161 Dizziness and Vertigo CHAPTER 22

Nose is pointed 45°

Step 1 Step 2 Step 3 Step 4 Step 5

Nose is pointed 45°

FIGURE 22-1 Modified Epley maneuver for treatment of benign paroxysmal positional vertigo of the right (top panels) and left (bottom panels) posterior semicircular canals.

Step 1. With the patient seated, turn the head 45 degrees toward the affected ear. Step 2. Keeping the head turned, lower the patient to the head-hanging position and hold

for at least 30 s and until nystagmus disappears. Step 3. Without lifting the head, turn it 90 degrees toward the other side. Hold for another 30 s. Step 4. Rotate the patient

onto her side while turning the head another 90 degrees, so that the nose is pointed down 45 degrees. Hold again for 30 s. Step 5. Have the patient sit up on the side of the

table. After a brief rest, the maneuver should be repeated to confirm successful treatment. (Reproduced with permission from Chicago dizziness and Hearing (CDH). Figure

adapted from http://www.dizziness-and-balance.com/disorders/bppv/movies/Epley-480x640.avi)

glucocorticoids or gentamicin into the middle ear may be considered.

Nonablative surgical options include decompression and shunting of

the endolymphatic sac. Full ablative procedures (vestibular nerve section, labyrinthectomy) are seldom required.

■ VESTIBULAR SCHWANNOMA

Vestibular schwannomas (sometimes termed acoustic neuromas) and

other tumors at the cerebellopontine angle cause slowly progressive

unilateral sensorineural hearing loss and vestibular hypofunction.

These patients typically do not have vertigo, because the gradual vestibular deficit is compensated centrally as it develops. The diagnosis often

is not made until there is sufficient hearing loss to be noticed. The vestibular examination will show a deficient response to the head impulse

test when the head is rotated toward the affected side, but nystagmus

will not be prominent. As noted above, patients with unexplained unilateral sensorineural hearing loss or vestibular hypofunction require

MRI of the internal auditory canals to look for a schwannoma.

■ BILATERAL VESTIBULAR HYPOFUNCTION

Patients with bilateral loss of vestibular function also typically do not

have vertigo, because vestibular function is lost on both sides simultaneously, and there is no asymmetry of vestibular input. Symptoms

include loss of balance, particularly in the dark, where vestibular input

is most critical, and oscillopsia during head movement, such as while

walking or riding in a car. Bilateral vestibular hypofunction may be

(1) idiopathic and progressive, (2) part of a neurodegenerative disorder, or (3) iatrogenic due to medication ototoxicity (most commonly

gentamicin or other aminoglycoside antibiotics). Other causes include

bilateral vestibular schwannomas (neurofibromatosis type 2), autoimmune disease, superficial siderosis, and meningeal-based infection or

tumor. It also may occur in patients with peripheral polyneuropathy;

in these patients, both vestibular loss and impaired proprioception may

contribute to poor balance. Finally, unilateral processes such as vestibular neuritis and Ménière’s disease may involve both ears sequentially,

resulting in bilateral vestibulopathy.

Examination findings include diminished dynamic visual acuity

(see above) due to loss of stable vision when the head is moving,

abnormal head impulse responses in both directions, and a Romberg

sign. Responses to caloric testing are reduced. Patients with bilateral

vestibular hypofunction should be referred for vestibular rehabilitation

therapy. Vestibular suppressant medications should not be used, as they

will increase the imbalance. Evaluation by a neurologist is important

not only to confirm the diagnosis but also to consider any other associated neurologic abnormalities that may clarify the etiology.

■ CENTRAL VESTIBULAR DISORDERS

Central lesions causing vertigo typically involve vestibular pathways in

the brainstem and/or cerebellum. They may be due to discrete lesions,

such as from ischemic or hemorrhagic stroke (Chaps. 426–428),

demyelination (Chap. 444), or tumors (Chap. 90), or they may be due

to neurodegenerative conditions that include the vestibulocerebellum

(Chaps. 431–434). Subacute cerebellar degeneration may be due to

immune, including paraneoplastic, processes (Chaps. 94 and 439).

Table 22-1 outlines important features of the history and examination

that help to identify central vestibular disorders. Acute central vertigo

is a medical emergency, due to the possibility of life-threatening stroke

or hemorrhage. All patients with suspected central vestibular disorders

should undergo brain MRI, and the patient should be referred for full

neurologic evaluation.

■ PSYCHOSOMATIC AND FUNCTIONAL DIZZINESS

Psychological factors play an important role in chronic dizziness. First,

dizziness may be a somatic manifestation of a psychiatric condition

such as major depression, anxiety, or panic disorder (Chap. 452).

Second, patients may develop anxiety and autonomic symptoms as a

consequence or comorbidity of an independent vestibular disorder.

One particular form of this has been termed variously phobic postural

vertigo, psychophysiologic vertigo, or chronic subjective dizziness, but

is now referred to as persistent postural-perceptual dizziness (PPPD).

These patients have a chronic feeling (3 months or longer) of fluctuating dizziness and disequilibrium that is present at rest but worse while

standing. There is an increased sensitivity to self-motion and visual

motion (e.g., watching movies), and a particular intensification of

symptoms when moving through complex visual environments such as

supermarkets. Although there may be a past history of an acute vestibular disorder (e.g., vestibular neuritis), the neuro-otologic examination

162 PART 2 Cardinal Manifestations and Presentation of Diseases

and vestibular testing are normal or indicative of a compensated vestibular deficit, indicating that the ongoing subjective dizziness cannot

be explained by a primary vestibular pathology. Anxiety disorders are

particularly common in patients with chronic dizziness; when present,

they contribute substantially to the morbidity. Treatment approaches

for PPPD include pharmacological therapy with selective serotonin

reuptake inhibitors (SSRIs), cognitive-behavioral psychotherapy, and

vestibular rehabilitation. Vestibular suppressant medications generally

should be avoided.

