Characterized by chronic inflammation and selective destruction of CNS myelin; peripheral nervous system is spared. Pathologically, the multifocal scarred lesions of multiple sclerosis (MS) are termed plaques. Etiology is autoimmune, with susceptibility determined by genetic and environmental factors. MS affects >350,000 in the United States and 2.5 million worldwide; onset is often in early to middle adulthood, and women are affected three times as often as men.

CLINICAL FEATURES

Onset may be abrupt or insidious. Some pts have symptoms that are so trivial that they may not seek medical attention for months or years. Recurrent attacks of focal neurologic dysfunction lasting weeks or months and followed by variable recovery, are typical; some pts initially present with slowly progressive neurologic deterioration. Symptoms often transiently worsen with fatigue, stress, exercise, or heat. Manifestations include weakness and/or sensory symptoms, visual difficulties, abnormalities of gait and coordination, urinary urgency or frequency, and abnormal fatigue. Motor involvement can present as a heavy, stiff, weak, or clumsy limb. Localized tingling, “pins and needles,” and “dead” sensations are common. Optic neuritis produces monocular blurring of vision, especially in the central visual field, often with associated retro-orbital pain accentuated by eye movement. Involvement of the brainstem may result in diplopia, nystagmus, vertigo, or facial pain, numbness, weakness, hemispasm, or myokymia (rippling muscular contractions). Ataxia, tremor, and dysarthria may reflect disease of cerebellar pathways. Lhermitte’s symptom, a momentary electric shock–like sensation evoked by neck flexion, indicates disease in the cervical spinal cord. Diagnostic criteria are listed in Table 190-1; MS mimics are summarized in Table 190-2.

TABLE 190-1: DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS (MS)
Clinical PresentationAdditional Data Needed for MS Diagnosis
2 or more attacks; objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attackNone
2 or more attacks; objective clinical evidence of 1 lesion

Dissemination in space, demonstrated by

• ≥1 T2 lesion on MRI in at least 2 out of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)

or

• Await a further clinical attack implicating a different CNS site

1 attack; objective clinical evidence of 2 or more lesions

Dissemination in time, demonstrated by

• Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time

or

• A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan

or

• Await a second clinical attack

1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome)

Dissemination in space and time, demonstrated by:

For dissemination in space

• ≥1 T2 lesion in at least 2 out of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)

or

• Await a second clinical attack implicating a different CNS site

and

For dissemination in time

• Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time

or

• A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan

or

• Await a second clinical attack

Insidious neurologic progression suggestive of MS (PPMS)

1 year of disease progression (retrospectively or prospectively determined)

plus

2 out of the 3 following criteria

Evidence for dissemination in space in the brain based on ≥1 T2+ lesions in the MS-characteristic periventricular, juxtacortical, or infratentorial regions

Evidence for dissemination in space in the spinal cord based on ≥2 T2+ lesions in the cord

Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

Abbreviations: MS, multiple sclerosis; PPMS, primary progressive multiple sclerosis.
Source: From CH Polman et al: Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the “McDonald Criteria.” Ann Neurol 69:292, 2011.
TABLE 190-2: DISORDERS THAT CAN MIMIC MULTIPLE SCLEROSIS (MS)
Acute disseminated encephalomyelitis (ADEM)
Antiphospholipid antibody syndrome
Behçet’s disease
CADASIL
Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy)
HIV infection
Ischemic optic neuropathy (arteritic and nonarteritic)
Lyme disease
MELAS
Neoplasms (e.g., lymphoma, glioma, meningioma)
Sarcoid
Sjögren’s syndrome
Stroke and ischemic cerebrovascular disease
Syphilis
Systemic lupus erythematosus and related collagen vascular disorders
Tropical spastic paraparesis (HTLV-1/2 infection)
Vascular malformations (especially spinal dural AV fistulas)
Vasculitis (primary CNS or other)
Vitamin B12 deficiency
Abbreviations: AV, arteriovenous; CADASIL, cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy; HTLV, human T-cell lymphotropic virus; MELAS, mitochondrial encephalopathy with lactic acidosis and stroke.

PHYSICAL EXAMINATION

Abnormal signs usually more widespread than expected from the history. Check for abnormalities in visual fields, loss of visual acuity, disturbed color perception, optic pallor or papillitis, afferent pupillary defect (paradoxical dilation to direct light following constriction to consensual light), nystagmus, internuclear ophthalmoplegia (slowness or loss of adduction in one eye with nystagmus in the abducting eye on lateral gaze), facial numbness or weakness, dysarthria, weakness and spasticity, hyperreflexia, ankle clonus, upgoing toes, ataxia, sensory abnormalities.

DISEASE COURSE

Three major subtypes:

  • Relapsing-remitting MS (RRMS) is characterized by recurrent attacks of neurologic dysfunction over days to weeks with or without recovery; between attacks, no progression of neurologic impairment is noted. Accounts for 85% of new-onset MS cases.
  • Secondary progressive MS (SPMS) always initially presents as RRMS but evolves in many pts into SPMS (~1–2% each year).
  • Primary progressive MS (PPMS) is characterized by gradual progression of disability from onset without discrete attacks; 15% of new-onset MS cases.

