Chapter 192: Multiple Sclerosis

Characterized by inflammation, selective destruction of CNS myelin, and neurodegeneration; 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 >900,000 in the United States and 3 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 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 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 192-1; MS mimics are summarized in Table 192-2.

TABLE 192-1: 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: CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PPMS, primary progressive multiple sclerosis.
Source: From Polman CH et al: Diagnostic criteria for multiple sclerosis: 2010 Revisions to the “McDonald Criteria.” Ann Neurol 69:292, 2011. Reprinted with permission from John Wiley & Sons, Inc.
TABLE 192-2: Disorders That Can Mimic Multiple Sclerosis (MS)
Acute disseminated encephalomyelitis (ADEM)
Antiphospholipid antibody syndrome
Behçet’s disease
Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL)
Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy)
Human immunodeficiency virus (HIV) infection
Ischemic optic neuropathy (arteritic and nonarteritic)
Lyme disease
Mitochondrial encephalopathy with lactic acidosis and stroke (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; CNS, central nervous system; HTLV, human T cell lymphotropic virus.

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 MS (RMS) is characterized by discrete attacks of neurologic dysfunction over days to weeks with or without recovery; between attacks, no progression of neurologic impairment is noted. Accounts for 90% of new-onset MS cases.
  • Secondary progressive MS (SPMS) always begins as RMS. At some point, however, the clinical course changes so that the pt experiences deterioration in function unassociated with acute attacks. SPMS produces more fixed neurologic disability than RMS. For a pt with RMS, risk of developing SPMS is ∼1–2% each year.
  • Primary progressive MS (PPMS) accounts for ∼10% of cases. These pts experience a steady decline in function from disease onset. Compared to RMS, the sex distribution is more even, the disease begins later in life (mean age ∼40 years), and disability develops faster. Despite these differences, PPMS appears to represent the same underlying illness as RMS.

Progressive MS and Disease Activity. Pts with SPMS or even PPMS will occasionally experience relapses, albeit less often than in RMS. Progressive MS pts experiencing relapses or who are found to have acute new lesions on MRI are considered to have “active” MS. In contrast, the term “progression” is reserved to describe neurological worsening that accumulates independently from disease activity.

Most pts ultimately develop progressive neurologic disability. In older studies, 15 years after onset, only 20% of pts had no functional limitation, and between one-third and one-half of RMS pts progressed to SPMS and required assistance with ambulation. The long-term prognosis for MS has improved greatly in recent years due, at least in part, to widespread use of therapies for RMS.

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. 192-1). MRI is 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 192-1
hmom20_ch192_f001.png

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: Multiple Sclerosis

(See Fig. 192-2)

FIGURE 192-2
hmom20_ch192_f002.png

Therapeutic decision-making for relapsing MS. Options are shown for different clinical scenarios and based on JCV status. Active MS is defined by clinical relapses or the development of new focal MRI white matter lesions. Treatment options can also include trials of different preparations of interferon β (IFN-β), particularly advancing from once-weekly (Avonex) to a more frequent (e.g., Rebif, Betaseron/Extavia) dosing regimen, as well as use of natalizumab in JC virus–positive pts.

THERAPIES FOR RELAPSING FORMS OF MS (RMS, SPMS WITH EXACERBATIONS)

More than a dozen are available.

Frequently Used

OCRELIZUMAB (OCR) (HIGHLY EFFECTIVE; ANTI-CD20 [B-CELL] MONOCLONAL ANTIBODY)

Dose 600 mg IV every 24 weeks (first dose split as two 300-mg infusions spaced 2 weeks apart); IV methylprednisolone 100 mg prior to each infusion and prophylaxis with analgesics/antipyretics and antihistamines recommended. Generally well tolerated; infusion-related reactions in a minority of pts, most with first infusion and mild in degree. OCR trials showed a small imbalance of malignancies including breast cancer, but no excess cancer risk has been found in the postmarketing setting. Another anti-CD20 antibody, rituximab, was tested against MS in preliminary trials and is also used in some settings despite lack of pivotal trial data.

NATALIZUMAB (NTZ) (HIGHLY EFFECTIVE; ANTI-INTEGRIN MONOCLONAL ANTIBODY)

Dose 300 mg IV each month. Well tolerated; a small percentage of pts experience hypersensitivity reactions (including anaphylaxis) or develop neutralizing antibodies. Major concern is risk of life-threatening progressive multifocal leukoencephalopathy (PML). Measure serum antibodies against JC virus (JCV) to stratify risk, as pts who test negative have minimal risk; with treatment repeat testing at 6 month intervals, as seroconversion can occur.

FINGOLIMOD (FGL) (MODERATELY EFFECTIVE; INHIBITS LYMPHOCYTE TRAFFICKING)

Dose 0.5 mg, oral each day. Lab abnormalities (e.g., elevated liver function tests or lymphopenia) usually mild but may require discontinuation. Heart block and bradycardia can occur when therapy is initiated; a 6-h period of first dose observation (including ECG monitoring) recommended. Other side effects: macular edema and, rarely, disseminated varicella-zoster virus (VZV) and cryptococcal infection.

