new insights in lumbosacral plexopathy - aanem.org · lumbosacral plexus disease and will learn...

2006 COURSE C AANEM 53rd Annual Meeting

Washington, DC

Copyright © October 2006 American Association of Neuromuscular & Electrodiagnostic Medicine

2621 Superior Drive NW Rochester, MN 55901

Printed by Johnson Printing ComPany, inC.

Kerry H. Levin, MD

Gérard Said, MD, FRCP

P. James B. Dyck, MD

Suraj A. Muley, MD

Kurt A. Jaeckle, MD

New Insights in Lumbosacral Plexopathy


Faculty

Kerry H. Levin, MDVice-ChairmanDepartment of NeurologyHeadSection of Neuromuscular Disease/ElectromyographyCleveland ClinicCleveland, OhioDr. Levin received his bachelor of arts degree and his medical degree from Johns Hopkins University in Baltimore, Maryland. He then performed a residency in internal medicine at the University of Chicago Hospitals, where he later became the chief resident in neurology. He is currently Vice-chairman of the Department of Neurology and Head of the Section of Neuromuscular Disease/Electromyography at Cleveland Clinic. Dr. Levin is also a professor of medicine at the Cleveland Clinic College of Medicine of Case Western Reserve University. His current research interests include myasthenia gravis, polyneuropathy, and radiculopathy.

Gérard Said, MD, FRCPProfessor and ChiefService of NeurologyUniversity Hospital of BicêtreParis, FranceDr. Said is Secretary-general of the European Neurological Society (ENS) which he co-founded in 1986. He has also organized the yearly ENS congress since 1988. He has been Professor and Chief of the Service of Neurology of the University Hospital of Bicêtre since 1987. Starting in 2006, Professor Said became the Director of the Research Group on Neuromuscular Disorders of the World Federation of Neurology, and from 1998 through 2000 he was President of the Peripheral Nerve Society. His main fields of investigation are disorders of the peripheral nervous system, diabetic neuropathy, vasculitic neuropathy, and infectious neuropathies.

P. James. B. Dyck, MDAssociate ProfessorDepartment of NeurologyMayo ClinicRochester, MinnesotaDr. Dyck received his medical degree from the University of Minnesota School of Medicine, performed an internship at Virginia Mason Hospital in Seattle, Washington, and a residency at Barnes Hospital and Washington University in Saint Louis, Missouri. He then performed fellowships at the Mayo Clinic in peripheral nerve and electromyography. He is cur-rently Associate Professor of Neurology at the Mayo Clinic. Dr. Dyck is a member of several professional societies, including the AANEM, the American Academy of Neurology, the Peripheral Nerve Society, and the American Neurological Association. His current research interests include pathological studies of peripheral nerve disorders and clinical trials in peripheral neuropathies.

Suraj A. Muley, MDAssistant ProfessorDepartment of NeurologyUniversity of Minnesota Medical CenterMinneapolis, MinnesotaDr. Muley received his medical degree from the University of Bombay, and later performed a residency in neurology and a fellowship in clinical neu-rophysiology and neuromuscular diseases at the University of Minnesota. He is currently Assistant Professor at the University of Minnesota and Neuromuscular Director at the Minneapolis Veteran’s Administration Medical Center. He is involved in clinical studies of diabetic amyotrophy and is leading the nerve biopsy program and the University of Minnesota. Dr. Muley is also the Director of the Myasthenia Gravis Program at the University. His current research includes a clinical study of the use of in-travenous immunoglobulin in myasthenia gravis, as well as a multicenter study about thymectomy in myasthenia gravis.

C-ii

Kurt A. Jaeckle, MDProfessorDepartments of Neurology and OncologyMayo ClinicJacksonville, FloridaDr. Jaeckle is currently Professor of Neurology and Professor of Oncology at the Mayo Clinic Jacksonville and has had an interest in clinical research involving primary and metastatic central nervous system cancer for over 20 years. After completing his residency at Vanderbilt University, he re-ceived his training in neuro-oncology at Memorial Sloan-Kettering Cancer Center, which was followed by faculty appointments at the University of Utah and, subsequently, the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Jaeckle has served as a past chair for the American Academy of Neurology’s section on neuro-oncology and was instrumental in the development of a subspecialty certification and acccreditation program neuro-oncology. That program recently received United Council of Neurologic Subspecialties approval. His initial research interests involved the study of paraneoplastic disorders, and in particular, anti-yo antibody-positive cerebellar degeneration and limbic encephalitis. His current research focus involves clinical trial development as chair of the Neuro-oncology Committee of the North Central Cancer Treatment Group, and the study of the neurologic complications of cancer.

C-iii

Course Chair: Kerry H. Levin, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM.

Authors had nothing to disclose.

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the specific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may be used if, in the judgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041.


Contents

Faculty i

Objectives ii

CourseCommittee iv

Update on Lumbosacral Plexopathy: Anatomy and Electrodiagnostic Considerations 1KerryH.Levin,MD

Diabetes and the Lumbosacral Plexus 9GérardSaid,MD,FRCP

Nondiabetic Lumbosacral Radiculoplexus Neuropathy 13P.JamesB.Dyck,MD

Treatment Strategies in Lumbosacral Plexopathy 23SurajA.Muley,MD

Lesions of the Lumbosacral Plexus 27KurtA.Jaeckle,MD

CMESelf-AssessmentTest 35

Evaluation 39

Ob j e c t i v e s—After attending this course, participants will understand the anatomy of the lumbosacral plexus and electrodiagnostic testing available to uncover lesions of the lumbosacral plexus. Participants will learn how to differentiate diabetic from nondiabetic idiopathic lumbosacral plexus disease and will learn about treatment strategies for these conditions. Participants will learn about other lesions of the lumbosacral plexus and their diagnosis.

Pr e r e q u i s i t e—This course is designed as an educational opportunity for residents, fellows, and practicing clinical EDX physicians at an early point in their career, or for more senior EDX practitioners who are seeking a pragmatic review of basic clinical and EDX principles. It is open only to persons with an MD, DO, DVM, DDS, or foreign equivalent degree.

Ac c r e d i tAt i O n stAt e m e n t—The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians.

cme cr e d i t—The AANEM designates this activity for a maximum of 3.25 hours in AMA PRA Category 1 Credit(s)TM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is avail-able 10/06 - 10/09.

C-v

C-vi

ThomasHyattBrannagan,III,MDNewYork,NewYork

HopeS.Hacker,MDSanAntonio,Texas

KimberlyS.Kenton,MDMaywood,Illinois

DaleJ.Lange,MDNewYork,NewYork

SubhadraNori,MDBronx,NewYork

JeremyM.Shefner,MD,PhDSyracuse,NewYork

T.DarrellThomas,MDKnoxville,Tennessee

BryanTsao,MDShakerHeights,Ohio

2005-2006 AANEM PRESIDENT

JaniceM.Massey,MDDurham,NorthCarolina

2005-2006 AANEM COURSE COMMITTEE

KathleenD.Kennelly,MD,PhDJacksonville,Florida

Update on Lumbosacral Plexopathy: Anatomy and Electrodiagnostic

Considerations

Kerry H. Levin MDVice-Chairman,DepartmentofNeurology

Head,SectionofNeuromuscularDisease/EMGClevelandClinicCleveland,Ohio

ANATOMY OF THE LUMBOSACRAL PLEXUS

The lumbosacral plexus is constituted from the L1-S4 spinal nerve roots, with a minor contribution from the T12 spinal nerve root. The structure can be divided into the lumbar and sacral plexus (Figure 1). The lumbosacral plexus is further divided anatomically into an anterior division that contains motor fibers innervating muscles responsible for flexion and adduction, and a posterior divi-sion innervating muscles responsible for extension and abduction.

The Lumbar Plexus

The lumbar plexus is constituted from the L1-L3 roots, most of the L4 root, and a small component of the T12 root. It courses posterior to, or mingles with, fascicles of the psoas muscle before convergence of the lumbar anterior primary rami to form the lumbar plexus, branches distribute to the psoas muscle and the quadratus lumborum. Major branches of the lumbar plexus are described below (Figure 2).

Iliohypogastric Nerve

The iliohypogastric nerve is constituted from the L1 nerve root, with occasional contribution from T12. It supplies motor branches to lower abdominal wall muscles. It supplies cutaneous innervation to a narrow band of skin overlying the iliac spine and inguinal ligament, upper lateral buttock, skin of the groin, and skin overly-ing the symphysis pubis (Figure 3). The nerve can be damaged by paravertebral and flank lesions and by incisions in the flank.

Ilioinguinal Nerve

The ilioinguinal nerve is constituted from L1 nerve fibers and travels with the iliohypogastric nerve, giving off motor branches to lower abdominal wall muscles. Its sensory branches supply the skin over the symphysis, root of the penis, upper scrotum (men), skin over the mons pubis and labia majora (women), and proximal medial thigh (Figure 3). Aside from the lesions previously noted, the ilioinguinal nerve may also be damaged during herniorrhaphy.

Genitofemoral Nerve

The genitofemoral nerve is constituted from L1 and L2 nerve fibers. The genital branch supplies a motor branch to the cremas-ter muscle and a sensory branch to the skin of the scrotum, labia majora, and mons pubis (Figure 3). The femoral branch passes under the inguinal ligament to supply the skin of the groin. It can be damaged by retroperitoneal masses and procedures such as herniorrhaphy.

Lateral Femoral Cutaneous Nerve of the Thigh

The lateral femoral cutaneous nerve is a pure sensory nerve derived from the anterior divisions of the L2 and L3 roots (Figure 3). It tends to pass under the inguinal ligament over the sartorius muscle, and subcutaneously onto the lateral thigh, but variations can occur.2

C-C-� AANEMCourseC-� UpdateonLumbosacralPlexopathy AANEMCourse

Femoral Nerve

The femoral nerve trunk is derived from the posterior divisions of the L2-L4 nerve roots. It exits the psoas muscle at its lateral border and travels between the psoas and iliacus muscles beneath the inguinal ligament. Within the pelvis, branches are distributed to the psoas and iliopsoas muscles. The femoral nerve passes below the inguinal ligament and divides into motor branches (innervating the vastus, sartorius, iliacus, and pectineus muscles) and sensory branches to the anterior and medial thigh, ending as the saphenous nerve.

Obturator Nerve

The obturator nerve trunk is derived from the anterior divisions of the L2-L4 nerve roots. It travels through the psoas muscle to its medial border, then through the pelvic cavity, and through the ob-

Figure 1LumbosacralPlexusn=nerve

Figure 2 NerveTrunksDerivedfromtheLumbarPlexus.ModifiedfromStewart.14

m=muscle;n=nerve

Figure 3 Cutaneous Distributions of the LumbosacralPlexus in the Perineal Region. Modified from Stewart.14

n=nerve

turator foramen into the thigh. Motor branches reach the adductor longus and brevis. Sensory fibers supply a small area of skin on the medial thigh (Figure 3).

The Sacral Plexus

The sacral plexus is constituted from the L5-S3 roots, with a small contribution from the L4 root. Anatomically, the sacral plexus is formed at the point where sacral anterior primary rami are joined by the lumbosacral trunk (also known as the nerve of Furcul), which is comprised of the entire L5 anterior primary ramus and a few fascicles of the L4 anterior primary ramus. The plexus lies on the posterior and posterolateral walls of the pelvis close to the sacroiliac joint and just lateral to the prostate and cervix.

The L4-S2 fibers segregate into anterior and posterior divisions. From the posterior division, superior and inferior gluteal nerves branch off to innervate the gluteus medius and maximus, respec-tively. A small posterior division branch innervates the piriformis muscle. Other posterior division fibers converge with S3 fibers to form the posterior femoral and perforating cutaneous nerves. Branches from the anterior division form nerve branches to the obturator internus, superior genellus, quadratus femoris, and in-ferior gemellus muscles. Remaining nerve fibers combine to form the sciatic nerve, maintaining separation between anterior division fibers that will constitute the tibial nerve, and posterior fibers that will become the common peroneal nerve.

Separate branches from the S2-S5 anterior primary rami form pelvic nerves, including the pudendal nerve, pelvic splanchnic nerves, and nerve branches to the levator ani, coccygeus, and external anal sphincter muscles. Autonomic nerve fibers from lumbar and sacral segments combine with somatic fibers from the pudendal nerve to serve bladder, rectal, anal, sexual, and circulatory functions. Preganglionic parasympathetic nerve fibers are carried in the S2-S4 anterior rami, and then branch off to form the pelvic splanchnic nerves, which supply motor fibers to the bladder detru-sor and rectum, inhibitory fibers to the internal urethral sphincter, and vasomotor fibers to the penis and clitoris.14

ELECTRODIAGNOSTIC FEATURES

The electrodiagnosic (EDX) examination of lumbosacral plexopa-thy is complex and requires a specific pattern of nerve conduction study (NCS) abnormalities in combination with a specific distribu-tion of changes on the needle electrode examination (NEE). Both the NCS pattern and the NEE pattern observed in lumbosacral plexopathy can be seen in other lower extremity disorders, but when combined, the NCS and NEE patterns form a relatively specific signature of lumbosacral plexopathy. Tables 1 and 2 list the typical NCS and NEE patterns in various lower extremity disor-ders. The challenge for the EDX physician is to define the level of

certainty in the diagnosis, given the potential for other diagnoses to have a similar EDX pattern.

Sacral plexopathy and sciatic neuropathy, affecting both the pero-neal and tibial divisions, have identical patterns of NCS abnormali-ties. The distinction lies in the NEE, where muscles innervated by the superior and inferior gluteal nerves are not involved in sciatic neuropathy. However, the experienced EDX physician will know that patchy or mild cases of sacral plexopathy may also spare those muscles. Thus, in cases where the degree of axon loss in involved muscles is mild, the final impression in sciatic neuropathy may require the disclaimer that sacral plexopathy cannot be completely excluded.

Confusion in using EDX studies can also occur in distinguishing an L5 radiculopathy, a lumbosacral trunk lesion, and a peroneal neuropathy. Radiculopathy is classically distinguishable from plexus and peripheral nerve lesions because the sensory responses are preserved. An occasional exception arises due to a variation in the anatomy of the L5 spinal nerve root, whose dorsal root ganglion resides in an intraspinal canal location in up to 30% of individu-als.7,8 In this situation an intraspinal L5 root compression can cause axon loss along both the sensory and motor nerve trunks, giving rise to a pattern of NCS abnormality identical to a lumbosacral trunk lesion or peroneal neuropathy (either above or below the popliteal fossa).9 A lesion of the common peroneal nerve demonstrates a NCS pattern identical to that of a lumbosacral trunk lesion, but the NEE easily distinguishes these two conditions.

A lumbosacral trunk lesion and L5 radiculopathy have an essen-tially identical pattern of abnormalities on the NEE of the leg. While the lumbosacral plexus is organized topographically into pe-ripheral nerve distributions, the lumbosacral trunk is almost purely a continuation of the L5 anterior primary ramus, making its motor content indistinguishable from the intraspinal spinal nerve root. Furthermore, while acute motor radiculopathy is classically associ-ated with paraspinal fibrillation, this finding is not reliably present, especially at the low lumbar spinal segments.6,16

The distinction between lumbar plexopathy and L2-L3-L4 radicu-lopathy is one of the most difficult tasks for the EDX physician. Nerve conduction studies available to assess these conditions are limited to the femoral motor response and the saphenous sensory response. The femoral motor response will not distinguish either lumbar plexopathy or L2-L3-L4 radiculopathy, and the saphenous sensory response is likely to be absent beyond middle age and in those with increased thigh girth. In regard to the NEE, there is an essentially complete overlap of muscle involvement in the two con-ditions. The presence of lumbar or high sacral paraspinal fibrillation in the setting of acute L2-L3-L4 radiculopathy is the only potential distinguishing feature. As a result of these limitations, it is difficult to separate L2-L3-L4 radiculopathy and lumbar plexopathy elec-trodiagnostically, unless there is paraspinal fibrillation or saphenous

AANEMCourse NewInsightsinLumbosacralPlexopathy C-3

C-C-4 AANEMCourseC-4 UpdateonLumbosacralPlexopathy AANEMCourse

Table 1NerveConductionFindingsinVariousLowerExtremityDisorders

SP SN LT P P L5 T T S1 L3/4 LP APF BPF APF BPF

Peroneal M ++ ++ ++ ++ ++ + Sup Per S ++ ++ ++ ++ +/- +/- Tibial M ++ ++ ++ ++ + H Reflex ++ ++ ++ ++ Sural S ++ ++ ++ Plantar S ++ ++ ++ ++ Femoral M + +Saph S +/- +/-

+=degreeofabnormality;L3/4=L3/4radiculopathy;L5=L5radiculopathy;LP=lumbarplexopathy;LT=lumbosacraltrunk;M=motor;P/APF=peronealneuropathyabovepoplitealfossa;P/BPF=peronealneuropathybelowpoplitealfossa;T/APF=tibialneuropathyabovepoplitealfossa;T/BPF=tibialneuropathybelowpoplitealfossa;SN=sciaticneuropathy;S=sensory;S1=S1radiculopathy;SP=sacralplexopathy;SupPer=superficialperoneal;Saph=saphenous

Table 2 DistributionofNeedleElectrodeExaminationChangesinVariousLowerExtremityDisorders

SP LT L5 S1 S P P T T L2/3/4 LP APF BPF APF BPF

PSP +/- +- +/-GMed ++ ++ ++ TFL ++ ++ ++ GMax ++ ++ BFSH ++ ++ ++ +/- BFLH ++ ++ ++ +/- ST ++ ++ ++ ++ +/- TA ++ ++ ++ ++ ++ ++ Gast ++ ++ ++ ++ PT/FDL ++ ++ ++ ++ ++ +/- EDB ++ + + +/- ++ ++ ++ AH ++ ++ ++ ++ ++ Quads ++ ++

+=degreeofabnormality;AH=abductorhallucis;BFSH=bicepsfemoris(shorthead);BFLH=bicepsfemoris(longhead);EDB=extensordigitorumbrevis;Gast=gastroc-nemius;GMax=gluteusmaximus;GMed=gluteusmedius;PSP=paraspinalmuscles;PT/FDL=posteriortibialis/flexordigitorumlongus;Quads=quadricepsmuscles;ST=semitendinosus;TA=tibialisanterior;TFL=tensorfascialata.

AANEMCourse NewInsightsinLumbosacralPlexopathy C-C-5

sensory nerve action potential (SNAP) change. The clinical setting may help inform the EDX findings, but a disclaimer in the EDX report describing the differential diagnosis of the electrical pattern is usually unavoidable.

Unusual Sensory Nerve Conduction Studies

Several infrequently studied sensory nerve trunks may be of value in the assessment of lumbosacral plexopathy. These nerve trunks are difficult to study due to their variable anatomic courses, small caliber, small SNAP responses, and deep subcutaneous location in overweight individuals. Even in patients of normal size, the stimu-lation and recording sites may be relatively deep, hampering the technique and resulting in a diminished SNAP amplitude. Nerve conduction studies of the saphenous nerve, the lateral femoral cutaneous nerve of the thigh, and the posterior cutaneous nerve of the thigh will be reviewed.

Saphenous Nerve Conduction Study

Several NCS techniques have been described in literature for study-ing the saphenous nerve.5,12,15,17 The technique of Wainapel and colleagues places the R2 (reference) electrode just anterior to the prominence of the medial malleolus, in the space between the mal-leolus and the medial border of the tibialis anterior tendon17 (Figure 4). The R1 electrode is placed 3 cm proximal to the R2, parallel to the medial border of the tibialis anterior tendon. Stimulation is applied 14 cm proximal to the R1 electrode, deep to the medial border of the tibia. Pressure is required between the tibia and the medial gastrocnemius muscle to allow penetration of the stimulus to the nerve.3 The recorded negative peak latency is 3.6 ± 0.4 ms (± 1 SD), and the amplitude is 9.0 ± 3.4 µV.

The method described by Ma, Kim, and Liveson employs stimula-tion at the medial knee, between the tendons of the sartorius and gracilis muscles, 1 cm above the inferior border of the patella of the slightly flexed knee11 (Figure 5). The R1 electrode is placed 15 cm distal to the stimulation site along a line from the stimulation point to the medial border of the tibia. The R2 electrode is placed 3 cm distal to the R1 electrode. The recorded onset latency is 2.5 ± 0.19 ms (range 2.2-2.8) at a distance from 13-16 cm. The recorded amplitude is 10.23 ± 2.05 µV (range 7.0-15.0).

Lateral Femoral Cutaneous Nerve Conduction Study

The technique of lateral femoral cutaneous NCS as described by Ma and Liveson employs stimulation either above or below the

inguinal ligament 1 cm medial to the anterior superior iliac spine, over the origin of the sartorius muscle10 (Figure 6). The R1 record-ing electrode is placed 17-20 cm distally, along a line connecting the anterior superior iliac spine and the lateral border of the patella. The R2 electrode is placed 3 cm distal to the R1 electrode. With stimulation above the inguinal ligament, the recorded onset latency is 2.8 ± 0.4 ms (range 2.3-3.2) at a distance from 17-20 cm; the recorded amplitude is 6.0 ± 1.5 µV (range 3.0-10.0). With stimu-lation below the inguinal ligament, the recorded latency is 2.5 ± 0.2 ms (range 2.2-2.8) at a distance from 14-18 cm; the recorded amplitude is 7.0 ± 1.8 µV (range 4.0-11.0). Other techniques have been described.1,13

A number of technical challenges are encountered with the study of the lateral femoral cutaneous nerve of the thigh. Shock artifact and the compound muscle action potential response can obscure the SNAP. The orientation of the stimulating electrodes (anode and cathode) should be changed to minimize artifact and search


Figure 4SaphenousSensoryNerveConductionStudy.Wainapeltechnique.17

m=muscle;n=nerve

Figure 5 SaphenousSensoryNerveConductionStudy.Matechnique.11

m=muscle;n=nerve

C-� UpdateonLumbosacralPlexopathy AANEMCourse

Figure 6 LateralFemoralCutaneousSensoryNerveConductionStudy.Matechnique10

n=nerve

for maximal amplitude of the SNAP response. Stimulation should be delivered at various locations until the patient feels the stimulus radiating down the nerve trunk. The response cannot be obtained in overweight individuals.

Posterior Cutaneous Nerve of the Thigh Conduction Study

The posterior cutaneous nerve of the thigh conduction study described by Dumitru and Nelson requires that the patient be placed in the prone position with their legs completely relaxed.4 The R1 electrode is placed in the midline of the posterior thigh 6 cm proximal to the mid popliteal region, with the R2 electrode 3 cm distal (Figure 7). Stimulation is performed 12 cm proximal to the R1 electrode along a line connecting the R1 electrode and the ischial tuberosity in the groove between the medial and lateral hamstring muscles. The recorded negative peak latency is 2.8 ± 0.2 ms (normal limit 3.2 ms) and the peak-to-peak amplitude is 6.5 ± 1.5 µV (normal limit 4.4 µV).

SUMMARY

Electrodiagnostic studies are important in the diagnosis of lum-bosacral plexopathy. They help localize and confirm the presence of nerve damage at that level and rule out other neuromuscular disorders in the differential diagnosis. A knowledge of the periph-eral neuroanatomy of this complex region improves EDX decision making and clinical skills.

REFERENCES

1. Butler ET, Johnson EW, Kaye ZA. Normal conduction velocity in lateral femoral cutaneous nerve. Arch Phys Med Rehabil 1974;55:31-32.

2. de Ridder VA, de Lange S, Popta JV. Anatomical variations of the lateral femoral cutaneous nerve and the consequences for surgery. J Orthop Trauma 1999;13:207-211.

3. Delisa JA, Mackenzie K, Baran EM. Manual of nerve conduction velocity and somatosensory evoked potentials, 2nd edition. New York: Raven Press; 1987. p 134.

4. Dumitru D, Nelson MR. Posterior femoral cutaneous nerve conduc-tion. Arch Phys Med Rehabil 1990;71:979-982.

5. Ertekin C. Saphenous nerve conduction in man. J Neurol Neurosurg Psychiatry 1969;32:530-540.

6. Gough J, Koepke G. Electromyographic determination of motor root levels in erector spinae muscles. Arch Phys Med Rehabil 1966;47:9-11.

7. Hamanishi C, Tanaka S. Dorsal root ganglia in the lumbosacral region observed from the axial views of MRI. Spine 1993;18:1753-1756.

8. Kikuchi S, Sato K, Konno S, Hasue M. Anatomic and radiographic study of dorsal root ganglia. Spine 1994;19:6-11.

Figure 7 PosteriorFemoralCutaneousSensoryNerveConductionStudy.Dumitrutechnique.4

n=nerve


9. Levin KH. L5 radiculopathy with reduced superficial peroneal sensory responses: intraspinal and extraspinal causes. Muscle Nerve 1998;21:3-7.

10. Ma DM, Liveson JA. Nerve conduction handbook. Philadelphia: FA Davis Company; 1983. p 183-185.

11. Ma DM, Liveson JA. Nerve conduction handbook. Philadelphia: FA Davis Company; 1983. p 192-194.

12. Senden R, Van Mulders J, Ghys R, Rosselle N. Conduction velocity of the distal segment of the saphenous nerve on normal adult sub-jects. Electromyogr Clin Neurophysiol 1981;21:3-10.

13. Stevens A, Rosselle N. Sensory nerve conduction velocity of n. cuta-neous femoris lateralis. Electromyogr 1970;10:397-398.

14. Stewart JD. Focal peripheral neuropathies, 3rd edition. Philadelphia: Lippincott Williams and Wilkins; 2000. p 490-491.

15. Stohr M, Schumm F, Ballier R. Normal sensory conduction in the saphenous nerve in man. Electroencephalogr Clin Neurophysiol 1978;44:172-178.

16. Tsao B, Levin KH, Bodnar RA. Comparison of surgical and electro-diagnostic findings in single root lumbosacral radiculopathies. Muscle and Nerve 2003;27:60-64.

17. Wainapel SF, Kim DJ, Ebel A. Conduction studies of the saphenous nerve in healthy subjects. Arch Phys Med Rehabil 1978;59:316-319.

C-� UpdateonLumbosacralPlexopathy AANEMCourse

INTRODUCTION

The development of sensorimotor deficits in the territory of one or several nerve trunks, radicular, or plexus territories, occurs without evidence of a superimposed cause for neuropathy in diabetic patients. Such cases are extremely rare considering the frequency of distal symmetrical diabetic neuropathy and should always be investigated as in nondiabetic patients. In particular, it is necessary to perform electrophysiological testing to more accurately local-ize the lesions. When clinical and electrophysiological data point to spinal root lesions, magnetic resonance imaging of the spine, or other testing should be performed to exclude another cause of neuropathy. When nerve trunks are clearly affected clinically and electrophysiologically, a nerve and muscle biopsy in an affected ter-ritory should be considered to exclude primary necrotizing arteritis, sarcoidosis, or leprosy. In some cases however, no other cause than diabetes is found and the diagnosis of diabetic neuritis is likely. In the lower limbs, the most common pattern of focal neuropathy is characterized by proximal sensory and motor manifestations. It is worth noting that markers of systemic inflammation are normal in diabetic multifocal neuropathy, but dramatic weight loss is common.

PROXIMAL DIABETIC NEUROPATHY OF THE LOWER LIMBS

Diabetic patients over the age of 50 may present with proximal neuropathy of the lower limbs characterized by a variable degree of pain and sensory loss associated with uni- or bilateral proximal

muscle weakness and atrophy. This syndrome, which was origi-nally described by Bruns in 1890,5 has been subsequently reported under the terms of diabetic myelopathy,15 diabetic amyotrophy,14 femoral neuropathy,6,16 proximal diabetic neuropathy (PDN),2,6,28 femoral-sciatic neuropathy,27 the Bruns-Garland syndrome,3,8 and diabetic lumbosacral radiculoplexus neuropathy.11 The neurological picture is limited to the lower limbs and is usually asymmetrical.1 Clinically, the different patterns and the course of PDN strikingly differ from those of distal symmetrical sensory polyneuropathy (DSSP) suggesting different pathophysiologic features. In a study of 27 patients,9 24 had noninsulin dependent diabetes mellitus (NIDDM), 3 had insulin-dependent diabetes (IDDM), and the mean age at diagnosis was 62 years (range 46-71); the male to female ratio was 16:11.

The onset of the neuropathy is acute or subacute. The patient complains of numbness or pain of the anterior aspect of the thigh, often of the burning type and worse at night. Difficulty in walking and climbing stairs occurs, due to weakness of the quadriceps and iliopsoas muscles. Muscle wasting is also an early and common phe-nomenon, which is often easier to palpate than to see in overweight patients. The patellar reflex is decreased or more often abolished. The syndrome progresses over weeks or months in most cases, then stabilizes and spontaneous pains decreases, sometimes rapidly. In many instances, as in those originally reported, there is little or no sensory loss, as emphasized by Garland.14 He found inconsis-tent extensor plantar responses and increased cerebrospinal fluid protein content, and believed that they resulted from a metabolic myelopathy in patients who were treated for diabetes but not under full diabetic control.14 In approximately one-third of the patients,

Diabetes and the Lumbosacral Plexus

Gérard Said, MD, FRCPProfessorandChief

ServicedeNeurologieCentreHospitalierUniversitairedeBicêtre

UniversitéParis-SudParis,France

C-9

there is a definite sensory loss over the anterior aspect of the thigh, and in the others a painful contact dysesthesia in the distribution of the cutaneous branches of the femoral nerve, without definite sensory loss.

Bruns, who had described the condition, found that the disorder was reversible by dietetic restriction only.5 Garland also noticed a striking recovery of power with less obvious improvement of muscle wasting in four of his five patients.14 Most of the features identified by Garland were subsequently confirmed, including the usually good long-term prognosis, independent of the quality of diabetic control.

In most cases, the patient’s condition improves after months, but sequelae including disabling weakness and amyotrophy, sensory loss, and patellar areflexia are common.9,25 In a long-term follow-up survey covering a 14-year span, recovery began after a median inter-val of 3 months (range 1-12 months).25 Pain was the first symptom to improve, with resolution being comparatively rapid, beginning within a few weeks and becoming nearly complete at 12 months. Residual discomfort took up to 3 years to subside in the patients of Coppack and Watkins.9 Motor recovery was satisfactory and none of their 27 cases showed disabling residual deficits, but 7 com-plained of some persisting weakness, and significant wasting of the thigh was evident in half of the cases.9 Denervation atrophy found in the muscle samples fit well with the long-term, or permanent, weakness and amyotrophy that often affect distal muscles. Relapses on the other side were common, often in spite of good diabetic control. In one-fifth of the patients investigated for this syndrome, relapses occurred on the other side within a few months, the same proportion as reported in a study by Coppack and Watkins.9 Thus the clinical features of PDN (frequent motor involvement, asym-metry of the deficit, gradual yet often incomplete spontaneous recovery) markedly differ from those of DSSP in which the length-dependent symmetrical sensory deficit is associated with motor signs only in extreme cases, and which virtually never improves. In the syndrome described by Garland as “diabetic amyotrophy,” motor manifestations were more prominent and both sides were affected. However, the syndrome is a variant of PDN, because lesions of the sensory branch of the femoral nerve were also present in patients who had no sensory signs or symptoms.25

ELECTROPHYSIOLOGICAL STUDIES

Needle electromyography reveals signs of denervation in affected muscles with spontaneous fibrillation, usually bilaterally even in cases with weakness restricted to one side. In more severe cases, there may be evidence of widespread denervation affecting distal leg muscles as well, and also those innervated by the lower thoracic spinal roots. In cases of long duration, motor unit action potentials (MUAPs) are of increased amplitude, reflecting reinnervation by collateral sprouting from surviving motor axons. The MUAPs may be polyphasic and of low amplitude leading to the misperception of

myopathy.19,28 Nerve conduction studies indicate axonal loss rather than demyelination19 and the compound muscle action potential in the quadriceps muscles on femoral nerve stimulation is reduced in amplitude. The F-wave latencies to distal muscles8,37 are difficult to interpret in view of the frequent co-existence of a distal polyneu-ropathy.4,17,28

PATHOLOGICAL ASPECTS OF PROXIMAL DISTAL NEUROPATHY

In a recent pathological study of biopsy specimens of the interme-diate cutaneous nerve of the thigh, a sensory branch of the femoral nerve which conveys sensation from the anterior aspect of the thigh (a territory commonly involved in PDN) this author and colleagues found that the pathology of proximal nerves varied with the clinical aspects of the neuropathy.25 Examination of the biopsy specimen in patients with the most severe sensory and motor deficit revealed lesions characteristic of severe nerve ischemia, including total axon loss in two patients with the most severe deficit, and centrofascicu-lar degeneration of fibers associated with a large number of regen-erating fibers in one, following a pattern of axonal loss observed in clinical and experimental nerve ischemia.13,22 Lesions of nerve fibers coexisted with occlusion of a perineurial blood vessel in one patient in the study. This finding was consistent with the only detailed postmortem study of PDN available.23 The authors in this study found a small infiltration with mononuclear cells associated with the occlusion of an interfascicular artery of the obturator nerve, in a patient with a proximal and distal deficit of the left lower limb. In a patient who developed a rapid, asymmetrical, distal, sensorimotor deficit shortly after the onset of the proximal deficit, recent occlu-sion of a perineurial blood vessel and perivascular, perineurial, and subperineurial inflammatory infiltration with mononuclear cells was demonstrated, along with axonal degeneration of the major-ity of nerve fibers of the superficial peroneal nerve. In the other patients, lesions of nerve fibers and of endoneurial capillaries were similar to those observed in the sural nerve in diabetic patients with symptomatic DSSP. In four patients, mixed, axonal, and demy-elinative nerve lesions were associated with increased endoneurial cellularity made of mononuclear cells that suggested the presence of a low-grade endoneurial inflammatory process. In a recent study of patients with extremely painful PDN, this author’s group found similar inflammatory lesions with B and T lymphocytes mixed with macrophages.24 Similar observations were made by others in biopsy specimens of the intermediate cutaneous nerve of the thigh20 and in the sural nerve.11 In the author’s series, the patients, who were already treated with insulin for weeks or months, became pain-free shortly after performance of the biopsy, without additional treat-ment. These observations show that the presence of inflammatory infiltrates does not preclude spontaneous recovery.24

The relationship among the occurrence of inflammatory infiltrates, vasculitis, and diabetes is not clear. Small inflammatory infiltrates have been occasionally encountered in sural nerve biopsy specimens

C-10 DiabetesandtheLumbosacralPlexus AANEMCourse

of diabetic patients with neurological deficit18 and in autonomic nerve bundles and ganglia.10 Lesions of nerve fibers and of blood vessels due to diabetes may trigger an inflammatory reaction and reactive vasculitis in some patients. Alternatively, diabetes may make the nerves more susceptible to intercurrent inflammatory or immune processes. In both cases, lesions of epi- or perineurial blood vessels can induce ischemic nerve lesions responsible for severe proximal sensory and motor deficits. Conversely, in milder forms the lesions are more reminiscent of those observed in distal symmetrical polyneuropathy.

MULTIFOCAL DIABETIC NEUROPATHY

In a small proportion of diabetic patients, a multifocal diabetic neuropathy (MDN) is observed with successive or simultaneous involvement, of roots and nerves of the lower limbs, trunk, and upper extremities. The author’s group prospectively studied 22 consecutive diabetic patients with MDN, for which other causes of neuropathy were excluded by appropriate investigations, including biopsy of a recently affected sensory nerve.26 Three patients had a relapsing course, the others an unremitting subacute-progressive course. Painful multifocal sensory-motor deficit progressed over 2 to 12 months. Distal lower limbs were involved in all patients, unilaterally in seven, bilaterally in the others, with an asynchro-nous onset in most cases. In addition, proximal deficits of the lower limbs were present on one side in seven patients, on both sides in six. Thoracic radiculoneuropathy was present bilaterally in two patients, unilaterally in one. The ulnar nerve was involved in one patient, the radial nerve in two. The cerebrospinal fluid protein ranged from 0.40 to 3.55 g/l. The mean was 0.87 g/l. Electrophysiological testing showed severe, multifocal, axonal nerve lesions in all cases. Multifocal diabetic neuropathy is comparable to the lumbosacral radiculoplexus neuropathy;12 however, since this subacute neuropathy can also affect territories beyond the lumbosacral area MDN seems more appropriate. It is also obvious that MDN or lumbosacral radiculoplexopathy is not specific to diabetic patients, as further shown,12 which underlines the need to exclude other causes of neuropathy in this setting, including a su-perimposed cause in diabetic patients, such as necrotizing arteritis or chronic inflammatory demyelinating polyneuropathy, both of which require specific treatment.21

PATHOLOGICAL ASPECTS OF MULTIFOCAL DIABETIC NEUROPATHY

Asymmetrical axonal lesions were present in all nerve specimens of patients with MDN. The mean density of myelinated and of un-myelinated axons was reduced to 1340 per mm2 of endoneurial area and to 5095 per mm2 (extremes: 0-26,600), respectively. On teased fiber preparations one-third of the fibers were at different stages of axonal degeneration while 7% showed segmental demyelination or

remyelination. Necrotizing vasculitis of perineurial and endoneu-rial blood vessels were found in six patients. Evidence of present or past endoneurial bleeding that included seepage of red cells, haem-orrhage, or ferric iron deposits, were found in the majority of the specimens. Perivascular mononuclear cell infiltrates were present in the nerve specimens of 21 of 22 patients, prominently in 4 pa-tients. In comparison, nerve biopsy specimens of 30 patients with severe DSSP showed mild epineurial mononuclear cell infiltrate in 1 patient and endoneurial seepage of red cells in another. Thus, this author believes that MDN is related to precapillary blood vessel involvement in elderly diabetic patients with a secondary inflam-matory response.

Besides the high frequency both of endoneurial bleeding and of inflammatory infiltrates, occlusion of small- and middle-sized epineurial and perineurial arteries differentiates MDN from DSSP. The intensity and distribution of the lesions seemed more severe in MDN than in PDN, but both patterns can be included in MDNs. The outcome is better in MDN than in DSP. Improvement occurs in all patients after a few months, but sequelae are common.

TREATMENT OF FOCAL DIABETIC NEUROPATHIES

Proximal diabetic neuropathy is often very painful and should be treated with paracetamol (acetaminophen) and codeine. As some of our patients with disabling painful proximal neuropathy responded only to corticosteroids, this treatment should be con-sidered in severe forms.25 This will require adjustment of diabetic control with insulin in most cases. Others have suggested the use of immunosuppression or immunomodulation, such as intravenous immunoglobulins, but one should keep in mind that the overall spontaneous prognosis of focal diabetic neuropathies is good.

SUMMARY

Proximal diabetic neuropathy represents a form of ischemic neu-ropathy from a pathological point of view. Inflammatory compo-nents are now also recognized. These factors should help with the development of improved treatment strategies in the future.

REFERENCES

1. Asbury AK. Focal and multifocal neuropathies of diabetes. In: Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D Jr, editors. Diabetic neuropathy. Philadelphia: WB Saunders; 1987. p 43-55.

2. Asbury AK. Proximal diabetic neuropathy. Ann Neurol 1977;2:179-180.

3. Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol 1991;48:1130-1135.


4. Bastron JA, Thomas JE. Diabetic polyradiculopathy: clinical and elec-tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725-732.

5. Bruns L. Ueber neuritische Lähmungen beim diabetes mellitus. Berl Klin Wochenscher 1890;27:509-515.

6. Calverley JR, Mulder DW. Femoral neuropathy. Neurology 1960;10:963-967.

7. Chokroverty S. Proximal nerve dysfunction in diabetic proximal amy-otrophy. Electrophysiology and electron microscopy. Arch Neurol 1982;39:403-407.

8. Chokroverty S, Reyes MG, Rubino FA. Bruns-Garland syndrome of diabetic amyotrophy. Trans Am Neurol Assoc 1977;102:173-177.

9. Coppack SW, Watkins PJ. The natural history of diabetic femoral neuropathy. Q J Med 1991;79:307-313.

10. Duchen LW, Anjorin A, Watkins PJ, Mackay JD. Pathology of auto-nomic neuropathy in diabetes mellitus. Ann Intern Med 1980;92:301-303.

11. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;10:2113-2121.

12. Dyck PJ, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculo-plexus neuropathy: natural history, outcome and comparison with the diabetic variety. Brain 2001;124:1197-1207.

13. Fujimura H, Lacroix C, Said G. Vulnerability of nerve fibers to isch-emia. Brain 1991;114:1929-1942.

14. Garland HT. Diabetic amyotrophy. Br Med J 1955;2:1287-1290.15. Garland HT, Taverner D. Diabetic myelopathy. Br Med J 1953;1:1405-

1408.16. Goodman JI. Femoral neuropathy in relation to diabetes mellitus:

report of 17 cases. Diabetes 1954;3:266-273.17. Isaacs H, Gilchrist G. Diabetic amyotrophy. S Afr Med J 1960;134:501-

505.

18. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995;52:1053-1061.

19. Lamontagne A, Buchthal F. Electrophysiological studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry 1970;33:442-452.

20. Llewelyn JG, Thomas PK, King RH. Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 1998;245:159-165.

21. Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM, Said G. Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol 2002;249:569-575.

22. Nukada H, Dyck PJ. Microsphere embolization of nerve capillaries and fiber degeneration. Am J Pathol 1984;115:275-287.

23. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. Arch Neurol 1968;18:487-499.

24. Said G, Elgrably F, Lacroix C, Planté V, Talamon C, Adams D, et al. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favourable outcome. Ann Neurol 1997;41:762-770.

25. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A. Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 1994;35:559-569.

26. Said G, Lacroix C, Lozeron P, Ropert A, Planté V, Adams D. Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 2003;126:376-385.

27. Skanse B, Gydell K. A rare type of femoral-sciatic neuropathy in diabetes mellitus. Acta Med Scand 1956;155:463-468.

28. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy. Clinical and electromyographic studies. J Neurol Sci 1982;53:293-304.

29. Williams IR, Mayer RF. Subacute proximal diabetic neuropathy. Neurology 1976;26:108-116.

C-1� DiabetesandtheLumbosacralPlexus AANEMCourse

INTRODUCTION

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) (also known as diabetic amyotrophy, proximal diabetic neuropathy, diabetic polyradiculopathy, and other names) is an asymmetrical lower limb syndrome of pain, weakness, paresthesia, and weight loss that usually occurs in patients with mild type II diabetes mel-litus.16 Although the condition is severe and debilitating, it usually is monophasic with the symptoms and deficits resolving in months or years, but improvement is often incomplete.16

A similar syndrome of unilateral or asymmetrical lower limb pain, weakness, and paresthesia that affects patients without diabetes is nondiabetic lumbosacral radiculoplexus neuropathy (LRPN). This condition has been recognized more recently than DLRPN; the first descriptions were not published until 1981 when two groups de-scribed a subacute painful, paralytic lower-limb neuropathy attrib-utable to pathological involvement of the lumbosacral plexus.17,27 Like its diabetic counterpart, it appears to be a monophasic illness that usually has incomplete recovery and prolonged morbidity with pain and weakness.15,17 Both DLRPN and LRPN are part of a bigger category of neuropathies that begin suddenly with pain and weakness and involve the roots, plexus and peripheral nerves, and are called the radiculoplexus neuropathies (RPN). Radiculoplexus neuropathies can be divided into three subtypes: (1) a lower limb syndrome, diabetic and nondiabetic lumbosacral radiculoplexus neuropathy (DLRPN, LRPN); (2) a truncal syndrome, diabetic and nondiabetic thoracic radiculoneuropathy (DTRN, TRN); and (3) an upper limb syndrome, diabetic and nondiabetic cervical ra-

diculoplexus neuropathy (DCRPN, CRPN).11 The syndromes are similar in diabetic and nondiabetic patients.

Much remains to be learned about the diabetic and the nondiabetic RPNs. It seems best to group these conditions together under the heading of RPN due to the patchy involvement of roots, plexuses, and peripheral nerves in these disorders based on abnormalities observed in clinical, electromyographic (EMG), laboratory, and histopathological studies of nerves. These syndromes are best grouped together given their strong clinical similarities; they begin with pain followed by weakness, are asymmetrical, usually are monophasic illnesses, often the same patient has several anatomical sites involved (for example both thoracic and lumbosacral levels), and are associated with weight loss. The clinical, laboratory, elec-trophysiologic, and pathologic features of the lower limb form of RPN that occurs in diabetic patients will be outlined and the natural history and treatment will be discussed. Because all of these syndromes appear to be caused by a microvasculitis and ischemic injury, immunotherapy may be the best treatment, but this has not yet been demonstrated.

CLINICAL FEATURES OF LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Most commonly, the first symptom of LRPN is pain, which usually comes in several forms. In almost all cases, there is hurting or deep-aching pain. Other frequently described pains include sharp, lanci-nating or electrical-shock-like pain, burning or fire-like pain, and

Nondiabetic Lumbosacral Radiculoplexus Neuropathy

P. James B. Dyck, MDPeripheralNeuropathyResearchLaboratory

MayoClinicCollegeofMedicineRochester,Minnesota

C-13

contact allodynia. Patients with allodynia often do not like to wear clothes or to have bedsheets touch them because these stimuli cause excessive pain. The pain in this disorder may be severe. In a series by this author and colleagues, essentially all patients received an-algesic pain medication and most required narcotics.15 Most com-monly, the pain begins asymmetrically (usually unilaterally) and focally, involving proximal segments (the hip and thigh) somewhat more commonly than distal segments (the foot and leg) (Table 1). However, the disorder quickly spreads to involve the initially unaffected segments and the contralateral side so that by time of evaluation the disorder is much more widespread and symmetrical than when it first began. Occasionally, it can begin bilaterally and symmetrically. In this author’s series, the syndrome began unilater-ally in 50 of 57 patients, but eventually became bilateral in 51 of 57.15 The median time to bilateral disease was 3 months (Table 2). Consequently, early in the disease course, one segment (back, buttock, hip, thigh, leg, or toe) is often primarily involved. These initially involved segments can be proximal or distal. For example, it is not uncommon to find isolated weak thigh muscles and absent knee reflexes in one patient and a foot drop and no proximal find-ings in another. The process is multifocal, so a patient may have proximal involvement of one lower limb and distal involvement of the other limb.

