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Table of Contents

Reviewed May 10, 2004

Robert J. Fox, MD

Department of
Neurology

Patrick J.
Sweeney, MD

Department of
Neurology

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Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

National Guidelines Paralyzed Veterans of America: Management of Fatigue Paralyzed Veterans of America: Management of Urinary Dysfunction National Multiple Sclerosis Society

 

DEFINITION

As outlined in Figure 1, there are several different forms of MS. Since these classifications were based upon clinical characteristics, they are empiric and not reflective of specific biologic pathophysiology. Nonetheless, they provide an organized framework for diagnosis and long-term management. Relapsing remitting MS (RRMS) is the most common form of the disease, where symptoms appear for several days to weeks, after which they usually resolve spontaneously. After tissue damage accumulates over many years, patients usually enter the secondary progressive stage of MS (SPMS), where preexisting neurologic deficits gradually worsen over time. Relapses can be seen during the early stages of SPMS, but become uncommon as the disease progresses. About 15% of patients have gradually worsening manifestations from the onset without clinical relapses, which defines primary progressive MS (PPMS). Patients with PPMS tend to be older, have fewer abnormalities on brain MRI and generally respond less effectively to standard MS therapies. Progressive relapsing MS is defined as gradual neurologic worsening from the onset with subsequent superimposed relapses. Progressive relapsing MS (and possibly much of PPMS) is suspected to represent secondary progressive MS, where the initial relapses were unrecognized, forgotten or clinically silent.

MS affects more than 350,000 people in the United States and 2.5 million worldwide. In the United States, prevalence estimates vary between 5 and 119 per 100,000 population. MS symptoms can start anywhere between 10 and 60 years of age, but usually begins between 20 and 40 years, with a mean of 32 years. Women outnumber men by a ratio of almost 2 to 1, although in PPMS the ratio is closer to equal. MS appears to affect Caucasians more than Blacks. The prevalence of MS varies by location, and generally increases the further one travels from the equator in either hemisphere. It remains unclear whether this altered incidence represents an environmental influence, genetic difference or variable surveillance.

Initially in the disease course, MS involves recurrent bouts of CNS inflammation that results in damage to both the myelin sheath surrounding axons as well as the axons themselves. Histologic examination reveals foci of severe demyelination, decreased axonal and oligodendrocyte numbers, and gliotic scarring. The exact cause of inflammation remains unclear, but an autoimmune response directed against CNS antigens is suspected. Recent pathological studies suggest that different patients may have different etiologies for inflammation: some patients appear to have T-cell-mediated or T-cell-plus-antibody-mediated autoimmune responses, while others suggest a primary disorder within the myelin-producing oligodendrocyte cells.¹ This latter mechanism is reminiscent of virus- or toxin-induced demyelination rather than autoimmunity in this subset of patients. Further research is needed to understand how these different pathologic subtypes affect prognosis and response to treatments. Currently, brain biopsy is the only method to determine pathologic subtype, but studies are underway to find blood, Cerebrospinal fluid (CSF) or MRI markers.

In the past, inflammation was thought to involve only demyelination, but recent studies have found significant axonal pathology as well. In active MS lesions, an average of more than 11,000 transected axons/mm³ were observed, while control brain tissue had < 1 transected axon/mm³.² Clearly, axonal injury is significant in the early stages of disease.

Later in the disease course, gradual progression of disability is observed. However, there is little active inflammation during this period, so this clinical progression probably involves significant chronic degenerative changes. Nonetheless, oligodendrocyte progenitor cells capable of remyelinating axons have been observed even in chronic plaques from patients with chronic MS (Figure 2).³ This observation suggests that the potential for remyelination persists even very late in the disease course, which is an encouraging indicator for possible therapeutic targets at this late stage of disease.

