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Neurology
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Primary Headaches
Headache, neuralgia, and facial pain disorders not already mentioned
Source: Headache Classification Subcommittee of the International Headache Society. The
International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):16-22.
PMID: 14979299.
Figure 1.
Algorithmic approach to a patient with headache. CRP = C-reactive protein level; CTA = CT angiography; ESR =
erythrocyte sedimentation rate; GCA = temporal (giant cell) arteritis; IIH = idiopathic intracranial hypertension; LP
= lumbar puncture; MRA = magnetic resonance angiography; SAH = subarachnoid hemorrhage; SUNCT = shortlasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome.
Secondary Headaches
Although most of these warning signs are found in the history, a focused neurologic
examination is essential in the complete evaluation of a patient with headache. In addition to
cognitive, sensorimotor, and reflex testing, a thorough cranial nerve assessment is essential,
with examination of the optic discs, visual fields, and eye movements. Further information may
be gained by evaluating the cranium, cervical spine, carotid and temporal arteries,
temporomandibular joint, and the ears and sinuses.
Further diagnostic evaluation is required when a red flag of secondary headache is identified.
Neuroimaging is the most sensitive diagnostic tool in the assessment of this type of headache.
CT of the head is the preferred imaging modality in the settings of skull fracture, acute
subarachnoid or intracerebral hemorrhage, and paranasal sinus disease. Although CT may be
more widely available and less expensive than MRI, an MRI of the brain is more sensitive in
identifying intracranial pathology and, therefore, is the study of choice in most other clinical
settings of acute or chronic headache. Contrast administration may be helpful in settings of
malignant or inflammatory disease. The addition of CT or MR angiographic or venographic
studies may be useful when vascular pathology, such as vascular occlusion, aneurysm, or
Thunderclap Headache
Key Points
Approximately 25% of thunderclap headache presentations result from a subarachnoid
hemorrhage.
Calcium channel blockers, such as verapamil and nimodipine, are considered first-line
therapies for thunderclap headache associated with reversible cerebral vasoconstriction
syndrome.
Thunderclap headache is defined as a severe headache that reaches maximum intensity
within 60 seconds of onset. Although classically associated with SAH, thunderclap headache
also may be caused by other conditions, ranging from benign to life-threatening ones (Table
2). Because approximately 25% of thunderclap headache presentations result from an SAH,
this type of headache should be approached as a neurologic emergency, and CT of the head
without contrast should be performed without delay. CT sensitivity within the first 24 hours of
the hemorrhage is approximately 90% to 95% but decreases markedly with each successive
day. When results of CT are negative for SAH, lumbar puncture must be performed. CSF
analysis should include determination of opening pressure, protein and glucose levels,
erythrocyte and leukocyte counts (with leukocyte differential), and the presence of
spectroscopic xanthochromia; this last finding is reported to be 98% sensitive in documenting
hemorrhage within 12 hours of the event.
Vascular causes other than SAH also must be considered with the initial presentation of
thunderclap headache. Ischemic stroke, intracerebral hemorrhage, and acute venous
thrombosis all may manifest as a thunderclap headache, typically with signs of cortical or
brainstem dysfunction. Dissection of the internal carotid or vertebral arteries additionally may
present with acute headache or neck pain, which is sometimes complicated by ipsilateral
Horner syndrome or findings indicative of subsequent embolic stroke. Arterial dissections are
rarely spontaneous and often associated with cervical trauma, sometimes of a relatively minor
nature.
The term reversible cerebral vasoconstriction syndrome, previously known as Call-Fleming
syndrome, was applied in 2007 to a group of disorders characterized by recurrent thunderclap
headache associated with transient segmental cerebral vasoconstriction. The diagnostic
criteria proposed for this syndrome consist of recurrent thunderclap headache with possible
focal neurologic signs, normal or near-normal CSF, and angiographic documentation of
adequate trial of at least three drugs or drug combinations before interventional or surgical
treatment is considered.
Medical management is unsuccessful in approximately 30% of patients with trigeminal
neuralgia. Other options include selective nerve fiber destruction (rhizotomy), which may
require balloon compression, radiofrequency thermal lesioning, glycerol injection, or focused
stereotactic (gamma knife) radiation. Microvascular decompression, which can manually
separate the compressing vessel from the trigeminal nerve, may be appropriate for younger
patients in relatively good health. Compared with noninvasive procedures, which have success
rates of 50% to 85%, microvascular decompression has long-term success rates of 90%, with
lower risks of postoperative numbness in the face or cornea.
Primary Headaches
Most primary headaches can be diagnosed on the basis of a comprehensive history and
physical examination and do not require neuroimaging or other diagnostic tests (such as
electroencephalography, lumbar puncture, and blood testing). The diagnostic yield of a brain
MRI or a head CT scan in patients with a chronic headache and no concerning signs or
symptoms is less than 1%.
Migraine
Key Points
The headache of migraine with aura occurs within 1 hour of onset of transient focal
neurologic symptoms, such as visual, sensory, or language abnormalities, that develop
over a minimum of 5 minutes and last a maximum of 60 minutes.
NSAIDs, dihydroergotamine, and triptans are effective in the management of acute
migraine.
The pharmacologic agents with the strongest evidence of effectiveness in the prevention
of episodic migraine are propranolol, timolol, amitriptyline, divalproex sodium, and
topiramate.
Women with any migraine type who use combined oral contraceptives have a twofold to
fourfold increased risk of stroke compared with women without a history of migraine who
use these contraceptives.
Because potential risk to the fetus exists for most drugs used in migraine prevention,
their use during pregnancy should be limited to women with particularly frequent or
disabling migraine attacks.
Common nonvisual auras include spreading unilateral numbness or tingling affecting the face
and upper extremities, disturbed thinking or speech, and dizziness. An aura is defined as
typical if it involves any combination of visual, hemisensory, or language abnormalities, with
each symptom developing over a minimum of 5 minutes and lasting a maximum of 60 minutes.
The associated migraine usually occurs within 1 hour, but some auras do not progress to head
pain. Auras should be investigated further if they extend beyond 60 minutes, involve any focal
motor weakness (hemiplegic migraine), or display brainstem symptoms, such as diplopia,
dysphagia, ataxia, vertigo, dysarthria, or synchronous bilateral sensory dysfunction (basilar
migraine).
Migraine is subclassified according to not only the presence or absence of aura, but also the
monthly frequency of headache occurrences. Most episodes occur fewer than 15 days per
month and are classified as episodic migraine. Chronic (previously transformed) migraine
occurs at least 15 days per month for more than 3 months, with the individual headache
episodes meeting the criteria for migraine on at least 8 of those days. Chronic migraine affects
2% of the world population and results in substantial individual disability and enormous societal
costs. Transformation of episodic into chronic migraine has been shown to occur at a rate of
3% per year in the general population and 14% per year in headache clinic populations. Risk
factors for such transformation, as suggested by available evidence, are listed below:
Older age
Major life changes or significant stressors
Female sex
Low education/socioeconomic status
Head/neck trauma
Obesity
Presence of comorbid pain and sleep or psychiatric disorders
High caffeine or nicotine intake
Overtreatment with acute headache medications
The final risk factor listed for migraine transformation, overtreatment with acute medication,
results in what is now termed medication overuse headache (rather than rebound headache).
Medication overuse headache is present in up to 80% of persons with chronic migraine
seeking medical attention, and thus it is critical to question all these patients about the use of
both prescription and nonprescription products while taking a headache history. Several
studies assessing the relationship between migraine transformation and acute medication use
have drawn the same conclusions, namely, that opiates (critical exposure 8 days per month)
and barbiturates (critical exposure 5 days per month) are associated with high rates of
migraine progression, but NSAIDs and triptans induce progression only in those with frequent
episodic migraine (10-14 days per month).
Patients with migraine in urgent or emergent care settings may have either a particularly
severe acute attack or status migrainosus, which by definition is a single migraine attack
extending beyond 72 hours. For most of these patients, prescribed NSAID or triptan therapies
have not worked. Intravenous dopamine antagonists, often in combination with intravenous
diphenhydramine (to limit or eliminate possible dystonic reactions) and hydration, may be
helpful. Intravenous preparations of ketorolac and sodium valproic acid also are quite useful,
and the addition of a single dose of dexamethasone appears to lower the rate of recurrence.
Parenteral dihydroergotamine is an extremely effective option for patients who have not taken
triptans or ergots within 24 hours and represents the cornerstone of inpatient management of
refractory migraine.
Migraine Prevention
Migraine prevention begins with identification and reduction or elimination of triggers and risk
factors. Regular sleep and eating patterns, adequate hydration, daily exercise, and a reduced
intake of dietary caffeine, artificial sweeteners, and additives (such as monosodium glutamate)
can help prevent migraine attacks. Regular school or work attendance should be strongly
encouraged in patients with migraine. Behavioral therapies of value include relaxation training,
electromyographic and thermal biofeedback, and cognitive behavioral therapy. Evidence is
currently insufficient to recommend acupuncture, chiropractic manipulation, oxygen therapy,
occlusion adjustment, hypnosis, and transcutaneous electrical nerve stimulation for the
prevention of migraine. The herbs feverfew and butterbur root, the mineral magnesium, the
vitamin riboflavin, and the antioxidants coenzyme Q10 and -lipoic acid all have some evidence
of efficacy in migraine prevention. Pharmacologic prophylaxis of migraine is indicated in the six
situations listed below.
1. Headache frequency greater than 2 days per week (or 8 days per month)
2. Use of acute medications, successfully or unsuccessfully, more than 2 days per week
3. Headache attacks that remain disabling despite aggressive acute intervention, as
documented by impaired lifestyle, unimproved disability status, or use of rescue
medications more frequently than monthly
4. Presence of prolonged aura (>1 hour), complex aura (basilar or hemiplegic), or migraineinduced stroke
5. Contraindications to, failure or overuse of, or adverse events with acute therapies
6. Patient preference
The major classes of agents available for migraine prevention are -adrenergic blockers,
antidepressants, anticonvulsants, calcium channel antagonists, nonsteroidal agents, and
serotonin receptor antagonists. The selection of a drug should be based first on efficacy, with
consideration given to coexisting psychiatric or medical disease, patient preference, and
patient adherence. Evidence for episodic migraine prevention is strongest for propranolol (60240 mg/d), timolol (5-30 mg/d), amitriptyline (30-150 mg/d), divalproex sodium (500-2000
mg/d), and topiramate (100-200 mg/d). Recent trials have documented the efficacy of only two
agents for chronic migraine: oral topiramate and injectable onabotulinumtoxinA. Topiramate is
contraindicated in patients with a history of kidney stones. Patients taking oral topiramate who
have no history of kidney stone formation should be advised to keep well hydrated because of
the increased risk of kidney stone formation associated with the drug.
Patient education about the goals, use, and expectations of migraine preventive therapies is
crucial in maximizing the chances of therapeutic success. The patient must understand that
although these therapies may reduce the frequency or severity of attacks, improve the efficacy
of acute medications, and assist in the management of comorbidities, they rarely result in
complete headache eradication. Prophylactic agents are generally titrated upward over a few
weeks and then sustained for 4 to 8 weeks before benefit is realized. Adherence can be
enhanced with the use of daily or twice-daily dosing. Most clinicians recommend a 6- to 12month maintenance phase after a response (often defined as a 50% reduction in headache
frequency) has been achieved, followed by a tapering phase. Avoiding the use of acute
headache medications, analgesics, decongestants, and stimulants for more than 10 days per
month is critical in ensuring optimal benefit from the prophylactic drug. In those patients
overusing acute medications, such as butalbital and opiate compounds, a gradual taper over
several weeks may be necessary, and full response to preventive therapies may be delayed by
several months.
Migraine in Women
Migraine and Menstruation
The influence of estrogen on migraine is shown by the threefold greater prevalence of migraine
in women than men and by the significant changes in migraine incidence associated with
changes in female reproductive status. Menstrually related migraine is defined as migraine that
occurs both during (days 2 through 3) and outside menses, whereas pure menstrual migraine
occurs exclusively during the menstrual period. Recent data confirm that menstrual attacks
exhibit greater intensity and duration compared with nonmenstrual episodes. Evidence
supports acute treatment with sumatriptan, rizatriptan, mefenamic acid, and combination
sumatriptannaproxen sodium. For predictable attacks offering the possibility of perimenstrual
prophylaxis (5-7 days), transcutaneous estradiol, oral frovatriptan, and naratriptan have
established efficacy. Because multiple studies have linked menstrual migraine attacks with
estrogen withdrawal, some have advocated continuous hormonal therapy with monophasic
oral contraceptives as a means of prevention.
Controversy exists regarding the use of estrogen-containing oral contraceptives in women with
migraine with aura. The literature suggests that women with any migraine type who use
combined oral contraceptives have a twofold to fourfold increased risk of stroke compared with
women without a history of migraine. The relationship between use of combined oral
contraceptives and stroke appears to be dose dependent, with pills containing more than 50
micrograms of estrogen carrying the greatest risk. However, many women without other risk
factors for stroke or a history of smoking have been managed safely and successfully with
lower-dose combined preparations. In one study of young women (age 25-29 years) with a
baseline 10-year ischemic stroke rate of 2.7 per 10,000, the rate climbed to 11 for those with
migraine with aura and 23 for those with migraine with aura who used oral contraceptives. The
World Health Organization recommends that women with aura avoid oral contraceptive use,
and the American College of Obstetrics and Gynecology recommends using alternative forms
of contraception for most women with migraine with aura.
Progestin-only contraceptives and copper and progesteronecontaining intrauterine devices
can be safely used in women with migraine.
Recommended Dose
NSAIDsa
Aspirin
325-900 mg
Ibuprofen
400-800 mg
Naproxen sodium
250-1000 mg
Combination of acetaminophen/aspirin/caffeine
2 tablets
6.25-12.5 mg
Eletriptan
20-40 mg
Frovatriptan
2.5 mg
Naratriptan
1-2.5 mg
Rizatriptan
5-10 mg
Sumatriptan
25-100 mg
Sumatriptan-naproxen
85-500 mg
Zolmitriptan
2.5-5 mg
Nonoral Therapiesa
Dihydroergotamine
1 mg nasally
Dihydroergotamine
1 mg subcutaneously
Prochlorperazine
10 mg intravenously
Sumatriptan
5-20 mg nasally
Sumatriptan
4-6 mg subcutaneously
Drug
Recommended Dose
Zolmitriptan
5 mg nasally
Tension-Type Headache
Key Points
The diagnosis of tension-type headache relies on negative characteristics that rule out
migraine or secondary headaches.
Stress and sleep disruption are the two most commonly reported triggers of tension-type
headache, and disability is typically minimal or nonexistent.
Tension-type headache is the most common, but least distinct, of the primary headache
disorders. Although the most prevalent headache type in the general population, tension-type
headache typically does not have the severity or impact of migraine and thus infrequently
provokes a visit to a physician. This category of headache is divided into episodic and chronic
subtypes, with the episodic subtype including attacks that occur fewer than 15 days per month
or 180 days per year and the chronic subtype including more frequent attacks. Populationbased studies suggest 1-year prevalence rates of 40% for the episodic subtype and 2.5% for
the chronic subtype; the lifetime prevalence of tension-type headache approaches 90%.
Diagnosis of tension-type headache by ICHD-2 criteria is based on negative characteristics
(that rule out migraine or secondary headaches). Whereas migraine is characterized primarily
by the positive features of photophobia and/or phonophobia, nausea and/or vomiting, and pain
worsening with activity, tension-type headache is characterized by the absence of these
features. By definition, a single tension-type headache episode can last from 30 minutes to 7
days.
Unlike the unilateral, throbbing, moderate-to-severe pain of migraine, tension-type headache is
characterized by bilateral, steady, mild-to-moderate discomfort. Prodrome, aura, and residual
symptoms after the headache (postdrome) are not present, and headaches rarely develop
nocturnally. Many persons report gradual escalation of discomfort throughout the day. Stress
and sleep disruption are the two most commonly reported triggers. Disability is typically
minimal or nonexistent, and physical activity often decreases headache intensity. Some
patients with tension-type headache report scalp tenderness or muscular tension or soreness
in the cervical region. Because the clinical features of tension-type headache are somewhat
vague and nonspecific, the label has been mistakenly applied to both secondary headache
and migraine. The latter two diagnoses must be excluded before a headache can be
considered to be tension type. The episodic subtype generally requires no diagnostic
procedures, but the chronic subtype warrants brain MRI.
Aspirin and acetaminophen have been shown to be equally effective and superior to placebo
for treating tension-type headache in controlled clinical trials, whereas comparative studies of
these agents versus others suggest superior benefits from ibuprofen and naproxen sodium.
The addition of caffeine significantly increases the efficacy of aspirin and acetaminophen.
Muscle relaxants and benzodiazepines have no role in the management of this disorder.
The evidence supporting preventive treatments for tension-type headache is much less robust.
For example, scientific support for relaxation and biofeedback therapies for tension-type
headache is strong, and stress management programs using cognitive behavioral techniques
have proved useful. However, no evidence supports the use of cervical manipulation and
physical therapy. Although tricyclic antidepressants are frequently used for prevention of
tension-type headache, a recent meta-analysis found antidepressants no more effective than
placebo in reducing headache frequency or intensity.
Cluster Headache
Key Point
Cluster headache episodes, which generally last several weeks or months with headache
recurring one to eight times daily for 15 to 180 minutes each time, are associated with
exquisite pain that is typically periorbital or temporal, intense, boring, and associated with
restlessness and ipsilateral ocular or nasal autonomic features.
Cluster headache is a rare and exquisitely painful primary headache disorder that occurs in
either episodic or chronic patterns. Male sex and tobacco use are risk factors for development
of this type of headache, and alcohol may trigger attacks during a cluster cycle. Headache
clusters generally last several weeks or months, with attacks of pain potentially recurring one
to eight times daily and lasting 15 to 180 minutes each. The pain is typically periorbital or
temporal, intense, boring, and associated with restlessness and ipsilateral autonomic features,
such as ptosis, lacrimation, conjunctival injection, and nasal congestion and rhinorrhea. The
attacks often exhibit circadian rhythm and most commonly occur within a few hours of falling
asleep. To exclude structural mimics, patients with symptoms suggestive of cluster headache
should undergo brain MRI.
The medical treatment of cluster headache includes acute, transitional, and maintenance
prophylaxis. The acute treatment of choice is inhaled oxygen delivered by face mask at 6 to 12
L/min for 10 minutes, which is effective in greater than 75% of patients. A recent meta-analysis
of existing trials of acute pharmacotherapy documented the best evidence for oxygen,
subcutaneous sumatriptan, and nasal zolmitriptan. No evidence supports the use of opioids in
the treatment of cluster headache. Transitional prophylaxis, which refers to the short-term use
of fast-acting agents, typically involves either corticosteroids or an occipital nerve block. The
mainstay of prophylactic therapy is verapamil, often at high doses. Serial electrocardiograms
also may be necessary to monitor potential cardiac conduction defects in patients on
verapamil. Some evidence supports the use of lithium and melatonin. For medically refractory
cluster headache, surgical intervention and occipital nerve or deep brain stimulators are being
studied.
Key Points
Secondary Headaches
In addition to cognitive, sensorimotor, and reflex testing, a thorough cranial nerve
assessment, with examination of the optic discs, visual fields, and eye movements,
is essential in patients with headache.
Approximately 25% of thunderclap headache presentations result from a
subarachnoid hemorrhage.
Calcium channel blockers, such as verapamil and nimodipine, are considered firstline therapies for thunderclap headache associated with reversible cerebral
vasoconstriction syndrome.
Carbamazepine is a first-line drug for medical management of trigeminal neuralgia,
and patients should receive an adequate trial of at least three drugs or drug
combinations before interventional or surgical treatment is considered.
Primary Headaches
The headache of migraine with aura occurs within 1 hour of onset of transient focal
neurologic symptoms, such as visual, sensory, or language abnormalities, that
develop over a minimum of 5 minutes and last a maximum of 60 minutes.
NSAIDs, dihydroergotamine, and triptans are effective in the management of acute
migraine.
The pharmacologic agents with the strongest evidence of effectiveness in the
prevention of episodic migraine are propranolol, timolol, amitriptyline, divalproex
sodium, and topiramate.
Women with any migraine type who use combined oral contraceptives have a
twofold to fourfold increased risk of stroke compared with women without a history
of migraine who use these contraceptives.
Because potential risk to the fetus exists for most drugs used in migraine
prevention, their use during pregnancy should be limited to women with particularly
frequent or disabling migraine attacks.
The diagnosis of tension-type headache relies on negative characteristics that rule
out migraine or secondary headaches.
Stress and sleep disruption are the two most commonly reported triggers of
tension-type headache, and disability is typically minimal or nonexistent.
Cluster headache episodes, which generally last several weeks or months with
headache recurring one to eight times daily for 15 to 180 minutes each time, are
associated with exquisite pain that is typically periorbital or temporal, intense,
boring, and associated with restlessness and ipsilateral ocular or nasal autonomic
features.
Bibliography
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population-based study. Neurology. 2010;74(8):628-635. PMID: 20147658
Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a
randomized trial. JAMA. 2009;302(22):2451-2457. PMID: 19996400
Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic treatment
of cluster headache. Neurology. 2010;75(5):463-473. PMID: 20679639
Gillman PK. Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a
review. Headache. 2010;50(2):264-272. PMID: 19925619
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guideline update: NSAIDs and other complementary treatments for episodic migraine
prevention in adults: Report of the Quality Standards Subcommittee of the American
Academy of Neurology and the American Headache Society. Neurology. 2012;78
(17):1346-1353. PMID: 22529203
Kruit MC, van Buchem MA, Launer LJ, Terwindt GM, Ferrari MD. Migraine is associated
with an increased risk of deep white matter lesions, subclinical posterior circulation
infarcts and brain iron accumulation: the population-based MRI CAMERA study.
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quantitative systematic review. Cephalalgia. 2008;28(5): 531-540. PMID: 18355348
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guideline update: Pharmacologic treatment for episodic migraine prevention in adults:
Report of the Quality Standards Subcommittee of the American Academy of Neurology
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22529202
Torelli P, Allais G, Manzoni GC. Clinical review of headache in pregnancy. Neurol Sci.
2010;31 (suppl 1):S55-S58. PMID: 20464584
Verhagen AP, Damen L, Berger MY, Passchier J, Koes BW. Lack of benefit for
prophylactic drugs of tension-type headache in adults: a systematic review. Fam Pract.
2010;27(2):151-165. PMID: 20028727
Head Injury
Points
Eye-Opening Response
Spontaneous (eyes open with blinking at baseline)
No response
Verbal Response
Oriented
Inappropriate words
Incomprehensible speech
No response
Motor Response
Obeys commands for movement
No response
Coma classification (total points): 8 points, severe; 9-12 points, moderate; 13-15 points, mild.
ataxia, slurred speech, or visual anomalies, are detected on examination. The management of
grade 3 concussions in athletes is outlined in Table 7.
The immediate postconcussion assessment and cognitive testing (ImPACT) test is a validated
instrument now applied to most athletes competing at the high school, collegiate, or
professional level. The ImPACT test provides computerized neurocognitive assessment tools
and services used by physicians, athletic trainers, and other licensed health care professionals
to help determine an athlete's ability to return to play after a concussion. Return to competition
is often based on resolution of symptoms and return to baseline on the ImPACT test.