TREATMENT

Vertigo

Table 22-2 provides a list of commonly used medications for suppression of vertigo. As noted, these medications should be reserved

for short-term control of active vertigo, such as during the first few

days of acute vestibular neuritis, or for acute attacks of Ménière’s

disease. They are less helpful for chronic dizziness and, as previously stated, may hinder central compensation. An exception is

that benzodiazepines may attenuate psychosomatic dizziness and

the associated anxiety, although SSRIs are generally preferable in

such patients.

Vestibular rehabilitation therapy promotes central adaptation

processes that compensate for vestibular loss and also may help

habituate motion sensitivity and other symptoms of psychosomatic

dizziness. The general approach is to use a graded series of exercises

that progressively challenge gaze stabilization and balance.

■ FURTHER READING

Altissimi G et al: Drugs inducing hearing loss, tinnitus, dizziness and

vertigo: An updated guide. Eur Rev Med Pharmacol Sci 24:7946,

2020.

Huang TC et al: Vestibular migraine: An update on current understanding and future directions. Cephalalgia 40:107, 2020.

Kim JS, Zee DS: Benign paroxysmal positional vertigo. N Engl J Med

370:1138, 2014.

Popkirov S et al: Persistent postural-perceptual dizziness (PPPD):

a common, characteristic and treatable cause of chronic dizziness.

Pract Neurol 18:5, 2018.

TABLE 22-2 Treatment of Vertigo

AGENTa DOSEb

Antihistamines

Meclizine 25–50 mg 3 times daily

Dimenhydrinate 50 mg 1–2 times daily

Promethazine 25 mg 2–3 times daily (also

can be given rectally and IM)

Benzodiazepines

Diazepam 2.5 mg 1–3 times daily

Clonazepam 0.25 mg 1–3 times daily

Anticholinergic

Scopolamine transdermalc Patch

Physical therapy

Repositioning maneuversd

Vestibular rehabilitation

Other

Diuretics and/or low-sodium (1000 mg/d) diete

Antimigrainous drugsf

Selective serotonin reuptake inhibitorsg

a

All listed drugs are approved by the US Food and Drug Administration, but most

are not approved for the treatment of vertigo. b

Usual oral (unless otherwise stated)

starting dose in adults; a higher maintenance dose can be reached by a gradual

increase. c

For motion sickness only. d

For benign paroxysmal positional vertigo. e

For

Ménière’s disease. f

For vestibular migraine. g

For persistent postural-perceptual

vertigo and anxiety.

Fatigue is one of the most common symptoms in clinical medicine. It

is a prominent manifestation of a number of systemic, neurologic, and

psychiatric syndromes, although a precise cause will not be identified

in a substantial minority of patients. Fatigue refers to the subjective

experience of physical and mental weariness, sluggishness, low energy,

and exhaustion. In the context of clinical medicine, fatigue is most

practically defined as difficulty initiating or maintaining voluntary

mental or physical activity. Nearly everyone who has ever been ill with

a self-limited infection has experienced this near-universal symptom,

and fatigue is usually brought to medical attention only when it is

either of unclear cause, fails to remit, or the severity is out of proportion with what would be expected for the associated trigger.

Fatigue should be distinguished from muscle weakness, a reduction

of neuromuscular power (Chap. 24); most patients complaining of

fatigue are not truly weak when direct muscle power is tested. Fatigue is

also distinct from somnolence, which refers to sleepiness in the context

of disturbed sleep-wake physiology (Chap. 31), and from dyspnea on

exertion, although patients may use the word fatigue to describe any

of these symptoms. The task facing clinicians when a patient presents

with fatigue is to identify the underlying cause and develop a therapeutic alliance, the goal of which is to spare patients expensive and fruitless

diagnostic workups and steer them toward effective therapy.

■ EPIDEMIOLOGY AND GLOBAL CONSIDERATIONS

Variability in the definitions of fatigue and the survey instruments used

in different studies makes it difficult to arrive at precise figures about

the global burden of fatigue. The point prevalence of fatigue was 6.7%

and the lifetime prevalence was 25% in a large National Institute of

Mental Health survey of the U.S. general population. In primary care

clinics in Europe and the United States, between 10 and 25% of patients

surveyed endorsed symptoms of prolonged (present for >1 month) or

chronic (present for >6 months) fatigue, but in only a minority was

fatigue the primary reason for seeking medical attention. In a community survey of women in India, 12% reported chronic fatigue. By

contrast, the prevalence of chronic fatigue syndrome (Chap. 450), as

defined by the U.S. Centers for Disease Control and Prevention, is low.

■ DIFFERENTIAL DIAGNOSIS

Psychiatric Disease Fatigue is a common somatic manifestation

of many major psychiatric syndromes, including depression, anxiety,

and somatoform disorders (Chap. 452). Psychiatric symptoms are

reported in more than three-quarters of patients with unexplained

chronic fatigue. Even in patients with systemic or neurologic disorders

in which fatigue is independently recognized as a symptom, comorbid

psychiatric disease may still be an important contributor.