Although pain is the most problematic early symptom, weakness soon becomes the biggest problem (Table 1). As with the pain, the weakness usually begins focally either proximally or distally but progresses to become multifocal and bilateral. Consequently, both proximal weakness (difficulty rising from low chairs or climbing and decending stairs) and distal weakness (foot drop and difficulty walking on toes) are frequent complaints from LRPN patients. The thigh muscles are often affected, causing the knee to buckle and the patient to fall. Consequently, bone fractures—especially hips—can occur in patients with LRPN. The weakness is usually severe and half of the patients in this author’s series (28 of 57) were wheelchair-bound at the time of evaluation and almost all of them required some form of aid to ambulate (brace, cane, or walker) (Table 1). When the disease remains unilateral, patients usually can continue ambulating, although they often will need help. However, when the disease becomes bilateral with predominant involvement of thigh muscles, patients usually become wheelchair-dependent.

In many cases of LRPN, autonomic and sensory systems are prominent. Essentially, all patients with LRPN suffer from pain, which implies involvement of sensory fibers. Furthermore, 49 of 57 patients from this author’s series had paresthesias and most had distal or proximal sensory loss on examination. Quantitative sensory testing showed that there is unequivocal sensory abnormal-ity at different anatomical sites (foot, leg, and thigh) to all sensory modalities (large and small fibers resulting in abnormalities of vi-bration, cooling, and heat-pain).15 Similarly, autonomic symptoms are common in LRPN and one-half of patients in this study had new autonomic symptoms at the time of their illness, including

orthostatic intolerance, change in sexual function, urinary dysfunc-tion, diarrhea, constipation, or change in sweating. Quantitative autonomic testing showed abnormalities in almost all patients tested, and the median composite autonomic severity score (CASS) showed moderate autonomic dysfunction.15 Consequently, LRPN is not just a motor neuropathy—sensory and autonomic systems are involved.

Weight loss is also common in LRPN15 and 42 of the 57 patients in this series had weight loss exceeding 10 pounds. In DLRPN, the weight loss is often attributed to poorly controlled diabetes mel-litus, but this explanation is not applicable in LRPN because these patients are not diabetic.

One reassuring fact about LRPN is that it is a monophasic illness and some improvement occurs in almost all patients.15,17 This is a moderately severe neuropathy; the median value of the Neuropathy Impairment Score (NIS)10 (a global score of neurologic impairment taking into account weakness, reflex change and sensory loss) was 36.5 points (Table 2). This NIS is indicative of moderate to severe impairment. Recovery is usually delayed and is commonly incom-plete as nerves regrow slowly, often incompletely and incorrectly. It is difficult to know in a specific patient whether there still is active disease or whether there is residual damage to nerves and partial regeneration. There usually is long-term morbidity in LRPN from pain, sensory loss, and weakness. Of 42 LRPN patients followed over time, only 3 believed that they had completely recovered after a median time of 3 years.15 Most patients have substantial improve-ment of both pain and weakness, and few require the long term use of wheelchairs (in this author’s series, only 5 of the 25 patients who initially needed wheelchairs still used them 3 years later). However, some degree of ongoing pain, sensory loss, and weakness are common. In general, younger patients fare better than older patients and proximal injury usually recovers earlier and more ef-fectively than does distal injury. Consequently, foot drop tends to be a common long-term problem for LRPN patients. It is believed that the explanation for this is that reinnervation occurs sooner and more completely in proximal nerve segments. Many patients also have some long-term pain and sensory loss, which is usually much less severe than it was early in the disease course. In this author’s LRPN cohort, approximately 17% of patients (7 of 42) had recur-rent episodes of lumbosacral plexopathy (pain and weakness of the lower extremities).

COMPARISON OF LUMBOSACRAL RADICULOPLEXUS NEUROPATHY TO DIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Diabetic lumbosacral radiculoplexus neuropathy is a clinical syndrome that has received much more attention than LRPN.1,3,

6,8,14,18,19,23 Based on large cohorts of LRPN (n = 57) and of DLRPN (n = 33) evaluated by this author, it is believed that the

C-14 NondiabeticLumbosacralRadiculoplexusNeuropathy AANEMCourse

two conditions are essentially the same except for the occurrence of diabetes mellitus in DLRPN.12,14-16 The clinical features are almost indistinguishable. As in LRPN, DLRPN begins focally with pain involving the back, buttock, thigh, or leg. It starts in an acute or subacute fashion and patients frequently will remember the day their symptoms began. Over time, the symptoms will spread so that within months the disorder usually involves both proximal and distal segments and becomes bilateral. Early in the course, pain is the predominant symptom, whereas later weakness is more impor-tant (Table 1). As in LRPN, the proximal segments in DLRPN are initially involved somewhat more frequently than the distal seg-

ments. However, with time, most patients develop proximal and distal symptoms and have bilateral involvement (in this author’s series, 32 of 33). The NIS is similar to that of patients with LRPN (Table 2).

As is the case for LRPN, DLRPN is not solely a motor neu-ropathy and sensory and autonomic systems are unequivocally involved. Essentially, all patients with DLRPN have pain (a sensory symptom) and there is involvement of all classes of sensory fibers (vibration, cooling, and heat-pain) at different anatomical sites (foot, leg, and thigh). About one-half of patients have new auto-

Table 1Severityofsymptoms,anatomiclocationanduseofambulatingaidsinDLRPNandLRPN

DLRPN LRPN DLRPNvs.LRPN Mayo Telephone Mayo Telephone Mayo Telephone Onset EvaluationFollowUp Onset EvaluationFollowUp Onset EvaluationFollowUp (n=33) (n=33) (n=31)† (n=57) (n=57) (n=4�)† Mostseveresymptom Pain �7 13 � 49 10 1� Prickling 0 0 � 1 0 1 Weakness � �0 �1 7 47 �� None 0 0 � 0 0 3 significance* <0.001 0.05 <0.0001 0.03 NS 0.03 NS

Mostinvolvedsite FootorLeg 1� 14 �4 �1 �7 3� HiporThigh 1� 19 5 33 30 7 ButtockorBack 3 0 0 3 0 0 None 0 0 � 0 0 3 significance NS <0.001 NS 0.0001 NS NS NS

Aidsinambulation Wheelchair 1� 3 �� 5 Walker,CaneorBrace 14 1� �� 1 None 3 1� 1 1� significance <0.001 <0.0001 NS NS

DLRPN=diabeticlumbosacralradiculoplexusneuropathy;LRPN=lumbosacralradiculoplexusneuropathy;NS=notsignificant(p>0.05).*Fisher’sexacttest.†ThreeLRPNandtwoDLRPNpatientsreportedtheywererecovered.(DyckPJB,NorellJ,DyckPJ,Non-diabeticlumbosacralradiculoplexusneuropathy.Naturalhistory,outcomeandcomparisonwiththediabeticvariety.Brain�001;1�4:1197-1�07.Modifiedandreprintedwithpermission.)


C-1� NondiabeticLumbosacralRadiculoplexusNeuropathy AANEMCourse

Table 2ClinicalandlaboratorycharacteristicsofDLRPNandLRPNpatientsandapopulation-baseddiabeticcohort(RDNS)

DLRPN LRPN RDNS p* DLRPN DLRPN vs. vs.Continuous n Median Range SD n Median Range SD n Median Range SD LRPN RDNSAge,years 33 �5.4 35.� - 75.9 10.4 57 �9.4 �7.� - ��.5 1�.3 195 �5.0 19.0 - ��.0 15.1 0.03 NSDurationof 33 4.1 0.0 - 35.� 7.9 NA 195 15.0 5.9 - 74.� �.5 <0.001diabetes,yearsDurationof 33 �.7 1.4 - 4�.0 �.9 57 7.0 0.5 - �0.0 1�.4 NA NS neuropathyatevaluation,monthsOnsetto 3� 3.0 0.0 - �0.0 10.� 45 3.0 0.0 - 7�.0 11.� NA NS bilateral,monthsFastingplasma 30 144.5 75.0 -��5.0 44.3 57 9�.0 �9.0 -1�4.0 11.5 195 1�9.9 94.� -3�9.0 41.9 0.0001 0.001glucose,mg/dLGlycated 30 7.5 5.1 - 1�.9 �.0 34 5.5 4.3 - 7.1 0.7 195 9.� 5.5 - 1�.5 �.0 0.0001 <0.001hemoglobin,%Bodymass �9 �5.7 17.� - 3�.7 4.9 50 �5.1 17.� - 35.4 4.� 195 ��.� 17.� - 50.� 5.7 NS 0.00�index,kg/m�

Weightchange,lb† 33 -30.0 -1�0.0 - 0.0 3�.� 57 -15.0 -90.0 - 0.0 19.� 195 0.4 -�.7 - 10.1 �.� 0.00� <0.001Creatinine,mg/dL 30 0.9 0.7 - 3.4 0.5 53 1.0 0.� - 1.9 0.� 195 1.0 0.5 - �.5 0.� NS 0.0�3Cerebrospinalfluid �� 5.0 5�.0 -130.0 19.4 49 �3.0 4�.0 - ��.0 9.3 0.0001glucose,mg/dLCerebrospinalfluid �� 9.5 44.0 -�14.0 35.3 50 ��.5 1�.0 -��3.0 5�.9 0.009protein,mg/dLCerebrospinalfluid �� 1.0 1.0 - 11.5 �.1 49 1.0 0.0 - 1�.0 �.� NScells,cells/µLErythrocyte 31 �.0 0.0 - �0.5 14.� 5� 13.5 0.0 - ��.0 14.4 0.0�sedimentationrate,mm/hNISTotal 33 43.0 7.0 - �7.0 1�.� 57 3�.5 �.0 -10�.3 �1.� 195 0.0 0.0 - 1�.0 �.5 NS 0.0001NISLowerlimb 33 37.0 7.0 - ��.0 14.4 57 33.5 �.0 - 77.0 17.0 195 0.0 0.0 - 14.0 �.3 NS 0.0001Dichotomous Yes No Yes No Yes NoSex,male 33 �0 13 57 �9 �� 195 9� 99 NS NSDiabetes,typeII 33 3� 1 NA 194 14� 4� 0.005Insulinuse 31 13 1� NA 195 134 �1 0.007Retinopathy 17 4‡ 13 195 1�� 7 0.001Nephropathy 33 � 31 195 �0 175 NSCardiovasculardisease33 3 30 195 73 1�� 0.001Rheumatoidfactor, �7 � �5 40 � 34 NSreactiveANA,positive 3� 7 �5 50 � 4� NS

DLRPN=diabeticlumbosacralradiculoplexusneuropathy;LRPN=lumbosacralradiculoplexusneuropathy;RDNS=RochesterDiabeticNeuropathyStudy;SD=standarddeviation;NS=notsignificant(p>0.05);NA=notapplicable;NIS=NeuropathyImpairmentScore.*WilcoxonranksumtestforcontinuousdataandFisher’sexacttestfordichotomousdata.†ForDLRPNandLRPN,weightchangeisfromonsettovaluation;forRDNS,weightchangeisoveroneyear.‡Nonproliferativeretinopathy.(DyckPJB,NorellJ,DyckPJ,Non-diabeticlumbosacralradiculoplexusneuropathy.Naturalhistory,outcomeandcomparisonwiththediabeticvariety.Brain�001;1�4:1197-1�07.Modifiedandreprintedwithpermission.)

nomic symptoms which include orthostatic hypotension, urinary dysfuntion, diarrhea, constipation, change in sexual function, or change in sweating.14

Long-term morbidity is severe in both LRPN and DLRPN. From this author’s series, only 2 of 31 DLRPN patients reported that they had complete recovery after a median follow-up time of 2 years. The others still had residual weakness, pain or sensory loss (Table 1). However, as in DLRPN, real improvement had occurred in most patients. At the time of initial evaluation, 16 DLRPN patients used a wheelchair, whereas only 3 used a wheelchair at the time of follow-up. The most problematic long-term impairments were confined to the distal segments (legs and feet)—this often was foot drop (as in LRPN). As in LRPN, DLRPN can be a recurrent condition.

TESTING IN LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Previous authors have argued that markers of altered immunity, especially elevated erythrocyte sedimentation rates, distinguish pa-tients with immune mediated lumbosacral plexopathies from ones with different etiologies.5 It is agreed that an elevated sedimentation rate may imply an immune etiology. However, it has not been this author’s experience that patients with elevated erythrocyte sedimen-tation rates differ markedly from other RPN patients.15 Some of the patients from the DLRPN and LRPN cohorts had elevated sedi-mentation rates, reactive rheumatoid factors, positive antinuclear antibodies, or other markers of altered immunity, but most did not (Table 2). It is believed that an immune cause underlies all of the RPNs. In both DLRPN and LRPN, the cerebrospinal fluid (CSF) protein concentration is significantly elevated (Table 2)—evidence that the disease process extends to the nerve root level.

The nerve conduction study (NCS) and electromyogram (EMG) abnormalities in LRPN and DLRPN have been extensively studied.4,15,28 Bastron and Thomas emphasized the multifocal and patchy involvement of lumbosacral and thoracic myotomes in DLRPN.4 Subramony and Wilbourn proposed that there were two distinct electrophysiological subtypes of DLRPN: one group in which there are focal abnormalities confined to the affected lower limb(s) (multiple lumbosacral radiculopathies) and a second group in which there is evidence of a diffuse peripheral neuropathy with more severe abnormalities superimposed in the affected lower limb(s) (multiple lumbosacral radiculopathies).28 While this author believes that the observation of these authors is correct, it is not believed to be helpful to divide patients into two groups. It is likely that the subgroup reported to have a separate polyneuropathy are the more severely affected patients and have more diffuse electro-physiological abnormalities. It is also believed that two separate,

coexisting neurological disorders are unlikely for most patients; rather, it is more likely that there is unequal pathological involve-ment of different nerve segments producing a widespread but asymmetric radiculoplexus neuropathy.

The NCS and needle EMG findings in LRPN and DLRPN are more suggestive of axonal degeneration than of segmental demy-elination. In this author’s cohorts of LRPN and DLRPN, there are marked reductions in amplitudes of the compound muscle action potentials and of the sensory nerve action potentials with only mild slowing of nerve conduction velocities.14,15 Needle EMG shows fibrillation potentials, decreased recruitment, long duration, high amplitude motor unit action potentials in muscles innervated by multiple nerve roots and different peripheral nerves. Upper lumbar and lower lumbar levels both tend to be involved. Paraspinal muscles are also usually involved. Fibrillation potentials in lumbo-sacral paraspinal muscles were seen in 33 of 48 LRPN patients and 29 of 30 DLRPN patients who had paraspinal muscles examined. The electrophysiological abnormalities tend to be more widespread than the clinical deficits. The findings are essentially the same in the two conditions with the diabetic group having slightly more severe abnormalities.14,15 Although axonal degeneration is the main abnormality, an occasional patient will show slowed conduction velocities somewhat suggestive of demyelination. In general, the electrophysiological abnormalities are in keeping with a pathologi-cal process that involved the roots, plexus, and peripheral nerves (a radiculoplexus neuropathy) which usually predominantly involves the lumbosacral segments, but which often also involves the tho-racic and cervical segments.

PATHOLOGY OF LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Previously, only a few studies exist about the underlying patho-logical mechanisms of LRPN. Bradley and coworkers showed in six patients with painful lumbosacral plexopathies and elevated sedimentation rates (three with and three without diabetes mel-litus) that there were perivascular inflammatory cell cuffing and multifocal fiber loss.5 In contrast, much more has been written about the pathology of DLRPN. In the only autopsy case by Raff and colleagues, ischemic injury was reported.23,24 Some authors have argued that ischemic injury is the most important finding,3 whereas others have argued that metabolic factors were more im-portant.7,8 Others have found evidence that some cases are due to ischemic injury and vasculitis, whereas other cases are due to meta-bolic derangement.25 Some have stressed that DLRPN is due to microvasculitis causing ischemic injury.14,21,22,26 Because of the simi-larity in the clinical, laboratory, and electrophysiological features of DLRPN and LRPN, it seemed likely that the two conditions are due to the same pathophysiological mechanisms. Consequently, a


pathological study was performed identifying LRPN patients who had nerve biopsies in order to determine whether the pathological findings were the same in the two conditions.

It was found that the pathological findings in LRPN are strikingly similar to those of DLRPN (Table 3).12 There was multifocal fiber loss, regions of abortive regeneration within or beyond the original fascicle forming microfasciculi (injury neuroma), focal degenera-tion or scarring of the perineurium, and epineurial neovasculariza-

tion (Figure 1). All of these changes are attributable to ischemic damage. As in DLRPN, the ischemic changes seemed to be caused by altered immunity and microvasculitis. Epineurial perivascular inflammatory collections were seen in all nerves. There were fea-tures suggestive of microvasculitis with inflammatory cells separat-ing microvessel wall elements in half of nerves. Serial skip sections demonstrated that the microvasculitis regions were focal with some areas affected and adjacent areas unaffected (Figure 2). Fibrinoid degeneration (typical of large vessel vasculitis) was rarely seen.

C-1� NondiabeticLumbosacralRadiculoplexusNeuropathy AANEMCourse

Table 3 PathologicresultsofdistalcutaneousnervebiopsiesfromDLRPNcomparedwithLRPN,diabeticpolyneuropathy(DPN)andhealthycontrolnerves

DLRPN LRPN DPN HealthyControlsVariable n n p* n p* n p*Characteristics of Patients Biopsied n 33 47 �1 14 Sex,male �0 �4 NS 15 NS 9 NS MedianAge,years �5.4 �7.� NS 57.0 0.00� �1.5 NS Paraffin and Epoxy Sections Endoneurial and Perineurial Abnormality Fiberdegenerationorloss �5 37 NS 15 NS 0 <0.001 Multifocalfiberdegenerationorloss 19 31 NS � <0.001 0 <0.001 Focalperineurialdegeneration � 7 NS 0 NS 0 NS Focalperineurialthickening �4 �7 NS � <0.001 � <0.001 Injuryneuroma† 1� 1� NS 0 0.00� 0 0.009 Interstitial Abnormality Perivascularinflammation 33 47 NS � <0.001 � <0.001 Individualcells(<10cells) 0 5 5 � Smallcollections(11-50cells) �1 �9 1 0 Moderatecollections(51-100cells) 7 � 0 0 Largecollections(>100cells) 5 7 0 0 Inflammationofvesselwall 15 �4 NS 0 <0.001 0 0.00� Diagnosticofmicrovasculitis � 7 NS 0 NS 0 NS Hemosiderininmacrophages 19 �5 NS 0 <0.001 0 <0.001 Neovascularization �1 �1 NS 1 <0.001 1 <0.001

DLRPN=diabeticlumbosacralradiculoplexusneuropathy;LRPN=lumbosacralradiculoplexusneuropathy;NS=notsignificant(p>0.05). *WilcoxonranksumtestforcontinuousdataandFisher’sexacttestfordichotomousdata.†Injuryneuroma=abortiveregenerativeactivityoutsideoftheoriginalperineurium.(DyckPJB,EngelstadJ,NorellJ,DyckPJ,MicrovasculitisinNon-DiabeticLumbosacralRadiculoplexusNeuropathy(LSRPN):Similarity totheDiabeticVariety(DLSRPN),JNeuropatholExpNeurol�000;59:5�5-53�.DyckPJB,NorellJE,DyckPJ,Microvasculitisandischemiaindiabeticlumbosacralradiculoplexusneuropathy,Neurology1999;53:�113-�1�1.Modifiedandreprintedwithpermissions.)

Overall, the pathological findings of DLRPN and LRPN are very much alike. Findings provide evidence that the primary event in both DLRPN and in LRPN is nerve ischemia due to a microvas-culitis.

It is believed these conditions are forms of nonsystemic vasculitis of nerve. A vasculitic process could explain the clinical pattern of sudden onset, painful, asymmetric neuropathy. Weight loss is common in vasculitis disorders (as it is in DLRPN and LRPN). The small size of blood vessels involved may help explain the patchy, widespread asymmetric process rather than discrete mul-tiple mononeuropathies more typical of large-nerve vessel necro-tizing vasculitis. It is unclear why the lumbosacral roots, plexus, and nerves are particularly susceptible in LRPN and DLRPN, but as noted above, it is common to get co-existing truncal radicu-lopathies (DTRN, TRN) and upper limb neuropathies (DCRPN, CRPN) in these patients. Furthermore, EMG changes tend to be more diffuse than clinical involvement would suggest.

One of the most compelling arguments that DLRPN is not due to metabolic derangement from hyperglycemia is the similarity between the clinical course and pathology of DLRPN and LRPN. As LRPN patients are not diabetic, it is difficult to implicate hyperglycemia and metabolic derangement as the cause of their neuropathy. Consequently, chronic hyperglycemia also probably does not play the major role in the pathogenetics of DLRPN. One could ask whether patients with LRPN really have undetected mild diabetes mellitus. This seems unlikely as only 2 of 42 LRPN patients eventually developed diabetes mellitus.15 It is possible that they have mild glucose impairment, but this has not been definitely demonstrated, although others have found abnormal glucose tolerance tests in some LRPN patients.20 It is believed that hyperglycemia probably is a risk factor for developing DLRPN, if not the direct cause. The frequency of DLRPN is about 1% among diabetic patients,9 whereas the frequency of LRPN among the general population is not known. Nonetheless, most investigators believe that lumbosacral radiculoplexus neuropathies occur more commonly among diabetic patients. Consequently, the diabetic state (hyperglycemia) probably plays a role in the disease process, even if it is not the direct cause of the condition.

IMMUNOTHERAPY

Little is known about the treatment of LRPN. Bradley and col-leagues5 reported that four of their six patients had improvement with prednisone. Awerbuch’s group2 reported that their patients treated with prednisone did not have improvement. Verma and Bradley30 reported two patients who responded to high-dose in-travenous immunoglobulin (IVIg), and Triggs and colleagues29 reported that five patients had improvement with IVIg.


Figure 1Transverseparaffinsectionsofsuralnervesshowingtypicalchanges seen in diabetic and nondiabetic lumbosacral radiculoplexusneuropathies. The upper frame (Masson’s trichrome stain) showsinflammation in the wall of an epineurial microvessel (right upper),probably fibrinoiddegenerationof theperineurium (longarrow), andaregionofneovascularization(arrowhead).Themiddleframe(Luxolfastblue-periodic acid Schiff stain) shows several fascicles surrounded bynormal thickness perineurium (right middle, between two arrowheads)andonefasciclewithextremelythickperineurium(leftmiddle,betweentwo arrowheads). The latter is attributed to scarring and repair afterischemic injury(noteall fasciclesaredevoidofmyelinatedfibers).Thelower frame (Turnbull blue stain) shows accumulation of hemosiderin(iron stains bright blue, arrow) deposited along the inner aspects ofthe perineurium. All of these pathologic features are frequently seentogether and are best explained by ischemic injury. (Dyck PJB andcolleagues. Microvasculitis in nondiabetic lumbosacral radiculoplexus[LSRPN]: Similarity to the diabetic variety. J Neuropathol Exp Neurol�000;59:5�5-53�.Reprintedwithpermission.)

C-�0 NondiabeticLumbosacralRadiculoplexusNeuropathy AANEMCourse

Figure 2 Paraffin sections of sural nerve from patients with nondiabetic lumbosacral radiculoplexus neuropathy(LRPN) (upper three panels) anddiabetic lumbosacral radiculoplexus neuropathy (DLRPN) (lower panel) reacted for anti-human smooth muscle actin (Dako) and counter-stained withhematoxylinandeosinshowingmicrovasculitisoffournervevessels(rightcolumn)andanunaffectedlevelofthesamevesselproximalordistaltothelesion(leftcolumn).Comparedwiththerelativelyunaffectedregionsofthesamemicrovessels(left),intheregionsofmicrovasculitis(right)thesmoothmuscle is separated by mononuclear cells, fragmented, displaced outward, and decreased in amount. These changes were interpreted as typical ofmicrovasculitis.Theywereencounteredmostcommonlyintheepineuriumbutwerealsofoundintheendoneuriumandperineurium.NotethesimilarityofthemicrovasculitisintheLRPNnerves(topthree)andtheDLRPNnerve(bottom).Notealsotheadjacentunaffectedvesselsareoftenlargerinsize.(DyckPJBandcolleagues.Microvasculitisinnondiabeticlumbosacralradiculoplexus[LSRPN]:Similaritytothediabeticvariety.JNeuropatholExpNeurol�000;59:5�5-53�.Reprintedwithpermission.)

An open trial of weekly intravenous infusions of methylpredniso-lone in 11 LRPN patients was conducted over 9 to 16 weeks.13 All had marked improvement of pain and many had complete resolu-tion of the pain. All patients had some improvement of weakness, and 9 of the 11 graded this improvement as marked. The median neuropathy impairment score was statistically improved after treat-ment (Figure 3). Before treatment one-half of the patients were in wheelchairs and all but one used an aid in ambulating. After treatment, only one patient was still in a wheelchair and six walked independently. These treatment data are considered preliminary and not definitive. There were no control patients, and LRPN can improve spontaneously. However, it is believed that the treatment

probably was helpful because in all cases the improvement of symp-toms began with the initiation of treatment. Placebo-controlled double-blind prospective studies are needed to answer whether im-munomodulating therapies are effective in treating LRPN.

SYMPTOMATIC TREATMENT

All of the RPNs (including LRPN and DLRPN) are severe illnesses with great morbidity. Because they are usually monophasic and improve with time, physicians may underappreciate the suffering and disability experienced. Patients frequently are so weak and have such severe pain that they are unable to work; they often require hospitalization to achieve adequate pain control. Most patients with an RPN will need narcotic medication at some point in their illness as well as treatment with other chronic neuropathic pain medications (such as tricyclic antidepressants and anti-seizure agents). Patients should be warned that it is often impossible to relieve the pain completely, and the goal is to make the pain toler-able. Because the RPNs begin abruptly and severely, these condi-tions are often misdiagnosed, and many patients get unnecessary operations for suspected disk disease. Patients often worry that the disease will be progressive and fatal, and because of the associated weight loss they (or their physicians) believe they may have a cancer or amyloidosis. Commonly, patients with RPNs become depressed due to protracted pain, weakness, sensory loss, and loss of sleep.

Patients should be advised that although the disease may be self-limited and monophasic, its course tends to be long and recovery is often incomplete. Axonal degeneration is the main pathological process, and although nerves do regenerate, they do so at a very slow rate. Patients who are younger and have predominantly proxi-mal disease have a better prognosis. Depression should be treated with appropriate antidepressant medication and patients should be encouraged to stay involved with hobbies and other interests. Physical therapy should be used and homes should be made as safe as possible. Bracing such as ankle-foot orthoses should be fitted and used if needed. Physicians need to be aggressive in helping patients with pain control and in obtaining health and disability insurance when needed. Patients need to keep the perspective that although the illness may get worse in the short term, nearly all patients with RPN (including LRPN) will improve to some degree, even if in-completely, over time.

SUMMARY

Nondiabetic lumbosacral radiculoplexus neuropathy has re-ceived much less attention than its diabetic counterpart DLRPN. Comparison of large cohorts with DLRPN and LRPN demon-strated that age of onset, course, type and distribution of symptoms and impairments, laboratory findings, and outcomes are similar.

AANEMCourse NewInsightsinLumbosacralPlexopathy C-�1

Figure 3 Neuropathy impairment score (NIS) of 11 patients withnondiabetic lumbosacral radiculoplexus neuropathy plotted with timeafter a course of intravenous methylprednisolone therapy. Each linerepresents a different patient, the dots represent patient evaluations,and the solid lines represent the treatment period. Without exception,theNISimproved(scoredecreased)duringthetreatmentperiod,some-timesdramatically(seetextfordiscussion).(DyckPJBandcolleagues.Methylprednisolonemay improve lumbosacral radiculoplexusneuropa-thy.CanJNeurolSci,�001;��:��4-��7.Reprintedwithpermission.)

Both conditions are lumbosacral radiculoplexus neuropathies that are associated with weight loss and begin focally with pain, but that evolve into widespread, bilateral paralytic disorders. Although both are monophasic illnesses, patients have prolonged morbidity from pain and weakness, and many patients become wheelchair-depen-dent. Although motor predominant, there is unequivocal evidence that autonomic and sensory nerves are also involved. Cutaneous nerves from patients with LRPN and DLRPN show pathologi-cal evidence of ischemic injury and microvasculitis. Controlled trials with immune-modulating therapies in DLRPN have been completed, and there is preliminary data that such therapy may be beneficial in LRPN. It is likely that DLRPN or LRPN are immune-mediated neuropathies that should be separated from chronic inflammatory demyelinating polyneuropathy and from systemic necrotizing vasculitis.

REFERENCES

1. Auche MB. Des alterations des nerfs peripheriques. Arch Med Exp Anat Pathol 1890;2:635-676.

2. Awerbuch GI, Nigro MA, Sandyk R, Levin JR. Relapsing lumbosa-cral plexus neuropathy. Eur Neurol 1991;31:348-351.

3. Barohn RJ, Sahenk Z, Warmolts JR, Mendell JR. The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol 1991;48:1130-1135.

4. Bastron JA, Thomas JE. Diabetic polyradiculopathy: clinical and elec-tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725-732.

5. Bradley WG, Chad D, Verghese JP, Liu HC, Good P, Gabbai AA, Adelman LS. Painful lumbosacral plexopathy with elevated eryth-rocyte sedimentation rate: a treatable inflammatory syndrome. Ann Neurol 1984;15:457-464.

6. Bruns L. Ueber neuritsche Lahmungen beim diabetes mellitus. Berlin Klin Wochenschr 1890;27:509.

7. Chokroverty S. Proximal nerve dysfunction in diabetic proximal amyotrophy. Electrophysiology and electromicroscopy. Arch Neurol 1982;39:403-407.

8. Chokroverty S, Reyes MG, Rubino FA, Tonaki H. The syndrome of diabetic amyotrophy. Ann Neurol 1977;2:181-199.

9. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neu-ropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993;43:817-824.

10. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O’Brien PC, Grina LA, et al. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol 1980;8:590-596.

11. Dyck PJB. Radiculoplexus neuropathies: diabetic and nondiabetic varieties. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy, 4th edition. Philadelphia: Elsevier; 2005. p 1993-2015.

12. Dyck PJB, Engelstad J, Norell J, Dyck PJ. Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similar-ity to the diabetic variety (DLSRPN). J Neuropath Exp Neurol 2000;59:525-538.

13. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lum-bosacral radiculoplexus neuropathy. Can J Neurol Sci 2001;28:224-227.

14. Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113-2121.

15. Dyck PJB, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculo-plexus neuropathy: natural history, outcome, and comparison with the diabetic variety. Brain 2001;124:1197-1207.

16. Dyck PJB, Windebank AJ. Diabetic and non-diabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2002;25:477-491.

17. Evans BA, Stevens JC, Dyck PJ. Lumbosacral plexus neuropathy. Neurology 1981;31:1327-1330.

18. Garland H. Diabetic amyotrophy. Br Med J 1955;2:1287-1296.19. Garland H. Diabetic amyotrophy. Br J Clin Pract 1961;15:9-13.20. Kelkar P, Hammer-White S. Impaired glucose tolerance in non-

diabetic lumbosacral radiculoplexus neuropathy. Muscle Nerve 2005;31:273-274.

21. Kelkar PM, Masood M, Parry GJ. Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 2000;55:83-88.


23. Raff MC, Asbury AK. Ischemic mononeuropathy and mononeurop-athy multiplex in diabetes mellitus. N Engl J Med 1968;279:17-22.

24. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy mul-tiplex associated with diabetes mellitus. Arch Neurol 1968;18:487-499.


26. Said G, Lacroix C, Lozeron P, Ropert A, Plante V, Adams D. Inflammatory vasculopathy in multifocal diabetic neuropathy. Brain 2003;126:376-385.

27. Sander JE, Sharp FR. Lumbosacral plexus neuritis. Neurology 1981;31:470-473.

28. Subramony SH, Wilbourn AJ. Diabetic proximal neuropathy: clinical and electromyographic studies. J Neurol Sci 1982;53:293-304.

29. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idio-pathic lumbosacral plexopathy with intravenous immunoglobulin. Muscle Nerve 1997;20:244-246.

30. Verma A, Bradley WG. High-dose intravenous immunoglobulin therapy in chronic progressive lumbosacral plexopathy. Neurology 1994;44:248-250.

C-�� NondiabeticLumbosacralRadiculoplexusNeuropathy AANEMCourse

INTRODUCTION

The clinical course and the natural history of diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) suggest that pain, weakness, and the resultant difficulty with ambulation are the major sources of morbidity. The disease evolves over months or years and recovery is slow and incomplete.2,3,18

Various treatment strategies for DLSRPN have been explored and the approach to treatment has varied with time based on the prevail-ing concepts regarding the pathogenetic mechanisms. Originally, DLSRPN was thought to be related to metabolic derangement in diabetic patients.6 Treatment consisted of improving glycemic control by more aggressive treatment of the diabetes. Response to treatment was variable with reports of marked improvement in some patients and significant residual disability in others.5

The overwhelming pathological evidence from various studies over the last decade indicates that an immune-mediated vasculopathy is the most likely mechanism underlying DLSRPN.7,14,17,19 It was therefore intuitive that immunosuppressive treatments would be effective in treatment. This was first suggested in a study by Bradley and colleagues of six patients with painful lumbosacral plexopathy.4 Three of the six patients had diabetes, but all had elevated eryth-rocyte sedimentation rate (ESR) and mononuclear infiltration of epineurial arterioles. The three diabetic patients worsened despite control of their diabetes, which supports the current notion that DLSRPN is likely not related to impaired metabolism and the

resultant microangiopathy of diabetes. Three patients were treated with prednisone and two patients with prednisone and cyclophos-phamide; four patients had improvement in pain, two patients had improvement in weakness, and in two patients weakness stabilized without worsening. Interestingly, in the three diabetic patients, there was significant improvement despite marked worsening of diabetic control.

In another study by Krendel and colleagues, 13 patients with DLSRPN were treated with prednisone or intravenous immuno-globulin (IVIg) either alone or in conjunction with azathioprine or cyclophosphamide.16 All symptoms stopped worsening and there was improvement in strength, which lead to improvement in the performance of daily living activities in the majority of the patients. The interval between the onset of the disease and the institution of treatment was not mentioned. Pascoe and colleagues18 reported im-provement in 9 of 12 patients with diabetes and proximal leg weak-ness. It is unclear whether these patients had DLSRPN because patients with significant demyelination were also included in the study. Two patients had conduction block and four had temporal dispersion on needle electromyography (EMG), and patients with unilateral weakness were excluded. It is possible that some of these patients may have had DLSRPN, but the clinical syndrome was not characteristic of DLSRPN in all patients. These studies would seem to suggest that immunosuppression is efficacious in the treatment of DLRPN. However, when another study by Said and colleagues reported four patients with DLSRPN who underwent a biopsy of the intermediate cutaneous nerve of the thigh and reported resolu-

Treatment Strategies in Lumbosacral Plexopathy

Suraj A. Muley, MDAssistantProfessor

DepartmentofNeurologyUniversityofMinnesotaMedicalCenter

Minneapolis,Minnesota

C-�3

tion of pain within 1 week of the nerve biopsy procedure without any other form of treatment, doubt was cast.20 It is unclear whether the weakness also improved. Moreover, inflammatory nerve lesions were found suggesting that spontaneous improvement was possible despite an immune-mediated pathophysiology in this condition.

The overall conclusion that can be drawn from these studies is that an immune-mediated vasculopathy with secondary nerve infarction is the pathological basis of DLSRPN and that it is possible that im-munosuppressive treatments in the form of prednisone or IVIg may alter the natural course of the disease.

In order to further study the issue of immunosuppressive treat-ments, Dyck and colleagues conducted a randomized double-blind multi-center study investigating the role of intravenous methyl-prednisolone in the treatment of DLSRPN.9 A significant differ-ence in the primary outcome measure (neuropathy impairment score of the lower limb) was not found, suggesting a lack of efficacy. Even so, there was improvement in pain and positive neuropathy symptoms in the treatment group, indicating some beneficial effects of treatment. Lack of efficacy may have been from delay in institution of treatment.

In a retrospective study conducted by this author’s group,5 10 epi-sodes in 9 patients with DLSRPN were treated with oral or intra-venous pulsed methylprednisolone 500 mg for 2 days every 2 weeks for up to 3 months depending on response to treatment. Treatment was instituted from 1 week to 5 months from symptom onset. There was dramatic improvement in pain in 6 of 8 episodes treated within 3 months of symptom onset. In patients treated at 4 and 5 months, there was delayed improvement which was probably con-sistent with the natural history of the disease. When treatment was instituted within 3 months of onset, moderate to severe weakness either resolved or improved markedly after 3 months of treatment in 7 of 9 episodes (78%). In conclusion, treatment started within 3 months of disease onset improves pain and weakness sooner and perhaps more than the natural history of the disease. In an addi-tional three patients treated at this author’s center, treatment with oral methylprednisolone within 3 months of symptom onset lead to dramatic improvement in pain and significant improvement in weakness that was clearly greater than the natural history described in the literature. The delay in the institution of treatment in the multicenter study was probably the reason why treatment was inef-fective and does not rule out the possibility of efficacy with early treatment.

In conclusion, although no controlled data exist that demonstrate treatment efficacy, this author’s experience and that of other inves-tigators (along with the fact that microvasculitis is commonly seen in nerve biopsies of DLSRPN patients), suggest that immunosup-pressive treatments may be a reasonable approach in the manage-ment of these conditions especially if instituted within 3 months of

symptom onset. Further controlled studies with early treatment are needed to establish this with certainty.

NONDIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Lumbosacral radiculoplexus neuropathy (LRPN) can also occur in patients without diabetes and is similar to DLSRPN in its presenta-tion, clinical course, prognosis and pathogenetic mechanisms.8

Lumbosacral radiculoplexus neuropathy was described relatively recently by Evans and Said13,21 as a painful asymmetric weakness and atrophy affecting proximal leg muscles, essentially identical to DLSRPN. As in the DLSRPN, long-term morbidity can be severe. A study by Dyck and colleagues reported that 3 of 42 patients had complete recovery at 3 years.12 The histopathology is also similar to DLSRPN with epineurial perivascular inflammation in all nerves biopsied and features suggestive of microvasculitis in half the nerves, as reported by Dyck and colleagues.10

It is therefore likely that treatment responses to immunosuppres-sion would be similar in both DLSRPN and LRPN. There are no controlled studies investigating efficacy of immunosuppressive treatments in LRPN, but observational studies suggest a benefit from immunosuppression.

In a study by Bradley and colleagues, treatment with prednisone lead to improvement in four of six patients with lumbosacral plexopathy three of whom were diabetic.4 In a study by Awebuch and colleagues, one patient treated with prednisone had no re-sponse to treatment.1 Time interval between onset of symptoms and treatment was not mentioned in either of these studies. High dose IVIg (0.8 g/kg/day for 5 days) lead to marked improvement in a patient with progressive lumbosacral plexopathy who did not respond to the regular dose of IVIg (0.4 g/kg/day for 5 days) or to prednisone or plasmapheresis.23 In another study by Triggs and colleagues, 4 patients treated with regular dose IVIg (0.4 g/kg/day for 5 days) and 1 patient with high-dose IVIg (0.8 g/kg/day for 3 days) at a mean of 3.8 months from onset had significant improve-ment in pain and weakness, suggesting treatment efficacy.22 Lastly, 10 patients treated with intravenous methylprednisolone and 1 patient treated with prednisone at a comparable dose had improve-ment in pain, weakness, and ability to ambulate, again suggesting efficacy. Treatment was instituted at a median of 5 months from onset (range 1-48 months).11

SUMMARY

The overall conclusion that can be drawn from these observational studies, supported by the fact that an immune-mediated vasculopa-

C-�4 TreatmentStrategiesinLumbosacralPlexopathy AANEMCourse

thy is the underlying pathogenetic mechanism, is that immunosup-pressive treatments such as IVIg or steroids may be efficacious in the treatment of LRPN. Controlled studies are necessary to estab-lish this with certainty.

REFERENCES

1. Awerbuch GI, Nigro MA, Sandyk R, Levin JR. Relapsing lumbosa-cral plexus neuropathy. Report of two cases. Eur Neuol 1991;31:348-351.

2. Barohn RJ, Sahenk Z, Warmolts JR and Mendell JR. The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later. Arch Neurol 1991;48:1130-1135.

3. Bastron JA, Thomas JE. Diabetic polyradiculopathy. Clinical and elec-tromyographic findings in 105 patients. Mayo Clin Proc 1981;56:725-732.

4. Bradley WG, Chad D, Verghese JP, Liu H, Good P, Gabbai AA, Adelman LS. Painful lumbosacral plexopathy with elevated eryth-rocyte sedimentation rate: a treatable inflammatory syndrome. Ann Neurol 1984;15:457-464.

5. Casey EB, Harrison MJ. Diabetic amyotrophy: a follow-up study. Br Med J 1972;1:656-659.

6. Chokroverty S, Reyes MG, Rubino FA, Tonaki H. The syndrome of diabetic amyotrophy. Ann Neurol 1977;2:181-194.

7. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113-2121.

8. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2002;71:477-491.

9. Dyck PJ, O’Brien P, Bosch PE, Grant I, Burns T, Windebank A, Klein C, Haubenschild J, Peterson D, Norell J, Capelle S, Lodermeier K, Dyck P. S27.005. AAN Abstract 2006.

10. Dyck PJB, Engelstad J, Norell J, Dyck PJ. Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similar-ity to the diabetic variety (DLSRPN). J Neuropathol Exp Neurol 2000;59:525-538.

11. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lum-bosacral radiculoplexus neuropathy. Can J Neurol Sci 2001;28:224-227.

12. Dyck PJB, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculo-plexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain 2001;124:1197-1207.

13. Evans BA, Stevens JC, Dyck PJ. Lumbosacral plexus neuropathy. Neurology 1981;31:1327-1330.

14. Kelkar P, Masood M, Parry GJ. Distinctive pathological findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology 2000;55:83-88.

15. Kilfoyle D, Kelkar P, Parry GJ. Pulsed methylprednisolone is a safe and effective treatment for diabetic amyotrophy. J Clin Neuromus Dis 2003;4:168-170.

16. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995;52:1053-1061.


18. Pascoe MK, Low PA, Windebank AJ, Litchy WJ. Subacute diabetic proximal neuropathy. Mayo Clin Proc 1997;72:1123-1132.


20. Said G, Elgrably F, Lacroix C, Plante V, Talamon C, Adams D, Tager M, Slama G. Painful proximal diabetic neuropathy: inflammatory nerve lesions and spontaneous favorable outcome. Ann Neurol 1997;41:762-770.

21. Sander JE, Sharp FR. Lumbosacral plexus neuritis. Neurology 1981;31:470-473.

22. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idio-pathic lumbosacral plexopathy with intravenous immunoglobulin. Muscle Nerve 1997;20:244-246.

23. Verma A, Bradley WG. High-dose intravenous immunoglobulin therapy in chronic progressive lumbosacral plexopathy. Neurology 1994;44:248-250.


C-�� AANEMCourse

INTRODUCTION

Metastasis to the brachial or lumbosacral plexus is generally a late stage complication of cancer. Patients often have concomitant, active systemic disease. The most commonly involved plexuses are the cervical, brachial, and lumbosacral plexus; the latter two are most frequently encountered in clinical practice.

Table 1 lists common tumors associated with neoplastic plexopathy. The frequency of neoplastic brachial plexopathy is 0.43% in cancer patients; lumbosacral plexopathy occurs in approximately 0.71% of patients.16,21 The frequency is probably higher in breast carcinoma patients with 1.8%-4.9% of patients developing symptomatic plexopathy by 5 years following treatment.27,28,32

NEOPLASTIC PLEXOPATHY: CLINICAL SYNDROMES

Cervical Plexopathy

The cervical plexus is usually invaded by tumor from the neigh-boring tissues. The cervical plexus is generally involved via direct extension from soft or bony tissues in the case of head and neck tumors, or from regional lymph nodes involved by lymphoma or metastases from distant organs. The most common tumors include squamous cell carcinoma of the head and neck, follicular and diffuse non-Hodgkin’s lymphomas, and metastases from adenocar-cinomas of the lung and breast.

Typically, patients develop deep, aching pain located in the lateral or anterior neck, shoulder, or throat. The pain can be exacerbated by cough, neck movement, and swallowing. Occasionally the neck musculature may be tender. Neck pain from other causes is common, therefore the diagnosis may be delayed until the pain becomes severe and unrelenting and provokes further investiga-tion. The diagnosis is supported by the finding of palpable tumors within the region, or in situations where there is a known history of tumor involving the head and neck or cervical chain lymph nodes. Sensory loss is often patchy and a vague tingling or numbness may be present in the anterior neck region or over the upper clavicle and shoulder. Prior surgery, such as radical neck dissections, can make interpretation of sensory symptoms difficult. Head and neck dis-section usually affects superficial branches of the greater auricular nerve or the transverse cervical branches, producing numbness of the upper anterior neck and submandibular area, and there is a temporal relationship to the surgery.

Involvement of the spinal accessory XI cranial nerve may affect the upper trapezius, producing shoulder weakness. There may be phrenic nerve involvement, producing a paralyzed hemidiaphragm with associated shortness of breath, particularly when the patient lies recumbent. Chest radiograph or fluoroscopy with a “sniff ” test can confirm phrenic nerve involvement.

One important point to stress is that involvement of the cervical plexus implies proximity of the neoplasm to the cervical spine. It is important to suspect and rule out impending epidural spinal cord

Lesions of the Lumbosacral Plexus

Kurt A. Jaeckle, MDProfessor

DepartmentsofNeurologyandOncologyMayoClinic

Jacksonville,Florida

C-�7

involvement in this situation. If sharp pain occurs with neck move-ments, then spine percussion tenderness or Horner’s syndrome is present and appropriate neuroimaging procedures (including the cervical spine) are warranted.

Brachial Plexopathy

Lung and breast carcinomas most commonly are associated with neoplastic brachial plexopathy21 (Figure 1). Earlier reports called attention to the frequent involvement of the lower plexus in this disorder, particularly the inferior trunk and medial cord, which is presumably due to extension from the upper lung field or nodes within the supraclavicular space or surrounding the plexus. This syndrome was first clearly described as the superior sulcus or “Pancoast” syndrome,26 which includes a palpable mass in the supraclavicular or axillary area and involvement of the inferior trunk or medial cord producing C8-T1 weakness in the hand and associated electromyographic (EMG) findings. However, more recent publications have called attention to the involvement of the mid- or upper plexus, particularly when head and neck neoplasms or lymphomas grow inferiorly, invading the superior plexus from above. Sometimes the pattern of plexus involvement includes skip or patchy areas, presumably due to irregular and random involve-ment of different areas of the plexus proximally and distally. This is perhaps due to random distribution of metastases to local lymph nodes or soft tissues within the plexus and the axilla.

