Neurology

Multiple Sclerosis

Robert J. Fox

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). It usually affects people beginning in their 20s or 30s and is one of the most common causes of nontraumatic disability among young and middle-aged people. MS-related health care costs are estimated to be more than $10 billion annually in the United States. Symptoms of MS are extremely variable and often subtle, so diagnosis and management have been greatly enhanced by the development of magnetic resonance imaging (MRI). Because therapies that slow the progression of the disease are now available, early diagnosis and treatment are important in limiting the impact of this potentially devastating disease.

Definition

As outlined in Figure 1, there are several different forms of MS. Because these classifications were based on clinical characteristics, they are empirical and do not reflect 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, wherein symptoms appear for several days to weeks, after which they usually resolve spontaneously. After tissue damage accumulates over many years, patients typically enter the secondary progressive stage of MS (SPMS), in which pre-existing neurologic deficits gradually worsen over time. Relapses can be seen during the early stages of SPMS, but they 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.1 Progressive relapsing MS is defined as gradual neurologic worsening from the onset with subsequent superimposed relapses. Progressive relapsing MS (and possibly a portion of PPMS) is suspected to represent secondary progressive MS, in which the initial relapses were unrecognized, forgotten, or clinically silent.

Neuromyelitis optica (NMO), or Devic's disease, is an uncommon variant of MS.2 NMO manifests as recurrent optic neuritis and longitudinally extensive transverse myelitis (extending over three or more vertebral segments). A relatively specific antibody, named NMO antibody, has been identified and recognizes the aquaporin-4 water channel in astrocyte foot processes located adjacent to capillary walls.3,4 Recognition of the NMO antibody suggests the pathogenic role of autoantibodies in this form of MS, which has therapeutic implications.

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Prevalence

MS affects more than 350,000 people in the United States and 2.5 million worldwide. In the United States, prevalence estimates are approximately 90 per 100,000 population. MS symptoms can start anywhere between 10 and 80 years of age, but they usually begin between 20 and 40 years, with a mean age of 32 years. Women outnumber men by a ratio of almost 2 to 1, although in PPMS the ratio is closer to equal. MS affects whites more than blacks, although blacks appear to become disabled earlier, suggesting more destructive tissue injury in blacks. The prevalence of MS varies by location, and it generally increases the farther one travels from the equator in either hemisphere. It remains unclear whether this altered incidence represents an environmental influence, genetic difference, or variable surveillance.

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Pathophysiology

Initially in the disease course, MS involves recurrent bouts of CNS inflammation that result in damage to both the myelin sheath surrounding axons and to 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 pathologic studies suggest that different patients might have different etiologies for inflammation: Some patients appear to have T cell–mediated or T cell–plus-antibody–mediated autoimmune responses, whereas others have a primary disorder within the myelin-producing oligodendrocyte cells.5 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 under way to find blood, cerebrospinal fluid (CSF), or MRI markers.

In the past, inflammation was believed to involve only demyelination, but pathologic studies have found significant axonal pathology as well. In active MS lesions, observed transected axons were an average of more than 11,000/mm3, whereas control brain tissue had less than 1/mm3.6 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 degenerative changes. Nonetheless, oligodendrocyte progenitor cells capable of remyelinating axons have been observed, even in white matter plaques from patients with chronic MS (Fig. 2).7 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.

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 believed 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.

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Signs and symptoms

Because 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 can cause sensory or motor changes involving one side of the body or below a certain spinal cord level (i.e., hemiparesis or paraparesis). Brainstem involvement can manifest as diplopia, altered sensation in the face, or ataxia. Inflammation of the optic nerve (optic neuritis) usually manifests as blurry vision with painful eye movements.

Of all the lesions in MS, cerebral lesions are most common, but they cause the fewest symptoms. Very large cerebral lesions can manifest with weakness or numbness and rarely 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's sign is a nonspecific sign, whereby flexion of the neck causes an electric shock–like shooting sensation extending into the arms or down the back. Lhermitte's sign is believed to arise from 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 the diagnosis of MS, they are also nonspecific and can be seen in a multitude of disorders.