Neurologic Disease Patients complaining of fatigue often say they

feel weak, but upon careful examination, objective muscle weakness is

rarely discernible. If found, muscle weakness must then be localized

to the central nervous system, peripheral nervous system, neuromuscular junction, or muscle, and appropriate follow-up studies obtained

(Chap. 24). Fatigability of muscle power is a cardinal manifestation

of some neuromuscular disorders such as myasthenia gravis and is

distinguished from fatigue by finding clinically evident diminution of

the amount of force that a muscle generates upon repeated contraction

(Chap. 448). Fatigue is one of the most common and bothersome

symptoms reported in multiple sclerosis (MS) (Chap. 444), affecting nearly 90% of patients; fatigue in MS can persist between MS

attacks and does not necessarily correlate with magnetic resonance

imaging (MRI) disease activity. Fatigue is also increasingly identified

as a troublesome feature of many neurodegenerative diseases, including Parkinson’s disease (Chap. 435), amyotrophic lateral sclerosis

23 Fatigue

Jeffrey M. Gelfand, Vanja C. Douglas

163 Fatigue CHAPTER 23

(Chap. 437), and central nervous system dysautonomias (Chap. 440).

Fatigue after stroke (Chap. 426) is a well-described but poorly understood entity with a widely varying prevalence. Episodic fatigue can

be a premonitory symptom of migraine (Chap. 430). Fatigue is also

a frequent consequence of traumatic brain injury (Chap. 443), often

occurring in association with depression and sleep disorders.

Sleep Disorders Obstructive sleep apnea is an important cause of

excessive daytime sleepiness in association with fatigue and should be

investigated using overnight polysomnography, particularly in those

with prominent snoring, obesity, or other predictors of obstructive

sleep apnea (Chap. 297). Whether the cumulative sleep deprivation

that is common in modern society contributes to clinically apparent

fatigue is not known (Chap. 31).

Endocrine Disorders Fatigue, sometimes in association with

true muscle weakness, can be a heralding symptom of hypothyroidism

(Chap. 383), particularly in the context of hair loss, dry skin, cold

intolerance, constipation, and weight gain. Fatigue associated with heat

intolerance, sweating, and palpitations is typical of hyperthyroidism

(Chap. 384). Adrenal insufficiency (Chap. 386) can also manifest with

unexplained fatigue as a primary or prominent symptom, often with

anorexia, weight loss, nausea, myalgias, and arthralgias; hyponatremia,

hyperkalemia, and hyperpigmentation may be present at time of diagnosis. Mild hypercalcemia can cause fatigue, which may be relatively

vague, whereas severe hypercalcemia can lead to lethargy, stupor, and

coma (Chap. 410). Both hypoglycemia and hyperglycemia can cause

lethargy, often in association with confusion; diabetes mellitus, and in

particular type 1 diabetes, is also associated with fatigue independent

of glucose levels (Chap. 403). Fatigue may also accompany Cushing’s

disease, hypoaldosteronism, and hypogonadism. Low vitamin D status

has also been associated with fatigue.

Liver and Kidney Disease Both chronic liver failure and chronic

kidney disease can cause fatigue. Over 80% of hemodialysis patients

complain of fatigue, which makes it one of the most common symptoms reported by patients in chronic kidney disease (Chap. 311).

Obesity Obesity (Chap. 401) is associated with fatigue and sleepiness independent of the presence of obstructive sleep apnea. Obese

patients undergoing bariatric surgery experience improvement in

daytime sleepiness sooner than would be expected if the improvement

were solely the result of weight loss and resolution of sleep apnea. A

number of other factors common in obese patients are likely contributors as well, including physical inactivity, diabetes, and depression.

Physical Inactivity Physical inactivity is associated with fatigue,

and increasing physical activity can improve fatigue in some patients.

Malnutrition Although fatigue can be a presenting feature of

malnutrition (Chap. 334), nutritional status may also be an important comorbidity and contributor to fatigue in other chronic illnesses,

including cancer-associated fatigue.

Infection Both acute and chronic infections commonly lead to

fatigue as part of the broader infectious syndrome. Evaluation for

undiagnosed infection as the cause of unexplained fatigue, and particularly prolonged or chronic fatigue, should be guided by the history,

physical examination, and infectious risk factors, with particular attention to risk for tuberculosis, HIV, chronic hepatitis, and endocarditis.

Infectious mononucleosis may cause prolonged fatigue that persists

for weeks to months following the acute illness, but infection with the

Epstein-Barr virus is only very rarely the cause of unexplained chronic

fatigue. Postinfectious fatigue may also occur following a variety of

acute infections. For example, a substantial minority of patients who

have recovered from SARS-CoV-1, SARS-CoV-2, and Ebola virus

complain of persistent fatigue.

Drugs Many medications, drugs, drug withdrawal, and chronic

alcohol use can all lead to fatigue. Medications that are more likely to

be causative include antidepressants, antipsychotics, anxiolytics, opiates, antispasticity agents, antiseizure agents, and beta blockers.

Cardiovascular and Pulmonary Disorders Fatigue is one of

the most taxing symptoms reported by patients with congestive heart

failure and chronic obstructive pulmonary disease and negatively

affects quality of life. In a population-based cohort study in Norfolk,

United Kingdom, fatigue was associated with an increased hazard

of all-cause mortality in the general population, but particularly for

deaths related to cardiovascular disease.

Malignancy Fatigue, particularly in association with unexplained

weight loss, can be a sign of occult malignancy, but cancer is rarely

identified in patients with unexplained chronic fatigue in the absence

of other telltale signs or symptoms. Cancer-related fatigue is experienced by 40% of patients at the time of diagnosis and by >80% at some

time in the disease course.

Hematologic Disorders Chronic or progressive anemia may

present with fatigue, sometimes in association with exertional tachycardia and breathlessness. Anemia may also contribute to fatigue in

chronic illness. Low serum ferritin in the absence of anemia may also

cause fatigue that is reversible with iron replacement.

