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Neurology Update for 2013
Vanja Douglas, MDSara & Evan Williams Foundation Endowed
Neurohospitalist ChairUCSF Department of Neurology
Neurohospitalist Division
Disclosures
2012: Received an honorarium for speaking about neurohospitalists for Grifols, Inc. (manufacturers of IVIG)
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Learning Objectives
• Describe how to work up and treat dementia
• Understand effective delirium prevention and treatment measures
• List the new oral treatments for multiple sclerosis
• Initiate treatment of Parkinson disease
• Know several new options for prevention of migraine headache
Case 1
• A 74 y/o man is brought to you by his son because of concerns about his memory. He occasionally forgets the names of his grandchildren and will often forget to buy all the items he intended to at the grocery store. He still performs all his ADLs and balances his own checkbook.
• His mini mental status exam score is 27/30, with 2 points off for recall and one off for orientation.
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Question 1: What is the most likely diagnosis?
1. Frontotemporal dementia
2. Alzheimer dementia
3. Vascular dementia
4. Mild cognitive impairment
5. Dementia with Lewy Bodies
Mild Cognitive Impairment
• Concern regarding a change in cognition
• Impairment in one or more cognitive domains
– Objective impairment on bedside testing
• Preservation of independence in functional abilities
• Not demented
– No significant impairment in social or occupational functioning
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Dementia: Differential Diagnosis
Alzheimer’s Disease
Hippocampus
and posterior parietal
Amyloid plaques,
tau tangles
Memory loss
FrontotemporalDementia (FTD)
Frontal and temporal lobes
Tau inclusions
TDP‐43
Apathy, behavior, anxiety
Dementia with Lewy Bodies (DLB)
Brainstem Alpha‐synuclein Hallucinations, parkinsonism
Vascular Dementia
Diffuse or focal Gliosis Executive slowing
Name Anatomy Pathology First Symptoms
Alzheimer Disease Staging
Braak and Braak, Acta Neuropathol 1991
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Dementia: Reversible Causes
• Depression
• B12 deficiency
• Hypothyroidism
• Structural disorders (subdural hematoma, hydrocephalus, slowly growing brain tumor)
• Syphilis
• HIV
• Delirium masquerading as dementia (liver disease, uremia, hypoparathyroidism)
Alzheimer Disease Treatment
Rogers et al., Neurology 1998
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Alzheimer Disease Treatment
• Cholinesterase inhibitors (donepezil, rivas gmine, galantamine) → Mild to moderate dementia (MMSE score 10 – 26)– Diarrhea, nausea and vomiting, bradycardia, syncope, and heart block
• Memantine→ Moderate to advanced dementia (MMSE score 3‐14)– Some studies show benefit with combination therapy
Tariot et al., JAMA 2004
Delirium
• You are called to the hospital because your 74 year‐old patient with MCI has been admitted with pneumonia.
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Question 2: Which of the following is NOT an evidence‐based method to prevent his developing delirium in the
hospital?