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Diagnosis

There are no pathognomonic clinical, laboratory, or imaging findings in MS. The diagnosis ultimately is a clinical decision based on 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.8 These criteria render MS a diagnosis of exclusion, which continues today. However, the Schumacher criteria also required that the patient's age be between 10 and 50 years and required the finding of objective abnormalities on examination, both of which are now outdated. However, the main concepts captured by these criteria remain relevant today.

Criteria from the Revised International Panel on MS Diagnosis, also called the Revised McDonald Criteria, is the latest attempt to clearly define diagnostic criteria for MS.9 Diagnostic classifications are reduced to definite MS and possible MS (Boxes 1 and 2). Advantages to the Revised International Panel criteria include the capability of making a definitive diagnosis of MS either after a monosymptomatic presentation or in the context of a primary progressive course. As the boxes illustrate, the diagnostic classification scheme and MRI criteria remain complicated and tedious, and this complexity limits their use in everyday practice. Furthermore, the specificity of these criteria is relatively low, emphasizing the importance of clinical judgment in excluding other diagnoses. Finally, studies have observed that standard MS disease-modifying medications can benefit patients who do not yet fulfill these diagnostic criteria.

Box 1: International Panel Criteria (McDonald Criteria) for the Diagnosis of Multiple Sclerosis
Additional data needed for a diagnosis of multiple sclerosis for a given clinical presentation (in descending order of objective clinical evidence)
Two or More Attacks
Objective Clinical Evidence of Two or More Lesions
  • None*
Objective Clinical Evidence of One Lesion
Dissemination in space demonstrated by:
  • MRI or
  • Two or more MRI lesions consistent with MS plus positive CSF or
  • Await further clinical attack implicating a different site
One Attack
Objective Clinical Evidence of Two or More lesions
Dissemination in time demonstrated by:
  • MRI or
  • Second clinical attack
Objective Clinical Evidence of One lesion (Clinically Isolated Syndrome)
Dissemination in space demonstrated by:
  • Two or more MRI lesions consistent with MS plus positive CSF
and
Dissemination in time demonstrated by:
  • MRI or
  • Second clinical attack
Insidious Neurologic Progression Suggesting MS
One year of disease progression and dissemination in space, demonstrated by two of the following:
  • ≥9 T2 lesions in brain, or four to eight T2 lesions in brain with positive visual-evoked potentials or
  • ≥2 T2 focal lesions in spinal cord
  • Positive CSF

*Brain MRI is recommended to help exclude other etiologies.
MRI criteria for dissemination in space or time are described in Box 2.
Positive CSF defined as oligoclonal bands different from those in serum or raised immunoglobulinG index.
CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis.
Adapted from Polman CH, Reingold SC, Edan G, et al: Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840-846.
©2002 The Cleveland Clinic Foundation.


Box 2: MRI Criteria for Brain Abnormality: Space and Time Dissemination
MRI Lesions Disseminated in Space
At least three of the following criteria must be met:
  • One gadolinium-enhancing lesion or nine T2-hyperintense lesions in the brain or spine
  • At least one infratentorial or spine lesion
  • At least one juxtacortical lesion
  • At least three periventricular lesions
MRI Lesions Disseminated in Time
At least one criterion must be met:
  • Gadolinium-enhancing lesion ≥3 mo after initial presentation, but in a different location from the initial event.
  • New T2 lesion, compared with a reference MRI done ≥30 days after onset of initial event

Adapted from Polman CH, Reingold SC, Edan G, et al: Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840-846.


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Treatment

Initial treatment of MS usually starts during the acute relapse. Several studies have found that treatment with corticosteroids can shorten the length of relapse and might even improve long-term outcome.10,11 A typical regimen is 500 to 1000 mg of intravenous methylprednisolone followed by a tapering dose of oral prednisone over several weeks. The standard protocol at the Mellen Center, Cleveland Clinic Foundation, is 1000 mg of intravenous methylprednisolone daily for three days, followed by a 12-day prednisone taper (60 mg daily, decreasing every 4 days by 20 mg). Evaluation of a relapse should include a search for precipitating factors such as bladder infection.

