Management of Multiple Sclerosis

Amy A. Pruitt

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), affecting approximately 2.5 million young adults worldwide, some 350,000 of whom live in the United States. Severe disability develops in approximately 30% of patients. The manifestations of the disease are protean, and its clinical course is highly variable from patient to patient. Although most patients with MS will be under the care of the neurologist during periods of marked exacerbation, they often depend on the primary physician for initial diagnostic suspicion; help with decisions about whether, when, and with what to initiate long-term therapy; monitoring of blood tests for the treatment of adverse effects; interpretation of symptoms; treatment of intercurrent infections; discussion of the effects of pregnancy on the disease; and decisions regarding the need for referral. Since several drugs new to the market have increased options for MS patients, but at the same time exposed some to greater risk of serious adverse effects, the primary physician must be familiar with the range of clinical presentations for MS, its natural history, and the therapeutic options. Such knowledge facilitates the provision of proper primary care and ensures the optimal timing of referrals.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8 and 9)

The etiology of MS is unknown, but research suggests an interplay of genetic susceptibility, environmental exposure(s), and defective regulation of the immune response. Epidemiologic and virologic studies show an association between Epstein-Barr virus (EBV) infection and risk of MS, suggesting a role for EBV as a possible environmental factor in genetically predisposed persons. Antigen-specific cytotoxic T cells directed against an external antigen are believed to recognize and cross-react with myelin antigens in genetically susceptible persons, producing an autoimmune response. There is no evidence that vaccinations increase the risk of developing MS that patients with MS should not receive annual influenza vaccinations.

The consequence of immunologic cross-reactivity is a series of discrete episodes of myelin-specific autoimmune injury to the CNS, separated both in time and space. Acutely, an infiltrate of lymphocytes, macrophages, and plasma cells forms in areas of involvement. T cells are believed to initiate the process, and activated macrophages to damage the myelin. Localized edema and transient breakdown of the blood-brain barrier occur. Evidences suggesting an important role for B cells include the appearance of oligoclonal bands (markers of B-cell activation) in the cerebrospinal fluid (CSF), clinical improvement in response to monoclonal antibodies (e.g., rituximab) that target the CD20 B-cell antigen, and factors that influence B-cell proliferation (e.g., vitamin D and EBV) affecting MS susceptibility.

The chronicity of the inflammatory process results in the formation of a plaque or glial scar, made up of proliferated astrocytes that cluster in response to inflammatory injury of the myelin sheath. Lesions occur predominantly in the white matter of the brain and spinal cord; occasionally, gray matter is involved to a minor degree. Demyelination is characteristically focal, but axonal injury can occur early in the course of the disease. Brain atrophy also has been documented during early, clinically silent phases of the illness. Plaques are most commonly found in the optic nerves, spinal cord, brainstem, cerebellum, and periventricular areas.

After an attack, some remyelination occurs, which accounts for a partial resolution of symptoms. However, partially demyelinated axons are susceptible to dysfunction, particularly under conditions of heat stress or intercurrent infection. The finding that transected axons are common in the lesions of MS reverses a long-held pathologic axiom and suggests that early treatment is needed to prevent such irreversible damage. In the 27 years since the advent of clinical magnetic resonance imaging (MRI) scanning, progressive brain volume loss from the earliest stages of the disease has been documented.

Clinical Presentation

Clinical presentation is a function of the site of the inflammatory process. Attacks are by definition those that produce symptoms that last more than 24 hours.

Sensory Deficits

Transient sensory deficits are the most common initial presentation, affecting about 40% to 50% of patients. They include paresthesias or diminution of sensation in the upper or lower extremities. The sensory disturbance may be bilateral and symmetric, extending to involve the adjacent trunk.

