2014 Step 1 Review Clinical Neuroscience

1. 2014 Step 1 ReviewClinical Neuroscience Monday, February 27th Seth Wander sawander@med.miami.edu

2. Clinical Neuroscience • General comments • Degenerative/movement disorders • Demyelinating disorders • Brain tumors • Glaucoma • Sample questions

3. Degenerative Diseases Alzheimer’s: • Most common cause of dementia • Key findings: • Senile plaques (extracellular) - A amyloid core • 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)

4. Parkinson’s • Hypokinetic disorder • Depigmentation of substantianigra, 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 Lewy Bodies Degradation via proteosome Parkin -synuclein

5. 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

6. Cortical motor output Basal Ganglia ++++ + - Striatum (caudate +putamen) GABA GABA D1 D2 Glu - INDIRECT Subthalamic nucleus Thalamus VLo - DA - GABA Glu Substantia nigra Globus pallidus externus DIRECT + GABA - Direct:  motor output Indirect:  motor output GP internus

7. Parkinson’s Pharmacological strategies: • 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)

8. 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

9. 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

10. Brain Tumors Adult 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

11. Brain Tumors Childhood 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

12. Glaucoma Clinical symptoms: • Increased intraocular pressure (normal 10-21 mmHg) • Optic nerve damage ( cup:disc ratio) • Visual field defects (peripheral) Two scenarios: • 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 production PGF - increased uveoscleral outflow (2nd route)

13. 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

14. 2) Which of the following statements regarding neural tumors is true? A) The vast majority of brain tumors are primary in origin B) Glioblastomamultiforme tends to occur in children and is often indolent C) Schwannomas are often localized to the 7th nerve D) Medulloblastomas often occur at the cerebellarvermis, and are characterized as “primitive neuroectodermal” in origin

15. 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

16. 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

17. 5) Phenytoin and carbamazepine both act through which of the following mechanisms? A)  inhibitory tone via enhanced GABAergichyperpolarization B)  axonal conductance via Na+ influx channel block C)  excitatory glutamatergic signaling D)  presynaptic Ca2+ influx via voltage-gated T-type channels

18. 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) Glioblastomamultiforme C) Pilocyticastrocytoma D) Meningioma

19. 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 substantianigra C) Infectious spread of misfolded proteins D) Vitamin B12 deficiency

20. 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

21. 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 substantianigra 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 globuspallidusinternus results in increased cortical motor output

22. 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

23. 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