Postconcussion Syndrome
Postconcussion syndrome (PCS) can occur after a closed head injury or after a cervical spine
extension-flexion injury, also known as whiplash. This syndrome is characterized by a complex
of somatic and neuropsychological symptoms that by definition develops within 2 weeks of the
injury (Table 8). Pathophysiology may vary considerably between patients and is usually
multifactorial. Pain in the head and neck may arise from injury to nervous system (brain,
cervical roots) or cervical spine musculoskeletal elements; vertigo or imbalance from damage
to the brain or vestibular system; and cognitive, psychological, and sleep disturbances from
trauma to brain structures. Brain dysfunction may result from destruction that is obvious on
neuroimaging or may arise from less apparent diffuse axonal injury, impaired cerebrovascular
autoregulation, neurochemical perturbations, or psychological decompensation. Women are
twice as likely as men to be affected, and older age is associated with less rapid and less
complete recovery. Neither the intensity nor the persistence of the syndrome easily correlates
with the severity of injury or the duration of unconsciousness.
Management of PCS is largely supportive and rehabilitative, with medical treatments directed
at specific symptoms. Headache, mood or anxiety disorders, and vestibular dysfunction are all
often treated with a combination of pharmacologic and nonpharmacologic approaches.
Cognitive symptoms are more difficult to address directly but may necessitate retraining of
attention and executive functioning skills.
Key Points
Traumatic Brain Injury
Patients with moderate to severe brain injuries on presentation should be staged
according to the Glasgow Coma Scale.
The neuroimaging procedure of choice for traumatic brain injury in acute settings is
CT of the head.
Concussive Head Injury
Brain MRI is recommended for persons with grade 2 and 3 concussions who have
persistent abnormalities on examination or symptoms lasting longer than 1 week.
Epidural and Subdural Hematoma
Without immediate surgical evacuation, patients with epidural hematomas can die
within a matter of hours.
Head Injury in a Military Population
All military personnel should be screened for the effects of traumatic brain injury
when they return from combat.
Bibliography
Afari N, Harder LH, Madra NJ, et al. PTSD, combat injury, and headache in veterans
returning from Iraq/Afghanistan. Headache. 2009;49(9):1267-1276. PMID: 19788469
DeKosky ST, Ikonomovic MD, Gandy S. Traumatic brain injuryfootball, warfare, and
long-term effects. N Engl J Med. 2010;363(14):1293-1296. PMID: 20879875
Mansell JL, Tierney RT, Higgins M, McDevitt J, Toone N, Glutting J. Concussive signs
and symptoms following head impacts in collegiate athletes. Brain Inj. 2010;24(9):10701074. PMID: 20597635
Theeler BJ, Erickson JC. Mild head trauma and chronic headaches in returning US
soldiers. Headache. 2009;49(4):529-534. PMID: 19220499
Wilk JE, Thomas JL, McGurk DM, Riviere LA, Castro CA, Hoge CW. Mild traumatic brain
injury (concussion) during combat: lack of association of blast mechanism with persistent
postconcussive symptoms. J Head Trama Rehabil. 2010;25(1):9-14. PMID: 20051900
Epilepsy
Precipitating factors, such as sleep deprivation and toxic exposures, should also be
ascertained.
If a first seizure results from a toxic or metabolic cause, further diagnostic evaluation may not
be necessary, and management should focus on correcting the underlying cause.
Neuroimaging is recommended in any patient with a first seizure and is essential in all patients
with an abnormal neurologic examination or a history suggestive of a partial seizure. Lumbar
puncture should be considered in a patient with a seizure in the setting of fever, headache, stiff
neck, or altered mental status. Seizures are a common presentation of viral encephalitis, in
which only subtle clinical signs of infection, such as low-grade fever and personality change,
may be present. All immunocompromised patients with a first seizure should have a brain MRI
and a lumbar puncture. Electroencephalography (EEG) typically is not indicated on an
emergent basis, unless there is a prolonged postictal state.
Because seizures are unpredictable, all patients who have experienced a seizure should be
counseled to avoid situations in which a loss of consciousness would be dangerous, including
unsupervised swimming or bathing and climbing to a height. Driving privileges are restricted in
patients who have had a seizure in the United States, but the laws differ from state to state.
State laws typically do not distinguish between a patient who has had a single seizure and a
patient with epilepsy. Some states mandate that a physician report a seizure occurrence to the
Department of Motor Vehicles.
Nonepileptic Syncope
Seizure
TIA
Migraine
Vertigo
Warning/aura
Variable (<1
min)
Variable
Lightheaded
feeling; sweating
None
Variable
(15-30 min)
None
Duration
1-2 min
5-15 min
Seconds to
minutes
Minutes to
hours
Hours
Minutes
to days
Effect of
posture
None
Variable
Variable
None
None
Variable
Symptoms
during episode
Tonic-clonic
movement,
paresthesias,
aphasia
Pelvic
thrusting,
jerking that
waxes and
wanes,
forced eye
closure
Hemiparesis
hemisensory
loss, visual
loss,
aphasia
Visual
disturbance,
vertigo,
paresthesias
Nausea,
ataxia
Altered
consciousness
Common
Common
Sometimes
Rare
Rare
None
Incontinence
Variable
Variable
Variable
None
None
None
Heart rate
Increased
Variable
Irregular/decreased
Variable
No effect
Variable
Symptoms
after episode
Confusion,
fatigue
Variable
Alert
Alert
Fatigue
Alert
EEG during
event
Epileptiform
pattern
No effect
Diffuse slowing
Focal
slowing
Rare
slowing
No
effect
Partial Seizures
Key Point
A simple partial seizure does not impair awareness, whereas a complex partial seizure
involves an alteration of consciousness that typically occurs when the seizure spreads to
involve one or both temporal lobes.
In a partial seizure, the abnormal electrical discharge may remain localized to a small
population of neurons or spread to involve larger regions of the cortex. Partial seizures are
subclassified as simple, complex, or secondarily generalized seizures. A simple partial seizure
is a focal seizure that does not impair awareness, whereas a complex partial seizure involves
an alteration of consciousness that typically occurs when the seizure spreads to involve one or
both temporal lobes. When a partial seizure spreads to involve both hemispheres diffusely, the
result is a generalized convulsion that is known as a secondarily generalized seizure.
The classic jacksonian march is a simple partial motor seizure characterized by rhythmic
contraction of a group of muscles, typically the fingers, followed by a spread of motor activity to
the arm and then to the ipsilateral face; this pattern reflects the spread of electrical discharge
across the motor homunculus of the primary motor cortex. If a seizure begins in the sensory
cortex of the parietal lobe, the patient may experience paresthesias that spread in a similar
pattern but have no outward clinical manifestations. These types of simple partial seizures,
which cause purely subjective symptoms, are known as epileptic auras.
The most common epileptic auras originate in the temporal lobe. These sensations are often
difficult for a patient to describe but are highly stereotyped; a patient may only be able to
indicate that he or she knows the feeling. Common auras of temporal lobe seizures include
vague, rising epigastric sensations; experiential phenomena, such as dj vu or intense fear;
or autonomic disturbances, such as palpitations or temperature changes. Temporal lobe auras
can be misdiagnosed as panic attacks. Because only a small part of the cortex is involved,
EEG during simple partial seizures often does not demonstrate epileptiform patterns, which
makes the diagnosis more difficult.
Simple partial seizures can progress to complex partial seizures or secondarily generalized
seizures. Complex partial seizures are defined as an alteration of consciousness that typically
lasts 1 to 2 minutes, but patients may remain confused for as long as 5 to 10 minutes after the
seizure has ended. During complex partial seizures, patients often appear to have a blank
stare and exhibit stereotyped automatisms, such as lip smacking, repetitive swallowing, or
fumbling movements of the hands. Many patients with this type of seizure only remember the
aura and do not report any change in consciousness; other patients have no aura or have no
memory of their seizures. For these reasons, it is essential to obtain a history of the seizure
from a reliable observer.
Secondarily generalized tonic-clonic seizures are convulsions that begin as partial seizures
and are characterized by impaired awareness, diffuse muscle contraction (tonic phase), and
rhythmic jerking of all limbs (clonic phase). These seizures, which are often accompanied by
urinary incontinence or tongue biting, usually resolve within 1 to 2 minutes and may be
followed by postictal confusion or agitation for 10 to 15 minutes. Secondarily generalized
convulsions are sometimes clinically indistinguishable from convulsions that begin as
generalized seizures. Focal features, such as unilateral twitching or the patient's report of an
epileptic aura before the onset of the convulsion, can help make the diagnosis of a secondarily
generalized seizure. Sometimes a patient will have a focal deficit (such as limb weakness)
contralateral to the site of seizure onset, a phenomenon known as Todd paralysis.
Generalized Seizures
Key Point
Absence seizures, which are uncommon in adult patients, are a type of generalized
seizure characterized by a momentary lapse of consciousness.
Generalized seizures involve both hemispheres at the onset of the ictus. Primary generalized
tonic-clonic seizures are convulsions that occur with little or no warning. Absence seizures are
another type of generalized seizure characterized by a momentary lapse of consciousness
(typically less than 5 seconds). The term absence seizure is often misused to describe a
complex partial seizure. Absence seizures are most characteristic of childhood absence
epilepsy, which typically resolves by puberty but can also occur in adults with idiopathic
generalized epilepsy syndromes.
Myoclonic seizures are brief shocklike muscular contractions that can occur in rapid
succession and usually are not associated with an impairment of consciousness. These
seizures are characteristic of juvenile myoclonic epilepsy and also can occur in toxic-metabolic
states and after anoxic brain injury.
Epilepsy Syndromes
Patients with epilepsy often experience more than one seizure type. An epilepsy syndrome is
defined by the constellation of seizure types in a given patient and by his or her EEG and MRI
findings. As with individual seizures, epilepsy syndromes are classified as partial (focal) or
generalized. Most epilepsy syndromes presenting in adulthood are focal epilepsies.
Figure 2.
Mesial temporal sclerosis. Coronal flair MRI shows increased signal intensity and atrophy of
the left mesial temporal lobe (arrow).
Figure 3.
Figure 4.
Focal cortical dysplasia with periventricular nodular heterotopia. Coronal MRI showing a focal
area of thickened cortex in the right temporal region (thick arrow) and nodules of abnormal
neuronal tissue along the ventricular surface (thin arrow).
Mood Disorders
Cognitive Problems
Osteoporosis
Sudden Unexplained Death in Epilepsy
Mood Disorders
Both major depressive disorder and bipolar disorder are more common in persons with
epilepsy (20% to 60% of patients) than in those with other chronic diseases. All antiepileptic
drugs (AEDs) carry a black box warning indicating a potentially increased risk of suicide, which
is based on a pooled analysis of clinical trials. Although somewhat controversial, these studies
emphasize the need to routinely screen patients with epilepsy for depressive symptoms and
suicidal ideation.
Cognitive Problems
Key Point
Major depressive disorder, bipolar disorder, and cognitive problems are common in
patients with epilepsy.
Cognitive problems are common in patients with epilepsy. Although this symptom may be a
manifestation of depression or an adverse effect of AEDs, many patients experience
independent cognitive decline as a manifestation of their epilepsy. In particular, patients with
temporal lobe epilepsy exhibit deficits in visual or verbal memory. Attention problems are
common in patients with frontal lobe epilepsy and generalized epilepsy syndromes.
Neuropsychological testing may be useful in differentiating between the global effects of
antiseizure medications and specific neurocognitive deficits. At times, video EEG monitoring
also is indicated to determine whether subclinical or unrecognized seizures are contributing to
a patient's cognitive difficulty.
Osteoporosis
The risk of skeletal fractures in patients with epilepsy is two to six times greater than in the
general population. Subclinical osteoporosis is also more common in patients with epilepsy
who take AEDs. Baseline and interval bone mineral density screening is recommended for all
patients with epilepsy, particularly those who have been taking enzyme-inducing antiepileptic
medications for over 5 years. Calcium and vitamin D supplementation also is recommended.
Imaging Studies
In the acute setting, a head CT is the imaging study of choice for most patients with a newonset seizure. A CT scan will identify an acute symptomatic cause of the seizure, such as
hemorrhage. Eventually, patients with an unprovoked seizure also should undergo brain MRI,
which is more sensitive for detecting the structural lesions associated with epilepsy. Additional
imaging tests often used to evaluate patients for epilepsy surgery include
magnetoencephalography, single-photon emission CT, PET, and functional MRI.
Electroencephalography
A routine EEG is a 30- to 60-minute scalp recording of electric potentials from the brain,
optimally in both the awake and the sleep state. Seizures are rarely recorded on a routine
EEG, but the presence of interictal epileptiform discharges is highly correlated with an
increased risk of recurrent seizures. The likelihood that a single 30-minute EEG will record
interictal epileptiform discharges in a patient with epilepsy is approximately 25% to 50%,
varying by the type of epilepsy. An EEG can help confirm the presence of epilepsy but cannot
be used to exclude the diagnosis. EEG also can be useful to discriminate between a focal and
generalized epilepsy syndrome (Figure 5 and Figure 6).
Figure 5.
Characteristic electroencephalogram (EEG) of a patient with idiopathic generalized epilepsy shows a generalized
interictal epileptiform discharge during drowsiness. A concurrent electrocardiogram is shown below the EEG.
Figure 6.
Characteristic electroencephalogram (EEG) of a patient with temporal lobe epilepsy demonstrating an interictal
right temporal epileptiform discharge during sleep. Unlike the epileptiform discharge in Figure 5, the spike-wave
discharge in this EEG is focal and is maximal in the F8 and T8 electrodes, which are over the right temporal
region. Even numbers to the left of the EEG represent electrodes over the right side of the head, and odd
numbers represent electrodes over the left side of the head.
A high index of suspicion is critical for making a diagnosis of nonepileptic events, particularly in
patients who do not respond to AED therapy. Early diagnosis by video EEG and referral to
appropriate psychological resources provide the best chance of a good outcome. Limiting or
eliminating unnecessary AEDs is critical, particularly in women of childbearing age.
Approximately 10% to 30% of patients with psychogenic nonepileptic seizures also have
epileptic seizures, which underscores the need for a careful and complete assessment.
Treatment of Epilepsy
Antiepileptic Drug Therapy
Nonpharmacologic Therapy
Only limited data are available on the effects of other AEDs in pregnancy. Early studies of
levetiracetam and oxcarbazepine also have demonstrated low rates of fetal malformations.
Phenytoin and phenobarbital have been associated with relatively higher fetal malformation
rates (3%-7% and 6.5%-14%, respectively); both of these drugs are considered pregnancy
category D medications (evidence of human fetal risk, but potential benefits may warrant use
of these drugs in pregnant women, despite potential risks). Additionally, recent data showing
an increased risk of cleft palate with fetal exposure to topiramate (1.4% versus 0.07% for
unexposed fetuses) has elevated this AED to a category D drug.
In general, the most appropriate AED for a pregnant woman is the drug that has best
controlled her seizures at the lowest possible dosage. Switching AEDs during pregnancy is not
typically recommended because polytherapy further increases the risk of malformations.
Furthermore, most fetal malformations occur in the first 4 to 6 weeks of pregnancy, typically
before a woman knows she is pregnant. Because most pregnancies are not planned,
prepregnancy optimization of a patient's AED regimen should occur well before a woman with
epilepsy plans to start a family. Additionally, all women with epilepsy should take folic acid, 0.4
to 5 mg/d, which may decrease the likelihood of neural tube defects.
AED levels must be followed closely during pregnancy. Lamotrigine and oxcarbazepine are
particularly sensitive to the effect of estrogen on glucuronidation, which leads to an increase in
hepatic metabolism. The levels of these AEDs can drop precipitously during pregnancy and
result in increased seizure frequency.
dosage is not increased. Lamotrigine also can decrease progestin levels, thereby making
certain forms of contraception less effective.
Carbamazepine
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Irritability, sedation
Oxcarbazepine
Phenobarbital
Phenytoin
Pregabalin
Topiramate
Word-finding difficulty,
anorexia
ECG = electrocardiogram.
Drug
Valproic acid
Vigabatrin
Sedation, headache,
dizziness
Zonisamide
Sedation, anorexia
ECG = electrocardiogram.
Partial
Generalized Metabolism
(Focal)
Epilepsy
Epilepsy
Added Considerations
Carbamazepine
Hepatic
Renal
Lacosamide
Hepatic/Renal
Lamotrigine
Hepatic/Renal
Levetiracetam
Renal
Drug
Partial
Generalized Metabolism
(Focal)
Epilepsy
Epilepsy
Added Considerations
Oxcarbazepine
Hepatic/Renal
Hepatic
Pregabalin
Renal
Topiramate
Renal
Valproic acid
Hepatic
Vigabatrin
Hepatic/Renal
Restricted prescribing in US
due to risk of irreversible
peripheral vision loss
Drug
Partial
Generalized Metabolism
(Focal)
Epilepsy
Epilepsy
Added Considerations
Renal
Nonpharmacologic Therapy
Key Point
Epilepsy surgery to remove the area of the cortex that is the epileptogenic focus is often
used in patients with refractory focal epilepsy.
Status Epilepticus
Generalized Convulsive Status Epilepticus
Nonconvulsive Status Epilepticus
anesthetic agent should be used or the ideal depth or duration of anesthesia, but it is known
that prolonged infusions of high-dose propofol can lead to a syndrome characterized by
rhabdomyolysis and multiorgan failure. The anesthetic infusion should be titrated upward, at
least until convulsive activity has ceased, and then the patient should be monitored with
continuous EEG to exclude nonconvulsive status epilepticus or ongoing electrographic
seizures.
Figure 7.
Algorithm for treatment of generalized convulsive status epilepticus. ABG = arterial blood gas;
AED = antiepileptic drug; CBC = complete blood count; CMP = comprehensive metabolic
panel; ECG = electrocardiogram; EEG = electroencephalographic; IM = intramuscular; IV =
intravenous; PE = phenytoin equivalent; PR = per rectum.
a
Monitor ECG and blood pressure with fosphenytoin and phenytoin; monitor for drug
extravasation with phenytoin.
Consider valproic acid (valproate) as first-line therapy in those with known idiopathic
generalized epilepsy; avoid when possible in women of childbearing age.
Should be obtained for all patients not recovering mental status, including those receiving IV
anesthesia.
epilepticus and complex partial status epilepticus outside the intensive care unit. These two
subtypes typically present with fluctuating mental status that can mimic delirium and persist for
days before diagnosis. Patients may maintain some degree of interaction with their
environment but typically are confused and may exhibit frequent blinking or automatisms.
Absence status epilepticus and complex partial status epilepticus typically occur in patients
with a history of generalized and focal epilepsy, respectively, but de novo absence status
epilepticus (spike-wave stupor) can also occur in older patients without a history of epilepsy,
particularly in the setting of benzodiazepine withdrawal.
The diagnosis of nonconvulsive status epilepticus can be confirmed by video EEG monitoring
or by a paradoxical improvement in mental status in response to a low-dose benzodiazepine.
Although prompt control of seizures is considered important in patients with this disorder, the
management approach is typically different from that in other forms of status epilepticus.
Patients are treated with benzodiazepines and other AEDs, but intravenous anesthesia and
intubation are sometimes deferred, if possible, because these interventions may cause a
greater morbidity than nonconvulsive status epilepticus itself, particularly in older patients.
Key Points
Initial Approach to the Patient with a First Seizure
Neuroimaging is recommended in any patient with an unprovoked seizure and is
essential in all patients with an abnormal neurologic examination, a history
suggestive of a partial seizure, or impaired immune function.
Clinical Presentations of Seizures
A simple partial seizure does not impair awareness, whereas a complex partial
seizure involves an alteration of consciousness that typically occurs when the
seizure spreads to involve one or both temporal lobes.
Absence seizures, which are uncommon in adult patients, are a type of generalized
seizure characterized by a momentary lapse of consciousness.
Epilepsy Syndromes
Temporal lobe epilepsy, the most common form of epilepsy in adults, typically
presents with complex partial seizures.
Juvenile myoclonic epilepsy, one of the most common forms of idiopathic
generalized epilepsy in adult patients, requires life-long antiepileptic therapy to
prevent future convulsions.
Comorbidities and Complications of Epilepsy
Major depressive disorder, bipolar disorder, and cognitive problems are common in
patients with epilepsy.
The risks of skeletal fracture and sudden unexplained death are higher in persons
with epilepsy than in the general population.
Diagnostic Evaluation of Seizures and Epilepsy
Because negative results on MRI and electroencephalography do not exclude the
diagnosis of epilepsy, a careful clinical history is critical in the diagnostic evaluation
of a patient with seizures.
Inpatient video electroencephalographic monitoring should be considered in any
patient whose seizures have not responded to two or more antiepileptic drugs or
require further characterization.
Treatment of Epilepsy
After two or more unprovoked seizures, the risk of recurrent seizures is greater than
60%, and antiepileptic drug therapy is usually recommended.
Valproic acid should be avoided in women of childbearing age because of its high
risk of teratogenesis.
Epilepsy surgery to remove the area of the cortex that is the epileptogenic focus is
often used in patients with refractory focal epilepsy.
Status Epilepticus
The management of generalized convulsive status epilepticus, which has an overall
30-day mortality rate of 20%, should begin as soon as a seizure has lasted longer
than 5 minutes.
The diagnosis of nonconvulsive status epilepticus can be confirmed by video
electroencephalographic monitoring or by a paradoxical improvement in mental
status in response to a low-dose benzodiazepine.
Bibliography
Arif H, Buchsbaum R, Pierro J, et al. Comparative effectiveness of 10 antiepileptic drugs
in older adults with epilepsy. Arch Neurol. 2010;67(4):408-415. PMID: 20385905
Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated
with 15 antiepileptic drugs. Neurology. 2007;68(20):1701-1709. PMID: 17502552
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Harden CL, Meador KJ, Pennell PB, et al; American Academy of Neurology; American
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Stroke
Diagnosis of Stroke
Key Point
In the acute setting, head CT without contrast is the initial test of choice to confirm or
exclude hemorrhagic stroke; subsequent MRI can identify acute ischemia or a
nonvascular cause.
The initial evaluation of a patient with suspected stroke includes careful consideration of the
sequence and timing of neurologic events, an appraisal of all risk factors and medical
contributors to stroke, and a detailed neurologic examination. The initial assessment can
identify candidates for acute treatment and provide an early prognosis of mortality or recovery.
The focused and highly structured National Institutes of Health Stroke Scale (Table 12) is used
by qualified practitioners as the initial examination. This scale is well validated and correlates
with short- and long-term outcomes and objective measures, such as the size of the cerebral
infarction. Performing the scale on all stroke patients is a common requirement for stroke
center certification.
Hemorrhagic stroke cannot be reliably distinguished from ischemic stroke on clinical grounds
alone. The presence of coma, meningismus, seizures at onset, vomiting, headache, and a
diastolic blood pressure greater than 110 mm Hg makes the diagnosis of hemorrhagic stroke
more likely, but hemorrhagic stroke can present without any of these findings. Modern
neuroimaging is necessary to identify the brain territory involved in a stroke and understand
the pathophysiology involved. In the acute setting, head CT without contrast is the initial test of
choice to confirm or exclude hemorrhagic stroke (Figure 8). MRI is the subsequent test of
choice and can identify acute and subacute ischemia, hemorrhage, nonvascular lesions, or
another underlying cause. Diffusion-weighted MRI (Figure 9) can reveal hyperintensity within
minutes of acute cerebral infarction, whereas other sequences are helpful in identifying
vasogenic edema or cerebral microhemorrhages.
The gold standard for evaluating the cerebral vasculature remains catheter-based
angiography, but its invasiveness and unavailability in most hospitals make it impractical.