Immune-Mediated Disorders Fatigue is a prominent complaint

in many chronic inflammatory disorders, including systemic lupus

erythematosus, polymyalgia rheumatica, rheumatoid arthritis, inflammatory bowel disease, antineutrophil cytoplasmic antibody (ANCA)–

associated vasculitis, sarcoidosis, and Sjögren’s syndrome, but is not

usually an isolated symptom. Fatigue is also associated with primary

immunodeficiency diseases.

Pregnancy Fatigue is very commonly reported by women during

all stages of pregnancy and postpartum.

Disorders of Unclear Cause Myalgic encephalomyelitis (ME)/

chronic fatigue syndrome (CFS) (Chap. 450) and fibromyalgia

(Chap. 373) incorporate chronic fatigue as part of the syndromic

definition when fatigue is present in association with other criteria, as

discussed in the respective chapters. Chronic multisymptom illness,

also known as Gulf-War syndrome, is another symptom complex with

prominent fatigue; it is most commonly, although not exclusively,

observed in veterans of the 1991 Gulf War conflict (Chap. S7). Idiopathic chronic fatigue is used to describe the syndrome of unexplained

chronic fatigue in the absence of enough additional clinical features to

meet the diagnostic criteria for ME/CFS.

APPROACH TO THE PATIENT

Fatigue

A detailed history focusing on the quality, pattern, time course,

associated symptoms, and alleviating factors of fatigue is necessary to

define the syndrome and help direct further evaluation and treatment.

It is important to determine if fatigue is the appropriate designation,

whether symptoms are acute or chronic, and if the impairment is

primarily mental, physical, or a combination of the two. The review

of systems should attempt to distinguish fatigue from excessive

sleepiness, dyspnea on exertion, exercise intolerance, and muscle

weakness. The presence of fever, chills, night sweats, or weight

loss should raise suspicion for an occult infection or malignancy.

A careful review of prescription, over-the-counter, herbal, and

recreational drug and alcohol use is required. Circumstances surrounding the onset of symptoms and potential triggers should be

investigated. The social history is important, with attention paid

to life stressors and adverse experiences, workhours, the social

support network, and domestic affairs including a screen for intimate partner violence. Sleep habits and sleep hygiene should be

questioned. The impact of fatigue on daily functioning is important

to understand the patient’s experience and gauge recovery and the

success of treatment.

164 PART 2 Cardinal Manifestations and Presentation of Diseases

The physical examination of patients with fatigue is guided by

the history and differential diagnosis. A detailed mental status

examination should be performed with particular attention to

symptoms of depression and anxiety. A formal neurologic examination is required to determine whether objective muscle weakness

is present. This is usually a straightforward exercise, although

occasionally patients with fatigue have difficulty sustaining effort

against resistance and sometimes report that generating full power

requires substantial mental effort. On confrontational testing, full

power may be generated for only a brief period before the patient

suddenly gives way to the examiner. This type of weakness is often

referred to as breakaway weakness and may or may not be associated

with pain. This is contrasted with weakness due to lesions in the

motor tracts or lower motor unit, in which the patient’s resistance

can be overcome in a smooth and steady fashion and full power

can never be generated. Occasionally, a patient may demonstrate

fatigable weakness, in which power is full when first tested but

becomes weak upon repeat evaluation without interval rest. Fatigable weakness, which usually indicates a problem of neuromuscular

transmission, never has the sudden breakaway quality that one

occasionally observes in patients with fatigue. If the presence or

absence of muscle weakness cannot be determined with the physical examination, electromyography with nerve conductions studies

can be a helpful ancillary test.

The general physical examination should screen for signs of cardiopulmonary disease, malignancy, lymphadenopathy, organomegaly, infection, liver failure, kidney disease, malnutrition, endocrine

abnormalities, and connective tissue disease. In patients with

associated widespread musculoskeletal pain, assessment of tender

points may help to reveal fibromyalgia. Although the diagnostic

yield of the general physical examination may be relatively low in

the context of evaluation of unexplained chronic fatigue, elucidating the cause of only 2% of cases in one prospective analysis, the

yield of a detailed neuropsychiatric and mental status evaluation

is likely to be much higher, revealing a potential explanation for

fatigue in up to 75–80% of patients in some series. Furthermore, a

complete physical examination demonstrates a serious and systematic approach to the patient’s complaint and helps build trust and a

therapeutic alliance.

Laboratory testing is likely to identify the cause of chronic fatigue

in only about 5% of cases. Beyond a few standard screening tests,

laboratory evaluation should be guided by the history and physical

examination; extensive testing is likely to lead to incidental findings

that require explanation and unnecessary follow-up investigation,

and should be avoided in lieu of frequent clinical follow-up. A

reasonable approach to screening includes a complete blood count

with differential (to screen for anemia, infection, and malignancy),

electrolytes (including sodium, potassium, and calcium), glucose,

renal function, liver function, and thyroid function. Testing for

HIV and adrenal function can also be considered. Published guidelines for chronic fatigue syndrome also recommend an erythrocyte

sedimentation rate (ESR) as part of the evaluation for mimics,

but unless the value is very high, such nonspecific testing in the

absence of other features is unlikely to clarify the situation. Routine

screening with an antinuclear antibody (ANA) test is also unlikely

to be informative in isolation and is frequently positive at low titers

in otherwise healthy adults. Additional unfocused studies, such as

whole-body imaging scans, are usually not indicated; in addition to

their inconvenience, potential risk, and cost, they often reveal unrelated incidental findings that can prolong the workup unnecessarily.

