Neurology Review

1. Neurology Review MKSAP

2. Dementia • Acquired chronic impairment of memory and other aspects of cognition that impair daily function. • MCI = Mild Cognitive Impairment • MCI does not impair daily function • Degenerative or vascular disease that causes widespread or multifocal brain abnormalities.

3. Dementia • Alzheimer’s Disease most prevalent • Non-AD ~1/3+ of Dementias • Different clinical presentations and different Rx • FTD – presents with executive function impairment and personality change vs Memory problems of AD • Cholinergic Rx does not help FTD • Relieve FTD patients of responsibilies

4. DSM-IV criteria for Dementia • A. Development of multiple cognitive deficits with both: • 1. Memory impairment • 2. One or more of the following • a. Aphasia • b. Apraxia • c. Agnosia • d. Impair executive functions (planning, organizing, sequencing, abstracting) • B. A1 and A2 cause significant impairment in social or occupational functioning and represents a decline from prior functions • C. Deficits do not occur exclusively as part of a delerium

5. Pathology of Alzheimer’s Diseasse • Deposition of insoluble beta-amyloid protein in extracellular parenchymal plaques • Amyloid Plaques surrounded by dystrophic tau-positive neurites and activated microglia • Neurofibrillary tangles are microtubule-associated tau-protein; hyperphosphorylated and abnormally conformed. • Number of tangles correlates with severity of dementia • Beta-Amyloid neurotoxicity is most likely key feature. • Early degeneration of Basal Forebrain (Nucleus basalis of Meynert) results in Cholinergic deficit. • Mesial Temporal lobe degeneration results in memory impairment • Association area involvment in inferior temporal lobes, prefrontal, and parietal areas are other features • Relative sparing of subcortical and primary motor and sensory cortex.

6. Beta-Amyloid • 1 – 42 fragment is cleaved by abnormal cleavage of larger Amyloid Precursor Protein. • Alpha-secretase cleavage produces soluble product. • Cleavage by beta or gamma-secretase produces toxic, insoluble 1-42 fragment. • Cascade or inflammatory and toxic events initiated.

7. APP cleaving

8. APP processing

9. Epidemiology of AD • Risk factors: advanced age, genetic predisposition, cardiovascular conditions, post-menopausal state. • Prevalence* 1.5% for age 65- 69 • Doubles every 5yrs to 85 • Increases 10% every 5 yrs age 85 to 100 • 45% at age 100

10. Genetics etc of AD • ~5% of cases are Mendelian • Dementia <65 some caused by Autosomal Dominant mutations in presenilin 1, presenilin 2, or APP • ~25% of genetic cases are presenilin 1 mutations. Most common familial AD. • Genetic test available • Good genetic counseling required. • For late onset, no known one gene mutations known, but FH is risk factor. • RR ~2.5 if affected relative • High risk of AD in Trisomy 21. APP is on #21 • Apolipoprotein e4 is risk factor; onset about 10yrs earlier • Hypertension is risk factor • Estrogen replacement controversy • ? Benefit of Statin Rx • ?NSAIDs

11. Mild Cognitive Impairment (MCI) • MCI is conceptually the intermediate stage between presymptomatic disease and Dementia • MCI – memory impairment without other cognitive problems and without impairment in functional independence • Progression from MCI to AD is about 10 -15% per year. In one study ~80% had AD at 6 yr follow-up.

12. Progression of AD • Steadily progressive deterioration over 8 – 10 yrs. • MMSE 20 – 26 = mild dementia with mild functional dependency needing some assistance (ex. Financial) • MMSE 10 – 20 = moderate dementia. More impairment and help needed. Unable to drive. • MMSE <10 = severe dementia with total dependency and constant supervision.

13. Diagnosis of Alzheimer’s Disease • Clinical diagnosis supported by imaging and tests. • Typically normal neuro exam except for cognition • No pathognomonic features or reliable biomarkers. • Diagnostic Crieteria – next slide • Not very specific. ~70% accuracy • Think other Dementias or dx when early symptoms are: impaired social behavior, gait disturbance, aphasia, hallucinations, delusions; or not insidious or chronic

14. NINCDS-ADRDA criteria • 1. Dementia established by clinical examination and standardized brief mental status test and confirmed by neuropsychologic tests • 2. Deficits in two or more areas of cognition • 3. Progressive worsening of memory and other cognitive functions • 4. No disturbance of consciousness • 5. Onset between 40 – 90 years old • 6. Absence of other systemic or neurologic disorder sufficient to account for the progressive cognitive defects

15. R/O secondary causes of Dementia • 5 – 15% of dementias are at least partially reversible • Depression, medication induced encephalopathy and metabolic disorders most likely. • D/C unnecessary Rx, especially sedatives and anticholinergic agents. • Screen for depression, B12, hypothyroidism. • Syphilis screening if risk factors • CT or MRI to exclude structural pathology and eval for strokes or hydrocephalus • Formal Neuropsych testing may be needed if atypical, ?depression, medico-legal decisions such as competency.

