INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS lesions, characterized by perivascular infiltration of monocytes and lymphocytes, appear as indurated areas in pathologic specimens; hence, the term sclerosis in plaques.

MS is a dynamic disease, with almost constant lesion formation and a progressive clinical course leading to physical disability. For every 8-10 new lesions detected on magnetic resonance imaging (MRI), only one clinical manifestation typically can be demonstrated. Patients with relapsing remitting MS have an average of 5-10 new lesions per year and 1 or 2 clinical exacerbations.¹

With the advent of MRI, the ability to confirm the diagnosis of MS has improved dramatically. MRI characteristically shows lesions of high T2 signal intensity of variable location in the white matter of the brain, brain stem, optic nerves, or spinal cord. In typical cases, the lesions tend to occur in periventricular areas and may occur in the corpus callosum. Newer MRI techniques (eg, magnetization transfer ratio [MTR], fluid attenuated inversion recovery [FLAIR], magnetic resonance spectroscopy [MRS]) promise to yield important information regarding MS heterogeneity, prognosis, and treatment effects.

Despite intensive efforts in finding the source of the disease, no etiologic agent for MS has been identified. The disease presumably can be exacerbated by hormonal changes during the postpartum period. Some argue that MS could be a heterogeneous disorder triggered or perpetuated by several different environmental agents. In fact, only 1 of every 4 MS attacks is associated with an intercurrent infection.

The disease can present in different forms, such as primary progressive, relapsing remitting, relapsing progressive, and secondary progressive phenotypes. Genetic susceptibility factors may play a role, as the disease is more common in Caucasian populations living in northern latitudes. This susceptibility may be part of a complex and heterogeneous group of genetic and epigenetic factors that have an impact, along with environmental factors, on the initiation and maintenance of disease. In addition, migration to high-risk areas before 15 years of age seems to increase the risk of developing MS, lending further support to the environmental factor hypothesis.

For related information, see Medscape's Multiple Sclerosis Resource Center.

Pathophysiology

Multiple sclerosis is characterized by perivenular infiltration of lymphocytes and macrophages in the parenchyma of the brain, brain stem, optic nerves, and spinal cord. Expression of adhesion molecules on the surface seems to underlie the ability of these inflammatory cells to penetrate the blood-brain barrier. The elevated immunoglobulin G (IgG) level in the cerebrospinal fluid (CSF), which can be demonstrated by an oligoclonal band pattern on electrophoresis, suggests an important humoral (ie, B cell activation) component to MS. In fact, variable degrees of antibody-producing plasma cell infiltration have been demonstrated in MS lesions (depicted in Media file 1).

Molecular studies of the white matter plaque tissue have shown that interleukin (IL)–12, a potent proinflammatory substance, is expressed at high levels in early-formed lesions. A molecule required to stimulate lymphocytes to release proinflammatory cytokines, B7-1, is also expressed at high levels in early MS plaques. Evidence exists of higher frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing remitting MS and higher IL-12 production in immune cells of patients with progressive MS, when compared with healthy controls.

Recently, decreased function of immune cells with a regulatory role (Tregs) has been implicated in MS. These Tregs are CD4⁺CD25⁺ T cells that can be identified by their expression of a transcription factor known as Foxp3. Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4⁺ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17, hence being referred to as T_H17 cells. Tregs and T_H17 cells are not the only critical immune cells in the pathogenesis of MS. Immune cells such as microglia (resident macrophages of the CNS), dendritic cells, natural killer (NK) cells, and B cells are gaining increased attention by MS researchers. In addition, nonimmunecells (ie, endothelial cells) have also been implicated in mechanisms that lead to CNS inflammation.²

The favorable clinical responses to the disease-modifying immunomodulatory agents (ie, interferon beta-1a and beta-1b, glatiramer acetate) suggest that these medications modify disease progression, at least in part, based on their ability to counteract the proinflammatory phenotype of immune cells. Other disease-modifying treatments for MS include mitoxantrone (a DNA intercalator that affects lymphocyte counts) and natalizumab (a monoclonal antibody against the adhesion molecule VLA-4 that prevents migration of immune cells to the CNS). The exact mechanisms leading to the efficacy of all these agents are unknown.

MS is a complex and heterogeneous disease, and our understanding of the disease initiation mechanism and its wide clinical variability is limited.

Frequency

United States

In the United States, multiple sclerosis has a prevalence of nearly 400,000 cases, and approximately 10,000 people are newly diagnosed with this disease every year.³

International

More than 2.5 million people worldwide are estimated to be affected by multiple sclerosis.³

Mortality/Morbidity

Multiple sclerosis causes considerable disability in the working age group. People with MS usually die of complications rather than of MS itself, including recurrent infections (especially in bedridden patients). Patients with MS are thought to have an average life expectancy 5-7 years shorter than that of the general population.

Race

Multiple sclerosis presents more often in populations of northern European ancestry. Disease severity or drug treatment effect variability may be accounted for, at least in part, by racial or geographic differences.

Sex

Multiple sclerosis affects females more than males (1.6-2:1), but the basis for this difference is unknown. This ratio is even higher (3:1) among patients in whom onset of MS is before age 15 years or after age 50 years, suggesting a hormonal component to the disease process. Males have a greater tendency to develop primary progressive MS, while females tend to experience more relapses.

Age

Multiple sclerosis most commonly afflicts people aged 18-50 years, but any age group can be affected.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Attacks or exacerbations of multiple sclerosis are characterized by new symptoms that reflect CNS involvement. These symptoms are typically separated in time (eg, by months or years) and in anatomical location (eg, weakness of one or more limbs, optic neuritis, sensory symptoms). Recognizing that physical and cognitive disability progression in MS may occur in the absence of clinical exacerbations is important.

