NEUROLOGIC PEARLS AND NUGGETS
From the Medical Masters Class, sponsored by the North Staffordshire (England) Postgraduate Education Association
Karl E. Misulis, MD, PhD, Clinical Professor of Neurology, Vanderbilt University School of Medicine, and Neurologist,
Semmes-Murphey Neurologic and Spine Institute, Jackson, TN
Headaches and Peripheral Neuropathy
| Migraine: differentiating—neurologic deficits key; if headache out of proportion to previous episodes or patient has had
no previous headache and older than early middle age, consider possibility that pain not migraine; migraines do not typically
start at age 60 yr; do not miss papilledema; look for meningeal inflammation; in individuals ≥50 yr of age with temporal
pain, consider temporal arteritis; acute treatment—treat early and aggressively with triptans; nonsteroidal anti-
inflammatory drug (NSAID) and triptan frequently combined (combination superior to either one alone); chronic analgesia
headaches—watch for in those taking analgesics ≥2 times/wk; rebound headaches possible with narcotic analgesics,
opiates, triptans, or NSAIDs; number one reason for referral to specialist or headache clinic; no matter which drug used
for preventive treatment, make sure adequate dose used for adequate time
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| Peripheral neuropathy: differential diagnosis—includes diabetes; screen for diabetes ≤2 yr from diagnosis; substantial
portion of idiopathic neuropathies due to genetic causes; other less common causes include toxins, ethanol, chemotherapy,
and vitamin B12 deficiency; chronic inflammatory demyelinating neuropathy (CIDP)—previously chronic
Guillain-Barré syndrome (GBS; renamed acute IDP [AIDP]); CIDP has different immunology from GBS; progressive
sensory and motor neuropathy; treated by immune-modulating therapy (eg, intravenous immunoglobulin [IVIG], steroids);
AIDP or GBS—acute sensory and motor neuropathy; loss of reflexes, with descending paralysis; treated with
IVIG or plasma exchange; HIV—produces variety of neuropathies; also leads to loss of reflexes; different from idiopathic
sensory neuropathies (affects arms and legs early and nerves of chest, nose, and face); fairly abrupt; can have GBS-
type appearance; treat early and aggressively (study showed that having peripheral neuropathic pain for >2 yr associated
with lower response to medications); treatment—most patients treated with amitriptyline (tricyclic antidepressant
[TCA]), duloxetine (serotonin-norepinephrine reuptake inhibitor [SNRI]), or gabapentin or pregabalin (anticonvulsants);
amitriptyline more potent but duloxetine has fewer side effects; duloxetine effective antidepressant but amitriptyline (at
doses used for neuropathy) has minimal antidepressant effect; if patient has severe neuropathic pain and severe depression,
duloxetine not most potent antidepressant; among anticonvulsants, gabapentin typically used first-line (due to insurance
concerns); >1800 mg/day of gabapentin provides no additional benefit (true of medications used for neuropathic
pain); antidepressant doses and doses for seizures much higher than doses for neuropathic pain; with amitriptyline, doses
>75 to 100 mg seldom needed (60 mg for duloxetine; 1800 mg for gabapentin; 300 mg [150 mg bid] for pregabalin); antidepressant
and anticonvulsant frequently combined
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Dementia, Parkinson’s Disease, and Essential Tremor
| Dementia: majority vascular dementia; distinction between vascular dementia and degenerative dementia blurred; many
patients with vascular disease also have Alzheimer’s pathology; autopsies of patients with Alzheimer’s disease (AD)
show many with vascular changes as well; Parkinson’s disease (PD) with dementia—2 categories (dementia subsequent
to PD or dementia with Lewy bodies [DLB]); pathology and treatment same; patients with prominent hallucinations who
present with DLB respond better to dementia drugs than patients with AD; patient typically presents with memory loss,
disorientation, and difficulty with task completion; look for other neurologic signs, eg, gait difficulty; treatment—
cholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine) for all stages of AD; not all indicated for all stages,
but all shown effective; in patients with mild dementia, not only do such drugs improve functioning, but they may also
slow disease progression; memantine (Namenda)—in moderate to severe dementia, typically combined with cholinesterase
inhibitor; studies show poor efficacy in mild dementia; mild cognitive impairment (MCI)—subtle cognitive difficulty
(does not meet diagnostic criteria for AD); ≈70% of those with MCI eventually develop AD; some evidence that
treatment helps to reduce development; medications cost-effective
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| Parkinson’s disease: akinetic-rigid syndromes—in PD, patient hunched over and stiff; in Steel-Richardson-Olszewski
syndrome or progressive supranuclear palsy (PSP), patient hunched back and stiff; drug-induced parkinsonism—now number