Pain is the most common presenting symptom (75%) in brachial plexopathy,21 and is usually located in the axilla and shoulder. Radicular pain is typically located along the medial aspect of the arm and forearm, and the fourth and fifth digits. Motor weakness and reflex loss is commonly located (approximately 75%) in the lower plexus distribution, especially C8-T1. Horner’s syndrome occurs in 23% of patients with neoplastic brachial plexopathy, but implies proximity of the tumor to the vertebral column and the T1 level, and the potential of impending epidural involvement by neoplasm. Lymphedema in the involved extremity is relatively infrequent (15%), and is more typical of postsurgical node dissec-

tions or as a late stage complication of radiotherapy to the region of the plexus.

Lumbosacral Plexopathy

Pelvic primary neoplasms, particularly colorectal malignancies, gy-necologic malignancies, lymphoma, and retroperitoneal sarcomas are most frequently associated with neoplastic lumbosacral plexopa-thy (Figure 2).16,30 In patients who ultimately develop neoplastic plexopathy, 15% have plexus involvement at the time of presenta-tion of the malignancy. Tumor can directly invade the plexus, or in-directly invade by tracking along the epineurium.11 This tendency to extend in a linear fashion along nerve trunks without necessarily producing bulky disease, may explain the frequent initial discor-dance between the physical examination and the neuroimaging procedures (Ladha and colleagues, in press).

Relatively distinct clinical syndromes of upper plexus (L1-L4), lumbosacral trunk (L4-L5), and lower plexus (S1-S4) have been described.16 Plexopathy is usually clinically unilateral, but needle EMG suggests a bilateral component in up to 25% of patients. Many of these patients have received radiotherapy to the region, which probably accounts for the bilateral involvement detected only on neurophysiologic evaluation in a portion of these patients.

Lumbosacral plexopathy generally begins with leg pain, but within a month most patients will develop local numbness and weakness. Pain is so typical that its absence suggests an alternative cause of the focal neurologic dysfunction, and too often this turns out to be due to neoplastic meningitis. As with brachial plexopathy, the pain is constant, dull, and aching with superimposed sharp components or cramping in the lower extremity. Pain is often worse when the patient is supine or recumbent, but later in the course patients complain of the pain despite all alterations of their position. On occasion, there is a crescendo pattern whereby the patient develops increasing and severe pain in episodes lasting minutes to several hours, only to remit for unclear reasons for intervening periods of relative comfort. This latter pain syndrome is particularly distress-ing to the patient and when episodes are frequent, patients may express suicidal thoughts. Often this type of pain requires continu-ous administration of systemic opiate analgesics, and it is important that this complication not be undertreated. Irritation of the soft tissues of the paravertebral gutter and proximal iliopsoas muscle may make patients rest with their legs and hips flexed, similar to that seen with meningeal inflammation. Pain is often exascerbated by valsalva, weight bearing, or sitting for prolonged periods.

Weakness and sensory complaints eventually occur develop in most patients (60%). The most common findings on neurologic examination include leg weakness (86%), sensory loss (73%), asymmetrical reflex loss (64%), and edema of the extremity (47%). Patients may have positive straight leg and reverse-straight leg tests, and tenderness or pain induced by pressure in the sciatic notch and buttock or on rectal examination.

C-�� LesionsoftheLumbosacralPlexus AANEMCourse

Table 1 NeoplasticPlexopathyAssociatedCancers* BRACHIAL LUMBOSACRALTumor % Tumor %Lung 37 Colorectal �0Breast 3� Sarcoma 1�Lymphoma � Breast 11Sarcoma 5 Lymphoma 9 Cervix 7Others 1� Others 37

*Korandcolleagues;�0Jaeckleandcolleagues.1�


Figure 1 Brachialplexopathyfromlungadenocarcinoma.Magneticresonanceimaging,T1nonenhancedimage.Mass(arrows)inshoulderofpatientwithdiffuseweaknessinupperarm.

Rectal and cervical carcinomas typically are associated with lower plexus involvement. In this situation, pain typically radiates down the posterior leg, calf or posterior thigh, and is associated with cramping in the calf and often foot dorsiflexor weakness. Dalmau and colleagues have described lateralized sympathetic denervation producing a “hot dry foot.”10

Higher involvement of the lumbar plexus typically produces pain in the anterior thigh and foreleg with weakness of hip flexion. Typically patients will complain that they have to lift the involved extremity onto the bed or out of the car. Numbness is usually in the groin in the distribution of the ilioinguinal and iliohypogastric nerves, or the anterior or lateral femoral cutaneous nerve distribu-tions. A positive reverse-straight leg raising test on the involved side raises suspicion of this level of involvement by stretching the ilio-psoas and its insertion into the lateral processes of the upper lumbar vertebrae, and can be useful (although not specific) for distinguish-ing this complication from neoplastic meningitis, which less com-monly is associated with a positive reverse-straight leg raising test. The lumbosacral trunk syndrome includes foot drop and numbness of the dorsum of the foot, and implies involvement of the plexus anterior to the sacral ala, over which the lumbosacral trunk courses,

between the true and false pelvis. This complication can be dis-tinguished from common peroneal neuropathy (also common in cachetic patients) by associated involvement of the posterior tibial nerve with weakness of medial plantar flexors, which are typically spared in peroneal neuropathy. Incontinence and impotence gener-ally implies bilateral plexus involvement, or associated meningeal or epidural metastases.16

DIAGNOSIS

Neuroimaging Procedures

Neuroimaging of the abdomen and pelvis with either magnetic resonance imaging (MRI) or computed tomography (CT) is ap-propriate in patients with clinical symptoms or signs suggestive of lumbosacral plexopathy. Magnetic resonance imaging has been shown to be more sensitive than CT in the identification of tumor plexopathy.30,34,36 However, CT is necessary in patients where MRI is contraindicated. Computed tomography is a shorter procedure and can facilitate completion of the study in confused or agi-tated patients. Magnetic resonance imaging should be performed

C-30 LesionsoftheLumbosacralPlexus AANEMCourse

Figure 2Metastasestoleftupperlumbarparaspinalregionandiliacusmuscle(arrows)apatientwithcarcinomaofthecervixandleftsidelumbosacralplexopathy.

with and without contrast and include T2-weighted images. Occasionally, linear enhancement along one or more nerve trunks resulting from tumor invasion is present in the absence of a mass. Increased T2 intensity within nerve trunks with or without en-hancement has been identified in patients with neoplastic plexopa-thy.37 Even if the scan does not disclose clear plexus invasion, the presence of a regional tumor recurrence, by clinical examination or imaging, supports the diagnosis of tumor plexopathy. For example, most (95%) of patients with CT evidence of brachial plexus tumor have a palpable axillary mass.24

Positron emission tomography (PET) scans can also detect active neoplasm in the area of the plexus. This procedure is very helpful in screening for plexopathy in a patient with known metastatic disease, although not specific for neoplasm. In one study, 14 of 19 breast carcinoma patients with symptoms of brachial plexopathy had abnormal fluorodeoxyglucose uptake by PET in the area of the plexus.1

Needle Electromyography

Needle EMG can also supplement the neuroimaging studies. The distribution of active denervation often is more extensive than would have been predicted clinically. In addition, bilateral plexus involvement that is not suspected clinically can be identified. It should be remembered, however, that bilateral involvement is more typical of neoplastic meningitis, which should also be con-sidered in these patients. Needle EMG can be helpful in follow-ing the clinical course after treatment, and is somewhat helpful in distinguishing tumor plexopathy from radiation plexopathy. Finally, when planning radiation treatment ports, the distribution of electrophysiologic involvement should be considered in addition to the neuroimaging findings, as occasionally these studies reveal discordant results.

TREATMENT

There is only limited published information regarding neuro-logic outcome following treatment of metastatic plexopathy. Radiotherapy produced subjective improvement of symptoms in 85% of patients with lumbosacral plexopathy and objective improvement in 48%, which was defined as neurologic improve-ment or reduction in measurable tumor. The average duration of response, however, was only 4 months.35 In another study, treat-ment with radiotherapy (>3000 cGy) and systemic chemotherapy (if indicated) produced subjective responses in 35% of patients, and objective responses as well (neurologic improvement - 17%; radio-graphic response - 28%).16 In a study involving patients with bra-chial plexopathy due to tumor, radiotherapy relieved pain in 46% of cases.21 Regional intra-arterial chemotherapy received limited use in earlier studies but was largely ineffective.

Palliation of pain is an important part of management of patients with neoplastic plexopathy. Studies have shown that pain is often poorly controlled in these patients. A multimodality approach is necessary, including appropriate use of opiate analgesics, local and regional blocks, infusion pumps or epidural opiate analgesia, and on occasion sympathetic ganglion blocks, rhizotomy, or other spe-cialized procedures. If the quality of the pain includes a causalgic or dysesthetic component, gabapentin, tricyclic antidepressants, carbamazepine, topirimate, valproic acid, or phenytoin may be helpful. Transcutaneous nerve stimulators may also provide relief when the pain is localized. Occasional relief of chronic pain has been achieved with plexus dissection and neurolysis.33

The relative immobility produced by plexopathy can result in delayed complications, including painful contractures, compres-sive neuropathies, pressure ulcerations, respiratory or urinary tract infections, joint subluxations, and deep venous thromboses. Lymphedema may be treated with compressive devices and eleva-tion. Preventative measures, including adequate pain management, initiation of physical rehabilitation measures, and excellent nursing care may have a significant impact on quality of life.

Other Causes of Plexopathy in the Cancer Patient

Other causes of plexopathy in cancer patients are listed in Table 2. The most frequent differential diagnostic consideration is radia-tion-induced plexopathy. Many patients receive radiotherapy to the area of the plexus in treatment of their primary neoplasm, and later develop plexopathy that can be difficult to distinguish from tumor plexopathy. Both conditions may also be present in the patient. Radiation causes direct toxic effects on axons and delayed effects on the vascular supply to the nerve, with secondary microinfarction.14 This injury appears dose-related, and is generally not observed at doses below 1000 cGy. Histopathologic abnormalities occur in Schwann cells, endoneurial cells, and fibrocytes.8 Experimentally, 3500 cGy produced anterior and posterior nerve root damage in a rodent model.7

Table 2OtherCausesofPlexopathyinCancerPatients

RadiationplexopathyParaneoplasticplexopathy

RetroperitonealhemorrhagePost-infectiousplexopathyToxicityofchemotherapy

EpiduralcordcompressionNeoplasticmeningitis


There are several excellent prior studies describing the clinical features of radiation plexopathy.2,3,5,15,19,21,23,25,27,28,32,35 It should be remembered that many of these studies were based on older radiation techniques, including orthovoltage therapy, and it is pre-sumed that plexopathy was more common with this technique. In the older literature, the overall frequency of radiation plexopathy was approximately 1.8%-4.9%.27,28,32 Radiation plexopathy was diagnosed in 2% of patients with stage III breast cancer at 5 years following treatment with 4500-5000 cGy.32 A 34-year follow-up of 71 breast cancer patients receiving loco-regional radiotherapy at 57 Gy identified clinically relevant brachial plexopathy in 12 (17%).17 Typically, radiation plexopathy has its onset at 3 months to 14 years, with a median of approximately 1.5 years.19,21 One recent review of breast cancer patients treated with supraclavicular lymph node telecobalt irradiation found the median onset of plexopathy at 88 months, and determined that the risk of development of this complication remained linear throughout the remainder of the patient’s life.4 Radiation plexopathy has been reported to begin as long as 20 years following treatment.12 Radiation-induced lumbo-sacral plexopathy most frequently develops between 12 months and 5 years following treatment, with a range from 1 month to 31 years; it is more commonly bilateral in this case than in tumor plexopathy.2,35 This disorder has been reported at doses as low as 1700 cGy. In one review, the use of 2.2-4.58 Gy per fraction, with total doses between 43.5-60 Gy, may be associated with an increased frequency of brachial plexus injury (1.7%-73%). The

risk was less than 1% when dose fractions of 2.2-2.5 Gy were utilized, and total doses received were in the range of 34-40 Gy.13 It is not clear whether radiation damage to the plexus is enhanced by concomitant administration of chemotherapy; however, in one descriptive retrospective analysis, radiation plexopathy was present in 5% of breast cancer patients treated with radiotherapy versus 9% in those receiving radiotherapy and chemotherapy.9

There are clinical features which help distinguish radiation plexop-athy from neoplastic plexopathy, although none are completely specific. Radiation plexopathy often presents with dysesthesias and numbness and often lymphedema, whereas pain is less common (10%) at initial diagnosis.16 In tumor plexopathy, pain is usually present at diagnosis and lymphedema is less common. The most common symptoms in radiation plexopathy are weakness (60%), numbness, and paresthesias (50%).35 Radiation brachial plexopathy has been reported to affect the upper plexus more often (77%); in tumor plexopathy, the lower plexus (75%) is more frequently af-fected.21,23 Other reports describe diffuse involvement of the plexus with radiation plexopathy.6 Radiation plexopathy generally is ac-companied by additional evidence of radiation effects within neigh-boring tissues.27 Often, skin telangectasias, atrophy, and induration of soft tissues may be noted on physical examination. Imaging studies may show fibrotic or other changes in organ parenchyma within the prior treatment port, such as the lung, marrow, and even osteonecrosis of bone in the local field. Edema of the associ-

Figure 3Radiationplexopathy.Edema(arrows)notedinregionofrightbrachialplexusandupperarminthispatientwithhistoryofmetastaticbreastcarcinoma.

C-3� LesionsoftheLumbosacralPlexus AANEMCourse

ated extremity can be seen from lymphatic obstruction (Figure 3). The course of progression is generally slower than with neoplastic plexopathy. In general, evidence of active systemic neoplasm, and in particular, tumor within the region of the involved plexus in-creases the risk of the plexopathy being due to neoplasm.36

Diagnostic studies can also help aid in the distinction. Myokymia can be identified on needle EMG in approximately 60% of patients with a clinical diagnosis of radiation-induced plexopathy, but is less common with tumor plexopathy.31 Neuroimaging can be helpful, with MRI being the preferred technique.24,34 Neoplasm generally produces enhancement of nerve trunks, and there may be hyperin-tensity within involved nerve on T2-weighted images. In radiation plexopathy, enhancement is less common, although patchy increase in T2 signal may be present.30 There has been increasing use of whole body 2-fluorodeoxyglucose PET as a detection method for systemic metastases, and this may be helpful as a companion study to anatomical imaging with MRI or CT, and may be more sensi-tive. In one study of 14 plexopathy patients, 6 had positive PET scans but normal CT imaging.1

Most patients with radiation plexopathy require supportive care, and there is no specific treatment to date which has unequivocally been associated with benefit. There are only a few studies in the literature which describe outcome following treatment. Limited recovery of motor function has been anecdotally observed follow-ing anticoagulants. Hyperbaric oxygen has been used, but no large randomized prospective trials have been reported. A study of 34 patients treated with hyperbaric oxygen for clinically diagnosed radiation plexopathy showed no benefit in motor function, and no evidence of delay in the progression of the plexopathy.29

There are also other causes of plexopathy in cancer patients. Paraneoplastic plexopathy has been described and may partially respond to steroid therapy in some cases.22 Intra-arterial chemo-therapy has also produced plexopathy.18 Of course, patients with cancer may development plexopathy that might otherwise appear in noncancer patients, such as those with a postinfectious or posttraumatic etiology. Hemorrhage into the retroperitoneum or iliopsoas muscle may affect the lumbosacral plexus, and can be observed in association with anticoagulation or thrombocytopenia resulting from chemotherapy, or in association with hematologic malignancies. Since patients with metastatic systemic cancer often have more than one site of nervous system involvement, one must always consider the possibility of concomitant leptomeningeal or epidural metastases, which can have a similar clinical appearance.

SUMMARY

Metastatic (neoplastic) plexopathy is usually a late stage, disabling accompaniment of systemic cancer. Cervical plexopathy is most

commonly associated with head and neck tumors and lymphoma; brachial plexopathy is most common with breast and lung ad-enocarcinomas, and lumbosacral plexopathy generally is associ-ated with colorectal adenocarcinomas, gynecologic malignancies, lymphomas and retroperitoneal sarcomas. Typically, neoplastic plexopathy often presents with unrelenting pain followed by weak-ness and numbness in the distribution of plexus involvement. The distribution and associated findings often allow clinical distinc-tion from peripheral nerve, epidural or meningeal involvement by tumor; however, these conditions do show symptom overlap and may co-exist in the same patient. The main differential diagnostic consideration in previously treated patients is radiation-induced plexopathy. Treatment of metastatic plexopathy is palliative, and often includes a combination of radiotherapy to the tumor mass, appropriate chemotherapy for the tumor type, aggressive pain management, and rehabilitative therapy to prevent complications of immobility resulting from neuromuscular dysfunction.

REFERENCES

1. Ahmad A, Barrington S, Maisey M, Rubens RD. Use of positron emission tomography in evaluation of brachial plexopathy in breast cancer patients. Br J Cancer 1999;79:478-482.

2. Ashenhurst EM, Quartey GR, Starreveld A. Lumbo-sacral radicu-lopathy induced by radiation. Can J Neurol Sci 1977;4:259-263.

3. Bagley FH, Walsh JW, Cady B, Salzman FA, Oberfield RA, Pazianos AG. Carcinomatous versus radiation-induced brachial plexus neu-ropathy in breast cancer. Cancer 1978;41:2154-2157.

4. Bajrovic A, Rades D, Fehlauer F, Tribius S, Hoeller U, Rudat V, et al. Is there a life-long risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients? Radiother Oncol 2004;71:297-301.

5. Basso-Ricci S, della Costa C, Viganotti G, Ventafridda V, Zanolla R. Report on 42 cases of postirradiation lesions of the brachial plexus and their treatment. Tumori 1980,66:117-122.

6. Boyaciyan A, Oge AE, Yazici J, Aslay I, Baslo A. Electrophysiological findings in patients who received radiation therapy over the bra-chial plexus: a magnetic stimulation study. Electroencephalogr Clin Neurophysiol 1996;101:483-490.

7. Bradley WG, Fewings JD, Cumming WJ, Harrison RM. Delayed my-eloradiculopathy produced by spinal X-irradiation in the rat. J Neurol Sci 1977;31:63-82.

8. Cavanaugh JB. Prior x-irradiation and the cellular response to nerve crush: duration of effect. Exp Neurol 1968;22:253-258.

9. Dale E, Olsen DR. Regarding, Ting, IJROBP 38:1105-1111. Int J Radiat Oncol Biol Phys 1998;40:1010-1011.

10. Dalmau J, Graus F, Marco M. “Hot and dry foot” as initial manifesta-tion of neoplastic lumbosacral plexopathy. Neurology 1989;39:871-872.

11. Ebner I, Anderl H, Mikuz G, Frommhold H. Plexus neuropathy: tumor infiltration or radiation damage. Rofo 1990,152:662-666.

12. Fathers E, Thrush D, Huson SM, Norman A. Radiation-induced brachial plexopathy in women treated for carcinoma of the breast. Clin Rehabil 2002;16:160-165.


13. Galecki J, Hicer-Grzenkowicz J, Grudzien-Kowalska M, Michalska T, Zalucki W. Radiation-induced brachial plexopathy and hypofraction-ated regimens in adjuvant irradiation of patients with breast cancer--a review. Acta Oncol 2006;45:280-284.

14. Greenfield MM, Stark GM. Post-irradiation neuropathy. AJR Am J Roentgenol 1948;60:617-622.

15. Harper CM, Thomas JE, Cascino TL, Litchy WJ. Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology 1989;39:502-506.

16. Jaeckle KA, Young DF, Foley KM. The natural history of lumbosa-cral plexopathy in cancer. Neurology 1985;35:8-15.

17. Johansson S, Svensson H, Larsson LG, Denekamp J. Brachial plexopathy after postoperative radiotherapy of breast cancer pa-tients--a long-term follow-up. Acta Oncol 2000;39:373-382.

18. Kahn CE Jr, Messersmith RN, Samuels BL. Brachial plexopathy as a complication of intraarterial cisplatin chemotherapy. Cardiovasc Intervent Radiol 1989;12:47-49.

19. Killer HE, Hess K. Natural history of radiation-induced brachial plexopathy compared with surgically treated patients. J Neurol 1990;237:247-250.

20. Kori SH. Diagnosis and management of brachial plexus lesions in cancer patients. Oncology (Williston Park) 1995;9:756-760.

21. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology 1981;31:45-50.

22. LaChance VH, O’Neill BP, Harper CM Jr, Banks PM, Cascino TL. Paraneoplastic brachial plexopathy in a patient with Hodgkin’s disease. Mayo Clin Proc 1991;66:97-101.

23. Mondrup K, Olsen NK, Pfeiffer P, et al. Clinical and electrodiagnos-tic findings in breast cancer patients with radiation-induced brachial plexus neuropathy. Acta Neurol Scand. 1990, 81:153-8.

24. Moskovic E, Curtis S, A’Hern RP, Harmer CL, Parsons C. The role of diagnostic CT scanning of the brachial plexus and axilla in the follow-up of patients with breast cancer. Clin Oncol (R Coll Radiol) 1992;4:74-77.

25. Olsen NK, Pfeiffer P, Mondrup PK, Rose C. Radiation-induced brachial plexus neuropathy in breast cancer patients. Acta Oncol 1990;29:885-90.

26. Pancoast HK. Superior pulmonary sulcus tumor. J Am Med Assoc 1932;99:1391-1396.

27. Pierce SM, Recht A, Lingos TI, Abner A, Vicini F, Silver B, Herzog A, Harris JR. Long-term radiation complications following conser-vative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915-923.

28. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 1990;18:213-220.

29. Pritchard J, Anand P, Broome J, Davis C, Gothard L, Hall E, Maher J, McKinna F, Millington J, Misra VP, Pitkin A, Yarnold JR. Double-blind randomized phase II study of hyperbaric oxygen in patients with radiation-induced brachial plexopathy. Radiother Oncol 2001;58:279-286.

30. Qayyum A, MacVicar AD, Padhani AR, Revell P, Husband JE. Symptomatic brachial plexopathy following treatment for breast cancer: utility of MR imaging with surface-coil techniques. Radiology 2000;214:837-842.

31. Roth G, Magistris MR, Le Fort D, Desjacques P, Della Santa D. [Post-radiation branchial plexopathy. Persistent conduction block. Myokymic discharges and cramps.] Rev Neurol (Paris) 1988;144:173-180.

32. Sheldon T, Hayes DF, Cady B, Parker L, Osteen R, Silver B, Recht A, Come S, Henderson IC, Harris JR. Primary radiation therapy for locally advanced breast cancer. Cancer 1987;60:1219-1225.

33. Sundaresan N, DiGiacinto GV. Antitumor and antinociceptive ap-proaches to control cancer pain. Med Clin North Am 1987;71:329-348.

34. Taylor BV, Kimmel DW, Krecke KN, Cascino TL. Magnetic reso-nance imaging in cancer-related lumbosacral plexopathy. Mayo Clin Proc 1997;72:823-829.

35. Thomas JE, Cascino TL, Earle JD. Differential diagnosis between radiation and tumor plexopathy of the pelvis. Neurology 1985;35:1-7.

36. Thyagarajan D, Cascino T, Harms G. Magnetic resonance imaging in brachial plexopathy of cancer. Neurology 1995;45:421-427.

37. Wouter van Es H, Engelen AM, Witkamp TD, Ramos LM, Feldberg MA. Radiation-induced brachial plexopathy: MR imaging. Skeletal Radiol 1997;26:284-288.

C-34 LesionsoftheLumbosacralPlexus AANEMCourse

1. The lumbosacral trunk contains nerve fibers that can best be described as primarily:A. Peroneal. B. Tibial.C. Femoral.D. L5.E. S1.

2. The typical findings on nerve conduction study (NCS) in a patient with a common peroneal neuropathy are identical to those in which of the following conditions?A. Lumbosacral trunk lesion.B. L5 radiculopathy.C. S1 radiculopathy.D. Sacral plexopathy.E. Lumbar plexopathy.

3. The electrodiagnostic examination cannot easily distinguish which of the following pairs of diagnoses?A. Sacral plexopathy and tibial neuropathy.B. Sacral plexopathy and sciatic neuropathy.C. Sacral plexopathy and S1 radiculopathy.D. Lumbar plexopathy and L3 radiculopathy.E. Lumbar plexopathy and lumbosacral trunk lesion.

4. Sacral plexopathy can be distinguished from sciatic neuropathy when which of the following muscles demonstrates fibrillation potentials?A. Biceps femoris short head. B. Biceps femoris long head.C. Tensor fascia lata.D. Semitendinosus.E. Semimembranosus.


CME SELF-ASSESSMENT TEST

Select the ONE best answer for each question.

AANEMCourse C-35

Fill

in an

swer

s here Last 4 digits of

your phone number

1 2 3 4

Instructions for filling out your parSCORE sheet

Ontheright-handsideoftheparSCOREsheet, you will need to fill in the following:

Under ID number, please write out and fill inthelast4digitsofyourphonenumber.Be sure to start in the first box on the left (asshown).

Under Test Form, please fill in “A”.

Leavethecompletedformatthetableoutsideyoursession.

5. One reliable method for obtaining the saphenous sensory response uses recording electrodes in which of the following locations:A. Over the medial mid-thigh.B. Anterior to the medial malleolus.C. Anterior to the lateral malleolus.D. Over the mid-anterior thigh.E. Over the lateral thigh.

6. The underlying pathology in lumbosacral radiculoplexus (LRPN) is:A. The result of chronic hyperglycemia.B. The result of ischemic injury from microvasculitis.C. The result of ischemic injury caused by damaged endo-

neurial vessels from chronic hyperglycemia.D. The result of compressive injury.E. None of the above.

7. LRPN and diabetic lumbosacral radiculoplexus neuropathy (DLRPN) are alike in the following ways:A. Both usually begin with pain.B. Weakness usually follows pain but becomes the primary

problem in both.C. Sensory symptoms and findings are common in both.D. Both syndromes begin focally but become more wide

spread.E. All of the above.

8. In LRPN, the anatomical site exclusively involved by the pathological process is:A. The lumbosacral roots.B. The lumbosacral plexus.C. The proximal lower extremity nerves.D. The distal lower extremity nerves.E. All of the above.

9. In LRPN, there are occasionally associated upper limb neu-ropathies and thoracic radiculopathies:A. True.B. False.

10. Immunosuppressant medications and steroids have been shown in controlled trials to be effective treatment in LRPN:A. True.B. False.

11. Immunosuppressive treatments should be considered in the treatment of diabetic and nondiabetic lumbosacral radiculo-plexus neuropathy because pathogenesis is related to:A. Diabetic microangiopathy.B. Microvasculitis.C. Nerve infarction.D. Metabolic abnormalities.E. Inflammation.

12. It is important to treat diabetic and nondiabetic lumbosacral plexopathies because:A. Pain can be disabling.B. Weakness can be severe and lead to difficulty with ambu-

lation.C. Progressive phase of the disease may be prolonged.D. Treatment may be effective.E. All of the above.

13. Treatment of diabetic lumbosacral plexopathy with which agents has been shown to be useful in anecdotal reports:A. Steroids (prednisone or methyl-prednisolone) and intra-

venous immunoglobulin (IVIg).B. Plasma exchange and IVIg.C. Steroids and plasma exchange.D. Steroids and interferons.E. IVIg and interferons.

14. A recent randomized, double-blind, multicenter study investi-gating the effect of intravenous methylprednisolone in treating diabetic lumbosacral plexopathy demonstrated:A. Improvement in neuropathy impairment scores in the

lower limbs.B. Improvement in pain and positive neuropathy symp-

toms.C. Improvement in weakness and disability.D. Lack of efficacy in regards to pain, positive neuropathy

symptoms and neuropathy impairment scores.E. Worsening of neuropathy related to treatment.

15. Lack of improvement in neuropathy impairement scores with methylprednisolone in treating diabetic lumbosacral plexopa-thy, seen in the controlled trial may be related to:A. Inadequate dose of methylprednisolone.B. Shorter duration of treatment.C. Worsening of diabetes with steroid use. D. Delay in the institution of treatment.E. Lack of aggressive treatment of diabetes.

16. Generally, brachial plexopathy due to tumor invasion occurs in the setting of:A. Widespread metastases.B. Localized disease.C. Disease in remission.D. Known brain metastases.E. None of the above.

17. If a patient with brachial plexopathy due to cancer also has an ipsilateral Horner’s syndrome, the most important and likely associated condition that one must exclude is/are:A. Brain metastasis.B. Leptomeningeal metastases.C. Paravertebral tumor with epidural extension.D. Use of opiate analgesics.E. None of the above.

C-3� CMESelf-AssessmentTest AANEMCourse

18. Lumbosacral plexopathy due to tumor most typically presents with:A. Weakness in the leg.B. Numbness in the leg.C. Pain.D. Incontinence.E. All of the above.

19. Radiation plexopathy, as compared with tumor plexopathy, can be implicated by the needle electromyographic finding of:A. Sharp waves.B. Brief short amplitude multiphasic potentials.D. Myokymia.D. Myotonic discharges.E. None of the above.

20. In a cancer patient who has undergone prior radiotherapy and has no obvious mass lesion on imaging in the area of the plexus, one of the features on magnetic resonance imaging which is of relative help in the distinction of plexus invasion by tumor from radiation plexopathy is the presence of:A. Epidural metastases.B. Vertebral invasion.C. T2 hyperintensities in the trunks of the plexus.D. Enhancement in the trunks of the plexus.E. None of the above.

AANEMCourse CMESelf-AssessmentTest C-37

C-3� AANEMCourse

21. How would you rate the quality of instruction received during Dr. Levin’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

22. Select any item(s), that, if changed, would have appreciably improved Dr. Levin’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-

tion.D. Amount of scientific content in the presentation.E. Other: please explain on the comment form at the back of

this handout.

23. Did you perceive any commercial bias in Dr. Levin’s presenta-tion?A. Yes.B. No.

24. How would you rate the quality of instruction received during Dr. Said’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

25. Select any item(s), that, if changed, would have appreciably improved Dr. Said’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-

tion.D. Amount of scientific content in the presentation.E. Other: please explain on the comment page at the back of

this handout.

26. Did you perceive any commercial bias in Dr. Said’s presenta-tion?A. Yes.B. No.

27. How would you rate the quality of instruction received during Dr. Dyck’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

28. Select any item(s), that, if changed, would have appreciably improved Dr. Dyck’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

29. Did you perceive any commercial bias in Dr. Dyck’s presenta-tion?A. Yes.B. No.

30. How would you rate the quality of instruction received during Dr. Muley’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

C-39


EVALUATION

Select ANY of the answers that indicate your opinions.

Your input is needed to critique our courses and to ensure that we use the best faculty instructors and provide the best course options in future years. Make additional comments or list suggested topics or faculty for future courses on the comment form provided at the end of this handout.

31. Select any item(s), that, if changed, would have appreciably improved Dr. Muley’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

32. Did you perceive any commercial bias in Dr. Muley’s presenta-tion?A. Yes.B. No.

33. How would you rate the quality of instruction received during Dr. Jaeckle’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

34. Select any item(s), that, if changed, would have appreciably improved Dr. Jaeckle’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

35. Did you perceive any commercial bias in Dr. Jaeckle’s presenta-tion?A. Yes.B. No.

36. As a result of your attendance at this educational session, did you learn anything that will improve the care of your pa-tients?A. Yes, substantially.B. Yes, somewhat.C. Not sure.D. Probably not.E. This session was not applicable to my patients.

37. Do you feel that the information presented in this session was based on the best evidence available?A. Yes.B. No: please explain on the comment page at the back of

this handout.

38. Select ALL items where improvement was needed.A. The accuracy of advance descriptions of this course.B. The specific topics selected for presentation.C. The number of speakers in this course.D. The amount of time allotted for discussion in this

course.E. Other: please add other areas and outline specific rec-

ommendations for areas needing improvement on the comment page at the back of this handout.

39. I plan to attend the 2007 AANEM Annual Meeting in Phoenix, AZ October 17-20.A. Yes, definitely.B. No, definitely.C. Will wait to see the program content.D. Will wait to see if budget allows my attendance.

40. We would like the AANEM Annual Meeting to be one of your “must attend” meetings each year. In order to do this, we would have to do what to make it happen? Please explain on the comment page at the back of this handout.

41. If you are a member of the AANEM, what would you rate as the most valuable benefit of your membership?A. My subscription to the journal Muscle & Nerve.B. Receiving free educational materials such as the Muscle &

Nerve Invited Reviews and the AANEM Resource CD.C. The availability of CME opportunities.D Member discounts on AANEM CME products and ser-

vices.E. AANEM’s advocacy work on issues that impact my pro-

fession.

42. In 2006, the AANEM distributed 6 bound copies of the Muscle & Nerve Invited Reviews. How would you rate this new member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I do not receive this since I am not an AANEM

member.E. Other: please explain on the comment page at the back of

this handout.

C-40 Evaluation AANEMCourse

43. When you receive the bound copies of the Muscle & Nerve Invited Reviews, you can visit the AANEM website and complete CME questions to receive a certificate at no charge. Have you utilized this new service?A. Yes, I have completed CME for the Invited Reviews

online and found the system easy to utilize.B. Yes, I have completed CME for the Invited Reviews

online, but found the system difficult to utilize.C. No, I have not utilized this service because I was unaware

it was available. D. No, I have not utilized it although I was aware of its avail-

ability: please explain on the comment page at the back of this handout.

E. Other: please explain on the comment page at the back of this handout.

44. In 2006, the AANEM added Online Case Studies to the website which are also available for CME credit. How would you rate this new member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I was not aware that this was available on the AANEM

website.E. Other: please explain on the comment page at the back of

this handout.

45. The AANEM has recently launched new Marketing Slides on the website that can assist EDX physicians in marketing to referral sources. How would you rate this member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I have not reviewed the marketing slides yet.E. Other: please explain on the comment page at the back of

this handout.

AANEMCourse Evaluation C-41

2006 COURSE D AANEM 53rd Annual Meeting

Washington, DC




Arthur P. Hays, MD

Anthony A. Amato, MD

Kurenai Tanji, MD, PhD

Annabel K. Wang, MD

Muscle and Nerve Pathology


Faculty

Arthur P. Hays, MDDirectorLaboratory of Neuromuscular PathologyColumbia University Medical CenterNew York, New YorkDr. Hays earned his medical degree at the University of Colorado in Denver, and went on to specialize in pathology. He is certified in neu-ropathology by the American Board of Pathology. He is currently the director of the Laboratory of Neuromuscular Pathology at New York Presbyterian Hospital, and an associate professor of clinical neuropathol-ogy in the College of Physicians and Surgeons at Columbia University. He has trained many fellows in clinical research, and belongs to several societies, including the American Association of Neuropathologists, the New York Pathological Society, and the Peripheral Nerve Society. Dr. Hays is also an ad hoc reviewer for Neurology and the Journal of Neurological Sciences.

Anthony A. Amato, MDVice ChairmanDepartment of NeurologyBrigham and Women’s HospitalBoston, MassachusettsDr. Amato is the vice-chairman of the Department of Neurology, the chief of the Neuromuscular Division, and the director of the neuromuscular medicine fellowship at Brigham and Women’s Hospital in Boston. He is also an associate professor of neurology at Harvard Medical School. Dr. Amato is an author or co-author of over 125 articles, chapters, and books. He has been involved in clinical research trials involving patients with amyotrophic lateral sclerosis, peripheral neuropathies, neuromuscular junction disorders, and myopathies.

Kurenai Tanji, MD, PhDAssistant ProfessorDepartment of Clinical PathologyColumbia University Medical CenterNew York, New YorkDr. Tanji stepped into the clinical research of mitochondrial diseases in 1991 as a postdoctoral research fellow from Japan at Columbia University’s Department of Neurology, led by Drs. L.P. Rowland and S. DiMauro. Her primary project was related to muscle biology in Duchenne and Becker muscular dystrophies, but she simultaneously developed a great interest in mitochondrial diseases. After the fellowship, Dr. Tanji remained in the mitochondrial research group to concentrate her efforts on clinical research, particularly the correlation between mitochondrial genetics and tissue morphology in various mitochondrial encephalomyopathies. She subsequently took the pathology residency and neuropathology fellow-ship at Columbia’s Department of Pathology and became an attending neuropathologist in 2004. Her current interests include the dysfunctional blood-brain barrier in mitochondrial encephalomyopathies, especially Leigh syndrome and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.

Annabel K. Wang, MDAssistant ProfessorDepartment of NeurologyMount Sinai Medical CenterNew York, New YorkDr. Wang is an assistant professor in the Department of Neurology at the Mount Sinai Medical Center in New York City. She received her bachelor of science degree in neurobiology and her medical degree from McGill University in Montréal, Canada. In addition to the pathology of motor neuropathies, she is interested in the somatic and autonomic neuropathies of disorders such as diabetes and amyloidosis. She is currently a Hartford Center of Excellence Scholar in Geriatrics and a Reynolds’ Master Clinician Educator in Geriatrics.

Course Chair: Arthur P. Hays, MD


Dr. Hays is a consultant for Therapath, a company that performes epidermal nerve fiber analysis (skin) biopsies. Other authors had nothing to disclose.

D-ii


Contents

Faculty i

Objectives ii

CourseCommittee iv

Muscle and Nerve Biopsy: An Introduction 1ArthurP.Hays,MD

Histopathology of Muscular Dystrophies 7AnthonyA.Amato,MD

Pathology of Muscle in Mitochondrial Disorders 27KurenaiTanji,MD,PhD

Pathology of Motor Nerve Biopsy 37AnnabelK.Wang,MD


Evaluation 45

Ob j e c t i v e s—After attending this course, participants will understand muscle and nerve biopsy and the histopathology of muscular dystrophies. The pathology of muscle in mitochondrial disorders as well as the pathology of motor nerve biopsy will also be discussed.





D-iii

D-iv

ThomasHyattBrannagan,III,MDNew York, New York

HopeS.Hacker,MDSan Antonio, Texas

KimberlyS.Kenton,MDMaywood, Illinois

DaleJ.Lange,MD New York, New York

SubhadraNori,MDBronx, New York

JeremyM.Shefner,MD,PhDSyracuse, New York

T.DarrellThomas,MDKnoxville, Tennessee

BryanTsao,MDShaker Heights, Ohio


JaniceM.Massey,MDDurham, North Carolina


KathleenD.Kennelly,MD,PhDJacksonville, Florida

Muscle and Nerve Biopsy: An Introduction

Arthur P. Hays, MDDirector

LaboratoryofNeuromuscularPathologyColumbiaUniversityMedicalCenter

NewYork,NewYork

INTRODUCTION

Muscle and nerve biopsies are performed in patients with neuro-muscular disorders.33 The pathological findings may be diagnostic (e.g., a necrotizing arteritis) and provide a basis for proper clini-cal management. Unfortunately, biopsies are often nonspecific or supply limited information. The yield of a biopsy is significantly influenced by the quality of the tissue, sample size, and site of surgi-cal removal, and it is worthwhile to restate a few general principles to guide physicians at each step of the procedure.31,33

First, expert physicians recommend a muscle or nerve biopsy only after thorough clinical and laboratory evaluation of the patient, including electrodiagnostic (EDX) studies. Second, the site of the biopsy should be selected using the clinical and electrophysiologi-cal findings to maximize diagnostic yield. The general rule for both muscle and nerve is to choose a biopsy specimen that is affected clinically, but that is not severe, in order to avoid end-stage tissue. Third, the surgeon or physician who performs the biopsy must be experienced and provide tissue of good quality. In particular, the tissue should never be submerged in saline.31 Surgeons are often trained to place tumor specimens into a jar of saline prior to pro-viding a frozen section diagnosis. In some instances, surgeons are familiar with the proper handling of the muscle and nerve, but then the specimen is transferred to a general pathologist who may then place it into a jar of saline before sending it to a neuromuscular laboratory. Exposure of tissue to an excess of saline causes lysis of

cells and other artifacts and can render it useless for enzyme histo-chemical analysis. It is recommended that the tissue be wrapped in a piece of gauze or surgical tefla that is barely moistened to prevent drying. Once the sample is removed surgically it must be kept cold during transportation using regular ice or cold packs. Fourth, in the case of muscle as well as nerve, the procedure requires an open biopsy rather than a needle biopsy, to provide an adequate sample size. Sample size is a major issue in focal disorders such as derma-tomyositis or necrotizing arteritis, and requires generous sampling. In addition, specimens should be submitted for routine histology, electron microscopy (EM), and biochemical analysis. Biochemical assay and deoxyribonucleic acid (DNA) analysis have become es-sential for the diagnosis of inherited disorders and require a cube of tissue about 1 cm in each dimension that is frozen immediately, preferably in liquid nitrogen. Finally, the physician formulates a preliminary diagnosis and informs the pathologist to perform analysis of the sample using special histochemistry and immuno-histochemistry, as well as other methods. If these special methods are not available locally, the service may be provided at a regional research center.

MUSCLE BIOPSY

The three major goals of a muscle biopsy are to (1) distinguish between a myopathy from a neurogenic disorder; (2) screen my-opathies for inherited disorders to direct biochemical analysis and

D-� Muscle and Nerve Biopsy: An Introduction AANEMCourse

achieve a molecular diagnosis, and (3) identify acquired disorders of muscle with particular emphasis on treatable disorders such as polymyositis and dermatomyositis.

Inherited Disorders

Genetic defects affecting muscle fall into three major groups based on the muscle biopsy. The first group includes the muscular dys-trophies. These disorders often show increased variation of muscle fiber size, necrotic fibers, regenerating fibers, and fibrosis of the endomysium.10,22

The second group consists of the congenital myopathies and is defined by morphological distinctive alterations within muscle fibers such as nemaline rods, central cores, numerous fibers with central nuclei (myotubular myopathy), and others.10,22 These dis-orders usually appear in infants with hypotonia, but rarely present in children or adults. Central core disease is normally inherited in an autosomal dominant pattern, myotubular myopathy is x-linked, and nemaline myopathy is either autosomal recessive or autosomal dominant. As a rule, muscle biopsy in congenital myopathies is often associated with predominance and atrophy of type 1 fibers and does not exhibit necrotic fibers, regenerating fibers, or fibrosis of the endomysium. Deoxyribonucleic acid analysis of such patients is gradually becoming available in commercial laboratories and re-search centers for molecular diagnosis. The name and addresses of these laboratories are provided at www.genetests.org. At this time, gene sequencing is available for nemaline myopathy, central core disease, x-linked myotubular myopathy, and certain others.

A third group of inherited disorders of muscle result in defects of intermediary metabolism and include disorders of glycogen and lipid metabolism.9,19,32 Clinical presentations are quite variable, but most patients with muscle symptoms exhibit either exercise intol-erance or progressive weakness. The muscle biopsy often provides a clue to these inborn errors by demonstrating accumulation of glycogen, triglyceride, or mitochondria in muscle fibers. In general, the muscle biopsy does not exhibit necrotic fibers, regenerating fibers, or fibrosis of the endomysium. One exception to this rule exists in muscle biopsies of patients with exercise intolerance when vigorous activity triggers acute breakdown of muscle fibers (so-called rhadomyolysis). If the physician suspects that the patient has an inherited disorder during an episode of exercise-induced symp-toms, the muscle biopsy should be delayed for at least 1 month to allow myofiber regeneration to restore a normal or nearly normal structure. The delay facilitates biochemical analysis of the tissue as the results are easier to interpret in muscle without superimposed acute muscle fiber necrosis and reactive changes.

In disorders of glycogenolysis (deficiency of phosphorylase or deb-rancher enzyme) or glycolysis (deficiency of phosphofructokinase and other enzymes of the pathway that lead to lactic acid), glyco-gen typically accumulates in the subsarcolemmal zone.19 Glycogen storage is often too subtle to detect in paraffin or frozen sections

of muscle with the exception of debrancher enzyme deficiency in adults who have slowly progressive weakness and marked accu-mulation of glycogen in the subsarcolemmal region. Fortunately, the most common disorder in this group is myophosphorylase deficiency (McArdle disease), which can be tested by a simple histo-chemical stain of muscle. Most patients have clinical manifestations of exercise intolerance, such as cramps and myalgia, but a minority have persistent weakness or elevated serum creatine kinase (hyper-CKemia) activity with no muscle symptoms. The histochemical reaction for phosphorylase should be performed in this clinical setting. It also should be considered by pathologists as a screening procedure in all muscle biopsies that are not definitive, particularly with little or no abnormalities.19,26 The diagnosis requires confir-mation by biochemical assay of the enzyme or by documentation of a PGYM gene mutation. If phosphorylase activity is normal, the frozen muscle should be subjected to additional biochemical analysis of other enzymes involved in glycogen or lipid metabolism depending on the patient’s clinical symptoms.

The physician can strongly suspect adult-onset acid maltase defi-ciency by the clinical features, needle electromyography examina-tion (complex repetitive discharges and other features), and the presence of glycogen storage within lysosomes of muscle biopsy specimens.23 However, adult-onset acid maltase may not be typical and may mimic polymyositis or a muscular dystrophy. In patients with adult-onset acid maltase deficiency, the muscle biopsy shows variable accumulation of glycogen within lysosomes. These appear as a few vacuoles that are distributed throughout the cytoplasm. In some cases the biopsy may not display overt glycogen accumula-tion by routine histology in paraffin sections or frozen sections. However, the muscle provides a clue to this disorder if there is an increase in the size and number of lysosomes based on the histochemical stain of the lysosomal enzyme, acid phosphatase. Electron microscopic examination can offer additional evidence of adult-onset acid maltase deficiency by displaying accumulation of membrane-bound glycogen particles. The diagnosis requires confirmation by biochemical assay of the muscle enzyme or by documentation of a mutation of the GAA gene.

Muscle biopsy plays an especially important role in mitochondrial disorders.32 Ragged red fibers are the hallmark of mitochondrial DNA mutations, but the recognition of this alteration is only the first step in the full pathological workup of muscle. Analysis of the oxidative enzymes, succinate dehydrogenase (complex II), and cy-tochrome c oxidase (complex IV) are essential to assess mitochon-dria in more detail. The results may help to narrow the possibilities and direct molecular analysis of enzymes and DNA.