Magnetic resonance angiography without contrast is widely available and commonly included
in stroke-protocol MRI. The presence of arterial stenoses and aneurysms can be readily shown
with this technique, although it is prone to artifact and tends to overestimate the degree of
stenosis. CT angiography is generally less prone to artifact and can reveal significant details
about vascular anatomy, including the presence of arterial stenoses, aneurysms, or
Scores
1a. LOC
0 = normal
1 = not alert but arousable by minor stimulation
2 = not alert and requires constant verbal or
painful stimuli to remain interactive
3 = unresponsive or responds with only
reflexive movements
0 = normal
1 = partial gaze palsy or isolated cranial nerve
paresis
2 = forced gaze deviation or total gaze paresis
0 = no visual loss
1 = partial hemianopia
2 = complete hemianopia
3 = bilateral hemianopia
0 = normal
1 = minor paralysis (flattening of the nasolabial
fold or asymmetry on smiling)
Scores
2 = partial paralysis (paralysis of the lower face
only)
3 = complete paralysis (upper and lower face)
0 = no drift
1 = some drift but does not hit bed
2 = drifts down to bed
3 = no effort against gravity
4 = no movement
0 = no drift
1 = some drift but does not hit bed
2 = drifts down to bed
3 = no effort against gravity
4 = no movement
0 = absent
1 = present in one limb
2 = present in two limbs
0 = normal
1 = mild to moderate sensory loss or loss of
sensation in only one limb
2 = complete sensory loss
0 = no aphasia
1 = mild to moderate aphasia (difficulty with
fluency and comprehension; meaning can be
identified)
2 = severe aphasia (fragmentary language,
meaning cannot be clearly identified)
Scores
3 = global aphasia or mute
0 = normal
1 = mild to moderate
2 = severe (speech not understandable)
0 = normal
1 = visual or tactile extinction or mild
hemispatial neglect
2 = profound hemi-inattention or extinction to
more than one modality
Figure 8.
Top panel, noncontrast CTs of the head showing an acute left thalamic intracerebral hemorrhage (arrows)
without hydrocephalus or intraventricular extension. Bottom panel, noncontrast CTs of the head showing an
acute subarachnoid hemorrhage that involves the basal cisterns (thinner arrows) with associated hydrocephalus
(thicker arrows).
Figure 9.
Diffusion-weighted MRIs from a patient with symptomatic left middle cerebral artery
atherosclerosis reveal an acute infarction in deep (thinner arrows) and superficial (thicker
arrows) structures in the left cerebral hemisphere.
Figure 10.
Images from a patient with symptomatic internal carotid artery stenosis. Top left, CT angiogram of the
extracranial internal carotid artery showing high-grade stenosis at its origin. Top right, digital subtraction
angiography from the same patient. Bottom, Duplex ultrasonograms from the same patient; arrow on left
indicates the plaque and associated stenosis. PICA = proximal internal carotid artery.
Stroke Subtypes
Transient Ischemic Attack
Ischemic Stroke
Hemorrhagic Stroke
Scoreb
Age 60 y
Clinical symptoms
Focal weakness with the TIA
Duration of TIA
60 min
10-59 min
Based on Age, Blood pressure, Clinical presentation, Duration of symptoms, and the presence of
Diabetes mellitus.
Score and 2-day stroke risk based on score: 0-1 = 0%; 2-3 = 1.3%; 4-5 = 4.1%; 6-7 = 8.1%.
Ischemic Stroke
Key Point
Ischemic stroke connotes the presence of cerebral infarction, although the lesion is not
always evident on CT scans or diffusion-weighted MRIs.
Ischemic stroke is now defined by the presence of cerebral infarction on imaging, although the
absence of a lesion on a CT scan or diffusion-weighted image (which can occur if the infarct is
small or located in the brainstem) does not exclude ischemic stroke as a diagnosis. In the
United States, 20% of ischemic strokes are cardioembolic, 20% result from large artery
atherosclerosis, 25% are small subcortical infarcts, and 30% are cryptogenic strokes, for which
no cause is identified. The remaining 5% have rare causes, such as cerebral artery dissection
or vasculitis.
Cardioembolic Stroke
The most clearly documented cause of cardioembolic stroke is atrial fibrillation, although other
conditions also predispose to this type of stroke, including a low ejection fraction, an
intracardiac thrombus, a cardiac tumor, and valvular vegetations. Atrial fibrillation is the most
likely cause of ischemic stroke in patients older than 85 years, a population also most at risk of
mechanical falls, which are a relative contraindication to anticoagulation. Cardioembolic stroke
is more likely in patients with multiple infarcts on neuroimaging or infarcts involving the surface
of the brain.
Among patients with intracranial atherosclerosis, recurrent stroke is most common in those
with a greater than 70% stenosis and in those whose blood pressure remains greater than
140/80 mm Hg. Whether patients with intracranial atherosclerosis should undergo stenting in
addition to the best medical treatment is unknown.
Cryptogenic Stroke
Cryptogenic stroke is the most prevalent ischemic stroke subtype and is characterized by
imaging findings that suggest an embolic event without any evidence on evaluation of a
cardioembolic source or large artery atherosclerosis. The recurrent stroke rate of this type of
ischemic stroke is relatively low. A proportion of patients (close to 25% in recent studies) with
this stroke subtype may have paroxysmal atrial fibrillation, which can be identified by
prolonged cardiac rhythm monitoring.
Structure(s) Involved
Artery(ies) Involved
Internal capsule,
corona radiata
Pons, medullary
pyramids
Pure sensory
Thalamus
Sensorimotor
Thalamus, internal
capsule, caudate,
putamen
Ataxic hemiparesis
Pons
Internal capsule
Internal capsule
(anterior limb)
Basal ganglia
Brainstem
Hemorrhagic Stroke
Key Point
The differential diagnosis of intracerebral hemorrhage, which has a much higher mortality
than ischemic stroke, includes vascular malformation, infection, and brain tumor with
hemorrhage.
Hemorrhagic stroke comprises 17% of all strokes in the United States, with an equal proportion
of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).
Intracerebral Hemorrhage
ICH is more common in Asian countries, which perhaps reflects the greater impact of
hypertension in those countries. Two distinct pathologies of ICH exist. A deep-location
hemorrhage is most likely due to hypertension and typically originates in the basal ganglia or
cerebellum. A lobar hemorrhage located near the surface of the brain can also be caused by
hypertension, although cerebral amyloid angiopathy is a more likely cause. The differential
diagnosis of ICH includes vascular malformation, infection, and brain tumor with hemorrhage.
Because a cerebral hemorrhage may obscure an underlying tumor, a repeat imaging study
must be obtained 4 to 6 weeks after the initial event. ICH has a much higher mortality than
ischemic stroke.
Subarachnoid Hemorrhage
SAH is typically caused by a ruptured cerebral saccular aneurysm, although other rare causes,
such as an arteriovenous malformation and mycotic aneurysms, do exist. A chief symptom of
sudden-onset severe headache, especially if associated with impaired consciousness, should
prompt consideration of SAH. If a CT scan of the head is negative for subarachnoid blood but
the clinical suspicion remains high, a lumbar puncture to look for erythrocytes and
xanthochromia is required. The mortality associated with SAH is higher than with other brain
hemorrhages because most affected patients die before reaching the hospital. SAH is graded
by a clinical and radiographic scale, both of which have a good association with medical and
neurologic complications and with long-term outcome.
Clinical Diagnosis
An algorithm for the evaluation of acute ischemic stroke is provided in Figure 11. The initial
goal of the diagnostic evaluation is to achieve medical and cardiorespiratory stabilization. The
primary focus of the subsequent evaluation is to determine whether the patient is a candidate
for thrombolytic treatment. Determining the time of onset is key to this process. For patients
whose strokes are not witnessed, the time of onset is when they were last witnessed to be
without symptoms, which often is when they went to bed. Patients outside the treatment
window should not receive thrombolysis.
Determination of the blood glucose level is a critical component of the acute stroke evaluation
to exclude other conditions that may mimic stroke and to identify hyperglycemia, which is
associated with poor outcome after stroke. Other laboratory studies required acutely include a
complete blood count, basic metabolic panel, measurement of the serum troponin level, and a
coagulation profile. An electrocardiogram is needed to rule out acute myocardial infarction and
evaluate for atrial fibrillation, and a chest radiograph is commonly obtained to rule out aortic
dissection, although this step is not required.
Figure 11.
Clinical pathway for the evaluation of acute ischemic stroke. NIH = National Institutes of Health.
Imaging Techniques
A CT of the head without contrast will easily rule out ICH, the principal initial criterion for
excluding thrombolysis (see Figure 8). Subtle signs of early infarction can sometimes be seen
on a head CT scan (Figure 12), but many patients with acute ischemic stroke have normal
results on head CT. Other imaging modalities have been proposed for the acute setting,
although none is required before beginning thrombolysis; waiting for results of these studies
should never delay the initiation of treatment.
Figure 12.
Head CT findings in acute ischemic stroke. Top left, sulcal effacement and loss of the gray-white
differentiation (oval circle) in a patient 1.5 hours after the witnessed onset of global aphasia. Top
right, hyperdensity (arrow) in the proximal right middle cerebral artery in a patient with left
hemiparesis and left hemi-inattention 60 minutes after last being seen well. Bottom left, CT
angiogram of the patient from panel B that shows absent contrast in the right internal carotid and
proximal middle cerebral arteries (arrow), consistent with a thrombus in the artery. Bottom right, loss
of the insular ribbon on the right (arrow) compared with the left where the gray-white differentiation is
clearly seen in a patient 2 hours after onset of left hemiparesis.
Treatment
Key Points
Algorithms based on the nature and duration (usually <3 hours) of neurologic symptoms
can identify patients with acute stroke for whom the emergent administration of
recombinant tissue plasminogen activator can reduce subsequent functional impairment.
The most serious complication of administering recombinant tissue plasminogen
activator is symptomatic intracranial hemorrhage, which occurs in 6.4% of treated
patients and has a mortality rate approaching 50%.
In patients who are candidates for thrombolytic therapy, blood pressure should be less
than 185/110 mm Hg, which can be achieved by the continuous infusion of labetalol or
nicardipine; for those who are not candidates for such therapy, blood pressure should be
less than 220/120 mm Hg until hospital discharge.
Thrombolysis
The effectiveness of thrombolysis with recombinant tissue plasminogen activator (rtPA)
administered within 3 hours of acute ischemic stroke was examined in the National Institute of
Neurological Diseases and Stroke trial. Compared with a placebo infusion, rtPA was
associated with improved functional outcomes at 3 months but not with earlier neurologic
improvement or lower mortality. National guidelines recommend that treatment be initiated
within 1 hour of arrival at the emergency department. rtPA is a fibrinolytic agent that converts
plasminogen to plasmin in the presence of fibrin to initiate fibrinolysis at the site of thrombus
formation, which improves blood flow to areas of the brain that are ischemic but not yet
infarcted (ischemic penumbra). A small number of patients with acute ischemic stroke will be
eligible for reperfusion therapy, and an even smaller number will actually receive it. Figure 13
presents a proposed algorithm for the treatment of acute ischemic stroke. More recent
evidence has shown a benefit of rtPA up to 4.5 hours after stroke onset, although exclusion
criteria (age greater than 80 years, severe stroke, diabetes mellitus with a previous infarct, and
any anticoagulant use) are more restrictive than for treatment 3 hours or less from onset.
Despite the extended window for rtPA administration, patients derive the greatest benefit the
sooner they are treated. The exclusion criteria for rtPA are provided in Table 15; some of these
criteria are relative rather than absolute.
The most feared complication of rtPA treatment is symptomatic intracranial hemorrhage, which
occurs in 6.4% of treated patients and has a mortality rate approaching 50%. The principal risk
factors for hemorrhage after rtPA administration include a large infarct size, poor blood
pressure control, hyperglycemia, and treatment after the appropriate time window. The
presence of nausea, headache, or worsening findings on neurologic examination should
prompt immediate discontinuation of rtPA infusion and repeat head CT. All patients who
receive intravenous rtPA should be monitored for 24 hours in an intensive care unit or stroke
unit, where blood pressure and neurologic status can be monitored closely. Surgical
procedures and antithrombotic treatment should be avoided for 24 hours after rtPA
administration, but arterial puncture is permitted at a compressible site, if necessary.
In recent years, catheter-based approaches to treat acute ischemic stroke have been
developed. These techniques include local delivery of the thrombolytic agent at the site of a
vascular occlusion or mechanical thrombectomy. Both methods have been shown to improve
recanalization rates. A previous study showed intra-arterial thrombolytic agents to be superior
to intravenous heparin alone if started within 6 hours of stroke onset in patients with largevessel occlusions. However, subsequent clinical trials have not shown improved outcomes
when catheter-based therapies are added to intravenous thrombolysis or a benefit in using
intra-arterial therapies alone compared with intravenous thrombolysis. Further, no findings on
neuroimaging have been identified that predict a favorable response to intra-arterial therapies.
Therefore, intravenous thrombolysis is considered first-line therapy for patients with acute
ischemic stroke seen within 4.5 hours of stroke onset. Mechanical thrombectomy remains a
reasonable alternative for patients seen in this time frame who have an occlusion of a large
intracranial artery but have a contraindication to thrombolytic therapy.
Figure 13.
Algorithm for treating patients within 6 hours of an ischemic stroke. AVM = arteriovenous malformation; ICU =
intensive care unit; IV = intravenous; MCA = middle cerebral artery; NIHSS = National Institutes of Health Stroke
Scale; PTT = partial thromboplastin time; rtPA = recombinant tissue plasminogen activator.
Table 15. Exclusion Criteria for Administering Intravenous Tissue Plasminogen Activator 3
Hours or Less After an Ischemic Stroke
Contraindications to rtPA
Minor or rapidly improving symptoms
Seizure at stroke onset
Other stroke or trauma within 3 months
Major surgery within the last 14 days
History of intracerebral hemorrhage
Sustained blood pressure 185/110 mm Hg
Aggressive drug therapy needed to control blood pressure
Suspicion of subarachnoid hemorrhage
Arterial puncture at a noncompressible site within 7 days
Heparin received within the last 48 hours and PTT elevated
INR >1.7
Platelet count <100,000/L (100 109/L)
Plasma glucose level <50 mg/dL (2.8 mmol/L) or >400 mg/dL (22.2 mmol/L)
PTT = partial thromboplastin time; rtPA = recombinant tissue plasminogen activator.
Source: Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological
Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587. PMID:
7477192
Intracerebral Hemorrhage
Key Point
For patients with elevated intracranial pressure resulting from an intracerebral
hemorrhage, the mainstay of therapy is medical stabilization and emergent neurosurgical
evaluation to determine if the hematoma should be surgically evacuated.
Patients who sustain an ICH are at high risk of immediate neurologic and cardiac
complications and should be admitted to an intensive care unit with staff experienced in
treating neurologic diseases. The immediate neurologic complications of ICH include
expansion of the hematoma and elevated intracranial pressure.
Strategies aimed at preventing hematoma expansion have been disappointing, although
lowering blood pressure is safe and effective. In patients with a systolic blood pressure greater
than 200 mm Hg or a mean arterial pressure greater than 150 mm Hg, aggressive blood
pressure lowering by means of an intravenous infusion of medication (such as labetalol or
nicardipine) with frequent monitoring of vital signs (at least every 5 minutes) should be
considered. If the systolic blood pressure is greater than 180 mm Hg or the mean arterial
pressure is greater than 130 mm Hg, intravenous medications should still be considered. A
blood pressure target of 160/90 mm Hg or mean arterial pressure of 110 mm Hg is
recommended, although in patients with ICH whose systolic blood pressure is 150 to 220 mm
Hg, lowering it to 140 mm Hg seems safe. Blood pressure in patients with elevated intracranial
pressure may need to be managed with the help of an intracranial pressure monitor. Elevated
intracranial pressure can occur because of mass effect from the hematoma and associated
edema or from extension of blood into the ventricular system with subsequent hydrocephalus.
The latter occurrence is a neurosurgical emergency and requires emergent ventricular
shunting. Attempting to reduce hematoma expansion with recombinant factor VII does not yield
an overall improved prognosis and is associated with a greater incidence of thrombotic events.
In patients with oral anticoagulantassociated ICH, treatment should include reversing the
hemorrhagic diathesis as quickly as possible by stopping the anticoagulant and administering
an appropriate reversal agent, such as intravenous vitamin K, fresh frozen plasma, or
prothrombin complex concentrates. The efficacy and safety of platelet transfusions in the
setting of antiplatelet-associated ICH have not been established. For patients with ICH who
experience elevated intracranial pressure, the mainstay of treatment is medical stabilization
followed by surgical evacuation of the hematoma. Intubation and short-term hyperventilation
are the initial steps in treatment followed by osmotherapy with either mannitol or hypertonic
saline.
Whether clot removal should be performed in all patients with ICH remains uncertain. In
selected patients, such as those with a cerebellar ICH greater than 3 cm in size or with
neurologic deterioration, surgical removal is recommended. In patients with a superficial
hemorrhage greater than 30 mL, this approach can also be considered.
Subarachnoid Hemorrhage
Key Points
Angiography is essential to delineate the anatomy of a ruptured cerebral aneurysm and
to rule out other causes of subarachnoid hemorrhage, such as intracranial arterial
dissection or mycotic aneurysms.
The chief causes of a decline in neurologic status after subarachnoid hemorrhage are
rebleeding and elevated intracranial pressure in the acute setting and arterial vasospasm
5 days or more after the hemorrhage.
SAH is associated with neurologic decline and early mortality. The main risk factors for
aneurysmal SAH are tobacco use and hypertension. In the acute setting, patients with SAH
have sudden-onset severe headache (worst headache ever) with associated coma or other
impairments in alertness and consciousness. The presence of a large dilated pupil is an
additional localizing feature and occurs because of cerebral herniation or mass effect from a
posterior communicating artery aneurysm. Funduscopic examination may reveal subhyaloid
hemorrhages. These signs and symptoms should prompt an immediate investigation with head
CT to confirm or exclude hydrocephalus or global cerebral edema. The initial clinical grade
(Hunt-Hess scale) has a high predictive value for mortality and medical complications: grade 1
patients have isolated headaches and have excellent outcomes, whereas grade V patients
who present with coma have a greater than 60% mortality rate and a high risk for medical
complications. CT angiography may help identify the source of the SAH, which is most
commonly a saccular aneurysm at major arterial bifurcations (Figure 14). Angiography is
essential to delineate the anatomy of a ruptured cerebral aneurysm and to rule out other
causes of SAH, such as intracranial arterial dissection or mycotic aneurysms.
Early complications of SAH include rebleeding, elevated intracranial pressure, global cerebral
edema, and hydrocephalus from the presence of blood in the ventricular system. External
shunting of the cerebrospinal fluid is often required with SAHs and has the additional benefit of
enabling monitoring of intracranial pressure. By the fifth day after initial aneurysmal bleeding,
secondary cerebral injury can result from seizures, worsening hydrocephalus, or delayed
cerebral ischemia because of arterial vasospasm. Nimodipine is administered to prevent
vasospasm, and cerebral ischemia is sometimes prevented by elevating mean arterial
pressures with the use of systemic vasopressors.
Figure 14.
Angiograms showing an internal carotid artery aneurysm in a patient with a subarachnoid hemorrhage.
Top left, CT angiogram showing an extensive subarachnoid hemorrhage with intraventricular extension.
Top right, CT angiogram showing a large right internal carotid artery aneurysm. Bottom left,
anteroposterior view of a digital subtraction angiogram of the right intracranial internal carotid artery
showing the same large aneurysm. Bottom right, lateral view of the digital subtraction angiogram showing
the same large aneurysm.
Figure 15.
Imaging studies of a patient with dural sinus venous thrombosis. Top left, fluid-attenuated inversion recovery
(FLAIR) MRI showing extensive vasogenic edema in the basal ganglia. Top right, magnetic resonance
venogram (MRV) of the brain at presentation showing absent deep cerebral venous structures (thicker arrow)
and absence of the anterior half of the superior sagittal sinus (thinner arrow). Bottom left, MRV 1 week after
initiating intravenous heparin showing improved flow in the superior sagittal sinus (arrow). Bottom right, MRV
6 months after initiation of warfarin showing reconstitution of the deep cerebral venous structures and
superior sagittal sinus (arrow).
Figure 16.
Left internal carotid artery (ICA) dissection in a 32-year-old woman with a left frontal cerebral
infarct. Top left, magnetic resonance angiogram of the neck showing mild irregularity in the
distal extracranial internal carotid artery with a possible pseudoaneurysm (arrow). Top right,
T1-weighted MRI of the soft tissues in the neck showing a crescent-shaped hematoma (arrow)
within the ICA wall. Bottom, carotid Duplex ultrasonograms from the same patient showing
turbulent flow in the mid- to distal internal carotid artery with associated accelerated systolic
and diastolic velocities. DICA = distal ICA; LT = left; PICA = proximal ICA.
Asymptomatic Aneurysm
Key Point
Size and location are the major predictors of subsequent rupture for incidentally
discovered cerebral aneurysms; the most prudent management is watchful waiting with
repeated neuroimaging to monitor increasing aneurysmal size, particularly for anterior
cerebral aneurysms less than 12 mm in diameter and posterior circulation aneurysms
less than 7 mm in diameter.
Advances in modern neuroimaging have led to the identification of frequent, often incidental,
unruptured cerebral aneurysms in otherwise healthy persons. Aneurysm size and location are
the most important predictors of subsequent rupture. In the anterior cerebral circulation, the
risk of rupture over 5 years is negligible until an aneurysm reaches 12 mm in diameter; in the
posterior circulation, the risk of rupture increases as aneurysms become greater than 7 mm.
The risk of endovascular or open neurosurgical procedures to occlude or clip aneurysms is
significant, and thus the most prudent approach is watchful waiting with repeated
neuroimaging to monitor increasing aneurysmal size. Modifiable risk factors for aneurysmal
rupture, such as hypertension and tobacco use, should be treated.
Hypertension
The presence of hypertension has the greatest effect on the risk of stroke, regardless of the
cause. Therefore, hypertension should be treated after a stroke, even in the absence of a
history of hypertension. Clinical trial data indicate that the risk of recurrent stroke increases in
those patients whose blood pressure is allowed to remain above 140/80 mm Hg. For more
information on hypertension and stroke risk, see MKSAP 16 Nephrology.
Dyslipidemia
Hyperlipidemia is a key and modifiable risk factor in stroke recurrence. In all patients with a
serum LDL cholesterol level greater than 100 mg/dL (2.59 mmol/L) who have stroke, recent
clinical trial data support the use of a high-dose statin for the prevention of recurrent ischemic
stroke and myocardial infarction, despite the mild increase in the risk of ICH.
Antithrombotic Treatment
Key Points
All patients with atrial fibrillation who have a transient ischemic attack or stroke should
receive anticoagulation unless a clear contraindication exists.
Clopidogrel is indicated for patients with ischemic stroke and peripheral arterial disease
to prevent recurrent stroke; the combination of aspirin and clopidogrel has no additional
benefit over a single antiplatelet agent alone in stroke prevention.
The pathophysiology of ischemic stroke will frequently dictate the choice of an antithrombotic
agent. Only in atrial fibrillation and intracardiac thrombus have warfarin and direct thrombin
inhibitors been established as the treatment of choice for stroke prevention. All patients with
atrial fibrillation who have a TIA or stroke should receive anticoagulation unless a clear
contraindication exists. In aortic arch atheroma, the optimal antithrombotic treatment remains
controversial, with no evidence supporting warfarin over antiplatelet agents. If full
anticoagulation with warfarin or dabigatran is not possible, as in patients with recurrent falls or
a previous ICH due to amyloid angiopathy, other effective strategies for stroke prevention in
patients with atrial fibrillation exist, including aspirin, 325 mg/d, or aspirin combined with
clopidogrel.
