 252Genotype 288, 289Germinoma 258, 377Gerstmann syndrome 128Gerstmann–Sträussler–Scheinker syndrome 280

Giant axon neuropathy 397Gibberish, fluent 124

Gilles de la Tourette syndrome68

Glasgow coma scale 378Glatiramer acetate 220Glioblastoma 260, 261, 265,

377Glioma

butterfly 260mixed 377

Gliomatosis cerebri 260Globushystericus 102pallidus 210

Glomeruli, olfactory 76Glomus

carotid 150tumor 377

Glutamate 140, 210antagonists 212

Glutamate decarboxylase 300Glycerol 264Glycogen storage disease 340Goiter 311Gonadotropins 143Gordon reflex 40Granulomatosislymphomatoid 180Wegener 180

Growth hormones 143, 367GH-secreting tumors 258

Guillain–Barré syndrome 244,326–327, 395clinical spectrum 395diagnosis 326, 396pathogenesis 326symptoms and signs 326treatment 326

Gustatory pathway 78Gyrus(i)

angular 124cingulate 144dentate 144postcentral 12precentral 12

H

Haemophilus influenzae 376chemoprophylaxis 226vaccination 226

Hair cells 100Hallucinations

olfactory 76Parkinson disease 208

Haloperidol 204Hand grip test 369Hangover 188

Hartnup disease 306Head injury 267

assessment criteria 379classification 267complications 269, 379see also Trauma

Head, zones of 110, 111Headache 182–191, 373

brain tumors and 254, 255cervical syndrome 188, 189

upper 188chronic daily 182

causes 373chronic paroxysmalhemicrania (CPH) 186, 190

cluster 186, 187, 190chronic 186, 190episodic 186, 190pathogenesis 186

combination 182diagnostic classification 191ice-pick 182intracranial hypertension

and 158intracranial hypotension and160

migraine 184–185, 190, 373symptoms and signs 184

aura 184, 185headache phase 184prodromal phase 184resolution phase 184

nociceptive transmission188, 189

posttraumatic 270, 271prophylaxis 190sinus 186, 187substance-induced 188, 189

acute 188rebound 188

tension 182, 183chronic 182, 190, 373episodic 182, 190pathogenesis 182

treatment 182, 190trigeminal neuralgia 186,187, 190idiopathic 186pathogenesis 186symptomatic 186

vascular processes and 166,182, 183subarachnoid hemorrhage176

Hearing 100–101age-related changes 382sound perception 100

Index


424

Inde

x

Heart 148–149Heel–knee–shin test 276Heerfordt syndrome 362Helicotrema 100Hemangioblastoma 256, 257Hemangioma 294Hemangiopericytoma 377Hematoma 268

epidural 268, 270intracerebral 270intraparenchymal 268posttraumatic 267subarachnoid 268subdural 268, 270

chronic 379Hemianopsia 82

heteronymous 82homonymous, altitudinal 82

Hemiballism 66–67Hemicrania, chronic paroxys-

mal (CPH) 186, 190Hemineglect 132Hemiparesis 47, 122

contralateral 46, 158Hemiplegia 122

alternans 46Hemodynamic abnormalities148, 174

Hemorrhage 166, 176–179intracerebral 166, 167, 176

basal ganglia 176brain stem 176caudate 176cerebellar 176complications 176lobar 176massive hypertensive 178pathogenesis 178pontine 176putaminal 176thalamic 176treatment 178

intraventricular 166, 176,177, 270complications 176symptoms and signs 176

spinal 282subarachnoid 166, 176–177,

270complications 176pathogenesis 178symptoms and signs 176

treatment 178see also Stroke

Hepatic encephalopathy 308,309, 387

Hereditary diseases 288

diagnosis 288inheritance 288, 289mutations 288phenotype 288see also specific diseases

Hereditary hemorrhagic tel-angiectasia (HHT) 294

Hereditary motor–sensoryneuropathy (HMSN) 332,333, 396type I 332, 333, 396type II 332, 396type III 332, 396

Hereditary neuropathy withpressure palsies (HNPP) 332,

333Hering–Breuer reflex 150Herniation

intervertebral disk 318, 319,392

intracranial hypertensionand 158, 159, 162

subfalcine 162transtentorial 118, 158

Herpes labialis 236Herpes simplex 236–237, 376

pathogenesis 236symptoms and signs 236treatment 236type 1 (HSV-1) 236, 237type 2 (HSV-2) 236

Herpes zoster 180, 238, 239occipitocollaris 238ophthalmicus 238oticus 238sine herpete 238symptoms and signs 238

Hiccups 68Hippocampus 144, 145Histiocytoma, malignant

fibrous 260History taking 350Holmes tremor 357Homocystinuria 307Hormones

aglandotropic 142glandotropic 142growth 143thyroid 143see also specific hormones

Horner syndrome 48, 92, 152,318central 92

Hospital hopper 138Human immunodeficiency

virus (HIV) 240–241, 376antiretroviral therapy 240

pathogenesis 240, 241primary infection 240secondary complications

240symptoms and signs 240

Huntington 300Huntington disease 66, 300,

301inheritance 300

anticipation 300pathogenesis 300symptoms and signs 300Westphal variant 300

Hydranencephaly 290, 381Hydrocephalus 161–163, 290,

291, 366, 379, 381acute 162, 290brain edema 162–163chronic 162communicating/malresorp-

tive 162congenital 290external 162non-communicating/ob-structive 162, 258, 290

normal-pressure 160, 161,162

subarachnoid hemorrhageand 176

symptoms and signs 290treatment 290

Hydrochlorothiazide 338Hydrophobia 246, 247Hydroxocobalamin 286Hygroma, subdural 379Hyperalgesia 316Hyperammonemia 386Hypercalcemia 310Hypercapnia 308Hypereosinophilia syndrome

344Hyperesthesia 316Hyperglycemia 308, 324

hyperosmolar nonketonic308

Hyperglycinemia, nonketonic386

Hyperhidrosis, Parkinson dis-ease and 208

Hyperkalemia 52, 338, 401Hyperkinesia 383Hypermetria 70Hyperprolactinemia 258Hypersomnia 114, 116Hypertension 148

intracerebral hemorrhageand 178

Index


425

Inde

x

I

Iatrogenic encephalopathy 314,315, 389

Idiopathiccerebellar ataxia (IDCA) 276orthostatic hypotension 302Parkinson disease 302torsion dystonia 64trigeminal neuralgia 186

Immunization see VaccinationIncisura, tentorial 6Inclusion body myositis 52,

252, 344, 345Incontinence

fecal 216, 370urinary see Bladder dys-function

Incus 100Infantile cerebral palsy

see Cerebral palsyInfarction 172, 174

anterior cerebral artery 168anterior choroidal artery 168border zone 168, 172, 173cerebellar arteries 170dementia and 298multi-infarct dementia

298strategic infarct dementia

298dorsolateral 170end zone 172, 173hemodynamic 172internal carotid artery 168,169border zone 168territorial 168

lacunar 168, 172low-flow 172paramedian 170pontine 170spinal

central 282complete 282

territorial 168, 172, 173, 224hemorrhagic conversion172

threshold 174types of 172

Infections see Central nervoussystem (CNS); specific

infectionsInflammatory response 224

multiple sclerosis 220tuberculous meningitis 232

Infundibulum 6

Inheritance 288, 289monogenic 288multifactorial 288polygenic 288

Innervation ratio 44Insomnia 114

fatal familial 114, 280psychogenic 114

Inspiration 150Interoceptors 104Intervertebral disks 30Intestine

colon 154pseudo-obstruction 370small 154

Intoxication 312, 313Intracranial pressure (ICP)158–163brain tumors and 254compliance 162elastance 162hypertension 158–160, 268,