TREATMENT

Fatigue

The first priority is to address the underlying disorder or disorders that account for fatigue, because this can be curative in select

contexts and palliative in others. Unfortunately, in many chronic

illnesses, fatigue may be refractory to traditional disease-modifying

therapies, but it is nevertheless important in such cases to evaluate

for other potential contributors because the cause may be multifactorial. Antidepressants (Chap. 452) may be helpful for treatment of

chronic fatigue when symptoms of depression are present and are

generally most effective as part of a multimodal approach. However,

antidepressants can also cause fatigue and should be discontinued

if they are not clearly effective. Cognitive-behavioral therapy has

also been demonstrated to be helpful in ME/CFS as well as cancerassociated fatigue. Both cognitive-behavioral therapy and graded

exercise therapy, in which physical exercise, most typically walking, is gradually increased with attention to target heart rates to

avoid overexertion, were shown to modestly improve walking

times and self-reported fatigue measures when compared to standard medical care in patients in the United Kingdom with chronic

fatigue. These benefits were maintained after a median follow-up

of 2.5 years. Psychostimulants such as amphetamines, modafinil,

and armodafinil can help increase alertness and concentration and

reduce excessive daytime sleepiness in certain clinical contexts,

which may in turn help with symptoms of fatigue in a minority

of patients, but they have generally proven to be unhelpful in randomized trials for treating fatigue in posttraumatic brain injury,

Parkinson’s disease, cancer, and MS. In patients with low vitamin

D status, vitamin D replacement may lead to improvement in

fatigue.

Development of more effective therapy for fatigue is hampered

by limited knowledge of the biologic basis of this symptom, including how fatigue is detected and registered in the nervous system.

Proinflammatory cytokines, such as interleukin 1α and 1β and

tumor necrosis factor α, might mediate fatigue in some patients.

While preliminary studies of biologic therapies that inhibit cytokines have suggested a benefit against fatigue in some patients

with inflammatory conditions, this approach has largely not led

to improvement in clinical trials that focused on fatigue as the

primary endpoint. Nonetheless, specific targeting with cytokine

antagonists could represent a possible future approach for some

patients.

■ PROGNOSIS

Acute fatigue significant enough to require medical evaluation is more

likely to lead to an identifiable medical, neurologic, or psychiatric cause

than is unexplained chronic fatigue. Evaluation of unexplained chronic

fatigue most commonly leads to diagnosis of a psychiatric condition

or remains unexplained. Identification of a previously undiagnosed

serious or life-threatening culprit etiology is rare, even with longitudinal follow-up of patients with unexplained chronic fatigue. Complete

resolution is uncommon, at least over the short term, but multidisciplinary treatment approaches can lead to symptomatic improvements

that substantially improve quality of life.

■ FURTHER READING

Basu N et al: Fatigue is associated with excess mortality in the general

population: Results from the EPIC-Norfolk study. BMC Med 14:122,

2016.

Dukes JC et al: Approach to fatigue: Best practice. Med Clin North

Am 105:137, 2021.

Roerink ME et al: Interleukin-1 as a mediator of fatigue in disease: A

narrative review. J Neuroinflammation 14:16, 2017.

Sharpe M et al: Rehabilitative treatments for chronic fatigue syndrome: Long-term follow-up from the PACE trial. Lancet Psychiatry

2:1067, 2015.

White PD et al: Comparison of adaptive pacing therapy, cognitive

behaviour therapy, graded exercise therapy, and specialist medical

care for chronic fatigue syndrome (PACE): A randomised trial.

Lancet 377:823, 2011.

165 Neurologic Causes of Weakness and Paralysis CHAPTER 24

Normal motor function involves integrated muscle activity that is modulated by the activity of the cerebral cortex, basal ganglia, cerebellum,

red nucleus, brainstem reticular formation, lateral vestibular nucleus,

and spinal cord. Motor system dysfunction leads to weakness or paralysis, discussed in this chapter, or to ataxia (Chap. 439) or abnormal

movements (Chap. 436). Weakness is a reduction in the power that

can be exerted by one or more muscles. It must be distinguished from

increased fatigability (i.e., the inability to sustain the performance of

an activity that should be normal for a person of the same age, sex,

and size), limitation in function due to pain or articular stiffness, or

impaired motor activity because severe proprioceptive sensory loss prevents adequate feedback information about the direction and power of

movements. It is also distinct from bradykinesia (in which increased

time is required for full power to be exerted) and apraxia, a disorder

of planning and initiating a skilled or learned movement unrelated to a

significant motor or sensory deficit (Chap. 30).

Paralysis or the suffix “-plegia” indicates weakness so severe that a

muscle cannot be contracted at all, whereas paresis refers to less severe

weakness. The prefix “hemi-” refers to one-half of the body, “para-” to

both legs, and “quadri-” to all four limbs.

The distribution of weakness helps to localize the underlying lesion.

Weakness from involvement of upper motor neurons occurs particularly in the extensors and abductors of the upper limb and the flexors

of the lower limb. Lower motor neuron weakness depends on whether

involvement is at the level of the anterior horn cells, nerve root, limb

plexus, or peripheral nerve—only muscles supplied by the affected

structure are weak. Myopathic weakness is generally most marked in

proximal muscles. Weakness from impaired neuromuscular transmission has no specific pattern of involvement.

Weakness often is accompanied by other neurologic abnormalities

that help indicate the site of the responsible lesion (Table 24-1).