Antiplatelet agents are recommended over anticoagulation in patients with stroke who have
intracranial atherosclerosis because warfarin was associated in one clinical trial with an
increase in mortality compared with high-dose aspirin. For patients with cryptogenic and smallvessel stroke, warfarin and aspirin are equivalent in reducing the risk of recurrent ischemic
stroke, although antiplatelet agents are sometimes favored because of their ease of use. For
stroke prevention in patients without atrial fibrillation, the most commonly used aspirin dosage
is 81 mg/d. Several studies have shown modest differences between aspirin, clopidogrel, and
dipyridamole in preventing recurrent stroke and adverse cardiovascular outcomes in patients
with stroke. In one trial, clopidogrel showed an overall modest benefit in the primary outcome
of composite vascular events (recurrent ischemic stroke, myocardial infarction, or vascular
death), particularly in patients with peripheral arterial disease. However, clopidogrel versus the
combination of aspirin and dipyridamole was equivalent in a recent clinical trial. Clopidogrel is
prescribed for stroke prevention in patients who have peripheral arterial disease, and
clopidogrel or aspirin and dipyridamole are reasonable options for those who have had a
recurrent ischemic stroke despite optimal risk factor management while treated with aspirin.
Adherence to an aspirin and dipyridamole regimen can be difficult because of the high
incidence of headache, and the cost of the combination agent or clopidogrel can be
problematic for many patients. At this time, the combination of aspirin and clopidogrel is not
commonly used in patients without cardioembolic stroke unless dictated by the presence of
vascular stents or a previous myocardial infarction. See MKSAP 16 Cardiovascular Medicine
for more information.
Hemicraniectomy
Infarctions of the middle cerebral artery involving more than 50% of the arterial territory that
are accompanied by severe brain swelling have a mortality rate of 80%. According to data from
three pooled European studies, hemicraniectomy significantly reduces mortality and severe
disability (from 76% to 25%) in patients with malignant middle cerebral artery infarction. This
benefit is greatest if hemicraniectomy is performed within 48 hours of stroke onset, before
clinical herniation has occurred. The procedure opens the bony encasement of the skull and
decompresses the brain.
Neurologic Worsening
Patients with an ischemic stroke or a TIA may have a recurrent stroke while still hospitalized,
although the risk appears higher with TIAs and can be determined by the ABCD2 score. In
patients with stroke recurrence, two major mechanisms have been noted: (1) extension of the
previous infarct due to expansion of the area of the ischemic territory and (2) a separate,
distinct stroke due to either ongoing stroke pathophysiology or a complication of stroke
therapy. Preventing expansion of the ischemic territory can be achieved by not treating
hypertension while using antithrombotic medication. The hemorrhagic conversion of an
ischemic stroke typically occurs in the first 24 hours but can occur up to 2 weeks after the initial
infarction. Hemorrhagic conversion is most likely to occur with large infarcts and cardiac
embolism and is also associated with vessel recanalization during thrombolytic treatment.
Neurologic decline after stroke may also result from seizure, urinary tract infection, pneumonia,
hypoglycemia, or sedative medication use.
Medical Complications
Key Point
Deep venous thrombosis and the subsequent development of a pulmonary embolism
after stroke can be prevented with early implementation of prophylaxis strategies, such
as early mobilization, administration of low-molecular-weight or unfractionated heparin,
and mechanical compression devices.
Medical complications after stroke are common, particularly in older patients with medical
comorbidities and in patients with more severe stroke syndromes, and result in increased
length of hospital stay, poor functional outcome, and mortality. During the first week after a
stroke, medical complications include cardiac disease, deep venous thrombosis, urinary tract
infection, and pneumonia. Many of these complications stem from immobility, and thus early
physical and occupational therapy with an emphasis on ambulation and moving out of bed has
a critical role. After 1 week, the same complications pertain but additional complications also
arise, including falls and fractures, depression, and skin breakdown because of immobility.
Cardiac complications after stroke also occur, which is not surprising because heart disease
and stroke share common risk factors. Heart failure after stroke has been attributed to new
myocardial infarction or arrhythmia, hypertension due to withholding antihypertensive agents,
and a cerebral stressrelated cardiomyopathy that is associated with mild elevations in serum
troponin levels, nonspecific ischemic changes in the anterolateral leads on
electrocardiography, and a reversible global decline in left ventricular systolic function. The
latter is most likely to occur in patients with ICH, high-grade SAH, and large ischemic strokes.
Infectious complications after stroke are primarily due to pneumonia and urinary tract
infections. Most pneumonia is attributed to aspiration of food and drink taken orally, a more
likely occurrence in older patients and those with dysphagia and early speech impairment.
Implementation of dysphagia screening protocols early in the hospital admission can reduce
the incidence of pneumonia in patients with stroke and are recommended by the Joint
Commission National Quality Core Measures. Feeding through a nasogastric tube or
percutaneous endoscopic gastrostomy tube can achieve nutritional goals in patients unable to
swallow safely, although aspiration may still occur from regurgitation of gastric contents if the
head of the bed is not kept higher than 30 degrees. The timing of when to place a
percutaneous endoscopic gastrostomy tube remains unclear. Urinary tract infections also are
common after stroke because of urinary retention after cerebral injury or the unnecessary use
of urine catheters; these catheters can be safely removed in many patients with stroke.
The presence of hemiparesis makes the incidence of deep venous thrombosis particularly
common in patients with stroke, especially within the first week after onset. Deep venous
thrombosis and the subsequent development of a pulmonary embolism can be prevented with
early implementation of prophylaxis strategies. In patients with ischemic stroke, unfractionated
heparin (5000 units every 8 hours) or low-molecular-weight heparin is effective in reducing the
risk of deep venous thrombosis and should be started by the first hospital day. In hemorrhagic
stroke, either agent should be started by hospital day 1 to 4 as long as the source of the
bleeding, such as an aneurysm, has been identified and treated or there is no evidence of
active intracranial bleeding; in the interim, mechanical (pneumatic) compression devices
should be used for prophylaxis. Graded compression stockings do not appear to be effective in
reducing the risk of deep venous thrombosis. In patients with stroke who have acute-onset
hypoxemia, pulmonary embolism should be considered as a cause, although pneumonia,
sleep apnea, and diaphragmatic dysfunction are other possibilities.
Infectious complications and poststroke depression can have a significant effect on long-term
recovery after stroke. Other complications that may emerge in the more chronic setting are
sleep-disordered breathing, fatigue, pain, falls and fractures, diabetes mellitus, and cognitive
dysfunction.
Perioperative Stroke
With increasing numbers of surgical procedures has come an increase in the incidence of
perioperative stroke. Most of these strokes are ischemic and occur as a complication of
cardiothoracic surgery. The most common cause of perioperative stroke after cardiothoracic
surgery is postoperative atrial fibrillation rather than hypotension. Preexisting symptomatic
carotid artery disease and coronary artery bypass grafting with valve replacement increase the
likelihood of perioperative stroke in cardiac surgery. Spinal cord infarcts also can occur in the
perioperative period as a complication of aortic dissection or subsequent aortic grafting.
Table 16. Common Risk Factors for Ischemic and Hemorrhagic Stroke
Ischemic Stroke/TIA
Intracerebral
Hemorrhage
Subarachnoid
Hemorrhage
Hypertension
Hypertension
Hypertension
Cocaine abuse
Cocaine abuse
Cocaine abuse
Tobacco use
Tobacco use
Tobacco use
Arteriovenous
malformation
Arteriovenous
malformation
Diabetes mellitus
Amyloid angiopathy
Atrial fibrillation
Decreased LDL
cholesterol level
Intracranial artery
dissection
Polycystic kidney
disease
Key Points
Diagnosis of Stroke
In the acute setting, head CT without contrast is the initial test of choice to confirm
or exclude hemorrhagic stroke; subsequent MRI can identify acute ischemia or a
nonvascular cause.
Stroke Subtypes
The ABCD2 score (based on Age, Blood pressure, Clinical presentation, Duration of
symptoms, and the presence of Diabetes mellitus) can help clinicians identify
patients with transient ischemic attacks who are at highest risk of subsequent
stroke and would benefit from hospital admission.
Ischemic stroke connotes the presence of cerebral infarction, although the lesion is
not always evident on CT scans or diffusion-weighted MRIs.
The differential diagnosis of intracerebral hemorrhage, which has a much higher
mortality than ischemic stroke, includes vascular malformation, infection, and brain
tumor with hemorrhage.
Acute Ischemic Stroke
Algorithms based on the nature and duration (usually <3 hours) of neurologic
symptoms can identify patients with acute stroke for whom the emergent
administration of recombinant tissue plasminogen activator can reduce subsequent
functional impairment.
The most serious complication of administering recombinant tissue plasminogen
activator is symptomatic intracranial hemorrhage, which occurs in 6.4% of treated
patients and has a mortality rate approaching 50%.
In patients who are candidates for thrombolytic therapy, blood pressure should be
less than 185/110 mm Hg, which can be achieved by the continuous infusion of
labetalol or nicardipine; for those who are not candidates for such therapy, blood
pressure should be less than 220/120 mm Hg until hospital discharge.
Acute Hemorrhagic Stroke
For patients with elevated intracranial pressure resulting from an intracerebral
hemorrhage, the mainstay of therapy is medical stabilization and emergent
neurosurgical evaluation to determine if the hematoma should be surgically
evacuated.
Angiography is essential to delineate the anatomy of a ruptured cerebral aneurysm
and to rule out other causes of subarachnoid hemorrhage, such as intracranial
arterial dissection or mycotic aneurysms.
The chief causes of a decline in neurologic status after subarachnoid hemorrhage
are rebleeding and elevated intracranial pressure in the acute setting and arterial
vasospasm 5 days or more after the hemorrhage.
Bibliography
Adams HP Jr, del Zoppo G, Alberts MJ, et al; American Heart Association; American
Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology
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Care Outcomes in Research Interdisciplinary Working Groups. Guidelines for the early
management of adults with ischemic stroke: a guideline from the American Heart
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Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral
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Dementia
General Overview
Alzheimer Disease
Non-Alzheimer Dementias
Key Points
Bibliography
General Overview
Dementia
Delirium
Persistent
vegetative or
minimally
conscious state
evaluation when the patient sits quietly as the spouse or caretaker provides the historical
details. Primitive neurologic reflexes also may appear in patients with dementia, such as grasp
and rooting reflexes, a snout reflex, a palmomental sign, a glabellar sign, and a tendency to
retropulse (move backward) on standing. Depression should be excluded as the apparent
cause of the cognitive decline because the psychomotor retardation of depression can mimic
dementia but does not correlate with brain pathology and is reversible with effective treatment.
The clinical manifestations of dementia depend more on the location of pathologic changes
than on the disease process itself. Most neurodegenerative diseases are not site specific but,
rather, involve overlapping brain regions. The overall clinical pattern of dementia often can be
divided into cortical and subcortical types. The prototypic cortical dementia is Alzheimer
disease, which produces characteristic memory deficits, language impairment, and other
features attributable to disease of the associative parietotemporal cortices. By contrast,
subcortical dementias, of which the prototype is Parkinson diseaseassociated dementia,
include features of parkinsonism, apathy, bradyphrenia, and depression.
Brain biopsy is the most definitive diagnostic test, but its routine use cannot be justified
because of its risks and costs.
Inflammatory and
autoimmune
Infectious
Endocrine
Structural
Toxic/metabolic
Psychiatric
Alzheimer Disease
Prevalence
Pathogenesis
Clinical Features
Pathologic Features
Treatment
Prevalence
Alzheimer disease is the leading cause of dementia in developed countries, accounting for
enormous suffering, loss of productivity, and caregiver burden. Over 4 million people in the
United States have Alzheimer disease, which is the leading cause of institutionalization in
chronic care facilities. Although Alzheimer disease is not an inevitable consequence of getting
older, the prevalence of the disease doubles every 5 years after age 65 years. It is estimated
that 20% to 40% of individuals older than 85 years have Alzheimer disease. Alzheimer disease
usually occurs sporadically, but a small number (<1%) of affected persons have a familial form
inherited in an autosomal dominant mode with early onset. Mutations in the genes for tau
protein metabolism, such as presenilin, account for a fraction of cases and reveal clues about
the biologic events leading to the pathologic changes.
Pathogenesis
The pathogenesis of Alzheimer disease remains incompletely understood. Converging
evidence from genetic and immunohistochemical studies implicates -amyloid protein as a key
pathologic agent. -Amyloid is derived from the amyloid precursor protein, which is normally
bound to neuronal membranes. The pathologic cleavage of this protein results in elevated
levels of -amyloid.
The normal sequence of proteolysis of the amyloid precursor protein by a series of secretases
does not result in neuronal toxicity, but in Alzheimer disease, the resulting 42amino acid
product leads to amyloid and neuronal damage. Apolipoprotein E interacts with the -amyloid
protein, and the E4 isoform of apolipoprotein E is a genetic marker that increases the accuracy
of diagnosis by approximately 4%. Notably, the gene encoding the amyloid precursor protein
resides on chromosome 21, where the gene for familial Alzheimer disease is located.
Clinical Features
The onset of dementia is usually so insidious that the diagnosis can be made only in retrospect
after cognitive decline or disengagement from routine activities or behavioral pattern becomes
obvious. Persistent forgetfulness is the hallmark of Alzheimer disease, beginning with objects,
appointments, names, and other apparently trivial items. As the disease progresses past the
point of normal age-related forgetfulness, memories are lost and problems with word-finding
ability become apparent. Sometimes, a confusional episode is triggered by an environmental
stress, such as a surgery, a head injury, or a medication. The ability to perform complex
mental operations, such as reading or calculating, or to execute multistep tasks, such as
planning a meal or shopping, declines. Visuospatial impairment and apraxia develop, with
patients losing the ability to dress themselves, perform complex motor actions, or use tools,
such as a television remote control or a telephone.
Patients may be anxious or confused and may report chronic vague cephalic sensations, such
as dizziness or not feeling right. In the absence of gait or motor impairment, they may wander
and become lost. Patients lose their ability to empathize with others and become absorbed in
their immediate needs, regressing to the psychological dependence of a child. They may
become demanding, belligerent, paranoid, agitated, or anxious. Some patients develop a
misidentification delusion, or Capgras syndrome, in which they believe their family members or
caretakers are imposters. Agitation, psychosis, aggression, and disinhibited behavior are
common, may overwhelm the level of supervision and resources available in the home
environment, and may lead to institutionalization. The sleep cycle is disturbed, with prolonged
daytime somnolence and nocturnal agitation. Impairments in bladder and bowel control leading
to incontinence are typical. Balance is eventually impaired, and patients may develop aspects
of parkinsonism. With time, patients who survive deteriorate to a flexion posture and a
persistent vegetative state, becoming bedridden and prone to the complications of prolonged
immobility. The disease course may take 5 to 15 years, depending on the length of the
prodrome, rate of progression, and development of complications.
To date, no reliable or convenient disease-specific biologic markers for Alzheimer disease
exist, and the diagnosis essentially depends on the exclusion of other causes of dementia by
using the diagnostic approach detailed earlier. A number of CSF biologic markers-amyloid
protein 1-42 and tau proteinsare under investigation as ways of diagnosing Alzheimer
disease but are not standard tests. The role of single-photon emission CT or PET scans, which
provide markers of regional brain metabolic activity and blood flow and generally reflect
cerebral atrophy, is not established. Amyloid imaging is a promising diagnostic modality that is
currently under development.
Pathologic Features
Key Point
The gross pathologic features of Alzheimer disease include diffuse brain atrophy, with
corresponding widening of the sulci and enlargement of the ventricles appreciable on CT
scans and MRIs.
The gross pathologic features of Alzheimer disease include diffuse brain atrophy, with
corresponding widening of the sulci and enlargement of the ventricles appreciable on CT
scans and MRIs. The degree of the widening and enlargement correlates with the impairment
in cognition. The histologic features of Alzheimer disease include neurofibrillary tangles
(composed of knotted loops, strands of silver-stained material within the cell bodies of
neurons, and helices of hyperphosphorylated tau microtubular protein), amyloid-containing
neuritic plaques, and granulovacuolar degeneration of neurons (Figure 17). The most severely
affected brain regions are the hippocampus, temporal lobe, and the acetylcholine-containing
basal nucleus of Meynert.
Figure 17.
Photomicrograph showing Alzheimer disease. Neuritic plaques and neurofibrillary tangles are
evident in this photomicrograph of an immunohistologic slide of an autopsy specimen from the
amygdala of a 71-year-old man (Bielschowsky, original magnification 200).
Photomicrograph courtesy of Dr. Jean-Paul Vonsattel.
Treatment
Key Point
Although no effective strategies exist for reversing or slowing the progression of
Alzheimer disease, donepezil, rivastigmine, tacrine, galantamine, and memantine may
provide short-lived improvements in cognition.
Alzheimer disease is not curable, and no approach is effective in slowing the disease
progression. The pharmacologic approach is aimed at improving the brain cholinergic deficit in
Alzheimer disease by using cholinesterase inhibitors (donepezil, rivastigmine, tacrine, and
galantamine). In randomized, multicenter, double-blind trials, these agents have been shown
to improve the cognitive function of persons with mild, moderate, or severe dementia due to
Alzheimer disease and to improve caregivers' ratings of patients' capacity for daily living
activities. Memantine, a drug that blocks the glutamatergic N-methyl-D-aspartate receptor, has
also shown clinical benefit in patients with moderate to severe Alzheimer disease and as an
adjunctive agent for patients on a cholinesterase inhibitor. The antioxidants vitamin E and
selegiline may reduce the rates of institutionalization for patients with Alzheimer disease,
although the effect is modest. New approaches targeting the overproduction of -amyloid are
the focus of research. Table 19 summarizes the pharmacologic approach to Alzheimer
disease.
In addition to improving cognitive performance of patients with Alzheimer disease, the
therapeutic approach has several other goals: (1) managing the behavioral complications of
agitation, psychosis, confusion, aggression, insomnia, depression, and anxiety; (2) identifying
and eliminating medications that may cause cognitive impairment or excessive sedation, such
as anticholinergic agents (to which older patients with dementia are especially susceptible) or
benzodiazepines; (3) identifying and treating intercurrent medical illness that may cause acute
changes in cognition, such as infection or dehydration; (4) providing comfort and safety to
patients; (5) providing support to caregivers and preventing caregiver burnout; and (6)
preventing the late-stage neurologic and medical complications of motor impairment and
immobility, such as falls, dysphagia, aspiration, infections, and skin breakdown.
A clinician's first reaction to a new behavioral disturbance may be to prescribe a new
medication, but it is important to explore, if possible, nonpharmacologic strategies to modify
patient behavior, such as reassurance or distraction. Depression is common in Alzheimer
disease and can be treated with serotonin reuptake inhibitors; drugs with anticholinergic
effects, such as tricyclic antidepressants, should be avoided because they can potentiate
cognitive impairment. Psychosis, paranoia, agitation, and violent behavior can be treated with
sedatives and tranquilizers, including neuroleptic agents and benzodiazepines. In general,
agents with less of a dopamine receptorblocking effect are preferred because dopamine
antagonists can cause parkinsonism and gait impairment. Agents for anxiety and insomnia are
often needed but carry a risk of inducing confusion. Additional treatment guidelines are
provided in Table 20.
End-stage dementia is complicated by feeding impairment, the loss of bladder and bowel
control, and the inability to transfer, ambulate, or perform any activity. Patients with advanced
dementia may be subjected to burdensome interventions of questionable benefit
(hospitalization, emergency department visits, parenteral therapy, and tube feeding). Palliative
care is currently underutilized in this population.
Class
Target
Dosage
Titration
Schedule
Adverse Effects
Donepezil
Acetylcholinesterase
inhibitor
10 mg/d
4-6 wk
Nausea, vomiting,
diarrhea, vivid
dreams
Rivastigmine
Acetylcholinesterase
inhibitor
6 mg
twice daily
2-4 wk
Nausea, vomiting,
diarrhea, dizziness
Tacrine
Acetylcholinesterase
inhibitor
20-40 mg
four times
daily
8-12 wk
Hepatic toxicity
requiring liver
enzyme monitoring
Galantamine
Acetylcholinesterase
inhibitor; nicotinic receptor
agonist
12 mg
twice daily
4 wk
Nausea, vomiting,
diarrhea, dizziness;
possible cardiac
effects
Memantine
N-methyl-D-aspartate
inhibitor
10 mg
twice daily
4 wk
Agitation and
confusion
Table 20. Guidelines for Treating Alzheimer Disease and Other Dementias
Ensure a safe, familiar, nonthreatening, well-lighted environment with simple routines,
vigilance, and reassurance.
Address causes of frustration and irritability, such as pain, infection, and hunger.
Treat depression and anxiety.
Treat agitation and psychosis with low-dose atypical neuroleptics.
Encourage frequent engagement and socialization.
Encourage exercise.
Encourage cognitive tasks.
Optimize hearing, vision, and orientation.
Avoid dehydration, falls, infections, and aspiration.
Non-Alzheimer Dementias
Figure 18.
Photomicrograph showing diffuse Lewy body disease, neocortical type. This image is from the
fifth cortical layer of the cingulate gyrus subjected to antibodies directed against -synuclein
aggregates and shows at least six Lewy bodycontaining neurons (discrete black dots). The
normal neuropil has a golden finely granular appearance (-synuclein, original magnification
100).
Photomicrograph courtesy of Dr. Jean-Paul Vonsattel.
Frontotemporal Dementia
Key Point
The clinical features of frontotemporal dementia include disinhibition, poor judgment,
impulsivity, perseveration, obsessionality, apathy, depression, memory loss, executive
dysfunction, and loss of verbal fluency.
Frontotemporal dementia is a heterogeneous clinical syndrome of behavioral and cognitive
deterioration combined with parkinsonism and motoneuron disease. The cognitive and
behavioral features include disinhibition, poor judgment, impulsivity, perseveration,
obsessionality, apathy, depression, memory loss, executive dysfunction, and loss of verbal
fluency. Originally described as a syndrome of circumscribed cerebral atrophy confined to the
frontal and temporal lobes (Pick disease), frontotemporal dementia is now considered a family
of disorders defined by the abnormal accumulations of tau protein. Pathologically, the tau
protein appears to become hyperphosphorylated and then to aggregate in neurons or glia
(Figure 19). Several frontotemporal dementias are familial with autosomal dominant
inheritance and are caused by mutations in the tau protein, located on chromosome 17.
Figure 19.
Vascular Dementia
Key Point
The radiologic hallmark of vascular dementia is the presence of cerebral ischemia in the
form of multiple strokes or confluent ischemia.
Vascular dementia, at one time considered the second most common progressive dementia
after Alzheimer disease, is much less common than formerly believed. In many cases, brain
tissue formerly thought to show arteriosclerotic dementia later revealed Alzheimer changes
when modern histochemical techniques were applied.
Vascular dementia is a consequence of progressive ischemic brain injury and comprises two
main patterns of disease: (1) a series of obvious stepwise deteriorations in cognition
corresponding to clinical strokes affecting the territories of large cerebral vessels and (2) a
more gradual accumulation of cognitive deficits that reflects a spreading confluence of cerebral
ischemia. The category of vascular dementia includes the autosomal dominant syndrome of
cerebral arteriopathy with subcortical infarcts and leukoencephalopathy. The radiologic
hallmark of vascular dementia is the demonstration of cerebral ischemia, whether in the form
of multiple strokes or confluent ischemia. The differential diagnosis includes conditions that
cause multiple discrete infarcts, such as endocarditis or vasculitis, and conditions that cause
progressive leukoencephalopathy, such as progressive multifocal leukoencephalopathy or
advanced multiple sclerosis.
Key Points
General Overview
Persons with mild cognitive impairment develop Alzheimer disease at an
approximate rate of 10% to 15% per year.
A score less than 22 on either the Folstein MiniMental State Examination or the
Montreal Cognitive Assessment indicates dementia.
