Neurology Update for 2013 Disclosures · 6/27/2013 1 Neurology Update for 2013 Vanja Douglas, MD UCSF Department of Neurology Neurohospitalist Division ... MRI of the brain and cervical

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Neurology Update for 2013

Vanja Douglas, MDUCSF Department of Neurology

Neurohospitalist Division

Disclosures

2012: Received an honorarium for speaking about neurohospitalists for Grifols, Inc. (manufacturers of IVIG)

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?

F r on t o

t e mp o r

a l . . . A l z

h e i me r d

e m e. . .

V a sc u l a

r d em e n

. . . M i

l d co g n

i t i ve . . .

D em e n

t i a wi t h

. . .

0%4%

9%

78%

9%

1. Frontotemporal dementia2. Alzheimer dementia3. Vascular dementia4. Mild cognitive impairment5. 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

Dementia: Differential DiagnosisAlzheimer’s Disease

Hippocampusand posterior parietal

Amyloid plaques, tau tangles

Memory loss

FrontotemporalDementia (FTD)

Frontal and temporal lobes

Tau inclusionsTDP-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 SymptomsAlzheimer 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

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?

E a rl y a

m bu l a t

i . . . O r a

l r eh y d

r a t i. . .

F r eq u e

n t re - o

r . . . L o w

- d os e h

a l o p. . .

A vo i d

i n g n a p

s . . . P o

r t a bl e a

m pl i . . .

3% 6% 3%0%

84%

3%

1. Early ambulation and bed exercises2. Oral rehydration3. Frequent re-orientation 4. Low-dose haloperidol at bedtime5. Avoiding naps and schedule

adjustments to allow sleep at night6. Portable amplifying devices and visual

adaptive equipment

Model of Delirium

Risk Factors

Specific Insults

Delirium

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 interventionCognitive Impairment Board with names of care team members and

day’s scheduleFrequent 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 interventionCognitive Impairment Board with names of care team members and

day’s scheduleFrequent 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)

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 CommentsHaloperidol 0.5 mg to 1 mg BID One placebo-controlled

RCTRisperidone 0.5 mg BID Equivalent to haloperidol

in one RCTOlanzapine 1.25 mg to 2.5 mg

dailyBetter 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?

B i l at e r a

l c ar o . .

. M R

I o f t h e

b r a. . .

N on - c o

n t r as t C

. . . M R

I o f t h e

b r a. . .

M RI o f

t h e c e r

. . . L u m

b a r p u n

c t u r. . .

0%

19%

4%4%

56%

19%

1. Bilateral carotid ultrasound2. MRI of the brain3. Non-contrast CT of the brain4. MRI of the brain and cervical spine5. MRI of the cervical spine6. Lumbar puncture

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, antiphospholipid

antibodies, 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 CriteriaClinical 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

A Comparison of MS DrugsDrug Route of

AdministrationEffect 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 reactionsNatalizumab Monthly IV Reduce by 2/3 PMLFingolimod Oral Reduce by 1/2 Symptomatic bradycardia

Macular edemaDisseminated VZV

Teriflunomide Oral Reduce by 1/3 Alopecia, NauseaNeutropeniaTransaminitis

Dimethyl Fumarate Oral Reduce by 1/2 FlushingAbdominal discomfortDiarrheaLymphopenia, transaminitis

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?

M et o c

l o pr a m

i d e P r o

c h lo r p

e r az i . . .

P r om e

t h az i n e

( . . . M a

n g an e s

e H e

a d t r a u

m a R i s

p e ri d o

n e o r . .

.

0% 0%

16%

42%42%

0%

1. Metoclopramide2. Prochlorperazine (compazine)3. Promethazine (phenergan)4. Manganese5. Head trauma6. Risperidone or other second

generation antipsychotics

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

Question 6: With what medication would you initiate treatment?

L e vo d o

p a /c a r b

i . . . P r o

p r an o l

o l P r a

m i pe x o

l e G a

b a pe n t

i n R a s

a g i li n e

E n ta c a

p o ne

72%

8%4%4%

0%

12%

1. Levodopa/carbidopa2. Propranolol3. Pramipexole4. Gabapentin5. Rasagiline6. 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 agonistsYears of follow-up

Pramipexole Levodopa p

UPDRS (mean changefrom baseline)

2 -4.5 -9.2 <0.0014 3.2 -2.0 0.0036 2.4 0.5 0.11

First dopaminergicmotor complication

2 28% 51% <0.0014 52% 74% <0.0016 50% 78% 0.002

Quality of Life scores (mean change from baseline)

2 1 -1 0.0064 ~4 ~4 NS6 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

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

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?

P r op r a

n o lo l

A t en o l

o l V e

r a pa m

i l T o p

i r a ma t e

G ab a p

e n ti n

P e ta s i t

e s (b u t

. . .

0% 0% 0%0%0%0%

1. Propranolol2. Atenolol3. Verapamil4. Topiramate5. Gabapentin6. Petasites (butterbur)

Countdown

10

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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

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