one cause of parkinsonism; in addition to neuroleptics, also seen with amiodarone and divalproex (Depakote); vascular
parkinsonism—consider when patient presents with history of stroke or corticospinal sign (eg, toe turning upward, some
clonus), despite parkinsonism; other degenerative diseases—do not respond well to medication, but if presentation similar
to PD, whether vascular or otherwise, try medication for PD; key to always consider drug-induced parkinsonism
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| Treatment: symptom-related—anticholinergic agents or dopamine agonists for tremor; in patients with dementia and
tremor, anticholinergic agents aggravate cognitive functioning; use dopamine agonist (carbidopa and levodopa [Sinemet]) in
patient with tremor; for bradykinesia and rigidity, levodopa still best; for psychosis, quetiapine (Seroquel) and clozapine (eg,
Clozaril) effective; however, due to hematologic adverse effects, clozapine almost never used; quetiapine used more frequently
than olanzapine (Zyprexa), due to near-zero incidence of extrapyramidal effects; if patient develops dementia, use
other cholinesterase inhibitor (rivastigmine [Exelon] has best data and now available as transdermal system); multiple small
doses of levodopa helpful; sustained-release formulation helpful but usually requires additional agent; characteristics—
dopamine agonists (with fluctuations) have longer duration of action (ropinirole has once-daily version); rotigotine transdermal
system (Neupro) effective long term; often, small doses of levodopa combined with dopamine agonist; catechol-O-methyltransferase
(COMT) inhibitors prolong effect of dopamine agonist (lessen peaks and troughs); managing disease
progression—with fluctuations, need to level dopaminergic activity (same with dyskinesias), since peaks and valleys result
in drug-induced dyskinesias; if possible, utilize sustained-release levodopa preparations, or lower dose and add dopamine
agonist; if unable to lower dose of levodopa, and sustained-release formulation ineffective, amantadine helpful; failure to respond
to treatment most commonly due to worsening of disease; use combined dopamine agonist and levodopa at higher
doses (if patient develops psychosis, use quetiapine to counteract)
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| Essential tremor: often misdiagnosed; frequently familial; onset at any age, with gradual worsening; action and partial
tremor (PD tremor occurs at rest and worsens with walking); no other associated neurologic deficits; occasionally essential
tremor and parkinsonism occur together (“mixed tremor”); also caused by thyroid storm and cortisol; treatment—
primidone, starting with one-half of 50-mg tablet; in most people, dose 50 mg qhs (up to 150 mg; maximum dose 250 mg
qhs); propranolol, gabapentin, and topiramate also effective
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Strokes and Seizures
| Stroke: acute neurologic deficit; clopidogrel and dipyridamole not appropriate for primary prevention, but some evidence
that clopidogrel effective for people with risk factors; aspirin—for primary prevention in patients without risk factors; if
aspirin started at too young age, more intimal bleeding because of blood pressure; aspirin more appropriate as patient
grows older and develops hypertension and dyslipidemia; high-dose dipyridamole with aspirin—treatment of choice for
patients with stroke or transient ischemic attack (TIA) with isolated cerebrovascular disease; clopidogrel (usually without
aspirin)—more effective for coronary disease in individuals with serious coronary disease who had stroke or TIA;
warfarin—used in those at high risk for cardiac emboli; some advantage in patients with patent foramen ovale, antiphospholipid
antibody syndrome (APS), carotid or vertebral artery dissection, and those with severe stenosis of intracranial artery;
statins—given in emergency department (ED); those not candidates for tissue plasminogen activator (tPA) given
aspirin and atorvastatin (Lipitor; rosuvastatin [Crestor] and simvastatin [Zocor] also used); some patients cannot be controlled
on simvastatin alone (note, patient with TIA most likely to have stroke in next 6 mo and myocardial infarction in
next 5 yr); therefore, speaker believes there will be support for combination therapy over time; atorvastatin and rosuvastatin
have anti-inflammatory properties, independent of cholesterol-lowering effects (dramatically lower likelihood of developing
stroke); starting statin immediately in ED associated with lower failure rate of stenting or carotid endarterectomy
after stroke
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| Seizures: overdiagnosed in young and underdiagnosed in elderly; in patients with typical tonic-clonic seizures, phenytoin
(Dilantin), divalproex (Depakote), and valproic acid typically used; for absence epilepsy, valproic acid useful, but usually
ethosuximide and lamotrigine used; in partial seizures, almost all new drugs used; epilepsy in pregnancy—avoid carbamazepine,
valproic acid, and phenobarbital; treatment of first seizure—American Academy of Neurology practice parameters