Alzheimer Disease
The gross pathologic features of Alzheimer disease include diffuse brain atrophy,
with corresponding widening of the sulci and enlargement of the ventricles
appreciable on CT scans and MRIs.
Although no effective strategies exist for reversing or slowing the progression of
Alzheimer disease, donepezil, rivastigmine, tacrine, galantamine, and memantine
may provide short-lived improvements in cognition.
Non-Alzheimer Dementias
The pathologic hallmark of dementia with Lewy bodies is the widespread presence
of eosinophilic intracytoplasmic accumulations of -synuclein (Lewy bodies).
The clinical features of frontotemporal dementia include disinhibition, poor
judgment, impulsivity, perseveration, obsessionality, apathy, depression, memory
loss, executive dysfunction, and loss of verbal fluency.
The radiologic hallmark of vascular dementia is the presence of cerebral ischemia
in the form of multiple strokes or confluent ischemia.
The best treatment of normal pressure hydrocephalus is shunt placement using an
externally controlled programmable valve that allows the careful regulation of
cerebrospinal fluid pressure.
A rating scale that assesses orientation, judgment, participation in community
affairs, self-directed participation in home activities, and personal care has been
shown to be helpful in assessing driving risk in persons with dementia.
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Movement Disorders
Clinical Features
Selected Causes
Akinesia/bradykinesia, rigidity,
tremor at rest, postural instability,
gait freezing, and flexion posture
Tic
Stereotyped, automatic,
purposeless movements and
vocalizations
Dystonia
Chorea
Huntington disease,
neuroacanthocytosis, postinfectious
chorea, drug-induced chorea,
vascular chorea, autoimmune
chorea, and chorea gravidarum
Hypokinetic
Parkinsonism
Hyperkinetic
Tremor
Type of
Movement
Clinical Features
Selected Causes
Myoclonus
Akathisia
Parkinson Disease
Parkinson disease is the only neurodegenerative disease linked to the loss of a specific
neurotransmitter, namely, dopamine. The prevalence of Parkinson disease is estimated to be
between 0.1% and 0.5% in the United States, with approximately 1 million persons affected by
the disorder. Parkinson disease has a median onset of approximately 56 years and is rare
before age 30 years. Approximately 13% of patients with Parkinson disease have an affected
first-degree relative. As with all neurodegenerative diseases, the major risk factor for Parkinson
disease is aging. Epidemiologic studies also have established an association between the
disorder and the use of well water, herbicide and pesticide exposure, and manganese toxicity.
Trauma is also a risk factor for Parkinson disease, on the basis of evidence in retrospective
case-control studies, and cigarette smoking appears to have an inverse correlation with the
subsequent development of the disorder.
Sporadic Parkinson disease is common, accounting for 90% of affected patients, but in a small
number of families, the disorder is clearly inherited as a genetic disorder. Within the past 10
years, the identification of several Parkinson diseasecausing gene mutations has contributed
to the hypothesis that defective ubiquitin proteolysis may lead to a cascade of events that
results in the formation of -synucleincontaining Lewy bodies and the death of dopaminergic
cells. An LRRK2 gene mutation is the most common cause of monogenic Parkinson disease.
backward. When combined with axial rigidity and bradykinesia, the loss of postural reflexes
places a person at extreme risk of falling, which often results in fractures and is the cause of
severe morbidity and mortality in this disorder.
In recent years, focus has intensified on the many symptoms of Parkinson disease that do not
involve the motor system and may not relate directly to a simple defect of dopamine. Parkinson
disease is a true multisystem disorder that may affect all of the body's physiologic systems,
including the musculoskeletal system, swallowing, respiration, the gastrointestinal system, and
the genitourinary system. Olfactory function typically is impaired in Parkinson disease, even in
the very early stages. Drooling (sialorrhea) is one of the most socially disabling symptoms of
Parkinson disease. Parkinson-related dementia is the second most common cause of
dementia after Alzheimer disease. A list of nonmotor complications of Parkinson disease is
provided in Table 22.
Symptoms
Cognitive
Behavioral
Sleep related
Autonomic
Musculoskeletal
Truncal and neck flexion, falls and fractures, arthritis and other
mechanical complications of Parkinson disease
Pain related
initiate levodopa in patients with Parkinson disease, and many physicians delay its use as long
as possible. The general, but not unanimous, consensus is that dopamine agonists should be
used as first-line symptomatic treatment. However, these drugs dysregulate the brain's
dopamine-dependent reward systems and result in a higher incidence of sedation and
compulsive behaviors than levodopa. Patients taking dopamine agonist medication to control
Parkinson disease should be warned about the potential for developing abnormal, compulsive
behaviors, such as excessive gambling, excessive shopping, hypersexuality, and other
uncontrollable urges. In older patients, their use also is associated with confusion and
hallucinations. Many clinicians, therefore, recommend levodopa as an initial treatment for
patients older than 70 years. Most specialists in Parkinson disease consider balance
impairment, gait freezing, and falling to be absolute indications for levodopa treatment.
In late-stage Parkinson disease, the focus of treatment is on avoiding falls or injury, preventing
the complications of immobility, treating dysphagia, preventing aspiration, maintaining nutrition,
and addressing the cognitive and psychiatric complications of the disorder, such as
depression, sleep disturbances, and psychosis.
Patients with advanced Parkinson disease who undergo surgery are at increased risk of
confusion, aspiration, autonomic dysfunction (hypotension, constipation, urinary retention), and
a slow recovery from immobility. Surgery that requires patients to stop taking oral medication
places special demands on those who are dependent on dopamine drugs for mobility and
function. Patients with Parkinson disease may have difficulty being weaned from mechanical
ventilation because of dysphagia, aspiration, and poor chest wall mobility.
Within 5 years of treatment with a dopamine agonist or levodopa, 50% of patients notice two
major complications, namely, motor fluctuations and dyskinesias. Wearing-off motor
fluctuations involve a return of parkinsonian symptoms and signs, such as bradykinesia,
tremor, rigidity, immobility, and gait freezing, within 3 hours of the patient's taking the
medication. Sometimes, the motor fluctuations are accompanied by anxiety, depressive
feelings, painful symptoms, dystonia, and autonomic disturbances. The wearing-off episodes
tend to be mild at first but become more severe, prolonged, and disabling over time.
Dyskinesias are choreic twisting, writhing movements caused by dopaminergic medications. In
a few patients, dyskinesias can be violent and ballistic. The presence of wearing-off motor
fluctuations and dyskinesias heralds a phase of complex medical management in which many
patients with Parkinson disease should be under the care of a specialist. Attempts to limit
dyskinesias by reducing the medication dosage tend to cause more parkinsonism, and treating
the prolonged wearing-off states with more medication exacerbates the dyskinesias.
Amantadine can help suppress dyskinesias in some patients.
Deep brain stimulation of the globus pallidus interna or subthalamic nucleus was approved by
the FDA approximately a decade ago as an effective means of controlling wearing-off motor
fluctuations and dyskinesias and should be considered in selected patients with advanced
Parkinson disease (Table 24). Additionally, deep brain stimulation of the ventral intermediate
thalamus suppresses medication-refractory parkinsonian tremor. The largest series available
provides 5-year follow-up data documenting long-term reductions of tremor, bradykinesia, and
rigidity with concomitant long-term improvements in quality of life. However, Parkinson disease
involves progressive neurodegeneration, and many patients develop the long-term
complications of speech impairment, postural instability, gait freezing, truncal flexion, and
dementia, symptoms that do not respond to deep brain stimulation.
Available in Europe.
Table 24. Patient Selection for Deep Brain Stimulation in Parkinson Disease
Characteristics of Good Candidates
Typical Parkinson disease with tremor
Good response to individual doses of levodopa
Dyskinesias
Wearing-off motor fluctuations
Good general health
Strong family and social support network
Characteristics of Poor Candidates
Atypical parkinsonism
Poor response to levodopa
Dementia or apathy
Depression or anxiety
Severe medical illness
Poor social support
Parkinson-Plus Syndromes
Key Point
Parkinson-plus syndromes are unresponsive to levodopa replacement, advance rapidly,
and lead to death within 8 to 12 years, on average.
Approximately 10% of patients with generalized bradykinesia and rigidity have an atypical form
of parkinsonism marked by a more rapid disease progression, a poor response to levodopa
replacement, and defining clinical features, including ocular palsy, dystonia, cerebellar signs,
myoclonus, autonomic failure, and apraxia (inability to perform familiar, purposeful movements
in the absence of any motor or sensory impairment). Although tremor is absent in up to 25% of
patients with classic idiopathic Parkinson disease, the absence of a tremor should raise the
suspicion of atypical parkinsonism. When falling is an early symptom, the diagnosis is almost
never Parkinson disease but instead a Parkinson-plus syndrome.
The three main types of Parkinson-plus syndromes, which account for approximately 10% to
15% of patients with parkinsonism, are progressive supranuclear palsy, corticobasal ganglionic
degeneration, and multiple system atrophy. In general, these syndromes are characterized by
atremulous symmetric parkinsonism that is more aggressive than Parkinson disease and leads
to early falling and dysphagia. These syndromes are unresponsive to levodopa replacement,
advance rapidly, and lead to death within 8 to 12 years, on average.
The clinical hallmarks of progressive supranuclear palsy are distinctive eye findings (including
impairment of vertical eye movements [square wave jerks, slow saccades, and a supranuclear
gaze paresis]), facial dystonia, and axial rigidity. Corticobasal ganglionic degeneration
presents as an asymmetric dystonic syndrome with apraxia, cortical sensory loss, tremor,
myoclonus, and dementia. The multiple system atrophy category includes a variant with
autonomic failure, sometimes termed Shy-Drager syndrome; a variant characterized by a
progressive cerebellar syndrome; and a form dominated by dystonia, termed striatonigral
degeneration.
Gait Disturbance
The neurologic examination of a patient who falls should focus primarily on detecting
weakness, whether of corticospinal tract or peripheral origin; proprioceptive deficits due to
neuropathy or dorsal column degeneration; parkinsonism; or ataxia. The gait is observed for
speed, stability, symmetry, stride length, floor clearance, posture, arm swing, base width, and
turning.
The hallmark of an ataxic gait is a widened stance with a tendency to lurch and veer. The
tandem stepping test, in which the patient is asked to walk a straight line, can reveal ataxia, as
can having the patient attempt to stand on one foot. In contrast, the parkinsonian gait is a
narrow-based and shuffling gait, with a stooped or tilted posture, short steps, hesitation, and
en bloc turning due to axial core rigidity. The characteristic hemiparetic gait is accompanied by
upper motoneuron signs of weakness, spasticity, and hyperreflexia. The choreic gait is
characterized by twitching and lurching, and the dystonic gait by twisting and posturing of the
foot or leg. The antalgic gait, which results from mechanical factors and pain in the foot, leg,
knee, or hip, is accompanied by pain on weight bearing that is compensated for by a quick
weight transfer to the unaffected side. This maneuver produces a shortened stepping phase on
the affected side and allows patients to spend less time on the painful side. A psychogenic gait
is typically inconsistent, incongruous, and elaborate, often with expressions of great effort,
unconvincing displays of weakness or impairment, sudden genuflections, and extreme lurching
without falling.
The Romberg test for ataxia is performed by having the patient stand with feet together and
eyes closed. Excessive sway requiring a corrective step is abnormal. The Romberg test
supports the diagnosis of ataxia but does not specifically localize its source, whether
myelopathic, cerebellar, vestibular, or peripheral, because all types of ataxia worsen in the
absence of visual cues.
The pull test, which is often omitted from a routine neurologic examination, is the prime
determinant of falling risk from parkinsonism. In this test, the examiner stands behind the
patient and, after giving a warning, pulls backward sharply enough to draw the patient off his or
her base. The normal response is a quick corrective backward step. More than one step
backward, a series of ineffective backward steps, or frank toppling into the examiner's arms
are abnormal responses and indicate a substantial future risk of backward falls.
Normative performance standards for gait testing in an older population are not established,
but a good starting point for the clinician is that falling is always pathologic. For more
information on falls in older patients, see MKSAP 16 General Internal Medicine.
Ataxia
Key Point
Most adult-onset chronic ataxia syndromes involve cerebellar degeneration, with
cerebellar and brainstem atrophy visible on MRI.
Ataxia is a syndrome of gait and stance impairment. The differential diagnosis depends on
whether the symptoms are acute, subacute, or chronic. Acute ataxia is caused by an intoxicant
(such as alcohol), a benzodiazepine, phenytoin, or a vascular event (such as a cerebellar or
brainstem hemorrhage or ischemic stroke). Subacute ataxia, in which a severe cerebellar
syndrome develops over several weeks, is typical of a paraneoplastic syndrome (such as
paraneoplastic cerebellar degeneration) or prion disease. Most adult-onset chronic ataxia
syndromes involve cerebellar degeneration, with cerebellar and brainstem atrophy visible on
MRI. Further evaluation includes measurement of serum vitamin B12 and vitamin E levels and,
in familial cases of chronic ataxia, genetic tests for spinocerebellar ataxia. Some persons with
sporadic ataxia have antigliadin antibodies, without celiac disease.
The most common adult-onset progressive ataxia syndromes are multiple system atrophy,
cerebellar type (formerly called olivopontocerebellar atrophy), and the spinocerebellar atrophy
disorders, including Machado-Joseph disease (spinocerebellar ataxia type 3). There is
essentially no effective medical treatment of cerebellar ataxia. The mainstay of treatment is
physical therapy, the use of assistive devices, and vigilance to prevent falls.
Essential Tremor
Key Points
Essential tremor is familial in approximately 50% of affected patients.
The oldest and most effective medications to treat essential tremors are propranolol and
primidone.
One of the most prevalent movement disorders, essential tremor is a syndrome that causes
tremors of the hands. The onset has a bimodal distribution, with peaks in adolescence and
middle age. The condition is familial in approximately 50% of affected patients. Epidemiologic
studies have linked essential tremor with anxiety disorder and alcohol dependence in some
families.
Essential tremor presents clinically as a fine tremor of the hands that impairs manual tasks,
such as pouring, using eating utensils or tools, placing a key in a lock, holding objects, and
writing. The tremor may involve the neck, which produces a horizontal or vertical head tremor.
Essential tremor also may cause a vocal tremor. In contrast to the tremor at rest of Parkinson
disease, which typically vanishes with action, essential tremor is present with action and,
therefore, more disabling. Whereas the handwriting of a patient with Parkinson disease is
typically cramped but usually free from tremor, the handwriting of a patient with essential
tremor is large and tremulous. Moreover, a unilateral tremor is characteristic of Parkinson
disease; essential tremor can affect both hands and be even slightly more pronounced in the
nondominant hand.
All healthy persons manifest a fine action tremor that is virtually invisible under ordinary
circumstances but may become evident under conditions of fatigue, muscular exertion,
anxiety, stimulant use, sleep deprivation, alcohol use, caffeine or benzodiazepine withdrawal,
or strong emotion, such as fear, anger, or anxiety (including stage fright). On the basis of
appearance alone, it is difficult to distinguish mild essential tremor from physiologic tremor, but
the latter occurs in relation to readily identifiable inciting factors. The list of drugs that can
cause or exacerbate tremor is long and includes -agonists (theophylline, terbutaline, and
epinephrine), stimulants (amphetamines, methylphenidate, cocaine, and caffeine),
cyclosporine, interferon, valproic acid, lithium, corticosteroids, and serotonin reuptake
inhibitors. In the evaluation of patients with action tremors, the possibility of drug-induced
tremor should always be considered. Identifying and removing the offending agent, if possible,
will lead to resolution of the tremor. Propranolol is effective for situational physiologic tremor.
Unlike essential tremor, physiologic tremors are generally confined to the hands and voice and
do not progress over time.
The term benign essential tremor is misleading. Although not fatal, essential tremor is a
progressive and disabling disorder, and affected patients do not experience their increasing
disability as trivial. Patients with advanced chronic essential tremor may develop ataxia with
balance impairment and cerebellar signs of dysarthria and dysmetria that cannot be explained
purely by the tremor. Autopsies of persons with essential tremor have revealed pathologic
changes in the cerebellum.
A small percentage of persons with essential tremor of many years' duration will develop a
unilateral tremor at rest. These persons typically exhibit ipsilateral signs of mild parkinsonism,
including decreasing speed of repetitive finger tapping, a decreased arm swing, mild rigidity,
and an asymmetric gait. The development of Parkinson disease is not considered part of the
natural history of essential tremor, but there are rare families in which both disorders occur
together. Additionally, autopsy studies have detected Lewy body pathology in a small subset of
patients with essential tremor.
The treatment of essential tremor is distinct from that of Parkinson disease. The oldest and
most effective medications are propranolol and primidone. Secondary, less effective
medications include gabapentin, methazolamide, and topiramate. Alcohol can temporarily
abolish essential tremor but is obviously not recommended as a treatment because of its
effects on cognition and behavior, the risk of addiction, and the rebound in tremor that occurs
when the alcohol wears off. Deep brain stimulation of the ventral intermediate thalamic nucleus
is effective at controlling even medication-refractory essential tremor.
Fragile X tremor ataxia syndrome causes a tremor resembling essential tremor as well as
causing ataxia, dysarthria, parkinsonism, and dementia. In the evaluation of an adult with
tremor and dementiaan association that does not occur in essential tremortesting for the
fragile X premutation should be considered, especially if there is a family history of mental
retardation.
Dystonia
Key Point
Although focal dystonia can be dramatically relieved by injections of botulinum toxin A or
B, the treatment of generalized dystonia is generally limited and unsatisfactory.
The pathology of dystonia, whether infectious, ischemic, hypoxic, drug-induced, metabolic,
genetic, or degenerative, always involves the basal ganglia. Dystonia describes a torsional,
twisting movement that is slightly sustained at the peak of contraction and may cause twisted
postures. Dystonia that is confined to a body part is known as focal or generalized dystonia. As
with hemicerebral symptoms of any type (hemiparesis, hemisensory loss, hemineglect,
hemiparkinsonism), hemidystonia implies a structural lesion of the brain, such as a stroke,
hemorrhage, tumor, or focal infection.
The most common types of focal dystonia involve the neck (spasmodic torticollis), face and jaw
(craniofacial dystonia), eyelids (blepharospasm), or hands. Examples of occupational overuse
or task-induced manual dystonia include writer's cramp and musician's dystonia. The
differential diagnosis of dystonia includes Parkinson disease (which can cause dystonia in
addition to the cardinal symptoms of bradykinesia, tremor, and rigidity), tardive dystonia
(induced by certain drugs), and postanoxic or posthypoxic dystonia (most likely caused by a
cardiac arrest or delayed cardiopulmonary resuscitation). Major causes of dystonia include
birth injury, Wilson disease, and various metabolic and genetic abnormalities.
Dopamine-responsive dystonia is caused by a defect in bioamine synthesis. All persons with
generalized dystonia should receive an early trial of levodopa to detect this rare but treatmentresponsive condition.
Focal dystonia can be dramatically relieved by injections of botulinum toxin A or B. Overall, the
treatment of generalized dystonia is limited and unsatisfactory. Except for the dopamineresponsive type, generalized dystonia typically does not respond to medication. High-dose
anticholinergic agents and baclofen are considered first-line drugs. Tardive dystonia may
respond to the dopamine-depleting agents reserpine and tetrabenazine. Patients with
refractory disease may be considered for bilateral continuous electric stimulation of the globus
pallidus internal nuclei.
Chorea
Like dystonia, chorea is linked pathologically to the basal ganglia. The hallmark of chorea is its
pattern of discrete, randomly occurring jerks or twitches that may be generalized or confined to
a single body part. The chewing and grimacing movements of classic orobuccolingual tardive
dyskinesia have a choreic appearance but also a pattern that is not strictly random; these
movements are sometimes termed choreiform.
The most common type of chorea encountered in clinical practice is the dyskinesia produced
by dopamine drugs in patients with Parkinson disease. The most common neurodegenerative
choreic disorder is Huntington disease, a progressive fatal degeneration of the caudate
nucleus that causes generalized chorea, dysarthria, parkinsonism, psychiatric disease,
personality deterioration, dementia, and death. The differential diagnosis of chorea includes
systemic lupus erythematosus and other autoimmune diseases, use of estrogen-containing
drugs, thyrotoxicosis, and pregnancy (chorea gravidarum, a self-limited chorea that resolves
after delivery). Acute severe chorea can result from hyperglycemic nonketotic acidosis.
Ballism, the large-amplitude twitching and flinging of one or more limbs on one (hemiballism)
or both (biballism) sides of the body is actually a proximal chorea. The acute development of
hemiballism suggests an infarct of the contralateral subthalamic nucleus. All types of chorea
can be reduced in severity by dopamine-depleting or D2 receptorblocking agents, although
these agents carry the risk of inducing tardive dyskinesia. Most cases of chorea resolve over
weeks to months.
Tardive Dyskinesia
The term neuroleptic was coined in reference to tranquilizers that block central D2 receptors,
such as haloperidol. Neuroleptic-induced movement disorders are sometimes referred to as
extrapyramidal symptoms, a phrase that oversimplifies a complex group of disorders, each
with its own distinct clinical features, treatment, and prognosis (Table 25).
All D2 receptorblocking agents have the potential to cause persistent acute, subacute, and
chronic movement disorders. Classic tardive dyskinesia is a choreiform movement of the face
that, once developed, may persist permanently, even if the offending agent is withdrawn.
Newer agents marketed as atypical or second generation neuroleptics may also induce tardive
syndromes through their D2 receptorblocking action, but these agents are less potent and
appear to have a lower propensity to cause tardive dyskinesia and drug-induced parkinsonism.
Most D2blocking agents are neuroleptics used for the treatment of psychosis. In addition,
many other agents used for depression (amoxapine), gastrointestinal illness (metoclopramide),
and cardiac disease (flunarizine) are dopamine antagonists with the potential to cause tardive
dyskinesia syndromes. All physicians who prescribe these agents must warn their patients of
the possibility of developing a permanent movement disorder.
Table 25. Movement Disorders and Symptoms Caused by Dopamine Receptor Antagonists
Type of
Movement
Disorder
Symptoms
Acute Reaction
Acute dystonia
Acute akathisia
Tardive dystonia
Tardive akathisia
Myoclonus
Myoclonus is a single, rapid, shocklike muscle jerk. This disorder can be distinguished from a
tremor, which is a repetitive oscillation, or a tic, which is stereotyped purposeless movement
that is partly suppressible and preceded by an uncomfortable inner prodrome or urge.
Myoclonus may be the dominant symptom of a neurologic illness, such as posthypoxic
(postanoxic) myoclonus or essential myoclonus, or part of a large constellation of neurologic
symptoms, such as Creutzfeldt-Jakob disease. Furthermore, myoclonus may arise from any
level of the neuraxis, including the cortex, subcortex, spinal cord, or peripheral nerves. Some
forms of myoclonus, such as a hiccup, which is a myoclonic spasm of the diaphragm, are
physiologic. Focal myoclonus, which is restricted to a body part, may result from a focal lesion
in the cerebral cortex, such as a tumor or stroke. A hemifacial spasm is a focal myoclonus
confined to the muscles of the facial nerve and is usually caused by focal neurovascular
compression or demyelination. Palatal myoclonus results from a focal brainstem lesion, such
as a tumor or one caused by trauma. Multifocal or generalized myoclonus is caused by a
disease involving the cerebral cortex diffusely, such as prolonged cerebral hypoxia (or anoxia)
or encephalitis. Spinal myoclonus involves a spinal segment and is caused by a focal lesion,
such as a stroke or tumor. The treatment of myoclonus consists of anticonvulsant agents with
antimyoclonic activity, such as valproic acid, clonazepam, and levetiracetam. The differential
diagnosis of myoclonus is provided in Table 26.