290causes 371clinical features 158–160treatment 264, 270

hypotension 160–161causes 372symptoms 160

pathogenesis 162Introns 288Involution 296Iodine–starch (Minor) test 152Iris 90Ischemia 166, 268

cerebral 148delayed 176global 172

hypoxic–ischemic ence-phalopathy 308, 309

threshold 174transient ischemic attack(TIA) 166

see also StrokeIschemic penumbra 174Isocortex 24Isoniazid 232Itraconazole 248

J

Jaw jerk reflex 26JC virus 244Jefferson’s fracture 380Jet lag 114Joints, Charcot 230Jugum sphenoidale 4

intracranial 158–160, 224,268, 290causes 371treatment 264, 270

Hyperthermiacentral 152malignant 346–347

Hypertrophy, muscular 334,338, 397

Hyperventilation syndrome204, 205, 370

Hypervolemia 310Hypesthesia 106Hypocalcemia 310Hypochondriacal disorder 138,139

Hypogeusia 78Hypoglycemia 308, 309, 324

acute 308chronic 308subacute 308

Hypokalemia 52, 338Hypokinesia 206Hypomagnesemia 310Hypometria 70Hypomimia 206, 207, 362Hypoperfusion 174Hypophonia 206Hyposmia 76Hypotension 148, 268

antiparkinsonian medica-tions and 208

idiopathic orthostatic 302intracranial 160–161

causes 372Hypothalamic–pituitary regu-

latory axis 367Hypothalamus 24, 140, 142–143functions 142

fluid balance 310thermoregulation 152

neuroendocrine control 142,143

pain and 108Hypothermia 152Hypothyroidism 311Hypoventilation 370Hypovolemia 310Hypoxia 268

global cerebral 172hypoxic–ischemic ence-

phalopathy 308, 309

Index


426

Inde

x

K

Karnofsky scale 26, 378Kearns–Sayre syndrome (KSS)

403Keratoconjunctivitis 236Kernig’s sign 222King–Denborough syndrome

347Klippel–Feil syndrome 292,

293Klumpke–Dejerine palsy 318Korsakoff syndrome 76, 308,

312Krabbe disease 307, 332, 387Kufs disease 307Kussmaul’s respiration 118

L

Labyrinth 56Lacrimation, test of 98Lacunar state 172, 173Lacunes 172, 298Lambert–Eaton myasthenicsyndrome (LEMS) 50, 52,342, 343, 406

Lamotrigine 198Lance–Adams syndrome 308Language 124–125

aphasia 124, 126–127model 124

Larynx, voice production 130Lasègue’s sign 318Laterocollis 64Lathyrism 286, 304, 384Law of Bell and Magendie 30Leigh disease 306

maternally-inherited (MILS)403

Lemniscus, trigeminal 94Lennox–Gastaut syndrome196, 198

Lens accommodation 90Leprosy 328, 329Leptomeninges 6

metastases 262, 263treatment 265

Leukoaraiosis 298Leukodystrophy

globoid cell 387metachromatic 306, 307,

332, 333Leukoencephalitis 234Levetiracetam 198Levodopa 208, 212

adverse effects 389

Levomepromazine 264Lewy bodies 208, 210, 302Lhermitte’s sign 48, 49, 214Life expectancy 296

active 296Lifespan 296Ligament, denticulate 30Light reflex 90, 91Light–near dissociation 92Limb girdle dystrophy 336,

337, 400Limbic system 80, 135, 144–145functions 144nerve pathways 144pain and 108structure 144, 145syndromes 368

Lipid metabolism disorders332, 333

Lissencephaly 381Listeria 376Lisuride 212Lobe

frontalhemorrhage 176lesions 122

left 122right 122

occipital, hemorrhage 176parietal, hemorrhage 176temporal, hemorrhage 176

Locked-in syndrome 120, 121,170, 359

LSD abuse 314Lumbar puncture 2, 407

intracranial hypotension and160

multiple sclerosis and 218,219

Lungs 150Lyme disease 228–229

chronic 228clinical manifestations 228,

229diagnosis 228pathogenesis 228treatment 228

Lymphadenosis benigna cutis228

Lymphoma 180, 377, 385cerebral, primary 260, 261,

265ocular manifestations 260

non-Hodgkin 260, 261

M

McLeod syndrome 300Macroadenoma 258Macrocephaly 290, 381Macrographia 276Macrophages 220Maculae 56saccular 56utricular 56

Magnesium balance 310Magnetic resonance imaging

(MRI) 354brain tumors 260, 264–265multiple sclerosis 218, 219

Major histocompatibility com-plex (MHC) 220

Malaise, brain tumors and 254Malaria, cerebral 250, 251Malformations 288, 381

Chiari 292, 293Dandy–Walker 292

Malignancy see Brain tumors;specific tumors

Malignant hyperthermia 346–347

Malignant neuroleptic syn-drome 208, 347

Malingering 138Malleus 100Mannitol 264Maple syrup urine disease 386Marcus–Gunn pupils 214MDMA abuse 314Mean arterial pressure (MAP)162, 174

Mechanoreceptors 104, 150Medulla, adrenal 140Medulla oblongata 2, 26

caudal 148lesions 70rostral 148syndromes 70, 73, 361

dorsolateral 361Medulloblastoma 260, 261,

265Megalencephaly 381Meige syndrome 64, 362Melkersson–Rosenthal syn-

drome 362Melperone 264Membrane(s)

arachnoid 6spinal 30

basilar 100tympanic 100

Memory 134–135

Index


427

Inde

x

declarative (explicit) 134, 135disorders 134, 368

Alzheimer disease 297head trauma and 269Parkinson disease 208

episodic 134examination 134, 353long-term 134nondeclarative (implicit)134, 135

semantic 134short-term 134

Ménière’s disease 58Meningeosis, neoplastic 262Meninges 6–7Meningioma 256, 257, 377

anaplastic 377extracranial 256familial 256treatment 264

Meningism 222Meningitis 222, 268

aseptic 234, 236, 242postinfectious 234postvaccinal 234

asymptomatic 230bacterial 180, 226, 376

borrelia-related (Lyme)228

tuberculous 232–233pathogenesis 232symptoms and signs

232, 233treatment 232

Candida and 248carcinomatous 262chronic 232clinical manifestations 222Lyme disease and 228Mollaret 234neurosyphilis and 230, 231prophylaxis 226viral 234, 376pathogens 234poliovirus 242

Meningococcus 376vaccination 226

Meningoencephalitis 222arteritis and 226bacterial 226, 376Candida and 248cryptococcosis and 248neurosyphilis and 230prophylaxis 226treatment 224

guidelines 375tuberculous 232

viral 234–235herpes zoster 238pathogens 234

Meningopolyradiculitis 230Mental retardation 381Mesencephalon 2, 26Metachromatic leukodystrophy

306, 307, 332, 333Metastatic disease 262–263

cascade hypothesis 262drop metastasis 260, 262intracranial 262, 263, 265spinal 262, 263, 265treatment 265