Acquired Disorders

The most important group of acquired disorders are the inflamma-tory myopathies. These can subclassified into three major groups; dermatomyositis, polymyositis, and inclusion body myositis (IBM).2,3,4,11,14,15,16,24 The first two disorders are thought to be

AANEMCourse MuscleandNervePathology D-�

autoimmune disorders and respond to glucocorticoids and other immunomodulatory treatments, although the target antigens are not known. Inclusion body myositis may also be an autoimmune disorder, but it does not usually respond to therapy. In many cases, all three disorders are likely based on the clinical features, labora-tory tests, and EDX studies, but muscle biopsy is important to help confirm the diagnosis before starting treatment, as therapy entails potential adverse side effects. Rarely, the biopsy indicates some other type of muscle disease, such as an inherited disorder. It is impor-tant to realize that roughly 20%-30% or more of muscle biopsies classified as inflammatory myopathies by clinical and laboratory testing do not show significant lymphocytic infiltration.14,18,24,41 In this instance, the biopsy findings expand the differential diagnosis to include a side effect of a lipid-lowering medication (statin), muscular dystrophy, and many others. Muscular dystrophy is tricky as occasionally the biopsy may be accompanied by significant lymphocytic infiltration, most notably dysferlin deficiency, fa-cioscapulohumeral dystrophy, or merosin deficiency. The finding of dysferlin deficiency (limb-girdle muscular dystrophy [LGMD], LGMD type 2B, or Miyoshi myopathy) can lead to a misdiagnosis of polymyositis or IBM.3,27

Dermatomyositis is believed to be an antibody-mediated disorder and targets blood vessels.7,8,11,12,16,17,24,29 The vessels show pathologi-cal signs of endothelial necrosis and regeneration with the eventual disappearance of capillaries, presumably resulting in ischemic injury of muscle fibers.7,12,17 Pathological evidence of vasculitis is well-described in autopsies in muscle, skin, and gastrointestinal organs,8 but is rare in muscle biopsies. The findings in the biopsy are extremely variable and range from normal to a clear multifocal disorder pathologically. Perifascicular atrophy of muscle fibers is typical. The tissue sample rarely shows focal tissue infarcts, often predominating along the edge of muscle fascicles in a perifascicular fashion. The muscle may demonstrate little or no inflammatory cells as in other antibody-mediated disorders such as myasthenia gravis, acute motor axonal neuropathy, and anti-myelin associated glycoprotein neuropathy. The inflammatory cells are significant perhaps in 60% of specimens, and they predominate in the peri-mysium. The inflammatory cells consist of chiefly B cells, CD4 T cells, and histiocytes.6

An uninformative biopsy in a patient with suspected dermato-myositis requires further pathological evaluation of the sample to provide supportive evidence of the diagnosis by demonstrating: (1) deposits of membrane attack complex (C5b-9) in the walls of blood vessels;20,35 (2) focal expression of major histocompatibility complex (MHC) class I antigen (HLA-ABC) at the surface membrane and within cytoplasm of muscle fibers, most pronounced at the edge of muscle fascicles;21,37 or (3) EM detection of tubuloreticular aggre-gates in endothelial cells of blood vessels.7,17 Immunohistochemical stains of immune complexes are performed on frozen, unfixed tissue and are nearly specific for the disorder, but exhibit variable sensitivity in different studies. Unfortunately, a delay in freezing the tissue or other adverse handling can result in alterations of immu-

noglobulins and complement components and can interfere with reliable interpretation. The findings in the other two procedures, immunohistochemical analysis of MHC class I molecules and EM of blood vessels, are not completely specific but are strongly supportive of the diagnosis of dermatomyositis. Limited literature suggests that both tests are specific and sensitive for diagnostic evaluation of muscle biopsies.7,43 The characteristic pathological findings of dermatomyositis may be seen also in weak patients with systemic lupus erythematosus, mixed connective tissue disease, sys-temic sclerosis, and rarely, other collagen vascular diseases.

Polymyositis is uncommon in comparison to IBM and dermatomy-ositis.3,41 T cells and histiocytes infiltrate chiefly the endomysium5,24 and occasionally appear to invade nonnecrotic muscle fibers in the context of MHC class I antigen expression in polymyositis.21 The invading T cells are CD8 positive and are activated as indicated by expression of MHC class II antigens (HLA-DR)25 and other pro-teins. In addition, nearly half of the cells that make contact with the muscle fibers contain perforin, a molecule that plays a major role in cytotoxicity.28 The findings suggest that the disorder is mediated by T cells. Morphologically, the muscle biopsy demonstrates necrotic fibers and regenerating fibers that seem to be randomly distributed throughout the muscle.14,24 T cells and histiocytes predominate in the endomysium with few, if any, B cells. The pattern of muscle fiber injury, the type of lymphocytes, and inflammatory infiltration of the endomysium help to distinguish this disorder from derma-tomyositis. Because polymyositis is usually a subacute disorder, there is often little evidence of chronic changes such as atrophic fibers, hypertrophic fibers, or prominent endomysial fibrosis. In addition, immunohistochemical stains of MHC class I antigens are helpful for diagnosis as most or all of the muscle fibers express these molecules at the surface of muscle fibers, even in the absence of lymphocytes.21,34 This widespread immunostaining of MHC class I proteins in muscle fibers contrasts with the patchy, perifascicular pattern observed in dermatomyositis or the limited expression in noninflammatory myopathies. The interpretation of the biopsy in polymyositis is a diagnosis by exclusion as the pathological findings are characteristic, but not entirely specific.14 Similar muscle biopsy findings may be found in patients with collagen vascular disease and human immunodeficiency virus infection.

Inclusion body myositis resembles polymyositis pathologically but is chronic and typically demonstrates small groups of atrophic fibers, hypertrophic fibers, and endomysial fibrosis.4,6,13,14,15,30,38 The abnormalities are not as evenly distributed as in polymyositis. In addition, IBM displays characteristic rimmed vacuoles that are occasionally associated with small eosinophilic inclusions. The inclusions are weakly congophilic indicating that they represent an intracellular form of amyloid.6,39 The most distinctive congophilic inclusions have a fibrillar substructure and help to establish the diagnosis. The Congo red stain has largely replaced EM to identify the characteristic abnormal 12-18 nm tubular filaments of the inclusions for diagnostic purposes. The congophilic inclusions are composed, in part, of the microtubular-associated protein, tau.6

This protein expresses a cross-reacting phosphorylated epitope that binds the anti-neurofilament protein monoclonal antibody, SMI-31, and is reported to be useful in the diagnosis.42 The pathological features of IBM are nearly diagnostic, but they rarely resemble the muscle biopsies of muscular dystrophies and other disorders. In ad-dition, the biopsy in IBM may not demonstrate rimmed vacuoles or congophilic inclusions. If the muscle biopsy is not informative in IBM or other suspected inflammatory myopathies, the physician can justify a second biopsy.

NERVE BIOPSY

Biopsy of a cutaneous nerve (sural or superficial peroneal nerve) allows identification of a specific disorder in a minority of patients with peripheral neuropathy such as necrotizing arteritis, amyloido-sis, sarcoidosis, and others.40 Diagnostic yield is greatest in patients with mononeuritis multiplex or an enlarged nerve identified by palpation or radiographic imaging. Symmetrical neuropathies are often not informative. The biopsy in patients with chronic inflammatory demyelinating neuropathy was initially proposed as a mandatory part of the diagnostic criteria. This was subsequently modified for making this diagnosis because the biopsy was often uninformative. This is related, in part, because cutaneous biopsy is typically limited to the distal part of the nerve and may not reflect abnormalities located in motor nerve fibers or in sensory fibers in places other than the biopsy site. In addition, distinction between primary demyelination and secondary demyelination as a result of axonal degeneration is particularly problematic in chronic disorders. Occasionally, biopsy may be necessary in chronic inflammatory demyelinating polyneuropathy patients because of an equivocal or atypical presentation or because another diagnosis, such as vasculi-tis, is suspected based on the clinical or laboratory profile.

Skin biopsy for epidermal nerve fiber analysis has become estab-lished as an important part of the assessment of patients with painful or other small fiber neuropathy.36 The procedure is most useful in patients with no signs of a neuropathy by neurological examination and no detectable EDX abnormalities. The biopsy provides objective evidence of a neuropathy by counting the number of epidermal nerve fibers for a given length of epidermis (epidermal nerve fiber density) and demonstrating a significant reduction of normal values (below the fifth percentile). The sample of skin biopsy could also potentially establish a specific diagnosis of amyloidosis or other disorders, but is rare.

Motor nerve biopsy has been limited in the past because of con-cerns that it will make the patient even weaker. This has been overcome by selecting a motor nerve that supplies a “dispensable” muscle, such as the gracilis muscle.1 In this case, other large adduc-tor muscles take over the function of the muscle after motor nerve biopsy.

SUMMARY

The pathological findings of nerve biopsy may be diagnostic and provide a basis for proper clinical management. Expert physicians recommend a muscle or nerve biopsy only after thorough clinical and laboratory evaluation of the patient. The site of the biopsy should be selected by clinical and electrophysiological findings to maximize diagnostic yield. The surgeon or physician that performs the biopsy must be experienced and provide tissue of good quality. The muscle biopsy can help distinguish between a myopathy from a neurogenic disorder, screen myopathies for inherited disorders to direct biochemical analysis and achieve a molecular diagnosis, and identify acquired disorders of muscle with particular emphasis on treatable disorders such as polymyositis and dermatomyositis.

REFERENCES

1. Abouzahr MK, Lange DJ, Latov N, Olarte M, Rowland LP, Hays AP, Corbo M. Diagnostic biopsy of the motor nerve to the gracilis muscle. Technical note. J Neurosurg 1997;87:122-124.

2. Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615-648.

3. Amato AA, Griggs RC. Unicorns, dragons, polymyositis, and other mythological beasts. Neurology 2003;61:288-289.

4. Amato AA, Gronseth GS, Jackson CE, Wolfe GI, Katz JS, Bryan WW, Barohn RJ. Inclusion body myositis: clinical and pathological boundaries. Ann Neurol 1996;40:581-586.

5. Arahata K, Engel AG. Monoclonal antibody analysis of mono-nuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984;16:193-208.

6. Askanas V, Engel WK. Inclusion-body myositis: newest concepts of patholgenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 2001;60:1-14.

7. Banker BQ. Dermatomyostis of childhood, ultrastructural altera-tious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 1975;34:46-75.

8. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of childhood. Medicine (Baltimore) 1966;45:261-289.

9. Bruno C, Hays A, DiMauro S. Glycogen storage diseases of muscle. In: Jones HR, De Vivo DC, Darras BT, editors. Neuromuscular disorders of infancy, childhood, and adolescence. A clinicians’s ap-proach. New York: Butterworth-Heinemann; 2003. p 813-832.

10. Carpenter S, Karpati G. Pathology of skeletal muscle. New York: Oxford University Press; 2001.

11. Carpenter S, Karpati G. The pathological diagnosis of specific in-flammatory myopathies. Brain Pathol 1992;2:13-19.

12. Carpenter S, Karpati G, Rothman S, Watters G. The childhood type of dermatomyositis. Neurology 1976;26:952-962.

13. Dalakas MC. Inflammatory, immune, and viral aspects of inclusion-body myositis. Neurology 2006;66:S33-38.

14. Dalakas MC. Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am 2002;28:779-798.

D-4 Muscle and Nerve Biopsy: An Introduction AANEMCourse

15. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991;325:1487-1498.

16. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:971-982.

17. De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle. J Neurol Sci 1989;94:181-192.

18. DeVere R, Bradley WG. Polymyositis: its presentation, morbidity and mortality. Brain 1975;98:637-666.

19. DiMauro S, Hays A, Tsujino S. Non-lysosomal glycgenoses. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: McGraw-Hill; 2004.

20. Emslie-Smith A, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990;27:343-356.

21. Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibility complex class I antigen expression, immunolocalization of inter-feron subtypes, and T cell-mediated cytotoxicity in myopathies. Hum Pathol 1989;20:224-231.

22. Engel A. The muscle biopsy. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: McGraw-Hill; 2004.

23. Engel A, Hirschhorn R, Huie M. Acid maltase deficiency. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: McGraw-Hill; 2004. p 1559-1586.

24. Engel A, Reinhard H. The polymyositis and dermatomyositis syn-dromes. In: Engel A, Franzini-Armstrong C, editors. Myology, 3rd edition. New York: McGraw-Hill; 2004. p 1321-1366.

25. Engel AG, Arahata K. Monoclonal antibody analysis of mono-nuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984;16:209-215.

26. Fernandez C, de Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Chabrol B, et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006;66:1585-1587.

27. Gallardo E, Rojas-Garcia R, de Luna N, Pou A, Brown RH Jr, Illa I. Inflammation in dysferlin myopathy: immunohistochemical charac-terization of 13 patients. Neurology 2001;57:2136-2138.

28. Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, Pongratz D, et al. Differential expression of perforin in muscle-in-filtrating T cells in polymyositis and dermatomyositis. J Clin Invest 1996;97:2905-2910.

29. Greenberg SA, Amato AA. Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol 2004;17:359-364.

30. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, Rowland LP. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-713.

31. Hays A. Muscle biopsy. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of the neurological sciences, volume 3. Boston: Academic Press; 2003. p 270-274.

32. Hays A, Oskoui M, Tanji K, Kaufmann P, Bonilla E. Mitochondrial myopathy. II: myopathies and peripheral neuropathies. In: DiMauro S, Hirano M, Schon E, editors. Mitochondrial medicine. London: Taylor & Francis; 2006. p 47-74.

33. Hays AP, Daras MD. Muscle and nerve biopsy. In: Rowland LP, editor. Merritt’s neurology, 11th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. p 127-129.

34. Karpati G, Pouliot Y, Carpenter S. Expression of immunoreac-tive major histocompatibility complex products in human skeletal muscles. Ann Neurol 1988;23:64-72.

35. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:329-334.

36. Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren SI, Nolano M, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 2005;12:747-758.

37. Li CK, Varsani H, Holton JL, Gao B, Woo P, Wedderburn LR. MHC Class I overexpression on muscles in early juvenile dermatomyositis. J Rheumatol 2004;31:605-609.

38. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis. Observations in 40 patients. Brain 1989;112:727-747.

39. Mendell J, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of fila-ments. Arch Neurol 1991;48:1229-1234.

40. Mendell JR, Cornblath DR, Kissel JT. Diagnosis and management of peripheral nerve disorders. New York: Oxford University Press; 2001.

41. van der Meulen MF, Bronner IM, Hoogendijk JE, Burger H, van Venrooij WJ, Voskuyl AE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61:316-321.

42. van der Meulen MF, Hoogendijk JE, Moons KG, Veldman H, Badrising UA, Wokke JH. Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis. Neuromuscul Disord 2001;11:447-451.

43. van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen BG. Diagnostic value of MHC class I staining in idiopathic inflam-matory myopathies. J Neurol Neurosurg Psychiatry 2004;75:136-139.

AANEMCourse MuscleandNervePathology D-5

D-� AANEMCourse

INTRODUCTION

In order to understand the histopathology of the muscular dystrophies, it is important to have an understanding of the rel-evant muscle proteins that are affected in the various dystrophies. Interestingly, muscular dystrophies can result from mutations af-fecting structural proteins localizable to the sarcolemma proteins, nuclear membrane, basement membrane, and sarcomere as well as nonstructural enzymatic proteins.

DYSTROPHIN-GLYCOPROTEIN COMPLEX AND RELATED PROTEINS

Dystrophin

The identification and characterization of dystrophin as an abnor-mal gene product in Duchenne and Becker muscular dystrophies was the seminal event in medicine’s understanding of the muscular dystrophies.67,68,77 Dystrophin localizes to the cytoplasmic face of skeletal and cardiac muscle membrane and is 5% of sarcolemmal cytoskeletal protein. Dystrophin is a rod-shaped molecule com-posed of four domains.77 The amino-terminal domain binds to the cytoskeletal filamentous actin. The second domain bears similarity to spectrin, and provides structural integrity to red blood cells. The third domain is a cysteine-rich region and the fourth domain is the carboxy-terminal. The cysteine-rich domain and the first half of the carboxy-terminal domain of dystrophin are important in linking dystrophin to beta(β)-dystroglycan and the glycoproteins that span the sarcolemma.

Dystrophin is also present in the brain where it localizes subcel-lularly to the postsynaptic density (PSD), a disc-shaped structure beneath the postsynaptic membrane in chemical synapses. The PSD may play an important role in synaptic function by stabiliz-ing the synaptic structure, anchoring postsynaptic receptors, and transducing extracellular matrix-cell signals.

Dystrophin-associated Proteins/Glycoproteins

Dystrophin is tightly associated with a large oligomeric complex of sarcolemmal proteins forming the dystrophin-glycoprotein complex (DGC) (Figure 1).32,33,41 Mutations in the various genes that encode for the different proteins of the DGC are now known to be responsible for many forms of muscular dystrophy (Table 1). In addition to dystrophin, the DGC is composed of an en-tirely cytoplasmic group of proteins referred to as the syntrophin complex, the dystroglycan complex, and the sarcoglycan complex (Figure 1). The syntrophin complex binds to the carboxy terminus of dystrophin and is composed of three distinct 59 kD dystrophin-associated proteins (DAPs) that are encoded by separate genes. β-syntrophin is expressed only in muscle and the gene has been localized to chromosome 20q11.2. Beta-1-syntrophin and β2-syntrophin are more widely expressed and their genes have been localized to chromosomes 8q23-24 and 16q22-23, respectively. Dystrobrevin is encoded on chromosome 2p22-23 and is a cyto-plasmic protein that binds to the syntrophin complex and to the C-terminus of dystrophin. The dystroglycan complex is composed of alpha (α)-dystroglycan and β-dystroglycan. Beta-dystroglycan spans the sarcolemmal membrane and has a cytoplasmic tail that binds to dystrophin while the extracellular tail binds α-dystroglycan.

Histopathology of Muscular Dystrophies

Anthony A. Amato, MDViceChairman

DepartmentofNeurologyBrighamandWomen’sHospital

Boston,Massachusetts

D-�

Alpha-dystroglycan, which is entirely extracellular, also binds to α-laminin, a basal lamina protein. Of note, a gene located on chromosome 3p21 encodes for both the α- and β-dystroglycans. Importantly, α-dystroglycan undergoes N-linked and extensive O-linked glycosylation which appears to be important for normal binding to merosin and perhaps other extracellular matrix pro-teins.94

The sarcoglycan complex includes four membrane spanning pro-teins: (1) α-sarcoglycan (previously known as adhalin); (2) β-sar-coglycan; (3) gamma (γ)-sarcoglycan; and (4) delta (δ)-sarcoglycan. In addition, there is a 25 kD transmembrane protein, sarcospan, which co-localizes with the sarcoglycan complex. The sarcoglycan complex associates with the cysteine-rich domain and/or the first half of the carboxy terminal of dystrophin directly or indirectly via the dystroglycan complex. The exact relationship between the

sarcoglycan complex and the dystrophin-dystroglycan complex is still unclear. Mutations in the various sarcoglycan genes are responsive for limb girdle muscular dystrophy (LGMD) 2C, 2D, 2E, and 2F.

Merosin/Laminin

The basal lamina surrounding each muscle fiber is closely adher-ent to the sarcolemma and is composed of type I and IV collagen, heparan sulfate, proteoglycan, entactin, fibronectin, and laminin. Laminin is a large flexible heterotrimer composed of three differ-ent but homologous α, β, and γ chains held together by disulfide bonds. There are five different α chains, three β chains, and two γ chains that have been characterized. The major isoform of laminin heavy chains in muscle is laminin-2, which is composed of α2, β1, γ1 chains. Muscle also contains laminin-4, composed of α2,

D-� Histopathology of Muscular Dystrophies AANEMCourse

Figure 1 Sarcolemmal,sarcoplasmic,andbasementmembraneproteins responsible for formsofmusculardystrophy.From:Dalkilic I,KunkelLM.Musculardystrophies:genestopathogenesis.CurrOpinGenetDev�00�;1�:��1-��.4�

β2, γ1 subunits. Merosin is the collective name for laminins that share a common α2 chain. Alpha-dystroglycan binds specifically to laminin-2 but not to the other extracellular components (Figure 1). Ligands for the sarcoglycan complex are unknown, but it has been postulated that the complex is directly or indirectly linked to laminin-4.137

Merosin is also expressed in the endoneurial basement membrane surrounding the myelin sheath of peripheral nerves.89 Likewise, α-and β-dystroglycan are found in peripheral nerves. Expression α-and β-dystroglycan is restricted to where the Schwann cell’s outer membrane; they are not present in the inner membrane or on compact myelin. Transmembrane β-dystroglycan anchors ex-tracellular α-dystroglycan to the outer membrane of Schwann cells and myelin sheath. As in muscle, merosin serves as a ligand in the Schwann cell dystroglycan complex by binding to α-dystroglycan. This complex appears to have a role in peripheral myelinogenesis. Mutations involving the merosin gene not only result in a form of congenital muscular dystrophy (MDC), but they also are associated with mild dysmyelination in the central and peripheral nervous systems.

Integrins

Integrins are transmembrane, heterodimeric (α/β) receptors that play key roles in establishing linkages between the extracellular matrix and the cytoskeleton as well as in transducing extracellu-lar matrix-cell signals.132 Integrins are important in cell adhesion, migration, differentiation, proliferation, and cytoskeletal organiza-tion. The major integrin expressed throughout the sarcolemma in mature muscle fibers is α7β1D. Studies have demonstrated that α7β1D integrin binds to merosin in skeletal muscle and this inter-action appears to be as important as the linkage of α-dystroglycan to merosin in providing structural stability (Figure 1). Mutations of the α7 subunit lead to abnormal binding of merosin to integrin and are causative of some forms of MDC.

Utrophin (Dystrophin-related Protein)

Utrophin is an autosomal homologue of dystrophin. It is ubiqui-tously expressed but is localized exclusively at the neuromuscular junction in normal skeletal muscle. Utrophin associates with DAPs, suggesting that the utrophin-glycoprotein complex plays a role in the formation and integrity of the neuromuscular junction. Up-regulation of utrophin is evident in the dystrophinopathies, perhaps as a compensatory mechanism.

OTHER SARCOLEMMAL PROTEINS

Dysferlin

Dysferlin is another cytoskeletal protein present in skeletal and cardiac muscle. It is located predominantly on the subsarcolemmal

surface on the muscle membrane, but it has a small transmembrane spanning tail (Figure 1). The protein does not appear to be directly connected to the dystrophin-glycoprotein complex. The function of dysferlin is not entirely known. Dysferlin may have a role in membrane fusion and repair by regulating vesicle fusion with the membrane.9,38 Additionally, dysferlin may assist in stabilizing the sarcolemmal membrane, or in signal transduction.12,87

Caveolin

Caveolae are 10-100 nm invaginations in the sarcolemma derived by the oligomerization of approximately 14-16 caveolin-3mono-mers that form a scaffolding complex of proteins and lipids (Figure 1).37,96 It co-fractionates with the dystrophin-glycoprotein complex, but is thought to be part of a discrete complex. It does not directly bind to dystrophin or the sarcoglycans, but does apparently interact with dysferlin. Caveolin-3 is necessary for the proper formation of T-tubules and may assist in the organization of signally complexes, calcium channels (i.e., dihydropyridine and ryanodine receptors, and sodium channels). Mutations in the gene encoding for ca-veolin-3 are responsible for causing LGMD 1C, rippling muscle disease, a form of distal myopathy, and some cases of idiopathic increased serum creatine kinase (hyper-CK-emia).123,139

SARCOMERIC PROTEINS

In addition to the previously mentioned sarcolemmal and related proteins, there are a number of important proteins that compose and support the sarcomere. The major contractile myofibrillar proteins are the thick and thin filaments. The thin filament is com-posed of three subcomponents: actin, tropomyosin, and troponin. Polymerized globular or G-actin molecules form two helical strands of filamentous or F-actin. Two chains of tropomyosin molecules wind loosely within the helical structure of the F-actin. The tropo-myosin molecules overlie “active sites” on the actin molecules that link with the myosin heads forming the crossbridges. The third major subcomponent of the thin filament, troponin, consists of three globular proteins: troponin I, T, and C. Troponin I binds strongly to actin, troponin T is attached to tropomyosin, while troponin C has an affinity for calcium. The troponin complex at-taches the tropomyosin molecules to the actin molecules thereby forming the complete thin filament. The interaction between the myosin crossbridges and actin filaments causes the muscle fiber to shorten or contract because the above-noted filaments slide past each other.

One end of the actin filaments are firmly anchored to the Z disk and the other end projects out between myosin filaments. These Z disks extend from myofibril to myofibril across the diameter of a muscle fiber. The region of muscle or myofibril between two Z disks is called a sarcomere. The major protein of the Z disk is α-actinin. Nebulin is a giant protein that is attached to α-actinin at the Z disk and spans the entire length of the thin filament. There

AANEMCourse MuscleandNervePathology D-�

D-10 Histopathology of Muscular Dystrophies AANEMCourse

Table 1GeneticClassificationoftheMuscularDystrophies

Disease Inheritance Chromosome Affected Protein

X-linked dystrophies Duchenne/Becker XR Xp�1 DystrophinEmery-Dreifuss XR Xq�� EmerinLimb-girdle muscular dystrophies LGMD1A AD 5q��.�-�1.� MyotilinLGMD1B AD 1q11-�1 LaminA&CLGMD1C AD �p�5 Caveolin-�LGMD1D AD �q�� ?LGMD1E AD �q ?LGMD�A AR 15q15.1-�1.1 Calpain�LGMD�B* AR �p1� DysferlinLGMD 2C AR 13q12 γ-sarcoglycanLGMD 2D AR 17q12-21.3 α-sarcoglycanLGMD 2E AR 4q12 β-sarcoglycanLGMD 2F AR 5q33-34 δ-sarcoglycan LGMD�G AR 1�q11-1� TelethoninLGMD�H AR �q�1-�� E�-ubiquitin-ligase (TRIM��)LGMD�I AR 1�q1� Fukutin-related protein(FKRP)LGMD�J AR �q�1 Titin

Congenital muscular dystrophiesLaminin-α-�CMD AR �q��-�� Laminin-α-�chain

α-�IntegrinCMD AR 1�q1� α-�Integrin AR 1�q1� Fukutin-related protein(FKRP)FukuyamaCMD A �q�1-�� FukutinWalker-WarburgCMD AR �q�1 POMT1Muscle-eye-brainCMD AR 1p�� POMGnT1Rigidspinesyndrome AR 1p�5-�� SelenoproteinN1

Distal dystrophies/myopathiesLateadultonset1A(Welander) AD �p1� ?Lateadultonset1B(Udd) AD �q�1 TitinEarlyadultonset1A(Nonaka) AR �p1-q1 GNEEarlyadultonset1B*(Miyoshi) AR �p1� DysferlinEarlyadultonset1C(Laing) AD 14q11 myosinheavychain�


are two nebulin molecules for every thin filament. Desmin is an in-termediate-sized filament that encircles the Z disk and helps to link the Z disk to the sarcolemma, myonuclei, and adjacent myofibers. The cytoplasmic heat-shock protein, αB-crystallin, interacts with desmin in the assembly and stabilization of the Z disk. Syncoilin, together with plectin, also may link desmin filaments to the Z disk.118

Other filamentous proteins are also important in providing stability to the sarcomere. The giant protein titin (also known as connectin) is attached to the Z disk and spans from the M-line to the Z-line of the sarcomere. Titin serves to connect the myosin filaments to the Z disk. Telethonin is another sarcomeric protein present in skeletal and cardiac muscle. It co-localizes with titin to the Z disk and along the thick filaments. Telothonin is also linked to myotilin which in turn interacts with α-actinin and actin. The interaction of myotilin, telethonin, and titin may be important in myofi-brillogenesis. As will be discussed, mutations affecting the genes encoding for these various sarcomeric proteins are responsible for causing different dystrophies, congenital myopathies, and inherited cardiomyopathies.

NUCLEAR MEMBRANE PROTEINS

Emerin is a member of the nuclear lamina-associated protein (LAP) family and is located on the inner nuclear membranes of skeletal, cardiac and smooth muscle fibers (Figure 2).105,106,109,116 The nuclear lamina is a multimeric matrix composed of a complex of intermedi-ate-sized filaments (lamins -A, -B, and -C) that associates with the nucleoplasmic surface of the inner nuclear membrane. Of note, al-ternative splicing of a single gene produces lamins A and C. Emerin is attached to the inner nuclear membrane through its carboxy-ter-

minal tail, while the remainder of the protein projects into the nu-cleoplasm. The lamins bind to emerin, specific lamin receptors, and perhaps other LAPs located on the inner nuclear membrane. This complex of proteins is important in the organization and structural integrity of the nuclear membrane. In addition, LAPs, lamin recep-tors, and the lamins bind chromatin and promote its attachment to the nuclear membrane. Abnormalities in these nuclear envelope proteins apparently disrupt the structure of the nuclear membrane, the organization of interphase chromatin, and perhaps also signal transduction between the nucleus and sarcoplasm.20,57 Mutations in the genes that code for emerin and lamin A/C are responsible for X-linked Emery-Dreifuss muscular dystrophy (EDMD) and autosomal dominant EDMD/LGMD 1B, respectively.

ENZYMATIC (SARCOPLASMA) PROTEINS

Calpain-3 is a muscle-specific, calcium-dependent, nonlysosomal, proteolytic enzyme present in muscle. The pathophysiologic mechanism of how mutations involving this enzyme result in a dystrophic process is unknown. Calpain-3 exists in both the cytosol and nuclei of skeletal muscle fibers (Figure 1) where it may be di-rectly involved in or participate in the activation of another enzyme involved in muscle metabolism. Mutation in the calpain-3 gene are responsible for LGMD 2A.

Tripartite motif-containing protein 32 (TRIM 32), also known as E3-ubiquitine ligase, may function by tagging proteins (e.g., ubi-quination) for degradation by proteosomes. Mutations in TRIM 32 cause LGMD 2H.59

Fukutin is a glycosyltransferase and its deficiency is associated with abnormal glycosylation of α-dystroglycan and results in Fukuyama’s

Table 1 ContinuedOther dystrophiesFacioscapulohumeral AD 4q�5 ?Scapuloperonealdystrophy AD 5q��.�-�1.� Myotilin AD 1� ?Oculopharyngeal AD 14q11.�-1� PABP�Myotonicdystrophy-1 AD 1�q1�.� DMPKMyotonicdystrophy–� AD �q�1 ZNF�

*LGMD�BandMiyoshidistaldystrophyarethesamecondition

AD=autosomaldominant;AR=autosomalrecessive;CMD=congenitalmusculardystrophies;GNE=UDP-N-acetylglucosamine�-epimerase/n-acetylmannosaminekinase;LGMD=limb-girdlemusculardystrophy;POMT1=O-mannosyltransferasegene;POMGnT1=O-mannose β-1,2-N-acetylglucosaminyl transferase

congenital muscular dystrophy (FCMD). Mutations in a protein of similar function, fukutin-related protein (FKRP), are found in some patients with MDC with normal merosin (MDC 1C) and in LGMD 2I.27,29,30 Interestingly, impaired glycoslylation of α-dystroglycan are believed to be responsible for other forms of MDC (muscle-eye-brain [MEB] disease and Walker-Warburg syndrome[WWS]).16 Muscle-eye-brain disease is caused by mu-tations in O-mannose-β-1,2-N-acetylglucosaminyl transferase (POMGnT1) and WWS is the result of mutations in O-manno-syltransferase (POMT1). Mutations in the human LARGE gene (also is required for glycoslylation of α-dystroglycan) is responsible for another rare form of MDC with mental retardation.28,83 Thus, it appears that normal glycoslylation of α-dystroglycan is impor-tant for muscle function, but also normal development of the central nervous system which is affected in these forms of MDC. In addition, UDP-N-acetylglucosamine 2-epimerase/n-acetylman-nosamine kinase (GNE), which is involved in the post-translational glycosylation of proteins, is mutated in some forms of autosomal recessive inclusion body myopathy (IBM) also known as the Nonaka type of distal myopathy.

SPECIFIC MUSCULAR DYSTROPHIES

The muscular dystrophies are a group of hereditary, progressive muscle diseases in which there is necrosis of muscle tissue and replacement by connective and fatty tissue. Muscular dystrophies traditionally have been classified according to their pattern of weak-ness (e.g., limb-girdle, facioscapulohumeral, scapuloperoneal) and mode of inheritance (Table 1). Advances in genetics have led to the classification of muscular dystrophies based on the responsible gene defect.

THE DYSTROPHINOPATHIES

Duchenne Muscular Dystrophy

Histopathology

Muscle biopsy in Duchenne muscular dystrophy (DMD) reveals necrotic and regenerating muscle fibers, variability in muscle fiber size, and increased endomysial and perimysial connective tissue.

D-1� Histopathology of Muscular Dystrophies AANEMCourse

Figure 2 Nuclearmembraneandsarcomericproteins responsible forEmery-Dreifussmusculardystrophyand limb-girdlemusculardystrophy1B.From:DalkilicI,KunkelLM.Musculardystrophies:genestopathogenesis.CurrOpinGenetDev�00�;1�:��1-��.4�

AANEMCourse MuscleandNervePathology D-1�

There are also scattered hypertrophic and hypercontracted fibers in addition to small, rounded, regenerating fibers. Fiber splitting and central nuclei can also be seen but occur less often than in other muscular dystrophies. The process of degeneration and regenera-tion continues until the limited regenerative capacity of the satellite cells is exceeded at which time the necrotic muscle tissue is replaced with fat and connective tissue.

Endomysial inflammatory cells consisting of cytotoxic T-lym-phocytes (two-thirds) and macrophages (one-third) are present to a variable degree as well as phagocytize necrotic fibers.3 Rarely nonnecrotic fibers expressing major histocompatibility antigen are invaded by CD8+ cytotoxic T-cells. Immunohistochemistry demonstrates reduced or absent dystrophin on the sarcolemma. Approximately 60% of DMD patients will have some faint stain-ing of the muscle membrane utilizing antibodies directed against the amino-terminal or rod domain of dystrophin. However, less than 1% of muscle fibers have sarcolemmal staining with antibod-ies directed against the carboxy-terminal of dystrophin. The few dystrophin-positive muscle fibers are known as revertants. They arise secondary to spontaneous subsequent mutations that restore the “reading frame” and allow transcription of dystrophin, albeit of abnormal size and shape. On the other hand, utrophin, which is normally restricted to the neuromuscular junction, is overexpressed in DMD and is present throughout the sarcolemma.

Immunoblot or Western blot of muscle tissue assesses both the quantity and size of the dystrophin present. Using carboxy-terminal antibodies, Western blot reveals 0% to 3% of the normal amount of dystrophin present in muscle tissue, and the size of remain-ing dystrophin is usually diminished.68 With amino-terminal or rod-domain antibodies, approximately 50% of DMD patients have some detectable truncated dystrophin. Immunohistochemical analysis in dystrophinopathies may also demonstrate a reduction of dystroglycan, dystrobrevin, and all the sarcoglycan proteins, includ-ing sarcospan.

Becker Muscular Dystrophy

Histopathology

The histological features of Becker muscular dystrophy (BMD) are similar to those observed for DMD, but are less severe.73 Becker muscular dystrophy may be distinguished histologically from DMD with immune staining. In most BMD patients, the pres-ence of dystrophin utilizing carboxy-terminal antibodies on muscle membranes is present. In contrast, immunostaining with antibod-ies directed against the carboxy-terminal of dystrophin is usually negative in DMD. However, the degree and intensity of the dystro-phin staining is usually not normal in BMD. The staining pattern may be uniformly reduced or can vary between and within fibers. Western blot analysis of muscle tissue typically reveals an abnormal quantity and/or size of the dystrophin protein.68,69

Female Carriers

The daughters of men with BMD (males with DMD are usually in-fertile) and the mothers of affected children who also have a family history of DMD or BMD are obligate carriers of the mutated dystrophin gene. Mothers and sisters of isolated DMD or BMD patients are at risk for being carriers. Women carriers are usually asymptomatic, but a few develop muscle weakness.66 These cases are usually explained by the Lyon hypothesis: skewed inactivation of the normal X-chromosome and dystrophin gene results in in-creased transcription of the mutated dystrophin gene. Females with translocations at the chromosomal Xp21 site or Turner’s syndrome (XO genotype) may also develop dystrophinopathies.

Manifesting carriers typically have a mild limb-girdle phenotype similar to BMD. Prior to the recent advances in molecular genetics, these women were often diagnosed with LGMD, particularly when there was no family history of DMD or BMD. Rarely, females manifest severe weakness as seen in DMD.

Histological features of manifesting carriers are similar to those discussed for DMD and BMD. Immunostaining for dystrophin demonstrates an absent, decreased, or mosaic pattern of staining in many female carriers, however staining can be normal.4,40,66,95 Thus, immunostaining and Western blot analysis is not very sensitive in identifying the carrier status of asymptomatic females.

MOLECULAR GENETICS AND PATHOGENESIS OF THE DYSTROPHINOPATHIES

Dystrophin is a structural protein that is intimately bound to the sarcolemma and provides structural integrity to the muscle mem-brane (Figure 1).41 Abnormal quantity or quality of dystrophin results in the muscle losing its ability to maintain its integrity during contraction leading to membrane tears and subsequent muscle fiber necrosis.

The dystrophin gene, located on chromosome Xp21, is composed of approximately 2.4 megabases of genomic deoxyribonucleic acid (DNA), and includes 79 exons, which code for a 14 kb transcript.67,77 The large size of the gene probably accounts for the high spontaneous mutation rate responsible for one-third of new cases. Large deletions—several kilobases to over one million base pairs—can be demonstrated in approximately two-thirds of dystro-phinopathy patients. Approximately 5%-10% of DMD cases are caused by point mutations resulting in premature stop codons.112 Duplications are evident in another 5% of cases. Mutations occur primarily in the center (80%) and near the amino-terminal (20%) of the gene.112 Mutations that disrupts the translational reading frame of the gene lead to near total loss of dystrophin and DMD, while in-frame mutations result in the translation of semifunc-tional dystrophin of abnormal size and/or amount and in outlier or BMD clinical phenotypes.68 Although there are exceptions to the

“reading-frame rule,” 92% of phenotypic differences are explained by in-frame and out-of-frame mutations.112 The clinical severity does not appear to correlate with the location of mutations in DMD. It appears that the quality or remaining functional capabil-ity of the mutated dystrophin protein is more important than the actual quantity. The reduction in the various sarcoglycans, which is also evident on immunohistochemical studies of DMD and BMD, suggests that normal dystrophin is important for the integrity of the sarcoglycan complex.

LIMB-GIRDLE MUSCULAR DYSTROPHY

The LBMDs are a heterogeneous group of disorders that clinically resemble the dystrophinopathies except for the equal occurrence in males and females (Table 1).13,31,32,34,41 The incidence and prevalence of LGMD is approximately 6.5 per 100,000 live births. These dis-orders are inherited in an autosomal recessive or dominant fashion. In the past, patients with a phenotype similar to DMD have been called “severe childhood autosomal recessive muscular dystrophies” (SCARMD), while patients with milder phenotypes similar to BMD have been labeled with the term “limb girdle muscular dystrophy.” Autosomal dominant LGMDs are classified as type 1 (e.g., LGMD 1), while recessive forms are termed type 2 (e.g., LGMD 2). Further alphabetical subclassification has been applied to these disorders as they have become genotypically distinct (e.g., LGMD 2A, LGMD 2B, etc., Table 1). For the most part, the clini-cal, laboratory, and histopathological features of the LGMDs are nonspecific. There are a few that will be discussed later.

AUTOSOMAL DOMINANT LIMB-GIRDLE MUSCULAR DYSTROPHIES

Limb-Girdle Muscular Dystrophy 1A

Histopathology

In LGMD 1A, muscle biopsies are notable for the frequent occur-rence of rimmed vacuoles and occasional nemaline rod-like inclu-sions.39,85 Muscle biopsies can demonstrate features of myofibrillar myopathy on routine light microscopy, immunohistochemistry, and electron microscopy (EM).118

Molecular Genetics and Pathogenesis

Limb-girdle muscular dystrophy 1A is caused by mutations in the gene that encodes for myotilin located on chromosome 5q22.3-31.3.62,118 Myotilin is a sarcomeric protein that co-localizes with α-actinin at the Z-disc. Some of the clinical, laboratory, and histological features are similar to those described in autosomal dominant hereditary IBM (h-IBM) and myofibrillar myopathy. In fact, recently some patients with myofibrillar myopathy have been found to have mutations in the myotilin gene.118

Limb-Girdle Muscular Dystrophy 1B

Histopathology

In LGMD 1B, muscle biopsies demonstrate variation in fiber size, increased endomysial connective tissue, normal dystrophin, sarcoglycan, and emerin staining. Occasionally, rimmed vacuoles are evident on muscle biopsy similar to those seen in one of the IBMs.53,133 Lamin A/C expression on the nuclear membrane may be normal or reduced. On EM, myonuclei exhibit the loss of periph-eral heterochromatin or its detachment from the nuclear envelope, altered interchromatic texture, and fewer nuclear pores compared to normal.116


Limb-girdle muscular dystrophy 1B is caused by mutations in lamin A/C on chromosome 1q11-21.19,20,57 The pathogenic role of lamin A/C is discussed in more detail in the EDMD section.

Limb-Girdle Muscular Dystrophy 1C

Histopathology

Muscle biopsies in patients with LGMD 1C show nonspecific myo-pathic features with normal dystrophin, sarcoglycan, and merosin staining. In contrast, there is reduced caveolin-3 staining along the sarcolemma. Electron microscopy reveals a decreased density of caveoli on the muscle membrane.


Limb-girdle muscular dystrophy 1C is caused by mutations in the caveolin-3 gene located on chromosome 3p25.37,96 Caveolin-3 is localized by immunostaining to the sarcolemma (Figure 1). It co-fractionates with the dystrophin-glycoprotein complex, but is thought to be part of a discrete complex. Caveolins play a role in the formation of caveolae membranes, where they act as scaffolding proteins to organize and concentrate caveolin-interacting lipids and proteins.96 Caveolin-3 might also function to facilitate organization of signaling complexes and the sodium channels that might con-tribute to the pathogenesis of rippling muscle disease.

AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHIES

Limb-Girdle Muscular Dystrophy 2A

Histopathology

Muscle biopsies in patients with LGMD 2A show variation in fiber size and increased endomysial connective tissue. One of the striking features is the frequent lobulated appearance of fibers on nicotin-amide adenine dinucleotide hydrogen (NADH) staining. However,

D-14 Histopathology of Muscular Dystrophies AANEMCourse

this finding is not specific for calpainopathies. Interestingly, severe cases of eosinophic myositis in children were subsequently shown to be LGMD 2A.78 As this is a cytosolic enzyme, immunostaining cannot be performed for diagnosis. However, Western blot analysis demonstrates reduced calpain-3. Definite diagnosis requires dem-onstration of a mutation in calpain-3 gene because secondary defi-ciency in calpain-3 can be seen in other dystrophies, most notably the dysferlinopathies and titinopathies.


Limb-girdle muscular dystrophy 2A is caused by mutations in the calpain-3 gene.14,55,114,115,124 Large series of LGMD patients have shown that calpainopathies account for approximately 20%-26% of dystrophies with normal dystrophin and sarcoglycans.55,56 Over two-thirds of patients with calpainopathy manifest with a BMD-like phenotype, approximately 10% present with severe childhood onset weakness early similar to DMD, 3% have a distal myopathy, and 6% have asymptomatic hyper-CK-emia.56

Calpain-3 is a muscle-specific, calcium-dependent, nonlysosomal, proteolytic enzyme. The mutations lead to an absence or reduction in this enzyme, but how this results in the dystrophic process is unknown. Calpain-3 activates other enzymes involved in muscle metabolism.114 Lack of calpain-3 might lead to the accumulation of toxic substances in muscle cells. Perhaps calpain-3 plays a role in gene expression by regulating turnover or activity of transcription factors or their inhibitors.114

Limb-Girdle Muscular Dystrophy 2B

Histopathology

In patients with LGMD 2B, muscle biopsies show variation in fiber size and increased endomysial connective tissue. Immunostaining reveals absent or diminished sarcolemmal staining with dysferlin antibodies. In contrast, there may be increased cytoplasmic stain-ing. The reduced sarcolemmal immunostaining can be secondary and seen in other types of LGMD,111 therefore Western blot needs to be performed on the muscle or white blood cells to confirm a primary deficiency. Not uncommonly, a prominent mononuclear inflammatory cell infiltrate is evident in the endomysium and surrounding blood vessels. Many cases of dysferlinopathy are thus initially misdiagnosed as polymyositis.60 In contrast to polymyo-sitis, the inflammatory cells do not appear to invade nonnecrotic fibers. Another helpful immunohistological feature is demonstrat-ing deposition of membrane attack complex on the sarcolemma of nonnecrotic muscle fibers. This is seen as an early finding in dys-ferlinopathies and other dystrophies with inflammation not seen in primary inflammatory myopathies such as polymyositis, diabetes mellitus, and IBM. On EM, reduplication of the basal lamina, disruption in the sarcolemma, invaginations or papillary exophytic defects of the muscle membrane, and subsarcolemma vesicles may be appreciated.119


Mutations within the dysferlin gene are the cause of Miyoshi myopathy, LGMD 2B, and some distal myopathies with anterior tibial weakness.12,70,81 A study of 407 muscle biopsies from patients with unclassified myopathies (normal dystrophin and sarcoglycan) demonstrated that 6.5% had abnormal dysferlin by Western blot and immunostaining.56 Dysferlinopathy accounted for 1% of pa-tients with an unknown LGMD and 60% of patients with a distal myopathy. The clinical phenotype of patients with dysferlinopathy broke down as follows: 80% manifest with distal weakness, 8% have LGMD phenotype, and 6% present with asymptomatic hyper-CK-emia.

Dysferlin shares amino acid sequence homology with C. elegans sper-matogenesis factor FER-1, thus, the origin of its name. Dysferlin is located predominantly on the subsarcolemmal surface on the muscle membrane, but it has a small transmembrane spanning tail (Figure 1). It does not appear to have a significant interaction with the dystrophin-glycoprotein complex and immunostaining for dys-trophin, dystroglycans, merosin, and the sarcoglycans are normal. The major role of dysferlin is patching defects in skeletal membrane and mutations in the gene result in defective membrane repair.9,38 Dysferlin is present on white blood cells and therefore Western blot of these cells can confirm the deficiency.65

Sarcoglycanopathies

Histopathology

In sarcoglycanopathies (LGMD 2C, LGMD 2D, LGMD 2E, LGMD 2F), muscle biopsies demonstrate normal dystrophin, however, each of the sarcoglycans are absent or diminished on the sarcolemma, regardless of the primary sarcoglycan mutation.


