Multiple sclerosis (MS) is characterized by disseminated patches of demyelination in the brain and spinal cord. Common symptoms include visual and oculomotor abnormalities, paresthesias, weakness, spasticity, urinary dysfunction, and mild cognitive impairment. Typically, neurologic deficits are multiple, with remissions and exacerbations gradually producing disability. Diagnosis is by history of remissions and exacerbations plus clinical signs, test results, lesions seen on MRI, or other criteria (depending on symptoms) to objectively demonstrate ≥ 2 separate neurologic abnormalities. Treatment includes corticosteroids for acute exacerbations, immunomodulatory drugs to prevent exacerbations, and supportive measures.

MS is believed to involve an immunologic mechanism. One postulated cause is infection by a latent virus (possibly a human herpesvirus such as Epstein-Barr virus), which, when activated, triggers a secondary immune response. An increased incidence among certain families and presence of human leukocyte antigen (HLA) allotypes (HLA-DR2) suggests genetic susceptibility. MS is more common among people who spend their first 15 yr of life in temperate climates (1/2000) than in those who spend them in the tropics (1/10,000). One explanation is that lower levels of vitamin D are associated with an increased risk of MS, and vitamin D levels correlate with the degree of sun exposure, which is lower in temperate climates. Cigarette smoking also appears to increase risk. Age at onset ranges from 15 to 60 yr, typically 20 to 40 yr; women are affected somewhat more often.

Neuromyelitis optica (Devic disease), previously considered a variant of MS, is now recognized as a separate disorder (see Demyelinating Disorders: Neuromyelitis Optica).


Localized areas of demyelination (plaques) occur, with destruction of oligodendroglia, perivascular inflammation, and chemical changes in lipid and protein constituents of myelin in and around the plaques. Axonal damage is possible, but cell bodies and axons tend to be relatively preserved. Fibrous gliosis develops in plaques that are disseminated throughout the CNS, primarily in white matter, particularly in the lateral and posterior columns (especially in the cervical regions), optic nerves, and periventricular areas. Tracts in the midbrain, pons, and cerebellum are also affected. Gray matter in the cerebrum and spinal cord can be affected but to a much lesser degree.

Symptoms and Signs

MS is characterized by varied CNS deficits, with remissions and recurring exacerbations. Exacerbations average about 3/yr, but frequency varies greatly. Although MS may progress and regress unpredictably, there are typical patterns of progression:

Relapsing-remitting pattern: Exacerbations alternate with remissions, when partial or full recovery occurs or symptoms are stable. Remissions may last months or years. Exacerbations can occur spontaneously or can be triggered by an infection such as influenza.

Primary progressive pattern: The disease progresses gradually with no remissions, although there may be temporary plateaus during which the disease does not progress. Unlike in the relapsing-remitting pattern, there are no clear exacerbations.

Secondary progressive pattern: This pattern begins with relapses alternating with remissions, followed by gradual progression of the disease.

Progressive relapsing pattern: The disease progresses gradually, but progression is interrupted by sudden, clear relapses. This pattern is rare.

The most common initial symptoms are the following:

Paresthesias in one or more extremities, in the trunk, or on one side of the face

Weakness or clumsiness of a leg or hand

Visual disturbances (eg, partial loss of vision and pain in one eye due to retrobulbar optic neuritis, diplopia due to ocular palsy, scotomas)

Other common early symptoms include slight stiffness or unusual fatigability of a limb, minor gait disturbances, difficulty with bladder control, vertigo, and mild affective disturbances; all usually indicate scattered CNS involvement and may be subtle. Excess heat (eg, warm weather, a hot bath, fever) may temporarily exacerbate symptoms and signs.

Mild cognitive impairment is common. Apathy, poor judgment, or inattention may occur. Affective disturbances, including emotional lability, euphoria, or, most commonly, depression, are common. Depression may be reactive or partly due to cerebral lesions of MS. A few patients have seizures.