After the acute relapse is treated, 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) β-1a (Avonex, weekly intramuscular injection), IFNβ-1a (Rebif, three times-weekly subcutaneous injection), IFNβ-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 IFNβ-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%, decrease the severity of the relapses, and have beneficial effects on measures of disease activity on MRI.12-15 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 specific, and as a result, they have limited sensitivity for making the correct diagnosis at very early points in the disease. 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 are beneficial at this very early stage of disease.16,17 The benefits were observed despite MS not having been formally diagnosed in these subjects. 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 experienced in the diagnosis and treatment of MS.

The optimal initial treatment for relapsing MS remains controversial. Several head-to-head studies comparing interferon to glatiramer acetate found their efficacy to be similar on both clinical and imaging outcomes. Studies evaluating different doses and frequencies of interferon found greater short-term efficacy with high-dose, high-frequency interferon, which is balanced by increased adverse effects and greater incidence of neutralizing antibodies. Neutralizing antibodies significantly reduce the long-term efficacy of these medications, which is important when therapy is expected to continue for many years.18-20 Each of these treatments (interferons and glatiramer acetate) offers different advantages and disadvantages. All four medications are appropriate first-line therapies in relapsing-remitting MS and have rather similar efficacies. Perhaps the most important decision is determining when to initiate treatment. Currently, early treatment is recommended because it offers the greatest chance of preventing or delaying tissue injury and 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 between $25,472 and $26,832 per year. The most important limitation of these agents is their partial effectiveness. A substantial percentage of patients treated with each of these medications continue to have evidence of clinical disease as measured by clinical relapse, progression of disability, or new T2 lesions (i.e., lesions seen on T2-weighted images) on brain MRI. Monitoring patients clinically and with surveillance MRIs during treatment is important to detect nonresponders and to modify therapy accordingly.

Natalizumab (Tysabri) is the most recent MS therapy, first approved by the U.S. Food and Drug Administration (FDA) in November 2004. Natalizumab is a monoclonal antibody targeting the cellular adhesion molecule α4 intregin and is administered by intravenous infusion every 4 weeks. Adhesion molecules play an important role in attracting circulating leukocytes to leave the bloodstream and enter the brain parenchyma to cause inflammation. With blockade of α4 integrin, fewer inflammatory cells are allowed to enter the brain, and CNS inflammation is thus blunted. α4 integrin blockade within brain tissue can also lead to other beneficial immunologic effects, including anergy from lack of costimulation and apoptosis. Results from phase III clinical trials showed that natalizumab reduces clinical relapses by 55% to 67% and new brain lesions by 92%,21,22 although it is currently unclear whether the drug enters the central nervous system or exerts its effect entirely from the periphery.

Natalizumab is relatively well tolerated. Mild headache, fatigue, anxiety, menstrual irregularities, peripheral edema, and routine infections (upper respiratory infection, pharyngitis) are occasionally observed. Infusion-related hypersensitivity reactions (hives, pruritus, and rarely anaphylactoid) were observed in 2% to 4% of patients and are believed to represent immune-mediated hypersensitivity reactions. Patients who demonstrate an infusion hypersensitivity reaction should discontinue natalizumab immediately and not be re-treated.

Three cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with natalizumab.23 PML is a serious viral infection of the brain, arising from the ubiquitous JC virus carried by more than 85% of all adults. During periods of severe immune deficiency (i.e., acquired immunodeficiency syndrome [AIDS], solid organ transplantation, and cancer), the JC virus can enter the brain and cause a severe lytic infection. There are no known treatments for JC virus infection of the CNS, although prompt restitution of the aberrant immune system has helped some patients in the setting of AIDS. Plasmapheresis can accelerate removal of natalizumab and desaturation of α4 integrin, although its efficacy in treating natalizumab-related PML remains unknown.

Because of the serious complication of PML, natalizumab is not currently a first-line therapy for MS. Natalizumab is reserved generally for patients who respond suboptimally or who are unable to tolerate the standard MS therapies described earlier. Discussions with potential natalizumab recipients should review the risks and potential benefits of natalizumab. A decision to initiate therapy should be made only after a full appreciation of the risks involved. Monitoring for PML is currently limited to clinical surveillance, although ongoing studies are examining biomarkers that might indicate PML reactivation. Monitoring includes a screening questionnaire administered before each monthly infusion of natalizumab, at least semiannual evaluations by the prescribing clinician, and urgent brain MRI or cerebrospinal fluid testing (or both) for patients with suspected or possible PML.