Tone is the resistance of a muscle to passive stretch. Increased tone

may be of several types. Spasticity is the increase in tone associated with

disease of upper motor neurons. It is velocity dependent, has a sudden

release after reaching a maximum (the “clasp-knife” phenomenon),

and predominantly affects the antigravity muscles (i.e., upper-limb

flexors and lower-limb extensors). Rigidity is hypertonia that is present

throughout the range of motion (a “lead pipe” or “plastic” stiffness) and

affects flexors and extensors equally; it sometimes has a cogwheel quality that is enhanced by voluntary movement of the contralateral limb

(reinforcement). Rigidity occurs with certain extrapyramidal disorders,

such as Parkinson’s disease. Paratonia (or gegenhalten) is increased tone

that varies irregularly in a manner seemingly related to the degree of

relaxation, is present throughout the range of motion, and affects flexors and extensors equally; it usually results from disease of the frontal

lobes. Weakness with decreased tone (flaccidity) or normal tone occurs

with disorders of motor units. A motor unit consists of a single lower

motor neuron and all the muscle fibers that it innervates.

24 Neurologic Causes of

Weakness and Paralysis

Stephen L. Hauser

Muscle bulk generally is not affected by upper motor neuron lesions,

although mild disuse atrophy eventually may occur. By contrast, atrophy is often conspicuous when a lower motor neuron lesion is responsible for weakness and also may occur with advanced muscle disease.

Muscle stretch (tendon) reflexes are usually increased with upper

motor neuron lesions but may be decreased or absent for a variable

period immediately after onset of an acute lesion. Hyperreflexia is

usually—but not invariably—accompanied by loss of cutaneous reflexes

(such as superficial abdominals; Chap. 422) and, in particular, by an

extensor plantar (Babinski) response. The muscle stretch reflexes are

depressed with lower motor neuron lesions directly involving specific

reflex arcs. They generally are preserved in patients with myopathic

weakness except in advanced stages, when they sometimes are attenuated. In disorders of the neuromuscular junction, reflex responses

may be affected by preceding voluntary activity of affected muscles;

such activity may lead to enhancement of initially depressed reflexes in

Lambert-Eaton myasthenic syndrome and, conversely, to depression of

initially normal reflexes in myasthenia gravis (Chap. 448).

The distinction of neuropathic (lower motor neuron) from myopathic weakness is sometimes difficult clinically, although distal weakness is likely to be neuropathic, and symmetric proximal weakness

myopathic. Fasciculations (visible or palpable twitches within a muscle

due to the spontaneous discharge of a motor unit) and early atrophy

indicate that weakness is neuropathic.

■ PATHOGENESIS

Upper Motor Neuron Weakness Lesions of the upper motor

neurons or their descending axons to the spinal cord (Fig. 24-1) produce weakness through decreased activation of lower motor neurons.

In general, distal muscle groups are affected more severely than proximal ones, and axial movements are spared unless the lesion is severe

and bilateral. Spasticity is typical but may not be present acutely. Rapid

repetitive movements are slowed and coarse, but normal rhythmicity is

maintained. With corticobulbar involvement, weakness occurs in the

lower face and tongue; extraocular, upper facial, pharyngeal, and jaw

muscles are typically spared. Bilateral corticobulbar lesions produce a

pseudobulbar palsy: dysarthria, dysphagia, dysphonia, and emotional

lability accompany bilateral facial weakness and a brisk jaw jerk.

Electromyogram (EMG) (Chap. 446) shows that with weakness of the

upper motor neuron type, motor units have a diminished maximal

discharge frequency.

Lower Motor Neuron Weakness This pattern results from disorders of lower motor neurons in the brainstem motor nuclei and the

anterior horn of the spinal cord or from dysfunction of the axons of

these neurons as they pass to skeletal muscle (Fig. 24-2). Weakness is

due to a decrease in the number of muscle fibers that can be activated

through a loss of α motor neurons or disruption of their connections to

muscle. Loss of γ motor neurons does not cause weakness but decreases

tension on the muscle spindles, which decreases muscle tone and attenuates the stretch reflexes. An absent stretch reflex suggests involvement

of spindle afferent fibers.

When a motor unit becomes diseased, especially in anterior horn

cell diseases, it may discharge spontaneously, producing fasciculations.

When α motor neurons or their axons degenerate, the denervated

muscle fibers also may discharge spontaneously. These single muscle

TABLE 24-1 Signs That Distinguish the Origin of Weakness

SIGN UPPER MOTOR NEURON LOWER MOTOR NEURON MYOPATHIC PSYCHOGENIC

Atrophy None Severe Mild None

Fasciculations None Common None None

Tone Spastic Decreased Normal/decreased Variable/paratonia

Distribution of weakness Pyramidal/regional Distal/segmental Proximal Variable/inconsistent with daily

activities

Muscle stretch reflexes Hyperactive Hypoactive/absent Normal/hypoactive Normal

Babinski sign Present Absent Absent Absent

166 PART 2 Cardinal Manifestations and Presentation of Diseases

fiber discharges, or fibrillation potentials, cannot be seen but can be

recorded with EMG. Weakness leads to delayed or reduced recruitment of motor units, with fewer than normal activated at a particular

discharge frequency.

Neuromuscular Junction Weakness Disorders of the neuromuscular junction produce weakness of variable degree and distribution. The number of muscle fibers that are activated varies over time,

depending on the state of rest of the neuromuscular junctions. Strength

is influenced by preceding activity of the affected muscle. In myasthenia gravis, for example, sustained or repeated contractions of affected

muscle decline in strength despite continuing effort (Chap. 440). Thus,

fatigable weakness is suggestive of disorders of the neuromuscular

junction, which cause functional loss of muscle fibers due to failure of

their activation.