Methotrexate 220Methylprednisolone 220, 238Metoclopramide 204Mexiletine 338Microadenoma 258Microaneurysm 179Microangiopathy 172Microcephaly 381Microglia 220Micrographia 128, 206, 207Micturition 156Migraine 184–185, 373

pathogenesis 184symptoms and signs 184

aura 184, 185headache phase 184prodromal phase 184resolution phase 184

treatment 190Migration disorder 381Miller–Fisher syndrome 327,

395Mini-Mental Status Examina-

tion 136Mini-syndrome test 136Minor test 152Miosis 90, 382

unilateral 92Mitochondrial disorders 288,

307, 398encephalopathy 281myopathy 52, 398, 403

Mitoxantrone 220Möbius syndrome 362Mollaret meningitis 234Monoclonal gammopathy of

undetermined significance(MGUS) 328

Mononeuritis multiplex 240Mononeuropathy 50, 180, 316,

318, 322–323, 390, 394multiplex 316, 390see also Neuropathy

Monoparesis 46, 47Monoradiculopathy 316, 318

lumbar 318Monto–Kelli doctrine 162Motor end plate 2

lesions 50Motor evoked potentials (MEP)

218, 352Motor function

age-related changes 382Parkinson disease and 210

Motor neuron diseases 304–305, 384–386lower 50, 304, 385, 386treatment 304upper 46, 304, 384, 386

Motor unit 44Movements

mass 46periodic leg 114reflex 42respiratory 150, 151rhythmic 42spontaneous 50

coma staging 118voluntary 42see also Dyskinesia(s);Dystonia; Eye movements;Tics; Tremor

Mucor (mucormycosis) 248rhinocerebral 248, 249

Multi-infarct dementia 298Multifocal motor neuropathy

(MMN) 328, 329Multiple organ failure 312Multiple sclerosis (MS) 214–221

clinical manifestations 214–217, 218, 219autonomic dysfunction216, 217, 371

behavioral changes 216, 217fatigue 214incoordination 216, 217pain 214paresis 214paroxysmal phenomena

216, 217sensory disturbances 214,

215spasticity 214visual impairment 214, 215

course of 214, 216benign 216chronic progressive 214malignant 216relapsing-remitting 214

diagnostic criteria 375

Index


428

Inde

x

Multiple sclerosis (MS)differential diagnosis 216laboratory tests 218

bladder function 218cerebrospinal fluid exami-nation 218, 219

evoked potentials 218neuroimaging 218, 219

pathogenesis 218–221activation 220, 221antigen presentation andstimulation 220

demyelination 220passage through blood–

brain barrier 220scar formation 220

prognosis 216rehabilitation 220relapse 214, 220remission 214treatment 220symptomatic therapy 220

Multiple system atrophy(MSA) 276, 302, 303bladder dysfunction and 371

Mumps virus 376Münchhausen syndrome 138

by proxy 138Muscle phosphorylase defi-

ciency 402Muscle(s)

atrophy 49–52, 107, 281, 287,334, 406peripheral neuropathy and

316poliomyelitis and 242,

243spinal (SMA) 385spinobulbar 385

cramps 397detrusor 156expiratory, auxiliary 150,151

facial, syndromes affecting362

functional disorders 52hypertrophy 334, 338, 397levator palpebrae superioris

90pain 52

see also Myalgiarespiratory 150

auxiliary 150segment-indicating 32, 357spasms 334stiffness 52, 334tarsal, superior 90

tone 276weakness 334, 374, 397, 405see also Myopathy

Muscular dystrophies 336–337,398, 400Becker 336, 337, 400diagnosis 336Duchenne 52, 53, 336, 337,

400Emery–Dreifuss 336, 337facioscapulohumeral 337,

400pathogenesis 336, 337symptoms and signs 336treatment 336see also Dystrophy

Mutation 288chromosome 288gene 288genome 288germ-line 288somatic 288

Myalgia 52, 334, 346, 397causes 346toxic 405

Myasthenia gravis 52, 342–343, 406aggravating drugs 403crises 404diagnosis 342

ancillary tests 404pathogenesis 342symptoms and signs 342treatment 342

Mycobacteriumleprae 328tuberculosis 232, 376

Mycosis, opportunistic sys-temic 248see also Fungal infections

Mydriasis 90unilateral 92

Myelin sheath 2lesions, multiple sclerosis

220Myelinolysis, central pontine

310, 315alcoholism and 314

Myelinopathy 316Myelitis 222, 282

clinical manifestations 222Lyme disease and 228treatment 286viral 282, 376herpes simplex 236herpes zoster 238

Myelography 354

Myelomeningoradiculitis,tuberculous 232

Myelopathy 282–287acute 282–283cervical 284, 285chronic 48, 284–284diagnostic studies 286hereditary 186HIV 240subacute 284–285

subacute combined degene-ration (SCD) 286, 287

toxic 286, 287treatment 286

Myoclonus 66–69, 383epilepsy with ragged redfibers (MERRF) 403

essential 68myoclonic encephalopathies

68physiological 68progressive myoclonus

epilepsy with Lafora bo-dies 307

sleep 68, 114symptomatic 68

Myokymia 50Myopathy 50–52, 334–347,

397–405carnitine deficiency 304, 402causes 334centronuclear 402congenital 52, 340, 341, 398,

402critical illness (CIM) 347, 379diagnosis 334, 399endocrine 347, 398episodic paralyses 338, 339hereditary 398inflammatory 344, 398malignant hyperthermia

346–347metabolic 340, 341, 402mitochondrial 52, 340, 341,

398, 403myalgia 346myasthenic syndromes 342–

343myotonias 338, 339, 401nemaline 402paraneoplastic syndromes

347primary 52rhabdomyolysis 346secondary 52symptoms and signs 334toxic 398, 405

Index


429

Inde

x

neuromuscular syndromes347, 398

see also Muscular dystro-phies

Myopathy, encephalopathy,lactic acidosis and strokelike

episodes (MELAS) 403Myositis 52, 344–345

diagnosis 344inclusion body 52, 252, 344,

345infectious 344Lyme disease and 228ossificans 379pathogenesis 344syndromes 344toxoplasmosis and 250treatment 344viral 52

Myotomes 32, 33Myotonia 338, 339, 401, 405

action 338congenital 52, 338, 339Becker 401Thomsen 401

fluctuans 401paradoxical 338pathogenesis 338percussion 338symptoms and signs 338treatment 338

Myotonic dystrophy 52, 338,339, 400, 401

N

Nacrolepsy 114Nasal cavity 4Natalizumab 220Nausea

brain tumors and 254, 255intracranial hypertension

and 158, 159Near response 90Neck stiffness, meningitis and

222, 223Necrosis 174

focal 224Needle electromyography 391,

399Neocerebellum 54Neologisms 124, 126Nerve injuries 330, 331

pathogenesis 330compression 330crushing injuries 330transection 330

Nerve palsyabducens 86, 87facial 96, 98, 99Lyme disease 228, 229oculomotor 86, 87, 92, 158trochlear 86, 87complete 86, 87incomplete 86

Nerve rootsdorsal 2spinal 30

root filaments 30trauma 272avulsion 330

ventral 2spinal 30

Nerve(s)abducens, palsy 86, 87alveolarinferior 94superior 94

auriculotemporal 94axillary 35mononeuropathy 322, 394

buccal 94cochlear 100cranial 2, 6, 28–29, 356herpes zoster and 238motor cranial nerve nuclei130

nerve pathways 26, 28see also specific nerves

cutaneous, lateral, of thethigh 37mononeuropathy 323, 394

ethmoidanterior 94posterior 94

facial 96–99functional systems 96lesions 98–99

examination 98palsy 96, 98, 99

nerve pathways 96femoral 37

mononeuropathy 323, 394frontal 94gluteal, mononeuropathy

323infraorbital 94lacrimal 94lingual 94mandibular 94maxillary 94median 35

mononeuropathy 322, 394meningeal 94

mental 94musculocutaneous 35nasociliary 94obturator, mononeuropathy

323oculomotor, palsy 86, 87, 92,158, 325

olfactory 2ophthalmic 94optic 2, 372

atrophy 158, 159peripheral 2peroneal 37mononeuropathy 323, 394

phrenic 150radial 35

mononeuropathy 322, 394sciatic 37

mononeuropathy 394spinal 2, 31, 32, 150supraorbital 94supratrochlear 94sural, biopsy 391thoracic, long, mono-neuropathy 322, 394

tibial 37mononeuropathy 323, 394

trigeminal 6, 76, 94–95dysfunction 98mesencephalic nucleus 94motor nucleus 94principal sensory nucleus