Mitoxantrone (Novantrone) is a chemotherapy medication with demonstrated efficacy in very active relapsing and progressive MS.24 FDA labeling recommends intravenous infusion every 3 months, although a monthly induction course is sometimes used in patients with very active disease. Infusion side effects include nausea and alopecia. Long-term toxicities include cardiac injury and lymphoproliferative disorders, such as leukemia. Cardiac toxicity is cumulative over time, which limits its use to approximately 2 years. Cardiac monitoring with a transthoracic echocardiogram prior to each mitoxantrone infusion is recommended. The safety concerns of mitoxantrone limit its use to patients with persistently active MS despite standard injection therapy. As with natalizumab, the potential risks and benefits of mitoxantrone need to be weighed carefully and discussed in detail with the patient.

Cyclophosphamide, methotrexate, azathioprine and cyclosporine all have been studied in small- to medium-sized trials. An 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.25 Methotrexate, azathioprine, and cyclosporine were each found to be possibly effective (Type C recommendation) in altering the course of disease, but cyclosporine was found to have an unacceptable risk-to-benefit ratio. In their review, pulse cyclophosphamide treatment was found to not alter the course of MS (Type B recommendation), although a more recent clinical trial observed reduced relapses and MRI lesions in patients treated with cyclophosphamide.26

It is important to note that current therapies are preventive, not restorative. As the disease progresses, response to therapy typically 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, with a careful balancing of risks with potential benefits.

Treatment of SPMS is more difficult. Although interferon medications were found in some trials to prevent progression of disability in SPMS, the effect was modest. It appears worthwhile to use interferons during this stage if there are persistent clinical relapses and side effects are tolerated, but caution regarding reasonable clinical expectations is appropriate. There are no treatments with demonstrated clinical efficacy in primary progressive multiple sclerosis, although anecdotal evidence suggests that intermittent pulses of intravenous methylprednisolone can help slow the progression of clinical disability in some patients. Intermittent pulses of intravenous methylprednisolone also may be helpful in SPMS.

In addition to neurologic disability, MS can produce a variety of other symptoms that can interfere with daily activities. 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.

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Outcomes

MS is a heterogeneous disease with a variable clinical course. Patients can progress rapidly over several months to death, or they might have a few relapses and then remain clinically stable for many decades. Although there is significant variability between patients, 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. These observational studies were performed before the use of disease-modifying therapies, so these estimates may be different in patients receiving treatment.

It is difficult to predict which patients will progress and which will remain relatively stable over time. Although there are clearly patients in whom the disease remains benign, it is 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 (e.g., high attack frequency and increased disability progression in the first 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. MRI measures are also useful tools when evaluating the effects of MS therapies.27

Pregnancy appears to decrease the incidence of relapses, but there is a rebound in relapse frequency after delivery.28 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.29 Vaccines can be given safely in MS and should be administered if clinically indicated.

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Summary

  • MS is a chronic inflammatory disorder affecting the brain, optic nerve, and spinal cord.
  • Because symptoms of MS can involve almost any neurologic function, the diagnostic evaluation should include a thorough history, neurologic examination, MRI, and, sometimes, cerebrospinal fluid analysis.
  • Many therapies are available to decrease the clinical episodes of inflammation, slow progression of disability, and ameliorate the symptoms from previous injury.
  • Early diagnosis and treatment are of key importance, because effective treatment is difficult after the patient has progressed into the later stages of MS.