Remyelinating oligodendrocyte in a demyelinated region of brain from a patient with chronic MS. There are straight, healthy-appearing axons (green), and an oligodendrocyte (red) extending processes (arrowheads) to myelin internodes. (Adapted from Chang A, Tourtellotte WW, Rudick R, et al. N Engl J Med 2002; 346:165-73)

Figure 2

Current concepts of the pathophysiology of MS are illustrated in Figure 3. On average, patients have clinical relapses every 1 to 2 years during the relapsing-remitting phase of the disease. Serial MRI studies have shown that lesions develop up to 10 to 20 times more frequently than clinical relapses. Thus, although relapsing-remitting MS appears to have clinically active and quiescent periods, inflammatory lesions are developing and evolving almost continuously. A current hypothesis states that overt progression of disability (secondary progressive MS) occurs when ongoing irreversible tissue injury exceeds a critical threshold beyond which the nervous system can no longer compensate. It is thought that at this point the disease has become essentially a degenerative process, with neurologic deterioration independent of ongoing inflammation.

An important implication of this hypothesis is that the accumulation of irreversible tissue damage limits the potential for benefit from disease-modifying immunomodulatory therapy as the disease progresses and becomes a degenerative process. To be maximally effective, disease-modifying immunomodulatory therapy should be started early in the relapsing-remitting phase and before permanent disability develops.

Since MS can affect any area of the brain, optic nerve or spinal cord, MS can cause almost any neurologic symptom. Typical relapses of MS involve episodes of numbness, weakness or dyscoordination affecting an arm, a leg or both. Disease localized to the spinal cord may cause sensory or motor changes involving one side of the body or below a certain spinal cord level (ie, hemiparesis or paraparesis). Brain stem involvement may present as diplopia, altered sensation in the face or ataxia. Inflammation of the optic nerve (optic neuritis) usually presents as blurry vision with painful eye movements. Of all the lesions in MS, cerebral lesions are most common, but cause the least symptoms. Very large cerebral lesions may present with weakness or numbness, and rarely may cause aphasia or other cortical dysfunction. Most cerebral lesions are not in eloquent regions, and so are clinically silent and identified only by brain MRI. Lhermitte sign is a non-specific sign whereby flexion of the neck causes an electrical-like shooting sensation to extend into the arms or down the back. Lhermitte sign is thought to arise from irritation of partially demyelinated tissue, whereby mechanical stimulation leads to axonal activation.

Other common symptoms of MS include bladder and bowel dysfunction, decreased memory, fatigue and affective disorders such as depression. Although these symptoms are not uncommon at diagnosis of MS, they are also very non-specific and can be seen in a multitude of disorders.

There is no pathognomonic clinical, laboratory or imaging findings in MS. The diagnosis ultimately is a clinical decision based upon weighing the factors that support the diagnosis against those that fail to support it or point to the possibility of an alternative diagnosis.

The Schumacher criteria from 1965 capture the essence of the diagnosis of MS: CNS lesions disseminated in space and time, and the elimination of alternative diagnoses.⁴ These criteria render MS a diagnosis of exclusion, which continues today. The Schumacher Criteria required age between 10 and 50 years and objective abnormalities on examination, which are now outdated. However, the main concepts captured by these criteria remain relevant today.

The Washington Panel, or Poser, criteria were published in 1983.⁵ They include paraclinical tests (neuroimaging, evoked potential studies, urologic tests) and laboratory studies (intrathecal IgG production and IgG oligoclonal bands). The diagnosis of MS is divided into different categories: clinically definite, clinically probable, laboratory-supported definite and laboratory-supported probable. Although the Poser criteria were used widely in clinical studies over the last two decades, they have many shortcomings: the implications of the different diagnostic classifications were unclear, MRI criteria were not defined and primary progressive multiple sclerosis could not be diagnosed with these criteria.

Criteria from the International Panel on MS Diagnosis, or McDonald Criteria, is the latest attempt to clearly define diagnostic criteria for MS.⁶ Diagnostic classifications are reduced to Definite MS and Possible MS (Tables 1 and 2). Advantages to the International Panel criteria include the capability of making a definitive diagnosis of MS after either a monosymptomatic presentation or a primary progressive course. As the tables illustrate, the diagnostic classification scheme and MRI criteria are very complicated and tedious, and this complexity limits their use in everyday practice. Furthermore, studies have observed that standard MS disease modifying medications can benefit patients who do not yet fulfill these diagnostic criteria. So, the usefulness of this classification scheme may be limited to epidemiologic studies and enrollment criteria for clinical trials.