• Patients who improve after acute attacks have relapsing remitting MS (RRMS). However, during the natural course of RRMS, approximately 75-85% of patients enter a stage referred to as secondary progressive MS (SPMS).
• Patients with primary progressive MS (PPMS) tend to accumulate disability without interruption (ie, without remissions) from the time of disease onset. Some of these patients first present with weakness of only one limb, which gradually progresses to involve other limbs and may culminate in total paralysis. Patients with PPMS typically respond poorly to the current therapeutic options for MS, accumulate disability faster than other patients, and tend to have more weakness of the legs as well as incontinence (a reflection of greater spinal cord involvement).
• Patients who have RRMS but accumulate disability between and during attacks can be defined as having relapsing progressive disease (RPMS).
• Although most patients have a wide range of symptoms from lesions in different areas of the brain and spinal cord, others may present with predominantly visual, cognitive, or cerebellar symptoms.
• Patients with MS are now thought to reach a clinical threshold (itself a reflection of immune system dysfunction and axonal involvement), after which deterioration occurs in a continuous course and ominous MRI signs become more apparent (eg, T1 hypointensities, brain atrophy). These T1 "holes" (ie, T1 hypointensities that become permanent) and signs of brain or spinal cord atrophy are indicative of a neurodegenerative process, indicating that MS is not only an inflammatory disease. The clinical history often reflects these processes, as patients may report short-term memory problems, difficulty executing sequential tasks, or visuospatial disturbances.
  
  Keep in mind, however, that every patient with MS presents differently, with some exhibiting severe cognitive decline in the absence of widespread inflammation or atrophy by MRI and others performing well in cognitive tests despite the presence of numerous MRI lesions. The exact correlation of MRI findings with clinical outcome in MS is still unknown, and efforts to develop composite MRI indexes that allow better disease monitoring are underway.
• Use of the term benign MS should be discouraged, since almost all patients have relentless progression of the disease, even in the absence of clinical attacks. Not uncommonly, detailed examination of a patient with so-called benign MS encounters clear evidence of short-term memory difficulties, cognitive dysfunction, or brain atrophy on MRI of the head. In the author's view, the use of the term benign MS should be reserved for retrospective assessments of clinical course, as only a minority of patients end up having this form. The prospective use of the term benign MS leads to false expectations of disease outcome by the patients and their relatives, improper counseling, and inappropriate delay of treatment with disease-modifying drugs.
• Patients with MS tend to experience variable degrees of fatigue. This symptom is typically described as either physical exhaustion or mental/cognitive slowing. It must be differentiated from depression (which may, however, coexist), lack of sleep, and exertional exhaustion due to disability. Patients may feel particularly fatigued after taking a hot shower or after strenuous activity in heated environments. Heat exposure may also lead to episodes of optic nerve dysfunction (ie, Uhthoff phenomenon), the mechanisms of which remain poorly understood.
• MS may present in an acute and clinically fulminant form (termed Marburg variant of MS), which can lead to coma or death or may present with concomitant optic nerve involvement and a longitudinally extensive myelopathy (ie, neuromyelitis optica [NMO] or Devic disease, considered by some to be an MS variant). NMO can now be confirmed by the presence of serum antibodies against aquaporin 4, a water channel expressed at major fluid-tissue barriers across the CNS.⁴
• MS must also be distinguished from other neuroinflammatory disorders, including acute disseminated encephalomyelitis (ADEM), Schilder disease, and Baló concentric sclerosis.
• • ADEM is considered an isolated postinfectious or postvaccinial autoimmune attack on the CNS that leads to diffuse demyelination. It is often devastating and occasionally has a fulminant hemorrhagic component (in which case it is termed acute hemorrhagic encephalomyelitis or leukoencephalitis of Weston Hurst).
  • Schilder disease is characterized in children and young adolescents by massive demyelination, presenting often as asymmetrical foci (often the size of an entire lobe) in the white matter on MRI and presenting with a malignant course (ie, deterioration over months or a few years with cortical blindness, hemiplegia, or paraplegia). Some patients, however, may respond to steroids and immunosuppressive therapy.
  • Baló concentric sclerosis is considered by some authors to be a variant of Schilder disease, with MRI lesions showing a characteristic alternating pattern of spared and damaged white matter that suggests progression of the disease process from the ventricles outward. Baló disease is often associated with a more inflammatory CSF and a more fulminant progression than typical MS.
• MS may present in various forms. Some patients have a predominance of cognitive changes, while others present with prominent ataxia, hemiparesis or paraparesis, depression, or visual symptoms. Bipolar disorder and frank dementia may appear late in the disease course, but sometimes are found at the time of initial diagnosis. Symptoms can be exacerbated by intercurrent illness, including viral or bacterial upper respiratory or urinary tract infections. Trauma has no impact on disease exacerbation. The impact of emotional stress on exacerbations is probably minimal and remains controversial.
• Optic neuritis presents clinically as orbital pain, at rest or during eye movement, and loss of vision. Patients may complain of "patchy loss of vision," and upon examination, a cecocentral scotoma and an afferent pupillary defect may be found. Patients may experience color desaturation even with normal visual acuity, usually manifested as the perception of red color as different shades of orange or gray.
• Patients with MS may present with facial palsies or trigeminal neuralgia. In fact, the presence of bilateral facial weakness or trigeminal neuralgia strongly suggests the diagnosis of MS. Facial myokymia may also be a presenting symptom. Nystagmus (direction-changing) and internuclear ophthalmoplegia signs are other manifestations.
• Painful limb syndromes are important to recognize, as those with paroxysmal qualities may respond better to specific treatments. Patients with MS also commonly complain of numbness or tingling in one or more limbs, variable weakness, or sensory level-related symptoms. Some have difficulty describing weakness or numbness, as these symptoms are obscured by incapacitating fatigue.
• Episodes of central (as opposed to peripheral) vertigo are not uncommon. The nystagmus accompanying central vertigo has a rapid onset, does not fatigue easily, and changes with direction of gaze. CNS vertigo is usually accompanied by other complaints that can be directly attributed to brainstem or cerebellar pathway involvement (eg, diplopia, dysarthria).
• An often overlooked manifestation of MS is the pseudobulbar affect, whereby patients have difficulty controlling their emotions (laughing, crying) and are perceived to act inappropriately by coworkers or friends.
• • Behavioral/cognitive symptoms may also include social disinhibition, dementia, or depression.
  • A greater tendency for attempting and committing suicide in patients with MS is not related exclusively to a reactive depression, since this tendency is higher than that of patients with other devastating neurologic disorders such as chronic inflammatory demyelinating polyradiculopathy (CIDP).
  • The neurologist should be aware that patients with conversion reactions and inappropriate affect, such as la belle indifference, may on occasion have an underlying organic illness such as MS.
• Urinary retention and incontinence are common. Bowel habit changes may occur, but bowel incontinence is less frequent.
• Sexual dysfunction affects the great majority of patients with MS and includes symptoms such as lack of desire, erectile dysfunction, impaired sexual responsiveness, premature ejaculation, impaired genital sensation, or inability to physically interact with the partner due to painful leg adductor muscle spasms.

