All About Multiple Sclerosis

More MS news articles for April 2003

Perfect Pitch: Fine-tuning the Management of Multiple Sclerosis

http://www.medscape.com/viewprogram/2201

March 31, 2003
Author: Patricia K. Coyle, MD
Professor of Neurology, and Director, MS Comprehensive Care Center, School of Medicine, State University of New York at Stony Brook.

Introduction

Multiple sclerosis (MS) is the most common acquired neurologic disease of young adults. The prototype patient is a young woman of childbearing age, although men make up 25% to 30% of all cases. MS targets the central nervous system (CNS) to produce a wide array of brain and spinal cord syndromes, with 2 recognized clinical profiles. Typically, patients begin by experiencing episodic neurologic abnormalities (relapsing-remitting MS) -- acute disease attacks that can improve spontaneously. In most cases, this pattern yields to a steady progressive phase, with or without superimposed attacks and without meaningful recovery. In 10% to 15% of cases, the slowly progressive phase occurs from the start, with a small minority of these experiencing an occasional relapse that occurs some time later. The cause of MS is not known but is believed to involve 3 factors: genetic vulnerability (inheriting too many susceptibility genes and too few protection genes), some form of exposure to 1 or more environmental pathogen triggers, and the development of pathologic host immune responses directed against the CNS.

Until the last decade there was no treatment for MS. Since 1993, 5 disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (Table 1). Four are immunomodulators, and 1 is an immunosuppressant. All of the DMTs produce multiple effects on the immune system that should benefit MS. To understand current treatment strategies, it is important to appreciate new insights into the nature and extent of the MS disease process that have been gained over the past few years (Table 2). These concepts are also driving new therapeutic approaches.

Table 1. Current MS Disease-modifying Therapies for MS
 
Drug Type of Agent Dose Presumed Mechanism of Action Side Effects
Immunomodulator
bullet IFNbeta-1a (Avonex) bullet Type I IFN; anti-inflammatory cytokine bullet 30 mcg IM weekly bullet Multiple systemic immune effects:
- cell trafficking into CNS 
- blood brain barrier permeability 
- T-cell activation 
- suppressor cell activity 
- shift in cytokine milieu
( proinflammatory,  anti-inflammatory cytokines)
bullet Flu-like symptoms
bullet Injection-site reactions (SC IFNbeta)
bullet Depression
bullet CBC, liver abnormalities
bullet Menstrual disturbances
bullet Spasticity
bullet IFN beta-1a (Rebif) bullet See above bullet 44 mcg SC 3x weekly bullet See above bullet See above
bullet IFN beta-1b (Betaseron) bullet See above (3 molecular differences from IFNbeta-1a) bullet 250 mcg (8 MIU) SC qod bullet See above bullet See above
bullet Glatiramer acetate (Copaxone) bullet Random polymers of 4 amino acids; universal T cell antigen bullet 20mg SC qd bullet Systemic: activation of TH2 suppressor cells; intrathecal: bystander suppression, microglial inhibition, possible neuroprotective/ remyelination activity bullet Injection site reaction
bullet Systemic (immediate post-injection) reaction
bullet Wheals, hypersensitivity reactions
Immunosuppressor
bullet Mitoxantrone (Novantrone) bullet Anthracenedione (chemotherapy agent) bullet 12 mg/m2 IV q 3 mo (maximum 140 mg/m2) bullet Broad immunosuppression (T cells, B cells, macrophages) bullet Cardiotoxicity
bullet Leukopenia
bullet Menstrual disturbance
bullet Nausea
bullet susceptibility to infection
bullet Leukemia (rare)

IFNbeta = interferon beta; IM = intramuscular; IV = intravenous; MIU = million international units; SC = subcutaneous

Table 2. New Concepts About MS
 
  • The early disease process is a critical period: role of epitope spread
    • The fundamental nature of the damage process may change over time.

    •  
    • Axon and neuron involvement is a central feature.

    •  
    • Most MS disease activity is inapparent (subclinical).

    •  
    • There are extensive microscopic abnormalities in normal-appearing brain tissue.

    •  
    • MS is heterogeneous.