Epileptic symptoms
Symptoms associated
with static or progressive
encephalopathy
Wilson Disease
Key Point
Wilson disease should be considered in the differential diagnosis of any movement
disorder in a young patient because of the availability of curative treatment through
copper chelation or liver transplantation.
Despite its rarity, Wilson disease should be part of the differential diagnosis of any movement
disorder in a young adult because it is the only curable metabolic disease affecting the basal
ganglia. The consequence of overlooking the diagnosis is permanent neurologic impairment
due to irreversible copper deposition in the basal ganglia and cerebellum. Wilson disease
results from an autosomal recessive inborn error of metabolism caused by a mutation of the
copper P-type adenosine triphosphatase encoded on chromosome 13q14.3. This mutation
leads to a failure of copper excretion in bile, which results in copper accumulation in the liver
and brain.
Wilson disease presents clinically in three patterns: hepatic, psychiatric, and neurologic. The
most common neurologic presentation in a young adult is parkinsonism, although dystonia,
ataxia, and a cerebellar outflow tremor that is marked by large-amplitude proximal tremors and
dysmetria (wing-beating tremor) also can occur. Copper deposition in the Descemet
membrane of the cornea produces the characteristic brown Kayser-Fleischer ring, which is
present in virtually all persons with neurologic involvement but is sometimes difficult to discern
in brown-eyed persons. The diagnosis can be confirmed by a low serum ceruloplasmin level
(present in 95% of affected patients) or an elevated 24-hour urine copper excretion, but the
gold standard is an elevated level of copper in the liver. Unfortunately, no simple genetic test
for Wilson disease exists because of the number of mutations, but the diagnosis, once
considered, is readily made.
The treatment consists of the chelating agents D-penicillamine, trientine, tetrathiomolybdate,
zinc sulfate or acetate, and a copper-restricted diet. Liver transplantation is curative.
ng/mL (45-50 micrograms/L), iron replacement is indicated and may be curative. Any treatment
approach must also include optimization of sleeping habits, including avoidance of caffeine
and nicotine in the evening.
Key Points
Parkinson Disease
The classic presentation of Parkinson disease is the gradual development of an
intermittent tremor at rest in one hand, or even one digit, accompanied by slight
bradykinesia and rigidity.
Regardless of the stage of Parkinson disease, the primary goals of therapy are to
optimize the patient's level of motor, social, and intellectual function; to prevent
falls; and to minimize any treatment complications.
Within 5 years of treatment with a dopamine agonist or levodopa, the most effective
drugs for suppressing the motor signs of Parkinson disease, 50% of patients
develop motor fluctuations and dyskinesias.
Parkinson-Plus Syndromes
Parkinson-plus syndromes are unresponsive to levodopa replacement, advance
rapidly, and lead to death within 8 to 12 years, on average.
Gait Disturbance
Most adult-onset chronic ataxia syndromes involve cerebellar degeneration, with
cerebellar and brainstem atrophy visible on MRI.
Essential Tremor
Essential tremor is familial in approximately 50% of affected patients.
The oldest and most effective medications to treat essential tremors are propranolol
and primidone.
Dystonia
Although focal dystonia can be dramatically relieved by injections of botulinum toxin
A or B, the treatment of generalized dystonia is generally limited and unsatisfactory.
Tic Disorders and Tourette Syndrome
Tourette syndrome, the prototypic tic disorder, has a hereditary nature, a 3:1 male
predominance, and an association with psychiatric disease.
Although neuroleptic drugs are the most predictably effective tic-suppressing
medications, centrally acting -agonists, such as clonidine, should be used first
because neuroleptic drugs carry the small but grave risk of tardive dyskinesia.
Wilson Disease
Wilson disease should be considered in the differential diagnosis of any movement
disorder in a young patient because of the availability of curative treatment through
copper chelation or liver transplantation.
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Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of
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infectious agents during childhood has been proposed as an explanation, with Epstein-Barr
virus being the strongest candidate. Although serologic evidence of Epstein-Barr virus
exposure typically is greater in those with MS, this phenomenon is not universal. Also, it is
unclear whether this exposure acts as a primary trigger of the disease or is merely an
underlying characteristic of the immune system of persons with MS.
Although MS is the most common and well-known of the CNS demyelinating diseases, others
exist, such as neuromyelitis optica, acute disseminated encephalomyelitis, and idiopathic
transverse myelitis. Neuromyelitis optica, also known as Devic disease, causes demyelination
in the optic nerves and spinal cord but, unlike MS, tends to spare the brain. The disorder
appears more common in nonwhite populations and has a greater female to male ratio (9:1)
than MS.
The multifocal symptoms associated with acute disseminated encephalomyelitis, which
typically occurs during childhood but can occur in adults, usually present subacutely and result
from profound, simultaneous demyelination in multiple regions of the CNS. This disorder often
follows an infection. An initial episode of acute disseminated encephalomyelitis may be difficult
to distinguish from a first attack of MS, but patients with acute disseminated encephalomyelitis
typically have associated encephalopathy and fevers. Moreover, they typically have a greater
extent of brain involvement on MRI and a more significant cerebrospinal fluid (CSF)
lymphocytosis than do patients with a typical flare of MS.
For a discussion of transverse myelitis, see Disorders of the Spinal Cord.
Electrophysiologic studies also are sometimes helpful in the diagnosis of MS. Abnormalities on
electrophysiologic tests that measure the speed of conduction along central white matter
tracts, such as visual evoked potentials, somatosensory evoked potentials, or brainstem
auditory evoked responses, can provide indirect evidence of white matter lesions not evident
on imaging.
Optical coherence tomography, which uses near-infrared light to quantify the thickness of the
nerve fiber layer in the retina, also can be used as an ancillary testing technique. Reduced
thickness often is seen in patients with MS as a long-term sequela of previous optic neuritis but
also can be present in those without a distinct history of optic neuritis.
Figure 20.
MRI in the diagnosis of multiple sclerosis. Left, axial brain MRI, fluid-attenuated inversion recovery sequence,
showing typical ovoid periventricular lesions (yellow arrow). Center, MRI of the sagittal cervical spine, T2
sequence, showing multiple spinal cord lesions (red arrow). Right, axial brain MRI, postgadolinium T1 sequence,
showing multiple contrast-enhancing lesions that indicate active inflammation. Note the open ring appearance of
some of the lesions (green arrow), which helps to differentiate demyelinating lesions from contrast-enhancing,
infectious, or neoplastic lesions, which usually are closed rings.
Notes
Neoplastic
Primary CNS neoplasm
(glioma or lymphoma),
metastatic disease
Paraneoplastic syndromes
Metabolic disorders
Vitamin B12 deficiency
Copper deficiency
Zinc toxicity
Vitamin E deficiency
Vascular disorders
Sporadic and genetic
stroke syndromes
(hypercoagulability
disorders)
Disorder
Notes
CNS vasculitis
Susac syndrome
Dural arteriovenous
fistula
Systemic inflammatory
disease
SLE
Sjgren syndrome
Sarcoidosis
Behet syndrome
Migraine
Disorder
Notes
Somatoform disorders
Psychiatric disorders can sometimes present with neurologiclike symptoms that are due to somatization, conversion, and
similar conditions. Neurologic evaluation findings will be
normal.
devices even after 25 years). Although early studies of the natural history of this disease type
had implicated gender and age at onset as predictors of more rapid progression, more recent
studies have supported only early disability accrual as a predictor of long-term progression
rates.
With the increased availability of MRI and more liberal diagnostic criteria, the diagnosis of MS
also has been associated with a very mild form of the disease. Benign MS is the term used to
describe the disease in those persons who experience few relapses and minimal disability.
The existence of this entity is still under debate, and some long-term studies of patients with
this form have shown eventual secondary progression. Radiologically isolated syndrome, in
which patients with no demyelinating symptoms have incidental MRI changes that meet the
diagnostic criteria for MS, is an even more controversial entity, and the long-term prognosis of
patients with this condition is still being studied.
Figure 21.
Schematic representation of the varying clinical courses of multiple sclerosis (MS). Neurologic disability severity
is shown on the y axis, with time shown on the x axis. Relapsing-remitting MS (blue line) is characterized by
intermittent exacerbations (humps in line). Early in the disease course, residual disability from each exacerbation
is minimal, whereas later in the disease course, residual disability can be significant. After 10 to 15 years, most
patients with relapsing-remitting disease convert to secondary progressive MS (green line), although some
patients do not (dotted blue line). During the secondary progressive phase, disability accrues at a steady pace
without clear exacerbations. Some patients have a primary progressive form of MS from disease onset (red line)
and experience progressive disability accrual with no exacerbations.
Pregnancy can have a substantial effect on disease activity in MS, with a significantly reduced
risk of relapse in the third trimester but an increased risk of relapse in the first 3 months after
delivery. The impact of breast feeding on the relapse rate remains controversial, with various
studies presenting conflicting evidence.
Smoking cessation is advised for those with MS because of the threefold increase in the risk of
secondary progression associated with cigarette smoking.
Disease-Modifying Therapies
Key Point
In patients with relapsing-remitting multiple sclerosis, chronic maintenance therapy with
one of the eight FDA-approved disease-modifying therapies can reduce the relapse rate,
slow disability progression, and reduce the accumulation of new demyelinating lesions on
MRI.
In addition to treatment for individual relapses, most patients with relapsing-remitting MS
receive chronic maintenance therapy with immunomodulatory or immunosuppressive
medications. These disease-modifying therapies have been shown to reduce the relapse rate,
slow disability progression, and reduce the accumulation of new demyelinating lesions on MRI.
Additionally, the first-line therapies of interferon and glatiramer acetate have been shown to
delay conversion to clinically definite MS in patients with a clinically isolated syndrome and
suspicious brain lesions; early treatment initiation is recommended for these patients. Eight
disease-modifying therapies (Table 28) that differ in their route of administration, mechanism of
action, and potential adverse effects have been approved by the FDA. Choosing an
appropriate therapy from these options depends on patient tolerability and disease activity.
The interferon-beta preparations (beta-1a and beta-1b) use an immunomodulatory cytokine
that may direct the immune response away from autoimmunity and protect the blood-brain
barrier. Interferon beta-1a is administered either once weekly by intramuscular injection or
three times weekly by subcutaneous injection, whereas interferon beta-1b is administered
every other day by subcutaneous injection. The interferons have been shown to reduce the
relapse rate by approximately one third compared with placebo and to have positive effects on
disability progression and MRI findings. Head-to-head studies have shown general
equivalence for most of the interferons, although more frequent administration resulted in
slightly increased efficacy in some studies.
Glatiramer acetate is administered by daily subcutaneous injection. This medication is a
copolymer of four amino acids that, among other mechanisms of action, may bind major
histocompatibility complex molecules and induce a shift in the immune response away from
autoimmunity. Glatiramer acetate also has been shown to reduce the relapse rate by
approximately one third compared with placebo and appears equivalent to the interferons in
head-to-head studies.
Recommended
Monitoring
Pregnancy
Categorya
Glatiramer
acetate
None
Natalizumab
Rigorous, regimented,
industry-sponsored
monitoring (TOUCH
program)
Fingolimod
Elevated aminotransferase
levels, lymphopenia,
increased risk of serious
herpesvirus infection,
hypertension, bradycardia
(usually only with the first
dose), and macular edema.
Mitoxantrone
Required monitoring of
cardiac function by
echocardiography or
Pregnancy category definitions: B, fetal risk in animal studies but no adequate human studies or fetal
risk in animal studies but adequate human studies with no risk; C, fetal risk in animal studies and no
adequate human studies, but potential benefit to pregnant women may outweigh risk; D, fetal risk in
human studies, but potential benefit to pregnant women may outweigh risk.
Medication
Recommended
Monitoring
Pregnancy
Categorya
multigated radionuclide
angiography before each
infusion and regular CBC
Pregnancy category definitions: B, fetal risk in animal studies but no adequate human studies or fetal
risk in animal studies but adequate human studies with no risk; C, fetal risk in animal studies and no
adequate human studies, but potential benefit to pregnant women may outweigh risk; D, fetal risk in
human studies, but potential benefit to pregnant women may outweigh risk.
Symptomatic Management
Key Point
Muscle relaxants, such as baclofen, tizanidine, or cyclobenzaprine, and stretching
exercises help reduce spasticity and prevent painful muscle cramps in patients with
multiple sclerosis.
Although the disease-modifying therapies may help prevent further relapses and subsequent
disability, these medications do not address the neurologic symptoms that persist as long-term
sequelae of prior disease activity. Proper care of patients with MS involves attention to each of
these symptoms, with proper symptomatic therapy and nonpharmacologic support to increase
quality of life (Table 29).
Spasticity due to corticospinal tract involvement in MS can result in painful muscle cramps,
spasms, or even contractures. Muscle relaxants, such as baclofen, tizanidine, or
cyclobenzaprine, can be taken to reduce spasticity and prevent painful cramps. Physical
therapists also can suggest stretching exercises to help reduce spasticity and prevent
contractures. If symptoms are severe, botulinum toxin can be strategically injected to reduce
spasticity in a manner that may increase functional use of a limb. Intrathecal baclofen pumps
also may be implanted to reduce disabling or painful spasticity.
Neuropathic pain, a common symptom in MS, can be treated with tricyclic antidepressants,
gabapentin, pregabalin, duloxetine, tramadol, or similar agents; generic tricyclic
antidepressants (amitriptyline and nortriptyline) are generally better tolerated and much less
expensive than pregabalin, although their use may be limited by the development of
anticholinergic adverse effects. Treatment of trigeminal neuralgia with carbamazepine and
other modalities is discussed in Headache and Facial Pain.
Many patients with MS experience disabling fatigue that is typically worse in the afternoons
and early evening and of variable intensity. Before initiating pharmacologic therapy, clinicians
must ensure that the fatigue is not due to sleep apnea, restless legs syndrome, insomnia,
anemia, hypothyroidism, depression, or other medical conditions. Adjustment of sleep hygiene,
regular exercise, and treatment of underlying depression can often improve MS-related fatigue.
If fatigue persists despite such approaches, pharmacologic therapy with stimulants can be
useful. Modafinil, which is also used to treat narcolepsy, can be given at a dosage of 200 mg/d
to treat MS-related fatigue. Amantadine, which also has antiviral and antiparkinsonian
properties, can be used at 100 mg twice daily to reduce fatigue symptoms.
Many patients with MS experience symptoms of depression. Whether the depression stems
directly from the demyelinating process, occurs as an adverse effect of therapy (for example,
with an interferon-beta preparation), or arises as an emotional response to dealing with a
disabling chronic disease, the risk of suicide is increased among patients with MS. Clinicians
should be vigilant for signs of depression and have a low threshold for initiating pharmacologic
antidepressant therapy, scheduling prompt follow-up evaluation, and offering referrals for
individual or group therapy.
Cognitive dysfunction is present in at least 50% of patients with MS. An often misunderstood
and underdiagnosed component of the disease, this symptom can preclude employment and
impair patients' ability to perform activities of daily living. Data supporting any pharmacologic
therapies for this symptom are poor. Formal neuropsychological testing and consultation with a
neuropsychological specialist for cognitive rehabilitation and accommodative strategies
sometimes can be of benefit.
Maintenance of mobility in patients with MS is important. Physical and occupational therapy
consultations can provide therapeutic exercise to improve the efficacy and safety of gait.
Braces, canes, and rolling walkers also can be of use, as can electrostimulatory walk-assist
devices. The drug dalfampridine, a voltage-gated potassium channel antagonist, recently was
approved by the FDA for patients with gait impairment due to any form of MS. This medication
may increase conductance through demyelinated axons and has been shown in clinical trials
to improve walking speed and leg strength.
Bladder function is often impaired in patients with MS. Urinary frequency and urgency can be
managed by abstaining from caffeine, timed voiding, and anticholinergic agents, such as
oxybutynin and tolterodine. In patients with the additional symptoms of urinary hesitancy and
retention, however, anticholinergic agents should be avoided because they can cause
increased urinary retention. These mixed bladder symptoms should be evaluated by a
urologist, and intermittent catheterization should be considered.
Spasticity
Neuropathic pain
N/A
Gabapentin, pregabalin,
duloxetine, tricyclic
antidepressants, tramadol,
carbamazepine, topiramate,
capsaicin patch
Fatigue
Modafinil, amantadine
Depression
Cognitive
dysfunction
No proven therapy
Mobility
Dalfampridine
Urinary
urgency/frequency
Oxybutynin, tolterodine
Urinary retention
None
N/A = not applicable; SNRIs = serotonin norepinephrine reuptake inhibitors; SSRIs = selective
serotonin reuptake inhibitors.
Key Points
Spectrum, Pathophysiology, and Epidemiology
Neurologic symptoms and disability in multiple sclerosis most likely arise acutely
from disruption of white matter pathways and chronically from subsequent
degenerative changes occurring in both white and gray matter.
Presenting Signs and Symptoms of Multiple Sclerosis
Optic neuritis, which causes an acute loss of vision and pain with eye movement,
and myelitis, which is associated with sensory or motor symptoms below the
involved spinal level, are common symptoms of multiple sclerosis.
In contrast to cerebrovascular disease, multiple sclerosis (MS) is not associated
with cortical syndromes, such as aphasia and neglect; cortical involvement in MS
tends to cause more subtle, chronic symptoms, such as cognitive dysfunction and
fatigue
Diagnosis of Multiple Sclerosis
The diagnostic criteria for multiple sclerosis require evidence of dissemination of
disease activity in space and time.
MRIs of patients with multiple sclerosis show characteristic white matter lesions,
which are typically ovoid in shape and located in a periventricular distribution.
The cerebrospinal fluid of many patients with multiple sclerosis contains oligoclonal
bands not present in their serum, has an elevated IgG index and synthesis rate,
and sometimes shows mild elevations in leukocyte count or protein level.
Clinical Course of Multiple Sclerosis
Early in the course of MS, many patients (approximately 85%) experience
symptoms in a relapsing manner; approximately two thirds of patients with a
relapsing-remitting course eventually convert to secondary progressive MS, with a
median time to conversion of between 10 and 15 years.
Treatment of Multiple Sclerosis
In patients with multiple sclerosis, maintenance of the musculature of affected
areas through exercise may minimize disability.
Strong evidence suggests that the risk of relapse in multiple sclerosis is
significantly increased in the setting of common infections, and thus current
guidelines recommend strategies (including immunizations) designed to reduce the
risk of infection.
In patients with relapsing-remitting multiple sclerosis, chronic maintenance therapy
with one of the eight FDA-approved disease-modifying therapies can reduce the
relapse rate, slow disability progression, and reduce the accumulation of new
demyelinating lesions on MRI.
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Compressive Myelopathies
Clinical Presentation
Diagnosis
Treatment
Clinical Presentation
When a spinal cord syndrome is recognized clinically, prompt neuroimaging is the most useful
tool to differentiate between (and sometimes diagnose) intrinsic and extrinsic disorders. Spinal
cord compression, which should be treated as a neurologic emergency to prevent severe and
irreversible disability, can occur in various settings, such as a metastatic neoplasm, a vertebral
fracture (pathologic or traumatic), an epidural abscess, or an epidural hematoma. Neck or back
pain is often the initial symptom, followed rapidly by weakness, sensory changes, and bowel or
bladder dysfunction. However, many patients with compressive cervical myelopathy may not
experience these symptoms, and thus compressive cervical myelopathy should be part of the
differential diagnosis of leg weakness, especially in an older patient with arthritis, probable
osteoporosis, or frequent falls. Affected patients also may have focal tenderness on
examination. Fever can be a significant early finding in spinal epidural abscess. However, at
least half the patients with this condition lack fever or other signs suggestive of infection.
Recent neurosurgical intervention should suggest the possibility of an epidural abscess,
whereas a history of recent anticoagulation should suggest an epidural hematoma.
Diagnosis
Key Point
MRI of the spinal cord is the best tool to diagnose spinal cord compression.
MRI of the spinal cord is the best tool to establish the diagnosis of spinal cord compression.
Although CT myelography can also establish the diagnosis and may be needed in patients with
implantable devices that preclude the use of MRI, the technique is difficult to perform on an
emergent basis and does not produce images of the cord parenchyma.
Treatment
Therapeutic strategies for compressive myelopathies are determined by the underlying cause.
Epidural hematoma and abscess both require immediate surgical decompression, with
resolution of the underlying bleeding diathesis for a hematoma and antibiotic treatment for an
abscess. Despite conflicting evidence from clinical trials, most institutions give an immediate
bolus of high-dose corticosteroids to patients seen within 8 hours of a traumatic compressive
spinal cord injury; patients with this injury also may require spinal stabilization surgery.
Emergent administration of high-dose corticosteroids, most often dexamethasone, is also
indicated acutely for suspected epidural metastases (Figure 22). High-level evidence supports
the additional use of decompressive surgery followed by radiotherapy, as opposed to
radiotherapy alone, for most metastatic tumors that compress the spinal cord. Clinical trials
have shown that decompressive surgery provides the best chance for future ambulation.
Tumor types that are exceptionally sensitive to radiation (such as leukemia, lymphoma,
myeloma, and germ-cell tumors) may not require surgical decompression. Surgery is
sometimes deferred in patients with a poor overall prognosis or functional status, or if there is
no clear neurologic deficit.
Chronic spinal degenerative changes also can cause a compressive myelopathy. These
changes have a similar but more protracted presentation than any acute spinal cord
compression, with progressive leg weakness, spasticity, distal numbness, and bladder
impairment. Neuroimaging can reveal cervical spondylosis and canal stenosis caused by
hypertrophic changes of vertebral bodies and facet joints, usually in tandem with multiple disk
herniations. In severe cases, myelomalacia (scarring) may be seen as increased signal
intensity within the cord parenchyma. Examination often reveals upper motoneuron signs
(weakness, spasticity, hyperreflexia, and an extensor plantar response), but lower motoneuron
signs (atrophy, hyporeflexia) may be found at the level of stenosis because of anterior horn
and root compression; the combination of cervical spine stenosis and root impingement is
termed myeloradiculopathy. Spinal stenosis and disk herniation are uncommon in the thoracic
spine but quite common in the lumbar spine. Lumbar spinal stenosis can elicit symptoms of
groin, thigh, leg, or buttock pain and possibly neuroclaudication (pain, weakness, and
numbness that may increase with activity and improve with rest). Physical therapy and
symptomatic management of spasticity and pain can help some patients, but surgical
decompression is sometimes required.
Figure 22.
Spinal cord compression due to tumor. MRI of the thoracic spine of a 60-year-old woman with progressive lower
extremity weakness. A postcontrast T1 image (left) shows spinal cord compression by a mass lesion (arrow).
Right, compression was relieved (arrow) after surgical resection. Pathologic analysis of the lesion suggested
meningioma.
Noncompressive Myelopathies
Clinical Presentation, Diagnosis, and Management
Metabolic changes likewise can cause chronic noncompressive myelopathies. Severe vitamin
B12 deficiency may result in a subacute combined degeneration of corticospinal tracts and the
dorsal columns, which results in a spastic paresis and reduction in vibration and position
sense. An MRI may show increased signal in the affected white matter pathways, with results
of laboratory studies showing a low serum vitamin B12 level, an elevated serum methylmalonic
acid level, and macrocytic anemia. Replacement therapy will usually halt progression of but
may not improve symptoms. Similarly, copper deficiency, whether due to nutritional deficiency,
malabsorption, or zinc toxicity, can also cause subacute combined degeneration of the spinal
cord and may be clinically indistinguishable from vitamin B12 deficiency.