See related Medscape CME activity New Data on Comorbidities and Quality of Life in Patients With Multiple Sclerosis.

Physical

The Kurtzke Expanded Disability Status Scale (EDSS) is used as a measure of disease progression by assigning a severity score (0-10) to the patient's clinical status. Although the scale does not correspond linearly to common progression points for many patients, its widespread use and ease of implementation allow its use as a standardization measure for clinical trials.⁵

• 0 - Normal neurologic examination (all grade 0 in functional systems [FS]; cerebral grade 1 acceptable)
• 1 - No disability, minimal signs in one FS (ie, one grade 1 excluding cerebral grade 1)
• 1.5 - No disability, minimal signs in more than one FS (more than one grade 1 excluding cerebral grade 1)
• 2.0 - Minimal disability in one FS (one FS grade 2, others 0 or 1)
• 2.5 - Minimal disability in two FS (two FS grade 2, others 0 or 1)
• 3.0 - Moderate disability in one FS (one FS grade 3, others 0 or 1), or mild disability in three or four FS (three or four FS grade 2, others 0 or 1)
• 3.5 - Fully ambulatory but with moderate disability in one FS (one grade 3 and one or two FS grade 2) or two FS grade 3, others 0 or 1, or five FS grade 2, others 0 or 1
• 4.0 - Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combinations of lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 meters (0.3 miles)
• 4.5 - Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability, usually consisting of one FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk without aid or rest for some 300 meters (975 ft)
• 5.0 - Ambulatory without aid or rest for about 200 meters (650 feet); disability severe enough to impair full daily activities (eg, to work a full day without special provisions); usual FS equivalents are one grade 5 alone, others 0 or 1, or combinations of lesser grades usually exceeding specifications for step 4.0
• 5.5 - Ambulatory without aid or rest for about 100 meters (325 ft); disability severe enough to impair full daily activities; usual FS equivalents are one grade 5 alone, others 0 or 1, or combinations of lesser grades usually exceeding specifications for step 4.0
• 6.0 - Intermittent or constant unilateral assistance (cane, crutch, brace) required to walk about 100 meters (325 ft) with or without resting; usual FS equivalents are combinations with more than two FS grade 3+
• 6.5 - Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters (65 ft); usual FS equivalents are combinations with more than two FS grade 3+
• 7.0 - Unable to walk beyond about 5 meters (16 ft) even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair a full day and transfers alone; up and about in wheelchair some 12 hours a day; usual FS equivalents are combinations with more than one FS grade 4+; very rarely pyramidal grade 5 alone
• 7.5 - Unable to take more than a few steps; restricted to wheelchair; may need aid in transfers, wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair; usual FS equivalents are combinations with more than one FS grade 4+
• 8.0 - Essentially restricted to bed or chair or perambulated in wheelchair; but may be out of bed much of the day; retains many self-care functions; generally has effective use of arms; usual FS equivalents are combinations, generally grade 4+ in several systems
• 8.5 - Essentially restricted to bed for much of the day; has some effective use of arm(s); retains some self-care functions; usual FS equivalents are combinations, generally grade 4+ in several systems
• 9.0 - Helpless bed patient; can communicate and eat; usual FS equivalents are combinations, mostly grade 4
• 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; usual FS equivalents are combinations, almost all grade 4+
• 10 - Death due to MS

Causes

The cause of multiple sclerosis is unknown. Multiple factors (not a single identifiable agent or event) likely act in concert to trigger or perpetuate MS. These factors are in part environmental and in part hereditary (genes are thought to have a modest effect).

• An environmental agent or event (eg, virus, bacteria, chemicals, lack of sun exposure) has been hypothesized to act in concert with a specific genetic predisposition (ie, a set of genes or polymorphisms) to result in immune dysfunction. For instance, different variants of genes normally found in the general population, commonly referred to as polymorphisms, may lead to different gradations of cellular expression of those genes and, thus, of the proteins that they encode. Therefore, an individual with a polymorphism within the promoter region of a gene that is involved in immune reactivity may hypothetically generate an exaggerated response (eg, elevated gene expression of a proinflammatory gene) to a given antigen, leading to uncontrolled immune cell proliferation and autoimmunity.
• In population studies, the major histocompatibility complex (MHC) region in 6p21 harbors genes (particularly HLA-DRB1*1501 alleles) shown to confer susceptibility to MS. However, MS is a complex genetic disease (a category of diseases thought to develop from modest genetic inheritance and complex genetic-environmental interactions), and a person having the DRB1*1501 allele(s) will not necessarily develop MS. Multiple other genes (or gene variants) must interact in concert to provide susceptibility, and an environment that helps trigger or perpetuate autoimmunity or neurodegeneration must play a role.
  
  Genes that instead of conferring susceptibility to MS do confer relative protection are being investigated, and clues are also emerging from within the MHC region. Recently,  the HLA-C*05 allele was suggested to confer disease protection.⁶
  
  The concordance rate for MS is only 20-35% among monozygotic twins, suggesting only a modest effect by genetic factors. The presence of other predisposing, non-Mendelian factors (ie, epigenetic modification in 1 twin) along with environmental effects play an important role.
  