Visual and Oculomotor Deficits

About 15% to 20% of patients experience acute monocular visual loss because of optic neuritis. A central scotoma, transient pain on eye movement, and decreased pupillary reaction to light (Marcus Gunn pupil) are characteristic features. Diplopia resulting from internuclear ophthalmoplegia or an oculomotor defect is another common symptom heralding MS. Bilateral internuclear ophthalmoplegia is very characteristic of MS and strongly suggests the diagnosis. A failure of adduction and coarse nystagmus in the abducting eye are noted. Other oculomotor functions remain intact.

Motor and Cerebellar Deficits

Ataxia and intention tremor are manifestations of cerebellar involvement. Motor deficits may occur acutely or insidiously, with the insidious variety particularly common in older patients. Legs are more likely to be involved than arms, initially asymmetrically. However, upgoing toes (Babinski sign) are common bilaterally, even in patients with unilateral problems.

Autonomic Deficits

Urinary difficulties (frequency, urgency, incontinence) are consequences of upper motor nerve injury in the spinal cord. The external sphincter fails to relax adequately, causing incomplete emptying. Such autonomic injury may also produce constipation and impotence.

Cerebral Deficits

Later in the course of illness, cerebral involvement may produce memory loss, personality change, and emotional lability. More than 60% of MS patients demonstrate abnormalities on formal
neuropsychiatric testing, even if symptoms are not troubling and/or not reported.

Paroxysmal Symptoms and Fatigue

Paroxysmal symptoms may result from dysfunction of partially demyelinated axons and simulate a transient ischemic attack or focal seizure or produce an attack of tic douloureux (see Chapter 176). Fatigue (believed to be related to high circulating levels of immunomodulators) may be prominent and even predate exacerbations.

Clinical Course

The clinical course tends to follow one of several patterns, which are used as a basis for classification.

Clinically Isolated Syndromes

This term is used by some to describe the initial presentation, in which there is a single deficit. Such persons have a variable clinical course with 1/3 never progressing to fulfill the criteria for a formal diagnosis of MS.

Relapsing-Remitting Disease

Younger patients manifest a relapsing-remitting course, characterized by attacks followed by complete or nearly complete remission. If there are any residual manifestations, they remain stable between relapses. Some patients present with a clinically isolated syndrome yet develop new, asymptomatic white matter lesions on serial brain MRI without new clinical symptoms.

Secondary Progressive Disease

After years of an initial relapsing-remitting course, a secondary progressive course, with steady gradual worsening, develops in more than 50% of patients.

Primary Progressive Disease

About 10% of patients who present with MS in later life (40 to 60 years of age at onset) have a steadily progressive course; this pattern is called primary progressive and tends to be associated with prominent spinal cord involvement.

Relapsing-Progressive Disease

A fourth possible variant of MS—actually a combination of two others—is relapsing-progressive disease, which is diagnosed when patients have largely progressive disease exacerbated by acute attacks and little remission.

Neuromyelitis Optica

Neuromyelitis optica (NMO), also known as Devic disease, is a particularly aggressive form of demyelinating disease, in which patients sustain recurring attacks of optic neuritis; in addition, there are long areas of abnormality in the spinal cord and relapses. Diagnosis is made by demonstrating in the serum or CSF the NMO-Ig antibody (an antibody to aquaporin-4, the major water channel in the CNS).

Prognosis

After 15 years of clinical disease, about 50% of patients are still capable of walking and 30% are able to continue working. Frequent attacks early in the course of the disease increase the chances of disability, as does late onset, a progressive course, or early cerebellar or pyramidal involvement. In about 5% to 10% of patients, the disease seems to pursue a very “benign” course, but it is difficult to predict which patients safely can forego any disease-modifying therapy. Increasing volume of white matter lesions in persons who first present with clinically isolated disease (CIS) correlates to a moderate degree with the risk of long-term disability, but number of relapses does not. Pregnancy decreases the risk of relapse, but risk increases in the postpartum period.