recommend treatment when data abnormal and suggestive of high risk for recurrence; in absence of abnormal
magnetic resonance imaging (MRI) or abnormal electroencephalography (EEG), treatment not necessary
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Multiple Sclerosis, Syncope, and Chronic Fatigue
| Multiple sclerosis (MS): multifocal changes in white matter of brain, with multifocal symptoms; in individuals <40 yr
of age with intermittent multifocal symptoms, MS more likely; in those >50 yr of age, vascular disease more likely; in
migraine, more likely to develop benign white matter changes; recent data suggest that individuals with migraine more
likely to develop strokes and to have vascular disease; treatment—for acute attacks, methylprednisolone 1 g/day IV or
orally for 3 to 5 days; recent data indicate that patients receiving pulsed steroids have less disability over time; immune-
mediating therapy with pulsed steroids useful for relapsing-remitting MS
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| Syncope: individuals with vertebrobasilar TIA can “pass out,” although other neurologic findings almost always present; seizure
can present as syncope; clonic syncope (blackout spell with twitching) overdiagnosed as seizure; most of time, twitching
associated with cerebral hypoperfusion due to spontaneous discharge of nerve cells, and not seizure activity; obtain
history and physical examination (also MRI and EEG in select patients); chronic syncope—loss of consciousness major
symptom; usually not postictal; jerking major symptom in seizure; usually series of stiffening (tonic phase), then clonic
phase; clonic phase due to inhibition of discharge; prolactin and creatine kinase (CK) elevated in chronic syncope and seizure;
in pseudoseizure, prolactin not elevated, but CK may be
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| Additional thoughts on headache: most people with chronic daily headache have history of migraine and possibly
episodic severe headache 1 to 2 times/wk; transformation gradual; if nausea, photophobia, or osmophobia present, more
likely migrainous vascular headache; usually do not have scintillating scotoma; chronic pain syndrome less likely with
classic migraine than with common migraine (ie, without aura); in those with episodic migraine headaches, scans almost
always normal, whereas those with chronic daily headaches may have, eg, hydrocephalus, brain tumor; always consider
scan in those with chronic daily headache (even if likely benign); in young women with severe daily headaches, consider
venous thrombosis; patients with pseudotumor cerebri (benign intracranial hypertension) may actually have venous
thrombosis
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More on Strokes, TIAs, and Dementia
| Acute stroke: patients presenting in ED with stroke given IV tPA if criteria met; however, most patients have had deficit too
long to be candidates, and instead given aspirin (325 mg in ED, then 81 mg daily); patients allergic or intolerant to aspirin
given clopidogrel (300 mg in ED, then 75 mg daily); statin frequently given on day 1; heparin and other antithrombotics seldom
used; low-molecular-weight heparin (eg, enoxaparin [Lovenox]) of little benefit in reducing risk for secondary strokes
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| Transient ischemic attacks: give aspirin or clopidogrel immediately, statin often on day 1, and advise patient to have
work-up within 2 days if possible; recommended that patient go to hospital so that if stroke occurs within first 48 hr (most
common), patient can be given tPA; current antithrombosis recommendations—new data show aspirin choice for primary
prevention; for secondary prevention of TIA or stroke with mainly cerebrovascular disease, give aspirin and extended-release
dipyridamole; if patient unable to take aspirin, use extended-release dipyridamole alone; for secondary
prevention in patient with prominent cardiovascular disease, choose clopidogrel, usually without aspirin (risk for bleeding
exceeds improvement in risk for rethrombosis); if patient has TIA or stroke, with high risk for cardiac emboli, warfarin
given (also use warfarin in patient at high risk for stroke due to APS or coagulopathy); in cerebral venous
thrombosis, heparin initially, then warfarin; in cerebral artery dissection or severe intracranial stenosis, warfarin often
used
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| Risk factors for stroke: past TIA or stroke increases risk for recurrence 10-fold (risk greatest within first 48 hr); patients
with diabetes have 70% increased risk for stroke; smoking increases risk 4-fold and hypertension 6-fold;
hypertension—not only increases incidence of stroke and heart attack, but also incidence of cerebral degeneration; every
10-mm Hg increase of pulse pressure increases risk for stroke by 8% (5% for systolic pressure); diabetes substantially increases
risk for vascular disease and AD; hyperlipidemia—simvastatin reduces risk for recurrent stroke by 23%; statins