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References

  1. Cottrell DA, Kremenchutzky M, Rice GP, et al: The natural history of multiple sclerosis: A geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. Brain. 1999, 122: 625-639.
  2. Wingerchuk DM, Lennon VA, Pittock SJ, et al: Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006, 66: (10): 1485-1489.
  3. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004, 364: (9451): 2106-2112.
  4. Lennon VA, Kryzer TJ, Pittock SJ, et al: IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005, 202: (4): 473-477.
  5. Lucchinetti C, Brèuck W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol. 2000, 47: (6): 707-717.
  6. Trapp BD, Peterson J, Ransohoff RM, et al: Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998, 338: 278-285.
  7. Chang A, Tourtellotte WW, Rudick R, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002, 346: (3): 165-173.
  8. Schumacher GA, Beebe GW, Kibler RF, et al: Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci. 1965, 122: 552-568.
  9. Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol. 2005, 58: 840-846.
  10. Milligan NM, Newcombe R, Compston DAS. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry. 1987, 50: 511-516.
  11. Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology. 1998, 51: 529-534.
  12. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: Final outcome of the randomized, controlled trial. Neurology. 1995, 45: 1277-1285.
  13. Jacobs LD, Cookfair DL, Rudick RA, et al: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996, 39: 285-294.
  14. Johnson KP, Brooks BR, Cohen JA, et al: Copolymer 1 reduces the relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 1995, 45: 1268-1276.
  15. PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon b-1a in relapsing/remitting multiple sclerosis. Lancet. 1998, 352: 1498-1504.
  16. Jacobs LD, Beck RW, Simon JH, et al: The effect of initiating interferon beta-1a therapy during a first demyelinating event on the development of clinically definite multiple sclerosis. N Engl J Med. 2000, 343: 898-904.
  17. Comi G, Filippi M, Barkhof F, et al: Effect of early interferon treatment on conversion to definite multiple sclerosis: A randomised study. Lancet. 2001, 357: (9268): 1576-1582.
  18. Francis GS, Rice GP, Alsop JC. Interferon beta-1a in MS: Results following development of neutralizing antibodies in PRISMS. Neurology. 2005, 65: (1): 48-55.
  19. Sorensen PS, Koch-Henriksen N, Ross C, et al: Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005, 65: (1): 33-39.
  20. Rask C, Unger E, Walton M. Comparative Study of Rebif to Avonex and Orphan Exclusivity. Rockville, Md: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 2002.
  21. Rudick RA, Stuart WH, Calabresi PA, et al: Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006, 354: (9): 911-923.
  22. Polman CH, O’Connor PW, Havrdova E, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006, 354: (9): 899-910.
  23. Yousry TA, Major EO, Ryschkewitsch C, et al: Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006, 354: (9): 924-933.
  24. Hartung HP, Gonsette R, Kèonig N, et al: Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002, 360: (9350): 2018-2025.
  25. Goodin DS, Frohman EM, Garmany GP Jr, et al: Disease modifying therapies in multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002, 58: (2): 169-178.
  26. Smith DR, Weinstock-Guttman B, Cohen JA, et al: A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta. Mult Scler. 2005, 11: (5): 573-582.
  27. Rudick RA, Lee JC, Simon J, et al: Defining interferon beta response status in multiple sclerosis patients. Ann Neurol. 2004, 56: (4): 548-555.
  28. Confavreux C, Hutchinson M, Hours MM, et al: Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998, 339: 285-291.
  29. Confavreux C, Suissa S, Saddier P, et al: Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med. 2001, 344: (5): 319-326.

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Suggested Readings

  • Chang A, Tourtellotte WW, Rudick R, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002, 346: (3): 165-173.
  • Confavreux C, Hutchinson M, Hours MM, et al: Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998, 339: 285-291.
  • Francis GS, Rice GP, Alsop JC. Interferon beta-1a in MS: Results following development of neutralizing antibodies in PRISMS. Neurology. 2005, 65: (1): 48-55.
  • Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004, 364: (9451): 2106-2112.
  • Lucchinetti C, Brèuck W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol. 2000, 47: (6): 707-717.
  • Polman CH, O’Connor PW, Havrdova E, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006, 354: (9): 899-910.
  • Polman CH, Reingold SC, Edan G, et al: Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the “McDonald Criteria.”. Ann Neurol. 2005, 58: 840-846.
  • Trapp BD, Peterson J, Ransohoff RM, et al: Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998, 338: 278-285.
  • Wingerchuk DM, Lennon VA, Pittock SJ, et al: Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006, 66: (10): 1485-1489.
  • Yousry TA, Major EO, Ryschkewitsch C, et al: Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006, 354: (9): 924-933.