Transcript Neurology_Review_MKSAP

Neurology Review
MKSAP
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.
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
DSM-IV criteria for Dementia
• A. Development of multiple cognitive deficits with both:
– 1. Memory impairment
– 2. One or more of the following
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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
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.
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.
APP cleaving
APP processing
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
Genetics etc of AD
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~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.
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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
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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.
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.
Diagnosis of Alzheimer’s Disease
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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
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
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.
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.
AD
Tangles and Plaques
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.
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
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.
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 ?
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
Preventive Strategies
• Nothing as of yet.
– Goal: slow amyloid deposition in brain
• Amyloid vaccines
– Encephalitis
• Bad-Secretase inhibitors
• Good –Secretase enhancers
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.
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.
Vascular Dementia
• Multiple or strategically placed largevessel occlusions
• Multiple small vessel occlusions***
• Primary hemorrhagic process
• *** likely most common
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?
Vascular dementia
Dx of vascular dementia
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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
RX Vascular Dementia
• Treat systolic hypertension – primary
prevention. Secondary prevention –
evidence of benefit not proved.
• ASA
• Acetyl Cholinesterase inhibitors
Fronto-temporal dementia (FTD)
• Early, insidiously progressive impairment of personality
and executive functions – decision making, prioritizing,
planning.
• Consensus Criteria for FTD:
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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
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.
Pick’s Disease
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
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.
Dementia with Lewy Bodies (DLB)
• Dementia with intraneuronal inclusions in
cortex
• Visual hallucinations, fluctuating cognition,
parkinsonism
• Can co-occur with AD
Criteria for probable DLB
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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
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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
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3. Supportive features include repeated falls, syncope, neuroleptic sensitivity,
delusions, hallucinations in other modalities, REM behavior disorder.
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80 - 90% specificity but only 50 - 60% sensitivity
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“Fluctuating cognition”
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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.
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
Creutzfeldt-Jakob Disease (CJD)
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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
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
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
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Myoclonus
Visual or cerebellar signs
Pyramidal or extrapyramidal motor signs
Akinetic mutism
• 65% sensitivity, 95% specificity
• EEG normal in vCJD
EEG in sCJD
CJD
CJD pathology
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 strokelike 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
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
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.
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.
Migraine treatment
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Acute Rx with triptans or ergots: bind directly to trigeminal nerve endings and blood
vessel. Decreased release of inflammatory substances – stabilized nerve endings
and blood vessel swelling. Best for patients with moderate to severe headaches.
Milder, infrequent migraines can be treated with NSAIDs or Acetominophen.
Triptan orally, intranasally, injection.
Faster but more SEs with shot: chest discomfort, nausea, dizziness, numbness,
flushing
Longer half-life triptans have less side effects, but slower action and ?less effective.
Idiosyncratic responses of pateints. Long half-life triptans may be useful for
prophylaxis of menstrual migraine.
Low risk of cardiac side effects, but contraindicated in patients with significant
coronary risk factors. Chest pain may be side effect >>> diagnostic confusion.
IV dihydroergotamine ofr status migrainosus. SEs: nausea and akasthisia. Given with
anti-nausea rx. Intranasal DHE = triptans
Earlier use = better response. Rx not perfect
Central sensitization – brain hypersensitive to all stimuli – light, sound, smell, touch.
Treatment less effective once Central sensitization has occurred.
No class effect for triptans. Therefore try many to find the best.
Recurrence of headache – repeat dose.
Acute Migraine Rx
• 1 mg IV DHE
– With antiemetic. Pregnancy X
• 1mg DHE nasal spray. (Pregnancy X)
• Triptans
– Sumatriptan (Imitrex)
– Rizatriptan (Maxalt)
– Zolmitriptan (Zomig)
– Frovatriptan (Frova) – longest half life
Migraine rescue Rx
• For those who are resistent to triptan Rx or Rx
ineffective.
• Beware using opioids more than a few times per year.
Beware medication over use and rebound.
• Releive headache and cause sedation: cautions.
• Home vs clinic/ED
• IV medicaions: Haldol and Ativan together; lidocaine,
MgSO4, Valproate, Solumedrol, hydroxyzine,
Promethazine, Prochlorperazine, Metachopramide
• Oral: Olanzapine, Quetiapine, Tizanidine, Hydroxyzine
Migraine Prophylaxis
• Consider in patients with 2 or more migraines per week.