reduce inflammatory markers, which can further reduce risk for stroke and degenerative dementia; other factors—
nonsmoking for 5 yr leads to 75% reduction in incidence of stroke; also reduces risk for vascular dementia and AD; significant
stress impairs ability to deal with further stressors; high intake of fish associated with lower incidence of vascular
disease; polyunsaturated fatty acids (1 g daily) lower death rate from cardiac and cerebrovascular causes comparably; vitamin
E has no effect; triptans—United Healthcare study showed that present or past use of triptans had no effect on risk
for stroke, but migraineurs (regardless of use) had 63% increase in risk for stroke; true in individuals ≥70 yr of age who
no longer had migraines; ergots—increase risk for stroke by 49%
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| Dementia: differential diagnosis includes degenerative conditions, structural causes, and nondementia; cognitive changes
associated with aging—normal; happen over time; verbal IQ increases until 70 yr of age; mild cognitive impairment—
intellectual disturbance; may require detailed psychologic testing to distinguish from cognitive changes of aging; 50% of
patients progress to dementia; medications for memory have little (if any) protective effect; Chinese study showed that increased
mental activity reduced risk for MCI and transition into dementia; depression—higher incidence of dementia seen
in those who developed depression in middle age; protocol for treating dementia—cholinesterase inhibitors for all stages
of AD; donepezil highly effective; memantine added to cholinesterase inhibitors for moderate to severe dementia; rivastigmine
transdermal system major advance (intestinal side effects); long-acting galantamine improves compliance;
prevention—reducing vascular risk factors (eg, managing hypertension and diabetes); unknown whether protective medication
helpful; even in individuals without dementia, smoking impairs cognitive functioning; obesity—when body mass index
(BMI) ≥30, relative risk for AD 3.1, and patient has 5-times higher risk for vascular dementia; exercise—reduces risk for
AD and other types of dementia; intellectual activities—reduce cognitive decline; reduced risk for dementia seen in individuals
with high interest in music, reading, meditation, and arts and crafts; supplements—possibly effective
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Suggested Reading
Becker WJ et al: Treatment of migraine: a headache for the emergency department. Neurology 69:2034, 2007; DeFaria
Yeh D et al: Preventing and treating stroke and transient ischemic attack. Am J Cardiol 101:270, 2008; Dickerson
BC et al: Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment. Arch
Gen Psychiatry 64:1443, 2007; Dickerson LM et al: Prevention of recurrent ischemic stroke. Am Fam Physician
76:382, 2007; Frohman EM et al: Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med 354:942, 2006;
Gotkine M et al: Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity. Neurology
68:1162; author reply 1162, 2007; Hill KP et al: Combination of sumatriptan and naproxen for migraine. JAMA
298:1276; author reply 1276, 2007; Jain S et al: Common misdiagnosis of a common neurological disorder: how are we
misdiagnosing essential tremor? Arch Neurol 63:1100, 2006; Reitz C et al: Hypertension and the risk of mild cognitive
impairment. Arch Neurol 64:1734, 2007; Roach ES: Early multiple sclerosis: to treat or not to treat? Arch Neurol 63:619,
2006; Rozzini L et al: Re: Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology
70:735; author reply 735, 2008; Schapira AH: Treatment options in the modern management of Parkinson disease. Arch
Neurol 64:1083, 2007; Strachan MW et al: Diabetes, cognitive impairment, and dementia. BMJ 336:6, 2008; Sudlow
C: Dipyridamole with aspirin is better than aspirin alone in preventing vascular events after ischaemic stroke or TIA. BMJ
334:901, 2007.
Educational Objectives
| The goal of this program is to improve the management of neurologic conditions. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Prescribe appropriate treatment for peripheral neuropathy.
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| 2. Review the choices of drugs for the treatment of Parkinson’s disease.
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| 3. Determine whether the first seizure should be treated.
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| 4. Recognize risk factors for stroke.
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| 5. Distinguish cognitive changes of aging from mild cognitive impairment.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, Dr. Misulis and the planning committee reported nothing to disclose.
Acknowledgments
Dr. Misulis was recorded at Medical Masters Class series of lectures, held January 29-30, 2008, in Newcastle-under-Lyme,
UK, and sponsored by the North Staffordshire Postgraduate Education Association. The Audio-Digest Foundation thanks
Dr. Misulis and the sponsor for their cooperation in the production of this program.
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