Historically, 15 years after diagnosis only 20% of pts have no functional limitation and one-third to one-half have progressed to SPMS and require assistance with ambulation. With the introduction of disease modifying therapies for MS, the long-term course of the disease may have become less disabling.

LABORATORY EVALUATION

MRI reveals multifocal bright areas on T2-weighted sequences in >95% of pts, often in periventricular location; gadolinium enhancement indicates acute lesions with disruption of blood-brain barrier (Fig. 190-1). MRI also useful to exclude MS mimics, although findings in MS are not completely specific for the disorder. CSF findings include mild lymphocytic pleocytosis (5–75 cells in 25%), oligoclonal bands (>75% have two or more), elevated IgG (80%), and normal total protein level. Visual, auditory, and somatosensory evoked response tests can identify lesions that are clinically silent; one or more evoked response tests are prolonged in 80–90% of pts. Urodynamic studies aid in management of bladder symptoms.

FIGURE 190-1

MRI findings in MS. A. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS. B. Sagittal T2-weighted fluid-attenuated inversion recovery image (FLAIR) in which the high signal of CSF has been suppressed. CSF appears dark, while areas of brain edema or demyelination appear high in signal as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease. C. Sagittal T2-weighted fast spin-echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the midthoracic spinal cord. D. Sagittal T1-weighted image obtained after the IV administration of gadolinium reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows).

Treatment

FIGURE 190-2

Therapeutic decision-making for MS.

DISEASE-MODIFYING THERAPIES FOR RELAPSING FORMS OF MS (RRMS, SPMS WITH EXACERBATIONS)

  • Ten treatments are available in the United States: interferon (IFN)-β1a (Avonex; 30 μg IM once a week), IFN-β1a (Rebif; 44 μg SC thrice weekly), IFN-β1b (Betaseron; 250 μg SC every other day or Extavia; 0.25 mg SC every other day), glatiramer acetate (Copaxone; 12 mg/d SC), natalizumab (Tysabri; 300 mg IV every 4 weeks), fingolimod (Gilenya; 0.5 mg PO daily), dimethyl fumarate (Tecfidera; 240 mg PO twice daily after initial lower starting dose), teriflunomide (Aubagio; 7–14 mg PO daily), mitoxantrone (Novantrone; 12 mg/m2 IV every 3 months), and alemtuzumab (Lemtrada; 12 mg IV daily for 5 days followed 12 months later with 12 mg IV daily for 5 days) (see Fig. 190-2).
  • IFN preparations that are given multiple times weekly (e.g., Rebif or Betaseron/Extavia) appear to have slightly greater efficacy compared with once-weekly agents (e.g., Avonex).
  • Side effects of IFN include flulike symptoms, injection-site reactions (with SC dosing), and mild abnormalities on laboratory evaluation (e.g., elevated liver function tests or lymphopenia). Rarely, severe hepatotoxicity may occur. Side effects of IFN often subside with time. Injection-site reactions also occur with glatiramer acetate but are less severe than with IFN. Approximately 15% of pts receiving glatiramer acetate experience one or more episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety.
  • Fingolimod is generally well tolerated, and oral dosing is convenient for pts. First-degree heart block and bradycardia can occur, necessitating the prolonged (6-h) observation of pts receiving their first dose.
  • Dimethyl fumarate has a twice-daily oral dosing schedule that makes it somewhat less convenient for pts. GI side effects are common as treatment is initiated, but usually subside with continued administration.
  • Teriflunomide is well-tolerated and convenient for pts given its once daily oral dosing. However, there is less evidence of its superiority to the injectable medications than for the other oral agents A major limitation in women of childbearing age is its possible teratogenicity.
  • Natalizumab is the most effective MS agent available; however, because of the development of progressive multifocal leukoencephalopathy (PML) in 0.3% of pts, it is generally used only for pts who have failed other therapies or who have particularly aggressive presentations. A blood test to detect antibodies against the PML (JC) virus can identify individuals who are at highest risk for this complication.
  • Most pts with relapsing MS and a mild initial course receive an injectable (IFN-β or glatiramer acetate) or oral (dimethyl fumarate, fingolimod, or teriflunomide) agent as first-line therapy.
  • For pts presenting with a moderate or severe initial course, either an oral agent (dimethyl fumarate or fingolimod) or, if the pt is JC virus antibody seronegative, infusion therapy with natalizumab is recommended.
  • Regardless of which agent is chosen first, treatment should probably be altered in pts who continue to have frequent attacks (Fig. 190-2).
  • Several studies suggest that these agents can improve the long-term outcome of MS. Thus, early treatment with a disease-modifying drug is appropriate for most pts. It may be reasonable to delay initiating treatment in pts with (1) a normal neurologic examination, (2) a single attack or a low attack frequency, and (3) a low burden of disease as assessed by brain MRI.
  • Untreated pts need to be followed closely; the need for therapy is reassessed if there is evidence of ongoing disease.
  • Vitamin D deficiency should be corrected in all pts with MS, usually by oral supplementation with vitamin D3, 4000–5000 IU daily.