94spinal nucleus 94

trochlear, palsy 86, 87ulnar 35mononeuropathy 322, 394

vagus 6, 154zygomatic 94

Neural tube defects 292, 293Neuralgia 363

postherpetic 238trigeminal 186, 187, 190idiopathic 186multiple sclerosis 214pathogenesis 186symptomatic 186

Neuralgic amyotrophy 321,328, 329

Neurapraxia 330, 331Neurites, Lewy 210Neuritic plaques (NPs) 297Neuritis

optic, multiple sclerosis 214,218

retrobulbar 214toxoplasmosis and 250

Index


430

Inde

x

Neuroacanthocytosis 300,301

Neuroblastoma 377Neuroborreliosis 228–229

chronic 228clinical manifestations 228,

229diagnosis 228pathogenesis 228treatment 228

Neurocranium 4Neurocybernetic prosthesis

(NCP) 198Neurocysticercosis 250, 251Neurodegenerative diseases

296–305aging 296degenerative changes and

296disease and 296

see also specific diseasesNeurofibrillary tangles (NFTs)

297Neurofibroma 294, 295Neurofibromatosis 294, 295symptoms and signs 294type 1 (NF1) 294type 2 (NF2) 258, 294

Neurography 391, 399Neurohypophysis 142Neuroimaging 353–354, 391,

399brain tumors 254, 264–265multiple sclerosis 218, 219myasthenia gravis 404

Neuroleptics, adverse effects389, 403acute dystonic reaction204

malignant neuroleptic syn-drome 208

Neuroma, acoustic 258, 259,294

Neuromodulators, autonomicnervous system 140–141

Neuromuscular junction 2lesions 50, 347, 398

paraneoplastic syndromes406

postpolio syndrome and242

Neuromyotonia 52, 406Neuronal ceroid lipofuscinosis

307Neuronopathy 316, 390, 406Neurons

medium spiny-type 210

spinalparasympathetic 140sympathetic 140

Neuropathyacquired 317, 390acute motor-axonal (AMAN)

395acute motor-sensory axonal(AMSAN) 395

amyloid 333diagnosis 316, 391giant axon 397hereditary 317, 390peripheral 316–333

diabetic 324, 325hereditary 332–333

metabolic 332, 333nonmetabolic 332, 333

infectious origin 328inflammatory poly-

neuropathies 326–329mononeuropathies 318,

322–323, 390, 394multifocal motor (MMN)

328, 329nerve injuries 330–331

pathogenesis 330plexopathy 318radicular lesions 318, 320uremic 324vasculitic 328, 329

small fiber 316symptoms and signs 316

autonomic 316motor dysfunction 316sensory dysfunction 316

syndromes 316–317, 390tomaculous 332

Neuropeptides, pain receptionand 108

Neuroprotective therapy 212Neurosyphilis 230–231

clinical manifestations 230,231early meningitis 230, 231progressive paralysis 230,

231tabes dorsalis 230, 231

meningovascular 230pathogenesis 230treatment 230

Neurotmesis 330, 331Neurotransmitters

autonomic nervous system140–141

pain reception and 108Parkinson disease and 210

Neurotuberculosis 232Niemann–Pick disease 306,

307, 387Nightmares 114Ninhydrin test 152Nociception 108

see also PainNodes of Ranvier 2Nonneurological disorders138–139

Norepinephrine 140, 382Notch, tentorial 6Nucleus(i)

ambiguus 102, 148caudate 210cochlear


cuneatus 104detrusor 156Edinger–Westphal 26, 90gracilis 104lentiform 210motor cranial nerve 130oculomotor 90Onuf’s 156Perlia’s 90pulposus 30red 24respiratory group

dorsal 150ventral 150

solitary tract 148subthalamic 24, 210tractus solitarius 102ventral posterolateral (VPL)104

vestibular 26, 56Nystagmus 70, 86, 88–89

congenital 88end-position 88examination 88gaze-evoked 88, 89, 276, 277gaze-paretic 88jerk 88multiple sclerosis 214, 215optokinetic 84, 88pathological 88physiological 88positional 70, 88see-saw 70spontaneous 88, 89vestibularcentral 88, 89peripheral 88, 89

Index


431

Inde

x

O

Obstructive sleep apnea 114Occlusion 172

basilar artery 170, 171brachiocephalic trunk 168carotid artery

common 168internal 168

cerebellar arteries 170, 171cerebral arterymiddle 168, 169posterior 170, 171

lenticulostriate artery 168ophthalmic artery 168subclavian artery 170

Ocular deviation 70Oculomotor disturbances86–88, 276examination 86internuclear disturbances

86peripheral disturbances 86stroke and 166supranuclear disturbances

86Oculomotor function 84–85Odynophagia 102Olfaction 76–77

disturbances 76tests of 76

Olfactory pathway 76Oligoastrocytoma 256, 377

anaplastic 377Oligodendroglioma 256, 377

anaplastic 260, 261, 377One-and-a-half syndrome 86Onuf’s nucleus 156Ophthalmoplegia

chronic progressive external(CPEO) 403

internuclear 86, 87, 214Ophthalmoscopy 80Opiate abuse 314Oppenheim reflex 40Opportunistic infections 240fungal 248–249

aspergillosis 248, 249candidosis 248, 249cryptococcosis 248, 249mucormycosis 248, 249

Orbit 4, 372Organ(s)

circumventricular 140of Corti 100subfornical 140

Organum vasculosum 140

Orientation evaluation 353Orthostasis test 369Osler–Weber–Rendu disease

294Osmoregulation 310Ossicles, auditory 100Overlap syndrome 344Oxcarbazepine 198Oxidative stress 212

P

Pachygyria 381Pachymeninges 6Pain 108–111

classification of 363complex regional pain syn-

drome (CRPS) 110diabetic neuropathy and 324dysesthesia 106facial, atypical 373multiple sclerosis 214myelopathies 282nerve pathways 104, 109neurosyphilis 230Parkinson disease 208, 209pathogenesis 108persistent somatoform pain

disorder 138, 139processing 108, 109neurotransmitter/neu-

ropeptide role 108pseudoradicular 32radicular 32reception 108referred 108, 110, 363

headache 188, 189sensitization

central 108peripheral 108

transmission 108treatment 264, 324types of 108, 109, 363central 363chronic 363deafferentation 363neuropathic 108, 363nociceptive 108, 363phantom limb 363psychogenic 363radicular 363somatic 108, 363visceral 108, 110

zones of Head 110, 111see also Myalgia

Paleocerebellum 54Pallidotomy 212

Palsycerebral, infantile 288–291,

381causes 288symptoms and signs 288treatment 290

Erb 318Klumpke–Dejerine 318progressive supranuclear

(PSP) 208, 302, 303pseudobulbar 362see also Nerve palsy

Pancoast tumor 262Panic disorder 202, 203Papez circuit 144Papilledema 158, 159, 160

brain tumors and 254, 255chronic 158, 159meningitis and 222

Papilloma, choroid plexus 256,257, 377

Paraganglioma 258sympathetic 258

Paragrammatism 124, 126Paralysis

central 46–49upper motor neuron(UMN) lesions 46

crossed 46, 47, 70episodic 338, 339, 401

diagnosis 338pathogenesis 338prophylaxis 338symptoms and signs 338treatment 338

peripheral 50–53poliomyelitis and 242, 243progressive, neurosyphilis

and 230, 231spinal, familial spastic 286,

287Paramyotonia

cold-induced 52congenita 338, 339, 401

Paraneoplastic syndromes 312,347, 388neuromuscular 406

Paraparesis 46tropical spastic 384

Paraphasia 126phonemic 124semantic 124

Paraplegiafamilial spastic (FSP) 286,

287, 384in flexion 214spinal cord trauma and 274

Index


432

Inde

x

Parapraxia 128Paraproteinemic poly-

neuropathy 328, 329, 406Parasomnias 114Parasympathetic nervoussystem 90, 140, 147, 148, 154