    New Disease Concepts

    Although genetic vulnerability is probably a prerequisite for development of MS, it is not sufficient in the absence of other contributing factors. With recognized low-, medium-, and high-risk geographic disease zones, environmental factors clearly play a role. Exposures to common viruses and bacteria relatively early in life, in a way that is not yet understood, set the stage for MS. Infections probably act as disease triggers, although continued active neural or extraneural infection has not been ruled out as a disease factor in selected patients. Molecular mimicry (shared epitope sequences between ubiquitous infectious agents and autoantigens, including CNS antigens) is well documented. It is commonly believed, although not proven, that infection-triggered cross-reactivity to a myelin component initiates MS in genetically vulnerable individuals. Epitope spread occurs when CNS damage releases multiple sequestered antigens to the systemic immune system. Two types of epitope spreading may be involved: intermolecular epitope spread is when the immune response moves from 1 myelin antigen to another (ie, started against myelin basic protein (MBP), but with attack of myelin, other antigens such as myelin oligodendrocyte glycoprotein (MOG) are released and the immune response then spreads to MOG); and intramolecular epitope spreading, which occurs when the immune response is directed against a specific peptide of a specific protein (eg, MBP amino acid sequence 82-99) then with the destruction of myelin, it exposes other hidden or "cryptic" epitopes of MBP and the immune response shifts to these new epitopes (eg, MBP 102-118).[1] This expands the immune attack and acts to enhance and perpetuate organ-specific autoimmune disease. Epitope spread occurs in animal models of MS, and preliminary data indicate it is also a factor in MS.[2]

    Therapeutic Implications of Epitope Spread

    The concept of epitope spread carries important therapeutic implications. It argues for starting effective MS treatment at the earliest possible time point (ideally, at the first attack of definite MS), in order to minimize expansion and reinforcement of the damage process. The concept even provides a rationale for considering initial induction therapy (with broad-spectrum immunosuppression), followed by maintenance therapy. Supporting evidence that the early disease process is critical comes from natural history studies of first-attack, clinically isolated syndrome (CIS) patients. The number and volume of T2 brain lesions on the presenting MRI are the strongest correlates of disability at 14 years, followed by MRI lesion development during the first 5 years.[3]

    New Insights Into Pathophysiology: Axons

    MS is now believed to involve a biphasic disease process. Early on, inflammation is prominent, corresponding to the relapsing and potentially reversible phase of MS. Later, there is transition to a primarily neurodegenerative phase, corresponding to progressive MS with irreversible deficits. Although inflammation and neurodegeneration are detected at all time points, 1 process appears to dominate. This concept is consistent with natural history studies of MS, since most patients begin with relapsing disease but ultimately transition to secondary progressive disease. The presence of distinct MS phases argues for therapy that is tailored to the nature of the disease process.

    The classic view of MS is that it is a disease that involves CNS inflammation and demyelination. It is now clear from direct pathologic data and indirect neuroimaging data that it also involves damage to axons and neurons.[4,5]Both axon density and volume are reduced in MS, not just within the plaque but also in normal-appearing CNS tissue.[6,7]Analysis of n-acetyl aspartate (NAA), an axon/neuron marker measured by MR spectroscopy, indicates that whole brain NAA is reduced even in early MS.[8]Loss or shrinkage of axons is a major contributor to brain and spinal cord volume loss (atrophy). In patients with MS, prominent CNS atrophy is present very early, even at the time of the first clinical attack.[9,10] On a yearly basis, brain volume loss in MS is accelerated 3- to 10-fold over that of matched controls.

    The importance of axon damage in MS cannot be overstated; it is believed to be the neuroanatomic substrate of permanent disability and disease progression. Injury to axons undoubtedly reflects multiple factors (Table 3). At least some of the immune and inflammatory elements that injure axons are distinct from those that damage myelin. Axons or axon components (such as ion channels and neurofilaments) could be the target of a direct primary or secondary immune attack. Antibodies to neurofilament components, gangliosides, and myelin oligodendrocyte glycoprotein have been linked to progressive MS.[11-13]Alternatively, damage could reflect secondary bystander effects from inflammatory or toxic factors released into the microenvironment by intrinsic (microglia, astrocyte) or extrinsic (lymphocyte, macrophage) cells. Acute axon injury, measured by amyloid precursor protein expression, correlates with macrophage and CD8+ T-cell infiltration. In addition, ongoing myelin loss harms axons. It disrupts axon transport, with increased metabolic stress on neurons and axons.[14] The symbiotic relationship between myelin and axon means that demyelination itself is an axon damage mechanism. Loss of myelin also affects ion channel expression on the denuded axon surface.[15] These changes can restore nerve conduction, or produce axon destruction.