Initial treatment of MS usually starts during the acute relapse. Several studies have found that treatment with corticosteroids can shorten the course of relapse and may even improve long-term outcome. A typical regimen is 500 to 1,000 mg of intravenous methylprednisolone followed by a tapering dose of oral prednisone over several weeks. Evaluation of a relapse should include a search for precipitating factors such as infection.

After the diagnosis of MS is made, consideration should turn to disease-modifying therapy. Current therapies target the immune dysfunction in MS and resultant neural tissue damage with the goal of preventing or at least reducing the long-term risk of clinically significant disability. Four first-line therapies are currently available in the United States: interferon (IFN)ß-1a (Avonex, weekly intramuscular injection), IFNß-1a (Rebif, thrice-weekly subcutaneous injection), IFNß-1b (Betaseron, alternate-day subcutaneous injection), and glatiramer acetate (Copaxone, daily subcutaneous injection). The IFN medications are recombinant products with an amino acid sequence that is identical or nearly identical to that of human IFNß-1. Glatiramer acetate is a random polypeptide based on the amino acid sequence of a myelin protein. All of these medications appear to modulate the immune response in MS, although glatiramer acetate and interferon medications probably work through different mechanisms.

In randomized, placebo-controlled trials, all of these medications were shown to decrease the rate of clinical relapses by about 30 to 40%, decrease the severity of the relapses and have beneficial effects on measures of disease activity on MRI.^7-10 Based on these studies, The Medical Advisory Board of the National Multiple Sclerosis Society has recommended that treatment with MS disease modifying agents should be initiated as soon as possible following a definite diagnosis of MS and determination of a relapsing course. Furthermore, the Board recommends that "therapy is to be continued indefinitely, unless there is clear lack of benefit, intolerable side effects, new data that reveal other reasons for cessation or better therapy is available." If a patient chooses not to start treatment, routine clinical visits and interval brain MRI evaluations are strongly encouraged to monitor for active disease.

The International Panel Criteria for diagnosis of MS aimed to be very specific, and as a result, have limited sensitivity for making the correct diagnosis at very early points in the disease. However, several treatment trials have involved patients with a single inflammatory event who were at increased risk of developing MS, and these trials found that interferon medications can be beneficial.^11,12 These benefits were observed despite patients not having been formally diagnosed with MS. Accordingly, a report from a Consensus Panel of the Consortium of Multiple Sclerosis Centers emphasizes that the new diagnostic criteria should be used for diagnosis only, and not to make treatment decisions. Treatment decisions should be made based on the judgment of a clinician experience in the diagnosis and treatment of MS.

Long-term clinical superiority of one first-line treatment over any of the others remains somewhat unclear. There have been only two randomized, head-to-head short-term studies comparing therapies. Preliminary reports from these studies indicate that Betaseron and Rebif each reduce that short-term rate of clinical relapses better than Avonex. However, both Betaseron and Rebif have increased adverse effects (hepatic and hematological toxicities, and skin reactions including necrosis) and increased development of neutralizing antibodies compared to Avonex. Neutralizing antibodies appear to significantly reduce the long-term efficacy of these medications, which is important when therapy is expected to continue for many years. In summary, each of these treatments (interferons and glatiramer acetate) offer different advantages and disadvantages. The authors believe that all four medications are appropriate first-line therapies in relapsing-remitting MS. The most important decision is to start treatment early, since early treatment offers the greatest chance of preventing or delaying long-term disability.

It is important to note that all of these first-line, disease-modifying medications have limitations. All are given by injection, and all are expensive, costing about US$12,800 to $17,300 per year. The most important limitation of these agents is their partial effectiveness. A substantial proportion of patients treated with each of these medications continues to have evidence of clinical disease, as measured by clinical relapse, progression of disability or new T2 lesions on brain MRI. Monitoring of patients during treatment is important to detect nonresponders and modify therapy accordingly.