Cranial nerves: Unilateral or asymmetric optic neuritis and bilateral internuclear ophthalmoplegia are typical. Optic neuritis causes loss of vision (ranging from scotomas to blindness), eye pain, and sometimes abnormal visual fields, a swollen optic disk, or a partial or complete afferent pupillary defect (see Optic Nerve Disorders: Optic Neuritis).

Internuclear ophthalmoplegia results if there is a lesion in the medial longitudinal fasciculus connecting the 3rd, 4th, and 6th nerve nuclei. During horizontal gaze, adduction of one eye is decreased, with nystagmus of the other (abducting) eye; convergence is intact.

Rapid, small-amplitude eye oscillations in straight-ahead (primary) gaze (pendular nystagmus) are uncommon but characteristic of MS. Vertigo is common. Intermittent unilateral facial numbness or pain (resembling trigeminal neuralgia), palsy, or spasm may occur. Mild dysarthria may occur, caused by bulbar weakness, cerebellar damage, or disturbance of cortical control. Other cranial nerve deficits are unusual but may occur secondary to brain stem injury.

Motor: Weakness is common. It usually reflects corticospinal tract damage in the spinal cord, affects the lower extremities preferentially, and is bilateral and spastic. Deep tendon reflexes (eg, knee and ankle jerks) are usually increased, and an extensor plantar response (Babinski’s sign) and clonus are often present. Spastic paraparesis produces a stiff, imbalanced gait; in advanced cases, it may confine patients to a wheelchair. Painful flexor spasms in response to sensory stimuli (eg, bedclothes) may occur late. Cerebral or cervical spinal cord lesions may result in hemiparesis, which sometimes is the presenting symptom.

Cerebellar: In advanced MS, cerebellar ataxia plus spasticity may be severely disabling; other cerebellar manifestations include slurred speech, scanning speech (slow enunciation with a tendency to hesitate at the beginning of a word or syllable), and Charcot’s triad (intention tremor, scanning speech, and nystagmus).

Sensory: Paresthesias and partial loss of any type of sensation are common and often localized (eg, to one or both hands or legs). Various painful sensory disturbances (eg, burning or electric shocklike pains) can occur spontaneously or in response to touch, especially if the spinal cord is affected.

An example is Lhermitte’s sign, an electric shocklike pain that radiates down the spine or into the legs when the neck is flexed. Objective sensory changes tend to be transient and difficult to demonstrate.

Spinal cord: Involvement commonly causes bladder dysfunction (eg, urinary urgency or hesitancy, partial retention of urine, mild urinary incontinence). Constipation, erectile dysfunction in men, and genital anesthesia in women may occur. Frank urinary and fecal incontinence may occur in advanced MS.

Progressive myelopathy, a variant of MS, causes spinal cord motor weakness but no other deficits.


Clinical criteria

Brain and spinal MRI

Sometimes CSF IgG levels and evoked potentials

MS is suspected in patients with optic neuritis, internuclear ophthalmoplegia, or other symptoms that suggest MS, particularly if deficits are multifocal or intermittent. Most diagnostic criteria for MS require a history of exacerbations and remissions plus objective demonstration by examination or testing of ≥ 2 separate neurologic abnormalities. Brain and spinal MRI is done. MRI plus clinical findings may be diagnostic, but if they are inconclusive, additional testing may be necessary to objectively demonstrate separate neurologic abnormalities. Such testing usually begins with CSF analysis and, if necessary, includes evoked potentials.

MRI is the most sensitive imaging test for MS and can exclude other treatable disorders that may mimic MS, such as nondemyelinating lesions at the junction of the spinal cord and medulla (eg, subarachnoid cyst, foramen magnum tumors). Gadolinium-contrast enhancement can distinguish actively inflamed from older plaques. Alternatively, contrast-enhanced CT can be done. The sensitivity of MRI and CT is increased by giving twice the dose of contrast agent (which is standard practice) and delaying scanning (double-dose delayed scanning).