Vascular disorders also can cause noncompressive myelopathy. Spinal cord infarction, often in
the distribution of the anterior spinal artery, typically presents with acute onset of bilateral
weakness. Some loss of pain and temperature sensation also may occur, but vibration and
position sense are often spared because of the redundant vascular supply to the posterior
aspect of the cord. The underlying mechanism is usually cardioembolic or due to local
thrombosis but may result from prolonged hypotension during cardiovascular surgery or
surgery involving the aorta. Dural arteriovenous fistulas of the spinal vascular supply can result
in chronic myelopathy because of venous congestion; this disorder is most common in men
older than 50 years and in those who have had previous spinal surgical procedures. Although
MRI can occasionally show vascular flow voids, the gold standard of diagnosis is catheterbased angiography. These malformations can be treated by endovascular procedures or
surgical ligation.
Several genetic disorders cause noncompressive myelopathy. Hereditary spastic paraplegia
comprises a group of disorders that cause chronic, progressive, ascending weakness and
spasticity, often beginning in childhood or adolescence. Genetic screening is available for the
more commonly known mutations. Female carriers of X-linked adrenoleukodystrophy can
develop a chronic progressive myelopathy called adrenomyeloneuropathy. The diagnosis is
confirmed by elevated blood levels of very-long-chain fatty acids.
Figure 23.
Transverse myelitis. MRIs of a 53-year-old man with transverse myelitis. Sagittal (left) and axial (right) T2
sequences show an area of signal hyperintensity in the cervical cord (arrows), mostly posterior with lateral
extension to the left hemicord. This pattern could be consistent with disorders that have a predilection for the
posterior columns, such as vitamin B12 and copper deficiencies and neurosyphilis, although inflammatory
transverse myelitis and multiple sclerosis can also affect this region.
Key Points
Presenting Symptoms and Signs of Myelopathies
Accurate and timely recognition of spinal cord disorders (or myelopathies) is critical
because of the vulnerable and compartmentalized design of the spinal cord, in
which even a small lesion or injury can result in significant disability
The presenting symptoms and signs of a spinal cord syndrome often occur at or
below the site of a lesion.
In patients with myelopathy, the spinal sensory level is best determined with an
ascending pinprick examination, including the trunk; bowel and bladder function are
often involved, with incontinence occurring in more severe disease.
Compressive Myelopathies
MRI of the spinal cord is the best tool to diagnose spinal cord compression.
Noncompressive Myelopathies
Diagnostic criteria for idiopathic transverse myelitis require clinical features of the
syndrome, evidence of inflammation (such as contrast enhancement of a lesion on
MRI or leukocytosis in the cerebrospinal fluid), and exclusion of other potential
causes.
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Neuromuscular Disorders
Peripheral Neuropathies
Treatment of Neuropathic Pain
Amyotrophic Lateral Sclerosis
Neuromuscular Junction Disorders
Myopathies
Key Points
Bibliography
Peripheral Neuropathies
Overview
Classification, Findings, and Diagnosis
Mononeuropathies
Polyneuropathies
Overview
Key Point
Peripheral neuropathies may affect motor, sensory, or autonomic nerves or a
combination of these nerves.
Peripheral nerve disease or neuropathy is categorized by distribution into focal disease
(mononeuropathy or multiple mononeuropathies) or widespread disease (polyneuropathy) and
by underlying pathology into axonal (sparing the myelin sheath), demyelinating (sparing the
axon), or mixed types. Peripheral neuropathies may affect motor, sensory, or autonomic
nerves or a combination of these nerves. Peripheral neuropathies are differentiated from
central nervous system dysfunction by history and examination findings, although the
distinctions are not always clear (Table 30).
PNS Origin
CNS Origin
Onset
Subacute or insidious
Motor
symptoms/distribution
Yes/focal, unilateral, or
generalized
Sensory
symptoms/distribution
Possible/focal, unilateral, or
generalized
Possible/usually focal or
unilateral
Cramps and
fasciculations
Possible
No
Other CNS-related
symptoms
No
History
Fasciculations
Possible
No
Stretch reflexes
Normal or diminished
Sensory abnormalities
In an entire limb
EMG
Positive results
Negative results
CNS = central nervous system; EMG = electromyography; PNS = peripheral nervous system.
Electromyography (EMG), for the purpose of this discussion, includes nerve conduction
studies and needle electrode examination, which are separate but complementary techniques
that help confirm and quantify peripheral neuropathy. Nerve conduction studies evaluate only
larger myelinated sensory nerve fibers and thus cannot detect small-fiber neuropathies.
Needle electrode examination can detect active denervation of muscles only after at least 3
weeks have elapsed since nerve injury.
Small-fiber neuropathies are best evaluated by quantitative sensory testing for pressure and
thermal function, a quantitative sudomotor axon reflex test for sweating, and determination of
intraepidermal nerve fiber density on skin biopsy (Figure 24). Sural nerve biopsy can be useful
in suspected vasculitis or amyloidosis. Despite extensive testing, however, no cause is found
in up to one third of patients with peripheral neuropathy.
Differential Diagnosis
Weakness
Distal muscles
Ascending
Guillain-Barr syndrome
Proximal muscles
Fluctuating
Myasthenia gravis
Focal asymmetric
Extraocular muscles
With atrophy
Without atrophy
Cramps
Fasciculations
Generalized polyneuropathy
Hyperpathia
Small-fiber neuropathy
Dermatomal pattern
With hyporeflexia
ALS = amyotrophic lateral sclerosis; QSART = quantitative sudomotor axon reflex testing.
Differential Diagnosis
Without hyporeflexia
Small-fiber neuropathy
Autonomic Dysfunction
Decreased sweat output, abnormal
results on QSART
Figure 24.
Photomicrographs of skin biopsy samples. Samples were immunostained for protein gene
product 9.5 to reveal intraepidermal nerve fibers. Left, normal fibers in a healthy person
(arrows). Right, depleted fibers in a patient with small-fiber neuropathy (arrow).
Reprinted with permission from Tavee J, Zhou L. Small fiber neuropathy: a burning problem.
Cleve Clin J Med. 2009;76(5):297-305. PMID: 19414545 Copyright 2009 The Cleveland
Clinic Foundation. All rights reserved.
Mononeuropathies
Key Points
In carpal tunnel syndrome, compression of the median nerve results in sensory
symptoms of numbness and tingling in the thumb, index finger, and/or middle fingers
Treatment of carpal tunnel syndrome includes wrist splints, occupational therapy, local
corticosteroid injections, and improved control of metabolic contributors, such as
diabetes mellitus.
Corticosteroids improve clinical outcomes in patients with Bell palsy if administered within
the first 72 hours of symptom onset.
Mononeuropathies typically involve a single nerve (as in carpal tunnel syndrome) or two or
more nerves at different sites (as in mononeuropathy multiplex with wrist and foot drop).
Bell Palsy
Bell palsy refers to paralysis of the facial nerve resulting in weakness of ipsilateral facial
muscles. This peripheral nerve compression can be differentiated from central causes (such as
stroke) by evaluating forehead and periorbital muscles. With a lesion of the central nervous
system, lower facial muscles are primarily affected, and the forehead and orbicularis oculi
muscles are relatively spared. Peripheral nerve compression, as seen in Bell palsy, causes
more widespread facial paralysis, including the upper and lower face, with an inability to close
both eyes tightly or raise both eyebrows. Patients may also report hyperacusis, dry mouth, and
impaired taste. Abrupt onset of symptoms building over 1 to 2 days is typical.
Patching the eye and lubricating the cornea are essential to prevent abrasions. Spontaneous
recovery of function is good to excellent in approximately 70% of patients, although some
patients are left with substantial weakness and evidence of aberrant reinnervation causing
synkinesis (such as voluntary smiling causing involuntary eyelid closure). Use of prednisone in
the first 72 hours has been shown in clinical trials to hasten the time to recovery and increase
the percentage of patients with complete recovery. However, the use of antiherpesvirus agents
as monotherapy has not shown benefit, and studies evaluating combined corticosteroid and
antiherpesvirus therapy have reported inconsistent results.
Polyneuropathies
Key Points
In generalized polyneuropathy, the longest nerves are affected most severely, with
symptoms usually beginning in the feet, ascending up the limbs, and then affecting the
hands in a stocking-glove distribution.
Diabetes mellitus can cause almost any kind of neuropathy, and often different types of
neuropathy coexist in the same patient.
Guillain-Barr syndrome (GBS) is usually self-limited but may require aggressive
supportive treatment with intravenous immune globulin or plasma exchange therapy; if
deterioration is rapid and the clinical suspicion of GBS is high, therapy should not be
delayed while awaiting results of confirmatory studies.
Polyneuropathy, the dysfunction of multiple nerves at multiple sites, may be acquired or
hereditary. The pathophysiology involves damage to nerve axons (axonal neuropathies), the
myelin sheath (demyelinating neuropathies), or small to medium blood vessels supplying the
nerves (vasculitic neuropathies). Acquired polyneuropathies are most common with diabetes
mellitus and alcoholism and predominate in developed countries.
In generalized polyneuropathy, the longest nerves are affected most severely. Symptoms
usually begin in the feet, ascend up the limbs, and then affect the hands in a stocking-glove
distribution; progression along the limbs is distal to proximal. Symptoms of pain are common,
especially at night, because of small unmyelinated fiber involvement. Asymmetric involvement
in polyneuropathy should prompt consideration of other causes, such as radiculopathy,
plexopathy, mononeuritis multiplex, motoneuron disease, or compressive mononeuropathy.
prevalent. Tight glucose control and reduction of cardiovascular risk factors have been shown
to improve symptoms of diabetic neuropathy and slow disease progression.
Diabetic amyotrophy (also known as diabetic lumbosacral radiculoneuropathy) is a painful
proximal neuropathy affecting patients with even mild or previously undiagnosed diabetes.
Onset of severe unilateral leg pain with occasional numbness is acute or subacute and is
followed by proximal weakness and subsequent atrophy. Significant weight loss often
precedes its onset. Progression occurs over weeks to months, sometimes with spread to the
contralateral lower extremity or upper extremities. EMG reveals characteristic findings of L2 to
L4 radiculopathies, with or without evidence of a distal sensorimotor polyneuropathy.
Aggressive diabetic control, analgesia, and physical therapy are the mainstays of treatment.
The use of immunomodulators is controversial.
Small-fiber neuropathy occurs in patients with mild to severe diabetes and even in patients
with only impaired glucose tolerance. Patients typically report burning, lancinating extremity
pain without weakness. Careful screening for diabetes is essential in all patients with new
small-fiber neuropathy.
Hereditary Neuropathies
Hereditary neuropathies should be suspected in patients with few paresthesias and chronic
distal weakness progressing slowly over many years. The prototypic hereditary motor and
sensory neuropathy is Charcot-Marie-Tooth (CMT) disease, a spectrum of disorders arising
from mutations in several genes encoding for myelin formation, structure, and function. The
two most common forms are demyelinating (CMT1) and axonal (CMT2). Both share the clinical
features of numbness, distal extremity weakness, unsteady gait, areflexia, high arches,
hammer toes, and atrophy of distal extremity muscles and foreleg muscles (stork leg
deformity). In CMT1, which begins in the first or early second decade of life, peripheral nerves
become palpable as demyelination and remyelination proceed. CMT2 is the axonal form that
begins in the second or third decade with prominent sensory loss that can result in trophic foot
ulcers. In contrast to small-fiber neuropathies, dysesthetic pain is not present in CMT disease.
EMG helps differentiate between the demyelinating and axonal forms and thus guides genetic
testing. Treatment is supportive with physical therapy and appropriate orthotics.
Inflammatory Polyradiculoneuropathies
Guillain-Barr syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy
(CIDP) are inflammatory polyneuropathies caused by acquired immune-mediated inflammation
of nerve roots and peripheral nerves. The disorders are best distinguished by symptom
duration.
Guillain-Barr Syndrome
The most common cause of acute diffuse neuromuscular paralysis, GBS results from immunemediated attacks on peripheral nerve myelin or axonal components because of shared
epitopes. Affected patients initially experience rapid onset of symmetric weakness of the upper
and lower limbs over days to weeks, generally in the setting of a recent infection (particularly
with Campylobacter jejuni), trauma, or surgery. The disorder generally progresses over 2
weeks, with most patients (~90%) at their worst by 4 weeks. Facial, oropharyngeal,
oculomotor, and diaphragmatic muscles may be involved. Although many patients describe
paresthesias or neuropathic pain in the hands and feet, objective sensory loss is usually mild
or absent. Low back pain, presumably due to inflammatory demyelination at the spinal nerve
root level and often mistaken for compressive lumbosacral radiculopathy, can herald the onset
of GBS. In patients with severe weakness and respiratory failure, dysautonomia (for example,
labile blood pressure, severe constipation, and cardiac arrhythmias) may develop. All patients
with suspected GBS should be monitored carefully, and hospitalization should be considered
because of the risk of rapid progression to respiratory failure or autonomic instability.
The diagnosis of GBS rests on historical, physical examination, and lumbar puncture findings.
Neurologic examination typically reveals weakness and decreased or absent deep tendon
reflexes. CSF analysis usually reveals a normal cell count and an increased protein level
(albuminocytologic dissociation) in 80% to 90% of affected patients; glucose levels are normal.
Findings of CSF pleocytosis should prompt evaluation for other conditions that can mimic
GBS, including infections (such as Lyme disease or West Nile virus), vasculitis, or
leptomeningeal disease from sarcoidosis or carcinomatosis. EMG results typically show a
predominantly demyelinating process unless a rare axonal variant is present (5%-10% of GBS
presentations). Pulmonary function testing, including measurement of FVC and negative
inspiratory force, can help establish a baseline and monitor respiratory status during disease
progression, particularly because 15% to 30% of affected patients require ventilatory support.
GBS is usually monophasic and self-limited but may require aggressive supportive treatment.
Intravenous immune globulin and plasma exchange are equally effective in treating the
disorder, especially when started within 7 to 14 days of symptom onset. If deterioration is rapid
and the clinical index of suspicion for GBS is high, therapy should not be delayed while
awaiting results of confirmatory studies (such as nerve conduction studies). Either treatment
results in shortening of time to recovery by approximately 40% to 50%. Intravenous immune
globulin is usually given at a dosage of 0.4 g/kg/d for 3 to 6 days, although patients with more
severe disease may need therapy of longer duration. Plasma exchange is usually performed
four to six times over 8 to 10 days for a total of 200 to 250 mL/kg. Combination therapy does
not provide additional benefit. Corticosteroids are of no benefit in the treatment of GBS and
may even slow recovery.
Up to 10% of treated patients will relapse with increased weakness requiring repeated courses
of treatment. Markers of poor prognosis include older age, diarrheal illness as a prodrome,
rapidly progressive weakness, substantial axonal loss on early EMG, and the need for
ventilatory support. Supportive treatment is critical, including pain management, nutritional
support, bowel care, cardiorespiratory monitoring, treatment of dysautonomia, infection
surveillance, venous thrombosis prophylaxis, and physical and occupational therapy. Despite
disease severity, prognosis is good in 80% of patients, with only mild to no residual disability.
Many patients (up to 50%-70%) with sepsis and multiorgan failure in intensive care settings
longer than 7 to 14 days develop critical illness polyneuropathy. This polyneuropathy of
uncertain pathogenesis usually is identified during weaning from mechanical ventilation when a
patient is unable to progress to unassisted breathing despite adequate cardiopulmonary
function. It can also present as generalized or distal flaccid paralysis and atrophy of primarily
lower extremity muscles during or after recovery from critical illness. Typical findings include
distal sensory loss, decreased or absent deep tendon reflexes, and relative sparing of cranial
nerves. A careful history, physical examination, and EMG evaluation are required in these
severely ill patients to exclude similar disorders, although this is more difficult in patients who
are uncooperative or have encephalopathies. EMG findings that are relatively specific for
critical illness polyneuropathy include axonal sensory and motor polyneuropathy without
evidence of conduction block and decremental response on repetitive nerve stimulation.
Unless there is some coexistent critical illness myopathy, the needle electrode examination
reveals evidence of only motor axon loss. The serum creatine kinase (CK) level is normal, as
are CSF protein levels; the latter finding differentiates this condition from GBS.
Treatment is primarily supportive and includes aggressive management of underlying medical
conditions (including sepsis) and prevention of additional complications (such as deep venous
thrombosis). Aggressive physical and occupational therapy are essential. Neuromuscular
junction blocking agents should be avoided, if possible. Whether tight control of plasma
glucose levels with intensive insulin therapy (target level of 80-110 mg/dL) improves the
outcome of critical illness polyneuropathy remains undetermined. In addition to length of stay
in the intensive care unit, other contributors to a poor prognosis include increased plasma
glucose and decreased serum albumin levels. Long-term data are limited, but approximately
30% of patients with the disorder have significant residual weakness, including quadriplegia.
Autonomic neuropathy
Diabetic lumbosacral
radiculoneuropathy (diabetic
amyotrophy)
Mononeuropathy
Radiculopathy
Sensorimotor peripheral
neuropathy
Small-fiber neuropathy
ventilation. Presently, riluzole is the only FDA-approved drug to slow disease progression,
although it extends survival by only approximately 3 months in clinical trials.
Myasthenia Gravis
Key Point
Pyridostigmine, an acetylcholinesterase inhibitor, is first-line therapy for myasthenia
gravis and may be sufficient in very mild disease; in more severe or generalized disease,
immune suppression with prednisone, mycophenolate mofetil, azathioprine, cyclosporine,
or rituximab may result in disease remission.
Myasthenia gravis results from an autoantibody that blocks postsynaptic neuromuscular
junctions. A generalized form and a less common ocular/oculobulbar form exist. The classic
clinical feature of this disorder is fluctuating, fatigable muscle weakness that worsens with
activity and improves with rest. Symptoms also are aggravated by increased body
temperature, stress, and infection. All voluntary muscles can be affected, especially the ocular
and bulbar muscles. Approximately half of affected patients initially have diplopia or ptosis, and
half of these develop generalized disease within 2 years. Bulbar symptoms, including slurred
speech, dysphagia, nasal regurgitation of liquids, and fatigue while chewing, are presenting
features in approximately 15% of these patients.
Neurologic examination may reveal bilateral asymmetric ptosis worsened by prolonged upward
gaze, an expressionless or sagging appearance of facial muscles, a snarling smile, nasal
speech worsened by prolonged speaking, and limb weakness that increases with exercise.
Pupillary responses, deep tendon reflexes, and sensory examination findings are normal.
Myasthenia gravis has a bimodal age predominance, affecting younger women (age 20-30
years) and older men (age 50 years). Most affected patients have identifiable autoantibodies
directed against the postsynaptic acetylcholine receptor or against muscle-specific tyrosine
kinase (MuSK) receptors.
Thyroid-stimulating hormone levels should be checked because 30% of affected patients have
thyroid disease. Edrophonium testing may be insensitive but has a high positive predictive
value when unequivocal improvement in an objectively weak muscle can be shown. EMG
testing, including single-fiber EMG, has a 97% to 99% sensitivity but lacks specificity. Thymic
abnormalities, such as hyperplasia and thymoma, are present in 75% of affected patients,
although less often in those with autoantibodies against MuSK receptors. CT of the chest
should be performed. Other cancers occasionally associated with myasthenia gravis include
small cell lung cancer, breast cancer, and Hodgkin lymphoma.
Myopathies
Overview
Inflammatory Myopathy
Endocrine-Related Myopathies
Overview
Key Points
Myopathies typically present as painless progressive weakness, usually of the limbs,
without sensory deficit.
The serum creatine kinase (CK) level is elevated in most patients with myopathy and is
useful in monitoring disease activity and response to treatment; patients with slowly
progressive myopathies may have normal CK levels.
Myopathies are inherited or acquired disorders primarily affecting skeletal and cardiac
muscles, although facial, bulbar, and respiratory muscles also may be involved. Reflexes and
sensation are generally intact. Myopathies typically present as painless progressive weakness
without sensory deficit. The most common weakness is in the limbs and follows a symmetric
proximal to distal pattern. Some myopathies (such as inclusion body myositis and hereditary
myopathies) may present with focal or distal weakness. Asymmetric onset of weakness,
although common in inclusion body myositis, should prompt consideration of motoneuron
disease. Weakness of facial and ocular muscles suggests a neuromuscular junction disorder
or a hereditary myopathy.
Medical history taking should focus on age at onset, anatomic distribution, rate of progression,
medical comorbidities, medications, and family history. Minimal or very slow evolution over
years suggests congenital myopathies, muscular dystrophy, or inclusion body myositis;
subacute development over months to years suggests endocrine dysfunction; and rapid
progression over weeks to months suggests inflammatory and toxic myopathies. Episodic
weakness with normal interictal strength (signs of periodic paralysis) suggests certain
metabolic myopathies. Pain, although absent in most myopathies, can suggest myotonic
dystrophy and infectious, toxic, metabolic, and infiltrative myopathies (sarcoidosis,
amyloidosis). Myoglobinuria, although a rare finding, can suggest a metabolic myopathy.
Frontal balding, cataracts, and mental retardation are features associated with myotonic
dystrophy. The finding of a characteristic rash strongly suggests an inflammatory myopathy,
such as dermatomyositis.
The serum CK level is elevated in most patients with myopathy and is useful in monitoring
disease activity and response to treatment. However, patients with slowly progressive
myopathies (such as inclusion body myositis) may have a normal CK level, and elevated levels
also are associated with other disorders and medications (Table 33). Aldolase is a less specific
marker than CK in myopathy because the level can increase in hepatic and hematologic
disease.
EMG is useful in the evaluation of patients with suspected myopathy because it can show
myopathic features (short duration, low-amplitude, polyphasic motor unit potentials) in those
with normal or borderline CK levels, outline the extent and distribution of disease, and identify
muscle biopsy sites. CK levels should be determined before EMG because needle insertion
into muscle will itself cause enzymatic elevations. Biopsy should be performed in moderately
but not severely affected muscles to avoid nonspecific end-stage changes. Molecular genetic
testing is an essential adjunct to muscle biopsy in patients with suspected hereditary
myopathies and may even obviate the need for biopsy, if results are positive.
Table 33. Elevated Serum Creatine Kinase Levels and Associated Conditions
CK Level
Condition
Normal or <5
times the
upper limit of
normal
>5 to 10 times
the upper limit
of normal
Inflammatory Myopathy
For information on inflammatory myopathy, see MKSAP 16 Rheumatology.
Endocrine-Related Myopathies
Key Point
The clinical presentation of proximal muscle weakness, myalgia, and cramps should
prompt a careful review of current and recent medications, particularly statins, to detect
toxic myopathy.
Corticosteroid-Induced Myopathy
Corticosteroid-induced myopathy classically is associated with proximal limb weakness, mostly
of the legs, in patients taking chronic corticosteroids. A definitive diagnosis is difficult to
establish. Women reportedly are affected twice as often as men, with additional risk conferred
by the use of high-dose (30 mg/d) prednisone. Patients typically have a cushingoid body
habitus and may have other stigmata of chronic corticosteroid use. Neurologic examination
reveals intact ocular, facial, and distal extremity strength; normal sensory examination findings;
and normal deep tendon reflexes. Serum CK levels and results of EMG testing are normal; an
elevated CK level or abnormal EMG result suggests the presence of another myopathy or
recurrence of a partly treated myositis. In patients treated with corticosteroids for an
inflammatory myopathy, concern for corticosteroid-induced myopathy should be prompted by
continued or worsening proximal muscle weakness after a decrease in or normalization of CK
levels. Muscle biopsy is nondiagnostic in corticosteroid-induced myopathy and reveals only
atrophy of type IIb muscle fibers. Slow tapering of corticosteroid therapy with the goal of
discontinuation is the only effective treatment, although physical therapy also should be
emphasized.
Thyrotoxic Myopathy
Patients with classic hyperthyroidism or hypothyroidism may have symmetric proximal muscle
weakness. Patients with hyperthyroidism may have muscle atrophy and fasciculations,
whereas patients with hypothyroidism may have muscle hypertrophy. Serum CK levels and
EMG findings are usually normal. Correction of the endocrine disorder is associated with
resolution of the myopathy.