If less, consider the severity and level of disability.
• Antidepressants (tricyclics mostly), anticonvulsants,
beta-blockers (Inderal FDA approved).
• AEDs: decrease neuronal irritability.
– Depakote and Topamax FDA approved for migraine prophylaxis
• Start low, go slow. Titrate up over 1 - 2 months. Asses
effect for couple months. If controlled for 3 -6 months,
can consider tapering off
• Botox: may be useful. May prevent release of
inflammatory peptides peripherally
Prophylactic Medications
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Inderal LA – up to 160mg
Verapamil – may need big doses
Depakote ER – 1000mg qhs.
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Topamax – start at 25mg qhs up to 200mg
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Pregnancy D. Take Folate supplement
Check LFTs after 1 and 3 months
Weight gain
Weight loss, carbonic anhydrase effect, cognitive SEs
Neurontin – up to 4800mg in 3 divided doses
Keppra – start 500mg bid
Other AEDs
Elavil or Pamelor – start at 10mg or 25mg qhs.
SNRIs – Duloxetine etc
Methysergide – now not available in the US
Cyproheptadine
CoEnzyme Q10
Riboflavin
Magnesium Oxide
Non-pharmacologic Rx
• Behavioral modications, meditation, counseling,
hypnosis, acupuncture, PT, biofeedback, diet
modification, sleep hygiene.
• Coping strategies, reducing effect of
environmental stressors and triggers
• Dietary triggers (~20%): tyramines, nitrates,
dairy products,xanthines
• Sleep: 7 – 8 hours for adults >25. 8 -10 hours for
<25. Restful sleep decreases brain irritability.
Menstrual Migraine
• 60% of women with migraine
• Triggered by decrease in estrogen. Can
also happen around ovulation.
• Prophylaxis: estrogen rx instead of empty
pill during menses, oral magnesium.
• Beware estrogen in smokers or h/o
hypercoagulability – increased stroke risk.
• Preemptive therapy: NSAIDs or longer
acting triptans – Frova or Amerge.
Key Points: Migraine
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Migraine originates in the brainstam and higher brain structures that cause
pain coming from inflamed cerebral blood vessels.
Acute migraine Rx includes specific therapy with triptans or ergot
derivatives
Triptans are contraindicated in patients with significant coronary risk factors
or a history of coronary disease.
Treatment should be administered as early as possible in the attack to
ensure the greatest efficacy using the lowest dose of therapy.
Prophylactic therapy is indicated in patients who experience more than two
days with h/a per week.
Proper sleep hygiene may be the most effective migraine prophylaxis.
Consumption of foods containing tyramine, nitrates, dairy products, and
xanthines may trigger migraine in some patients.
Menstrual migraine prophylaxis includes administration of low-dose
estrogen therapy during menstruation, continuous estrogen therapy during
menses, or oral magnesium.
Tension-type Headache
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Most prevalent
Mild migraine vs unique disorder?
Squeezing/pressure, bilaterally
May have light or sound sensitivity – not both
Minutes to days, constant, no nausea
Alone or with migraine
Low level of disability
If interfere with activities, Rx as migraine
Mild headaches: rx with NSAIDs or muscle
relaxants
Medication overuse Headaches
• 4 - 5% of Americans have >15 headache days per month!
• ~75% due to medication overuse
• Acute Rx more than 2 days per week >>> risk for rebound
headache
• Pain on or soon after waking. Pain like migraine or tensiontype
• Medication response poor – vicious cycle
• ~25% have secondary headache – r/o mass lesions, infection,
inflammatory disorders, sleep disorders, cervical pathology
• Rx: complete withdrawal of offending agent(s), migraine
prophylactic Rx, breakthrough rx with NSAIDs, IV DHE, or
steroids
• 2 -12 weeks of therapy
• Caffeine withdrawal
Cluster Headache
• One of the most painful H/A syndromes
• Pain + autonomic features
• Episode lasts 15 minutes to 3 hours. (Migraine 4 hours
to 3 days)
• Unilateral and periorbital/temporal
• Associated with at least one on same side as Headache:
conjuctival irritation, lacrimation, rhinorrhea, nasal
congestion, eyelid edema, facial sweating, miosis/ptosis.