Paresiscrossed 47ipsilateral 46Lyme disease and 228, 229multiple sclerosis 214peripheral 47

Paresthesia 106, 316multiple sclerosis 214spinal artery syndrome 282

Parinaud syndrome 70, 92, 358Parkinson disease 62, 206–213

agraphia 128autonomic dysfunction 208,209bladder disorders 208, 371blood pressure changes208

constipation 208hyperhidrosis 208leg edema 208seborrhea 208sexual dysfunction 208sleep disorders 208, 209

behavioral changes 206–209anxiety 206dementia 208depression 206hallucinations 208

cardinal manifestations 206,207akinesia 206bradykinesia 206hypokinesia 206postural instability 206,

207rigidity 206, 207tremor 206, 207

dystonia 208, 209genetics of 213idiopathic 302pathogenesis 210–211

basal ganglia 210, 211connections 210, 211motor function 210neurotransmitters 210

sensory manifestations 208dysesthesias 208pain 208, 209

treatment 212–213deep brain stimulation 212neuroprotective 212

stereotactic neurosurgicalprocedures 212

symptomatic 212transplant surgery 212

visual disturbances 208Parkinsonism 374, 383

atypical 302–303Parosmia 76Paroxysmal depolarizationshift 198

Pathway(s)auditory 100, 101cranial nerves 26–28deglutition 102, 103direct 210facial nerve 96gustatory 78indirect 210limbic system 144olfactory 76pain 104, 109pupillomotor 90somatosensory 104visual 80–81

Peduncle, cerebellarinferior 54lesions 358middle 54superior 54

Pelizaeus–Merzbacher disease387

Penicillin 230Peregrinating patient 138Pergolide 212Pericranium 4, 6Perineurium 2, 30Peripheral nervous system

(PNS) 2, 3Peristalsis 154Peritonitis 226Perlia’s nucleus 90Perphenazine 204Perseveration 126Persistent somatoform pain

disorder 138, 139Persistent vegetative state 120,121

Personality 122Phakomatoses 294–295, 381Phencyclidine (PCP) abuse 314Phenobarbital 198Phenomenon

black-curtain 168doll’s-eye 26, 302, 303

coma and 118extinction 132rebound 276, 277

Uhthoff’s 214Phenotype 288, 289Phenylketonuria 306Phenytoin 198, 264Pheochromocytoma 258Phonation 130

dysphonia 130Phosphofructokinase defi-

ciency 402Photoreceptors 104Physical examination 350–351Pia mater 6spinal 30

Pick disease 298, 299Pineal region tumors 258, 259Pineoblastoma 258, 377Pineocytoma 258, 377“Pisa” syndrome 65, 66

Pituitary gland 6anterior lobe 142hypothalamic–pituitary reg-

ulatory axis 367posterior lobe 142Sheehan’s postpartumnecrosis 258

stalk 6tumorsadenoma 258, 259, 377metastases 262treatment 264

Plasmodium falciparum (cere-bral malaria) 250, 251

Platybasia 292, 293Plexopathy 50, 318, 321Plexus(es) 32–36

brachial 32, 34, 318infraclavicular region 318Pancoast tumor 262plexopathy 318, 321, 393supraclavicular region 318trauma 272, 330

cervical 32, 35cervicobrachial 34choroid 6, 8

carcinoma 377papilloma 256, 257, 377

coccygeal 32ganglionic, submucous 154lumbar 32, 36lumbosacral 36

plexopathy 318, 321, 393myenteric 154pterygoid 20sacral 32

lesions 318vertebral venousexternal 22internal 22

Index


433

Inde

x

Pneumococcus 376vaccination 226

POEMS syndrome 328Poliomyelitis 242–243

bulbar 242encephalitic form 242major 242

paralytic 242preparalytic 242

minor (abortive) 242pathogenesis 242, 243postpolio syndrome 242,

243, 385prevention 242spinal form 242symptoms and signs 242

Poliovirus 242Polyarteritis nodosa 180Polymyalgia rheumatica 52Polymyositis 52, 240, 344, 345,

405, 406Polyneuropathy 50, 316

critical illness (CIP) 347, 379diabetic (DPN) 324, 325, 395

diagnosis 324symptoms and signs 324treatment 324

distal symmetric 324, 325focal 316hereditary, genetic features

396hypoglycemic 395inflammatory 326–329paraproteinemic 328, 329,

406sensorimotor 406small-fiber 395see also Neuropathy

Polyradiculitis 236Polyradiculoneuropathy228,406

acute inflammatory demy-elinating (AIDP) 395

chronic inflammatory demy-elinating (CIDP) 327, 328

HIV and 240Polyradiculopathy 316

lumbosacral 244, 395Pons 2, 6

hemorrhage 176infarction 170lesions 70syndromes 70–72, 359–360

Pontocerebellum 54, 55Porencephaly 290, 291, 381Porphyria 332, 333Postpolio syndrome 242, 243,

385

Posttraumatic syndrome 379Posture 60, 61

disturbances 106, 276Parkinson disease and 206,

207test 276, 277

Pramipexol 212Praziquantel 250Predelirium 312Presbycusis 382Presbyopia 382Presenilin genes 297–298Primary complex 232Primary lateral sclerosis 384Primidone 198Primitive neuroectodermal

tumor (PNET) 260, 261, 265,377

Prion protein (PrP) 252, 253PRNP gene 252Progesterone 367Progressive multifocal

leukoencephalopathy (PMS)244–245diagnosis 244pathogenesis 244symptoms and signs 244

Progressive supranuclear palsy(PSP) 208, 302, 303

Prolactin 367Prolactinoma 258Proprioception evaluation 106Prosencephalon 2, 3Prosody 124Protein X 252Pseudo-lupus erythematosus

405Pseudodementia 297Pseudoinsomnia 114Pseudoradicular syndromes

318, 320, 392causes 320

Pseudoseizures 200Pseudotumor cerebri 160Pseudounipolar cells 2Pterion 4Pupillary dysfunction 92–93

examination 92swinging flashlight test 92

parasympathetic denerva-tion 92, 93

sympathetic denervation 92,93

Pupillomotor function 90–91pupilloconstriction 90

Pupil(s) 90–92Argyll–Robertson 92, 230

Marcus–Gunn 214pinpoint 92tonic 92

Putamen 210Pyramid, medullary 46Pyrazinamide 232Pyridostigmine bromide 342Pyrimethamine/sulfadiazine