  HLA-DRB1 is the only chromosomal locus that has been consistently associated with MS susceptibility. Some genes within the MHC region confer protection. Other gene variants (known as single nucleotide polymorphisms [SNIPS]), such as those recently found in the IL-7 and IL-2 receptor genes, are thought to play a less prominent role in disease susceptibility than MHC genes. More importantly, research on SNIPS that confer risk of more severe disease or risk of developing particular forms of MS will be of great interest to the clinicians treating this complex disease in the early stages.
• Other molecules involved in activation of T and B cells have been implicated in MS. For instance, the co-stimulatory molecule B7-1, necessary for activation of T cells as a second signal to antigen presentation, has been found to be elevated in early MS lesions, suggesting a triggering role for inflammation within the CNS. Other factors elevated in MS brain tissues include the proinflammatory interferon gamma and the prodemyelinative tumor necrosis factor alpha molecule. In addition, interactions between molecules on the surface of B and T cells, such as CD40 and CD40 ligand, may mediate elevated levels of IL-12 (a proinflammatory cytokine) in the circulation of patients with MS.
• The molecular mimicry hypothesis refers to the possibility that peripheral blood T cells may become activated to attack a foreign antigen, then erroneously direct their attack toward brain proteins that share similar protein epitopes.
• Others support the hypothesis that a virus may infect the immune system, activating self-reactive T cells (myelin reactive) that would otherwise remain quiescent.
• A virus that infects cells of both the immune and nervous systems can possibly be reactivated periodically and thus lead to acute exacerbations in MS. The Epstein Barr virus (EBV) has been found to become periodically reactivated, but a causation role in MS has been difficult to prove. Arguments supporting this view include long-term studies showing a higher association with MS in individuals with early presence of serum antibodies against specific EBV antigens, and high expression of EBV antigens within MS plaques. Arguments against demonstrating causation include the fact that MS is a highly heterogeneous disease (EBV could help trigger some cases but not others, making associations in populations difficult), and the notion that disease manifestations could precede viral reactivation (ie, the virus would be reactivated as an epiphenomenon of a dysregulated immune system and not be the actual trigger). 

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Neuromyelitis optica (Devic disease)
Diffuse cerebral sclerosis of Schilder (encephalitis periaxialis diffusa)
Concentric sclerosis of Balo

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Cerebrospinal fluid examination
• • Oligoclonal bands are distinct electrophoretic patterns that reflect substantial elevation of IgG produced by a restricted set of plasma cells and are demonstrated in CSF samples of approximately 85% of patients with multiple sclerosis.
  • Glucose level is usually normal. Protein level can be normal or slightly elevated. WBC count can be slightly to moderately elevated (6-40 x 10⁹/L) but is usually <5 (predominantly mononuclear cells).
  • IgG index is usually elevated. This index is derived from the following formula: IgG Index= [IgG_CSF/albumin_CSF]/[IgG_serum/albumin_serum]
    Although the sensitivity of measurements may vary among laboratories, a typically normal CSF IgG is <4.7 mg/dL (less than 12% of serum protein), and the normal IgG index is <0.77. Most patients with MS have a clearly elevated IgG index (>1.7).
  • Myelin basic protein (MBP) is a major component of myelin and levels may be elevated in the CSF of patients with MS. However, its clinical utility as a marker of disease activity or progression is limited (not recommended).
• Blood tests
• • Patients with MS and atypical features should initially be tested for B-12 and folate levels or antinuclear antibody (ANA) titers. For instance, rapid cognitive deterioration or evidence of subacute combined degeneration of the spinal cord by clinical examination should prompt testing for folate and B-12 levels.
  • Other patients with atypical features suggesting disorders other than MS must be recognized. Investigation for the antiphospholipid antibody syndrome must be undertaken in patients with evidence of blood dyscrasia and in women with unexplained miscarriages or history of deep venous thrombosis. This syndrome is typically assessed with blood tests for the following: anticardiolipin, anti-beta2 glycoprotein I, and antiprothrombin antibodies. Patients with optic neuritis and longitudinally extensive spinal cord lesions by MRI should be tested for neuromyelitis optica (NMO), searching for the presence of aquaporin 4 antibodies in the serum.
  • An elevated erythrocyte sedimentation rate (ESR) and positive titers of rheumatoid factor (RF) should help identify the presence of a vasculitic disorder that may be mimicking MS.
  • If patients come from an endemic region for Lyme disease or have been exposed to tick bites, the physician should check Lyme titers. Evaluation by a rheumatologist should be sought if positive Lyme or ANA titer, elevated ESR, or evidence of vasculitis is uncovered. For related information, see Medscape's Lyme Disease Resource Center. 
• If clinical suspicion for a peripheral neuropathy arises, electrophysiological studies and blood tests for metabolic or toxic neuropathies should be performed.