• Patient aggitated, can’t stay still. May touch head to help
alleviate pain (c/w migraine).
• May recur several times per day at the same time. No
pain between episodes.
• Clusters typically last 3 – 6 weeks.
Cluster Pathophysiology
• Probably similar to migraine except trigger
may be in the hypothalamus
– Periodicity
– Autonomic symptms
– PET scan evidence
• Increase levels of histamine
• Sensitivity to histominogenic triggers
Rx of Cluster
• Oral Steroid Rx for 2 – 4 weeks with taper
over 2 - 4 weeks
• Anticonvulsants
• Calcium Channel Blockers
• (Lithium – not mentioned in MKSAP)
• Fast acting triptan (injection), IV DHE, high
flow Oxygen
• Exclude primary sleep disorder
“Jabs and Jolts”
• H/As with Autonomic manifestations
• Paroxysmal hemicrania
• Short-lasting unilateral neuralgiform
headache with conjunctival injection and
tearing (SUNCT)
• Shorter duration, more frequent pains that
Cluster. Many per day. Seconds to
minutes.
• Indomethacin
Other primary headaches
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Benign thunderclap headache
Headache upon awakening
Headache a/w sexual activity
Exercise induced headache
Benign cough headache
?pathophysiology
R/O secondary causes
Rx triptans or NSAIDs (Indomethacin)
Secondary Headaches
• Low threshold for imaging (and Neuro consult)
– “CT of head is like CXR of the CNS”
• DDX: AVM, TIA/Stroke, dissection, vasculitis, Venous
thrombosis, tumor, seizure, acute HTN, pituitary apoplexy,
acute HC, infection.
• CT less sensitive for posterior fossa lesions and may miss up
to 10% of SAH.
• +/- MRI is less emergent situations
• MRI for significant change in pattern and for focal neurologic
sx/sx.
• If SAH suspected and CT negative >>> LP
– R/o mass lesion or obstructive HC prior to LP
– Get Opening pressure along with labs
• LP if fever, seizures, meningeal signs with headache.
Exam!
Giant Cell Arteritis
(temporal arteritis)
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Patients >50
Progressive worsening of headaches often with swollen tender scalp vasculature
Jaw claudication
Polymyalgia rheumatica
Visual blurring
Amaurosis fugax
Systemic disease affecting medium and large arteries. Predilection for cranial arteries
ESR elevated in >95% (above 50, usually 80 -100)
CRP
Rx with 60mg/d prednisone to prevent visual loss from AAION (inflamation of short
posterior ciliary arteries) AAION = Arteritic Anterior Ischemic Optic Neuropathy.
Ophthalmology eval for Temporal Artery Bx
May need to Bx both sides
High-dose Steroids indicated for Dx
Long term (1 -2+ years) steroid Rx may be needed if Dx proved by Bx
Monitor response to Rx by Sx and ESR
Blindness possible if not treated
GCA
Idiopathic Intracranial Hypertension
(Pseudotumor Cerebri)
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Increased intracranial pressure without evidence of intracranial disease.
R/o mass lesions, hydrocephalus, Venous sinus thrombosis.
Pathophysiology: ?decreased CSF reabsorption. (narrowed cerebral venous
drainage pathways.
Mostly in obese women of childbearing age.
Also a/w Tetracycline Rx, OCPs, and hypervitaminosis A
Daily non-throbbing headache worsens with cough/sneeze or lying down.
+/- diplopia, TVOs, pulsative tinnitus
Papilledema, enlarge blind spot or VF changes, +/- sixth nerve palsy.
Maybe get Optic nerve damage with visual loss.
Eval: MRI with MRV, LP with OP and labs.
Rx: weight loss. Diamox (carbonic anhydrase inhibitor) reduces CSF
production
Optic nerve sheath fenestration. Consider CSF shunting (second choice).
Ophthalmology follow-up to monitor vision.
PTC
MRV
Normal CSF flow
Chiari Malformation
Chiari
Syringomyelia
Trigeminal Neuralgia
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Paroxysms of pain in one or more divisions of CN V
Sharp, stabbing pains lasting seconds to a few minutes
Touching face can trigger pain
Exam typically normal. If sensory loss, this suggests secondary
cause
• Get MRI to exclude secondary cause in everyone
• Etiology sometimes compression by vascular loop.