Limb-girdle muscular dystrophy 2C, 2D, 2E, and 2F are caused by mutations in the γ-sarcoglycan, α-sarcoglycan, β-sarcoglycan, and δ-sarcoglycan genes, respectively.1,2,21,36,41,45,46,47,54,82,91 The clinical phenotypes appear to correlate with the expression of the sarcogly-cans. The proteins of the sarcoglycan complex appear to function as a unit. Mutations involving any of the sarcoglycans results in destabilization of the entire complex and reduced expression of the other proteins. As apparent with the dystrophinopathies, the clinical severity of the sarcoglycanopathies may correlate with the type of mutation (i.e., whether the reading frame is preserved) and subsequent level of functional protein expression.

Limb-Girdle Muscular Dystrophy 2G

Histopathology

In patients with LGMD 2G, besides the usual dystrophic fea-tures, many muscle fibers had one or more rimmed vacuoles.


Immunohistochemistry and Western blot analysis demonstrate a deficiency of telethonin.100


Limb-girdle MD 2G is caused by mutations in the telethonin gene located on chromosome 17q11-12.100 Telethonin is a 19 kD sarcomeric protein that is expressed in skeletal and cardiac muscles, where it localizes to the central parts of the Z-disk.101 It is a ligand for the giant sarcomeric protein, titin, which itself phosphorylates the C-terminal domain of telethonin in early differentiating myo-cytes. Telethonin may also overlap with myosin. It is one of the most abundant proteins in muscle. The interaction of telethonin with titin appears to be important in myofibrillogenesis.90,101

Limb-Girdle Muscular Dystrophy 2H/Sarcotubular Myopathy

Histopathology

Typical dystrophic features are seen on muscle biopsy of patients with LGMD 2H. Increases in internal nuclei, muscle-fiber splitting, and many fibers (mostly type 2) with small vacuoles are seen.72,117 These vacuoles abut T-tubules and appear to be membrane bound, and also appear empty or contain a small amount of amorphous debri on EM. The vacuoles immunostain for sarcoplasmic reticu-lum-associated adenosine triphosphase (ATPase).


Limb-girdle muscular dystrophy and sarcotubular myopathy are allelic disorders caused by mutations in the gene that encodes for E3-ubiquitine ligase (also known as TRIM 32)117 located on chro-mosome 9q31-q33, as was recently reported.59 E3-ubiquitine ligase may function by ubiquinating proteins that need degradation by proteosomes. The mechanism by which this leads to muscle de-struction is unclear, but it is speculated that it is related to the pos-sible toxic accumulation of “aged” or otherwise abnormal proteins not cleared by proteasomes.

Limb-Girdle Muscular Dystrophy 2I

Histopathology

Nonspecific dystrophic features are evident on muscle biopsy in patients with LGMD 2I. A clue to the diagnosis is that there is reduced α-dystroglycan and occasional merosin with immunostain-ing.


Limb-girdle muscular dystrophy 2I is caused by mutations in the gene that encodes for FRRP located on chromosome 19q13.29

Mutations in this gene are also responsible for MDC type 1C. Fukutin-related protein is a glycosyltransferase and its defi-ciency is associated with abnormal glycosylation of α-dystroglycan, which apparently disrupts the dystrophin-glycoprotein complex. Abnormalities in glycosylation of α-dystroglycan is a recurring theme in the MDCs as this is also a causative mechanism in FCMD, MEB, WWS, and LARGE-related MDC (MDC 1D). There is a correlation between a reduction in α-dystroglycan, the mutation, and the clinical phenotype in MDC 1C and LGMD 2I.30

Fukutin-related protein localizes in rough endoplasmic reticulum, while fukutin localizes in the cis-Golgi compartment.88 Fukutin and FKRP appear to be involved at different steps in O-mannosylg-lycan synthesis of α-dystroglycan, and FKRP is most likely involved in the initial step in this synthesis. Endoplasmic reticulum-reten-tion of mutant FKRP may play a role in the pathogenesis of these dystrophies and potentially explain why the allelic disorder LGMD 2I is milder, because the mutated protein is able to reach the Golgi apparatus.52

Limb-Girdle Muscular Dystrophy 2J

Histopathology

Muscle biopsies in patients with LGMD 2J demonstrate vari-ability in fiber size, increased central nuclei, split fibers, increased endomysial connective tissue and often rimmed vacuoles (as in Markesbery-Griggs/Udd distal myopathy, to be discussed later).


Limb-girdle muscular dystrophy 2J is caused by mutations in the titin gene.

CONGENITAL MUSCULAR DYSTROPHIES

The MDCs are a heterogeneous group of autosomal recessive in-herited disorders characterized by perinatal onset of hypotonia and weakness, dystrophic-appearing muscle biopsies, and the exclusion of other recognizable causes of myopathy of the newborn (Table 1). The abbreviation assigned by the Human Genome Organization is “MDC” for muscular dystrophy, congenital. The MDCs have been classified in the past according to clinical, ophthalmological, radiological, and pathological features. A more recent classification


was proposed based on the location of the defective proteins and purported pathogeneses of the individual dystrophies: (1) those associated with mutations in genes encoding structural proteins of the basal lamina, extracellular matrix, or sarcolemmal proteins that bind to the basal lamina, (2) those associated with impaired glycolylation of α-dystroglycan, and (3) those associated with sele-noprotein 1 mutations.

Congenital Muscular Dystrophy Associated With Genetic Defects of Structural Proteins of the Basal Lamina or Extracellular Matrix

Histopathology

Muscle biopsies of MDC 1A (also known as MDC with laminin α2 or merosin deficiency or the classic/occidental type) reveal a varia-tion in muscle fiber size, scattered regenerating and degenerating fibers, and increased endomysial connective tissue. Immunostaining reveals reduced or absent merosin.

Congenital muscular dystrophy 1A is associated with mutations in a-2 subchain of merosin on chromosome 6q21-22. The gene codes for a 390 kD protein that is synthesized as one chain but processed into two fragments. On immunoblot, these two fragments have molecular masses of approximately 80 kD (C-terminal) and 300 kD (N-terminal).120 Merosin binds to α-dystroglycan and α7b1D integrin (Figure 1). As with primary dystrophinopathies and ad-halinopathies, the merosinopathies may result in a disruption and loss of integrity of the dystrophin-glycoprotein complex. In addi-tion, mutations involving the α7 subunit of integrin that binds to merosin also results in a form of MDC.63

Ullrich Disease/Bethlem Myopathy

Histopathology

In patients with Ullrich disease, muscle biopsies reveal variation in muscle fiber size, scattered regenerating and degenerating fibers, and increased endomysial connective tissue. Immunohistochemistry reveals that collagen VI is present in the interstitium but absent from the sarcolemma.71 Ultrastructural studies demonstrate that collagen VI in the interstitium fails to anchor normally to the basal lamina surrounding muscle fibers.


Collagen VI is composed of three chains, α1, α2, and α3 and is a ubiquitously expressed extracellular matrix protein. The three chains are encoded by the genes COL6A1 and COL6A2 on chro-mosome 21q223 and COL6A3 on chromosome 2q37. Ullrich congenital muscular dystrophy (UCMD) had been considered a

recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In con-trast, the milder disorder Bethlem myopathy, shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2, and COL6A3.7 Recent studies have demonstrated that UCMD can be inherited in a dominant fashion as well.7

Congenital Muscular Dystrophies Associated With Impaired Glycoslylation of Alpha-Dystroglycan

The primary sequence of α-dystroglycan predicts a molecular mass of 72 kD; however, the mass of α-dystroglycan in skeletal muscle is 156 kDa.104 The increase in actual size is due to the post-trans-lational modification of α-dystroglycan. In this regard, O-linked glycosylation of the protein makes the major contribution to the observed molecular weight. The glycosyltransferase O-mannosyl-transferase 1 (POMT1) forms a complex with a second putative O-mannosyltransferase (POMT2) to catalyzes the first step in O-mannosylglycosylation.103,104 Subsequently, the transfer of N-acetylglucosamine to O-mannose of glycoproteins is catalyzed by O-mannose β-1,2-N-acetylglucosaminyltransferase (POMGnT1). Fukutin, FKRP, and LARGE are other secretory enzymes involved in posttranslational glycoslylation of α-dystroglycan although the exact reactions they catalyze are not known.103,104 Glycosylation of α-dystroglycan is required for normal binding to merosin.74 Impaired glycosylation of α-dystroglycan is not only important for proper muscle function, it also leads to defects in neuronal migra-tion and the abnormalities in the central nervous system (CNS) seen with FCMD, WWS, MEB disease, MDC 1C, and MDC 1D.

Muscle biopsy findings are indistinguishable from other forms of MDC using routine stains. A striking inflammatory infiltrate is occasionally present which has led to the erroneous diagnosis of a congenital inflammatory myopathy or polymyositis. Importantly, abnormal glycosylation of a-dystroglycan caused by mutations responsible for FCMD, MEB, WWS, MDC 1C, and MDC 1D can be appreciated by reduced immunostaining of the sarcolem-mal membrane with antibodies directed against α-dystroglycan and merosin.15,42,44,136

Fukuyama Congenital Muscular Dystrophy


Fukuyama congenital muscular dystrophy is caused by muta-tions in the fukutin gene which is located on chromosome 9q31.76,127,128,140 Fukutin is a secretory enzyme that localizes to the cis-Golgi compartment and is thought to have a role in posttransla-tional glycoslylation of α-dystroglycan.88 In addition to the skeletal muscle involvement, the disruption of normal glycosylation of


α-dystroglycan or other proteins leads to defects in neuronal migra-tion and differentiation that accounts for the many abnormalities seen within the CNS.

Walker-Warburg Syndrome


So far, four genes (the POMT1, POMT2, fukutin, and FKRP genes) have been implicated in WWS, but they account for only a minority of cases.15,42,44,104,135 Mutations in the POMT1 gene on chromosome 9q31-33 account for the majority of cases (20%) of WWS, but in most cases the genetic defects remain unknown.42,104 The clinical phenotype of patients with mutations in the POMT1 gene is also variable with rare cases reported with LGMD and mild mental retardation.8 Glycosylation of α-dystroglycan is required for normal binding to merosin.74

Muscle-Eye-Brain Disease or Santavouri Type


Muscle-eye-brain disease is caused by mutations in the gene that encodes for O-mannose-β-1,2-N-acetylglucosaminyl transferase (POMGnT1) on chromosome 1p32-p34.42,44,140 POMGnT1 cata-lyzes the transfer of N-acetylglucosamine to O-mannose of glyco-proteins.

Congenital Muscular Dystrophy 1C

Clinical Features

Congenital muscular dystrophy 1C is allelic to LGMD 2I and caused by mutations in the FKRP gene. The FKRP-related myopa-thies are common—especially among Caucasians—and give rise to the largest phenotypic spectrum of muscular dystrophies so far connected to mutations of a single gene.103,104 The age of onset can range from infancy (e.g., congenital) to the fourth decade of life with a pattern of weakness similar to MDC 1A, MDC with CNS abnormalities typical of WWS, or a mild proximal weakness with onset in adulthood similar to BMD or a LGMD.


Congenital muscular dystrophy 1C is caused by mutations in the gene that encodes for FRKP located on chromosome 19q13.3. Fukutin related protein localizes in rough endoplasmic reticulum and appears to be involved in one of the initial steps in O-man-nosylglycan synthesis of α-dystroglycan.88 Endoplasmic reticulum-retention of mutated FKRP may play a role in the pathogenesis

and potentially explain why the allelic disorder LGMD 2I is milder, because the mutated protein is able to reach the Golgi apparatus.52 There is a correlation between a reduction in α-dystroglycan, the mutation, and the clinical phenotype in MDC 1C and LGMD 2I.30 Patients with MDC 1C have a profound depletion of α-dys-troglycan, those with a Duchenne-like phenotype have a moderate reduction in α-dystroglycan, and individuals with the milder form of LGMD 2I demonstrate a variable but subtle alteration in α-dys-troglycan immunolabeling.

Congenital Muscular Dystrophy 1D


Mutations in the human LARGE gene (also required for glyco-slylation of α-dystroglycan) is responsible MDC 1D, a rare form of CMD.28,83 This gene encodes for another putative glycosyltrans-ferase.

Congenital Muscular Dystrophy Associated With Selenoprotein n1 Mutations

Rigid Spine Syndrome

Rigid spine syndrome or rigid spine muscular dystrophy (RSMD) is a heterogeneic disorder. One subtype, RSMD 1, manifests in infancy with hypotonia, proximal weakness, and delayed motor milestones.84,92,93,98,99,113,126 Affected patients develop progressive limitation of spine mobility often associated with scoliosis and contractures at the knees and elbows.

Histopathology

Muscle biopsies in RSMD patients reveal nonspecific myopathic features including variability in fiber size, increased internal nuclei, type-1 fiber predominance, and moth-eaten fibers and lobulated fibers on NADH dehydrogenase stains. Some cases are associated with multiple minicores. Cytoplasmic bodies, Mallory bodies, increased desmin expression, and sarcoplasmic and intranuclear tubulofilamentous inclusions may also be present.113 Endomysial fibrosis is apparent, particularly in axial muscles (i.e., rectus ab-dominus and paraspinal muscles). Immunostains for dystrophin, sarcoglycans, and the dystroglycans are normal.


Some cases of autosomal recessive RSMD have been linked to mutations in the gene that encodes for selenoprotein N1 located on chromosome 1p35-36.58,98,99 Mutations in this gene have also been shown in some patients with multi/minicore myopathy.


Selenoprotein N1 is an endoplasmic reticulum glycoprotein. The function of this protein is not known.

OTHER REGIONAL FORMS OF MUSCULAR DYSTROPHY

Facioscapulohumeral Muscular Dystrophy

Histopathology

Muscle biopsy in facioscapulohumeral muscular dystrophy (FSHD) demonstrates variation in muscle fiber size with atrophic and hy-pertrophic fibers, scattered necrotic and regenerating fibers, in-creased internalized nuclei, and increased endomysial connective tissue.75 Prominent mononuclear inflammatory infiltrate may be appreciated in the endomysium, which can lead to confusion with polymyositis.102 Immunostaining with antibodies directed against membrane attack complex may demonstrate deposition on the sarcolemma of nonnecrotic muscle fibers.


The pathogenesis of FSHD is unknown. Facioscapulohumeral muscular dystrophy is an autosomal dominant disorder linked to the telomeric region of chromosome 4q35.138 An EcoRI polymor-phism in this region is present in the majority of FSHD patients on chromosome 4q35. This EcoRI polymorphism is variable in size, but is reduced compared to normal subjects (FSHD 10 to 30 kB; normal subjects 50 to 300 kB). Within this EcoRI polymorphism lies a tandem array of 3.3 kB repeats. Normally there are 12-96 copies of this repeat, but in FSHD there are less than 8 copies.

X-Linked Emery-Dreifuss Muscular Dystrophy

Histopathology

The muscle biopsy findings for X-linked Emery-Dreifuss muscular dystrophy can be quite variable depending upon the degree of weakness of the biopsied muscle.51 There is usually muscle-fiber size variation with type-1 fiber atrophy. There can be a predominance of either type-1 or type-2 muscle fibers. Muscle fiber splitting, increased central nuclei, and endomysial fibrosis may be seen. Immunohistochemistry reveals the absence of emerin as well as abnormal lamin A/C and lamin B2 on the nuclear membrane.106,109 Ultrastructural studies demonstrates the focal absence of peripheral heterochromatin in areas between the nuclear pores, irregular and uniform thickening of the nuclear lamina, compaction of hetero-chromatin in areas of irregular thickening of the nuclear lamina, and areas where the peripheral heterochromatin does not adhere to the nuclear lamina.109 Diagnosis can be confirmed by immunos-taining muscle or skin tissue for emerin or by immunoblot analysis of leukocytes.


Emery-Dreifuss muscular dystrophy is caused by mutations in a gene (STA) located on chromosome Xq28 which encodes for emerin (Table 1).17 Emerin is located on the inner nuclear mem-branes of skeletal, cardiac, and smooth muscle fibers as well as skin cells.105,106 The carboxy-terminal tail anchors the protein to the inner nuclear membrane while the remainder of the protein projects into the nucleoplasm. Emerin is a member of the nuclear lamina-associated protein (LAP) family.105,106,109 The nuclear lamina is composed of intermediate sized filaments (i.e., lamins A, B, and C) associated with the nucleoplasmic surface of the inner nuclear membrane. These lamins bind to various LAPs, including LAP1, LAP2, and lamin B receptor, which are located on the inner nuclear membrane. Lamina-associated protein 2, lamin B receptor, and the lamins also bind to chromatin and thereby promote its attachment to the nuclear membrane. Mutations in emerin conceivably lead to disorganization of the nuclear lamina and heterochromatin that is apparent on EM and immunohistochemistry.109

Autosomal Dominant Emery-Dreifuss Muscular Dystrophy

The histopathological features of autosomal dominant Emery-Dreifuss muscular dystrophy (LGMD 1B) are identical to those described above for typical X-linked EDMD.19,20,57 Thus, as noted previously, AD-EDMD and LGMD 1B are allelic disorders caused by mutations in the lamin A/C gene (LMNA) located on chromo-some 1q11-23.13,19,20,134

Lamins A and C are produced by alternative splicing of the lamin A/C ribonucleic acid (RNA) transcript. As previously discussed with X-linked EDMD, these lamins are important in the organiza-tion and integrity of the nuclear membrane. Muscle biopsies dem-onstrate variation in fiber size, increased endomysial connective tissue, normal emerin expression, but lamin A/C expression may be reduced on nuclear membranes. However, immunostaining with lamin A/C antibodies is sometimes normal. Electron microscopy reveals nuclear alterations similar to X-linked EDMD in 10% of muscle fibers.105,116 There is loss of peripheral heterochromatin or detachment from the nuclear envelope, alterations in interchroma-tin texture, and fewer nuclear pores compared to normal.

Oculopharyngeal Muscular Dystrophy

Histopathology

The muscles most severely involved in oculopharyngeal muscular dystrophy (OPMD) are the extraocular and pharyngeal muscles, although minor abnormalities may be detectable in the limb muscles in advanced cases. Muscle biopsies reveal variation in fiber size, degenerating and regenerating fibers, increased internal nuclei,


and an increase in adipose and endomysial connective tissue.26,64 Rimmed vacuoles similar to those found in IBM/myopathy and some of the distal myopathies are often, though not universally, observed. Intranuclear inclusions are evident in up to 9% of muscle nuclei on EM.18 These tubulofilamentous inclusions have an outer diameter of approximately 8.5 nm, an inner diameter of 3 nm, are up to 0.25 µm in length, and are often arranged in tangles or palisades.18 In addition, 15-18 nm tubulofilaments may be evident in the cytoplasm as seen in inclusion body myositis, hereditary inclusion body myopathy, and some of the distal myopathies. Oculopharyngeal muscular dystrophy can be distinguished from various mitochondrial myopathies by the lack of ragged red fibers. However, there have been a few cases of abnormal mitochondrial structure and quantity on EM, although these findings are mostly suspected to be age-related. Further, muscle biopsies of pharyngeal muscles (taken at time of cricopharyngeal myotomy-anectdotal observations) reveal more severe abnormalities along with frequent rimmed vacuoles, ragged red fibers, and nemaline rods. Sural nerve biopsy in a few patients revealed a mild reduction in myelinated and unmyelinated nerve fibers; however, this could have been normal given the patients’ advanced ages.


Oculopharyngeal muscular dystrophy is caused by expansions of a short glucagons (GCG) repeat within the poly(A) binding protein nuclear (PABN1) gene on chromosome 14q11.1.18,25,26,64 Normally, there are six GCG repeats encoding for a polyalanine tract at the N-terminus of the protein, but approximately 2% of the population have polymorphism with seven GCG repeats (GCG)7. In OPMD, there is an expansion to 8-13 repeats (GCG)8-13. Patients who are heterozygous for (GCG)8-13 and the (GCG)7 polymorphism are also more severely affected. Interestingly, a late-onset, autosomal reces-sive form of OPMD can develop in patients who are homozygous for the (GCG)7 polymorphism. The PABN1 (GCG)7 allele was the first example of a polymorphism that could act as a modifier of a dominant phenotype or as a recessive mutation.

Poly(A) binding protein nuclear is found mostly in dimeric and oligomeric form in the nuclei.35,121 Poly(A) binding protein nuclear is involved in polyadenylation of mitochondrial RNA (mRNA) and is adjoined to the polyadenylated mRNA complex for transport through the nuclei pores into the cytoplasm. In the cytoplasm, the PABPN1 detaches from the mRNA. The mRNA is translated into protein and the PABPN1 is actively transported back into the nuclei. The expansion of the GCG repeats probably results in abnormal folding of the polyalanine domains of PABPN1. The misfolded proteins are ubiquinated but are resistant to nuclear proteosomal degradation. The mutated PABPN1 oligomers then accumulate as the 8.5 nm intranuclear tubulofilamentous inclu-sions become apparent on EM.25,35,121 The more severe clinical phe-notypes are associated with a large number of myonuclei containing intranuclear inclusions.18 The aggregation of mutated PABPN1

may lead to disruption of various nuclear or cytoplasmic processes leading to cell death.

DISTAL MUSCULAR DYSTROPHIES

This author considers the distal myopathies to be forms of muscular dystrophy.10,11 The distal myopathies are characterized clinically by progressive atrophy and weakness of distal arm or leg muscles and histologically by nonspecific myopathic features on muscle biopsy. Advances in the molecular genetics of these disorders support this notion as some types of distal myopathy have been found to be allelic with specific types of LGMD (Markesbery-Griggs/Udd distal myopathy and LGMD caused by titin mutations; Miyoshi my-opathy and LGMD 2B caused by dysferlin mutations). The distal myopathies can be subdivided based upon the clinical features, age of onset, CK levels, muscle histology, and mode of inheritance.

Welander Distal Myopathy

Histopathology

In Welander distal myopathy, muscle biopsies demonstrate vari-ability in fiber size, increased central nuclei, split fibers, increased endomysial connective tissue, and adipose cells in long-standing disease.22,23,24,48,80,86 Furthermore, rimmed vacuoles typical of IBM, h-IBM, and OPMD are seen in scattered muscle fibers. Electron microscopy also reveals 15-18 nm cytoplasmic and nuclear fila-ments similar to those observed in IBM, h-IBM, and OPMD. In addition, disruption of myofibrils and accumulation of Z-disk derived material similar to that found in myofibrillar myopathy also can be demonstrated. Nerve biopsies may reveal a moderate reduction of mainly small diameter, myelinated fibers.23


The pathogenesis of Welander distal myopathy is unknown. It has been linked to chromosome 2p13; the gene has not been identi-fied.

Udd Distal Myopathy

Histopathology

In Udd distal myopathy, muscle biopsies reveal nonspecific myopathic features similar to that seen in Welander myopa-thy.86,110,129,130


Mutations in the gene that encode for titin on chromosome 2q31-33 have been identified.61,131 The giant protein titin (also known as connectin) is attached to the Z disk and spans from the M-line

D-�0 Histopathology of Muscular Dystrophies AANEMCourse

to the Z-line of the sarcomere. Titin serves to connect the myosin filaments to the Z-disk and probably plays an important role in myofibrillogenesis.

Nonaka Distal Myopathy (Autosomal Recessive Inclusion Body Myopathy)

Histopathology

In Nonaka distal myopathy, muscle biopsies demonstrate rimmed vacuoles with muscle fibers as well as other nonspecific myo-pathic features as described in the other forms of distal myopa-thy.5,6,50,97,107,108,122,125 Because of the frequent rimmed vacuoles the biopsy can be erroneously interpreted as IBM. However, inflam-mation cell infiltrate is usually absent. Electron microscopy dem-onstrates 15-18 nm intranuclear and cytoplasmic tubulofilaments similar to that found in sporadic IBM.


Nonaka myopathy and autosomal recessive h-IBM are allelic disorders caused by mutations in the gene that encode for GNE on chromosome 9p1-q1.5,49,50 There is GNE involved in the post-translational glycosylation of proteins to form glycoproteins.

Laing Distal Myopathy

Histopathology

Muscle biopsies in Laing distal myopathy demonstrate nonspecific myopathic features. Rimmed vacuoles are not seen.


Laing distal myopathy has been linked to mutations in myosin heavy chain 7 (MHC7) located on chromosome 14q.79

SUMMARY

Muscular dystrophies can result from mutations affecting structural proteins localizable to the sarcolemma proteins, nuclear membrane, basement membrane, and sarcomere as well as nonstructural enzy-matic proteins. An understanding of the relevant muscle proteins that are affected in the various dystrophies is important in under-standing their histopathology.

BIBLIOGRAPHY

Modified from: Amato AA, Dumitru D. Hereditary myopathies. In: Dumitru D,

Amato AA, Zwarts MJ, editors. Electrodiagnostic medicine, 2nd edition. Philadelphia: Hanley & Belfus Inc; 2002. p 1265-1370.

Amato AA. Muscular dystrophy: Duchenne, Becker, and limb-girdle. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of the neurologi-cal sciences. San Diego: Academic Press; 2003. p 292-303.

Amato AA, Barohn RJ. Principles and practice of neuromuscular disease. New York: McGraw-Hill: (in preparation).

REFERENCES

1. Angelini C, Fanin M, Freda MP, Duggan DJ, Siciliano G, Hoffman EP. The clinical spectrum of sarcoglycanopathies. Neurology 1999;52:176-179.

2. Angelini C, Fanin M, Menegazzo E, Freda MP, Duggan DJ, Hoffman EP. Homozygous alpha-sarcoglycan mutation in two siblings: one asymptomatic and one steroid-responsive mild limb-girdle muscular dystrophy patient. Muscle Nerve 1998;21:769-775.

3. Arahata K, Engel AG. Monoclonal antibody analysis of mono-nuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984;16:193-208.

4. Arahata K, Ishihara T, Kamakura K, Tsukahara T, Ishiura S, Baba C, Matsumoto T, Nonaka I, Sugita H. Mosaic expression of dystrophin in symptomatic carriers of Duchenne’s muscular dystrophy. N Engl J Med 1989;320:138-142.

5. Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 2003;60:1519-1523.

6. Argov Z, Yarom R. “Rimmed vacuole myopathy” sparing the quadri-ceps. A unique disorder in Iranian Jews. J Neurol Sci 1984;64:33-43.

7. Baker NL, Morgelin M, Peat R, Goemans N, North KN, Bateman JF, Lamande SR. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 2005;14:279-293.

8. Balci B, Uyanik G, Dincer P, Gross C, Willer T, Talim B, Haliloglu G, Kale G, Hehr U, Winkler J, Topaloglu H. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retarda-tion is allelic to Walker-Warburg syndrome (WWS) caused by a muta-tion in the POMT1 gene. Neuromuscul Disord 2005;15:271-275.

9. Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, McNeil PL, Campbell KP. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003;423:168-172.

10. Barohn RJ, Amato AA. Distal myopathies. Semin Neurol 1999;19:45-58.

AANEMCourse MuscleandNervePathology D-�1

11. Barohn RJ, Amato AA, Griggs RC. Overview of distal myopathies: from the clinical to the molecular. Neuromuscul Disord 1998;8:309-316.

12. Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M, Richard I, Marchand S, Bourg N, Argov Z, Sadeh M, Mahjneh I, Marconi G, Passos-Bueno MR, Moreira Ede S, Zatz M, Beckmann JS, Bushby K. A gene related to Caenorhabditis elegans spermato-genesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 1998;20:37-42.

13. Beckmann JS, Brown RH, Muntoni F, Urtizberea A, Bonnemann C, Bushby KM. 66th/67th ENMC sponsored international workshop: The limb-girdle muscular dystrophies, 26-28 March 1999, Naarden, The Netherlands. Neuromuscul Disord 1999;9:436-445.

14. Beckmann JS, Richard I, Broux O, Fougerousse F, Allamand V, Chiannilkulchai N, Lim LE, Duclos F, Bourg N, Brenguier L, Pasturaud P, Quetier F, Roudaut C, Sunada Y, Meyer J, Dincer P, Lefranc G, Merlini L, Topaloglu H, Tome FM, Cohen D, Jackson CE, Campbell KP, Fardeau M. Identification of muscle-specific calpain and beta-sarcoglycan genes in progressive autosomal reces-sive muscular dystrophies. Neuromuscul Disord 1996;6:455-462.

15. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, van Bokhoven H, Brunner HG. Mutations in the O-man-nosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033-1043.

16. Beltran-Valero de Bernabe D, Voit T, Longman C, Steinbrecher A, Straub V, Yuva Y, Herrmann R, Sperner J, Korenke C, Diesen C, Dobyns WB, Brunner HG, van Bokhoven H, Brockington M, Muntoni F. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet 2004;41:e61.

17. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 1994;8:323-327.

18. Blumen SC, Brais B, Korczyn AD, Medinsky S, Chapman J, Asherov A, Nisipeanu P, Codere F, Bouchard JP, Fardeau M, Tome FM, Rouleau GA. Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. Ann Neurol 1999;46:115-118.

19. Bonne G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K. Mutations in the gene encod-ing lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999;21:285-288.

20. Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M, Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, Cuisset JM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C, Toniolo D, Fardeau M, Schwartz K, Muntoni F. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 2000;48:170-180.

21. Bonnemann CG, Modi R, Noguchi S, Mizuno Y, Yoshida M, Gussoni E, McNally EM, Duggan DJ, Angelini C, Hoffman EP. Beta-sarcoglycan (A3b) mutations cause autosomal recessive mus-cular dystrophy with loss of the sarcoglycan complex. Nat Genet 1995;11:266-273.

22. Borg K, Ahlberg G, Borg J, Edstrom L. Welander’s distal myopathy: clinical, neurophysiological and muscle biopsy observations in young and middle aged adults with early symptoms. J Neurol Neurosurg Psychiatry 1991;54:494-498.

23. Borg K, Solders G, Borg J, Edstrom L, Kristensson K. Neurogenic involvement in distal myopathy (Welander). Histochemical and mor-phological observations on muscle and nerve biopsies. J Neurol Sci 1989;91:53-70.

24. Borg K, Tome FM, Edstrom L. Intranuclear and cytoplasmic fila-mentous inclusions in distal myopathy (Welander). Acta Neuropathol Berl 1991;82:102-106.

25. Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, Blumen S, Korczyn AD, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau GA. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 1998;18:164-167.

26. Brais B, Rouleau GA, Bouchard JP, Fardeau M, Tome FM. Oculopharyngeal muscular dystrophy. Semin Neurol 1999;19:59-66.

27. Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 2001;69:1198-1209.

28. Brockington M, Torelli S, Prandini P, Boito C, Dolatshad NF, Longman C, Brown SC, Muntoni F. Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy. Hum Mol Genet 2005;14:657-665.

29. Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LV, Bashir R, Burgunder JM, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I, Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystro-phy MDC1C. Hum Mol Genet 2001;10:2851-2859.

30. Brown SC, Torelli S, Brockington M, Yuva Y, Jimenez C, Feng L, Anderson L, Ugo I, Kroger S, Bushby K, Voit T, Sewry C, Muntoni F. Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol 2004;164:727-737.

31. Bushby K. Genetics and the muscular dystrophies. Dev Med Child Neurol 2000;42:780-784.

32. Bushby K. The limb-girdle muscular dystrophies. Eur J Paediatr Neurol 2001;5:213-214.

33. Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain 1999;122:1403-1420.

34. Bushby KM, Beckmann JS. The 105th ENMC sponsored workshop: pathogenesis in the non-sarcoglycan limb-girdle muscular dystro-phies, Naarden, April 12-14, 2002. Neuromuscul Disord 2003;13:80-90.

35. Calado A, Tome FM, Brais B, Rouleau GA, Kuhn U, Wahle E, Carmo-Fonseca M. Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet 2000;9:2321-2328.

36. Campbell KP. Adhalin gene mutations and autosomal recessive limb-girdle muscular dystrophy. Ann Neurol 1995;38:353-354.

D-�� Histopathology of Muscular Dystrophies AANEMCourse

37. Carbone I, Bruno C, Sotgia F, Bado M, Broda P, Masetti E, Panella A, Zara F, Bricarelli FD, Cordone G, Lisanti MP, Minetti C. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCK-emia. Neurology 2000;54:1373-1376.

38. Cenacchi G, Fanin M, De Giorgi LB, Angelini C. Ultrastructural changes in dysferlinopathy support defective membrane repair mechanism. J Clin Pathol 2005;58:190-195.

39. Chutkow JG, Heffner RR Jr, Kramer AA, Edwards JA. Adult-onset autosomal dominant limb-girdle muscular dystrophy. Ann Neurol 1986;20:240-248.

40. Clerk A, Rodillo E, Heckmatt JZ, Dubowitz V, Strong PN, Sewry CA. Characterisation of dystrophin in carriers of Duchenne muscu-lar dystrophy. J Neurol Sci 1991;102:197-205.

41. Cohn RD, Campbell KP. Molecular basis of muscular dystrophies. Muscle Nerve 2000;23:1456-1471.

42. Cormand B, Pihko H, Bayes M, Valanne L, Santavuori P, Talim B, Gershoni-Baruch R, Ahmad A, van Bokhoven H, Brunner HG, Voit T, Topaloglu H, Dobyns WB, Lehesjoki AE. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 2001;56:1059-1069.

43. Dalkilic I, Kunkel LM. Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 2003;13:231-238.

44. Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B, Dobyns WB, Dieguez J, Valanne L, Joensuu T, Lehesjoki AE. POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J Med Genet 2004;41:e115.

45. Duggan DJ, Fanin M, Pegoraro E, Angelini C, Hoffman EP. alpha-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations. J Neurol Sci 1996;140:30-39.

46. Duggan DJ, Gorospe JR, Fanin M, Hoffman EP, Angelini C. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997;336:618-624.

47. Duggan DJ, Manchester D, Stears KP, Mathews DJ, Hart C, Hoffman EP. Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2). Neurogenetics 1997;1:49-58.

48. Edstrom L. Histochemical and histopathological changes in skeletal muscle in late-onset hereditary distal myopathy (Welander). J Neurol Sci 1975;26:147-157.

49. Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001;29:83-87.

50. Eisenberg I, Grabov-Nardini G, Hochner H, Korner M, Sadeh M, Bertorini T, Bushby K, Castellan C, Felice K, Mendell J, Merlini L, Shilling C, Wirguin I, Argov Z, Mitrani-Rosenbaum S. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat 2003;21:99.

51. Emery AE. Emery-Dreifuss muscular dystrophy - a 40 year retro-spective. Neuromuscul Disord 2000;10:228-232.

52. Esapa CT, McIlhinney RA, Blake DJ. Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. Hum Mol Genet 2005;14:295-305.

53. Fang W, Huang CC, Chu NS, Chen CJ, Lu CS, Wang CC. Childhood-onset autosomal-dominant limb-girdle muscular dystrophy with cardiac conduction block. Muscle Nerve 1997;20:286-292.

54. Fanin M, Duggan DJ, Mostacciuolo ML, Martinello F, Freda MP, Soraru G, Trevisan CP, Hoffman EP, Angelini C. Genetic epidemiol-ogy of muscular dystrophies resulting from sarcoglycan gene muta-tions. J Med Genet 1997;34:973-977.

55. Fanin M, Fulizio L, Nascimbeni AC, Spinazzi M, Piluso G, Ventriglia VM, Ruzza G, Siciliano G, Trevisan CP, Politano L, Nigro V, Angelini C. Molecular diagnosis in LGMD2A: mutation analysis or protein testing? Hum Mutat 2004;24:52-62.

56. Fanin M, Pegoraro E, Matsuda-Asada C, Brown RH Jr, Angelini C. Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology 2001;56:660-665.

57. Felice KJ, Schwartz RC, Brown CA, Leicher CR, Grunnet ML. Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene. Neurology 2000;55:275-280.

58. Flanigan KM, Kerr L, Bromberg MB, Leonard C, Tsuruda J, Zhang P, Gonzalez-Gomez I, Cohn R, Campbell KP, Leppert M. Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathologi-cal, radiological, and genetic study. Ann Neurol 2000;47:152-161.

59. Frosk P, Weiler T, Nylen E, Sudha T, Greenberg CR, Morgan K, Fujiwara TM, Wrogemann K. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet 2002;70:663-672.

60. Gallardo E, Rojas-Garcia R, de Luna N, Pou A, Brown RH Jr, Illa I. Inflammation in dysferlin myopathy: immunohistochemical charac-terization of 13 patients. Neurology 2001;57:2136-2138.

61. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscu-lar dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 2002;71:492-500.

62. Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 2000;9:2141-2147.

63. Hayashi YK, Chou FL, Engvall E, Ogawa M, Matsuda C, Hirabayashi S, Yokochi K, Ziober BL, Kramer RH, Kaufman SJ, Ozawa E, Goto Y, Nonaka I, Tsukahara T, Wang JZ, Hoffman EP, Arahata K. Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet 1998;19:94-97.

64. Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, Hammans SR. Oculopharyngeal muscular dystro-phy: phenotypic and genotypic studies in a UK population. Brain 2001;124:522-526.

65. Ho M, Gallardo E, McKenna-Yasek D, De Luna N, Illa I, Brown RH Jr. A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann Neurol 2002;51:129-133.

66. Hoffman EP, Arahata K, Minetti C, Bonilla E, Rowland LP. Dystrophinopathy in isolated cases of myopathy in females. Neurology 1992;42:967-975.

67. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987;51:919-928.

AANEMCourse MuscleandNervePathology D-��

68. Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, Harris JB, Waterston R, Brooke M, Specht L. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N Engl J Med 1998;318:1363-1368.

69. Hoffman EP, Kunkel LM, Angelini C, Clarke A, Johnson M, Harris JB. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 1989;39:1011-1017.

70. Illa I, Serrano-Munuera C, Gallardo E, Lasa A, Rojas-Garcia R, Palmer J, Gallano P, Baiget M, Matsuda C, Brown RH. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscu-lar dystrophy phenotype. Ann Neurol 2001;49:130-134.

71. Ishikawa H, Sugie K, Murayama K, Awaya A, Suzuki Y, Noguchi S, Hayashi YK, Nonaka I, Nishino I. Ullrich disease due to deficiency of collagen VI in the sarcolemma. Neurology 2004;62:620-623.

72. Jerusalem F, Engel AG, Gomez MR. Sarcotubular myopathy. A newly recognized, benign, congenital, familial muscle disease. Neurology 1973;23:897-906.

73. Kaido M, Arahata K, Hoffman EP, Nonaka I, Sugita H. Muscle histology in Becker muscular dystrophy. Muscle Nerve 1991;14:1067-1073.

74. Kim DS, Hayashi YK, Matsumoto H, Ogawa M, Noguchi S, Murakami N, Sakuta R, Mochizuki M, Michele DE, Campbell KP, Nonaka I, Nishino I. POMT1 mutation results in defective glycosyl-ation and loss of laminin-binding activity in alpha-DG. Neurology 2004;62:1009-1011.

75. Kissel JT. Facioscapulohumeral dystrophy. Semin Neurol 1999;19:35-43.

76. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388-392.

77. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509-517.

78. Krahn m, Lopez de Munain A, Streichenberger N, Bernard R, Pecheux C, Testard H, Pena Segura JL, Yoldi E, Cabello A, Romero NB, Poza JJ, Bouillot-Eimer S, Ferrer X, Goicoechea M, Garcia-Bragado F, Leturcq F, Urtizberea JA, Levy N. CAPN3 muta-tions in patients with idiopathic eosinophilic myositis. Ann Neurol 2006;59:905-911.

79. Lamont PJ, Udd B, Mastaglia FL, de Visser M, Hedera P, Voit T, Bridges LR, Fabian V, Rozemuller A, Laing NG. Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry 2006;77:208-215.

80. Lindberg C, Borg K, Edstrom L, Hedstrom A, Oldfors A. Inclusion body myositis and Welander distal myopathy: a clinical, neurophysi-ological and morphological comparison. J Neurol Sci 1991;103:76-81.

81. Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, Hamida MB, Bohlega S, Culper EJ, Amato AA, Bossie K, Oeltjen J, Bejaoui K, McKenna-Yasek D, Hosler BA, Schurr E, Arahata K, de Jong PJ, Brown RH Jr. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998;20:31-36.

82. Ljunggren A, Duggan D, McNally E, Boylan KB, Gama CH, Kunkel LM, Hoffman EP. Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin. Ann Neurol 1995;38:367-372.

83. Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, Feng L, Saran RK, Voit T, Merlini L, Sewry CA, Brown SC, Muntoni F. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dys-troglycan. Hum Mol Genet 2003;12:2853-2861.

84. Lotz BP, Stubgen JP. The rigid spine syndrome: a vacuolar variant. Muscle Nerve 1993;16:530-536.

85. Marconi G, Pizzi A, Arimondi CG, Vannelli B. Limb girdle muscular dystrophy with autosomal dominant inheritance. Acta Neurol Scand 1991;83:234-238.

86. Markesbery WR, Griggs RC, Herr B. Distal myopathy: electron mi-croscopic and histochemical studies. Neurology 1977;27:727-735.

87. Matsuda C, Aoki M, Hayashi YK, Ho MF, Arahata K, Brown RH Jr. Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy. Neurology 1999;53:1119-1122.

88. Matsumoto H, Noguchi S, Sugie K, Ogawa M, Murayama K, Hayashi YK, Nishino I. Subcellular localization of fukutin and fukutin-related protein in muscle cells. J Biochem Tokyo 2004;135:709-712.

89. Matsumura K, Yamada H, Saito F, Sunada Y, Shimizu T. Peripheral nerve involvement in merosin-deficient congenital muscular dystro-phy and dy mouse. Neuromuscul Disord 1997;7:7-12.

90. Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Furst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 1998;395:863-869.

91. McNally EM, Duggan D, Gorospe JR, Bonnemann CG, Fanin M, Pegoraro E, Lidov HG, Noguchi S, Ozawa E, Finkel RS, Cruse RP, Angelini C, Kunkel LM, Hoffman EP. Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy. Hum Mol Genet 1996;5:1841-1847.

92. Mercuri E, Talim B, Moghadaszadeh B, Petit N, Brockington M, Counsell S, Guicheney P, Muntoni F, Merlini L. Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1). Neuromuscul Disord 2002;12:631-638.

93. Merlini L, Granata C, Ballestrazzi A, Marini ML. Rigid spine syn-drome and rigid spine sign in myopathies. J Child Neurol 1989;4:274-282.

94. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, Campbell KP. Post-translational disruption of dystrogly-can-ligand interactions in congenital muscular dystrophies. Nature 2002;418:417-422.

95. Minetti C, Chang HW, Medori R, Prelle A, Moggio M, Johnsen SD, Bonilla E. Dystrophin deficiency in young girls with sporadic myopa-thy and normal karyotype. Neurology 1991;41:1288-1292.

96. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara F. Mutations in the caveo-lin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet 1998;18:365-368.

97. Mizusawa H, Kurisaki H, Takatsu M, Inoue K, Mannen T, Toyokura Y, Nakanishi T. Rimmed vacuolar distal myopathy: a clinical, electro-physiological, histopathological and computed tomographic study of seven cases. J Neurol 1987;234:129-136.

D-�4 Histopathology of Muscular Dystrophies AANEMCourse


98. Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Roy SQ, Merlini L, Romero N, Estournet B, Desguerre I, Chaigne D, Muntoni F, Topaloglu H, Guicheney P. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 2001;29:17-18.

99. Moghadaszadeh B, Topaloglu H, Merlini L, Muntoni F, Estournet B, Sewry C, Naom I, Barois A, Fardeau M, Tome FM, Guicheney P. Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome. Neuromuscul Disord 1999;9:376-382.

100. Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 2000;24:163-166.

101. Mues A, van der Ven PF, Young P, Furst DO, Gautel M. Two im-munoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin. FEBS Lett 1998;428:111-114.

102. Munsat TL, Piper D, Cancilla P, Mednick J. Inflammatory myopathy with facioscapulohumeral distribution. Neurology 1972;22:335-347.

103. Muntoni F, Voit T. 133rd ENMC International Workshop on Congenital Muscular Dystrophy (IXth International CMD Workshop) 21-23 January 2005, Naarden, The Netherlands. Neuromuscul Disord 2005;15:794-801.

104. Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 2004;14:635-649.

105. Nagano A, Arahata K. Nuclear envelope proteins and associated diseases. Curr Opin Neurol 2000;13:533-539.

106. Nagano A, Koga R, Ogawa M, Kurano Y, Kawada J, Okada R, Hayashi YK, Tsukahara T, Arahata K. Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystro-phy. Nat Genet 1996;12:254-259.

107. Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal myopa-thy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 1981;51:141-155.

108. Nonaka I, Sunohara N, Satoyoshi E, Terasawa K, Yonemoto K. Autosomal recessive distal muscular dystrophy: a comparative study with distal myopathy with rimmed vacuole formation. Ann Neurol 1985;17:51-59.

109. Ognibene A, Sabatelli P, Petrini S, Squarzoni S, Riccio M, Santi S, Villanova M, Palmeri S, Merlini L, Maraldi NM. Nuclear changes in a case of X-linked Emery-Dreifuss muscular dystrophy. Muscle Nerve 1999;22:864-869.

110. Partanen J, Laulumaa V, Paljarvi L, Partanen K, Naukkarinen A. Late onset foot-drop muscular dystrophy with rimmed vacuoles. J Neurol Sci 1994;125:158-167.

111. Piccolo F, Moore SA, Ford GC, Campbell KP. Intracellular accu-mulation and reduced sarcolemmal expression of dysferlin in limb--girdle muscular dystrophies. Ann Neurol 2000;48:902-912.

112. Prior TW, Bartolo C, Pearl DK, Papp AC, Snyder PJ, Sedra MS, Burghes AH, Mendell JR. Spectrum of small mutations in the dys-trophin coding region. Am J Hum Genet 1995;57:22-33.

113. Reichmann H, Goebel HH, Schneider C, Toyka KV. Familial mixed congenital myopathy with rigid spine phenotype. Muscle Nerve 1997;20:411-417.

114. Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dys-trophy type 2A. Cell 1995;81:27-40.

115. Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, Beckmann JS. Calpainopathy-a survey of mutations and polymor-phisms. Am J Hum Genet 1999;64:1524-1540.

116. Sabatelli P, Lattanzi G, Ognibene A, Columbaro M, Capanni C, Merlini L, Maraldi NM, Squarzoni S. Nuclear alterations in autoso-mal-dominant Emery-Dreifuss muscular dystrophy. Muscle Nerve 2001;24:826-829.

117. Schoser BG, Frosk P, Engel AG, Klutzny U, Lochmuller H, Wrogemann K. Commonality of TRIM32 mutation in causing sar-cotubular myopathy and LGMD2H. Ann Neurol 2005;57:591-595.

118. Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopa-thy. Neurology 2004;62:1363-1371.

119. Selcen D, Stilling G, Engel AG. The earliest pathologic alterations in dysferlinopathy. Neurology 2001;56:1472-1481.