250

Q

Quadrantanopsia 82Quadriparesis 46Quadriplegia, spinal cord

trauma and 274Quantitative sudomotor axonreflex test (QSART) 152

R

Rabies 246–247hyperexcitability stage 246,

247paralytic stage 246pathogenesis 246, 247prodromal stage 246prophylaxis 246sylvatic 246symptoms and signs 246urban 246

Radiation, optic 80Radiculitis 236, 238Radiculopathy 316, 318, 320,

390causes 320, 392

Radiography 354Radiotherapy 264–265

adverse effects 389Ramsay–Hunt syndrome 238Raymond–Céstan syndrome

360Reactions

acute dystonic 66, 204, 205acute epileptic 196

Reading 124, 125alexia 128

Rebound phenomenon 276,277

Receptor(s) 2, 104baroreceptors 148chemoreceptors 104, 150,151

cutaneous 104exteroceptors 104interoceptors 104mechanoreceptors 104, 150

Index


434

Inde

x

primary lateral 384tuberous (TSC) 294, 295see also Multiple sclerosis

Scotoma 82, 83central 82, 215homonymous

bilateral 82unilateral 82

junction 82Scrapie 252Seborrhea, Parkinson disease

and 208Segawa syndrome 64Segment-indicating muscles

32, 357Seizures

epilepticbrain injury and 268brain tumors and 254, 264generalized 193, 194–195,197absence 194, 195atonic 194grand mal 194, 195, 199myoclonic 194tonic-clonic 194, 195

isolated nonrecurring 196partial (focal) 192–194,197complex 192, 193, 194secondary generaliza-

tion 192simple 192, 193, 194

pathophysiology 198, 199postictal period 192status epilepticus 196

grand mal 196stroke and 166tuberous sclerosis and 294types of 192–195

nonepileptic 200–205acute dystonic reaction 66,204, 205

drop attacks 204, 205hyperventilation syn-

drome (tetany) 204, 205panic attacks 202, 203pseudoseizures 200psychogenic 200, 202, 203

postictal phase 202premonitory signs 202semiology 202

simulated 202syncope 200–201tonic spasms 204, 205

Selegiline 212Senescence 296

Receptor(s)olfactory 76photoreceptors 104thermoreceptors 104, 152

Reflex(es) 26, 40–42abnormalities 46, 50acoustic 26, 96age-related changes 382blink 96, 98coma staging 118corneal 26, 96cough 26cutivisceral 110, 111extrinsic 40, 42flexor 40Gordon 40Hering–Breuer 150intrinsic 40, 42light 90, 91masseter (jaw jerk) 26oculocephalic 26Oppenheim 40optokinetic 84orbicularis oculi 96orbicularis oris 96palmomental 96pathological 40, 46pharyngeal (gag) 26pupillary light 26reflex arc 40reflex response 40snout 96stapedius 98startle 68sucking 96trigeminal autonomic reflexcircuit 184

vasodilatory axon 110, 111vestibulo-ocular (VOR) 26,84coma and 118

viscerocutaneous 110, 111visceromotor 110, 111viscerovisceral 110visual blink 96

Refsum disease 332Renal failure 310Respiration 150–151

auxiliary muscles 150, 151Cheyne–Stokes 118costal 150diaphragmatic 150disorders 150, 151, 370stroke and 166

Kussmaul’s 118respiratory movements 150,151

rhythm 150Respiratory test 369Restless legs syndrome (RLS)114

Reticular formation 26medullary 26mid brain 26pain and 108pontine 26

paramedian 84Retina 80

lesions 372Retrocollis 64Rhabdomyolysis 346, 406Rhabdomyosarcoma 260Rhizopus 248Rhombencephalon 2Rhythm

circadian 112, 113disturbances 114

respiration 150Rifampicin 226, 232Rigidity 206, 207

cogwheel 206, 207Riluzole 304Romberg sign 276Ropinirol 212Ross syndrome 92

S

Saccades 84abnormal 70, 276, 277

Saccule 56Sacrum 30Salivation, test of 98Sarcoglycanopathy 398Sarcoidosis 234Sarcoma

cerebral, primary 260meningeal 260

Scalatympani 100vestibuli 100

Scalp 4, 7injuries 266

Scaphocephaly 381Scar formation, multiplesclerosis 220

Schellong’s test (orthostasis)369

Schizencephaly 381Schwann cells 2Schwannoma 258, 377Sclerosis

amyotrophic lateral (ALS)304, 386

Index


435

Inde

x

Sensation 104–105epicritic 104protopathic 104somatic 104superficial 106

Sensory disturbances 106–107age-related 382examination 106interpretation 106location 106, 316, 317peripheral neuropathies 316,

318, 390radicular 107stroke and 166

Sensory receptors see Recep-tors

Sepsis 312, 313, 347candida 248see also Bacterial infections

Sexual behaviour disturbances368

Sexual function 156multiple sclerosis and 216Parkinson disease and 208

Shingles see Herpes zosterShock, spinal 48, 274Shulman disease 344Shy–Drager syndrome 302Sign(s)Babinski 40, 49Bragard’s 318Brudzinski’s 222Kernig’s 222Lasègue’s 318Lhermitte’s 48, 49, 214Romberg 276

Sinus(es)carotid 10, 148massage 369

paranasal 4ethmoid 4frontal 4maxillary 4sphenoid 4

thrombosis 180, 181aseptic 180, 181etiology 180septic 180symptoms and signs 180treatment 180

venousdural 6, 18thrombophlebitis 226, 227

Sinusitis 186Skull 4–5

base 4, 5metastases 262

syndromes 74–75fracture 266

Sleep 112–113, 363age changes 112, 113circadian rhythm 112, 113

disturbances 114disorders 114–115neurogenic 114Parkinson disease 208,

209primary (dyssomnias) 114

extrinsic 114intrinsic 114parasomnias 114

psychogenic 114secondary 114systemic disease and 114

non-rapid eye movement(NREM) 112, 363

polygraphic recordings 112profile 112, 113rapid eye movement (REM)112, 363

Smell 76–77age-related changes 382olfactory disturbances 76tests of 76

Sodium balance 310, 311Sodium channel dysfunction

338, 398Somatization disorder 138Somatoform disorders 138

persistent somatoform paindisorder 138, 139

Somatosensory evoked poten-tials (SEP) 218, 352

Somnambulism 114Somnolence 116, 117Sound perception 100Space

epidural 6, 30infratentorial 6subarachnoid 6, 8

pathogen entry 224spinal 30

subdural 6supratentorial 6Virchow–Robin 6

Space-occupying lesions, in-tracranial pressure and 162–163

Spasmmultiple sclerosis and 214muscle 334right hemifacial 99tonic 204, 205

Spasmus nutans 88

Spasticity 46, 47multiple sclerosis 214

Spatial orientation distur-bances 132–133

Spectral analysis 100, 101Speech 130

articulation 130disorders 124, 130

dysarthria 124, 130, 276dysphonia 130

neural basis of 130, 131voice production 130

Sphenoid bone 4Spielmeyer–Vogt syndrome 307Spina bifida 292, 293Spinal automatisms 46Spinal cord 2, 30–32

blood supply 22–23claudication 282infarction

central 282complete 282

lesions 48, 275, 381bladder dysfunction and

371cervical 48lumbar 48sacral 48thoracic 48transection 48, 274, 282,

381trauma 274–275, 371acute stage (spinal shock)274

chronic stage–latesequelae 274

closed 274open 274rehabilitation stage 274treatment 380

Spinal dysraphism 292, 293Spinal muscular atrophy

(SMA) 385Spinal shock 48, 274Spine 30–31hemorrhage 282metastases 262, 263

treatment 265neoplasms 284, 285trauma 272–273, 380

brachial plexus 272diagnosis 272nerve roots 272treatment 380vertebral fracture 272whiplash injury 272, 273,380

