2014 Step 1 ReviewClinical Neuroscience

Monday, February 27thSeth Wandersawander@med.miami.edu

Clinical Neuroscience

• General comments• Degenerative/movement disorders• Demyelinating disorders• Brain tumors• Glaucoma• Sample questions

Degenerative Diseases

Alzheimer’s:• Most common cause of dementia

• Key findings:(1) Senile plaques (extracellular) - A amyloid core

(2) Neurofibrillary tangles (intracellular) - abnormally phosphorylated tau protein

• Degeneration at basal nucleus of Meynert = loss of cholinergic projections to cerebral cortex, amygdala, basal ganglia, thalamus• Tx: cholinesterase inhibitors

• Genetics: APP = amyloid precurser protein (ch. 21)

• Hypokinetic disorder

• Depigmentation of substantia nigra, loss of dopaminergic projection to striatum

• Clinical symptoms: 1) Bradykinesia, 2) Rigidity, 3) Resting tremor (pill-rolling), 4) Postural instability

• Histology: Lewy bodies, round eosinophilic inclusions of aggregated -synuclein

• Parkin gene defects

Parkinson’s

Degradation via proteosomeParkin-synuclein

Lewy Bodies

Huntington’s• Hyperkinetic disorder

• Autosomal dominant + anticipation

• CAG repeat expansion @ ch. 4 (HTT gene)

• Atrophy of caudate and putamen, loss of GABAergic projections to GPe

• Progressive chorea, psychiatric changes, dementia

DA

GABA GABA

GABA

GABA

Glu

Glu

Substantia nigra

Striatum(caudate +putamen)

Globus pallidusexternus

GP internus

Subthalamic nucleus Thalamus VLo

Cortical motor output

DIRECT

INDIRECT

+ -

-

+

- -

-

++++

D1 D2

Direct: motor outputIndirect: motor output

Basal Ganglia

Parkinson’sPharmacological strategies:

(1) Agonize dopamine receptors- Bromocriptine, pramipexole

(2) Increase dopamine- Amantidine ( dopamine release)- L-dopa, carbidopa (precursors)

(3) Prevent dopamine breakdown- Selegiline (MAO-B inhibitor)- entacapone, tolcapone (COMT inhibitors)

(4) Block excess cholinergic activity- Benztropine (antimuscarinic)

Demyelinating Disorders

Multiple Sclerosis:• Autoimmune destruction of myelin insulation

• >2 separate attacks, > 1 month apart, at least 2 distinct lesions

• Variable presentation: optic neuritis, MLF syndrome, hemiparesis, hemisensory symptoms, bladder/bowel incontinence

• MRI: multiple, asymmetric, high signal lesions @ white matter

• CSF: total protein, IgG, oligoclonal bands

• Tx: immunosuppressive therapy

Demyelinating Disorders

Progressive Multifocal Leukoencephalopathy (PML):• JC virus infects CNS oligodendroglial cells --> progressive demyelination• Aphasia, hemiparesis, cortical blindness, ataxia --> quadriparesis, coma• May be AIDS-defining illness!

Guillain-Barre syndrome:• Acute idiopathic polyneuritis, associated with infections, immune attack @

peripheral myelin• Symmetric ascending muscle weakness beginning in distal lower extremities• Antigenic cross-reactivity between Campylobacter (O:19) oligosaccharides

and glycosphingolipids on neural tissue• May severely impair autonomic function• Most patients fully recover

Brain TumorsAdult tumors:• Glioblastoma multiforme: poor prognosis, @

hemispheres, central necrosis and hemorrhage

• Meningioma: via arachnoid cell external to brain, resectable, osteoblastic overlying rxn, psammoma bodies

• Schwannoma: via Schwann cells, @ 8th nerve (acoustic), bilateral in NF type II

• Oligodendroglioma: via oligodendrocytes, frontal lobes, “fried-egg” cells

• Pituitary adenoma: prolactin secreting, bitemporal hemianopia

Brain TumorsChildhood tumors:• Pilocytic astrocytoma: benign, low-grade,

Rosenthal fibers

• Medulloblastoma: highly malignant, @ cerebellar vermis, primitive neuroectodermal tumor, Homer-Wright pseudorosettes

• Ependymoma: inside 4th ventricle, poor prognosis

• Hemangioblastoma: von Hippel-Lindau syndrome (w/ retinal angiomas), EPO production

• Craniopharyngioma (adamantinoma): benign, via Rathke’s pouch - odontogenic epithelium, calcification

GlaucomaClinical symptoms:• Increased intraocular pressure (normal 10-21 mmHg)• Optic nerve damage ( cup:disc ratio)• Visual field defects (peripheral)

Two scenarios:(1) Open-angle: aqueous regress via Schlemm’s canal

- Myopes, chronic + progressive

(2) Acute angle closure: physical obstruction at drainage route- Hyperopes, acute w/ secondary symptoms (pain, nausea, vomiting, etc).