• RX: AEDs +/- Baclofen
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Tegretol
Neurontin
Trileptal
Others
• Microvascular decompression in some patients,
– or Gamma-knife radiotherapy – directed at the trigeminal ganglion >>>
sensory loss, dry eye, anesthesia dolorosa
Trigeminal Neuralgia
Carotid Dissection
• May follow head or neck trauma, but may
be spontaneous
• Ipsilateral head, neck, or eye pain
– Sudden or gradual onset
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Possible Horner’s syndrome
+/- contralateral weakness or numbness
+/- ipsilateral visual symptoms
MRA, carotid duplex
Guess what’s next?
Movement Disorders
• Hypokinetic (too little movement)
– Ex) Parkinson’s Disease, Parkinsonian
Syndromes
• Hyperkinetic (too much movement)
– Ex) Chorea, Dystonia, Essential Tremor
Parkinsonism Syndromes
• Primary Parkinsism
– Idiopathic Parkinson’s Disease
– Juvenile parkinsonism
• Secondary Parkinsonism
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Medication induced
Hydrocephalus
Infectious
Metabolic – Calcium, parathyroid, Copper
Neoplastic
Toxin induced
Traumatic
Vascular
Psychogenic
Medication induced Parkinsonism
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Antipsychotics
Antiemetics
Tetrabenazine
Reserpins
Allpha-methydopa
Calcium Channel Blockers
Lithium
Infectious causes of Parkinsonism
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Lethargic encephalitis
AIDS
Fungal
Syphilis
SSPE
Spongiform Encephalopathy
Toxin induced Parkinsonism
• MPTP
– 1-methyl-4-phenyl-1,2,3,6-tetrapyridine
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CO
Manganese
CN
Carbon disulfide
Mercury
MeOH
EtOH
Basic idea of PD Rx
Parkinsonism-Plus Syndromes
• Corticobasal Ganglionic Degeneration
• Dementia Syndromes
– AD
– Dementia with Lewy Bodies
– Frontotemporal Degeneration
• Multisystem Atrophy
– Olivopontocerebellar Degeneration (OPCA)
– Shy-Drager Syndrome
• Progressive Supranuclear Palsy (PSP)
Hereditary and Degenerative
Parkinsonism
• Familial basal ganglionic degeneration
• FTD with parkinsonism
– Linked to chormosome 17
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Huntington’s Disease
Wilson’s Disease
Fragile X premutation carriers
Other rare disorders
Patho-physiology of PD
Loss of cells in Substantia Nigra
Lewy Bodies
Parkinson’s Disease
• James Parkinson, 1817 essay on the
“shaking palsy”. Charcot coined the term
“Parkinson’s Disease”.
Multiple Sclerosis
Multiple Sclerosis
• Most common cause of non-traumatic
neurologic disability in young adults
• Signs/Symptoms
• Diagnosis
• Course
• DDX
– Cervical spondylosis, myelopathies, DM,
neurosarcoid, SLE, Sjogren’s, Vit B12 deficiency
• NMO
MS cont’d
• Rx exacerbations
• Disease modifying Therapies
– Interferons
– Glatiramer
– Natalizumab (blocks migration of
inflammatory cells, a/w PML
– Mitoxantrone
– Other immunosuppressants
• Symptomatic Rx
MS keypoints
• On MRI, the presence of ovoid lesions perpendicular to the lateral
ventricles and corpus callosum are characteristic of MS
• Management of leg spaciticity a/w MS should involve PT for
stretching and pharmacologic Rx
• The decision to treat an exacerbation of neurologic deficit with
corticosteroids is determined by whether the patient’s function is
affected
• Plasma exchange may benefit patients with severe exacerbations of
MS that are refractory to steroids
• PT, OT, ST may be appropriate after severe MS exacerbations
• There is no therapy that convincingly slows degenerative processes
in MS or definitively provides neuroprotection.