Index


436

Inde

x

Spinocerebellar ataxia (SCA)280, 384

Spinocerebellum 54, 55Spironolactone 338Split-brain syndrome 24Spondylolisthesis 392Spondylosis deformans 392Spongiform encephalopathies

252–253bovine 252Creutzfeldt-Jakob disease

(CJD) 252, 253genetic 252infectious 252

Stapes 100Staphylococcus 376Startle reflex 68Status epilepticus 196

grand mal 196Steele–Richardson–Olszewskisyndrome 302

Stem cell transplantation,Parkinson disease 212

Stenosiscraniostenosis 381spinal 392

lumbar 284Stomach 154Strategic infarct dementia

298Striatal foot 64Striatonigral degeneration

(SND) 302Stroke 166–181

bladder dysfunction and 371causes 167, 172hemorrhage 166, 176–179

intracerebral 166, 176basal ganglia 176brain stem 176cerebellar 176lobar 176pathogenesis 178

intraventricular 166, 176complications 176symptoms and signs 176

subarachnoid 166, 176–177complications 176pathogenesis 178symptoms and signs 176

treatment 178in evolution 166ischemia 166–175

carotid artery territory168

pathophysiology 174, 175

hemodynamic insuffi-ciency 174

hypoperfusion 174prevention

primary 174secondary 174

risk factors 172treatment 174

treatment window 174vertebrobasilar territory170–171

major 166minor 166sinus thrombosis 180, 181

etiology 180symptoms and signs 180treatment 180

symptoms and signs 166Stupor 116, 117Sturge–Weber disease 294,

295Subacute combined degenera-

tion (SCD) 286, 287Subcortical arteriosclerotic en-

cephalopathy (SAE) 298Subdural

empyema 222hematoma 268, 270

chronic 379hygroma 379space 6

Subependymoma 256Substance abuse 312, 314, 315

see also AlcoholismSubstantia nigra 24, 210Sucking reflex 96Superoxide dismutase 1

(SOD1) 304Suture(s) 4

coronal 4lambdoid 4sagittal 4

Swallowing see Deglutition;Dysphagia

Sweatingdisturbances 152sweat gland innervation 152,153

Swinging flashlight test 92Sympathetic nervous system

90, 140, 147, 148, 154Sympathetic skin response

(SSR) 152Symptomsnature of 350onset 350severity of 350

time course 350see also specific conditions

Synchondroses 4Syncope 200–201

causes 374neurocardiogenic 148

Syndrome(s)acquired immunodeficiency(AIDS) 240

Adie 92alcohol withdrawal 312, 313alien hand 24, 302anterior horn 48, 50anterior spinal artery 48Anton 132apallic 117, 120, 121apraxia-like 128Bannwarth 228Bassen–Kornzweig 300Benedict 70, 358brain stem 70–71Brown–Séquard 48carpal tunnel 322cauda equina 319cavernous sinus 75central cord 48central salt-wasting 310cervical 188, 189

upper 188chiasm 75Churg–Strauss 180, 344clivus 75comalike 120–121complex regional pain syn-

drome (CRPS) 110conus medullaris 48Crow–Fukase 328decerebration 46, 47, 118,158, 159

decortication 46, 47, 118disconnection 24, 128disequilibrium 310encephalitic 222epileptic 196fetal alcohol 314Frey 362frontal lobe 122

lateralized 122nonlateralized 122

Ganser 138Gerstmann 128Gerstmann–Sträussler–Scheinker 280

Gilles de la Tourette 68Guillain–Barré 244, 326–327,

395–396Heerfordt 362

Index


437

Inde

x

herniation 158, 162Horner 48, 92, 152, 318

central 92hypereosinophilia 344hyperventilation 204, 205Kearns–Sayre 403King–Denborough 347Klippel–Feil 292, 293Korsakoff 76, 308, 312lacunar 359Lambert–Eaton 50, 52, 342,

343, 406Lance–Adams 308Lennox–Gastaut 196, 198limbic 368locked-in 120, 121, 170, 359McLeod 300malignantneuroleptic208,347medullary 70, 73, 361

dorsolateral 361Meige 64, 362Melkersson–Rosenthal 362meningitic 222, 234mid brain 70, 71, 358–359Miller–Fisher 327, 395Möbius 362Münchhausen 138myelitic 222myopathy 397myositis 344neuropathy 316–317, 390of inappropriate ADH secre-

tion (SIADH) 310olfactory nerve 75one-and-a-half 86orbital apex 75overlap 344paraneoplastic 312, 347, 388neuromuscular 406

parasagittal cortical 46Parinaud 70, 92, 358Parkinsonian, atypical 302–

303“Pisa” 65, 66POEMS 328pontine 70–72, 359–360lateral pontomedullary 70

postanoxic 308delayed 308

posterior column 48posterior cord 48posterior horn 48postpolio 242, 243, 385posttraumatic 379postviral fatigue 52pseudoradicular 318, 320,

392

radicular 50, 392Ramsay–Hunt 238Raymond–Céstan 360restless legs (RLS) 114Ross 92Segawa 64Shy–Drager 302skull base 74–75sphenoid wing 75Spielmeyer–Vogt 307spinal artery


spinal cord transection 274split-brain 24Steele–Richardson–

Olszewski 302Sturge–Weber 294, 295sulcocommisural artery 282tethered cord 292, 293top of the basilar 70, 359transverse cord 180, 232,

380, 381sensory 214

Vogt–Koyanagi–Harada 234Wallenberg 70, 170, 361Weber 70, 358Wernicke–Korsakoff 312,314

West 196Zellweger 386

Synkinesia 46, 99, 362Syphilis 180latent 230see also Neurosyphilis

Syringomyelia 107, 284, 285System

craniosacral 140dioptric 80epicritic/lemniscal 104limbic 80, 135, 144–145

functions 144nerve pathways 144pain and 108structure 144, 145syndromes 368

protopathic 104reticular activating (RAS) 116spinocerebellar 104thoracolumbar 140, 152trigeminovascular 184, 185

T

T lymphocytes, multiplesclerosis and 220

Tabes dorsalis 230, 231

Taenia solium (neurocysticer-cosis) 250, 251

Takayasu arteritis 180Tangier disease 332Tapeworm infection 250, 251Taste 78–79age-related changes 382disturbances 78tests of 78

Taste buds 78Tay–Sachs disease 387Tela choroidea 6Telangiectasia 280, 281, 294,295hereditary hemorrhagic

(HHT) 294Telencephalon 2Temperature see Thermoregu-lation

Temporal arteritis 180Temporomandibular joint 4Tension headache see Head-ache

Tentorium cerebelli 6Testosterone 367Test(s)

Aachen aphasia 124apnea 364Bárány’s pointing 276caloric 26confrontation test 82, 83edrophonium chloride 404finger–finger 276, 277finger–nose 276hand grip 369heel–knee–shin 276iodine–starch (Minor) test152

lacrimation 98neurophysiological 352neuropsychological 352–353ninhydrin test 152olfaction 76posture 276, 277quantitative sudomotor axonreflex test (QSART) 152

red vision test 82respiratory 369salivation 98Schellong’s (orthostasis) 369Schirmer test 98smell 76swinging flashlight test 92sympathetic skin response