Myopathic Weakness Myopathic weakness is produced by a

decrease in the number or contractile force of muscle fibers activated within motor units. With muscular dystrophies, inflammatory

myopathies, or myopathies with muscle fiber necrosis, the number of

muscle fibers is reduced within many motor units. On EMG, the size

of each motor unit action potential is decreased, and motor units must

be recruited more rapidly than normal to produce the desired power.

Some myopathies produce weakness through loss of contractile force

of muscle fibers or through relatively selective involvement of type II

(fast) fibers. These myopathies may not affect the size of individual

motor unit action potentials and are detected by a discrepancy between

the electrical activity and force of a muscle.

Psychogenic Weakness Weakness may occur without a recognizable organic basis. It tends to be variable, inconsistent, and with a

pattern of distribution that cannot be explained on a neuroanatomic

basis. On formal testing, antagonists may contract when the patient is

supposedly activating the agonist muscle. The severity of weakness is

out of keeping with the patient’s daily activities.

■ DISTRIBUTION OF WEAKNESS

Hemiparesis Hemiparesis results from an upper motor neuron

lesion above the midcervical spinal cord; most such lesions are above

the foramen magnum. The presence of other neurologic deficits helps

localize the lesion. Thus language disorders, for example, point to a

Ventromedial

bulbospinal

tracts

Lateral

corticospinal tract

Rubrospinal

(ventrolateral)

tract

Corticospinal

tract

Hip Trunk

Shoulder

Elbow

Wrist

Fingers

Thumb

Neck Brow

Larynx

Eyelid

Nares

Lips

Tongue

Knee

Ankle

Toes

Red nucleus

Rubrospinal tract

Lateral corticospinal

tract

Reticular nuclei

Vestibular nuclei

Vestibulospinal tract

Reticulospinal tract

FIGURE 24-1 The corticospinal and bulbospinal upper motor neuron pathways.

Upper motor neurons have their cell bodies in layer V of the primary motor cortex

(the precentral gyrus, or Brodmann area 4) and in the premotor and supplemental

motor cortex (area 6). The upper motor neurons in the primary motor cortex

are somatotopically organized (right side of figure). Axons of the upper motor

neurons descend through the subcortical white matter and the posterior limb of

the internal capsule. Axons of the pyramidal or corticospinal system descend

through the brainstem in the cerebral peduncle of the midbrain, the basis pontis,

and the medullary pyramids. At the cervicomedullary junction, most corticospinal

axons decussate into the contralateral corticospinal tract of the lateral spinal

cord, but 10–30% remain ipsilateral in the anterior spinal cord. Corticospinal

neurons synapse on premotor interneurons, but some—especially in the cervical

enlargement and those connecting with motor neurons to distal limb muscles—

make direct monosynaptic connections with lower motor neurons. They innervate

most densely the lower motor neurons of hand muscles and are involved in

the execution of learned, fine movements. Corticobulbar neurons are similar to

corticospinal neurons but innervate brainstem motor nuclei. Bulbospinal upper

motor neurons influence strength and tone but are not part of the pyramidal system.

The descending ventromedial bulbospinal pathways originate in the tectum of the

midbrain (tectospinal pathway), the vestibular nuclei (vestibulospinal pathway), and

the reticular formation (reticulospinal pathway). These pathways influence axial and

proximal muscles and are involved in the maintenance of posture and integrated

movements of the limbs and trunk. The descending ventrolateral bulbospinal

pathways, which originate predominantly in the red nucleus (rubrospinal pathway),

facilitate distal limb muscles. The bulbospinal system sometimes is referred to as

the extrapyramidal upper motor neuron system. In all figures, nerve cell bodies and

axon terminals are shown, respectively, as closed circles and forks.

Muscle spindle

(intrafusal fibers)

Afferent

neuron

Alpha and gamma

motor neurons

Motor end plates on

voluntary muscle

(extrafusal fibers)

α

γ

FIGURE 24-2 Lower motor neurons are divided into ` and f types. The larger α

motor neurons are more numerous and innervate the extrafusal muscle fibers of

the motor unit. Loss of α motor neurons or disruption of their axons produces lower

motor neuron weakness. The smaller, less numerous γ motor neurons innervate

the intrafusal muscle fibers of the muscle spindle and contribute to normal tone

and stretch reflexes. The α motor neuron receives direct excitatory input from

corticomotoneurons and primary muscle spindle afferents. The α and γ motor

neurons also receive excitatory input from other descending upper motor neuron

pathways, segmental sensory inputs, and interneurons. The α motor neurons

receive direct inhibition from Renshaw cell interneurons, and other interneurons

indirectly inhibit the α and γ motor neurons. A muscle stretch (tendon) reflex

requires the function of all the illustrated structures. A tap on a tendon stretches

muscle spindles (which are tonically activated by γ motor neurons) and activates

the primary spindle afferent neurons. These neurons stimulate the α motor neurons

in the spinal cord, producing a brief muscle contraction, which is the familiar tendon

reflex.

167 Neurologic Causes of Weakness and Paralysis CHAPTER 24

cortical lesion. Homonymous visual field defects reflect either a cortical or a subcortical hemispheric lesion. A “pure motor” hemiparesis of

the face, arm, and leg often is due to a small, discrete lesion in the posterior limb of the internal capsule, cerebral peduncle in the midbrain,

or upper pons. Some brainstem lesions produce “crossed paralyses,”

consisting of ipsilateral cranial nerve signs and contralateral hemiparesis (Chap. 426). The absence of cranial nerve signs or facial weakness suggests that a hemiparesis is due to a lesion in the high cervical

spinal cord, especially if associated with Brown-Séquard syndrome,

consisting of loss of joint position and vibration sense on the side of

the weakness, and loss of pain and temperature sense on the opposite

side (Chap. 442).