DIMETHYL FUMARATE (DMF) (MODERATELY EFFECTIVE; IMMUNOMODULATOR)

Dose 240 mg oral twice each day. GI side effects common at the start of therapy but often subside with continued use. Other adverse events include flushing, mild decrease in neutrophil and lymphocyte counts, and elevation in liver enzymes. In lymphopenic pts, consider alternate treatments due to PML risk.

INTERFERON (IFN)-A (MODESTLY EFFECTIVE; IMMUNOMODULATOR)

IFN-β-1a, 30 μg, IM once per week; IFN-β-1a, 44 μg, SQ three times per week. IFN-β-1b, 250 μg, SQ every other day. Pegylated IFN-β-1a, 125 μg, SQ every 14 days. Side effects: mild lab abnormalities (e.g., elevated liver function tests or lymphopenia), SQ injection site reactions. Some pts develop neutralizing antibodies to IFN-β which can degrade effectiveness.

GLATIRAMER ACETATE (GA) (MODESTLY EFFECTIVE; IMMUNOMODULATOR)

20 mg SQ every day or 40 mg three times weekly. Side effects: injection-site reactions, lipoatrophy; ~15% of pts experience one or more brief episodes of flushing, chest tightness, dyspnea, palpitations, and anxiety after injection.

Less Commonly Used

SIPONIMOD (MODERATELY EFFECTIVE; INHIBITS LYMPHOCYTE TRAFFICKING)

Maintenance dose 1 or 2 mg oral each day, initiated by gradual escalation to final dose. Possible side effects include lab abnormalities (e.g., elevated liver function tests or lymphopenia); bradycardia; macular edema; possibly teratogenic. Siponimod is a selective inhibitor of the sphingosine-1-phosphate (S1P) receptor, thus it works in a fashion similar to FGL.

TERIFLUNOMIDE (MODESTLY EFFECTIVE; BLOCKS PYRIMIDINE SYNTHESIS)

Dose either 7 or 14 mg PO each day. Side effects: mild hair thinning and gastrointestinal; rarely causes toxic epidermal necrolysis or Stevens-Johnson syndrome. A major limitation, especially in women of childbearing age, is possible teratogenicity.

ALEMTUZUMAB (HIGHLY EFFECTIVE; ANTI-CD52 [PAN-LYMPHOCYTE] MONOCLONAL ANTIBODY)

The toxicities of concern are (1) autoimmune diseases including thyroiditis, Graves’ disease, thrombocytopenia; (2) malignancies; (3) serious infections; and (4) infusion reactions. Because of its toxicity profile, the US FDA indicated alemtuzumab only in pts who have tried and failed at least two other DMTs.

INITIATING AND CHANGING TREATMENT

Previously, most pts with RMS received injectable agents (IFN-β or GA) as first-line therapy. However, with the introduction of more effective agents administered by infusion including OCR (irrespective of JCV status) and NTL (in JCV negative pts), and the oral agents FGL and DMF, this has begun to change. OCR can be used first-line, supported by the combination of high efficacy, infrequently administered infusions, and a favorable safety profile. NTL, which is highly effective, well tolerated, and apparently safe in JCV antibody–negative pts, provides another attractive option.

MILD INITIAL COURSE

In pts with recent onset, normal examination or minimal impairment (EDSS ≤2.5 or less), or low disease activity, either an injectable (IFN-β or GA) or an oral agent (FGL, DMF) is reasonable. High efficacy therapy such as OCR (irrespective of JCV status) or NTL (in JCV negative pts) can also be considered even in minimally affected pts. The injectable agents (IFN-β and glatiramer acetate) have a superb track record for safety but a high nuisance factor due to need for frequent injections, as well as bothersome side effects that contribute to noncompliance.

MODERATE OR SEVERE INITIAL COURSE

Either OCR or, if the pt is JCV seronegative, NTZ, or an oral agent (FGL or DMF) is recommended.

Regardless of which agent is chosen first, treatment should probably be changed in pts who continue to have relapses, progressive neurologic impairment or, arguably, ongoing evidence of subclinical MRI activity.

  • In addition, vitamin D deficiency should be corrected in all pts with MS, usually by oral supplementation with vitamin D3, 4000–5000 IU daily.

THERAPIES FOR 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.

THERAPIES FOR PROGRESSIVE MS

SPMS

Pts with SPMS who have continuing relapses or active disease by MRI should be treated as in RMS; siponimod has been recently approved specifically for this population. IFN-β is probably ineffective in pts with SPMS who do not have active disease. Other agents have not yet been studied in this population.

PPMS

OCR was shown to reduce progression of clinical disability in PPMS by 24% compared with placebo, and also to improve other clinical and MRI markers of inflammatory and degenerative disease activity. The dose for PPMS is identical as for RMS (above).

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).
  • Weakness can sometimes be improved with the use of potassium channel blockers such as extended release 4-aminopyridine (10 mg twice daily), particularly when lower extremity weakness interferes with the pt’s ability to ambulate.
  • 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.

VARIANTS OF MS

Acute Disseminated Encephalomyelitis (ADEM)

A fulminant, often devastating, demyelinating disease that has a monophasic course and may be associated with antecedent immunization or infection. Postinfectious encephalomyelitis is most frequently associated with measles, varicella, as well as numerous other virus infections and Mycoplasma pneumoniae. 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.

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