1. Early ambulation and bed exercises
2. Oral rehydration
3. Frequent re‐orientation
4. Low‐dose haloperidol at bedtime
5. Avoiding naps and schedule adjustments to allow sleep at night
6. Portable amplifying devices and visual adaptive equipment
Model of Delirium
Risk Factors
Specific Insults
Delirium
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Risk Factors
• Age
• Pre‐existing cognitive dysfunction
• Functional impairment– Mobility, vision, hearing
• Malnutrition/dehydration
• Severe illness
• Depression
• Alcohol abuse
Images from Wikimedia Commons
Iatrogenic Precipitants
• Medications (3 or more)
• Sleep deprivation
• Restraints
• Urinary catheters
• Frequent procedures
• Surgery (thoracic, vascular, and hip)
• Untreated pain
Images from Wikimedia Commons
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Prevention: Non‐pharmacologicRisk factor for delirium Targeted intervention
Cognitive Impairment Board with names of care team members and day’s schedule
Frequent reorientation
Sleep Deprivation Bedtime routine, avoid napsUnit‐wide noise‐reduction strategiesSchedule adjustments to allow sleep
Immobility Early ambulation, bed exercisesMinimal use of catheters and restraints
Vision impairment < 20/70 Use of visual aidsAdaptive equipment
Hearing impairment Portable amplifying devicesEarwax disimpaction
Dehydration (BUN/Cr ratio >18) Oral rehydration
Inouye et al, NEJM 1999
Prevention: Non‐pharmacologicRisk factor for delirium Targeted intervention
Cognitive Impairment Board with names of care team members and day’s schedule
Frequent reorientation
Sleep Deprivation Bedtime routine, avoid napsUnit‐wide noise‐reduction strategiesSchedule adjustments to allow sleep
Immobility Early ambulation, bed exercisesMinimal use of catheters and restraints
Vision impairment < 20/70 Use of visual aidsAdaptive equipment
Hearing impairment Portable amplifying devicesEarwax disimpaction
Dehydration (BUN/Cr ratio >18) Oral rehydration
Inouye et al, NEJM 1999
• Reduced delirium incidence from 15% to 9.9% (p = 0.02)
• NNT = 20
• Total delirium days 105 vs. 161 (p = 0.02)
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Treatment
• Treat the underlying cause
• Remove unnecessary medications
• Remove bladder catheters
• Early mobilization
• Normalize sleep‐wake cycles
• Sitters instead of restraints
• Sedation should be used only when the patient poses a danger to him/herself or staff
Pharmacologic TreatmentMedication Initial Dosage Comments
Haloperidol 0.5 mg to 1 mg BID One placebo‐controlled RCT
Risperidone 0.5 mg BID Equivalent to haloperidol in one RCT
Olanzapine 1.25 mg to 2.5 mg daily
Better than placebo and equivalent to haloperidol in one RCT
Quetiapine 25 mg BID Better than placebo in the ICU in one RCT
Lonergan et al, Cochrane Database Syst Rev 2007
• Off label• Black box warning: increased risk of sudden death in dementia patients
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Case 2
• A 33 year‐old woman comes to see you because of two weeks of left arm and leg numbness and tingling. The symptoms came on gradually over 2 days and have been stable since. She kept putting off coming to the doctor thinking she just slept on her left side awkwardly.
• Her exam shows decreased sensation in the left arm and leg and slow finger and foot taps on that side.
Question 3: What is the most appropriate next diagnostic step?
1. Bilateral carotid ultrasound
2. MRI of the brain
3. Non‐contrast CT of the brain
4. MRI of the brain and cervical spine
5. MRI of the cervical spine
6. Lumbar puncture
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Multiple Sclerosis: Workup
• MRI is the cornerstone of diagnosis
• Lumbar puncture is helpful but not always necessary if MRI is typical
• Labs: RPR/FTA‐abs, ANA, SSA/SSB, B12
• Consider: HIV, Lyme, antiphospholipidantibodies, RF, aquaporin‐4 antibodies, chest X‐ray
Multiple Sclerosis MRI
Axial T2: Cerebellar lesions Saggital T2: Spinal cord lesion
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Multiple Sclerosis MRI
Saggital FLAIR: Dawson’s fingers Axial T1 post‐gad: optic neuritis
Multiple Sclerosis: Diagnostic Criteria
Clinical Presentation Additional Data Needed for MS Diagnosis*
2 or more clinical attacks2 or more objective lesions
none
2 or more clinical attacks1 objective lesion
Dissemination in space by MRIAdditional clinical attack
1 clinical attack1 objective lesion
Dissemination in time by MRINew lesions on later MRISecond clinical attack