ACUTE RELAPSES

  • Acute relapses that produce functional impairment may be treated with a short course of IV methylprednisolone (500–1000 mg IV q a.m. × 3–5 days) followed often by oral prednisone (60 mg q a.m. × 4, 40 mg q a.m. × 4, 20 mg q a.m. × 3). This regimen modestly reduces the severity and shortens the duration of attacks.
  • Plasma exchange (seven exchanges: 40–60 mL/kg, every other day for 14 days) may benefit pts with fulminant attacks of demyelination (not only MS) that are unresponsive to glucocorticoids; cost is high and conclusive evidence of efficacy is lacking.

PROGRESSIVE SYMPTOMS

  • For pts with SPMS who continue to experience relapses, treatment with one of the IFNs is reasonable; however, the IFNs are ineffective against purely progressive MS symptoms.
  • Mitoxantrone is approved in the United States for treatment of SPMS; however, this is not the population studied in the pivotal trial, evidence for efficacy is relatively weak, and leukemia risk as well as dose-related cardiac toxicity are important concerns.
  • Methotrexate (7.5–20 mg PO once each week) or azathioprine (2–3 mg/kg per day PO) is sometimes tried.
  • Pulse therapy with cyclophosphamide is employed in some centers for young adults with aggressive forms of MS.
  • Other smaller studies have examined monthly pulses of IV immunoglobulin (IVIg) or IV methylprednisolone.
  • For pts with PPMS, symptomatic therapy only is recommended, although a preplanned secondary analysis of a negative rituximab trial was promising and a follow-up trial with a related agent (ocrelizumab) is ongoing.

SYMPTOMATIC THERAPY

  • Spasticity may respond to physical therapy, baclofen (20–120 mg/d), diazepam (2–40 mg/d), tizanidine (8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenzaprine hydrochloride (10–60 mg/d).
  • Dysesthesia may respond to carbamazepine (100–1000 mg/d in divided doses), phenytoin (300–600 mg/d), gabapentin (300–3600 mg/d), pregabalin (50–300 mg/d), or amitriptyline (25–150 mg/d).
  • Treatment of bladder symptoms is based on the underlying pathophysiology investigated with urodynamic testing: bladder hyperreflexia is treated with evening fluid restriction and frequent voiding; if this fails, anticholinergics such as oxybutynin (5–15 mg/d) may be tried; hyporeflexia is treated with the cholinergic drug bethanechol (30–150 mg a day), and dyssynergia due to loss of coordination between bladder wall and sphincter muscles is treated with anticholinergics and intermittent catheterization.
  • Depression should be treated aggressively.

CLINICAL VARIANTS OF MS

Neuromyelitis optica (NMO) consists of separate attacks of acute optic neuritis (bilateral or unilateral) and myelitis. In contrast to MS, the brain MRI is typically, but not always, normal. A focal enhancing region of swelling and cavitation, extending over three or more spinal cord segments, is typically seen on spinal MRI. A highly specific autoantibody directed against the water channel aquaporin-4 is present in the sera of two-thirds of pts with a clinical diagnosis of NMO. Acute attacks are usually treated with high-dose glucocorticoids as for MS exacerbations. Plasma exchange has also been used empirically for acute episodes that fail to respond to glucocorticoids. Prophylaxis against relapses can be achieved with mycophenolate mofetil, rituximab, or a combination of glucocorticoids plus azathioprine.

Acute MS (Marburg’s variant) is a fulminant demyelinating process that progresses to death within 1–2 years. No controlled trials of therapy exist; high-dose glucocorticoids, plasma exchange, and cyclophosphamide have been tried, with uncertain benefit.

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)

A fulminant, often devastating, demyelinating disease that has a monophasic course and may be associated with antecedent immunization or infection. Signs of disseminated neurologic disease are consistently present (e.g., hemiparesis or quadriparesis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss, and brainstem involvement). Fever, headache, meningismus, lethargy progressing to coma, and seizures may occur. CSF pleocytosis, generally 200 cells/μL, is common. MRI may reveal extensive gadolinium enhancement of white matter in brain and spinal cord. Initial treatment is with high-dose glucocorticoids. Pts who fail to respond may benefit from a course of plasma exchange or IVIg.

For a more detailed discussion

For a more detailed discussion, see Hauser SL, Goodin DS: Multiple Sclerosis and Other Demyelinating Diseases, Chap. 458, p. 2661, in HPIM-19.

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TY - ELEC T1 - Multiple Sclerosis ID - 623116 Y1 - 2017 PB - Harrison's Manual of Medicine UR - https://harrisons.unboundmedicine.com/harrisons/view/Harrisons-Manual-of-Medicine/623116/all/Multiple_Sclerosis ER -