120. Sewry CA, Naom I, D’Alessandro M, Sorokin L, Bruno S, Wilson LA, Dubowitz V, Muntoni F. Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabelling of two fragments of the laminin alpha 2 chain. Neuromuscul Disord 1997;7:169-175.

121. Shanmugam V, Dion P, Rochefort D, Laganiere J, Brais B, Rouleau GA. PABP2 polyalanine tract expansion causes intranuclear inclusions in oculopharyngeal muscular dystrophy. Ann Neurol 2000;48:798-802.

122. Sivakumar K, Dalakas MC. The spectrum of familial inclusion body myopathies in 13 families and a description of a quadriceps-sparing phenotype in non-Iranian Jews. Neurology 1996;47:977-984.

123. Sotgia F, Woodman SE, Bonuccelli G, Capozza F, Minetti C, Scherer PE, Lisanti MP. Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease. Am J Physiol Cell Physiol 2003;285:C1150-C1160.

124. Spencer MJ, Tidball JG, Anderson LV, Bushby KM, Harris JB, Passos-Bueno MR, Somer H, Vainzof M, Zatz M. Absence of calpain 3 in a form of limb-girdle muscular dystrophy (LGMD2A). J Neurol Sci 1997;146:173-178.

125. Sunohara N, Nonaka I, Kamei N, Satoyoshi E. Distal myopathy with rimmed vacuole formation. A follow-up study. Brain 1989;112:65-83.

126. Taylor J, Muntoni F, Robb S, Dubowitz V, Sewry C. Early onset autosomal dominant myopathy with rigidity of the spine: a possible role for laminin beta 1? Neuromuscul Disord 1997;7:211-216.

127. Toda T, Kobayashi K, Kondo-Iida E, Sasaki J, Nakamura Y. The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord 2000;10:153-159.

128. Toda T, Yoshioka M, Nakahori Y, Kanazawa I, Nakamura Y, Nakagome Y. Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome. Ann Neurol 1995;37:99-101.

129. Udd B, Haravuori H, Kalimo H, Partanen J, Pulkkinen L, Paetau A, Peltonen L, Somer H. Tibial muscular dystrophy--from clinical description to linkage on chromosome 2q31. Neuromuscul Disord 1998;8:327-332.

130. Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkila H, Ingo S, Kalimo H, Kaariainen H, Laulumaa V. Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 1993;50:604-608.

131. Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies and extension of the M-line mutation phenotype beyond distal my-opathy and LGMD2J. Neurology 2005;64:636-642.

132. Vachon PH, Xu H, Liu L, Loechel F, Hayashi Y, Arahata K, Reed JC, Wewer UM, Engvall E. Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy. J Clin Invest 1997;100:1870-1881.

133. van der Kooi AJ, Ledderhof TM, de Voogt WG, Res CJ, Bouwsma G, Troost D, Busch HF, Becker AE, de Visser M. A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement. Ann Neurol 1996;39:636-642.

134. van der Kooi AJ, van Meegen M, Ledderhof TM, McNally EM, de Visser M, Bolhuis PA. Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac in-volvement (LGMD1B) to chromosome 1q11-21. Am J Hum Genet 1997;60:891-895.

135. van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabe D, Sabatelli P, Merlini L, Boon M, Scheffer H, Brockington M, Muntoni F, Huynen M, Verrips A, Walsh C, Barth P, Brunner H, van Bokhoven H. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker Warburg syndrome. J Med Genet 2005;42:907-912.

136. Wewer UM, Durkin ME, Zhang X, Laursen H, Nielsen NH, Towfighi J, Engvall E, Albrechtsen R. Laminin beta 2 chain and adhalin deficiency in the skeletal muscle of Walker-Warburg syn-drome (cerebro-ocular dysplasia-muscular dystrophy). Neurology 1995;45:2099-2101.

137. Wewer UM, Engvall E. Merosin/laminin-2 and muscular dystrophy. Neuromuscul Disord 1996;6:409-418.

138. Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R. Chromosome 4q DNA rearrangements associated with facioscapu-lohumeral muscular dystrophy. Nat Genet 1992;2:26-30.

139. Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP. Caveolinopathies: mutations in caveolin-3 cause four distinct autoso-mal dominant muscle diseases. Neurology 2004;62:538-543.

140. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 2001;1:717-724.

D-�� Histopathology of Muscular Dystrophies AANEMCourse

INTRODUCTION

Mitochondrial diseases are a heterogeneous group of disorders which are a result of dysfunctional oxidative phosphorylation (OXPHOS). The OXPHOS system is composed of four enzyme complexes (Complex I – IV) that make up the mitochondrial respiratory chain (RC), and the adenosine triphosphate (ATP) synthase complex (Complex V) which use energy generated by electron transport along the RC to produce ATP. Impairment of this system can produce pathological alterations in any organ system. This makes the recognition, diagnosis, and classification of mitochondrial diseases challenging, because patients can present with a wide variety of signs and symptoms that often do not fit into preconceived clinical phenotypes.

The OXPHOS enzyme assembly is governed by two genomic systems, mitochondrial deoxyribonucleic acid (mtDNA) and nuclear DNA (nDNA). Of more than 80 structural subunits in 5 complexes, mtDNA encodes 13. In addition to the essential struc-tural components, a set of proteins is necessary for assembly and maintenance of the complexes, which are nDNA encoded. Thus, mitochondrial diseases can demonstrate any mode of inheritance: maternal, autosomal dominant or recessive, or sporadic.

The mitochondrial genome is a double-stranded circular molecule of 16,569 bp that encodes for 13 structural proteins of the RC, and the 22 transfer ribonucleic acid (tRNAs) and 2 ribosomal ribonucleic acids (rRNAs) that are necessary for their translation. There are basic rules to understund the mitochondrial genetics:18 (1) maternal inheritance; (2) polyplasmy; (3) heteroplasmy; (4) threshold effect; and (5) tissue and temporal variation. These rules explain at least in part clinical and pathological heterogeneity of mtDNA-related disorders.

The signature muscle pathology in many, but not all, patients are ragged red fibers (RRFs). Ragged red fibers are detected by the modified Gomori trichrome stain, but the most sensitive and precise method to demonstrate the segmental accumulations of mitochondria is succinate dehydrogenase (SDH) (Figure 1). The ragged appearance of RRFs is due to the proliferation of subsar-colemmal and interfibrillar mitochondria, which are abnormal ge-netically, morphologically, and histochemically. The percentage of RRFs can vary from 2%-70%. Ragged red fibers are usually absent of cytochrome c oxidase (COX) activity or have greatly reduced COX activity relative to the increased mitochondrial volume as seen by the SDH stain (Figure 2), and they are known as COX-negative or COX-deficient fibers. The mitochondrial proliferation

Pathology of Muscle in Mitochondrial Disorders

Kurenai Tanji, MD, PhDAssistantProfessor

DepartmentofClinicalPathologyColumbiaUniversityMedicalCenter

NewYork,NewYork

D-��

D-�� Pathology of Muscle in Mitochondrial Disorders AANEMCourse

Figure1 SerialsectionsstainedbyGomori trichrome(A)andsuccinatedehydrogenase(SDH)(B).Raggedred fibersaredetectedby themodifiedGomoritrichromestain,butthemostsensitiveandprecisemethodtodemonstratethesegmentalaccumulationsofmitochondriaisSDH.

Figure 2 Cytochromecoxidase(COX)-negativeraggedredfibers.Raggedredfibersareoftennegativeorshowgreatlyreducedcytochromecoxidase(COX)reactivity(A:succinatedehydrogenase,B:COX).

in RRFs is presumably a compensation mechanism, however, the signals triggering segmental proliferation of mitochondria remain to be elucidated.

MITOCHONDRIAL DEOXYRIBONUCLEIC ACID MUTATIONS

Mitochondrial DNA mutations have been classified into three main categories: large-scale deletions, point mutations in tRNAs or rRNAs, and point mutations in protein coding genes.

Large-scale Deletions

Genetics

Large-scale deletions (delta [Δ]-mtDNAs) remove multiple tRNAs and protein coding genes,37 and impair the translation of mito-chondrial genomes, producing multiple deficiencies in the RC enzyme activities. Most cases are sporadic except for rare reports of germline transmission.56 The mechanism by which Δ-mtDNAs are generated is unknown, although slip replication and recombination have been suggested.36 All patients with Δ-mtDNAs are hetero-plasmic,59 and the clinical phenotypes depend on the distribution of mutation load at birth and subsequent random segregation in daughter cells during growth. The sizes of deletions vary by patient, but each given patient has deleted molecules of the same size. It is suggested that the Δ-mtDNA arises early in oogenesis.

Clinical Aspects

The phenotypes vary from the most common and mildest form, a myopathy with progressive ophthalmoplegia (PEO), ptosis, and proximal limb weakness, to a more severe form, Kearns-Sayre syndrome (KSS), to the most severe form, Pearson syndrome (PS). Pearson syndrome is almost invariably fatal in infancy with sidero-blast anemia and exocrine pancreatic dysfunction. Children that outlive PS develop KSS later in life. Kearns-Sayre syndrome is clini-cally characterized by PEO, pigmentary degeneration of the retina, and heart block, plus a variety of less consistent additional symp-toms, such as ataxia, dementia, nephropathy, or endocrinopathy.

Pathology

Muscle biopsies show characteristic RRFs. The RRF segments contain large accumulation of Δ-mtDNAs and their transcripts, indicating that the mutation does not affect transcription.35 The relative proportion of wild-type mtDNAs in the RRF segments is always decreased and they have reduced or absent staining of COX. Polypeptides encoded by mtDNA are not detectable by im-munohistochemistry in RRFs, even those encoded outside the dele-tion, indicating that the pathogenicity of Δ-mtDNA is related to

compromised translation of the genome due to removal of mtDNA encoded tRNA genes by each deletion.38

Point Mutations in Transfer Ribonucleic Acid Genes

Genetics

Point mutations are the most common form of mtDNA muta-tions associated with mitochondrial myopathies. Over 60 differ-ent mutations in the tRNA genes have been reported, including the two most common clinical phenotypes of mitochondrial diseases, namely mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy and RRFs (MERRF). These mutations interfere with the translation of the mitochondrial genome, and they are always heteroplasmic. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes have been associated with at least 10 different point muta-tions, 4 of which are located in the same gene, tRNALeu(UUR). The most common point mutation (80% of cases) is an A3243G transi-tion in the tRNALeu(UUR).18 This mutation is also an important cause of PEO.39 The pathogenicity of A3243G mutation is well estab-lished. The altered tRNA fails to undergo proper posttranslational modification (misaminoacylation), leading to impaired mitochon-drial protein synthesis.72 In MERRF, 80% of the cases are associ-ated with A8344G mutations in the tRNALys gene and a smaller percentage of the patients have T8356C mutation in the same gene.57,61 These mutations also cause a defective aminoacylation of the tRNALys, resulting in premature translation termination.20 The threshold effect in the A8344G mutation has been demonstrated in muscle culture cells: Myotubes harboring the A8344G muta-tion show no biochemical defect until the proportion of mutant mtDNAs exceeds 85%,8 and there is a good correlation between the extent of the translation defect and the lysine content of different mtDNA-encoded polypeptides.20

Clinical Aspects

The majority of tRNA mutations are most commonly associ-ated with disorders of the central nervous system, peripheral nerve, skeletal muscle, and myocardium. In MELAS, the clinical hallmarks are the stroke-like episodes with hemiparesis or hemi-anopsia, almost invariably occurring before age 40, and often in childhood. Common additional findings include lactic acidosis, focal and generalized seizures, recurrent migraine-like headaches and vomiting, and dementia. The course is one of gradual dete-rioration, and MELAS families often have oligosymptomataic and asymptomatic maternal relatives. Myoclonic epilepsy and RRFs are characterized by myoclonus, seizures, ataxia, and myopathy with RRFs. Less consistent features include cardiomyopathy, dementia, neuropathy, multiple symmetrical lipomatosis, and short stature.


The myoclonic jerks occur at rest and worsen during movement (action myoclonus). Onset is usually in childhood, but adult onset has been described. As seen in MELAS, maternal family members in MERRF may be oligosymptomatic or asymptomatic.

Pathology

These mutations are almost always associated with RRFs, and all show threshold behavior in muscle. Characteristically, in MELAS, RRFs are COX-positive in contrast to many other tRNA point mutations and large-scale Δ-mtDNA, although careful analysis finds that the activity is usually reduced relative to the mito-chondrial proliferation observed by the SDH stain (Figure 3). In addition, blood vessels in MELAS show an interesting pathology called “strongly SDH reactive blood vessels (SSVs)”24 (Figure 4), indicating mitochondrial proliferation in smooth muscle, pericytes, and endothelial cells of arterial walls. Unlike MELAS patients muscle biopsies of MERRF patients reveal COX-negative RRFs and SSVs.

Point Mutations in Ribosomal Ribonucleic Acids Gene

Genetics and Clinical Aspects

A1555G substitution in the 12S rRNA gene has been associated with deafness,14 deafness and Parkinson’s disease,58 and cardiomy-opathy.52

Pathology

Rare RRFs are found in muscle biopsies from the patients with deafness. The RRFs are either COX-positive or COX-negative.14 No SSV has been demonstrated. In a cardiomyopathy case, the muscle biopsy showed central or paracentral minicores and reduc-tions in COX and nicotinamide adenin dinucleoacid hydrogen (NADH)-dehydrogenase activities.52

POINT MUTATIONS IN PROTEIN CODING GENES

Point mutations in protein coding genes defects lead to specific deficiencies in RC complexes. These mutations are less common than deletions and tRNA mutations. Most common phenotypes include: (1) complex I mutations; (2) ATPase 6 gene mutations;

(3) cytochrome b (Cyt b) mutations; and (4) COX subunit muta-tions.

Complex I Genes Mutations


Leber hereditary optic neuropathy (LHON) has been associated with G11778A (ND4 gene), G3460A (ND1), and T14484C (ND6) mutations.71 Isolated myopathy characterized by exercise intolerance, myalgia, lactic acidosis, and complex I deficiency has been linked to mutations in the ND1,40 ND2,53 and ND42 genes. In one case report, the 2-bp deletion in the ND2 gene of a patient was remarkable because it was discovered that the muscle mtDNA was mostly of paternal origin. Although this situation does not negate the general rule that mtDNA is transmitted maternally, it raises the possibility that tissue-specific paternal mtDNA inheri-tance might somehow favor mutagenesis, since the patient’s father was healthy and did not carry the mutation in blood. Mutations in the ND5 gene have been associated with multisystemic disorders such as MELAS51 and various overlap syndromes including MELAS and Leigh syndrome (LS),13 MELAS and MERRF,41 MELAS and LHON,47 and MELAS, LS, and LHON.30

Pathology

Leber hereditary optic neuropathy mutations cause pathology only in the optic nerve. Patients with other mutations in complex I invariably show isolated complex I deficiency in the muscle biop-sies. The myopathies associated with ND1 and ND4 genes show COX-positive RRF in muscle biopsies. The case report53 of paternal inheritance (ND2 mutation) also described the presence of RRFs (COX staining was not reported). In ND5 mutations associated with multisystemic disorders, RRFs (either COX-positive or COX-negative fibers) and SSV are usually evident.

ATP 6 Gene Mutations


A mutation in the ATP6 gene (T8993G) was first reported in a syndrome that includes neuropathy, ataxia, and retinitis pigmen-tosa (NARP).25 The onset occurs in infancy or early childhood. Myopathy is rare. Interestingly, patients with heteroplasmy that have a mutant load between 70%-90% of mtDNA manifest

D-�0 Pathology of Muscle in Mitochondrial Disorders AANEMCourse


Figure 3Cytochromecoxidase(COX)-positiveraggedredfibers(RRFs)inacaseofmitochondrialencephalomyopathywithlacticacidosisandstroke-like episodes (MELAS) (A: succinate dehydrogenase [SDH], B:COX). Characteristically, in MELAS, RRFs are COX-positive in contrast to many othertransferribonucleicacidgenepointmutationsandlarge-scaleΔ-mitochondrialdeoxyribonucleicacid,althoughtheactivityisusuallyreducedrelativetothemitochondrialproliferationobservedbytheSDHstain.

Figure 4 Strongly succinate dehydrogenase reactive blood vessels (SSVs) indicate mitochondrial proliferation in smooth muscle, pericytes, andendothelialcellsofarterialwalls.Inmitochondrialencephalomyopathywithlacticacidosisandstroke-likeepisodescases,SSVsarealsoCytochromecoxidase(COX)-positive(A:succinatedehydrogenase,B:COX).

variable clinical symptoms, while patients with more than 90% of mutant mtDNAs usually present with LS. Leigh syndrome, historically called subacute necrotizing encephalomyelopathy, is characterized by hypotonia, failure to thrive, seizures, respiratory dysfunction, and ataxia. T2-weighted magnetic resonance imaging (MRI) shows bilateral, often symmetrical, hyperintensity in the basal ganglia, cerebellum, and brainstem. A T8993G mutation causes a leucine to arginine substitution within the proton channel of the F0 segment of complex V that impairs ATP synthesis.67

Pathology

Patients with NARP mutation do not show RRFs in muscle biop-sies, although some cases reveal neurogenic (denervation) atrophy.

Cytochrome b Gene Mutations


Most patients with Cyt b mutations present with exercise intol-erance, myalgia, and lactic acidosis, sometimes accompanied by myoglobinuria.3 There is a single report of a patient with Cyt b mutation that clinically had juvenile Parkinson/MELAS overlap syndrome.15 Two other patients have been reported with severe hy-pertrophic cardiomyopathy.4 Most of them had mutations within or close to the ubiquinone-binding sites of Cyt b, suggesting that most Cyt b mutations are likely to have a severe effect on mito-chondrial energy production.

Pathology

Muscle morphology reveals COX-positive RRFs. In patients with the isolated myopathy, the mutant mtDNA was absent in blood and/or fibroblasts in all cases examined. This is consistent with the restriction of the clinical phenotype to skeletal muscle, the sponta-neous occurrence of these mutations, and the likelihood that they would not be transmitted to the patient’s offspring. It may also in-dicate that the mutation in these patients may have arisen in muscle progenitor cells, after differentiation of the primary germ layers.3

Cytochrome C Oxidase Genes Mutations

Genetics and Clinical Aspect

Mutations in each of the three COX subunits that are encoded by mtDNA can cause either tissue specific disorders such as myopathy (COX I and II)23,27 and sideroblastic anemia (COX I),21 or multi-systemic disorders such as MELAS (COX III),34 an amyotrophic lateral sclerosis-like phenotype (COX I),12 and encephalopathies (COX I and II).10,11

Pathology

Muscle morphology usually reveals RRFs. Strikingly, these muta-tions also show a number of COX-negative fibers that are not RRFs. Note, however, that there are no “dogmas” in muscle pathol-ogy, as two patients have been reported without RRFs.10,23

One case with COX III mutation and a typical clinical phenotype of MELAS showed a few RRFs, but surprisingly, no histochemical evidence of COX deficiency was present.34

NUCLEAR DIOXYRIBONUCLEIC ACID MUTATIONS

Nuclear DNA mutations are a particularly interesting group of disorders because the primary genetic defect is in the nDNA, but the consequence of the nDNA mutation is either a quantitative (mtDNA depletion syndromes) or a qualitative defect of mtDNA (multiple Δ-mtDNAs). This is due to the fact that, in the course of evolution, the symbiotic protobacteria have lost much of their autonomy and have become increasingly dependent on the host cell’s genome, which encodes the factors controlling mtDNA repli-cation, transcription, and translation.

NUCLEAR-MITOCHONDRIAL COMMUNICATION DISORDERS

Mitochondrial Dioxyribonucleic Acid Depletion Syndrome

Genetics

Mitochondrial DNA depletion syndrome is caused by a quan-titative defect of mtDNA. Muscular dystrophies are usually inherited as autosomal recessive (AR) traits, but they can be drug-induced.6,14,65 Mutations in two nuclear genes have been identified: the deoxyguanosine kinase (dGK) gene with the hepatic form,33,50 the thymidine kinase 2 (TK2) gene with the myopathic form.48 However, not all patients of muscular dystrophies have these two mutations, which indicates the involvement of other genes.

Clinical Aspects

The AR forms fall into two major groups; one dominated by my-opathy, and the other by hepatopathy, though both presentations involve other tissues including brain, kidney, and heart.70 The myopathic form can be apparent at birth and cause fatal respira-tory failure within a month, or develop at about 1 year of age and progress more slowly, often simulating muscular dystrophies. The differential diagnosis is sometimes difficult because of the fact that muscular dystrophies can show, unlike other mitochondrial



myopathies, marked elevation of serum creatine kinase (CK). In a case report, one of two siblings with a homozygous mutation in the TK2 gene was reported to present a phenotype of spinal muscular atrophy (SMA) type I.32 Another case report described a child with the SMA phenotype and mtDNA depletion.45 These cases with SMA phenotypes raise an important point—that mitochondrial dysfunction should be considered when patients do not show mu-tations in the survival motor neuron (SMN) gene.

Pathology

In the congenital myopathic form of mtDNA depletion syndrome, muscle biopsy shows RRF and diffuse COX deficiency. In addition, muscle biopsy of some muscular dystrophy patients may exhibit significant myopathic alterations, similar to what are observed in muscular dystrophies. In the later onset form, initial biopsies may show only nonspecific changes, while samples taken later show RRF and COX-negative fibers. The biopsies of cases with SMA phenotype reveal characteristic neurogenic abnormalities as seen in SMA with SMN gene mutations. Biochemical analysis of muscular dystrophy cases reveals combined defects of respiratory chain com-plexes that contain mtDNA-encoded subunits.

Multiple Deletions

Genetic and Clinical Aspects

Multiple deletions (MDs) are qualitative defects of mtDNA. Syndromes associated with MDs affect predominantly muscle, and usually present as PEO or as isolated proximal muscle weakness. Both AR and autosomal dominant (AD) traits have been reported. Autosomal dominnant-PEO, not unlike the sporadic form of PEO due to single Δ-mtDNA, is also a relatively benign condition with onset in adolescence or young adult life and slow progression. However, multisystemic symptoms can also occur in these patients such as dysphagia, dysphonia, neuropathy, hearing loss, cataracts, and depression.55,64 Mutations in three genes have been reported with AD-PEO: adenine nucleotide translocator 1 (ANT1),28 Twinkle,62 and polymerase γ (POLG).69 However, these three genes do not explain all cases of AD-PEO and other genes remain to be identified. Autosomal recessive-PEO is most often multisystemic, as illustrated by two syndromes, (1) AR cardiomyopathy and ophthal-moplegia (ARCO),7 and (2) mitochondrial neurogastrointestinal encephalopathy (MNGIE).43 Autosomal recessive cardiomyopathy and ophthalmoplegia presents with childhood-onset PEO, facial and proximal limb weakness, and severe cardiomyopathy requir-ing cardiac transplantation. Mitochondrial neurogastrointestinal encephalopathy is dominated by gastrointestinal tract symptoms such as intestinal pseudo-obstruction and chronic diarrhea leading

to cachexia and early death. Additional signs include ptosis, PEO, peripheral neuropathy, and leukoencephalopathy. Some AR-PEO had mutaions in the POLG gene,29,69 and MNGIE is caused by loss of function mutation in the thymidine phosphorylase (TP).42 This TP mutation may cause disruption of the mitochondrial nucleotide pool, resulting in mtDNA abnormalities, both MDs and mtDNA depletion.

Pathology

Muscle biopsy usually shows RRF and COX-negative fibers, and biochemical analysis reveals combined respiratory chain defects.

NUCLEAR GENE MUTATIONS CAUSING ISOLATED RESPIRATORY CHAIN COMPLEX DEFICIENCIES

Respiratory chain complex deficiencies diseases are caused by muta-tions in nuclear genes encoding proteins that are essential for the biosynthesis of specific cofactors for assembly of the complexes. Disorders associated with complex IV deficiency will be reviewed.

Complex IV-deficient Leigh Syndrome


One of the most common causes of LS is COX deficiency and it is inherited as an AR trait.60 Surprisingly, no mutation was found in the nDNA-encoded subunits of COX, despite extensive sequence studies.1,26 Recently, mutations were detected in several COX-as-sembly genes: the SURF1 gene in patients with LS,68,74 and the SCO2 gene with fatal cardioencephalomyopathy,44 and SCO1, COX10, and COX15 genes with multisystem disorders associated with COX deficiency.60

Pathology

In these patients COX activity is reduced in most tissues, with ap-parently little or no tissue specificity as reflected by the degree of enzyme deficiency.31 Muscle histochemistry in patients with SURF1 or SCO2 genes show only minor cytoarchitectural changes and no RRFs. Complex IV histochemical staining is diffusely reduced, but not totally absent, affecting equally type I and II myofibers, intrafusal muscle fibers, and the vascular walls.66 This pattern of COX deficiency is more severe in patients with SCO2 mutations than SURF1 mutations, and is consistent with results of biochemi-cal studies.63 The profuse COX-deficiency associated with SCO2 mutations may relate to the observation that all known SCO-like proteins bind copper, and that COX I and II contain copper.22 Pathogenesis of the SURF1 mutation is not yet well understood.

Complex IV-deficient Infantile Myopathy

Genetic and Clinical Aspects

Two myopathic variants, fatal and benign infantile myopathies, are presumably due to mutations in muscle-specific and developmen-tally regulated COX subunits or COX-assembly proteins, although gene defects have not been identified in either condition.9,19 The fatal infantile myopathy causes respiratory insufficiency and death before 1 year of age. Renal dysfunction is often associated, and patients suffer from Toni-Fanconi syndrome.16 The benign infantile myopathy also causes severe weakness early in life, often requiring assisted ventilation, but symptoms improve spontaneously and these children are usually normal by 2 or 3 years of age.17,49,54,73

Pathology

Muscle biopsy of fatal infantile myopathy shows RRFs and diffuse lack of COX reactivity in myofibers, but normal reaction in intra-muscular blood vessels and in the muscle spindles.49 Muscle biopsies from the benign form are peculiar. Biopsies taken from the neonatal period show no RRF but diffuse absence of COX stain, except for blood vessels and spindles. However, biopsies taken at later times show increasing numbers of COX-positive fibers and RRFs, which eventually return to a normal or near-normal morphology.

SUMMARY

Over the past 20 years, many mitochondrial diseases have been genetically, clinically, and pathologically defined. Many are associ-ated with mtDNA mutations, while others are caused by nDNA mutations that affect mtDNA and the respiratory chain in vari-able fashions. Certainly, many more new genetic and/or clinical phenotypes will be discovered, and the mechanisms by which such genetic alterations are ultimately demonstrated as human diseases remain to be elucidated. Mitochondrial disorders characteristically involve multiple organ systems, with a predilection for tissues that are highly dependent upon oxidative metabolism, such as muscle and brain. It is important to recognize neuromuscular involvement in the patients through muscle biopsy, and it is hoped that this manuscript provides a practical and theoretical guidance to biopsy interpretation.

REFERENCES

1. Adams PL, Lightowlers RN, Turnbull DM. Molecular analysis of cytochrome c oxidase deficiency in Leigh’s syndrome. Ann Neurol 1997:41:268-270.

2. Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CM, Jay C, et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999;45:820-823.

3. Andreu AL, Hanna MG, Reichmann H, Bruno C, Penn AS, Tanji K, et al. Exercise intolerance and mutations in the cytochrome b gene of mitochondrial DNA. N Eng J Med 1999;341:1037-1044.

4. Andreu AL, Checcarelli N, Iwata S, Shanske S, DiMauro S. A mis-sense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy. Pediatr Res 2000;48:311-314

5. Arbustini E, Diegoli M, Fasani R, Grasso M, Morbini P, Banchieri N, et al. Mitochondrial DNA mutations and mitochondrial abnormali-ties in dilated cardiomyopathy. Am J Pathol 1998;153:1501-1510.

6. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991;337:508-510.

7. Bohlega S, Tanji K, Santorelli FM, Hirano M, al-Jishi A, DiMauro S. Multiple mitochondrial DNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy. Neurology 1996;46:1329-1334.

8. Boulet L, Karpati G, Shoubridge EA. Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERFF). Am J Hum Genet 1992;51:1187-1200.

9. Bresolin N, Zeviani M, Bonilla E, Miller RH, Leech RW, Shanske S, et al. Fatal infantile cytochrome c oxidase deficiency: decrease of im-munologically detectable enzyme in muscle. Neurology 1985;35:802-812.

10. Bruno C, Martinuzzi A, Tang Y, Andreu AL, Pallotti F, Bonilla E, et al. A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the structure and function of respiratory chain complex IV. Am J Hum Genet 1999;65:611-620.

11. Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska-Lightowlers ZM, Andrews RM, et al. An mtDNA mutation in the initiation codon of the cytochrome c oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalopathy. Am J Hum Genet 1999;64:1330-1339.

12. Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol 1998;43:110-116.

13. Crimi M, Galbiati S, Moroni I, Bordoni A, Perini MP, Lamantea E, et al. A missense mutation in the mitochondrial ND5 associated with a Leigh-MELAS overlap syndrome. Neurology 2003;60:1857-1861.

14. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098-1105.

15. De Coo IF, Renier WO, Ruitenbeek W, Ter Laak HJ, Bakker M, Schagger H, et al. A 4-base pair deletion in the mitochondrial cy-tochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol 1999;45:130-133.

16. DiMauro S, Mendell JR, Sahenk Z, Bachman D, Scarpa A, Scofield RM, Reiner C. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome c oxidase deficiency. Neurology 1980;30:795-804.

17. DiMauro S, Nicholson JF, Hays AP, Eastwood AB, Papadimitriou A, Koenigsberger R, DeVivo DC. Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency. Ann Neurol 1983;14:226-234.

18. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656-2668.

19. DiMauro S, Bonilla E, Mancuso M, Filosto M, Sacconi S, Salviati L, et al. Mitochondrial myopathies. Basic Appl Myol 2003;13:145-155.

D-�4 Pathology of Muscle in Mitochondrial Disorders AANEMCourse

20. Enriquez JA, Chomyn A, Attardi G. MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and prema-ture translation termination. Nat Genet 1995;10:47-55.

21. Gattermann N, Retzlaff S, Wang YL, Hofhaus G, Heinisch J, Aul C, Schneider W. Heteroplasmic point mutation of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. Blood 1997;90:4961-4972.

22. Glerum D, Shtanko A, Tzagoloff A. SCO1 and SCO2 act as high copy suppresors of mitochondrial copper recruitment defect in Saccharomyces cerevisae. J Biol Chem 1996;271:20531-20535.

23. Hanna MG, Nelson IP, Rahman S, Lane RJ, Land J, Heales S, Cooper MJ, Schapira AH, Morgan-Hughes JA, Wood NW. Cytochrome c oxidase deficiency associated with the first stop-codon point muta-tion in human mtDNA. Am J Hum Genet 1998;63:29-36.

24. Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, lactic acidosis and stroke-like episodes. Ann Neurol 1991;20:601-605.

25. Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mito-chondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990;46:428-433.

26. Jaksch M, Hoffman S, Keinle S, Liechti-Gallati S, Pongratz DE, Muller-Hocker J, et al. A systemic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. J Med Genet 1998;35:895-900.

27. Karadimas CL, Greenstein P, Sue CM, Joseph JT, Tanji K, Haller RG, Taivassalo T, Davidson MM, Shanske S, Bonilla E, DiMauro S. Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA. Neurology 2000;55:644-649.

28. Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, Keranen S, et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 2000;289:782-785.

29. Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, et al. Mutations of mitochondrial DNA polymerase gamma are a fre-quent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol 2002;52:211-219.

30. Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mi-tochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol 2003;53:128-132.

31. Lombes A, Nakase H, Tritschler HJ, Kadenbach B, Bonilla E, DeVivo DC, et al. Biochemical and molecular analysis of cyto-chrome c oxidase in Leigh’s syndrome. Neurology 1991;41:491-498.

32. Mancuso M, Salviati L, Sacconi S, Otaegui D, Camano P, Marina A, et al. Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. Neurology 2002;59:1197-1202.

33. Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, et al. The deoxyguanosine kinase gene is mutated in individuals with de-pleted hepatocerebral mitochondrial DNA. Nat Genet 2001;29:337-341.

34. Manfredi G, Schon EA, Moraes CT, Bonilla E, Berry GT, Sladky JT, et al. A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul Disord 1995;5:391-398.

35. Mita S, Schmidt B, Schon EA, DiMauro S, Bonilla E. Detection of “deleted” mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci USA 1989;86:9509-9513.

36. Mita S, Rizzuto R, Moraes CT, Shanske S, Arnaudo E, Fabrizi GM, et al. Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res 1990;18:561-567.

37. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, et al. Mitochondrial DNA deletions in progressive exter-nal ophthalmoplegia and Kearns-Sayre syndrome. N Eng J Med 1989;320:1293-1299.

38. Moraes CT, Ricci E, Petruzzella V, Shanske S, DiMauro S, Schon EA, et al. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet 1992;1:359-367.

39. Moraes CT, Ciacci F, Silvestri G, Shanske S, Sciacco M, Hirano M, et al. Atypical clinical presentations associated with the MELAS muta-tion at position 3243 of human mitochondrial DNA. Neuromuscl Disord 1993;3:43-50.

40. Musumeci O, Andreu AL, Shanske S, Bresolin N, Comi GP, Rothstein R, et al. Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Am J Hum Genet 2000;66:1900-1904.

41. Naini AB, Lu J, Kaufmann P, Bernstein RA, Mancuso M, Bonilla E, et al. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol 2005;62:473-476.

42. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689-692.

43. Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, et al. Mitochondrial neurogastrointestinal encephalomy-opathy: an autosomal recessive disorder due to thymidine phos-phorylase mutations. Ann Neurol 2000;47:792-800.

44. Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 1999;23:333-337.

45. Pons R, Andreetta F, Wang CH, Vu TH, Bonilla E, DiMauro S, et al. Mitochondrial myopathy simulating spinal muscular atrophy. Pediatr Neurol 1996;15:153-158.

46. Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, et al. Mitochondrial ribosomal RNA mutation associated with both an-tibiotic-induced and non-syndromic deafness. Nat Genet 1993;4:289-294.

47. Pulkes T, Eunson L, Patterson V, Siddiqui A, Wood NW, Nelson IP, et al. The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol 1999;46:916-919.

48. Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 2001;29:342-344.

49. Salo MK, Rapola J, Somer H, Pihko H, Koivikko M, Tritschler HJ, et al. Reversible mitochondrial myopathy with cytochrome c oxidase deficiency. Arch Dis Child 1992;67:1033-1035.

50. Salviati L, Sacconi S, Mancuso M, Otaegui D, Camano P, Marina A, et al. Mitochondrial DNA depletion and dGK gene mutations. Ann Neurol 2002;52:311-317.

51. Santorelli FM, Tanji K, Kulikova R, Shanske S, Vilarinho L, Hays AP, et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun 1997;238:326-328.


52. Santorelli FM, Tanji K, Manta P, Casali C, Krishna S, Hays AP, et al. Maternally inherited cardiomyopathy: an atypical presentation of the mtDNA 12S rRNA gene A1555G mutation. Am J Hum Genet 1999;64:295-300.

53. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002;347:576-580.

54. Servidei S, Bertini E, Dionisi-Vici C, et al. Benign infantile mitochon-drial myopathy due to reversible cytochrome c oxidase deficiency: a third case. Clin Neuropathol 1988;7:209-210.

55. Servidei S, Zeviani M, Manfredi G, Ricci E, Silvestri G, Bertini E, et al. Dominantly inherited mitochondrial myopathy with multiple dele-tions of mitochondrial DNA: clinical, morphologic, and biochemical studies. Neurology 1991;41:1053-1059.

56. Shanske S, Tang Y, Hirano M, Nishigaki Y, Tanji K, Bonilla E, et al. Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with Pearson syndrome. Am J Hum Genet 2002;71:679-683.

57. Shoffner J, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990;61:931-937.

58. Shoffner JM, Brown MD, Huoponen K, et al. A mitochondrial DNA mutation associated with maternally inherited deafness and Parkinson’s disease. Neurology 1996;46:A331.

59. Shoubridge E, Karpati G, Hastings KE. Deletion mutants are func-tionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell 1990;62:43-49.

60. Shoubridge EA. Nuclear genetic defect of oxidative phosphoryla-tion. Hum Mol Genet 2001;10:2277-2284.

61. Silvestri G, Moraes CT, Shanske S, Oh SJ, DiMauro S. A new mtDNA mutation in the tRNA(Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992;51:1213-1217.

62. Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 2001;28:223-231.

63. Sue CM, Karadimas C, Checcarelli N, Tanji K, Papadopoulou LC, Pallotti F, et al. Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann Neurol 2000; 47:589-595.

64. Suomalainen A, Majander A, Haltia M, Somer H, Lonnqvist J, Savontaus ML, et al. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and fa-milial progressive external ophthalmoplegia. J Clin Invest 1992;90:61-66.

65. Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D’agati VD. Adefovir nephrotoxicity: Possible role of mitochondrial DNA deple-tion. Hum Pathol 2001;32:734-740.

66. Tanji K, Bonilla E. Neuropathologic aspects of cytochrome c oxidase deficiency. Brain Pathol 2000;10:422-430.

67. Tatuch Y, Robinson BH. The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. Biochem Biophys Res Commun 1993;192:124-128.

68. Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, et al. Mutations of SURF-1 in Leigh disease as-sociated with cytochrome c oxidase deficiency. Am J Hum Genet 1998;63:1609-1621.

69. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 2001;28:211-212.

70. Vu TH, Sciacco M, Tanji K, Nichter C, Bonilla E, Chatkupt S, et al. Clinical manifestations of mitochondrial DNA depletion. Neurology 1998;50:1783-1790.

71. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427-1430.

72. Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAsLeu(UUR) with pathogenic mutations of mitochondrial my-opathy, encephalopathy, lactic acidosis and stroke-like episodes. J Biol Chem 2000;275:4251-4257.

73. Zeviani M, Peterson P, Servidei S, Bonilla E, DiMauro S. Benign reversible muscle cytochrome c oxidase deficiency: a second case. Neurology 1987;37:58-63.

74. Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998;20:337-343.


INTRODUCTION

Traditionally, nerve biopsies have been utilized in sensory nerves such as the sural and superficial peroneal nerves, to avoid com-plications such as weakness. Pathological study of sensory nerves, however, is generally not useful in the evaluation of lower motor neuron syndromes. Recently, judicious use of fascicular biopsies in focal mononeuropathies of mixed motor and sensory nerves has been demonstrated to aid in the evaluation of neuropathies (Dyck PJB, personal communication). Biopsies of motor nerves—motor branches of mixed sensory and motor nerves—have been also helpful in the evaluation of polyneuropathies with either purely motor or predominantly motor features.

In patients with neuropathy, motor nerve biopsies may be used to improve treatment or, in some cases, avoid unnecessary treat-ment.5,13 The utility of motor nerve biopsies, of course, depends on patient selection, the expertise of the surgeon, and the expertise of the pathologists and their laboratories.

INDICATIONS FOR MOTOR NERVE BIOPSIES

Similar to sensory nerve biopsies, motor nerve biopsies should only be utilized if a thorough evaluation of the patient does not reveal the underlying diagnosis or if the results of the nerve biopsy will alter therapeutic decisions. Biopsies should be used to look for

interstitial changes and not to differentiate, for example, between demyelinating and axonal neuropathies. In a multifocal pattern, nerve biopsy can be used to make a diagnosis of vasculitis or ma-lignancy. When noninvasive tests are inconclusive, and diagnoses such as inflammation, vasculitis, granuloma, demyelination, infec-tion, neoplasia, or amyloidosis are suspected, nerve biopsy could be helpful. In focal nerve enlargements, nerve biopsy can differentiate between disorders such as focal infection (leprosy), tumor (lym-phoma, neurofibroma, Schwannoma), and inflammation.

Biopsies can be performed to obtain specimens from of the entire nerve (whole) or the individual fascicle(s). The advantage of a whole nerve biopsy (epineurium, perineurium, and endoneurium), is that additional information about the surrounding interstitial tissues, including blood vessels, is available for review. Small motor branches are usually obtained as whole nerve biopsies. Fascicular bi-opsies are obtained from mixed motor and sensory nerves to avoid leaving a significant motor deficit.

Although motor nerve biopsies have previously been described for focally enlarged nerves, more recently, motor nerves have been used in generalized polyneuropathies or predominantly motor neuropathies. Single cases have been reported using biopsies of the musculocutaneous7 and peroneal3,9 nerves. Taylor and colleagues examined fascicular biopsies of motor nerves in patients with multifocal motor neuropathy (MMN).14 In addition, biopsies of the obturator nerve to gracilis1 have been used in the evaluation of

Pathology of Motor Nerve Biopsy

Annabel K. Wang, MDAssistantProfessor

DepartmentofNeurologyMountSinaiMedicalCenter

NewYork,NewYork

D-��

Guillain-Barré Syndrome (GBS),10 amyloidosis,12 motor neuropa-thies, and motor neuron disease (MND).4

COMPLICATIONS OF MOTOR NERVE BIOPSIES

There are concerns about the complications of motor nerve biop-sies; however, only transient motor deficits have been reported with whole motor branch and fascicular biopsies.2,3,8,14 Complications of nerve biopsies are based on the data from sural nerve biopsies.6 Temporary discomfort can be present for approximately 3 months after the biopsy in approximately 40% of cases. Lasting discomfort has been reported in approximately 10% of cases, while severe complications, such as infection or neuroma, have been reported in less than 1% of cases.

TECHNIQUES FOR MOTOR NERVE BIOPSIES

It is important to understand the techniques used to obtain speci-mens for biopsy. In order to obtain fascicular biopsies at the site of conduction block,14 the lower edge of conduction block in the af-fected nerve is marked prior to biopsy. Intraoperatively, individual or small groups of fascicles are exposed surgically and stimulated with microelectrodes to determine the distal site of conduction block. Usually two to three fascicles are biopsied in order to include epineurial tissue for evaluation.

Although gracilis muscles and obturator nerves have been used for many years by plastic surgeons for grafting, the biopsy techniques were only first described in 1997.1 The obturator nerve to gracilis is exposed using a 7 cm longitudinal incision, which is made along an imaginary line between the pubic tubercle and medial tibial condyle, posterior to the adductor longus muscle. The intermus-cular plane between the adductor longus anteriorly and the gracilis posteriorly is then dissected. The vascular pedicle is identified piercing the inner surface of the muscle at a 90 degree angle. The motor nerve to the gracilis muscle can usually be found just deep to the vascular pedicle and coursing at a 45 degree angle to the long axis of the limb. A biopsy of the gracilis is often taken simultane-ously with the motor nerve.

Recently, median nerve and pronator muscle biopsies were used in the evaluation of patients with atypical motor neuropathy.15 In this technique, the median nerve is exposed with a longitudinal incision starting at the flexion crease of the antecubital fossa and extending 7-8 cm distally. The antecubital fascia and distal fibers of the lacer-tus fibrosis are divided. The brachial artery and its bifurcation into radial and ulnar arteries are dissected out at or just proximal to this level. The brachial artery is retracted out of harm’s way. The prona-tor teres muscle is then retracted to expose the median nerve which can usually be found deep in the muscle. The nerve is followed into the pronator tunnel, coursing between the two heads of the pro-nator muscle. The underside of the pronator muscle is examined and occasionally a small branch is seen coursing from the median

nerve to the muscle. More commonly, it is necessary to follow the median nerve more proximally in the antecubital fossa to find a small branch leaving its anterior surface to run on the underside of the pronator muscle. A biopsy of the pronator teres can also be obtained at the same level. (Ting J, personal communication.)

REVIEW OF MOTOR NERVE BIOPSIES

Guillain-Barré Syndrome

Motor nerve biopsies have been used to understand the patho-genesis of GBS and to differentiate severe forms of GBS from the axonal forms of GBS. In 1992, Hall and colleagues reported that a terminal branch biopsy of the musculocutaneous nerve from a patient with a severe case of GBS7 revealed pronounced subperi-neurial edema, macrophage infiltration, and complete demyelin-ation of many axons. This case was helpful in demonstrating that primary demyelination is the underlying pathological process of GBS. Another study by Massaro and colleagues11 tried to determine whether or not inexcitable motor nerves in early GBS represented a primary axonal attack. Two children with severe GBS and inex-citable motor nerves at days 6 and 7, underwent sural nerve and superficial peroneal motor nerve branch biopsies to extensor digi-torum brevis. Both children had delayed recovery and residual dis-ability despite early treatment with intravenous immunoglobulin (IVIg). Both sural and superficial peroneal nerves revealed severe macrophage-associated demyelination, abundant myelin debris in macrophages, and Schwann cells with completely demyelinated axons. The biopsy findings were consistent with the demyelinating form of GBS, although clinically and based on electrodiagnostic evaluation, both patients appeared to have the acute motor-sensory axonal neuropathy (AMSAN) variant of GBS. Only rare axonal degeneration was seen in their biopsies.

In another study of GBS patients,10 four obturator nerve and graci-lis muscle biopsies were reviewed to determine if immunological abnormalities were more evident in motor than sensory nerves. Three motor nerve biopsies revealed CD3 T cells and macrophages using immunostaining. Occasional Schwann cells devoid of axons were seen. Inflammation, a focus of perivascular lymphocytes, was only seen in one muscle biopsy. Two of the patients had medial cutaneous sensory nerve to thigh biopsies which were normal, sug-gesting that immunological abnormalities were more evident in motor compared to sensory nerves.

Amyloidosis

Biopsy of the motor nerve to gracilis has been helpful in the diag-nosis of amyloidosis. In 1998, Quattrini and colleagues reported the a case involving a 57-year-old man with progressive symmet-ric weakness and fasciculations affecting the legs. His evaluation was negative until amyloidosis was found on his obturator nerve biopsy.12 Autonomic and sensory symptoms, along with serum

D-�� Pathology of Motor Nerve Biopsy AANEMCourse

lambda light chains, did not manifest until 6 months after the motor nerve biopsy had been performed. In an unreported case, a 58-year-old man first developed bilateral proximal leg weakness after initation of a cholesterol-lowering agent, but subsequently developed a progressive sensorimotor polyneuropathy, with only mild autonomic symptoms. Initial evaluation, including sural nerve biopsy, was uninformative and there was no response to im-munotherapy (steroids, plasmapheresis, and IVIg). Biopsies of the obturator nerve and gracilis muscle were both positive for amyloid, and the patient was subsequently diagnosed with familial amyloi-dosis polyneuropathy through genetic testing. (Lange DJ, personal communication.)