Acute or episodic hemiparesis usually results from focal structural

lesions, particularly vascular etiologies, rapidly expanding lesions, or

an inflammatory process. Subacute hemiparesis that evolves over days

or weeks may relate to subdural hematoma, infectious or inflammatory disorders (e.g., cerebral abscess, fungal granuloma or meningitis,

parasitic infection, multiple sclerosis, sarcoidosis), or primary or metastatic neoplasms. AIDS may present with subacute hemiparesis due to

toxoplasmosis or primary central nervous system (CNS) lymphoma.

Chronic hemiparesis that evolves over months usually is due to a neoplasm or vascular malformation, a chronic subdural hematoma, or a

degenerative disease.

Investigation of hemiparesis (Fig. 24-3) of acute origin usually starts

with a CT scan of the brain and laboratory studies. If the CT is normal,

or in subacute or chronic cases of hemiparesis, MRI of the brain and/or

cervical spine (including the foramen magnum) is performed, depending on the clinical accompaniments.

Paraparesis Acute paraparesis is caused most commonly by an

intraspinal lesion, but its spinal origin may not be recognized initially

if the legs are flaccid and areflexic. Usually, however, there is sensory

loss in the legs with an upper level on the trunk; a dissociated sensory

loss (loss of pain and temperature but not touch, position, and vibration sense) suggestive of a central cord syndrome; or hyperreflexia in

the legs with normal reflexes in the arms (Chap. 442). Imaging the

spinal cord (Fig. 24-3) may reveal compressive lesions, infarction (proprioception usually is spared), arteriovenous fistulas or other vascular

anomalies, or transverse myelitis (Chap. 442).

Diseases of the cerebral hemispheres that produce acute paraparesis include anterior cerebral artery ischemia (shoulder shrug also is

affected), superior sagittal sinus or cortical venous thrombosis, and

acute hydrocephalus.

Paraparesis may also result from a cauda equina syndrome, for

example, after trauma to the low back, a midline disk herniation, or

an intraspinal tumor. The sphincters are commonly affected, whereas

hip flexion often is spared, as is sensation over the anterolateral thighs.

Rarely, paraparesis is caused by a rapidly evolving anterior horn cell

disease (such as poliovirus or West Nile virus infection), peripheral

neuropathy (such as Guillain-Barré syndrome; Chap. 447), or myopathy (Chap. 449).

Subacute or chronic spastic paraparesis is caused by upper motor

neuron disease. When associated with lower-limb sensory loss and

sphincter involvement, a chronic spinal cord disorder should be considered (Chap. 442). If hemispheric signs are present, a parasagittal

meningioma or chronic hydrocephalus is likely. The absence of spasticity in a long-standing paraparesis suggests a lower motor neuron or

myopathic etiology.

Investigations typically begin with spinal MRI, but when upper

motor neuron signs are associated with drowsiness, confusion, seizures, or other hemispheric signs, brain MRI should also be performed,

sometimes as the initial investigation. Electrophysiologic studies are

diagnostically helpful when clinical findings suggest an underlying

neuromuscular disorder.

Quadriparesis or Generalized Weakness Generalized weakness

may be due to disorders of the CNS or the motor unit. Although the terms

often are used interchangeably, quadriparesis is commonly used when

an upper motor neuron cause is suspected, and generalized weakness is

used when a disease of the motor units is likely. Weakness from CNS

disorders usually is associated with changes in consciousness or cognition

and accompanied by spasticity, hyperreflexia, and sensory disturbances.

Most neuromuscular causes of generalized

weakness are associated with normal mental function, hypotonia, and hypoactive

muscle stretch reflexes. The major causes

of intermittent weakness are listed in

Table 24-2. A patient with generalized

fatigability without objective weakness

may have chronic fatigue syndrome

(Chap. 450).

ACUTE QUADRIPARESIS Quadriparesis

with onset over minutes may result from

disorders of upper motor neurons (such

as from anoxia, hypotension, brainstem or

cervical cord ischemia, trauma, and systemic metabolic abnormalities) or muscle

(electrolyte disturbances, certain inborn

errors of muscle energy metabolism, toxins, and periodic paralyses). Onset over

hours to weeks may, in addition to these

disorders, be due to lower motor neuron disorders such as Guillain-Barré syndrome (Chap. 447).

In obtunded patients, evaluation

begins with a CT or MRI scan of the

brain. If upper motor neuron signs are

present but the patient is alert, the initial

test is usually an MRI of the cervical

cord. If weakness is lower motor neuron, myopathic, or uncertain in origin,

the clinical approach begins with blood

studies to determine the level of muscle

enzymes and electrolytes and with EMG

and nerve conduction studies.

Hemiparesis

UMN signs

Cerebral signs

Brain CT

or MRI†

Paraparesis Quadriparesis Monoparesis Distal Proximal Restricted

LMN signs*

Alert

UMN signs LMN signs*

UMN signs LMN signs*

EMG and NCS

UMN pattern LMN pattern Myopathic pattern

Anterior horn,

 root, or peripheral

 nerve disease

Muscle or

 neuromuscular

 junction disease

* or signs of myopathy

† If no abnormality detected, consider spinal MRI.

‡ If no abnormality detected, consider myelogram or brain MRI.

Yes No

Yes No

Spinal MRI‡

DISTRIBUTION OF WEAKNESS

FIGURE 24-3 An algorithm for the initial workup of a patient with weakness. CT, computed tomography; EMG,

electromyography; LMN, lower motor neuron; MRI, magnetic resonance imaging; NCS, nerve conduction studies;

UMN, upper motor neuron.