    Table 3. Potential Contributors to Axon Damage in MS

    Damage Mechanisms
    •  Direct immune attack

    • - primary

      - secondary
       

    • Indirect (bystander) immune damage

    • - from intrinsic CNS components

      - from extrinsic components
       

    • Loss of myelin

    • - disrupted axonal transport

      - damaging ion channel remodeling

      metabolic stress
       

    • Loss of neurons
    Damage Factors
    •  CD8+ T cells

    •  
    • Macrophages

    •  
    • Antibodies

    • - myelin oligodendrocyte glycoprotein

      - neurofilament components

      - gangliosides
       

    • Neurotoxic factors

    Therapeutic Implications of Axonal Damage

    Because insertion of new sodium channels allows conduction, enhanced or more rapid expression of such channels is a desirable therapeutic goal. By contrast, calcium channels (alpha 1-beta), normally expressed only at the presynaptic axon terminal, may also be inserted into demyelinated membrane. Because the insertion of these channels leads to axon damage (mediated by calcium-dependent proteases called calpains), one would want to prevent their expression. Ion-channel manipulation is likely to be a future therapeutic focus in MS.

    New Insights Into Pathophysiology: Neurons

    Axons are also lost when neurons die. A recent study of brain autopsy material examined the thalamus, a gray matter region rich in neurons. MS brains showed 30% to 35% fewer neurons than control brain tissue.[4] NAA measurements indicate diffuse gray matter disturbances even in patients with early MS. Loss of neurons likely reflects primary damage, from direct and indirect inflammatory injury, as well as secondary neurodegeneration, from a variety of toxic factors (Table 4).

    Table 4. Potential Neurotoxic Factors in MS

    • Proinflammatory cytokines

    •  
    • Excitotoxins

    •  
    • Free radicals

    •  
    • Oxidative and metabolic stress factors

    •  
    • Disturbed extracellular ionic milieu

    •  
    • Immune system cells/immunoglobulins

    The full significance of neuron involvement in MS is unclear, but it could well play a role in cognitive disturbances. The fact that axons and neurons are damaged, with proven correlates to clinical disability and MS disease progression and possible correlates to cognitive loss, highlights their importance as a therapeutic target. Neuroprotective strategies, neurotrophic growth factors, immunomodulatory therapies, cell transplantation, and even gene transfer are future approaches to make neurons and axons less vulnerable to injury; to promote remyelination and axon repair; and to replace lost oligodendrocytes and neurons.

    The Subclinical Nature of MS

    By definition, relapsing MS patients are clinically stable between disease attacks. Previously, scientists and clinicians believed that MS went into remission and that active disease was confined to periods of clinical relapse. Another common belief was that the MS disease process burned out over time. We now know that virtually all patients with MS experience ongoing subclinical disease activity and CNS damage, even when no obvious worsening or changes in the patient's neurologic examination have occurred.

    Frequent MRI studies indicate that 80% to 90% of new brain lesions are not associated with clinical relapse or detectable examination changes.[16] In untreated MS populations, brain lesion burden increases by 5% to 10% each year.[16] Accelerated brain atrophy is present even in early, mild, relapse-free patients with stable Kurtzke Expanded Disability Status Scale (EDSS) scores.[17] Clearly, then, clinical criteria underestimate disease activity.

    With the exception of benign relapsing MS, natural history studies indicate that all untreated patients develop disability. Furthermore, benign MS has never been formally defined and probably involves no more than 5% to 10% of patients.[18] This is a retrospective diagnosis, looking back after several decades of mild disease. In 1 recent study, half of patients diagnosed with benign MS at 10 years had significant disability at 20 years.[19] When MS is viewed as an active, ongoing disease process with accumulating permanent damage to the CNS, the importance of treatment at the earliest recognizable time point becomes even more apparent.