Imaging Studies

• MRI of head or spine, with and without gadolinium, should be performed according to clinical suspicion for lesion localization.
• • Typical multiple sclerosis lesions appear as T2 hyperintensities in the periventricular regions; they have an ovoid appearance with their largest axis oriented perpendicular to the ventricular surface; they typically involve only the white matter, and several arise from the corpus callosum (see Media files 2-3). This characteristic configuration has been demonstrated in pathologic specimens and sometimes is referred to as "Dawson fingers" on the basis of neuropathologic work done in 1916 at the University of Edinburgh by James Dawson, who identified the perivascular distribution of inflammatory cells and the resulting fingerlike appearance of affected veins and venules in MS brain tissues.
  • The most common infratentorial locations for plaque formation are the surface of the pons, the cerebellar peduncles, and white matter regions adjacent to the fourth ventricle.
  • Lesions that enhance with gadolinium are thought to reflect active disease, as enhancement may correspond to breakdown of the blood-brain barrier from an ongoing subacute inflammatory process (few days to a few weeks). Usually a combination of enhancing and nonenhancing lesions is seen, reflecting the chronicity of the demyelinating process.
  • In a patient with a first clinical attack who presents with numerous (ie, >10) lesions by MRI, the presence of gadolinium enhancement in most or all the lesions should prompt a differential diagnosis of ADEM versus an aggressive first presentation of MS. A history of recent exposure to a vaccine or viral illness may be helpful in supporting the diagnosis of ADEM. However, note that exceptions occur and some patients with MS present with a fulminant and active demyelinative disease form from the onset.
  • Chronic hypointensity of lesions in T1 images (T1 holes) may reflect some degree of axonal damage or more chronic tissue damage resulting in gliosis. The clinician should attempt to correlate lesions with high T2 signal intensity with their corresponding T1 images to assess chronicity.
  • • Although a lesion may appear old (low T1), it may exhibit a ringlike enhancement around the hypointense region after gadolinium, suggesting that even seemingly old lesions may have a component of active inflammation, especially at the advancing edge of lesion formation.
    • Additionally, a new lesion may present with T1 hypointensity, reflecting marked edema. Lesions range from a few millimeters to more than a centimeter in diameter with occasional large, rounded, tumorlike lesions. The latter are seen as areas of pronounced gliosis and demyelination on pathologic inspection.
  • The application of modern MRI techniques to detection and characterization of early lesions is changing rapidly. Recent MRI techniques such as FLAIR have increased the ability to detect demyelinating lesions due to MS. A disadvantage of FLAIR remains the less-than-optimal visualization of the posterior fossa. Other recent techniques, such as fast FLAIR and fast spin-echo, may increase the sensitivity of prediction for diagnostic and prognostic purposes. Short inversion imaging recovery (STIR) images of the spinal cord can enhance sensitivity in detecting lesions. Magnetization transfer ratio (MTR) abnormalities may precede the appearance of T2-weighted and proton-density high-intensity lesions. Finally, MRS, which can identify neutral fat, helps identify the appearance of myelin breakdown products that result from the active inflammatory response. Neuronal or axonal loss or dysfunction is identified on MRS by the detection of reduced levels of N-acetylaspartate (NAA), a marker of neuronalintegrity/metabolism.
  • Patients with normal-appearing white matter (NAWM) on conventional MRI may be found to harbor abnormalities by MRS.⁷
  • Recent MRI studies have begun to establish significant involvement of cortical (gray matter) tissues by inflammation or neurodegeneration in MS. In some cases, cortical atrophy can be more pronounced, relative to white matter tissue loss, and its association with cognitive and physical decline is beginning to emerge.⁸
  • Many of these imaging techniques are investigational and cannot be used by most centers to clinically monitor individuals with MS. The exact correlation of MRI to clinical outcomes in patients with MS remains unknown.

Other Tests

• Evoked potential testing (visual, auditory, or somatosensory) is especially helpful in 1) detecting clinically silent lesions, and 2) documenting an organic basis for vague complaints. The most sensitive are the visual evoked potentials (50-80% sensitivity), followed by the somatosensory potentials (50-70% sensitivity).

Procedures

• Lumbar puncture (see Lab Studies)

Histologic Findings

Histopathologic examination reveals that multiple sclerosis lesions are caused by perivenular infiltration of lymphocytes (most of which are CD4⁺ T cells) and macrophages (see Media file 4). Some lesions may have more infiltration by B cells. In fact, recent immunostaining reports by Lucchinetti et al show that MS lesions have considerable heterogeneity of microscopic appearance, with some lesions exhibiting oligodendrocyte apoptosis and others marked complement and antibody presence.⁹ Luxol fast blue stains (which stain myelin with an intense blue) reveal demyelinated areas as pale and confluent patches, with variable degrees of associated inflammation (see Media file 5). Transected axons may be found in chronic and sometimes in acute MS lesions, as demonstrated in recent studies by Trapp and collaborators¹⁰; these recent studies have helped refocus neurologists' attention to the issue of axonal loss in MS.

Expression of HLA, interferon gamma, IL-12, and B7 molecules is increased, especially in early MS lesions; this reflects the inflammatory nature of plaque formation. Matrix metalloproteinases (MMPs) and molecules involved in oxidative stress pathways, such as inducible nitric oxide synthase (iNOS), are also elevated in MS plaques.^{11, 12}

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Patients with multiple sclerosis have multiple needs, and the neurologist should be receptive and cooperative and try to allay fears, facilitate access to rehabilitation and orthotic equipment and home evaluations, and solve transportation issues. Bone densitometry studies are indicated for patients with MS who have received long-term corticosteroid treatment or are at higher osteoporosis risk from menopause or chronic immobility.

• Patients with more advanced forms of the disease who have lost all family support, are separated from their spouses, require constant psychiatric and nursing assistance, and are unable to walk are not rare. These patients create a challenge for the physician who is not trained in handling these demanding (administrative or ancillary) aspects of medical care. A social worker specialist can be instrumental in helping address these issues.
• The physician should not underestimate the impact of fatigue symptoms on the patient's daily activities. Treatment with amantadine (Symmetrel) or modafinil (Provigil) is often attempted when no contraindications exist. Pemoline, a drug that was gaining attention by MS clinicians for the treatment of fatigue is no longer being used due to reports of rare fatal liver damage events during its use. The United States Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all companies that produced generic versions of pemoline also agreed to stop sales and marketing of pemoline.
• Patients who have progressed beyond EDSS scores of 5.5-6 tend to respond poorly to the current treatments.
• • The impact of this disease on quality of life is reflected in the high suicide rate (7.5 times higher than in the general population). As already stated, however, reactive depression by itself does not fully account for this higher suicide incidence. Many believe that the accumulation of lesions in the brain eventually has an impact on mood.
  • Thus, preventing disease progression by using available medications is imperative in MS treatment, especially for patients who have been diagnosed early and probably will respond to treatment.
• Prevent relapses or disease progression by using the ABCR immunomodulatory drugs (ie, interferon beta-1a IM [Avonex], interferon beta-1b SC [Betaseron], glatiramer acetate SC [Copaxone], or interferon beta-1a SC [Rebif]). These 4 medications have been approved by the FDA and are currently used widely in the United States for MS. As a rule of thumb, the ABCR medications tend to decrease the rate of MS relapses by approximately one third, with the highest efficacy demonstrated in clinical trials for the high-dose, high-frequency (HDHF) beta interferons (ie, Betaseron [34%], Rebif [33%], Copaxone [29%]). In contrast, low-dose, low-frequency (LDLF) beta interferon (Avonex) decreased relapse rate by only 18%. However, trial comparisons do not necessarily reflect true differences and, therefore, head-to-head trials are carried out to answer questions on relative efficacy.
• Evidence for clinical superiority of HDHF to LDLF beta interferons has been provided by 2 head-to-head clinical trials (see INCOMIN and EVIDENCE below). Recent head-to-head trials failed to show superiority of HDHF interferons (Betaseron in the BEYOND study and Rebif in the REGARD study) to Copaxone in reducing relapse rates, although HDHF interferons better helped some MRI measures in these trials. The BECOME study, which also compared HDHF Betaseron with Copaxone, showed no significant difference in the primary outcome (an MRI-based outcome consisting of reduction in combined unique active lesions) and showed no difference in relapse reduction by these 2 agents, but showed superiority of HDHF in other MRI measures (ie, reduction in black holes).
  