Tx: 2 blockade - decrease aqueous productionPGF - increased uveoscleral outflow (2nd route)

1) A 25-year-old female presents with sudden uniocular vision loss and slightly slurred speech. She has a history of weakness and paresthesias that have resolved. Which of the following describes the underlying etiology of this disease?

A) A hormone-secreting tumor that compresses the optic nerve

B) A post-infectious immune response to self-antigens that will likely resolve completely

C) A progressive autoimmune disease in which CD4+ cells react against self myelin antigens

D) An autosomal dominant trinucleotide repeat expansion

2) Which of the following statements regarding neural tumors is true?

A) The vast majority of brain tumors are primary in origin

B) Glioblastoma multiforme tends to occur in children and is often indolent

C) Schwannomas are often localized to the 7th nerve

D) Medulloblastomas often occur at the cerebellar vermis, and are characterized as “primitive neuroectodermal” in origin

3) A patient presents with progressive dementia, aphasia, and certain aspects of Parkinsonian disease. Representative histology and anatomy at autopsy are shown below. What is the most likely diagnosis?

A) Multi-infarct dementia

B) Pick’s disease

C) Alzheimer’s disease

D) Guillan-Barre syndrome

4) A middle-aged man presents to the clinic for a regular follow-up. On neurological exam he demonstrates lower extremity muscle weakness, atrophy, and hyporeflexia. A representative spinal cord cross-section is shown below. At some earlier point, this patient was exposed to what sort of pathogen?

A) A gram+ bacterium

B) A single-stranded linear RNA virus

C) A gram- spirochete

D) A double-standed circular DNA virus

5) Phenytoin and carbamazepine both act through which of the following mechanisms?

A) inhibitory tone via enhanced GABAergic hyperpolarization

B) axonal conductance via Na+ influx channel block

C) excitatory glutamatergic signaling

D) presynaptic Ca2+ influx via voltage-gated T-type channels

6) An adult patient presents with a two-year history of progressively worsening headaches. Over the previous six months, in addition to severe headaches, the patient reports several episodes of seizures. Cranial CT reveals a large mass in the parasagittal region. The biopsy is shown below. Which of the following is the diagnosis?

A) Medulloblastoma

B) Glioblastoma multiforme

C) Pilocytic astrocytoma

D) Meningioma

7) A patient presents with a history of rapidly progressive dementia over a period of four months. Family members report severe memory loss and personality changes. EEG reveals recurrent burts of high voltage slow waves. A representative brain biopsy is shown below. This patient’s disease is due to which of the following underlying processes?

A) Deposition of amyloid throughout the cerebral cortex

B) Loss of dopaminergic neurons at the substantia nigra

C) Infectious spread of misfolded proteins

D) Vitamin B12 deficiency

8) A patient presents with a long history of progressive loss of vision in his periphery. Upon examination, you note an increased cup:disc ratio and the intraocular pressure is measure to be 30 mm Hg. This patient may benefit from timolol due to which of the following mechanisms?

A) Increased aqueous humor outflow via Schlemm’s canal

B)Decreased aqueous humor secretion from the ciliary body

C) Increased aqueous humor outflow via the uveoscleral route

D) Reduced pupillary constriction

9) Which of the following best describes the underlying neural defect in patient’s with advanced Huntington’s disease?

A) Degeneration of dopaminergic neurons within the substantia nigra impairs transmission via the direct pathway

B) Loss of glutamatergic neurons within the subthalamic nucleus results in increased cortical motor output

C) Degeneration of GABAergic neurons within the striatum impairs transmission via the indirect pathway

D) Increased activity of GABAergic neurons within the globus pallidus internus results in increased cortical motor output

10) Which of the following medications improves Parkinsonian symptoms by impairing the breakdown of endogenous dopamine?

A) Bromocriptine

B) L-dopa

C) Amantadine

D) Selegiline

11) A patient is receiving ventilatory support in the intensive care unit. Prior to hospital admission, the patient’s family reports that he had been experiencing progressive and symmetrical ascending muscle weakness. They also claim that he had recently recovered from a serious infection. Which of the following is the likely diagnosis?

A) Multiple sclerosis

B) Pick’s disease

C) Guillan-Barre syndrome

D) Progressive multifocal leukoencephalopathy