Vitamin D deficiency, whether alone or in the context of osteomalacia, can be associated with
myalgia, bone pain, and diffuse fatigue. Proximal limb weakness has been described in
osteomalacia but also in severe vitamin D deficiency alone. For a detailed discussion of
vitamin D deficiency, see MKSAP 16 Endocrinology and Metabolism.
Inherited Myopathies
The inherited myopathies are a heterogeneous group of disorders with a wide range of
presentations, including slowly progressive undiagnosed disease in adulthood. Diagnosis is
based on family history, overall clinical picture, muscle biopsy results, and genetic testing
(when available). Molecular and genetic abnormalities have been identified in some, but not
all, inherited myopathies. In muscular dystrophies, proximal muscle weakness is the usual
presenting symptom, with variable involvement of other muscles. Weakness can be
asymmetric and involve axial (shoulder and hip girdle) and facial musculature. Cardiomyopathy
and conduction defects at times may be more prominent than skeletal muscle weakness.
X-linked inheritance patterns are seen in Duchenne and Emery-Dreifuss muscular dystrophy.
Myotonia (inability to relax a muscle after isometric contraction, as when releasing a grip after
a handshake) is an important finding in myotonic dystrophy. A positive family history and
recognition of specific patterns of weakness aid in diagnosis. The serum CK level is generally
elevated. EMG and muscle biopsy can assist in the diagnosis but are not pathognomonic
unless specific markers of disease are identified by immunohistochemistry (such as absent
dystrophin immunostaining of a biopsy specimen from a patient with suspected Duchenne
muscular dystrophy).
Congenital myopathies often are associated with dysmorphic facial and skeletal features,
neuropathy, and cardiomyopathy. Muscle channelopathies (such as malignant hyperthermia
and periodic paralyses) may only manifest in adulthood under specific stressors, including high
carbohydrate meals, severe exertion, and anesthesia. In metabolic myopathies, glycogen and
lipid metabolism disorders result in cramping, stiffness, and pain shortly after exertion.
Mitochondrial myopathies present in various ways, including exercise intolerance (for example,
fatigue), myalgia, and occasionally ptosis or extraocular movement abnormalities
(ophthalmoplegia), which can mimic myasthenia gravis (Figure 25).
development, although neuromuscular blocking agents also increase the risk. Patients have
generalized flaccid weakness, usually of the proximal upper and lower extremities, neck,
diaphragm, and (sometimes) facial muscles. Sensation, if testable, is unaffected.
Serum CK levels often are elevated and tend to peak within a few days of corticosteroid
infusion. Muscle biopsy is nonspecific. Treatment is primarily supportive and aimed at
decreasing the corticosteroid dosage. No convincing evidence supports using tight control of
plasma glucose levels with intensive insulin therapy to improve outcomes in critical illness
myopathy.
Toxic Myopathies
Exposure to toxins should be considered in all patients with presenting symptoms of myopathy.
The clinical presentation of proximal muscle weakness, myalgia, and cramps should prompt a
careful review of current and recent medications, particularly statins. A recent increase in statin
dosage, a change from one statin to another, or the addition of another drug (such as a fibric
acid derivative) that increases myopathy risk can be accompanied by new muscle symptoms
and progression. The concomitant use of drugs that inhibit cytochrome P3A4, including
macrolides, cyclosporine, itraconazole, and protease inhibitors, will increase myopathy risk in
patients taking lovastatin, simvastatin, and atorvastatin because these drug are metabolized by
the same pathway. In these patients, other statin options (such as pravastatin, rosuvastatin, or
fluvastatin) that are not similarly metabolized may be preferable. Serum CK levels can range
from barely increased to the high values associated with rhabdomyolysis. Other medications
also are known to cause toxic myopathy (Table 34). Acute or chronic alcohol abuse also can
cause a dose-dependent myopathy. Discontinuation of the responsible medication or
substance generally results in gradual recovery.
Figure 25.
Zidovudine, HAART
Antiviral therapy
Interferon, clevudinea
Cholesterol-lowering therapy
Emetics
Emetine, ipecac
Immunosuppressants
Colchicine, vincristine
Rheumatologic therapy
(antimalarial class)
Chloroquine, hydroxychloroquine
Key Points
Peripheral Neuropathies
Peripheral neuropathies may affect motor, sensory, or autonomic nerves or a
combination of these nerves.
Appropriate laboratory tests in the diagnosis of peripheral neuropathy include
serum protein electrophoresis, a complete blood count, erythrocyte sedimentation
rate determination, and measurement of fasting plasma glucose, hemoglobin A1c,
and vitamin B12 levels; cerebrospinal fluid analysis may be required in patients with
rapidly progressive neuropathy.
Despite extensive testing, no cause is found in up to one third of patients with
peripheral neuropathy.
In carpal tunnel syndrome, compression of the median nerve results in sensory
symptoms of numbness and tingling in the thumb, index finger, and/or middle
fingers
Treatment of carpal tunnel syndrome includes wrist splints, occupational therapy,
local corticosteroid injections, and improved control of metabolic contributors, such
as diabetes mellitus.
Corticosteroids improve clinical outcomes in patients with Bell palsy if administered
within the first 72 hours of symptom onset.
In generalized polyneuropathy, the longest nerves are affected most severely, with
symptoms usually beginning in the feet, ascending up the limbs, and then affecting
the hands in a stocking-glove distribution.
Diabetes mellitus can cause almost any kind of neuropathy, and often different
types of neuropathy coexist in the same patient.
Guillain-Barr syndrome (GBS) is usually self-limited but may require aggressive
supportive treatment with intravenous immune globulin or plasma exchange
therapy; if deterioration is rapid and the clinical suspicion of GBS is high, therapy
should not be delayed while awaiting results of confirmatory studies.
Treatment of Neuropathic Pain
Neuropathic paintypically described as a tingling, burning, electrical, or
dysesthetic sensationusually involves the distal extremities, is worse at night, and
is typical of polyneuropathies affecting small fibers, as frequently occurs in diabetes
mellitus.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis is an incurable progressive neurodegenerative
disease of unknown cause that results in muscle paralysis and death from
respiratory failure, usually within 3 to 5 years of symptom onset.
Management of amyotrophic lateral sclerosis is largely supportive and directed
toward symptomatic relief, prolonging independence, and improving quality of life.
Neuromuscular Junction Disorders
Bibliography
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polyneuropathies. Muscle Nerve. 2009;39(5):563-578. PMID: 19301378
Bril V, England J, Franklin GM, et al; American Academy of Neurology; American
Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of
Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful
diabetic neuropathy: report of the American Academy of Neurology, the American
Association of Neuromuscular and Electrodiagnostic Medicine, and the American
Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.
PMID: 21482920.
Camdessanch JP, Jousserand G, Ferraud K, et al. The pattern and diagnostic criteria of
sensory neuronopathy: a case-control study. Brain. 2009;132(pt 7):1723-1733. PMID:
19506068
England JD, Gronseth GS, Franklin G, et al; American Academy of Neurology. Practice
parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing,
nerve biopsy, and skin biopsy (an evidence-based review). Report of the American
Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic
Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology.
2009;72(2):177-184. PMID: 19056667
Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Interventions for preventing
critical illness polyneuropathy and critical illness myopathy. Cochrane Database Syst
Rev. 2009;(1):CD006832. PMID: 19160304
Hughes RA, Swan AV, Raphal JC, Annane D, van Koningsveld R, van Doorn PA.
Immunotherapy for Guillain-Barr syndrome: a systematic review. Brain. 2007;130(pt
9):2245-2257. PMID: 17337484
Huisstede BM, Hoogvliet P, Randsdorp MS, Glerum S, van Middelkoop M, Koes BW.
Carpal tunnel syndrome. Part I: effectiveness of nonsurgical treatmentsa systematic
review. Arch Phys Med Rehabil. 2010;91(7):981-1004. PMID: 20599038
Huisstede BM, Randsdorp MS, Coert JH, Glerum S, van Middelkoop M, Koes BW.
Carpal tunnel syndrome. Part II: effectiveness of surgical treatmentsa systematic
review. Arch Phys Med Rehabil. 2010;91(7):1005-1024. PMID: 20599039
Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150
(12):858-868. PMID: 19528564
Miller RG, Jackson CE, Kasarskis EJ, et al; Quality Standards Subcommittee of the
American Academy of Neurology. Practice parameter update: the care of the patient with
amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and
cognitive/behavioral impairment (an evidence-based review): report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73
(15):1227-1233. PMID: 19822873
Tesfaye S, Selvarajah D. The Eurodiab study: what has this taught us about diabetic
peripheral neuropathy? Curr Diab Rep. 2009;9(6):432-434. PMID: 19954687
Thaera GM, Wellik KE, Barrs DM, Dunckley ED, Wingerchuk DM, Demaerschalk BM. Are
corticosteroid and antiviral treatments effective for Bell palsy? A critically appraised topic.
Neurologist. 2010;16(2):138-140. PMID: 20220455
Wieske L, Harmsen RE, Schultz MJ, Horn J. Is critical illness neuromyopathy and
duration of mechanical ventilation decreased by strict glucose control? Neurocrit Care.
2011;14(3):475-481. PMID: 21267673
Neuro-oncology
Intracranial Tumors
Primary Central Nervous System Tumors
Management of Intracranial Tumors
Paraneoplastic Syndromes
Key Points
Bibliography
Intracranial Tumors
Key Points
Intracranial tumors most commonly involve the cerebral hemispheres and typically
present with seizures; brain metastases, typically from lung or breast cancer or
melanoma, are the most common type.
The diagnostic evaluation of a patient with a suspected brain tumor should include MRI
with intravenous contrast.
The signs and symptoms of an intracranial tumor depend on its location and rate of growth.
Intracranial tumors most commonly involve the cerebral hemispheres and typically present with
seizures. More rapidly growing hemispheric tumors often present with focal neurologic deficits,
such as hemiparesis, hemineglect, or visual field cuts. The first sign of frontal lobe tumors may
be subtle personality changes only recognized after the diagnosis is made. Nonspecific
symptoms of a brain tumor include headache, nausea, vomiting, visual changes, and gait
disorders.
The differential diagnosis of an intracranial tumor includes abscess, demyelinating disease,
vascular malformation, toxoplasmosis, tuberculosis, sarcoidosis, and radiation necrosis.
Diagnostic evaluation of a patient with a suspected brain tumor should include MRI with
intravenous contrast. In many instances, specific signal characteristics on an MRI can
distinguish a tumor from other intracranial lesions and will often suggest the tumor pathology
(Table 35). CT can be useful in detecting calcifications and tumor invasion into bone. Magnetic
resonance spectroscopy, PET, and single-photon emission CT also can help clarify the
diagnosis.
Brain metastases are the most common type of intracranial tumor. The tumors most likely to
metastasize to the brain are lung cancer, breast cancer, and melanoma. Although identifying
and obtaining a tissue diagnosis from the primary lesion is best, brain biopsy may be
necessary if the primary lesion cannot be identified or is inaccessible.
Typical
Age at
Onset
Imaging Findings
Treatment
Median
Survival
Metastatic tumor
60+ y
Multifocal lesions at
gray-white matter
junction; ring
enhancement with
contrast
Radiation, with or
without surgery
10-16 mo
Infiltrating white
matter lesion
Surgery
Glioma
Astrocytoma
Low-grade
(fibrillary)
30-50 y
No enhancement
Surgery, with or
without radiation
7-8 y
Anaplastic
35-55 y
Contrast
enhancement
Surgery and
radiation, with or
without
chemotherapy
(temozolomide)
3-4 y
Glioblastoma
multiforme
45-65 y
Possible
hemorrhage,
possible multifocal or
butterfly lesions
(bihemispheric)
Surgery and
radiation, with or
without
chemotherapy
(temozolomide or
bevacizumab)
12-15 mo
Oligodendroglioma
30-50 y
Infiltrating white
matter lesion; vague
contrast
enhancement with a
honeycomb pattern
and calcifications
that are best seen on
CT scan
Surgery and
chemotherapy
(carmustine or
temozolomide),
with or without
radiation
(see below)
Age range given is for adult presentation; tumor is most common in children.
Tumor Type
Typical
Age at
Onset
Imaging Findings
Treatment
Median
Survival
Low-grade
6-10 y
Anaplastic
3-4 years
Ependymoma
30-40
ya
Meningioma
50-65 y
Posterior fossa or
spinal cord lesion;
contrast
enhancement and
calcifications, with or
without
hydrocephalus
Possible surgery,
possible radiation
15-20 y
Extradural (outside of
the brain); calcified,
with diffusely
enhancing lightbulb
sign
Possible surgery,
possible artery
embolization,
possible radiation
(rare)
(see below)
Benign
Rarely
limits life
expectancy
Atypical
13 y
Anaplastic
3-4 y
Schwannoma
40-50 y
Cerebropontine
angle; contrast
enhancement
Possible surgery
Rarely
limits life
expectancy
Medulloblastoma
20-30
Posterior fossa
(cerebellum);
contrast
enhancement and
hydrocephalus
Surgery and
radiation, with or
without
chemotherapy
17-18 y
Homogeneous white
matter lesion;
Corticosteroids
and chemotherapy
2-4 y
ya
Age range given is for adult presentation; tumor is most common in children.
Tumor Type
Typical
Age at
Onset
Primary central
nervous system
lymphoma
Immunocompetent
60-70 y
AIDS-related
30-40 y
Imaging Findings
Treatment
diffusely enhancing,
periventricular, and
often multifocal
(methotrexate),
with or without
radiation
HAART therapy
Age range given is for adult presentation; tumor is most common in children.
Median
Survival
1-2 y
Figure 26.
Postcontrast T1-weighted MRIs of a left glioblastoma that show an extensive mass with a ring
contrast enhancement surrounding a necrotic center.
Figure 27.
Coronal postcontrast T1-weighted MRI showing a right parafalcine meningioma with associated
edema and mass effect. Note the dural tail (arrow).
Paraneoplastic Syndromes
Key Points
The presence of a paraneoplastic syndrome should be suspected in a patient with an
unexplained subacute progressive neurologic disorder.
The diagnosis of a paraneoplastic syndrome can be confirmed by identifying one of the
causative antibodies in serum or cerebrospinal fluid.
The central and peripheral nervous systems are susceptible to tumor-associated immunemediated injury, which results in various paraneoplastic syndromes (Table 36). An immune
reaction to the primary tumor is thought to be responsible for the generation of autoantibodies
that cross-react with epitopes on specific nervous system structures. The presence of a
paraneoplastic syndrome should be suspected in a patient with an unexplained subacute
progressive neurologic disorder. The diagnosis can be confirmed by identifying one of the
antibodies known to be responsible for these clinical entities in serum or CSF. The absence of
a known paraneoplastic antibody does not exclude the diagnosis of a paraneoplastic
syndrome, however, because new antibodies are still being discovered. For example, an antiNMDA antibody has recently been identified and is associated with limbic encephalitis, a
syndrome of subacute psychosis, personality change, seizures, and oral dyskinesias
(involuntary mouth movements).
The suspicion of a paraneoplastic syndrome should prompt a thorough evaluation for cancer,
including PET and CT of the chest, abdomen, and pelvis. Some syndromes have been
associated with nonmalignant tumors. For example, the anti-NMDA encephalitis described
previously is most commonly associated with ovarian teratomas. An ultrasound or MRI of the
pelvis is recommended if this syndrome is suspected. The definitive treatment of a
paraneoplastic syndrome is removal of the primary neoplasm. Unfortunately, the neurologic
symptoms may precede the oncologic diagnosis by several years, and the tumor often is not
identifiable. Symptomatic treatment of paraneoplastic syndromes includes intravenous immune
globulin, plasmapheresis, and corticosteroid administration.
Symptoms
Tumor
Antibody
Cerebellar
degeneration
Ataxia, dysarthria,
dizziness, vertigo
Breast cancer
ANNA-1 (anti-Hu),
ANNA-3, MA, PCA-1
(anti-Yo)
Hodgkin
lymphoma
Tr
SCLC
ANNA-1 (anti-Hu),
ANNA-3, CRMP-5, MA,
PCA-2, VGCC
Ovarian cancer
ANNA-1 (anti-Hu),
ANNA-3, PCA-1 (antiYo)
Testicular
cancer
ANNA-1 (anti-Hu),
ANNA-3, CRMP-5, MA
Thymoma
CRMP-5
Ovarian or
testicular
teratoma
NMDA
Lung cancer,
thymoma
VGKC
Limbic
encephalitis
Personality change,
psychosis, seizures, oral
dyskinesiasa
Neuropathy
Painful sensory
neuropathy, sensory
ataxia, autonomic
dysfunction
SCLC
ANNA-1 (anti-Hu),
VGCC
Opsoclonusmyoclonus
Involuntary eye
movements and muscle
jerks, ataxia
Breast cancer,
SCLC
ANNA-2 (anti-Ri)
Limbic encephalitis also (but less commonly) can produce a rapidly progressive or subacute
dementia.
Paraneoplastic
Syndrome
Symptoms
Tumor
Antibody
Stiff-person
syndrome
Breast cancer,
lung cancer
Amphiphysin, CRMP-5
Thymoma
CRMP-5
Limbic encephalitis also (but less commonly) can produce a rapidly progressive or subacute
dementia.
Key Points
Intracranial Tumors
Intracranial tumors most commonly involve the cerebral hemispheres and typically
present with seizures; brain metastases, typically from lung or breast cancer or
melanoma, are the most common type.
The diagnostic evaluation of a patient with a suspected brain tumor should include
MRI with intravenous contrast.
Management of Intracranial Tumors
Corticosteroids may be used as treatment of intracranial tumors to minimize tumorassociated vasogenic edema (which can exacerbate symptoms of intracranial
pressure) except when primary central nervous system lymphoma is suspected.
Paraneoplastic Syndromes
The presence of a paraneoplastic syndrome should be suspected in a patient with
an unexplained subacute progressive neurologic disorder.
The diagnosis of a paraneoplastic syndrome can be confirmed by identifying one of
the causative antibodies in serum or cerebrospinal fluid.
Bibliography
Buckner JC, Brown PD, ONeill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous
system tumors. Mayo Clin Proc. 2007;82(10):1271-1286. PMID: 17908533
Dalmau J, Gleichman AJ, Hughes EJ, et al. Anti-NMDA-receptor encephalitis: case
series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.
PMID: 18851928
Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl
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Hoffman S, Propp JM, McCarthy BJ. Temporal trends in incidence of primary brain
tumors in the United States, 1985-1999. Neuro Oncol. 2006;8(1):27-37. PMID: 16443945
Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in
patients with newly diagnosed brain tumors. Report of the Quality Standards
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Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term
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Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and
Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer
Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and
adjuvant temozolamide versus radiotherapy alone on survival in glioblastoma in a
randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol.
2009;10(5):459-466. PMID: 19269895
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Brain Death
Apnea Test
Key Point
Two positive apnea tests performed at least 6 hours apart are diagnostic of brain death,
as long as mitigating factors, such as sedatives or hypothermia, are absent.
The apnea test, which is often required by institutions for brain death determination in patients
on artificial life support, evaluates the medullary respiratory center and its response to
hypercarbia. The patient is removed from the ventilator and given 100% oxygen by cannula. A
baseline arterial blood gas value is obtained, with a required starting PCO2 of 40 to 60 mm Hg.
At 1 and 5 minutes later, repeat arterial blood gas levels are obtained while the patient is
observed for spontaneous respirations. If the PCO2 increases by more than 20 mm Hg and
spontaneous respirations are lacking, the test is considered to be positive. Two positive tests
performed at least 6 hours apart are diagnostic of brain death, as long as no mitigating factors,
such as sedatives or hypothermia, are present. An electrically silent electroencephalogram or
the demonstration of absent cerebral blood flow provides physiologic confirmation of brain
death.
Key Points
Description and Findings
The determination of brain death requires knowing the cause of the catastrophic
brain damage and excluding reversible causes, such as a reversible brainstem
lesion (locked-in syndrome), hypothermia, drug intoxication, and metabolic
encephalopathy.
Apnea Test
Two positive apnea tests performed at least 6 hours apart are diagnostic of brain
death, as long as mitigating factors, such as sedatives or hypothermia, are absent.
Bibliography
Wijdicks EF, Varelas PN, Gronseth GS, Greer DM; American Academy of Neurology.
Evidence-based guideline update: determining brain death in adults: report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74
(23):1911-1918. PMID: 20530327
Neurology Contributors
Please note that a "1" following a contributor's name indicates that he or she has no
relationships to disclose. A "2" indicates that the contributor has disclosed relationships.
Neurology Committee
Blair Ford, MD, Editor2
Professor of Clinical Neurology
Department of Neurology, Neurological Institute
Columbia University Medical Center
New York, New York
Jack Ende, MD, MACP, Associate Editor1
Professor of Medicine
University of Pennsylvania
Chief, Department of Medicine
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania
Elizabeth E. Gerard, MD1
Assistant Professor of Neurology
Director, Womens Epilepsy Program
Northwestern Comprehensive Epilepsy Center
Department of Neurology
Feinberg School of Medicine
Northwestern University
Chicago, Illinois
Daniel M. Harrison, MD2
Assistant Professor of Neurology
Department of Neurology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Robert G. Kaniecki, MD2
Director, The Headache Center
Chief, Headache Division
Assistant Professor of Neurology
University of Pittsburgh
Pittsburgh, Pennsylvania
Erik P. Pioro, MD, PhD2
Staff Neurologist
Barry Winovich ALS Research Chair
Director, Section of ALS and Related Disorders
Department of Neurology, Neurological Institute
Cleveland Clinic
Cleveland, Ohio
Special Reviewer
Mark W. Green, MD2
Professor of Neurology
Director of Headache and Pain Medicine
Mount Sinai School of Medicine
New York, New York
Editor-in-Chief
Patrick C. Alguire, MD, FACP1
Senior Vice President, Medical Education
American College of Physicians
Philadelphia, Pennsylvania
Deputy Editor-in-Chief
Philip A. Masters, MD, FACP1
Senior Medical Associate for Content Development
American College of Physicians
Philadelphia, Pennsylvania
Neurology Reviewers
John K. Chamberlain, MD, MACP1
Randy Hendrickson1
Production Administrator/Editor
Megan Zborowski1
Staff Editor
Linnea Donnarumma1
Assistant Editor
John Haefele1
Assistant Editor
Developed by the American College of Physicians
1. Has no relationships with any entity producing, marketing, re-selling, or distributing health
care goods or services consumed by, or used on, patients.
2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing
health care goods or services consumed by, or used on, patients. See below.
Conflicts of Interest
The following committee members, reviewers, and ACP staff members have disclosed
relationships with commercial companies:
Blair Ford, MD
Consultantship
Medtronic, Inc.
Mark W. Green, MD
Honoraria
GlaxoSmithKline
Speakers Bureau
GlaxoSmithKline
Daniel M. Harrison, MD
Honoraria
Direct One Communications
Research Grants/Contracts
Bayer Schering Pharma
Robert G. Kaniecki, MD
Speakers Bureau
The figure shown in Self-Assessment Test item 7 is adapted with permission from Laforest C,
Selva D, Crompton J, Leibovitch I. Clinical observations: Entopic phenomenon as initial
presentation of acute myelogenous leukemia. Ann Intern Med. 2005;143(11):847. [PMID:
16330805]
The figure shown in Self-Assessment Test item 90 is adapted with permission from Virtual Dx,
Physical Examination Findings, item 23. Copyright 2010 American College of Physicians. All
Rights Reserved. Available (to program subscribers) at: http://virtualdx.acponline.org/selfassessment/questions/pef_q023. Accessed March 19, 2012.