  The long-term significance of the differences seen in MRI measures on these head-to-head trials (BEYOND, REGARD, and BECOME) remains unclear. Controversy also exists regarding the impact on the statistical power of such few on-drug relapse rates experienced by the cohorts entering these studies (particularly REGARD), compared with the higher on-drug relapse rates seen in the pivotal MS studies. Other compounds approved by the FDA for use in MS include mitoxantrone (Novantrone) and natalizumab (Tysabri). Tysabri showed a reduction in relapse rate of 67% and slowing in disability progression of 42%.¹³ These drugs carry black box warnings on their label but are not necessarily contraindicated in patients with MS who are naive to therapy (see Medication section for details).
• Interferon beta-1b (Betaseron) at 8 MIU SC every other day was shown in a 2-year, double-blind, placebo-controlled trial of 372 patients with RRMS to decrease the frequency of relapses from 1.27 per year to 0.84 per year, a 34% reduction in the relapse rate compared with placebo. Five-year follow-up data show that disease progression rate was 35% in the interferon beta-1b group and 46% in the placebo group. A 30% decrease in the yearly exacerbation rate in the treated group over 5 years also was demonstrated. While the placebo group had a median MRI lesion burden of 30.2% over 5 years, no significant increase (3.6%) was detected in the patients treated with interferon beta-1b. Interferon beta-1b was found to delay disability in European patients with SPMS.¹⁴ However, these results on disability were not replicated in a study on North American patients with SPMS. At the time of this report, Betaseron was not approved by the FDA for slowing disability progression.
• Interferon beta-1a (Avonex) was studied in a double-blind placebo-controlled study in 301 patients with RRMS receiving weekly intramuscular (IM) injections of 6 million units (30 mcg). Over 2 years, the annual exacerbation (ie, relapse) rate was 0.90 in the placebo group and 0.61 in the Avonex-treated group, a 29% reduction. At 2 years, the mean MRI lesion volume was 122.4 in the placebo group and 74.1 in the Avonex-treated group. The mean number of MRI enhancing lesions over 2 years was 1.65 in the placebo group and 0.80 in the Avonex-treated group. By the end of 104 weeks, the proportion of patients progressing was 34.9% in the placebo group and 21.9% in the Avonex group.
• Interferon beta-1a (Rebif) was evaluated in a randomized, double-blind, placebo-controlled study in patients with MS for at least a year and EDSS scores ranging from 0 to 5. Patients received SC injections of placebo, Rebif 22 mcg, or Rebif 44 mcg 3 times per week (tiw) for 2 years. Rebif significantly reduced the number of clinical exacerbations (the primary endpoint) and the number and area of brain active lesions by MRI. Rebif-treated patients also had a significantly longer time to reach sustained disability progression than placebo-treated patients.
• Controversy has also existed regarding the eventual clinical impact of raising the dose of these medications to higher or maximally tolerated levels—a study (BEYOND trial) failed to show superiority of Betaseron 500 mcg to both Betaseron 250 mcg (currently approved dose) and Copaxone in reducing relapses.
• Other head-to-head studies have directly addressed the issue of clinical and MRI superiority of HDHF beta-interferons (Betaseron and Rebif) to LDLF beta-interferon (Avonex). The INCOMIN trial, which compared the effects of interferon beta-1b (Betaseron) administered subcutaneously and interferon beta-1a (Avonex) administered intramuscularly, suggested that higher and more frequent doses delivered by Betaseron correlate with higher (clinical and MRI) efficacy.¹⁵ The EVIDENCE trial, which compared interferon beta-1a SC (Rebif) to interferon beta-1a IM, also found that higher dosing and more frequent administration led to higher (clinical and MRI) efficacy.¹⁶ Studies of combinations of beta interferons with other drugs such as glatiramer acetate are also underway.
• Glatiramer acetate (Copaxone) showed positive effects in a large randomized double-blind trial in 251 patients with RRMS. Patients on Copaxone had a 2-year relapse rate of 1.19, while patients on placebo had a rate of 1.68. The relapse rate reduction was 29% over 2 years for patients on Copaxone. Extension data show that over 140 weeks, 21.6% of patients treated with Copaxone worsened, while 41% of those on placebo worsened. Recent results of an 18-month study examining the impact of Copaxone on MRI outcome show a 35% reduction in the number of new T2 lesions.
• The safety and efficacy of mitoxantrone (Novantrone) was evaluated in 2 multicenter, randomized clinical trials.
• • Study 1 was conducted in patients with SPMS or RPMS. These patients had experienced a mean deterioration of the EDSS of about 1.6 points over the 18 months prior to study entry. Patients on mitoxantrone had a mean change in the EDSS of -0.13 compared with placebo (0.23), an ambulation index mean change of 0.30 (placebo, 0.77), and a mean number of relapses requiring steroids of 0.40 (placebo, 1.20). The number of patients with new gadolinium-enhancing lesions on mitoxantrone was 0 out of 31, compared with placebo (5 [16%] of 32).