    Neuroimaging and MS: Present and Future

    Not only does clinical observation underestimate the true MS damage process, but so too does the best current clinical MRI analysis. Conventional MRI techniques detect T2 hyperintense lesions (which have little to no pathologic specificity), T1 hypointense lesions (which, when chronic, indicate greater tissue damage and axon loss), and gadolinium contrast-enhancing lesions (indicating a focal major breach of the blood brain barrier and current disease activity). However, unconventional techniques can detect microscopic and physiologic changes in normal-appearing CNS tissue (Table 5).

    Table 5. Neuroimaging Techniques That Detect Abnormalities in Normal-appearing CNS Tissue of MS Patients

    • Magnetic resonance spectroscopy

    •  
    • Magnetic transfer imaging

    •  
    • Diffusion-weighted and diffusion-tensor imaging

    •  
    • Functional MRI

    •  
    • High magnet (>/= 3 Tesla) MRI

    •  
    • Positron emission tomography (PET) scanning

    In brain MRIs of patients with MS, up to 70% of normal-appearing white matter may actually be abnormal. Indeed, tracking changes in normal-appearing tissue may be a sensitive marker for disease severity and response to therapy. In a recent analysis, yearly whole brain NAA changes differentiated early relapsing patients into 3 groups. Approximately 20% of patients had stable NAA levels, 55% showed a modest reduction, and 25% showed a marked reduction in these levels.[8] Presumably those patients with marked reductions in NAA levels, consistent with greater axon damage, have more severe disease, a worse prognosis, and will ultimately develop more rapidly progressing disability.

    Magnetic transfer imaging measures signal changes in fluid and fixed phase molecules within regions of interest. This generates a magnetic transfer ratio (MTR). MTR allows lesion severity to be measured; the lower the MTR, the greater the tissue damage. Such nonconventional neuroimaging techniques are being used in research protocols, but ultimately some will come to routine clinical use.

    Heterogeneity of the Disease

    One final new concept about MS is that it is probably heterogeneous. The disease demonstrates clear clinical variability, based on distinct clinical subtypes and disease severity (Table 6).

    Table 6. MS Clinical Heterogeneity

    Subclinical (asymptomatic) MS
    •  Based on autopsy studies

    •  
    • May account for up to 20% of MS
    Clinical (symptomatic) MS
    •  Relapsing subtype

    • - 85% of MS at onset

      - 55% of MS overall

      - characterized by disease attacks, clinical stability in between
       

    • Primary progressive subtype

    • - 10% of MS

      - Slow worsening from onset

      - Distinctive disease onset features (older age onset, progressive myelopathy, equal gender ratio, no relapses)
       

    • Progressive relapsing subtype

    • - 5% of MS

      - Indistinguishable from primary progressive except for later superimposed relapses
       

    • Secondary progressive subtype

    • - 30% of all MS

      - ultimately 90% of untreated relapsing MS

      - prior relapsing patient who transitions to slow worsening

    There is also genetic heterogeneity, with distinct disease-associated genes based on race. MS also shows heterogeneity based on ability to remyelinate; only 70% of patients experience remyelination of MS plaques. The factors that prevent remyelination in 30% of patients are not known, although studies suggest that the presence of oligodendrocyte precursors, axon integrity, and axon surface molecule expression are important contributors.[20-24] Finally, recent studies suggest immunopathologic heterogeneity. A multinational consortium of neurologists and neuropathologists has studied acute plaque pathology in MS brain tissue samples obtained at biopsy or autopsy.[25] Results of this study reveal 4 distinct immunopathologies (Table 7). These observations await confirmation but, if true, suggest 4 distinct categories of MS based on primary damage mechanisms, and would have profound therapeutic implications.