DIFFERENTIAL DIAGNOSIS AND WORKUP (10, 11, 12, 13, 14 and 15)

The diagnosis is suggested clinically by the development of symptoms and signs suggesting CNS white matter disease separated both anatomically and in time (>1 month). At times, the symptoms suggest only a single lesion, but a careful physical examination reveals evidence of multiple lesions. Disease presenting with a spinal cord lesion may produce a clinical picture of transverse myelitis syndrome and thus mimic other conditions associated with that condition, such as spinal infection and postinfectious autoimmune disease.

The differential diagnosis is extensive, but among treatable conditions to rule out are a number of potentially treatable conditions with systemic potential, including Lyme disease, vitamin B₁₂ deficiency, syphilis, HIV infection, sarcoidosis, systemic lupus, and vasculitides.

Diagnostic Criteria

Diagnosis is confirmed using the updated McDonald criteria, which take advantage of advances in technology and understanding of MS to afford earlier diagnosis. For a diagnosis of definite relapsing-remitting MS, the following must be present:

Two clinical attacks and two objective lesions on examination
One clinical attack and dissemination in space and time by MRI

Criteria for Dissemination in Space and Time

Dissemination in space is specified by at least one enhancing lesion in any two of several specified locations that does not correspond to the presenting clinical manifestations. Dissemination in time is demonstrated by both a gadolinium-enhancing lesion not responsible for the clinical presentation and other enhancing lesions that are assumed to be older since enhancement usually persists for only a few weeks or by the presentation of a new lesion after the initial scan.

Diagnosis at Time of Initial Presentation

These revised criteria now enable a diagnosis of definite MS to be made at the time of the initial clinical presentation or repeat MRI scan rather than having to wait for two distinct clinical attacks to occur or two distinct clinical lesions to appear. While earlier versions of the criteria allowed appearance of oligoclonal antibodies and/or an elevated immunoglobulin G (IgG) index to be used as part of the criteria for dissemination in space when MRIs did not fulfill criteria, CSF is no longer included in the diagnostic scheme for relapsing forms of MS.

Cerebrospinal Fluid Testing

The CSF examination reveals abnormalities in 95% of MS patients. Modest increases in cell count and protein are common but nonspecific; increases in IgG and oligoclonal IgG bands on electrophoresis are more specific and suggest an increased risk for
disseminated disease. As noted, new diagnostic criteria for dissemination in space no longer depend on presence of CSF antibodies.

Neuroimaging by Magnetic Resonance Imaging

The most sensitive diagnostic test is MRI. Multiple periventricular plaques, presenting as areas of increased signal intensity on long TR-weighted and proton density-weighted images, are characteristic and found in more than 90% of patients with known MS. Patients with chronic progressive disease have more confluent periventricular and infratentorial lesions, but they are often most disabled by spinal cord lesions.

Diagnostic Significance

The hyperintense white matter lesions seen on long TR-weighted images on brain MRI are nonspecific, and similar white matter lesions occur in normal elderly persons and patients with chronic uncontrolled hypertension, advanced Lyme disease, and CNS vasculitis. Indeed, one of the most common reasons for referral to a neurologist is the incidental finding of such MRI lesions. Their prevalence in community-based population study of persons over the age of 45 is about 10%, most suspected of being due to asymptomatic small-vessel brain infarcts. A major error is to call hypertensive vascular disease MS.

About a third of asymptomatic patients with incidental suggestive MRI finding have been found to convert to CIS, and about a third of these had cervical cord lesions that suggested MS; over 80% of these developed symptoms with a median time of 1.6 years.

Spinal MRI can be of great benefit in the diagnosis of MS. Spinal cord abnormalities are common in patients even with early-stage MS, are less likely to be confused with other diagnostic entities, and help to determine dissemination in space at the time of diagnosis.

Evoked Potentials

Visual or auditory evoked potentials are abnormal in demyelinated tracts and may serve as additional evidence of MS when MRI results require supporting data.

Tests to Rule Out Other Causes

Exclusionary blood work in all patients suspected of having MS should include Lyme serology, vitamin B₁₂ level, RPR test for syphylis, antinuclear antibody, possibly HIV testing. Additional tests may be indicated by the specific clinical circumstances.