  • Study 2 lasted 6 months and evaluated mitoxantrone in combination with methylprednisolone in patients with SPMS or worsening RRMS. The average deterioration in EDSS was 2.2 points in the previous 12 months. Of patients who only received methylprednisolone in this study, 31% were without new gadolinium-enhancing lesions versus patients on mitoxantrone plus methylprednisolone (90% without new gadolinium-enhancing lesions) (primary endpoint of the study). The annualized relapse rate was 3 for methylprednisolone patients and 0.7 for methylprednisolone plus mitoxantrone patients. The percentage of patients without relapses was 33% for the methylprednisolone group and 67% for the methylprednisolone-mitoxantrone combination.
• Two large studies assessing the efficacy of natalizumab (Tysabri) have been conducted.
• • Study 1, Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM), was a randomized, placebo-controlled trial in RRMS patients. Patients were randomized to receive natalizumab (n = 627) or placebo (n = 315). The primary endpoints were the rate of clinical relapse at 1 year and the rate of sustained EDSS progression at 2 years. Natalizumab reduced the rate of clinical relapse at 1 year by 68%. The cumulative probability of progression was 17% in the natalizumab patient group versus 29% in the placebo group. Natalizumab also showed MRI efficacy, demonstrating a reduction in the accumulation of new or enlarging T2 lesions by 83% over 2 years and a 92% reduction in number of gadolinium-enhancing lesions in the natalizumab group at 1 and 2 years.¹³
  • Study 2, Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL), evaluated patients on Avonex and placebo (n = 582) vs. Avonex and Natalizumab (n = 589). The primary endpoints were the rate of clinical relapse at 1 year and the cumulative probability of sustained EDSS progression at 2 years. The patient group on Avonex plus natalizumab had a 24% reduction in the relative risk of sustained EDSS progression and a lower annualized relapse rate (0.34) versus Avonex plus placebo (0.75). As shown in study 1, fewer new or enlarging T2 lesions developed in the Avonex plus natalizumab group (0.9) than in the Avonex plus placebo group (5.4).
• Four studies have examined the efficacy of ABCR drugs in reducing conversion of clinically isolated syndrome (CIS) to clinically definite MS (CDMS): Interferon beta-1a was shown by the CHAMPS trial¹⁷ (for Avonex, given as 30 mcg IM once a week) and ETOMS trial (for Rebif, given as 22 mcg SC once a week) to delay the onset of CDMS in patients with CIS, when compared with placebo. The BENEFIT trial (for Betaseron) demonstrated the efficacy of Betaseron in reducing conversion from CIS to CDMS and to McDonald MS (ie, using MRI-based criteria). The PRECISE trial (for Copaxone) also showed that this drug is efficacious in reducing conversion to CDMS in patients with CIS.
• Considerable controversy exists regarding whether the delay in onset of new attacks by these drugs ultimately has a long-term impact on neurodegeneration and disability; these issues need to be addressed in future trials.
• Acute exacerbations
• • No highly effective treatment is currently available to counteract MS attacks after their onset. The most widely used treatment is intravenous (IV) methylprednisolone, 1 g IV qd for 3-5 days. This medication may help expedite the timing of recovery but will not affect the actual degree of recovery.
  • High-dose IV steroids may work more effectively than oral steroids for the acute attack, and home IV therapy is recommended if the patient does not require hospitalization. Alternatively, high-dose oral methylprednisolone should be used, when feasible.
• Secondary progressive forms
• • Patients with SPMS who are still experiencing relapses may be treated with Betaseron, especially when the clinical course reflects an early phase of progression (EDSS score <6).
  • Mitoxantrone is approved in North America and Europe for use in patients with MS. Patients on mitoxantrone need to be monitored with echocardiograms prior to and during treatment, as the drug carries a risk of cardiomyopathy (the drug carries a black box warning regarding this potential toxicity). Because of this risk, mitoxantrone is typically reserved for patients with aggressive clinical presentations of MS (ie, worsening MS) or in whom immunomodulatory drug therapy has failed.
  • Head-to-head studies are underway to compare the efficacy of mitoxantrone versus cyclophosphamide (Cytoxan) in large numbers of patients. When studied individually in adult populations, mitoxantrone seems effective for all age ranges tested. The data on cyclophosphamide, in contrast, indicate that the benefits of this drug may be restricted to male patients younger than 40 years. Controversy exists whether patients with dramatic and rapid progression of disease (regardless of the type and timing of MS) should be treated earlier with immunosuppressive agents to try and arrest the ongoing inflammatory cascade. Cytoxan is not approved by the FDA for use in MS.
  • Azathioprine and methotrexate have also been used as immunosuppressive oral treatments for MS, but these drugs should not substitute for ABCR drugs as first-line agents in newly diagnosed RRMS. They are not FDA indicated for MS. They are considered less suppressive than mitoxantrone or cyclophosphamide and are being considered increasingly as potential combination partners for the ABCR drugs.