CSF examination, including opening pressure, cell count and differential, protein, glucose, Ig, oligoclonal bands, and usually myelin basic protein and albumin, is done. IgG is usually increased as a percentage of CSF components, such as protein (normally < 11%) or CSF albumin (normally 10 yr. However, some patients, particularly men with onset in middle age, have frequent exacerbations and are rapidly incapacitated. Cigarette smoking may accelerate the course. Life span is shortened only in very severe cases.


Corticosteroids for acute exacerbations

Immunomodulators to prevent exacerbations


or tizanidine

for spasticity


or tricyclic antidepressants for pain

Supportive care

Goals include shortening acute exacerbations, decreasing frequency of exacerbations, and relieving symptoms; maintaining the patient’s ability to walk is particularly important.

Disease-modifying drugs: Acute exacerbations that cause objective deficits sufficient to impair function (eg, loss of vision, strength, or coordination) are treated with brief courses of corticosteroids (eg, prednisone

60 to 100 mg po once/day tapered over 2 to 3 wk,

500 to 1000 mg IV once/day for 3 to 5 days). Some evidence indicates
that IV corticosteroids shorten acute exacerbations, slow progression, and improve MRI measures of disease. Immunomodulatory therapy, such as interferons (IFNs) or glatiramer, decreases the frequency of acute exacerbations and delays eventual disability. Typical regimens include interferon beta-1b

8 million IU sc every other day, interferon beta-1a

million IU (30 μg) IM weekly, and interferon beta-1a

44 μg sc 3 times weekly. Common
adverse effects of IFNs include flu-like symptoms and depression (which tend to decrease over time), development of neutralizing antibodies after months of therapy, and cytopenias. Glatiramer acetate

20 mg sc once/day may be used.

The immunosuppressant mitoxantrone

, 12 mg/m2 IV q 3 mo for 24 mo, may be helpful,
particularly for progressive MS that is refractory to other treatments. Natalizumab

, an anti-
α4 integrin antibody, inhibits passage of leukocytes across the blood-brain barrier; given as a monthly infusion, it reduces number of exacerbations and new brain lesions but may increase the risk of progressive multifocal leukoencephalopathy. If immunomodulatory drugs are ineffective, monthly IV immune globulin may help.

Immunosuppressants other than mitoxantrone

(eg, methotrexate

, azathioprine

mycophenolate, cyclophosphamide

, cladribine

) have been used for more severe,
progressive MS but are controversial. Plasma exchange and hematopoietic stem cell transplantation may be somewhat useful for severe, intractable disease.

Symptom control: Other treatments can be used to control specific symptoms:

Spasticity is treated with escalating doses of baclofen

10 to 20 mg po tid to qid or

4 to 8 mg po tid. Gait training and range-of-motion exercises can help weak,
spastic limbs.

Painful paresthesias are usually treated with gabapentin

100 to 600 mg po tid;
alternatives include tricyclic antidepressants (eg, amitriptyline

25 to 75 mg po at
bedtime, desipramine

25 to 100 mg po at bedtime if amitriptyline

has intolerable
anticholinergic effects), carbamazepine

200 mg po tid, and opioids.

Depression is treated with counseling and antidepressants.

Bladder dysfunction is treated based on its underlying mechanism (see Voiding Disorders).

Fatigue can be treated with amantadine

100 mg po tid or modafinil

100 to 300 mg po

Supportive care: Encouragement and reassurance help. Regular exercise (eg, stationary biking, treadmill, swimming, stretching) is recommended, even for patients with advanced MS, because it conditions the heart and muscles, reduces spasticity, prevents contractures, and has psychologic benefits. Vitamin D supplements (800 to 1000 units daily) may decrease the risk of disease progression. Vitamin D also reduces the risk of osteoporosis, particularly in patients at increased risk because mobility is decreased or they take corticosteroids. Patients should maintain as normal and active a life as possible but should avoid overwork, fatigue, and exposure to excess heat. Cigarette smoking should be stopped. Vaccination does not appear to increase risk of exacerbations. Debilitated patients require measures to prevent pressure ulcers and UTIs; intermittent urinary self-catheterization may be necessary.

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