• Treatment of primary progressive MS is limited to symptomatic Rx
Peripheral Neuropathies
Peripheral Neuropathies
• Recent advance: Muscle-specific Kinase
antibodies in Myasthenia Gravis
• Axonal vs Demyelinating
• Acquired vs hereditary
– Charcot-Marie-Tooth disease is most
common hereditary neuropathy
• Toxins
Neuropathies a/w pain
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Cryptogenic Sensorimotor neuropathy
Diabetic Neuropathy
Vasculitis
GBS
Radiculopathy/plexopathy
Alcoholic neuropathy
HIV sensorimotor Neuropathy
Syphilis
Heavy Metal toxicity
Amyloidosis
Fabry’s disease
Hereditary sensory/autonomic neuropathy
Peripheral Neuropathy eval
• Standard:
– CBC, Chemistries, SPEP/IFE, B12, glucose assessment, RPR, TFTs
• Optional:
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HIV, ESR, ANA, RF, SS-A, SS-B
Anti-Hu
Genetic studies
Lyme titre
Heavy metals – 24 hour urine
Phytanic acid
• LP if suspecting CIDP or AIDP
• NCVs
• Sensory nerve Bx
– If vasculitis suspected
Symptomatic Rx of Neuropathic
pain
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TCAs
AEDs
Lidocaine Patch
Capsaicin cream
Acupuncture
Transcutaneous nerve Stim
Tramadol
Guillain-Barre
• Rapidily progressive, immune-mediated demyelinating
polyneuropathy
• Up to 75% a/w preceding infection, immunization, or
surgical procedure
– EBV, CMV, Campylobacter, Lyme, Hepatitis, HIV
• Weakness, pain, paresthesias, autonomic symptoms,
facial weakness, ophthalmoparesis, respiratory failure
(25%)
• 2 – 4 weeks
• Respiratory monitoring – FVCs etc
• EMG
• Rx: IVIG or Plasmapheresis
Polyneuropathy keypoints
• Asymmetric involvement should raise suspicion for MND,
radiculopathies, plexopathies, compressive neuropathies, or
mononeuritis multiplex
• Viral illness, immunization, or surgery may precede GBS
• DDX of neuropathy with Mental Status change should include B12,
thiamine, or niacin deficiency
• Immunosuppresive Rx indicated for CIDP
• NCV may be helpful to determine Axonoal vs demyelinating process
• Treatment of idiopathic polyneuropathy generally limited to pain Rx
• Hospitalize and do frequent respiratory monitoring for suspected
GBS
• Rx with IVIG or plasmapheresis GBS patients who are unable to
ambulate independently and have impaired respiratory functions or
rapidly progressive weakness
• Oral immunosuppressive rx for CIDP; IVIG or plasmapheresis
indicated for severe or refractory CIDP
Amyotrophic Lateral Sclerosis
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ALS – both UMN and LMN
Primary Lateral Sclerosis – UMN
Primary Bulbar palsy – Brain stem
Progressive muscular Atrophy – LMN
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~2/100,000 incidence.
Slight male predominance
95% sporadic
Mean survival 2 – 5yrs
Rx of ALS
• Riluzole is approved for ALS (very modest
effect)
• PEG
• Noninvasive PP ventilation with Bilevel
positive airway pressure may prolong
survival and improve quality of life
• Symtomatic Rx for spasticity, emotional
lability, muscle cramping, and drooling
may maintain dignity and quality of life
Myasthenia Gravis
• Antibodies against the AChR
• Characterized by fatigable weakness
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Ocular with diplopis, ptosis
Bulbar with dysarthria, dysphagia
Proximal extremity
Neck with head drop
Respiratory with dyspnea
• Dx: repetitive Nerve Stim, Tensilon (not
availbable) or SF-EMG may help
• Rx: Mestinon, immune Rx
– May initially get worse on Prednisone
Medications to avoid in MG
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Calcium channel blockers
Beta-blockers
Quinine
Quinidine
Procainamide
Lidocaine
Aminoglycosides
Polymyxin
Morphine
Barbiturates
Neuromuscular blocking agents
Magnesium
MG keypoints
• There is an increased incidence of thymic
abnormalities and thyroid disease in patients
with MG
• 85% of patients with generalized MG are AChR
antibody positive
• Mild cases may be treated with
acetylcholinesterase therapy (pyridostigmine
60mg tid or qid), whereas worse presentations
may benefit from immunosuppresive Rx
• IVIG or Plasmapheresis may help severe
weakness
Muscle Diseases
Neuro-oncology
Epilepsy
Epilepsy
Seizure or Syncope?