See related Medscape CME activities New Data on Disease-modifying Therapies for Multiple Sclerosis, New and Emerging Therapies for Multiple Sclerosis, and Specialty Pharmacy & Treatment Optimization: Applications for the Multiple Sclerosis Population.

Surgical Care

Surgical procedures that relate to multiple sclerosis are directed primarily at alleviating symptoms such as dysphagia, significant limb spasticity or contractures, or severe neuropathic pain. Measures include gastrojejunal tube placement, adductor leg muscle tendon release, and rhizotomy, respectively. Intrathecal pumps for delivery of antispasticity medications (eg, baclofen) can be implanted surgically. Caution should be used with baclofen pumps due to the risk of malfunction and baclofen overdose. Penile prostheses are an alternative for patients with erectile dysfunction that do not respond to medical management.

Consultations

Patients with multiple sclerosis may require multiple consultations to rule out other causes for their symptoms. For instance, patients with dysphonia may need an evaluation by an otolaryngologist (ie, ear, nose, and throat specialist) to rule out laryngeal lesions unrelated to MS. In addition, having MS does not exclude the possibility of concomitant peripheral neuropathy or other illnesses that may cause pain.

• Listed below are the most common consultant services involved in referrals from an MS clinic. Surgical consultation may be requested for gastric tube (G-tube) placement for feeding in persons with advanced MS. Urologic consultation might be warranted to help assess and treat incontinence. Neuropsychological evaluation, especially in patients with primary cognitive involvement, is advisable so that a baseline assessment for future reference can be obtained.
• • Otolaryngology
  • Neuropsychology
  • Ophthalmology
  • Physical therapy and rehabilitation
  • Psychiatry
  • Gastroenterology
  • Urology

Diet

No specific dietary restrictions apply to patients with multiple sclerosis; patients are encouraged to eat a balanced diet. Oral intake of calcium and multivitamin supplements is encouraged, as are adequate vitamin D sources. Although more studies are needed, recent observations suggest a role for vitamin D-related pathways in MS susceptibility.

Activity

• Patients are encouraged to exercise regularly. Inactivity can lead to deconditioning, which could further cause physical limitations.
• Strenuous exercise leading to physical exhaustion probably should be avoided; however, no studies have addressed this issue comprehensively in patients with MS.
• Patients with MS must adopt strategies for conserving energy by adjusting their schedules to prepare for daily tasks that require the most effort and to include periods of rest during the day.
• Patients with MS should avoid exposure to hot showers or saunas, as increased body temperature has been associated with reappearance of MS symptoms.
• Sunlight by itself is not considered to be deleterious, but excessive exposure may mimic the effects seen with hot showers or high temperatures.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

In the past 5 years, neuroimmunology has witnessed an unprecedented expansion in treatment options for CNS autoimmunity. Multiple MS drug trials are ongoing throughout the world, with many disappointments but occasional positive results.

Drugs for MS discussed in this article have been evaluated in clinical trials that measure one or several of the following endpoints:

• Reduction in relapse rate
• Increase in the proportion of relapse-free patients
• Increase in the time to first relapse
• Delay in progression to disability
• Decreased MRI lesion burden (T2 lesion volume or area)
• Presence of new (T2) lesions
• Presence of new (Gadolinium-enhancing T1) lesions
• Increase in brain atrophy
• Increase in T1 holes (permanent T1 hypointensities)

Patients should be educated and warned that these medications are preventive, not curative. Patients need to understand that mild sensory attacks may not warrant acute intervention with corticosteroids. Treatment of acute attacks should be reserved for functionally disabling symptoms and findings.

Therapeutic approaches such as combination therapy, intravenous immunoglobulin (IVIg), hormonal treatment, bone marrow transplantation, and plasmapheresis are not discussed here, as larger trials are needed for definitive recommendations. Combination therapy may be beneficial for some patients, however, and this practice may become commonplace within a few years. Treatments that can be used as combination partners include methotrexate, azathioprine, IVIg, and plasmapheresis. For reference about drug treatment of general neurologic symptoms (eg, neuropathic pain, depression, tonic spasms, spasticity, sexual dysfunction), please refer to the appropriate articles in eMedicine.

Briefly, treatments of choice include the following:

• Depression - Fluoxetine (Prozac), sertraline (Zoloft), amitriptyline (Elavil)
• Spasticity - Baclofen, tizanidine, dantrolene, diazepam (Valium), intrathecal baclofen delivered via programmable pump
• Painful tonic spasms - Baclofen, carbamazepine (Tegretol), gabapentin (Neurontin), phenytoin
• Fatigue - Modafinil, amantadine, fluoxetine, methylphenidate (Ritalin), selegiline
• Urinary dysfunction - Propantheline bromide (Pro-Banthine), tolterodine tartrate, oxybutynin (Ditropan), imipramine (Tofranil); intermittent self-catheterization
• Tremors/ataxia - Clonazepam (Klonopin), primidone (Mysoline), propranolol (Inderal), gabapentin; weighted bracelets
• Erectile dysfunction - Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), alprostadil (Muse), intracorporeal papaverine (not FDA approved), penile prostheses (Note that baclofen, fluoxetine, diazepam, and amitriptyline, listed above for therapy of other symptoms, may contribute to sexual dysfunction [eg, decreased libido, erectile dysfunction, abnormal ejaculation].)

Injection site reactions (ISR) seen with the ABCR drugs can be minimized by applying a topical steroid or cold packs at the intended site a few hours prior to administration of the drug or following the injection. These reactions include mild-to-severe erythema, skin induration or necrosis, and tissue loss or fibrosis, and may be complicated by superimposed bacterial infection.

Flulike symptoms (commonly experienced with Avonex, Betaseron, and Rebif) can be minimized by taking over-the-counter acetaminophen or ibuprofen 3-4 hours prior and 3-4 hours following the injection.  

Interferon beta-related ISR and flulike symptoms drastically decline with time as patients adjust and learn to use preventive techniques.

Acute exacerbations that lead to constant pain or to physical impairment may be treated with IV methylprednisolone. If available, alternative high-dose oral methylprednisolone treatment may circumvent the need for hospitalization.

See related Medscape CME activities New Data on Disease-modifying Therapies for Multiple Sclerosis, New and Emerging Therapies for Multiple Sclerosis, and Specialty Pharmacy & Treatment Optimization: Applications for the Multiple Sclerosis Population.

Drug Category: Immunomodulators

These agents reduce clinical attacks or the number of new MS lesions, and they may have an impact on disability progression.

Drug Category: Corticosteroids

These agents reduce acute inflammation and expedite recovery from acute exacerbations of MS. They may be used for "rescue" therapy as monthly boosters in patients who respond poorly to the ABC immunomodulators. Methylprednisolone, a glucocorticoid, has greater anti-inflammatory potency than prednisolone and even less tendency to induce water and sodium retention.

Drug Category: Immunosuppressors

These agents are used for their ability to suppress immune reactions.