Insidious progression from onset 1 year of progressionDissemination in space by MRI
Polman et al, Ann Neurol 2011
*No alternative diagnosis more likely
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MS: Natural History
• Relapsing‐remitting MS
– On average, one attack every 9 months
– After 15 years, 80% have functional limitation and 30‐50% have SPMS and require assistance walking
– After 25 years, 80% will require assistance walking
Multiple Sclerosis: Treatment
0
0.2
0.4
0.6
0.8
1
1.2
1.4
InterferonBeta‐1b
InterferonBeta‐1a
Glatiramer Natalizumab
Drug
Placebo
p<0.005 p<0.005 p=0.012 p<0.005
Neurology 1993; Lancet 1998; Comi et al, Ann Neurol 2001; Polman et al, NEJM 2006
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Multiple Sclerosis: Oral Treatment
0
0.1
0.2
0.3
0.4
0.5
0.6
Fingolimod vInterferon
Teriflunomide vPlacebo
Fumarate vGlatiramer
Drug
Control
p<0.01 p<0.05p<0.001
Cohen et al, NEJM 2010; O’Connor et al, NEJM 2011; Fox et al, NEJM 2012
A Comparison of MS Drugs
Drug Route of Administration
Effect on Relapses
Adverse Events
Interferon beta IM or Sub‐Q Reduce by 1/3 DepressionFlu‐like symptoms
Glatiramer acetate Sub‐Q Reduce by 1/3 Injection site reactions
Natalizumab Monthly IV Reduce by 2/3 PML
Fingolimod Oral Reduce by 1/2 Symptomatic bradycardiaMacular edemaDisseminated VZV
Teriflunomide Oral Reduce by 1/3 Alopecia, NauseaNeutropeniaTransaminitis
Dimethyl Fumarate Oral Reduce by 1/2 FlushingAbdominal discomfortDiarrheaLymphopenia, transaminitis
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Case 2
• Six months later your patient presents to the ED with left arm and leg numbness and mild weakness. She is afraid she is having a relapse of her multiple sclerosis and requests a course of steroids.
Question 4: Which of the following is the most appropriate next step?
1. Prescribe a one‐week course of oral steroids
2. Give three days of high dose IV steroids
3. Perform a thorough review of systems and check a urinalysis
4. Prescribe three days of high dose oral steroids
5. Make sure he is taking his interferon and has follow up with his neurologist
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MS: pearls for the primary care provider
• Treatment of exacerbations with steroids only speeds the pace of recovery but does not enhance the ultimate degree of recovery
• Pseudo‐exacerbations are a recapitulation of the symptoms of a prior attack
• Pseudo‐exacerbations can be caused by heat, stress, systemic illness or infection
• Pseudo‐exacerbations should not be treated with steroids
Case 3
• A 65 year‐old man comes to your clinic complaining of a tremor. It bothers him the most when he is sitting in business meetings. He also notes that he can’t keep up with his grandkids like he used to. His exam shows a rest tremor on the right, with cogwheelingrigidity in the right arm, and a slightly shuffling gait.
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Question 5: Which of the following exposures is LEAST important to ask about in this patient?
1. Metoclopramide
2. Prochlorperazine (compazine)
3. Promethazine (phenergan)
4. Risperidone or other second generation antipsychotics
5. Head trauma
6. Marijuana
Parkinson Disease
• Four cardinal signs– Bradykinesia, rigidity, resting tremor, postural instability
• Differential diagnosis
– Secondary parkinsonism (e.g., medications, trauma)
– Other neurodegenerative diseases
– Structural lesions uncommon
• Brain imaging not necessary for diagnosis
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Question 6: With what medication would you initiate treatment?
1. Levodopa/carbidopa
2. Propranolol
3. Pramipexole
4. Gabapentin
5. Rasagiline
6. Entacapone
PD: Treatment
• L‐dopa vs. dopamine agonists:
– Well known that the longer one is exposed to L‐dopa, the higher the risk of motor complications (dyskinesias, wearing off, on‐off fluctuations, freezing)
– Often dopamine agonists are used first in order to delay the use of L‐dopa
Image from Wikipedia Commons
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Levodopa vs. Dopamine agonists
Years of follow‐up
Pramipexole Levodopa p
UPDRS (mean changefrom baseline)
2 ‐4.5 ‐9.2 <0.001
4 3.2 ‐2.0 0.003
6 2.4 0.5 0.11
First dopaminergicmotor complication
2 28% 51% <0.001
4 52% 74% <0.001
6 50% 78% 0.002
Quality of Life scores (mean change from baseline)
2 1 ‐1 0.006
4 ~4 ~4 NS
6 7.1 8.6 0.90
Parkinson Study Group, JAMA 2000, Arch Neurol 2004 and 2009
MAO‐B Inhibitors: Neuroprotective?