(SSR) 152taste 78Wada 126

Index


438

Inde

x

Tetany 204Tethered cord syndrome 292,293

Thalamus 24hemorrhage 176pain and 108

Thermoreceptors 104, 152Thermoregulation 152–153disturbances 152neural control 152

Thiamin deficiency 312Thromboembolism, infectious226

Thrombophlebitis, bacterial226, 227

Thrombosis 172, 173prophylaxis 264see also Occlusion

Thyroid hormones 143Tiagabine 198Tic douloureux 186Tics 68–69, 362, 383Tobacco–alcohol amblyopia314

Toe-walking 60Tonotopicity 100, 101Top of the basilar syndrome70, 359

Topiramate 198Torcular Herophili 18Torticollis 64Toxoplasma gondii (toxoplas-mosis) 250, 251bradyzoites 250congenital 250oocysts 250tachyzoites 250

Tract(s)corticobulbar 44corticonuclear 96corticopontine 44corticospinal

anterior 44lateral 44

motor 44pyramidal 44, 45reticulospinal 44rubrospinal 44spinocerebellar 104spinothalamic

anterior 104lateral 104posterior 104

trigeminocortical 94vestibulospinal 44

Transcranial Doppler (TCD)353

Transient ischemic attack (TIA)166crescendo 166

Transient monocular blindness168, 372

Transmissible spongiform en-cephalopathies (TSEs) 252–253Creutzfeldt–Jakob disease

(CJD) 252, 253Transverse cord syndrome 180,232, 380, 381sensory 214

Trauma 266–275, 366multiorgan 266spinal 272–273

brachial plexus 272diagnosis 272nerve roots 272treatment 380vertebral fracture 272whiplash injury 272, 273,380

spinal cord 274–275acute stage (spinal shock)274

chronic stage–latesequelae 274

rehabilitation stage 274treatment 380

traumatic brain injury (TBI)266–271complications 269, 270evaluation 266pathogenesis 270, 271primary injury 266, 270prognosis 268secondary sequelae 268,

270treatment 270hospital 270scene of accident 270,

271types of 266

Tremor 62–63action 62, 63cerebellar 357essential 62, 357genesis of 62Holmes 357intention 62, 63, 276kinetic 62, 63palatal 357Parkinson disease and 206,

207, 357physiological 357polyneuropathic 357

postural 62psychogenic 357rest 62, 63task-specific 62types of 63, 357

Treponema pallidum 230Triflupromazine 204Triiodothyronine 367Tropical spastic paraparesis384

Trunkbrachiocephalic 10, 148occlusion 168

lumbar sympathetic, lesions318

Tuberculoma 232, 233Tuberculosis 180organ 232reactivated 232spinal 232

Tuberculous meningitis 232–233diagnosis 232pathogenesis 232symptoms and signs 232,

233treatment 232

Tuberous sclerosis (TSC) 294,295

TumorsPancoast 262paraneoplastic en-

cephalopathy 312primitive neuroectodermal

(PNET) 260, 261, 265, 377spinal 284, 285see also Brain tumors;

specific tumorsTuricephaly 381

U

Uhthoff’s phenomenon 214Ulegyria 381Ultrasonography 353duplex sonography 353transcranial Doppler (TCD)

353Uremia 310, 311Uremicencephalopathy 310, 311neuropathy 324

Urinary tract infection, multi-ple sclerosis 216

Utricle 56

Index


439

Inde

x

V

VaccinationHaemophilus influenzae 226Lyme disease 228meningococcus 226Pneumococcus 226poliomyelitis 242rabies 246

Valacyclovir 238Valproic acid 198Valsalva maneuver (VM) 369Varicella-zoster 238–239complications 238, 239ganglionic latency phase 238immunocompromised

patients 238pathogenesis 238, 239symptoms and signs 238, 239treatment 238viral reactivation 238

Vascular reserve 174Vasculitic neuropathy 328, 329Vasculitidesprimary 180secondary 180

Vasculitisbacterial 180, 226cerebral 180, 181

causes 180differential diagnosis 216immune 181Lyme disease and 228primary 180secondary 180symptoms and signs 180treatment 180

CMV 244neurosyphilis and 230

Vasospasm 176Vein(s)azygos 22basal (of Rosenthal) 18bridging 18central 18cerebral 18–19

deep 10, 18great (of Galen) 18inferior 18internal 18superficial 10, 18

middle 18superior 18thrombophlebitis 226

cervical 20deep 20, 22

cortical 18

cranial 20diploic 18emissary 18facial 20hemiazygos 22iliac, common 22intercostal, posterior 22jugular

external 20internal 20

lumbar 22occipital 18, 20radicular 22retromandibular 20sacral

lateral 22medial 22

spinal 22, 23anterior 22lateral 22posterior 22

vertebral 20, 22Vena cava, superior 22Ventriculitis 222, 226, 227Ventriculomegaly, long-stand-ing overt (LOVA) 290

Vertebrae 30cervical 30coccygeal 30fracture 272, 380

burst 380compression 380dens 380dislocation 380Jefferson’s 380stability 272, 273

lumbar 30thoracic 30

Vertebral column 30Vertigo 58–59benign paroxysmal posi-tional 58, 59

brain tumors and 254, 255episodic 58nonvestibular 58, 59physiological 58vestibularcentral 58peripheral 58

Vestibular system 56–57disorder 374

Vestibulocerebellum 54–56Villi, arachnoid 8Viral infections 234–247, 376,385cytomegalovirus (CMV) 244–

245

herpes simplex 236–237human immunodeficiency

virus (HIV) 240–241meningoencephalitis 234–

235pathogens 234

poliomyelitis 242–243progressive multifocalleukoencephalopathy(PMS) 244–245

rabies 246–247varicella-zoster 238–239see also specific infections

Virchow–Robin space 6Viremiaprimary 238secondary 238

Viscerocranium 4, 5Visioncolor 80

disturbances 80intracranial hypertension

and 158stereoscopic 80

Visual disturbancescolor vision 80multiple sclerosis 214, 215Parkinson disease 208stroke and 166see also Visual field

Visual evoked potentials (VEP)218, 219, 352

Visual field 80binocular 80confrontation test 82, 83defects 82–83

chiasmatic lesions 82perichiasmatic lesions 82retrochiasmatic lesions

82monocular 80red vision test 82

Visual pathway 80–81Vitamin B1 deficiency 312Vitamin B12 deficiency 286,287

Vitamin E deficiency 280Vogt–Koyanagi–Harada syn-drome 234

Voice production 130timbre 130volume 130whisper 130see also Speech

Volume regulation 310Vomiting 370brain tumors and 254, 255

Index


440

Inde

x

Vomitingintracranial hypertension

and 158von Heubner angiitis 230von Hippel–Lindau disease294, 295

hemangioblastoma and 256symptoms and signs 294

von Recklinghausen dis-ease 294

W

Wada test 126Wakefulness 116

see also ConsciousnessWallenberg syndrome 70, 170,361

Water balance see Fluidbalance

Watershed zones 22, 168Weber syndrome 70, 358Wegener granulomatosis 180Wernicke–Korsakoff syndrome312, 314

Wernicke’saphasia 126, 127area 124encephalopathy 312, 313

West syndrome 196Whiplash injury 272, 273severity classification 272symptoms and signs 272treatment 380

Whisper 130

White-matter lesions (WMLs)298

Wilson disease 208, 307Writer’s cramp 64, 65Writing 124agraphia 128, 129

X

Xanthoastrocytoma, pleomor-phic 256, 377

Z

Zellweger syndrome 386Zones, of Head 110, 111

Index


color atlas of neurology

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