Amyotrophic Lateral Sclerosis

Bradley and colleagues evaluated a combination of motor nerve biopsy and postmortem tissue in order to determine whether the underlying pathophysiology of amyotrophic lateral sclerosis (ALS) was due to neuronopathy.3 They reviewed postmortem studies on 11 patients with ALS and 9 control subjects, and collected phrenic nerves from the apex of the pleural cavity to the inser-tion in diaphragm. Sections of phrenic nerves were evaluated both proximally and distally. The common peroneal (mixed sensory and motor) nerves were also obtained 5 cm above the fibular head in the popliteal fossa. Fascicular biopsies from the common peroneal nerves were also taken from six live patients with ALS. Anterior tibial strength, which was assessed before and after the biopsy using dynamometric measurements, revealed transient impairment in one patient (20% compared to baseline), which improved after 24 hours. Severe loss of myelinated fibers with acute axonal de-generation and rare clusters of regenerating axons were seen in the phrenic nerves. The total number of myelinated fibers was reduced to 70% and large myelinated fibers were reduced by 33% in control subjects. Less than 18% of fibers were lost distally compared to proximally, consistent with neuronopathy rather than a dying back phenomena. The study reported that in the common peroneal nerve biopsies, a small number of myelinated fibers undergoing acute axonal degeneration, occasional clusters of regenerating fibers and a moderate number of denervated Remak processes were seen. There were no differences in myelinated and unmyelinated fibers compared to control subjects.

Obturator nerve biopsies from patients with MMN and MND have also been compared. In a study4 of nine patients with MND and six patients with MMN (two without anti-GM1 antibodies; three with conduction block; three with demyelination), evidence for demyelination with thinly myelinated axons and small onion bulb formation were seen only in three patients with MMN and not in patients with MND. A lower density of regenerative clusters was seen in the biopsies from patients with MND biopsies, con-firming the presence of neuronopathy.

Motor Neuropathies

In 1990, Kolimas and colleagues performed a biopsy of deep pe-roneal nerve to the extensor digitorum brevis to look for evidence of immunological and demyelinating changes in a patient with MMN.9 The biopsy revealed mild perivascular and endoneurial mononuclear cell infiltrates and demyelination. Subsequent studies have confirmed the demyelinating nature of MMN, but inflam-matory changes have rarely been seen. In one study, a 38-year-old man with 6 years of upper extremity wasting and weakness without sensory symptoms was found to have conduction block in proxi-mal median and ulnar motor nerves only. Biopsy of the proximal right ulnar nerve in axilla revealed a chronic demyelinating process: thinly myelinated fibers with onion bulbs without evidence of inflammation.2 In another case report,8 a 49-year-old man, with a 3-year history of right distal and proximal upper extremity weak-ness, atrophy, and fasciculations, was found to have a mass adjacent to the subclavian artery on magnetic resonance imaging. Surgical exploration revealed multifocal enlargements of the distal end of the lower trunk and proximal medial and posterior cords of the brachial plexus. Nerve biopsy of the medial pectoral nerve at the level of conduction block revealed subperineurial edema and slight thickening of perineurium. The perivascular area contained scat-tered axons without myelin, thinly myelinated axons, and small onion bulbs without inflammation. Eight fascicular biopsies,14 also at the site of conduction block, revealed multifocal fiber loss with loss of large fibers, and the presence of regenerating clusters. Unlike the two previous case reports, no onion bulbs or other evidence for demyelination were seen. Small inflammatory infiltrates were seen in two biopsies, suggestive of an inflammatory or immune process. The authors postulated that their pathological findings suggest the presence of a functional alteration due to the physiological block of motor axons, which can lead to fiber degeneration and faulty regeneration, as a possible explanation for decreasing responses to therapy over time. Eleven motor nerve biopsies from either the obturator nerve to gracilis or the median nerve to pronator were reviewed in patients with atypical motor neuropathies15 (Wang AK, submitted for publication). Biopsies revealed loss of large myelinated fibers, with some evidence for multifocal fiber loss, but no evidence for inflammation. Unlike previous studies, axonal clusters suggestive of regeneration and onion bulbs, suggestive for myelin remodeling, were abundant in several nerves. These findings suggest that there may be a spectrum of both clinical and pathologi-cal findings in motor neuropathies.

CONCLUSION

Biopsy of motor nerves can be useful in selected cases: focal mono-neuropathies, predominantly motor neuropathies, and purely motor neuropathies. Pathological findings from motor nerve biop-sies have provided information about the underlying pathogenesis


of GBS and ALS, and have provided clues into the pathogenesis of MMN. More research into the utility of motor nerve biopsy and normative data are required.

REFERENCES

1. Abouzahr MK, Lange DJ, Latov N, Olarte M, Rowland LP, Hays AP, Corbo M. Diagnostic biopsy of the motor nerve to the gracilis muscle. Technical note. J Neurosurg 1997;87:122-124.

2. Auer RN, Bell RB, Lee MA. Neuropathy with onion bulb formations and pure motor manifestations. Can J Neurol Sci 1989;16:194-197.

3. Bradley WG, Good P, Rasool CG, Adelman LS. Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral scle-rosis. Ann Neurol 1983;14:267-277.

4. Corbo M, Abouzahr MK, Latov N, Iannaccone S, Quattrini A, Nemni R, Canal N, Hays AP. Motor nerve biopsy studies in motor neuropathy and motor neuron disease. Muscle Nerve 1997;20:15-21.

5. Dyck PJ, Dyck PJ, Grant IA, Fealey RD. Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology 1996;47:10-17.

6. Dyck PJ, Dyck PJ, Engelstad J. Pathologic alterations of nerves. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadelphia: WB Saunders; 2005. p 733-830.

7. Hall SM, Hughes RA, Atkinson PF, McColl I, Gale A. Motor nerve biopsy in severe Guillain-Barré syndrome. Ann Neurol 1992;31:441-444.

8. Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, Kimura J. Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann Neurol 1993;33:152-158.

9. Kolimas RJ, Harati Y. Multifocal motor neuropathy: value of electrophysiologic studies and motor nerve biopsy. Muscle Nerve 1990;13:868.

10. Lange DJ, Abouzahr MK, Hays AP, Latov N. Motor nerve biopsy in Guillain-Barré syndrome. Ann Neurol 1997;42:450-451.

11. Massaro ME, Rodriguez EC, Pociecha J, Arroyo HA, Sacolitti M, Taratuto AL, Fejerman N, Reisin RC. Nerve biopsy in children with severe Guillain-Barré syndrome and inexcitable motor nerves. Neurology 1998;51:394-398.

12. Quattrini A, Nemni R, Sferrazza B, Ricevuti G, Dell’Antonio G, Lazzerini A, Iannaccone S. Amyloid neuropathy simulating lower motor neuron disease. Neurology 1998;51:600-602.

13. Said G. Indications and usefulness of nerve biopsy. Arch Neurol 2002;59:1532-1535.

14. Taylor BV, Dyck PJ, Engelstad J, Gruener G, Grant I, Dyck PJ. Multifocal motor neuropathy: pathologic alterations at the site of conduction block. J Neuropathol Exp Neurol 2004;63:129-137.

15. Wang AK, Kleinman GM, Lange DJ. Motor nerve and muscle biopsy findings in multifocal motor neuropathy: implications for pathogenesis. Ann Neurol 2005;58:S30.

D-40 Pathology of Motor Nerve Biopsy AANEMCourse

1. All of the following rules are true about the muscle biopsy procedure EXCEPT:A. The selected muscle should be weak but not flaccid.B. The specimen should be accompanied by clinical infor-

mation.C. An open biopsy is preferred rather than a needle biopsy. D. The sample for enzyme histochemistry should be sub-

merged in saline during transportation.E. The sample for enzyme histochemistry should be kept

cool during transportation.

2. All of the following statements about myophosphorylase defi-ciency are true EXCEPT:A. The patients may have either McArdle syndrome, slowly

progressive weakness, or asymptomatic elevated serum creatine kinase (CK) activity.

B. The biopsy should be performed shortly after an episode of myoglobinuria to document necrosis of muscle fibers.

C. Some patients may have a normal muscle biopsy with no detectable glycogen accumulation in muscle fibers based on histology and histochemistry.

D. Myophosphorylase deficiency can be detected by a histo-chemical stain for the enzyme.

E. Glycogen tends to accumulate in the subsarcolemmal region of myofibers.




AANEMCourse D-41

Fill

in an

swer


your phone number

1 2 3 4



Under ID number, please write out and fill inthelast4digitsofyourphonenumber.Be sure to start in the first box on the left (asshown).



3. Which one of the following disorders of glycogen metabolism typically shows large deposits of glycogen in the subsarcolem-mal region of muscle fibers?A. Myophosphorylase deficiency.B. Debrancher enzyme deficiency.C. Phosphofructokinase deficiency.D. Deficiency of enzymes in the terminal pathway of glycoly-

sis.E. Adult-onset acid maltase deficiency.

4. All of the following statements are true about the muscle biopsy of dermatomyositis EXCEPT:A. Necrotic myofibers and regenerating fibers are distributed

randomly throughout the muscle.B. Muscle fiber atrophy predominates at the edge of muscle

fascicles (perifascicular atrophy).C. B cells, CD4-positive T cells, and histiocytes predominate

in the perimysium.D. Blood vessels show ultrastructural features of endothelial

injury and reactive changes including tubuloreticular ag-gregates.

E. Express of major histocompatibility complex (MHC) class I antigens in muscle fibers are typically focal and are most pronounced along the edge of muscle fascicles.

5. All of the following pathological features of inclusion body myositis are true EXCEPT:A. Necrotic fibers and regenerating fibers seem to be ran-

domly distributed throughout the muscle as in polymyo-sitis.

B. CD8-positive T cells predominate in inflammatory in-filtrates and occasionally appear to invade non-necrotic muscle fibers.

C. Typically, the muscle shows widespread expression of MHC class I antigens at the surface of myofibers.

D. Rimmed vacuoles and congophilic inclusions are found in the cytoplasm of muscle fibers in most muscle biopsies.

E. Electron microscopic examination of the muscle is neces-sary to confirm the diagnosis by demonstrating the abnor-mal 12-18 nm filaments.

6. Which of the following muscular dystrophies would be con-sidered forms of secondary alpha-dystroglycanopathies?A. Fukuyama.B. Muscle-eye-brain disease.C. Walker-Warburg.D. Congenital muscular dystrophy (MDC) 1C caused by

fukutin-related protein mutation.E. All of the above.

7. Which is the most sensitive test in evaluation of a male for possible Becker muscular dystrophy?A. Serum creatine kinase (CK) level.B. Electromyography.C. Muscle biopsy with routine histochemistry.D. Muscle biopsy with immunostain for dystrophin expres-

sion on the sarcolemma of muscle fibers.E. Western blot analysis of dystrophin in a muscle biopsy

sample.

8. Rimmed vacuoles are noT a histological feature commonly seen in which type of muscular dystrophy?A. Nonaka type distal myopathy. B. Oculopharyngeal muscular dystrophy.C. Limb-girdle muscular dystrophy (LGMD) 2B or Miyoshi

myopathy.D. Welander type distal myopathy.E. Myotilinopathies.

9. Prominent endomysial and perivascular inflammatory cell infiltration can be seen in the following dystrophies:A. Facioscapulohumeral muscular dystrophy.B. LGMD 2A.C. LGMD 2B or /Miyoshi myopathy.D. All of the above.E. None of the above. Inflammatory cell infiltrate is diagnos-

tic of polymyositis.

10. The following dystrophy CannoT be diagnosed on muscle biopsy with routine immunohistochemistry: a. X-linked Emery-Dreifuss muscular dystrophy.b. LGMD 2A.c. LGMD 2C-F (one of the sarcoglycanopathies).d. MDC 1A. e. Duchenne muscular dystrophy.

11. The abnormality that is demonstrated by Gomori trichrome stain of muscle shown here is characteristic of:

A. LGMD 2D.B. Nemaline myopathy.C. Spinal muscular atrophy (SMA) type I.D. Kearns-Sayre syndrome (KSS).E. Centronuclear myopathy.

D-4� CME Self-Assessment Test AANEMCourse

12. The following statements about mitochondrial encephalomy-opathy with lactic acidosis and stroke-like episodes (MELAS) are true EXCEPT:A. The point mutation in the transfer ribonucleic acidleu(UUR)

gene, A3243G transition, is the most common genetic alteration found in MELAS.

B. Activity of complex II (succinate dehydrogenase [SDH]) is often reduced.

C. Ragged red fibers (RRFs) often stain positively with cyto-chrome c oxidase (COX).

D. Muscle biopsy often reveals strongly SDH reactive blood vessels (SSV).

E. A mutation in the ND5 (complex I) can be associated with the clinical phenotype of MELAS.

13. Which is the correct statement about KSS?A. KSS is associated with a nuclear gene mutation that

qualitatively affects mitochondrial deoxyribonucleic acid (mtDNA).

B. RRFs often stain positively with COX.C. The vast majority of cases are maternally inherited.D. Cerebrospinal fluid protein is usually found to be low.E. Patients who outlive Pearson’s syndrome develop KSS

later in life.

14. The following statements about mitochondrial depletion syn-drome (MDS) are correct EXCEPT:A. MDS is associated with a large deletion of mtDNA.B. MDS may present with similar clinical phenotypes to

those seen in SMA.C. Muscle biopsy shows RRFs that stain negatively with

COX.D. Drug-induced MDS is a serious complication of acquired

immunodeficiency syndrome treatment.E. Biochemical analysis of MDS reveals combined defects of

respiratory chain complexes containing mtDNA-encoded subunits.

15. Which statement is correct about mitochondrial disease and its pathology?A. MELAS and myoclonic epilepsy with RRFs are two

separate clinical entities caused by point mutations in the same mtDNA transfer ribonucleic acid gene.

B. In addition to RRFs, most of mitochondrial myopa-thies show necrotic and/or regenerative fibers in muscle biopsy.

C. Gomori trichrome stain has been widely used to demon-strate RRFs in muscle biopsy, but histochemical staining of SDH is the most sensitive method to visualize the segmental proliferation of mitochondria.

D. Recently discovered SCO2 and SURF1 mutations are as-sociated with ophtalmoplegia and late-onset myopathy.

E. RRFs are the specific, morphological alteration found only in mitochondrial myopathy.

16. The utility of motor nerve biopsies depends on:A. Patient selection.B. Expertise of the surgeon.C. Expertise of the neuropathologist.D. Quality of the pathology laboratory.E. All of the above.

17. Complications from motor nerve biopsy include: 1. Weakness. 2. Discomfort. 3. Hematoma. 4. Neuroma. 5. Infection.

A. Only 1, 2, and 3 are correct.B. Only 1 and 3 are correct.C. Only 2 and 4 are correct.D. Only 4 is correct.E. All are correct.

18. The main advantage of a fascicular nerve biopsy is:A. Evaluation of interstitial tissue.B. Evaluation of perineurium.C. Decreased likelihood of infection.D. Decreased likelihood of permanent deficit.E. Decreased likelihood of neuroma formation.

19. Fascicular motor nerve biopsies have been useful in the evalu-ation of all of the following EXCEPT:A. Focal mononeuropathies.B. Sensory neuronopathies.C. Predominantly motor neuropathies.D. Motor neuropathies.E. Motor neuron disease (MND).

20. Motor neuropathy can be differentiated from MND by the following changes on nerve biopsy EXCEPT:A. Onion bulbs.B. Thinly myelinated fibersC. Inflammation.D. Axonal degeneration.E. Axonal clusters.

AANEMCourse CMESelf-AssessmentTest D-4�

D-44 AANEMCourse

21. How would you rate the quality of instruction received during Dr. Hays’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

22. Select any item(s), that, if changed, would have appreciably improved Dr. Hays’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-

tion.D. Amount of scientific content in the presentation.E. Other: please explain on the comment form at the back of

this handout.

23. Did you perceive any commercial bias in Dr. Hays’s presenta-tion?A. Yes.B. No.

24. How would you rate the quality of instruction received during Dr. Amato’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

25. Select any item(s), that, if changed, would have appreciably improved Dr. Amato’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

26. Did you perceive any commercial bias in Dr. Amato’s presenta-tion?A. Yes.B. No.

27. How would you rate the quality of instruction received during Dr. Tanji’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.

28. Select any item(s), that, if changed, would have appreciably improved Dr. Tanji’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

29. Did you perceive any commercial bias in Dr. Tanji’s presenta-tion?A. Yes.B. No.

30. How would you rate the quality of instruction received during Dr. Wang’s presentation?A. Best possible.B. Good.C. Average.D. Poor.E. Worst possible.


EVALUATION

Select ANY of the answers that indicate your opinions.

Your input is needed to critique our courses and to ensure that we use the best faculty instructors and provide the best course options in future years. Make additional comments or list suggested topics or faculty for future courses on the comment form provided at the end of this handout.

AANEMCourse D-45

31. Select any item(s), that, if changed, would have appreciably improved Dr. Wang’s presentation:A. Quality of slides.B. Quality of handout.C. Amount of clinically relevant information in the presenta-


this handout.

32. Did you perceive any commercial bias in Dr. Wang’s presenta-tion?A. Yes.B. No.

33. As a result of your attendance at this educational session, did you learn anything that will improve the care of your pa-tients?A. Yes, substantially.B. Yes, somewhat.C. Not sure.D. Probably not.E. This session was not applicable to my patients.

34. Do you feel that the information presented in this session was based on the best evidence available?A. YesB. No: please explain on the comment page at the back of

this handout.

35. Select ALL items where improvement was needed.A. The accuracy of advance descriptions of this course.B. The specific topics selected for presentation.C. The number of speakers in this course.D. The amount of time allotted for discussion in this

course.E. Other: please add other areas and outline specific rec-

ommendations for areas needing improvement on the comment page at the back of this handout.

36. I plan to attend the 2007 AANEM Annual Meeting in Phoenix, AZ October 17-20.A. Yes, definitely.B. No, definitely.C. Will wait to see the program content.D. Will wait to see if budget allows my attendance.

37. We would like the AANEM Annual Meeting to be one of your “must attend” meetings each year. In order to do this, we would have to do what to make it happen? Please explain on the comment page at the back of this handout.

38. If you are a member of the AANEM, what would you rate as the most valuable benefit of your membership?A. My subscription to the journal Muscle & Nerve.

B. Receiving free educational materials such as the Muscle & Nerve Invited Reviews and the AANEM Resource CD.

C. The availability of CME opportunities.D Member discounts on AANEM CME products and ser-

vices.E. AANEM’s advocacy work on issues that impact my pro-

fession.

39. In 2006, the AANEM distributed 6 bound copies of the Muscle & Nerve Invited Reviews. How would you rate this new member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I do not receive this since I am not an AANEM

member.E. Other: please explain on the comment page at the back of

this handout.

40. When you receive the bound copies of the Muscle & Nerve Invited Reviews, you can visit the AANEM website and complete CME questions to receive a certificate at no charge. Have you utilized this new service?A. Yes, I have completed CME for the Invited Reviews

online and found the system easy to utilize.B. Yes, I have completed CME for the Invited Reviews

online, but found the system difficult to utilize.C. No, I have not utilized this service because I was unaware

it was available. D. No, I have not utilized it although I was aware of its avail-

ability: please explain on the comment page at the back of this handout.

E. Other: please explain on the comment page at the back of this handout.

41. In 2006, the AANEM added Online Case Studies to the website which are also available for CME credit. How would you rate this new member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I was not aware that this was available on the AANEM

website.E. Other: please explain on the comment page at the back of

this handout.

42. The AANEM has recently launched new Marketing Slides on the website that can assist EDX physicians in marketing to referral sources. How would you rate this member benefit?A. Very valuable.B. Somewhat valuable.C. Not very valuable.D. I have not reviewed the marketing slides yet.E. Other: please explain on the comment page at the back of

this handout.

D-4� Evaluation AANEMCourse

2006 Course E AANEM 53rd Annual Meeting

Washington, DC




Richard T. Abresch, MS

Craig M. McDonald, MD

Mark B. Bromberg, MD, PhD

Neuromuscular Quality of Life


Faculty

Richard T. Abresch, MSDirector of ResearchResearch and Training Center on Neuromuscular DiseaseDepartment of Physical Medicine and RehabilitationUniversity of California DavisDavis, CaliforniaRichard T. Abresch, MS is the Director of Research for the Rehabilitation Research and Training Center in Neuromuscular Diseases. His research interests include quality of life issues of the disabled, development of clini-cal trials and outcome measures in neuromuscular disease, and the effect of neuromuscular diseases on the body composition, strength, and function.

Craig M. McDonald, MDProfessorDepartments of Physical Medicine and Rehabilitation and PediatricsUniversity of California Davis School of MedicineDavis, CaliforniaDr. McDonald is Professor of Physical Medicine and Rehabilitation and Pediatrics and Director of the Neuromuscular Disease Clinics at the University of California Davis Medical Center. He is Director of the National Institute on Disability and Rehabilitation Research’s Rehabilitation Research and Training Center in Neuromuscular Diseases at UC Davis. His research interests include clinical endpoints in muscular dystrophy, exercise in neuromuscular disease, energy expenditure, quanti-tative assessment of physical activity, and quality-of-life assessment.

Mark B. Bromberg, MD, PhDProfessor and Vice-chairmanDepartment of NeurologyUniversity of UtahSalt Lake City, UtahDr. Bromberg began his academic career in basic science research. He received a doctorate in neurophysiology from the Department of Physiology at the University of Vermont and conducted research in the somatosensory and motor systems. Dr. Bromberg attended medical school at the University of Michigan and also completed his neurology training and neuromuscular/EMG fellowship there. He was on the faculty at the University of Michigan until 1994, when he joined the University of Utah. He is currently a professor and vice-chairman in the Department of Neurology. Dr. Bromberg is Director of the Neuromuscular Program and EMG laboratory, and the Muscular Dystrophy Association clinics. His research interests are in quantitative EMG, including motor unit number estimation (MUNE) and algorithms for automated motor unit analysis, and in clinical aspects of amyotrophic lateral sclerosis.

Course Chair: Gregory T. Carter, MD, MS


Authors had nothing to disclose.

E-ii



Contents

Faculty i

Objectives ii

CourseCommittee iv

Tools for Measuring Quality of Life 1RichardT.Abresch,MS

Outcome Measures for Clinical Trials of Muscle Diseases 7CraigM.McDonald,MD

Quality of Life in Amyotrophic Lateral Sclerosis 15MarkB.Bromberg,MD,PhD


Evaluation 23

Ob j e c t i v e s—After attending this course, participants will understand (1) the tools for measuring quality of life, (2) the issues that impact quality of life in Duchenne muscular dystrophy, and (3) the quality of life in amyotrophic lateral sclerosis.




E-iii

E-iv

ThomasHyattBrannagan,III,MDNew York, New York

HopeS.Hacker,MDSan Antonio, Texas

KimberlyS.Kenton,MDMaywood, Illinois

DaleJ.Lange,MD New York, New York

SubhadraNori,MDBronx, New York

JeremyM.Shefner,MD,PhDSyracuse, New York

T.DarrellThomas,MDKnoxville, Tennessee

BryanTsao,MDShaker Heights, Ohio


JaniceM.Massey,MDDurham, North Carolina


KathleenD.Kennelly,MD,PhDJacksonville, Florida

Tools for Measuring Quality of Life

Richard T. Abresch, MS DirectorofResearch

ResearchandTrainingCenteronNeuromuscularDiseaseDepartmentofPhysicalMedicineandRehabilitation

UniversityofCaliforniaDavisDavis,California

INTRODUCTION

The World Health Organization defines quality of life (QOL) as “individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns.27 It is a broad concept affected in a complex way by the person’s physical health, psychological state, personal beliefs, social relationships and their relationship to salient features of their environment.” Although many people discuss factors of QOL, few studies have systemati-cally assessed the QOL of individuals with peripheral neuropathies. The goals of this manuscript are to: (1) show the value of perform-ing health-related QOL (HRQOL) measurements, (2) briefly de-scribe methods used to assess QOL, and (3) to examine the results from studies that have assessed the HRQOL of individuals with peripheral neuropathies.

VALUE OF HEALTH-RELATED QUALITY OF LIFE MEASUREMENTS

Why should a clinician measure HRQOL? Whereas biochemical and physiological information is often of interest to clinicians, they are of limited interest to patients. Patients are more interested in functional status and emotional well-being. Two patients with the same clinical symptoms may function quite differently. Although two patients may have similar ratings of pain and mobility, they may have significantly different role functions. One might be

working, while another might quit their job and have significant depression.

In addition, the way an individual views their own QOL is fre-quently different than that reported by close relatives or caregivers. To determine if the opinions of close relatives can be used as proxies to assess QOL, McKusker and Stoddard examined the responses from patients who were terminally ill and proxy responses of close relatives.18 They found that the correlation between the two sets of responses on the Sickness Impact Profile, a general comprehensive measure of QOL, was only 0.55. Whereas the proxy reports of observable domains such as physical functioning were highly cor-related, reports of role functioning and physical limitations were poorly correlated. In general, the proxy respondents considered the patients more impaired than the patients themselves. This is important because clinicians frequently make judgments based upon reported behavior and perceptions of a patient’s relatives and caregivers.

Misconceptions regarding the QOL of individuals with disabilities are not limited to close relatives. Several studies have shown that healthcare professionals frequently underestimate the QOL of their patients. This misconception often affects their own expectations and their treatment choices.2,11,20 In the most glaring cases, a physi-cian’s subjective, but incorrect, assessment of a disabled individual’s QOL may prevent life-sustaining interventions. Since judging a patient’s QOL is often used to determine appropriate medical pro-cedures, an accurate assessment of a patient’s QOL is critical.2,11

2 AANEMPlenaryE-2 Tools for Measuring Quality of Life AANEMCourse

METHODS TO ASSESS QUALITY OF LIFE

Research methods used to measure QOL began in 1960 with a report of the President’s Commission on National Goals.21 Economists and social scientists performed the first measurements of QOL and equated it with the goods and services required for better living. Indicators in these studies included per capita energy consumption, life expectancy, percentage of children in the labor force, physicians per 1000 population, and gross domestic product.

To study the effect of disablement on QOL, investigators have traditionally focused on objective indicators, such as an individual’s functional ability in terms of their capacity to carry out activities of daily living, their ability to work, their employment status, their income, and the number of times an individual engages in social activities per week. Quality of life is inferred from these findings. The effectiveness of rehabilitation treatments is evaluated by the improvement in these domains. This method uses the sum total of a person’s scores on components that can objectively be measured to define QOL. These objective components are valued by most people as having easily established “best” and “worst” extremes. For example, being more educated is valued higher than being less edu-cated. The Craig Handicap Assessment and Reporting Technique (CHART) is an example of a QOL instrument that uses objective measurements to assess five dimensions of handicap in people with spinal cord injury.25 It measures physical independence, mobility, activity (occupation), social integration, and economic self-suf-ficiency by asking questions that a person without a disability will typically obtain with maximum scores. However, a person with a spinal cord injury, who has a number of impairments and disabili-ties, usually will score lower. A typical question to measure social integration would be, “How many relatives (not in your household) do you visit, telephone, or write to at least once a month?” Studies have shown that CHART scores discriminate between people who have high and low levels of handicap and between people who have high and low levels of impairment. This instrument has high test-retest reliability and validity. However, use of these objective instruments has not been able to explain the significant amount of variance in the QOL.9

Since these objective approaches do not take into account other dimensions affecting QOL (such as expectations), assessment in-struments have also been developed to ascertain patients’ subjective feelings about various aspects of their life. The purpose of these in-struments is to determine the congruence of aspirations and accom-plishments in a variety of different areas.1,5,19 The benefit of using subjective scales is that they permit individuals to ascribe meaning to their situation. It also permits comparison between the objective and subjective measurements. Many researchers and clinicians now agree that assessment of QOL requires a multifaceted approach in order to obtain a comprehensive assessment of the impact of an illness, a treatment, or rehabilitative services on QOL.1

In their landmark study entitled, “The Quality of American Life,” Campbell and colleagues measured satisfaction with respect to mar-riage, family life, health, neighborhood, friendships, housework, job, usefulness of education, amount of education, and standard of living.5 Individuals were asked to rate their satisfaction in a particu-lar domain on a seven-point Likert scale by reporting whether their QOL was excellent, good, poor, etc. These individuals were also asked to rate the importance of each domain. In this conceptualiza-tion, an individual could be dissatisfied with a domain considered to be of relatively little importance and still maintain a satisfactory overall QOL. Dissatisfaction with a domain of great importance, however, would clearly contribute to a lower overall life quality.

One of the criticisms of using subjective measures of QOL is that perceptions of well-being could mean different things to different people. Proponents of subjective tests argue that the individual is the best judge of whether or not their own needs are being met. They acknowledge that people can and do interpret tests differently, but as long as the methods are easy to use and psychometrically sound, they are valid, reliable, and replicable measures of QOL.

These types of studies are frequently referred to as “overall QOL” or “global QOL.” It is the broadest of all concepts and is influenced by all of the dimensions of life that contribute to its richness and reward, and its pleasure and pain. Quality of life is a broad concept that takes into consideration physical, psychological, social and financial attributes that describe an individual’s ability to function and derive satisfaction in his or her life (Table 1). Hundreds of in-struments have been developed to measure QOL. Excellent reviews of the conception and use of QOL assessment tools in rehabilita-tion have been presented by Ware,22 Dijkers,6 and Flanagan.8

To better define the major domains that affect the QOL of Americans, Flanagan used a critical incident technique to identify experiences that were especially satisfying or dissatisfying to the participant.8 Approximately 6500 critical incidents were collected and classified into a set of 15 dimensions, which are shown in Table 2. The five dimensions that were most frequently described as im-portant were health, children, understanding yourself, work, and spouse. The five dimensions that were the least well met were par-ticipating in government, active recreation, learning and education, creative expression, and helping others. The five dimensions that most highly correlated with overall QOL were material comforts, work, health, active recreation, and learning/education.

It should be noted that in Flanagan’s definition, health is not merely the absence of disease, but a concept that incorporates notions of well-being or wellness in all areas of life (physical, mental, emotional, social, and spiritual).8 The health domain ranges from negatively valued aspects of life, including death, to positive aspects such as happiness. Although health is affected by other factors such as income and freedom, these factors are not usually the focus of healthcare professionals. Health-related QOL concerns itself

primarily with those factors concentrated on by healthcare provid-ers and systems.26 These include health status, functional status (physical, psychological, social, and spiritual), emotional status, and impairment.

Health status is an individual’s relative level of wellness and illness, taking into account the presence of biological or physiological dysfunction, symptoms, and functional impairment. Health per-ceptions (or perceived health status) are subjective ratings by the affected individual of his or her health status. Some people perceive themselves as healthy despite suffering from one or more chronic diseases, while others perceive themselves as ill when no objective evidence of disease can be found.

Functional status is an individual’s ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and main-tain health and well-being. Functional status subsumes related con-cepts of interest: functional capacity and functional performance. While functional capacity represents an individual’s maximum capacity to perform daily activities in the physical, psychological,

AANEMCourse NeuromuscularQualityofLife E-3

Table 1DimensionsofQualityofLife

Physical Psychological Social Health Controlofone’slife Abilitytocommunicate Physicalfunctioning Levelofstress Rolefunctioning Ambulationandmotility Lifesatisfaction Socialsupportresources Exercisetolerance Meaningfulnessoflife Usefulnesstoothers Energy/stamina Bodyimage Recreation Adequatesleep/rest Self-acceptance Socialinteraction Nutrition Absenceofnegativemoods Maritalandfamilyrelations Absenceofpain Selfesteem/self-worth Standardofliving Controlofsymptoms Psychologicalwell-being Financialindependence Somaticcomfort Achievementoflifegoals Neighborhood Physicalindependence Intellectualfunctioning Sexualrelations Freedomfromillness Illnessconcerns&prognosis Employment Sexuality Adjustmenttoillness&disability Spiritualsupport Learningfulfillment Standardofliving

Table 2Flanagan’s15QOLDimensions

Physicalandmaterial Materialwell-beingandfinancialsecurity well-being HealthandpersonalsafetyRelationswith Relationswithspouse otherpeople Havingandrearingchildren Relationswithparents,siblings,orother relatives RelationswithfriendsSocial,community, Helpingandencouragingothers civicactivities ParticipatinginlocalandgovernmentalaffairsPersonaldevelopment, Intellectualdevelopment fulfillment Understandingandplanning Occupationalrolecareer CreativityandpersonalexpressionRecreation Socializingwithothers Passiveandobservationalrecreational activities Participatinginactiverecreation

� AANEMPlenary

social, and spiritual domains of life, functional performance refers to the activities people actually perform during the course of their daily lives. A maximal exercise test measures physical functional capacity, while a self-report of activities of daily living measures functional performance. Functional status can be influenced by biological or physiological impairment, symptoms, mood, and other factors. It is also likely to be influenced by health perceptions. For example, a person judged to be well by most, may view himself as ill and may have a low level of functional performance in relation to his capacity.12,16

Most QOL instruments assess the emotional responses to short- or long-term stressors such as changes in health state. These transient emotional reactions to life experiences are usually reflected in an individual’s affect: the face one presents to the world. Depression, anxiety, and anger are emotions that sometimes coexist with physi-cal illness, and may affect the individual’s functional performance, symptom and health perceptions, and QOL. Conversely, decreased functional status may contribute to a depressed emotional state.

WHAT MAKES A GOOD HEALTH-RELATED QUALITY OF LIFE INSTRUMENT?

Some goals of HRQOL measures are to differentiate between individuals who have a better HRQOL and those with a worse HRQOL, as well as to evaluate the degree of change to HRQOL. The measure must be suitable for its intended use in order to be an appropriate clinical tool. The results from the test must be valid, reliable, and accurate. Reliability in an HRQOL test means that stable patients would give the same response after repeated admin-istration. Accuracy in an HRQOL test means that the instrument is responsive and able to detect small longitudinal changes. These instruments must also be interpretable and sensitive enough to dis-

tinguish whether changes in their role or function is trivial, small, moderate, or large.

There are two basic approaches to HRQOL measurement instru-ments. There are (1) generic instruments that relate to particular dimensions of life that have been determined to be important to people in general, and (2) instruments that focus on problems associated with single-disease states, patient groups, or area of function. Hundreds of validated generic instruments have been developed that apply to a variety of populations and are good for broad comparisons between patients with different diseases. The more commonly used instruments that have been used to describe the HRQOL are shown in Table 3.

On the other hand, specific instruments may better determine the effect on the QOL for certain diseases. This is because detailed measures can be developed that are more specific, and hence, re-sponsive to the changes due to the disease (such as diabetes), the population studied (such as the elderly), a symptom (such as pain), or a certain function (such as sleep). The problem with specific instruments is that they: (1) do not allow cross-condition compari-sons, (2) may be limited in terms of populations or interventions, and (3) they must be independently validated. Generic instruments and specific instruments are often used in combination to provide information about the range and magnitude of treatment effects on HRQOL. This information is helpful in measuring the health of populations, assessing the effectiveness of clinical trials and reha-bilitation services and providing information for health care policy decisions. Table 4 describes the different types of measures that are used in HRQOL studies.

There are many reasons to perform HRQOL measurement. Assessing the patient’s QOL gives the clinician valuable informa-tion that can help in making the best choices patient care. By

E-� Tools for Measuring Quality of Life AANEMCourse

Table 3 Mostcommonlyusedinstrumentsformeasuringhealth-relatedqualityoflifein3921reports(fromGarratt10)

Instrument # of records Instrument # of recordsSF-36 �08 Healthutilitiesindex �1Sicknessimpactprofile 111 COOPcharts 33Nottinghamhealthprofile 93 Functionalassessmentofcancer 32EORTCQLQ-C30 82 WHOQOL 2�QALY79EuroQol 77 Healthyyearsequivalent 2�Healthassessmentquestionnaire 62 Beckdepressioninventory 23Arthritisimpactmeasurementscales 59 Asthmaqualityoflifequestionnaire 21Qualityofwell-beingscale 53 McGillpainquestionnaire 19Generalhealthquestionnaire �3 Hospitalanxietyanddepressionscale 18

COOP=CareCooperativeInformationProject;SF=shortform;EORTC=EuropeanOrganizationforResearchandTreatmentofCancer;EuroQOL=EuropeanQualityofLifescale;WHOQOL=WorldHealthOrganizationQualityofLife;QALY=quality-adjustedlife-year

AANEMPlenary NeuromuscularQualityofLife E-5

understanding how a disease affects the QOL of a patient, the in-teraction between the doctor and patient will improve. Information on how a disease affects the functional and emotional status of the patient gives the doctor better insight into the patient’s needs. It can provide longitudinal data regarding changes in the patent’s QOL. It may also indicate the functional and emotional trade-offs of a particular treatment such as chemotherapy, which may prolong a person’s life, but at considerable cost to their QOL. Reliable measurements of QOL can be an important tool in the appraisal of healthcare services and healthcare policy. Research that utilizes QOL as an outcome measurement will ensure that factors that affect the whole person over a range of areas will be taken into con-sideration. To determine whether a particular QOL measurement is appropriate for a given application, Higginson and Carr14 provided step-by-step methods of choosing a QOL measure (Table 5).

SUMMARY

It is now possible for the clinician to use multidimensional measures to assess the QOL of their patients. Some of the more widely used instruments include the Medical Outcomes Study short form6,23 the Nottingham Health Profile,15 the Sickness Impact Profile,4 and the World Health Organization Quality of Life instrument.28 Potential uses of QOL assessment tools for the clinician include: (1) monitoring the health and social status of a given population,


Table 4 TypesofMeasuresUsedinHRQOLstudies.

Dimension-specificmeasuresfocusonparticularaspectsofhealthsuchaspsychologicalwell-beingandusuallyproduceasinglescore—forexample,Beckdepressioninventory.3Diseaseorpopulationspecificmeasuresincludeaspectsofhealththatarerelevanttoparticularhealthproblemsandmaymeasureseveralhealthdomains—forexample,asthmaqualityoflifequestionnaire.17

Genericmeasurescanbeusedacrossdifferentpatientpopulations;theyusuallymeasureseveralhealthdomains—forexample,theMedicalOutcomesStudyshortform3623,theNottinghamHealthProfile,15theSicknessImpactProfile�andtheWorldHealthOrganizationQualityofLifeinstrument.28

Individualizedmeasuresallowrespondentstoincludeandweighttheimportanceofaspectsoftheirownlife;theyusuallysumtoproduceasinglescore—forexample,patientgeneratedindex.22

Utilitymeasureshavebeendevelopedforeconomicevaluation,incorporatepreferencesforhealthstates,andproduceasingleindex—forexample,EuroQolEQ-5D.7

EuroQol=EuropeanQualityofLifescale;HRQOL=health-relatedqualityoflife

Table 5QuestionstoAskWhenChoosinganHRQOLMeasure(fromHigginsonandCarr1�)

1. Arethedomainscoveredrelevant?2. Inwhatpopulationandsettingwasitdevelopedandtested,and

arethesesimilartothosesituationsinwhichitisplannedtobeused?

3. Isthemeasurevalid,reliable,responsive,andappropriate?�. Whatweretheassumptionsoftheassessorswhendetermining

validity?5. Aretherefloorandceilingeffect—thatis,doesthemeasure

failtoidentifydeteriorationinpatientswhoalreadyhaveapoorqualityoflifeorimprovementinpatientswhoalreadyhaveagoodqualityoflife?

6. Willitmeasuredifferencesbetweenpatientsorovertimeandtowhatextent?

7. Whocompletesthemeasure:patients,theirfamily,oraprofessional?Whateffectwillthishave–willtheycompleteit?

8. Howlongdoesthemeasuretaketocomplete?9. Dostaffandpatientsfinditeasytouse?10.Whowillneedtobetrainedandinformedaboutthemeasure?

HRQOL=health-relatedqualityoflife

(2) evaluating healthcare policy, (3) conducting clinical trials, (4) assessing the effectiveness of rehabilitation services, (5) justifying the allocation of limited social and healthcare resources, and (6) tailoring management to the needs of the patient.

REFERENCES

1. Andrews F, Withey S. Social indicators of well-being: American’s perception of life quality. New York:Plenum;1976.

2. Bach JR, Campagnolo DI. Psychosocial adjustment of post-po-liomyelitis ventilator assisted individuals. Arch Phys Med Rehabil 1992;73:934-939.

3. Beck A, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-571.

4. Bergner M, Bobbitt R, Carter W, Gilson B. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981;19:955-962.

5. Campbell A, Converse PE, Rodgers WL. In: Andrews FM, Robinson JP, editors. The quality of American life: perceptions, evaluation and satisfaction. New York: Russell Sage; 1976.

6. Djikers M. Measuring quality of life. In: Fuhrer MJ. Assessing medical rehabilitation practices: the promise of outcomes research. Baltimore: Paul H Brookes Publishing; 1997. p 153-180.

7. EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199-208.

8. Flanagan J. Measurement of quality of life: current state of the art. Arch Phys Med Rehabil 1982;63:56-59.

9. Foreman MD, Kleinpell R. Assessing the quality of life of elderly persons. Semin Oncol Nurs 1990;6:292-297.

10. Garratt A, Schmidt L, Mackintosh, Fitzpatrick R. Quality of life mea-surement: bibliographic study of patient assessed health outcome measures. BMJ 2002;324:1417.

11. Gerhart KA, Koziol-McLain J, Lowenstein SR, Whiteneck GG. Quality of life following spinal cord injury: knowledge and attitudes of emergency care providers. Ann Emerg Med 1994;23:807-812.

12. Gill TM, Feinstein AR. A critical appraisal of quality of quality-of-life measurements. JAMA 1994;272:619-626.

13. Grant M, Padilla GV, Ferrell BR, Rhiner M. Assessment of quality of life with a single instrument. Semin Oncol Nurs 1990;6:260-270.

14. Higginson IJ, Carr AJ. Measuring the quality of life: Using quality of life measures in the clinical setting. BMJ 2001;322:1297-1300.

15. Hunt SM, McEwen J. The development of a subjective health indica-tor. Sociolgy of Health and Illness 1980;2:231-246.

16. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832-838.

17. McKusker J, Stoddard AM. Use of surrogate for Sickness Impact Profile. Med Care 1984;22:789-795.

18. Oleson M. Subjectively perceived quality of life. Image 1990;22:187-190.

19. Paris MJ. Attitudes of medical students and health-care professionals toward people with disabilities. Arch Phys Med Rehabil 1993;74:818-825.

20. President’s Commission on National Goals: Goals for Americans. New York: Columbia University; 1960.

21. Ruta DA, Garratt AM, Russell IT. Patient centred assessment of quality of life for patients with four common conditions. Qual Health Care 1999;8:22-29.

22. Ware J, Sherbourne CD. The MOS 36-item short form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-483.

23. Ware JE. The status of health assessment 1994. Annu Rev Public Health 1995;16:327-354.

24. Whitneck G, Charlifue S, Gerhart K, Overholser J, Richardson G. Quantifying handicap: a new measure of long-term rehabilitation outcomes. Arch Phys Med Rehabil 1992;73:519-526.

25. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. JAMA 1995;1995:59-65.

26. World Health Organization. International classification of impair-ments, disabilities, and handicaps. A manual of classification relating to the consequences of diseases. Geneva: WHO Press; 1980.

27. World Health Organization. Measuring quality of life: the WHO Quality of Life instruments (WHOQOL-100 and WHOQOL-Brief). WHO Mental Health Bull 1999;5:8-10.

E-6 Tools for Measuring Quality of Life AANEMCourse

INTRODUCTION

Health-related quality of life (HRQOL) assessments have several potential uses. They can be used by physicians to measure the effects of chronic illness in patients and to better understand how an illness affects day-to-day life. Public health professionals use HRQOL to measure the effects of numerous disorders, short- and long-term disabilities, and diseases in different populations. Tracking HRQOL in different populations can identify subgroups with poor physical or mental health and can help guide policies or interventions to improve their health. Recently, HRQOL assess-ments and other personal reported outcomes have been used in conjunction with more traditional clinical measures to assess the efficacy and safety of new clinical treatments and new drugs. This manuscript will review some of the clinical outcome measures that are being used to assess the effect of potential drug therapies for individuals with muscle disease.

There are three critical steps to be taken from the identification of new disease/patient targets, to putting a new drug onto the market. The first concerns the integration of new bio-technolo-gies in a wider context; the second is the translation from basic research to early clinical research; and the third is the evaluation of the clinical incremental value of new health interventions and its prompt delivery to clinical practice. In bringing any agent to market that could benefit the lives of patients, the Food and Drug Administration (FDA) must assure both safety and efficacy, as well as advance the public health by bringing promising innovations to market in a timely fashion. One of the largest hurdles limiting the development of pharmaceutical therapies in muscle diseases is the

lack of appropriate, valid, and reliable clinical outcome measures that conform to regulatory policy.

Clinically meaningful outcomes must make a difference in the way a patient feels, functions, or survives. Death or major morbidities, such as the need for assisted positive-pressure ventilation or the development of congestive heart failure, have consensus as clinically meaningful events. Clinically meaningful endpoints may include measures at a specific time point or events such as occurrence of a complication or progression to a specific landmark. Specific mea-surements may provide relatively high sensitivity to detect a treat-ment effect, but they may represent unimportant changes to the patient or family. Events, on the other hand, may provide relatively low sensitivity to detect a treatment effect, but may be more clini-cally meaningful and interpretable than measurements. The use of specific measures which correlate with clinically meaningful events is often desirable.

In order to expedite the drug development process, the FDA has recently ruled that, in certain circumstances, drug approval may be based on demonstrated clinical effects (i.e., the surrogate measure) that can reasonably predict a clinically meaningful outcome. A sur-rogate endpoint is defined as “a laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy.” The surrogate measure itself need not confer direct clinical benefit, but ideally has a pathophysiological connection. This is well-illus-trated in cardiovascular disease where surrogates (such as lowering blood pressure or cholesterol), prolong life. For muscle disorders,

Outcome Measures for Clinical Trials of Muscle Diseases

Craig M. McDonald, MDProfessor

DepartmentsofPhysicalMedicineandRehabilitationandPediatricsUniversityofCaliforniaDavisSchoolofMedicine

Davis,California

E-7

identifying surrogates is more challenging. For example, a reason-able goal would be to demonstrate that an average muscle score for 34 muscle groups, assessed by manual muscle testing (MMT), could predict months or years of prolonged ambulation, or that a forced vital capacity less than a defined percentage predicts recur-rent episodes of pneumonia with certainty. The FDA requirements for clinical trials emphasize placing a high priority on the need to develope natural history databases that are disease-specific, incor-porate genotype-phenotype correlations, and establish the time of onset of specific, clinically meaningful outcomes. Such carefully constructed databases would help provide the surrogate clinical endpoints that predict critical, and life-altering events, setting the stage for implementation of short-term clinical trials that can be carried out over 6 to 12 months in contrast to decades.