16. Additional evaluation options • EEG and/or LP if fluctuating ecephalopathy or subacute progressive dementia • Functional imaging may help distinguish between FTD and AD. • Biomarkers in CSF not yet ready for primetime • Genetic testing not routinely needed.

17. AD

18. Tangles and Plaques

19. Treatment of AD • Cholinergic augmentation recommended for all mild to moderate AD. • Improves cognition and global functions • Effect lasts for about a year • Does not altered overall progression • Not shown to delay nursing home placement or death.

20. Anticholinesterase agents • Donepezil (Aricept). • Start at 5mg qd. Increase to 10mg qd in 4 – 6 weeks. Side effects: Nausea, diarrhea, Abdo pain, sleep disturbances • Rivastigmine(Exelon). • Start 1.5mg bid, titrate up to 3 – 6mg bid over 6 weeks. SE: N/V, anorexia, dizzines • Galantamine (Reminyl). • Start at 4mg/d, titrate up to 12mg bid over months. SE: N/V, anorexia, weight loss, diarrhea • Tacrine (Cognex) • not used anymore • These agents may be helpful in Lewy Body dementia and vascular dementia, but not in Fronto-temporal dementia

21. NMDA glutamate antagonist Rx • Memantine (Nemenda) – shown to be helpful for moderate to severe Alzheimer’s Disease. • Start at 5mg/d, increase up 10mg bid with weekly changes. • SE: hallucinations, confusion, restlessness, anxiety, dizziness, h/a, fatigue, constipation. • Can be combined with Anticholinesterase inhibitor.

22. Other Rx’s • ?Ginkgo biloba • Not proved. ?dose. ?standardization. ?effects on other medications • ?Vit E. 1000 IU twice daily was shown to benefit. But other studies with increased mortality. So ?

23. Treatment of Psychiatric Symptoms • More likely to lead to institutionalization • Behavioral approaches: predictable routines, repetition, patient redirection. • AChE inhibitors help: • apathy, hallucinations, psychosis, depression,anxiety. • Trazadone or atypical neuroleptics* may help delusional or agitated behaviors. • Resperidone, olanazapine, quetiapine • * increased risk of death shown in meta-analysis. Risk vs benefit. • Remember the care givers may need care. • Elder abuse or neglect

24. Preventive Strategies • Nothing as of yet. • Goal: slow amyloid deposition in brain • Amyloid vaccines • Encephalitis • Bad-Secretase inhibitors • Good –Secretase enhancers

25. AD – Keypoint and recent advancs • Normal Neuro exam except for memory and other cognitive domain impairments • MCI is likely a predemential stage • Cholinergic augmentation is standard therapy • AChE inhibitors modesty improve cognition, global function, and psychiatric symptoms • Memantine in moderate to severe AD improves function better than AChE inhibitors • ?Vit E • Antipsychotic therapy has Black Box warning.

26. Non-Alzheimer’s Dementias • Vascular dementia, Dementia with Lewy Bodies, Fronto-temporal Dementia – most common of the non-AD Dementias. • Often superimposed on AD • Prion Disease and other degenerative diseases (CBD) much less likely.

27. Vascular Dementia • Multiple or strategically placed large-vessel occlusions • Multiple small vessel occlusions*** • Primary hemorrhagic process • *** likely most common

28. Vascular dementia • ~25% of stroke patients meet criteria for dementia at 3 months • ~1/3 of dementias a/w proximate stroke • RR for dementia is 5.5 -8.4% per year in 4 years post stroke vs 1.3% per year • Vascular disease and AD synergism. • Why?

29. Vascular dementia

30. Dx of vascular dementia • H/o Stroke or risk factors • Neuro-imaging • Abrupt onset or step-wise progression • Poor sensitivity – most have insidious onset and gradual decline. • Many have no signs of stroke or h/o stroke • Often mixed • MMSE not sensitivity. Typically cognitive slowing, apathy, poor problem solving. “Subcortical dementia”. • Formal neuropsych testing may help

31. RX Vascular Dementia • Treat systolic hypertension – primary prevention. Secondary prevention – evidence of benefit not proved. • ASA • Acetyl Cholinesterase inhibitors

33. Fronto-temporal dementia (FTD) • Early, insidiously progressive impairment of personality and executive functions – decision making, prioritizing, planning. • Consensus Criteria for FTD: • Insidious onset and gradual decline • Early decline in social interpersonal conduct • Early impairment in regulation of personal conduct • Early emotional blunting • Early loss of insight • Apathy • Usually noticed by family not by patient • Memory impairment may be relatively mild

34. FTD • Disproportionate atrophy of frontal lobes and anterior temporal lobes • Pick’s Disease • Many have tau-positive inclusions in affected neurons. Cause not known • RF: age and family history • ~40% familial. Tau gene mutation in many.

35. Pick’s Disease

36. Dx of FTD • History from family • Poor 1 minute fluency test • List words from category in 1 minute. • 10,14,18 • Visuo-spatial functions preserved (cf AD) • Formal neuropsych testing • Neuro-imaging

37. Rx of FTD • Medicationss can help irritability, agitation, depressive symptoms, eating disorders • Trazadone, SSRIs, Modafinil etc • Not helpful for cognitition • AChE inhibitors don’t help. • Remove from responsibilites • No driving • Decision making: financial, medical etc • Neuropsych testing have help here.