Nonetheless, these first-line therapies appear to offer the best opportunity for preventing long-term disability. It is important to note that current therapies are preventive, not restorative. As the disease progresses, response to therapy gradually declines. The key to successful treatment of MS is to slow the inflammatory process early in the disease. It is likely that the accumulation of irreversible tissue damage limits the potential for benefit from disease-modifying immunomodulatory therapy as the disease progresses. The therapeutic nihilism of the past should be replaced by aggressive treatment and monitoring.

Treatment of secondary progressive multiple sclerosis is more difficult. Although interferon medications were found in some trials to prevent progression of disability in secondary progressive multiple sclerosis, the effect was modest. It appears worthwhile to use interferons during this stage if side effects are tolerated, but caution regarding reasonable clinical expectations is appropriate.

Mitoxantrone (Novantrone) is a chemotherapy medication with demonstrated efficacy in progressive MS. It is given by intravenous infusion every 3 months, although it is sometimes given every month for the first few doses to patients with very active disease. Side effects and potential toxicities, including cardiac toxicity, limit its use to patients with secondary progressive MS or very active relapsing-remitting MS. Long-term cardiac toxicity limits its use to approximately 2 years.

Cyclophosphamide, methotrexate, azathioprine and cyclosporin all have been studied in small- to medium-sized trials. A recent evaluation by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and MS Council for Clinical Practice Guidelines has made recommendations regarding these therapies.¹³ Methotrexate, azathioprine and cyclosporin were each found to be possibly effective (Type C recommendation) in altering the course of disease, but cyclosporin was found to have an unacceptable risk-benefit ratio. In their review, pulse cyclophosphamide treatment was found to not alter the course of MS (Type B recommendation), but preliminary results from a recently completed study of cyclophosphamide suggest that it may in fact have efficacy in progressive multiple sclerosis.¹⁴

There are no treatments with demonstrated clinical efficacy in primary progressive multiple sclerosis, although several clinical trials are underway using interferons, glatiramer acetate and mitoxantrone.

Besides neurologic disability, MS can produce a variety of other symptoms that can interfere with daily activities (Table 3). Identification and treatment of these symptoms should be considered throughout the disease course. Specific recommendations for management of fatigue and urinary dysfunction have been outlined by the Multiple Sclerosis Council for Clinical Practice Guidelines. Aggressive evaluation and treatment for these and other symptoms of MS can improve quality of life significantly and are an important component of long-term management of patients with MS.

MS is a heterogeneous disease, with a variable clinical course. Patients can progress rapidly over several months to death, or may have a few relapses and then remain clinically stable for many decades. Average time from disease onset to difficulty with walking is 8 years, walking with a cane is 15 years and wheelchair-bound is 30 years.¹⁵ These studies were performed prior to the use of disease-modifying therapies, so these averages may be different in patients receiving treatment.

It is difficult to predict which patients will progress and which will remain relatively stable. Although there are clearly patients in whom the disease remains benign, it is very difficult to predict which patients eventually will follow this course. There are several prognostic factors of later outcome. Older age at onset, initial symptoms involving cerebellar, spinal or pyramidal systems, and higher initial clinical activity (eg, early attack frequency, short first interattack interval, moderate disability reached by 5 years) are all unfavorable prognostic factors. Initial symptoms of optic neuritis or sensory dysfunction are favorable prognostic factors. Prognostic radiologic measures include brain and spinal cord atrophy and gadolinium-enhancing lesions, but surprisingly, not T2-lesion load.

Pregnancy appears to decrease the incidence of relapses, but there is a small rebound in relapse frequency following pregnancy.¹⁶ The effect of vaccines on MS has been studied very carefully in the past several years, and there appears to be no adverse effect of vaccines on the course of disease.¹⁷ Vaccines can be given safely in MS and should be administered where clinically indicated.

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