• Early vs. Delayed start rasagiline:
ADAGIO, NEJM 2009
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Treatment Options in PD
Image from Wikipedia Commons
Dopamine agonistsLevo‐DOPA 3‐MT
COMT Inhibitors(e.g. entacapone)
MAO‐B Inhibitors(e.g. rasagiline)
Other mechanisms:*Amantadine*Anticholinergics
PD: Treatment
• Starting levodopa:– Combine with carbidopa to prevent conversion to dopamine outside of the CNS
– Need at least 75 mg of carbidopa per day (e.g. Sinemet 25/100 TID)
– Can prescribe extra carbidopa
• Titrate up to 3 tablets TID before calling a patient unresponsive
• Taken on empty stomach
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PD: Treatment
• Carbidopa/Levodopa– Avoid use of CR formulation except at bedtime
• Dopamine agonists– Use with caution in the elderly (>70 years old):
• Daytime somnolence
• Hallucinations
• Obsessive behaviors (pathologic gambling)
– Use ropinerole or pramipexole; older ergot derived agonists such as pergolide can lead to cardiac valve fibrosis
PD: When to Refer
• To confirm or reconsider diagnosis:
– Patient not responding to L‐DOPA or agonist
– Rapid progression
• Significant off periods requiring more than TID dosing of L‐DOPA
• Significant dyskinesias or other dose‐limiting side effects of L‐DOPA
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Bonus Case
• A 34 year‐old woman has a 5‐year history of headache. The headaches occur 4 times per month and are severe. They are throbbing, usually bitemporal, often associated with vomiting, and force her to lie in a dark room for 2‐3 days. They are triggered by business travel.
Question 7: Which of the following medications has the LEAST evidence supporting its use for
migraine prevention?
1. Propranolol
2. Atenolol
3. Verapamil
4. Topiramate
5. Gabapentin
6. Petasites (butterbur)
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Migraine Therapy: Prophylaxis
• Consider when >3 headaches/month
• Anti‐epileptics
– Valproic acid, topiramate
• Beta blockers
– Propranolol, metoprolol, timolol, atenolol, nadolol
• Antidepressants
– Amitriptyline, venlafaxine
Silberstein et al, Neurology 2012
Migraine Therapy: Alternatives
• Level A evidence:
– Petasites (butterbur): 50‐75 mg BID
• Level B evidence:
– Magnesium
– MIG‐99 (feverfew)
– Riboflavin
Holland et al, Neurology 2012
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Migraine Therapy: Abortive
• Acetaminophen, NSAIDs, ASA, or Excedrin
• Triptans
• Antiemetics: metoclopramide, prochlorperazine, chlorpromazine
• Ergots: cafergot, dihydroergotamine
• Acetaminophen/butalbital/caffeine (Fioricet)
• Acetaminophen/dichloralphenazone/ isometheptene (Midrin)
Silberstein et al, Neurology 2000
Chronic Migraine and Medication Overuse Headache
• At least 15 headache days per month
• Medication overuse: regular overuse (>2
days/week) of a migraine abortive for >3 months
• Therapy:
– Chronic migraine: botulinum toxin
– Medication overuse: stop all analgesics
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Botulinum Toxin
Episodic migraine
Chronic migraine
Probability of >50% reduction in headache days
Jackson et al, JAMA 2012
Summary
• Dementia
• Delirium
• Multiple Sclerosis
• Parkinson Disease
• Migraine Headache