Pre-ictal features
• Seizure
– Warning: may be preceded by
aura
• Aura is actually part of
seizure (Simple Partial)
– Provocation: Alcohol or
medication withdrawal, CNS
infections, Trauma
– Appearance: no change; may
be staring
– Posture: Any
– Onset: Sudden
• Syncope
– Warning: lightheadness,
feeling of faintness or “doom”.
– Provocation: Change of
posture, pain, dehydration,
anxiety, cough, micturition, etc
– Appearance: Pale, ashen,
sweating
– Posture: Usually upright, may
be sitting
– Onset: Gradual
Ictal features
• Seizure
• Syncope
– Duration: Seconds to
minutes
– Duration: Seconds
– Incontinence: May be
present
– Incontinence: None
– Injuries: More Common
– Tonic/clonic movements:
Generalized or focal
– Autonomic features:
Tachycardia, increased
blood pressure
– Injuries: Infrequent
– Tonic/clonic movements:
Rare, usually bilateral
– Autonomic features:
Bradycardia, Low BP,
Dilated pupils
Post-ictal Features
• Seizure
– Confusion/Disorientation:
Present for several minutes
– Speech: May be garbled
– Pain/muscle soreness:
Present after a generalized
tonic-clonic seizure
– Focal transient
neurologic deficits: May
be present
• Syncope
– Confusion/Disorientation:
Usually rapid return to
baseline
– Speech: Normal
– Pain/muscle soreness:
Absent
– Focal transient
neurologic deficits: None
Stroke
• Sudden focal neurologic deficit caused by ischemia (80% - 85%) or
Hemorrhage (15% -20%).
• TIA = sudden ischemic focal neurologic deficit that resolves
completely. 24 hours is current definition. (Good cause for 1 hour as
cutoff.)
• Hemorrhagic Stokes: SAH (5% total) or intraparenchymal (10% 15%)
• Leading cause of disability in US
• Third leading cause of death in US
• Incidence: 700,000+ per year. 20% recurrent
• Risk increases exponentially with age.
• Racial differences: higher in AA
• Cost >$50,000,000,000 per year. About 50% hospital costs. Rehab
and long term care account for most of the rest.
• Costs of lost productivity not accounted for.
Pathophysiology
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Large vessel occlusions
– MCA: contralateral hemiparesis or hemisensory loss, visual field loss
– Left: aphasia
– Right: hemineglect
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Deep penetrating vessel occlusions
Lacunar syndromes
– Pure motor hemiparesis
• Internal Capsule, Corona radiata, or basis pontis
– Pure sensory syndrome
• VPL nucleus of Thalamus
– Clumsy hand – dysarthria syndrome
• basis pontis
– Ataxic hemiparesis
• Posterior limb of the internal capsule, basis pontis
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Spinal cord strokes can occur but rare
Ischemia and Hemorrhage may be indentical clinically
Clues for Hemorrhage: headache, n/v, Severe HTN
Artherosclerotic lesions
Cerebro-vascular Territories and
Syndromes
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Anterior Cerebral Artery
– Contralateral leg weakness
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Middle Cerebral Artery
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Contralateral face/arm >leg weakness
Hemisensory Loss
Visual Field cut
Aphasia/Neglect
Posterior Cerebral Artery
– Contralateral Visual Field Cut
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Deep or “Lacunar”
– Contralateral Motor or sensory loss with “cortical signs”
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Basilar Artery
– Occulomotor deficits +/- ataxia with crossed motor/sensory deficits
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Vertebral Artery
– Lower CN deficits +/- ataxia with Crossed sensory signs
– Ex) Wallenberg Syndrome
Blood supply to base of brain
Emergency Stroke Evaluation
• Stroke is time-critical medical emergency
• Area of infarct – minutes to hours of
ischemia leads to irreversible infarct
• Ischemic penumbra – area that could
infarct if perfusion not restored quickly.