CLINICAL ENDPOINTS IN MUSCLE DISEASES

Clinical endpoints in muscle disease have generally included strength measurement, functional assessments (including functional testing and self-report scales of function), pulmonary and cardiac assessments, and patient-reported outcomes. These measures vary in terms of clinical meaning to the patient and family, but many clinical assessments measured over the short term may be used as clinical surrogate markers for clinically meaningful outcomes and events. Additional surrogate markers may include enzyme levels, muscle histology, gene expression, and muscle imaging. There are some clinical endpoints related to muscle diseases that have been well developed for specific diseases and specific disease stages. Other measures need further development, refinement, and validation.

STRENGTH ASSESSMENT

Strength measures rely predominantly on two methodologies: MMT and quantitative muscle testing (QMT). Both methodolo-gies measure muscle strength (not endurance), and both have pros and cons when designing a clinical trial. A typical MMT protocol consists of an average of 34 muscle groups, scored on a modified Medical Research Council (MRC) 0 to 10 scale.3 Manual muscle testing is cost-effective and reliable when used by well-trained clinical evaluators.5 Its value has been demonstrated in defining the natural history in Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and myotonic dystrophy, and has been used to delineate a therapeutic benefit for corticosteroids.7,11,14,17 Manual muscle testing lacks sensitivity for testing individual muscle groups, making this method a poor choice for assessing efficacy following local muscle injections of anti-sense oligonucleotides, or recombinant gene transfer vectors. In contrast, QMT, expressed as maximal voluntary isometric contraction (MVIC), is ideally suited to test the efficacy of agents transferred to individual muscle groups. Quantitative muscle testing can document natural history progression as demonstrated for DMD, FSHD, and myotonic dystrophy.6,11,17 Its precision as a

tool for clinical trials is enhanced in muscle groups either too weak or too strong for MMT, a problem frequently encountered as an age-dependent correlate of muscle disorders. For example, MVIC demonstrates a decline in strength in older DMD boys while side-by-side MMT studies fail to reveal changes.6 A disadvantage of QMT is the equipment expense and the need for computer-dependent software. The critical challenge for clinical myologists employing either MMT or QMT is to demonstrate how changes in score correlate with clinically meaningful outcomes. This represents the major objective for future clinical studies.

FUNCTIONAL ASSESSMENTS

Functional testing, which provides objective measures derived by clinicians in the laboratory or clinic regarding functional status, has been traditionally used to measure functional status in patients with muscle disease. The lower extremity18 and upper extremity2 functional grading scales have historically been applied to patients with chronic muscle diseases in both natural history studies and clinical trials. Intra- and interrater reliability scores are exceptional (0.96 to 0.99 for DMD).3 However, these scales are nonlinear and show poor correlation when compared to loss of muscle strength. A weakness in functional grading scales is that important functional transitions occur in a nonlinear fashion when functional grades are compared to strength loss and age.

Timed testing protocols have included: the time needed to walk or run 30 feet, the time needed to climb four steps, and the time needed to stand from a supine position. Advantages to this approach are that it; measures changes in disease progression over short-time intervals, is highly reliable, and is easily obtained. Interclass correla-tions for these timed testing measures have exceeded 0.95 in DMD. Similar timed testing protocols involving fine motor skills (e.g., drinking water, cutting out a 3-inch square, pegboard activities), or speech rate have been applied to amyotrophic lateral sclerosis, spinal muscular atrophy, and myotonic dystrophy. The weaknesses to the use of timed testing as an outcome measure in isolation centers around the clinical meaningfulness of these measures to a patient or family. For example, a 1-second improvement in the time needed to climb 4 steps may have limited significance to a patient or family member.

An alternative approach has been to use strength or timed testing as clinical surrogates in the short-term to predict a clinically meaning-ful event or functional milestone, such as time or age of full-time wheelchair transition. In one natural history study of DMD the age at wheelchair transition ranged from ages 7 to 13 with a mean age of 10 years. Data concerning the time needed to walk or run 30 feet showed that this measure was highly predictive of time to full-time wheelchair transition. All boys who could walk/run 30 feet in less than 6 seconds were greater than 2 years to wheelchair transition. Those who took 6 to 12 seconds to travel this distance were 1 to 2 years from wheelchair transition. All boys who took greater than

E-8 Outcome Measures for Clinical Trials of Muscle Diseases AANEMCourse

12 seconds to walk 30 feet transitioned to a wheelchair in less than 1 year.12

There are alternative approaches which involve longer walking protocols or community-based measures. For example a 6-minute run or walk is used as a national fitness measure in the United States and a great deal of normative data is available for boys and girls. Measurement of distance traveled in 6 minutes may provide information about strength, fatigue, and cardiopulmonary reserve. Recently this author and colleagues applied a step-activity monitor to the measure of real-world community ambulatory activity or physical activity.13 The monitor is accurate at various gait cadences and can be a valid measure of physical activity versus heart rate while being unobtrusive and storing minute-to-minute step data for periods of weeks or months. The monitor has been shown to demonstrate a profound decrease in real-world ambulatory activity both in terms of total real-world activity and high-intensity activ-ity. A similar ability of the monitor to detect functional declines in the real world activities of adults with Becker muscular dystrophy, FSHD, and myotonic muscular dystrophy has been demonstrated. Thus, the monitor is a quantitative measure of real-world commu-nity mobility and physical activity and a potential clinically mean-ingful endpoint measure for a variety of muscle diseases. Examples of therapist-derived clinical functional assessments include the Pediatric Evaluation of Disability Inventory (PEDI), Gross Motor Function Measure (GMFM), Functional Independence Measure (WeeFIM), and Jebsen-Taylor Hand Function Test.3,4,8,10,16 The PEDI has been recently applied to Pompe’s disease and provides information about functional skills such as self-care and mobility. It is a fairly labor-intensive instrument that appears more useful in children with severe motor involvement. The GMFM consists of 88 questions in the full format, and includes information about such gross motor abilities as lying and rolling, sitting, crawling and kneeling, standing, and walking, running, and jumping. The FIM / WeeFIM includes 18 items including self care (e.g., eating, grooming, bathing, upper-body dressing, lower-body dressing, and toileting); sphincter control (i.e., bowel and bladder management); mobility (e.g., transfers for toilet, tub, or shower, as well as bed, chair, and wheelchair); locomotion (e.g., walking, wheelchair, and stairs); communication, including comprehension and expression; and social cognition (e.g., social interaction, problem solving, and memory). It was developed primarily for individuals receiving acute in-patient rehabilitation as a burden of disease measure. The disadvantages of WeeFIM involve its lack of applicability to muscle diseases, and differences between the independence scales and actual patient function. For example, provision of an ankle foot orthotic to improve gait would result in a patient declining in score from a 7 (completely independent) to a 6 (modified independence with a device).

Functional tests are useful to monitor disease natural history and to assess the efficacy of therapeutic agents in clinical trials. However, a single test is often not applicable throughout all stages

of the disease. Challenges and questions remain. Which functional testing approaches yield data clinically meaningful to patients and families? Which functional tests are sensitive to changes in the specific disease? Which functional testing approaches are reliable, objective/accurate, and practical? In addition, developmental and maturational considerations present a challenge because the norma-tive data is a moving target. There is a need for further refinement of burden of disease and QOL measures to yield disease specific measures. These function status measures need to be correlated with patient report measures of their functional ability.

PULMONARY TESTING

Pulmonary measures have obvious importance as clinically mean-ingful endpoints because restrictive pulmonary disease accounts for 80% of the morbidity in some muscle diseases such as DMD. Any therapy that improves respiratory muscle strength or compensates for respiratory muscle weakness will potentially improve ventila-tion and airway clearance and extend life expectancy. Measurable parameters include spirometry, peak cough flow, oxygen saturation both awake and asleep, peak inspiratory pressure, peak expiratory pressure, and occurrence of pneumonia, hospitalization, and respi-ratory failure.

Forced vital capacity (FVC) is reproducible and has been widely applied to natural history studies of DMD and other neuromus-cular diseases. It is effort dependent, and requires a cooperative patient and specialized equipment. To obtain consistent reliable measurement requires training on the part of the clinical evaluator, similar equipment, and the use of predicted values standardized to age, gender, and body size. An FVC less than 20% predicts carbon dioxide (CO2) retention and respiratory failure. The predictive value of FVC for survival is good for DMD.9 In addition, the peak obtained FVC (which usually occurs in the early second decade) is predictive of disease progression with regard to respiratory and limb weakness, level of function, and development of subsequent scolio-sis.12 Thus, FVC appears to be a useful clinical endpoint because it correlates with clinically meaningful progression, events, and clini-cal landmarks. Forced expiratory volume at one second (FEV1) is a useful measure in chronic obstructive pulmonary disease, cystic fibrosis, and asthma, but adds little to FVC in muscle diseases with respiratory weakness. An FEV1 less than 40% predicts nighttime hypoventilation and sleep hypoxemia.9 It is a part of routine spi-rometry parameter that is highly correlated with FVC so it is a rea-sonable clinical surrogate endpoint measure along with FVC. Peak inspiratory and expiratory pressures are easily obtained measures in the clinic that are fairly reproducible. Predictive values of FEV1for children are available are often the first pulmonary measures to show decline in boys with DMD ages 6 to 10.12

A peak expiratory pressure of less than 60 cm H2O predicts inef-fective cough. Thus, peak inspiratory and expiratory pressures


are useful clinical endpoints. Peak expiratory flow rate (PEFR) is reported in spirometry. Peak cough flow involves coughing into a Wright flow meter. This is an inexpensive bedside test that has a correlation with airway clearance (< 160 cm H2O predicts inad-equate airway clearance).1 A disadvantage of this measure is that it is effort-dependent and somewhat variable, but the ease of as-certainment and correlation with airway clearance make it a useful clinical endpoint.

Arterial oxygen saturation (SaO2) by pulse oximetry is easily ob-tained, reliable, and inexpensive. Forced vital capacity and FEV1 have been shown to correlate with sleep desaturation by pulse ox-imetry.9 However, oxygen saturation is influenced by airway disease, is poorly predictive of respiratory insufficiency, and daytime SaO2 may not predict nighttime SaO2. Daytime oxygen saturation is therefore not useful as a primary clinical endpoint or clinical surro-gate measure. However, nighttime oximetry appears to be a useful predictor of nighttime hypoventilation and sleep hypoxemia.

End-tidal CO2 corresponds to arterial CO2 tension (PaCO2), a noninvasive measure, but not readily available in the clinical setting. Wakeful end-tidal CO2 greater than 45 predicts nighttime respiratory failure. Unfortunately, wakeful end-tidal CO2 does not predict survival in DMD as normal values have been seen in those with poor survival.15 A reduced FEV1 less than 20% predicted has been shown to correlate with elevated PaCO2 in DMD.9 Thus, it appears that spirometry is much more readily obtainable and will suffice as a clinical endpoint measure.

While formal sleep studies may be sensitive and useful in DMD and other muscle diseases, very few pediatric sleep laboratories exist and these studies are fairly expensive. In addition, there is great variability in interpretation from laboratory to laboratory and normal standards have not been well developed in children. A formal sleep evaluation may certainly be useful clinically to sort out central versus obstructive sleep apnea in adults with neuromus-cular diseases. However, as an endpoint for large scale clinical trials formal sleep studies will likely play a limited role.

There is a need to include clinically meaningful pulmonary events and complications in both natural history data-gathering efforts and future clinical trials. These events should include pneumonia, hospitalizations, development of respiratory failure, use of various modes of ventilation and airway clearance strategies, and documen-tation of the occurrence of and cause of death.

PERSONAL REPORTED OUTCOMES AND HEALTH-RELATED QUALITY OF LIFE

Clinical and functional measures of disease status do not fully capture the ways in which chronic diseases and their treatment

affect individuals. Many aspects of patients’ subjective experience, such as symptom severity and frequency, emotional and social well-being, and perceived level of health and functional ability are important targets for disease intervention that are not measured by radiographs or laboratory results. Measurement of patient-reported outcomes is particularly important in clinical trials, in which changes in clinical measurements or imaging results may not trans-late into important benefit to the patients, or in trials where two treatments may be comparable in limiting or curing disease, but have different adverse-effect profiles differentially affecting symp-toms, functioning, or other aspects of patients’ QOL.

The last several decades have seen a proliferation of tools to measure symptoms, QOL, functional status, emotional status, and general perception of health. Although many of these instru-ments have demonstrated good reliability and validity, there are many limitations to current measurement approaches. One critical disadvantage is the inability to compare results of different studies when different measurement tools are used, as these instruments will have noncomparable or noncombinable scores because each scale may use a different number of items, different response options, different reference periods, or different item content. For example, progress in clinical pain research is slowed by the use of various pain measurement scales that are not directly comparable. The length and complexity of questionnaires and batteries can also be problematic, creating a level of respondent burden that hampers recruitment, results in too much missing data, or is detrimental to response validity and reliability.

Recently, the FDA suggested the use of patient-reported outcomes (PROs) to capture the patient’s perspective and subjective per-ception of treatment benefits in conjunction with clinical trials. There are a number of reasons for including PROs such as the HRQOL and the assessment of symptoms and more recently, treatment satisfaction, in clinical trials evaluating pharmaceuticals. The PROs assist in providing a better understanding of treatment outcomes from the patient’s perspective by translating clinical improvement into patient-centered outcomes. The PROs comple-ment and extend information provided by clinical endpoints, and add relevant outcome data not captured by these instruments. An increasing need to evaluate health care technologies with respect to individual and societal values and an increasing focus on recogniz-ing and valuing patient perceptions of changes with treatment are other reasons for including PROs such as the HRQOL assessment in clinical trials.

The PROs represent a unique indicator of the impact of disease and its treatment. In many situations, the physician relies almost entirely on patient reports in evaluating disease activity and symp-toms. The management and monitoring of conditions such as pain is based almost entirely on the patient’s report of symptoms and how those symptoms impact daily functioning and well-being. In


conditions in which there are no physical or physiological markers of disease activity, the PROs become the outcome of choice. Therapy-related improvement in such conditions is best measured by questioning patients about the severity of their symptomatic complaint and how troubled they are by it (i.e., how it affects their well-being and daily life).

In chronic diseases, which are the major causes of mortality and morbidity, more attention has been paid to the HRQOL issues in response to a change in the goals of treatment from a traditional curative aim to the prevention and control of disease. For those individuals diagnosed with a chronic condition where no cure is attainable and therapy may be prolonged, maintenance or improve-ment in the HRQOL is likely to be the most essential outcome. In other diseases, patient assessments are important elements in the evaluation of treatment impact, alongside other clinical indicators. This is because the therapy is frequently associated with significant toxicity, and in this situation it is important to evaluate the effect of adverse events versus potentially small gains in survival.

Treatment satisfaction could be a useful outcome in clinical trials to provide insight into the patient’s attitude towards treatment. Evaluating satisfaction with treatment may assist healthcare provid-ers in understanding the issues that influence adherence and may help identify aspects of the treatment that require improvement to enhance long-term treatment outcomes. For many patients, infor-mation about the impact therapy will have on their daily life and well-being is often much more relevant than information about small changes in exercise capacity, FEV1, or joint stiffness clinical endpoints that have been shown to be rather poorly correlated to the HRQOL.

Since PROs are based on the patient’s subjective perception, the best and easiest way to obtain this information is to directly ask the patient. Whereas clinicians often express concern over burden-ing their patients with PRO assessments, experience shows that the majority of patients welcome the opportunity to report how their disease and treatment are affecting their daily life. Clinical trials assessing PROs often involve large patient populations. Self-administered questionnaires represent an attractive solution because they enable uniform administration and unbiased scoring and quantification of data in a cost-effective fashion. Moreover, standard questionnaires provide valid and reproducible data, and are comparatively cheap.

The rationale for measuring PROs needs to be made explicit as part of the planning and documentation of clinical trials compar-ing medications in order to put forward labeling or promotional claims. The PROs relevance in assessing the outcome in relation to the disease, as well as the clinical characteristics of the patient popu-lation under study, needs to be described and linked to previous re-search and to the planned treatment. The reason for using the PRO

component in relation to the research question needs to be explicit, and the PROs need to be clearly defined in the study. The PRO measurement strategy should be operationalized according to what study questions are being asked. In this context, it is necessary to understand and demonstrate the relevance of the selected PROs to the target disease, patient population, treatments, and study setting. Identification of PRO measures for use in clinical trials requires an understanding of both the epidemiology and burden of the disease from the patient’s perspective and the theoretical and empirical relationships between treatment, clinical outcomes, and the PROs. There are many approaches to measure the PROs, including single domain, multiple domains, disease-specific, or generic measures. No one measurement approach is ideal for all clinical trial applica-tions and ultimately investigators need to determine how well the different approaches and instruments match their research ques-tion, study design, and targeted disease population.

Well-documented measurement properties are essential to the use of PROs in clinical trials. The psychometric evidence (i.e., reli-ability and validity) of potentially useful PRO instruments should be reviewed and evaluated to determine which of the instruments is best suited for the clinical trial. These measurement characteris-tics are widely accepted and considered essential for assuring that a PRO instrument is meaningful to patients and clinicians and provides accurate and valid documentation of treatment effects to industry and regulators.

The PROs must meet the same standards as traditional clinical measures used in randomized controlled trials. In order to be able to support a claim based on the PROs, the study must be powered adequately. The sample size for the endpoint of the PRO should therefore always be calculated before the final decision about in-cluding the PROs in a trial. The power calculation should be based on what is considered to be the minimal important difference between a PRO questionnaire based on developers’ recommenda-tions or be based on previous experience of using the questionnaire in clinical trials of similar patient populations.

Analysis of the PROs raises a number of issues to be considered in the analysis plan. Questions related to interpretability or “identifi-cation of the minimal important change” as well as how to handle missing data and the adjustment for multiplicity are all of critical concern. The statistical analysis procedures must be outlined and developed to relate to the prespecified hypotheses and the targeted claim, even when the PRO is a secondary endpoint. A full analysis plan must be developed a priori with specification of the data analy-sis strategy and statistical models. By definition, the HRQOL is a subjective and multi-dimensional construct. Hence most HRQOL instruments result in a number of repeated measurements for dif-ferent domains, which are more or less correlated—a situation that creates a multiplicity problem. It is important to identify these problems and describe how they should be dealt with in the study


protocol and the statistical analysis plan. In order to counteract problems related to multiplicity, the most relevant domains in rela-tion to the patient population and the drug under study should be prespecified as the “primary” PRO measures. Due to the complex-ity and multiplicity inherent in PRO measures missing data can occur. In clinical trials, missing data may lead to potential bias. Hence, every effort should be made when designing the study to ensure that patients and investigators are motivated to comply with the collection of PRO data.

Lack of clarity with regard to the definition of PRO, especially the HRQOL, will have an adverse impact on any scientific endeavor in the research area. Therefore, it is essential that there be a con-sensus on a clear definition and classification of outcomes, and, in particular, PROs (i.e., a term that captures the patient’s perspective and subjective perception). Current methods for selecting, develop-ing, validating, measuring, and reporting the PROs are similar to other measures of clinical effectiveness. However, the PROs focus attention on the patient’s perspective by highlighting the patient’s contribution to the drug evaluation process.

SUMMARY

The ideal clinical endpoint is reliable, clinically meaningful, fea-sible, objective, sensitive, and clinically interpretable. Clinical ef-ficacy ultimately is defined as an effect of direct clinical meaning (importance) to a patient in how they feel or function. It generally must be an effect of value to the patient directly. A clinical or bio-chemical surrogate measure validated to correlate with or predict a clinically meaningful endpoint (such as an event or landmark) may be a useful approach. However, the nature of the relationship between the surrogate measure and the clinically meaningful end-point must be defined through reliability and validation studies, natural history studies, and related clinical trials. Although some events appear to be life-altering, such as loss of ambulation, loss of ability to climb stairs, or loss of ability to get up from a toilet seat, they require correlation with a QOL scale. Natural history studies provide data that helps enormously in the selection of appropriate clinical endpoints. The design of natural history studies should ideally involve the selection of a combination of traditional clinical endpoints with patient-reported outcomes to capture all aspects of the specific disease. The use of combinations of measures may offer

a variety of advantages (e.g., feasibility, sensitivity, resistance to bias, and clinical meaningfulness at varied stages of the disease). Other factors which determine the appropriateness of endpoint selection include age and developmental status of the patient, and the extent of disease burden in terms of selection of both patient-centered and family-centered measures. These factors should be used to develop the primary and secondary endpoints for clinical trials.

REFERENCES

1. Bach JR, Saporito LR. Criteria for extubation and tracheostomy tube removal for patients with ventilatory failure. A different approach to weaning. Chest 1996;110:1566-1571.

2. Brooke MH, Griggs RC, Mendell JR, Fenichel GM, Shumate JB.Clinical trial in Duchenne dystrophy. 1. The design of the proto-col. Muscle Nerve 1981;4:186-197.

3. Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Miller JP, Province MA. Clinical investigation in Duchenne dystrophy: 2. Determination of the “power” of therapeutic trials based on the natural history. Muscle Nerve 1983;6:91-103.

4. Deutsch A, Braun S, Granger C. The Functional Independence Measure (FIM sm Instrument) and the Functional Independence Measure for Children (WeeFIM): ten years of development. Crit Rev Phys Med Rehabil 1996;8:267-281.

5. Escolar DM, Henricson EK, Mayhew J, Florence J, Leshner R, Patel KM, Clemens PR. Clinical evaluator reliability for quantitative and manual muscle testing measures of strength in children. Muscle Nerve 2001;24:787-793.

6. Escolar DM, Buyse G, Henricson E, Leshner R, Florence J, Mayhew J, et al. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Ann Neurol 2005;58:151-155.

7. Griggs RC, Moxley RT 3rd, Mendell JR, Fenichel GM, Brooke MH, Pestronk A, Miller JP. Prednisone in Duchenne dystrophy. A ran-domized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol 1991;48:383-388.

8. Haley SM, Fragala MA, Skrinar AM. Pompe disease and physical dis-ability. Dev Med Child Neurol 2003;45:618-623.

9. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventila-tion in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;161:166-170.

10. Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An objective and standardized test of hand function. Arch Phys Med Rehabil 1969;50:311-319.


11. Mathieu J, Boivin H, Richards CL. Quantitative motor assessment in myotonic dystrophy. Can J Neurol Sci 2003;30:129-136.

12. McDonald CM, Abresch RT, Carter GT, Fowler WM Jr, Johnson ER, Kilmer DD, Sigford BJ. Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil 1995;74:S70-S92.

13. McDonald CM, Widman L, Abresch RT, Walsh SA, Walsh DD. Utility of a step activity monitor for the measurement of daily ambu-latory activity in children. Arch Phys Med Rehabil 2005;86:793-801.

14. Mendell JR, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller JP, et al. Randomized, double-blind six-month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med 1989;320:1592-1597.

15. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker to patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;164:2191-2194.

16. Russell DJ, Rosenbaum PL, Cadman DT, Gowland C, Hardy S, Jarvis S. The gross motor function measure: a means to evaluate the effects of physical therapy. Dev Med Child Neurol 1989;31:341-352.

17. The FSH-DY Group. A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): impli-cations for therapeutic trials. Neurology 1997;48:38-46.

18. Vignos PJ, Spencer GE, Archibald KC. Management of progressive muscular dystrophy of childhood. JAMA 1963;184:89-96.


E-1� AANEMCourse

INTRODUCTION

When a patient with amyotrophic lateral sclerosis (ALS) says, “…I do not want to be totally dependent and have no quality of life…” how does a physician respond? Quality of life (QOL) is one of the most important concerns for an ALS patient and their family and a very challenging one to address for the physician both from pragmatic and emotional perspectives. From the pragmatic per-spective are the underlying questions, what is quality of life, how do we measure it, and what are the results? From the emotional perspective is the ability to convey to a patient at an early stage of the disease what it will be like at a later stage. Further, personal attitudes of the physician are incorporated in the answers to these questions. Given the uniform progression of ALS and the repeated clinical experiences of ALS physicians, it is appropriate for them to periodically review personal views of QOL. This manuscript reviews concepts of QOL, how it is measured, and data that indi-cate QOL for ALS patients. It concludes with suggestions on how to guide the patient.

WHAT IS QUALITY OF LIFE?

It is perhaps easy to dismiss the question, “what is quality of life?” by invoking the oft-used response: “it is difficult to define, but you will know it and know how well it is going when you experience it.” There are many factors that contribute to a person’s QOL, and at a minimum include a person’s background (ethnic, cultural, past ex-

periences), expectations (past and future), current support (family, friends), and spiritual beliefs (organized religion or beliefs). The World Health Organization states that quality of life “…is a broad-ranging concept affected in a complex way by the person’s physical health, psychological state, level of independence, social relation-ships, personal beliefs, and their relationship to salient features of their environment.” The environment in this case includes ALS, fears about dying, and concerns for others (caregiver and family).

When asked the question, “How is it going?” a person usually answers positively from a superficial perspective and rarely digs deep into their personal lives. Most people probably have a pretty good QOL. However, in a medical setting, the perspective may change and a new level may surface and the patient’s illness may drive the answer, especially with a serious illness such as ALS. Thus the question may not be answered from a global perspective, and negative aspects of the illness (and most illnesses are negative) govern the response. This unbalanced perspective likely leads to despair. In most medical settings the answer to the question of “How is it going?” is likely to be “Not so well!” However, it is im-portant to help the patient find a more distant viewpoint to provide an overall perspective.

HOW IS QUALITY OF LIFE MEASURED?

When one wants a more substantive answer to the question, “how is quality of life measured?” formal instruments or questionnaires

Quality of Life in Amyotrophic Lateral Sclerosis

Mark B. Bromberg, MD, PhDProfessorandVice-Chairman

DepartmentofNeurologyUniversityofUtah

SaltLakeCity,Utah

E-15

are used. Questionnaires may be simple or complex. The simplest is to ask the subject to rate their life using a visual analogue scale from 0 to 10 cm with marks being measured in metric units. This approach is similar to the answer “I know it when I see it” to the question, “what is quality of life?” Despite the simplicity, there is merit to letting the subject reach their own conclusion in a single score.

This approach is in contrast to the use of a complex questionnaire with a number of sections resulting in section subscores and a sum-mation score to yield an overall measure of QOL. Complex QOL questionnaires are developed and validated by a multi-step and rigorous process. The areas or elements of interest are frequently identified from interviews with the groups of interest (such as pa-tients and caregivers). Questions are then designed to address issues and concerns brought out in the interviews. The initial version of the questionnaire is then tested in the designated group. During the initial testing the various elements are assessed for validity by comparisons with other focused questionnaires that have been es-tablished as good measures of the element. To reduce the number of questions to a minimal number while retaining full informa-tion, the answers to each question are compared to each other to determine which questions are always answered in the same way. The final shortened version is then retested. The QOL question-naires developed for other patient populations can be used for ALS patients, but should be formally assessed in the new patient popu-lation. Frequently, when using an existing questionnaire, questions are changed, added or dropped, and therefore modified question-naires must be reassessed.

Early efforts to measure QOL in ALS made use of health status questionnaires, such as the Sickness Impact Profile (SIP),1 a shorter version (SIP/ALS-19),17 and the short form (SF)-36.28 A major concern with such questionnaires is that they include a functional element that assesses activities of daily living, in addition to ele-ments assessing physical, emotional, and mental well-being. Since strength will inexorably decline in ALS as will the ability to perform activities of daily living, the functional element subscores will fall over time even though the patient may judge their QOL as good and stable. Despite these issues, the SF-36 is being used as an overall measure, frequently supplemented by other more focused questionnaires in a battery of questionnaires.

There have been efforts to develop QOL questionnaires specific for ALS patients. The most basic approach is to design a question-naire from the ground up (interviews with patients and caregivers) with formal verification and statistical analysis. One such scale was developed in the United Kingdom and called the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)-40.10 This questionnaire included five dimensions: (1) physical mobility, (2) activities of daily living/independence, (3) eating and drinking, (4) communication, and (5) emotional functioning. There were

subscores for each dimension and a total score. For unclear reasons, the ALSAQ-40 (and a shorter version, ALSAQ-5) has not gained wide usage.

Another approach is to modify an existing validated QOL scale for another disorder. The McGill Quality of Life Questionnaire (MQOL) was originally designed for cancer and human immu-nodeficiency virus patients.6 It is attractive for ALS because it is not heavily weighted toward physical function and includes an existential element (perception of purpose, meaning in life, and capacity for personal growth). The existential element is likely important to ALS patients as it is to cancer patients. Recent efforts have been made to modify the MQOL questionnaire for ALS pa-tients, and the modified version is the ALS-specific Quality Of Life (ALSSQOL) questionnaire (Simmons and colleagues, in press). Changes include reformatting for ease of administration and incor-porating nondominant physical function, psychological, support and existential elements, and a broad spiritual element. There is also an open question asking the patient to list things that had the greatest effect on their QOL over the past 7 days. In addition to a questionnaire focusing on QOL, many studies in ALS focus on a specific area and include additional questionnaires that more directly assess specifics in the area of interest. Thus, a section was added asking the patient to identify troublesome symptoms from a list of 10 symptoms.

A different approach is to let the subject decide what elements make up their QOL at the time.21 This concept has been formal-ized in the Schedule of the Evaluation of Individual Quality of Life (SEIQoL) and a shorter direct weigh version (SEQoL-DW).9 In this questionnaire, the subject is asked to list five areas that make up their QOL at the time. In each area they should rank how well they are doing on a visual analogue scale. They are then asked to rank the importance of each area to each other. The available data include the five areas, how they are doing in each area, the relative importance of each area, and a combined index score. An advantage of this open questionnaire is that the same questionnaire can be used to assess QOL for both the patient and the caregiver.

It must be kept in mind that conclusions may differ because of the large number of psychometric instruments available and the vast number of combinations that can be assembled for a par-ticular study. What follows is a selection that appears stable across studies.

HOW IS QUALITY OF LIFE MEASURED IN AMYOTROPHIC LATERAL SCLEROSIS?

It is not unexpected that when one is asked to imagine QOL with impaired function one projects a poor rating. This is clearly the feeling when an ALS patient imagines being dependent upon

E-16 Quality of Life in Amyotrophic Lateral Sclerosis AANEMCourse

others for care. However, by reviewing life in overall general terms, as people age they are less able to perform certain tasks and often require more help. However, they still enjoy a good QOL. It is perhaps the innate ability to adapt that allows for satisfying changes to be made over time.

The issue of an ALS patient wishing to end their life through suicide or assisted death is perhaps the most significant example of predicting a QOL so poor that it is not felt to be worth living. A survey of ALS patients posed the question, “Under some circum-stances I would consider taking a prescription medicine for the sole purpose of ending my life,” and 56% answered in the affirmative.7 Differences between “considering” suicide and taking any further actions represents a broad spectrum. Further, there are differences between taking one’s life and aiding the dying process. In a study from the Netherlands, physicians were queried about their care of ALS patients and 17% said they participated in euthanasia while only 3% participated in suicide.26 One factor from both studies is that religion has a positive role in ALS patients’ attitude toward living. The final interpretation of these data must remain open and cannot be generalized because attitudes about life and death likely differ among cultures and what actually occurs with respect to possible assistance in the death process by patients, families, and healthcare providers as gathered by questionnaires will be inexact. Wishing for a hastened death and actively hastening death may be two different issues.22

When QOL has been measured in ALS patients either serially or at one specific time, it has remained relatively high. Quality of life does not fall even though strength and ability to carry out activi-ties of daily life falls. This adaptation is called the response shift, and is likely similar to the natural changes with aging.29 A striking example comes from a study using the SEQoL-DW in a German ALS patient who listed football (soccer) as one of the five important elements in his QOL.20 As he became weaker over time, he shifted from actively playing football to watching football. Despite a shift in his type of involvement in football, it remained high in satisfac-tion, and its relative contribution to QOL remained unchanged. Clearly this same shift in involvement would have occurred in this patient as he grew older even if he did not have ALS; the disease speeds up the response shift.

Cross-sectional studies show good QOL and a lack of depression in ALS patients.4,24,25 Longitudinal studies uniformly show a stable assessment of QOL in the setting of declining physical function.20,23 This is one of the most important findings to keep in mind when talking to patients. The likely explanation is the natural response shift, as discussed above. Important positive factors associated with a perceived good QOL are contributed to the strength and role of religion and spirituality in a patient’s life.27 Physical factors that can have a negative impact are general and increased physical fatigue,

impaired respiratory function, and inadequate nutrition (from dys-phagia).2,12,15 The latter two factors are amenable to treatment that can improve QOL.

The majority of ALS patients die from respiratory failure. There are efforts to assist respiration with noninvasive ventilation for patient comfort and possibly to increase longevity. A common issue in dis-cussing noninvasive ventilation with patients is their QOL. Quality of life as measured by a number of questionnaires has been shown to be improved with noninvasive ventilation.18 While few patients chose full-time tracheal (invasive) ventilation, studies indicate that QOL is perceived as good by the patient.3 Inadequate nutrition and the mechanics of eating in the setting of marked dysphagia can affect QOL, and a feeding tube can lead to improvements in quality for the patient and the caregiver who must officiate during long meals.16

In addition to the term “quality of life” it is appropriate to consider the term “quality of death.” The question “how am I going to die?” is a major concern of ALS patients and their caregivers, although it is rarely asked. Overall, death from ALS occurs peacefully, which can be defined as the manner of death one would chose if there were a choice.19 There are issues that can prevent such a death, including a poor ability to communicate, shortness of breath, dif-ficulty sleeping, and pain.8 These issues are manageable with the help of hospice services.13

As the ALS patient becomes weaker, they will need greater care. This burden usually falls to the caregiver, and as the patients loses independence, so does the caregiver. This results in greater numbers of hours spent in giving care leading to feelings of physical and psychological health.11 Quality-of-life questionnaires given to care-givers show this burden. The SEQoL-DW allows the same ques-tionnaire to be given to both the patient and caregiver, and in one study the caregiver scored lower than the patient.4 However, there are positive factors for the caregiver, including finding a positive meaning in providing care to the patient. Negative issues are stress (loss of independence, increased financial strain, and loss of prior coping mechanisms) that are correlated with the stresses perceived by the patient.22

Hospice services can contribute to the QOL and quality of death for the patient and the caregiver. Hospice services include home aids, nursing evaluation to assist in patient management, drugs for management of discomfort, and social and spiritual support. Despite hospice services being open to ALS patients, less than two-thirds use them.13 Most ALS patients meet hospice criteria for progression of a disability over 12 months, but have no wish for aggressive treatment or management. Other factors for admission into a hospice program are the need to show increased respiratory distress and impaired nutrition. The reasons behind patients not


embracing hospice services are many and include the feeling that the end is near.5 However, in practice it is hard to accurately predict a time course and ALS patients not infrequently remain on hospice care longer than 6 months if they continue to show a decline.

Quality of life for the caregiver and family should also be consid-ered after the death of the patient. There are often feelings of being burned-out from providing constant care, from changes in living arrangements to accommodate progressive weakness of the patient, and from financial hardships.14 One can also take the data on caregiver stress gathered after death and periodically ask caregivers about their QOL while the patient is living. While it may be chal-lenging to modify some of the issues, acknowledging that giving care is stressful can be an important message for the caregiver to hear.

CONCLUSION

What should a physician tell an ALS patient? First, acknowledge that ALS is a challenging disease. Emphasize that the physician will be there to guide them. Second, discuss the course of changes in ALS in a metered fashion. Explain that there will be time to look ahead, review, and make recommendations on care as issues arise. Third, review objective QOL data with the patient and note that QOL is perceived to be relatively high by ALS patients and that over time this remains stable. For some patients, ALS has allowed them to refocus their priorities and has had a positive impact on their life. Fourth, explain how people naturally adapt to the disease as it progresses. Emphasize that this adaptation will, in part, mirror the general challenges that everyone faces as they age. Fifth, assure patients that changes in ALS do not happen suddenly and there will be time to actively make adaptations. Explain that the physician is there to look ahead and make suggestions to enhance factors that affect QOL, such as durable equipment, feeding tubes, and nonin-vasive ventilation. Sixth, emphasize that the end of life is manage-able and patients die a peaceful death. Further, hospice services can aid in the quality of death. Seventh, acknowledge that there will be challenges for the caregiver and that they are important to discuss. Emphasize that hospice services can help both the patient and the caregiver. Eighth, remind patients that spirituality and religious connectedness are important factors that can have a positive influ-ence on a patient’s outlook and QOL and quality of death. Ninth, it is important to suggest counseling as an important part of adapt-ing, both for the patient and caregiver. Tenth, always call and write a letter of condolence to the patient’s family because it gives closure both to the family and to the physician.

REFERENCES

1. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981;19:787-805.

2. Bourke SC, Shaw PJ, Gibson GJ. Respiratory function vs sleep-disordered breathing as predictors of QOL in ALS. Neurology 2001;57:2040-2044.

3. Bromberg M, Forshew D, Iaderosa S, McDonald E. Ventilator de-pendency in ALS; management, disease progression, and issues of coping. J Neuro Rehab 1996;10:195-216.

4. Bromberg MB, Forshew D. Comparison of instruments addressing quality of life in patients with ALS and their caregivers. Neurology 2002;58:320-322.

5. Carter GT, Bednar-Butler LM, Abresch RT, Ugalde VO. Expanding the role of hospice care in amyotrophic lateral sclerosis. Am J Hosp Palliat Care 1999;16:707-710.

6. Cohen S, Mount B, Strobel M, Bui F. The McGill Quality of Life Questionnaire: a measure of quality of life appropriate for people with advanced disease. A preliminary study of validity and accept-ability. Pall Med 1995;9:207-219.

7. Ganzini L, Johnston WS, McFarland BH, Tolle SW, Lee MA. Attitudes of patients with amyotrophic lateral sclerosis and their care givers toward assisted suicide. N Engl J Med 1998;339:967-973.

8. Ganzini L, Johnston WS, Silveira MJ. The final month of life in pa-tients with ALS. Neurology 2002;59:428-431.

9. Hickey A, Bury G, O’Boyle C, Bradley F, O’Kelly F, Shannon W. A new short form individual quality of life measure (SEIQoL-DW): application in a cohort of individuals with HIV/AIDS. BMJ 1996;313:29-33.

10. Jenkinson C, Fitzpatrick R, Brennan C, Bromberg M, Swash M. Development and validation of a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone disease: the ALSAQ-40. J Neurol 1999;246:III16-III21.

11. Krivickas LS, Shockley L, Mitsumoto H. Home care of patients with amyotrophic lateral sclerosis (ALS). J Neurol Sci 1997;152:S82-S89.

12. Lou JS, Reeves A, Benice T, Sexton G. Fatigue and depression are associated with poor quality of life in ALS. Neurology 2003;60:122-123.

13. Mandler R, Anderson F, Miller R, Clawson L, Cudkowicz M, Del Bene M, The ALS C.A.R.E. The ALS Patient Care Database: insights into end-of-life care in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:203-208.

14. Martin J, Turnbull J. Lasting impact in families after death from ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:181-187.

15. Max M, Lynch S, Muir J, Shoaf S, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neu-ropathy. New Engl J Med 1992;326:1250-1256.

16. Mazzini L, Corrà T, Zaccala M, Mora G, Del Piano M, Galante M. Percutaneous endoscopic gastrostomy and enteral nutrition in amyolateral sclerosis. J Neurol 1995;242:695-698.

17. McGuire D, Garrison L, Armon C, Barohn R, Bryan W, Miller R, et al. A brief quality-of-life measure for ALS clinical trials based on a subset of items from the Sickness Impact Profile. The Syntex-Synergen ALS/CNTF Study Group. J Neurol Sci 1997;152:S18-S22.

18. Mustfa N, Walsh E, Bryant V, Lyall RA, Addington-Hall J, Goldstein LH, et al. The effect of noninvasive ventilation on ALS patients and their caregivers. Neurology 2006;66:1211-1217.

19. Neudert C, Oliver D, Wasner M, Borasio G. The course of the ter-minal phase in patients with amyotrophic lateral sclerosis. J Neurol 2001;248:612-616.

E-18 Quality of Life in Amyotrophic Lateral Sclerosis AANEMCourse

20. Neudert C, Wasner M, Borasio GD. Patients’ assessment of quality of life instruments: a randomised study of SIP, SF-36, and SEIQoL-DW in patients with amyotrophic lateral sclerosis. J Neurol Sci 2001;191:103-109.

21. O’Boyle C, McGee H, Joyce C. Quality of life: assessing the in-dividual. In: Albrecht G, Fitzpatrick R, editors. Quality of life in health care advances in medical sociology, volume 5. Greenwich, Connecticut: JAI Press Inc; 1994. p 159-180.

22. Rabkin J, Wagner G, Del Bene M. Resilience and distress among amyotrophic lateral sclerosis patients and caregivers. Psychosom Med 2000;62:271-279.

23. Robbins R, Simmons Z, Bremer B, Walsh S, Fischer S. Quality of life in ALS is maintained as physical function declines. Neurology 2001;56:442-444.

24. Simmons Z, Bremer B, Robbins R, Walsh S, Fischer S. Quality of life in ALS depends on factors other than strength and physical function. Neurology 2000;55:388-392.

25. Trail M, Nelson ND, Van JN, Appel SH, Lai EC. A study comparing patients with amyotrophic lateral sclerosis and their caregivers on measures of quality of life, depression, and their attitudes toward treatment options. J Neurol Sci 2003;209:79-85.

26. Veldink JH, Wokke JH, van der Wal G, Vianney de Jong JM, van den Berg LH. Euthanasia and physician-assisted suicide among patients with amyotrophic lateral sclerosis in the Netherlands. N Engl J Med 2002;346:1638-1644.

27. Walsh SM, Bremer BA, Felgoise SH, Simmons Z. Religiousness is related to quality of life in patients with ALS. Neurology 2003;60:1527-1529.

28. Ware JE Jr, Sherbourne C. The MOS 36-item short-form survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-483.

29. Wilson IB. Clinical understanding and clinical implications of re-sponse shift. Soc Sci Med 1999;45:1577-1588.


E-20 AANEMCourse

1. Which of the following is most correct?A. Quality of life (QOL) is a subjective assessment that

cannot be statistically measure quantitatively.B. Proxy reports of physical function do not correlate well

with assessments made by patients.C. Proxy reports of role functioning correlate well with as-

sessments made by patients.D. Objective indicators of disablement, such as the Craig

Handicap Assessment and Reporting Technique (CHART), are able to explain a significant amount of variance that is reported in subjective measures of QOL.

E. In general, proxy respondents consider patients more im-paired than the patients consider themselves.

2. Ideally instruments that measure QOL should be valid, re-sponsive, appropriate, sensitive, and interpretable. Which of the following questions needs to be answered to determine if the instrument devised to measure QOL is responsive?A. Does the instrument measure what it is intended to

measure?B. Does the measure produce the same results when repeated

in the same population?C. Is the measure suitable for its intended use?D. Does the measure detect clinically meaningful changes?E. Are results from the measure relevant?




E-21

Fill

in an

swer


your phone number

1 2 3 4



Under ID number, please write out and fill inthelast�digitsofyourphonenumber.Be sure to start in the first box on the left (asshown).



3. All of the following questions should be addressed before choosing a health-related QOL measure for a given application EXCEPT:A. Are the domains covered relevant?B. Is the population and setting in which the assessment

device was developed similar to those situations in which it is planned to be used?

C. Do the questions allow the respondents to include and weight the importance of aspects of their own life?

D. Is the measure sensitive enough to distinguish changes over time?

E. Has the measure been pretested on the patient popula-tion?

4. QOL assessments are used for the following reasons EXCEPT:A. Assessing the patient’s QOL gives the clinician valuable

information that can help in making the best choices patient care.

B. By understanding how a disease affects the QOL of a patient, the interaction between the doctor and patient will improve.

C. Information about how a disease affects the functional and emotional status of the patient gives the doctor a better insight into the patient’s needs.

D. Self-reported personal reported QOL measures are often used by the Food and Drug Administration as the primary outcome to determine the effectiveness of drug trials.

E. All of the above are true.

5. Potential uses for disease-specific QOL measures include all of the following EXCEPT:A. Comparing the health and social status of a diabetic and

asthmatic population.B. Tailoring management to the needs of the patient.C. Being the primary outcome measure for a clinical trial.D. Assessing the effectiveness of rehabilitation services.E. Justifying the allocation of limited social and healthcare

resources.

6. Quality of life represents:A. A static concept affecting an individual uniformly

throughout life.B. A dynamic concept that can change during life.C, A concept that cannot be defined in a useful manner.D. A concept that is fixed at an early age.E. An interesting but not clinically useful concept.

7. Quality of life can be measured by:A. Simple visual analogue scales.B. General health questionnaires.C. Disease-specific questionnaires.D. Battery of questionnaires. E. All of the above.

8. Quality of life questionnaires are most robust when:A. Based on simple questions.B. Modifications are made to established questionnaires.C. Based on single visual analogue scale.D. Statistically analyzed for validity.E. None of the above.

9. Quality of life in amyotrophic lateral sclerosis (ALS) is usually rated poor by all EXCEPT:A. Providers (physicians, nurses, etc.).B. Health caregivers.C. Patients.D. Family (parents, children, etc.).E. Friends.

10. Quality of life in ALS:A. Can remain high in the setting of progressive weakness.B. May be lower for the caregiver than the patient.C. Is not commonly influenced by patient depression.D. Can be influenced by the concept of “response shift”.E. All of the above.

E-22 CME Self-Assessment Test AANEMCourse

P:\DOC\Education\COURSE\Handout Answer Sheets\2006 Courses\2006 CDE Answers.doc

2006 AANEM Course C: New Insights in Lumbosacral

Plexopathy

SELF-ASSESSMENT EXAMINATION ANSWER SHEET

1. D

2. A

3. D

4. C

5. B

6. B

7. E

8. E

9. A

10. B

11. B

12. E

13. A

14. B

15. D

16. A

17. C

18. C

19. C

20. D

2006 AANEM Course D: Muscle & Nerve Pathology


1. D

2. B

3. B

4. A

5. E

6. E

7. E

8. C

9. D

10. B

11. D

12. B

13. E

14. A

15. C

16. E

17. E

18. D

19. B

20. C

2006 AANEM Course E: Quality of Life in Neuromuscular

Disease


1. E

2. D

3. C

4. E

5. A

6. B

7. E

8. D

9. C

10. E

new insights in lumbosacral plexopathy - aanem.org · lumbosacral plexus disease and will learn...

Documents