38. Dementia with Lewy Bodies (DLB) • Dementia with intraneuronal inclusions in cortex • Visual hallucinations, fluctuating cognition, parkinsonism • Can co-occur with AD

39. Criteria for probable DLB • 1. Persistent memory impairment may not occur early but is usually evident with progression. Deficits of attention, frontal-subcortical skills, and visuospatial ability may be particularly prominent • 2. Two of the following core features • a. Fluctuating cognition with pronounced variation in attention and alertness • b. Recurrent visual hallucinations that are typically well formed and detailed. • c. Spontaneous motor features of parkinsonism • 3. Supportive features include repeated falls, syncope, neuroleptic sensitivity, delusions, hallucinations in other modalities, REM behavior disorder. • 80 - 90% specificity but only 50 - 60% sensitivity • “Fluctuating cognition” • Daytime drowsiness and lethargy despite normal sleep • Falling asleep for > hours during the day • Staring into space for long periods • Episodes of disorganized speech marked by real words linked in a disjointed manner.

40. Treatment of DLB • AChE inhibitors first • Can help behavior symptoms, hallucinations and delusions • “standard neuroleptics” can be associated with neuroleptic malignant syndrome. • “Black box” warning of atypical neuroleptics • Sinemet etc

41. Creutzfeldt-Jakob Disease (CJD) • CJD is most common Prior disease • ~1 per million. • Degenerative disease that may be transmissible • Transformation of prion protein into insoluble conformation • Spongioform changes in brain • ~85% are sporadic • Familial forms with mutation of prion protein • Prion protein is normal constituent of CNS • New variant CJD (vCJD) in younger patients a/w consumption of meat affected with bovine spongiform encephalopathy

42. Dx of CJD • Rapidly progressive disease a/w myoclonus • Death usually in 3 – 6 months • DDX includes: primary angiitis of CNS and Hashimoto’s encephalitis • Hashimoto’s: antithyroglobulin antibodies • Seizures, dementia, myoclonus, ataxia • Brain Bx may be needed

43. Clinical criteria for probable CJD • 1. Rapidly progressive dementia • 2. Electroencephalogram with periodic sharp waves or elevated levels of 14-3-3 protein on CSF analysis • 14-3-3 is non-specific neuronal marker. • limitations • Two of the following • Myoclonus • Visual or cerebellar signs • Pyramidal or extrapyramidal motor signs • Akinetic mutism • 65% sensitivity, 95% specificity • EEG normal in vCJD

44. EEG in sCJD

45. CJD

46. CJD pathology

47. Key Points for non-AD dementias • Most common are Vascular dementia, DLB, FTD • Clinical Dx of VD: h/o or risk factors for stroke, a stroke-like course, and/or findings on imaging • DLB characterized by parkinsonism reponsive to dopaminergic Rx, visual hallucinations, and fluctuating cognition • Cholinergic augmentation may help psychiatric symptoms of DLB • FTD presents with early executive and personality changes, and pronounced or asymmetric atrophy of frontal lobes on imaging • CJD suspected if dementia with myoclonus that progressives of weeks to months

48. Headache and Facial Pain • Significant advances in the past 20 years • Migraine alone: 10% of people • 18% of women and 6% of men • 75% have moderate to severe headaches • Distinguish Primary from Secondary Headache • Primary: Migraine, Tension-type, Chronic Daily/rebound/medication overuse, Cluster. • Secondary: SAH, meningitis, PTC, Cerebral mass lesions, GCA

49. Migraine • Nausea, photophobia, phonophobia, throbbing pain. May worsen with movement and limit daily activities • Pathophysiology: begins in the brainstem and higher brain structures; distention and inflammation of meningeal vessels is FINAL manifestation. • Trigeminal vascular system: triggered to release of inflammatory peptides on blood vessels. • Autonomic and chemoreceptor systems triggered: nausea, pallor, flushing, tearing, rhinorhea, sinus congestion. • Sinus headache: fever, discolored nasal discharge and air-fluid level on CT.

50. Migraine cont’d • Prodrome in many, up to 24 hrs prior to attack: euphoria, depression, food cravings, fatigue, hypomania, cognitive slowing, dizziness, asthenia. • Auras in 15% - 20% - with hour of or during headache: visual loss or changes (ex. scintillating scotoma), hallucinations, numbness, tingling, weakness, confusion. Spreads. Caused by Spreading Cortical Depression = wave of neuronal depolarization. Auras last few minutes to up to an hour. ( Acephalgic migraine – aura without the headache.) • Complicated migraine. Rare. Aura persists over 24 hours. May result in infarction – from profound metabolic disturbance. Risk increased by OCPs and smoking. • Late life migraine accompaniments: patients over 50yrs. 20 – 60 minutes typically. (c/w TIA which usually lasts 10 -15 minutes.) May be repetative and not worsen in severity. (c/w TIA). ~50% a/w mild headache.