• Most damage in first 3 – 6 hours
• Penumbra is Target of Rx
Stroke Mimics
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Seizure with Todd’s Paresis
Intracranial mass
Migraine
Meningitis/encephalitis
Drug OD
Hyper or hypoglycemia
Unmasking of prior deficits due to acute illness
Cervical or head trauma
Post cardiac arrest ischemia
Hypertensive encephalopathy
Psychogenic
Emergent Eval and Rx
• Sudden neurologic dysfunction over minutes to hours
probably = stroke
• Stroke mimics
• Quick eval – NIH stroke scale
– GCS not very useful for stroke
• Full Neuro exam later
• With TIA, risk for stroke increased with
– TIA >10 minutes, limb weakness, speech disturbance, >60 yo,
DM
• Hospitalize TIAs – risk highest in first few days after TIA
for major vascular event
• Neuro-immaging: ischemic vs Hemorrhage vs ?
Emergent CT scan
NIH Stroke Scale
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LOC: (alert to coma)
LOC questions: month and age
LOC commands: close eyes, make fist
Best Gaze
Visual Fields
Facial palsy
Left Arm
Right Arm
Left Leg
Right Leg
Limb ataxia
Sensation to Pin
Best Language
Dysarthria
Extinction
Neuroimaging in acute Stroke
• Noncon CT first study – r/o hemorrhage
– Relatively insensitive to acute stroke in first few hours
– Subtle findings: Hyperdense vessels, loss of grey-white boundaries,
effacement of sulci. These findings are highly specific
– Noncon CT: ~100% sensitive for intraparenchymal hemorrhage; ~90%
for SAH.
– Xenon inhalation - map of cerebral blood flow – not widely available.
• MRI: More expensive, time consuming, less available; therefore not
the standard of care.
– DWI: sensitive to early cytotoxic edema. May slightly overestimate area
of infarction. Apparent Diffusion Coefficient (ADC) may be more
accurate.
– PWI: area of decreased perfusion
– PWI – DWI = ischemic penumbra area
– Spectroscopy: biochemical marker identification.
• Vessel imaging: Conventional angiogram, CTA, MRA, Transcranial
Doppler. (This info usually not critical for initial treatment decisions.
Neuro-imaging
Cerebral Angiogram
Acute Stroke Therapy
• IV t-PA (recombinant tissue plasminogen
activator) is effective for acute ischemic stroke if
given within 3 hours of onset, better if given
earlier.
• Rigorous selection of right patients necessary to
maximize efficacy and minimize risk.
• Knowing time of onset is crucial.
– Awaken with stroke – time last seen normal = onset
– Aphasic with no witness – onset time not known;
therefore contraindicated.
BP management in Acute Stroke
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BP may be up to maintain perfusion
Elevated BP increases risk of hemorrhage after t-PA.
BP should be under 185/110 for t-PA
Use Nitro paste or Labetalol acutely to get BP down if
necessary
• Maintain BP below 185/105 after Rx with nicardipine,
labetalol, or nitroprusside.
• t-PA dose is 0.9mg/kg to max of 90mg. 10% as one
minute bolus, other 90% infused over an hour.
• No antiplatelet Rx for 24 hours.
rt-PA
t-PA eligibility criteria
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Inclusion Criteria
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Exclusion Criteria – Historical
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Rapidly improving stroke symptoms
Seizure at onset
Symptoms suggestive of SAH
Persistent BP > 185/110 or aggressive rx needed to control BP
Acute/subacute MI or pericarditis
Exclusion Criteria – Radiographic
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Stroke or head trauma within 3 months
History of intracranial Hemorrhage
GI or GU bleeding in previous 21 days
Major surgery or trauma within previous 14 days
Arterial puncture at noncompressible site or LP in previous 21 days
Pregnant or lactating
Exclusion Criteria – Clinical
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Age >18
Clinical Dx of ischemic Stroke
Onset within 3 hours of Treatment
CT without hemorrhage
CT evidence of hemorrhage
CT sings of major early infarct *controversial
Exclusion Criteria – Laboratory
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Glucose <50 or >400 mg/dl
Platelet count <100,000
If on warfarin and PT >15secs
If on Heparin with 48 hours and PTT elevated
If worsening while on t-PA
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Stop infusion
Stat CT
Platelet count – treat if low
PT/PTT/fibrogen – Rx with cryoprecipitate
if necessary
• Neurosurgery consult
Effectiveness of t-PA
• Nearly doubles the odds of recovery to
independent function at 3 months: 47% vs
27%.
• Symptomatic intracranial Hemorrhage risk
is 6.4%
• No impact on mortality after stroke.
Antiplatelet therapy