    Table 7. Heterogeneous MS Brain Plaque Immunopathology
     
    Pattern Frequency Damage Mechanism Animal
    Model
    Oligodendrocyte Numbers Remyelination Clinical Correlations
    I 19% Macrophage
    mediated
    + (myelin-
    induced EAE)
    Preserved + Seen in all MS subtypes
    II 53% Antibody, 
    complement
    mediated
    + (MOG-
    induced EAE)
    Preserved + Neuromyelitis optica, + plasma exchange response
    III 26% Distal dying back oligodendrogliopathy with apoptosis (ischemic, toxic, virus induced) --- --- Balo's concentric sclerosis
    IV 2% Oligodendrocyte degeneration (metabolic defect) --- --- Atypical primary progressive MS

    EAE = experimental allergic/autoimmune encephalomyelitis; MOG = myelin-associated glycoprotein

    Therapy of MS

    The DMTs are expensive, and when trying to optimize cost-effective management of MS, several controversial issues must be confronted (Table 8). The remainder of this clinical update will address these topics and review the rationale for specific recommended approaches.

    Table 8. Current Controversial Topics in the Management of MS
     
    • Should DMT be recommended for all patients with MS?

    •  
    • How early should DMT be started?

    •  
    • How do you select which DMT to use?

    •  
    • How do you determine suboptimal response/treatment failure?

    •  
    • How do you deal with suboptimal response/treatment failure?

    •  
    • What future treatment approaches look promising?

    •  
    • What is the role of steroids for patients with MS?

    Should DMT Be Recommended for All Patients With MS?

    The National MS Society has recently updated its consensus guidelines for use of MS DMT (Table 9).[26] It endorses the use of immunomodulators for all relapsing forms of MS and for consideration of treatment for selected first-attack/high-risk patients. Thus, unless a specific contraindication exists, therapy is appropriate in all relapsing patients, secondary progressive patients with superimposed relapses, progressive relapsing patients, and many first-attack patients. The single exception is benign relapsing MS, which does not need to be treated. However, because benign MS is a strictly retrospective diagnosis, most patients and physicians will choose not to gamble on a benign course and risk missing the benefits of treatment. This approach is predicated on the fact that the immunomodulator DMTs are safe and well tolerated. Contraindications to therapy include pregnancy, attempts to become pregnant, breastfeeding, inability to tolerate DMT, allergy to the drugs or their carriers, and severe comorbidity (such as significant psychiatric disease that makes compliance impossible or risky).

    Table 9. NMSS Disease Management Consensus Statement (NMSS, 2002)[26]
     
    • Initiate immunomodulator treatment as soon as possible following diagnosis of MS with a relapsing course; consider for selected first-attack/high-risk patients.

    •  
    • Access to therapy should not be limited by relapse frequency, age, level of disability, or most medical conditions.

    •  
    • There should be access to/coverage for all FDA-approved agents; it is permissible to change drugs.

    •  
    • Immunosuppressant (mitoxantrone) therapy may be considered for selected worsening and/or relapsing patients.

    •  
    • None of the DMTs are approved for use in women who are pregnant, nursing, or trying to become pregnant.

    •  
    • Treatment should not be stopped while insurers evaluate for continuing coverage.

    •  
    • Therapy continues indefinitely except in the event of

    •  

       

      - clear lack of benefit;

      - intolerable side effects;

      - new data; or

      - better therapy.

    Treatment of Secondary Progressive MS Without Relapse

    Data to support treatment of patients with secondary progressive MS without relapses are mixed. The European study of IFN beta-1b found treatment to be quite effective in patients with secondary progressive MS, with or without relapses.[27] No other study has been as convincingly positive. The International MS Secondary Progressive Avonex Controlled Trial (IMPACT), using double-dose IM IFN beta-1a, documented a treatment effect on progression as measured by the MS functional composite (MSFC) (25-foot timed walk, 9-hole peg test, Paced Auditory Serial Addition Test [PASAT]), but not on the EDSS.[28] However, the only significant effect on the MSFC was in the 9-hole peg test component. Neither the North American IFN beta-1b study nor the SC IFN beta-1a Secondary Progressive Efficacy Clinical Trial of Recombinant IFN beta-1a in MS (SPECTRIMS) trial showed an effect on progression based on EDSS.[29,30]

    Despite the discrepancies in the effect of treatment on EDSS progression, all the trials of treatments for secondary progressive MS have shown benefits in suppressing superimposed relapses, and on MRI (T2 lesion burden, Gd+ lesions) parameters. The only DMT approved for secondary progressive MS in the United States is the immunosuppressor mitoxantrone. Because of concerns about cardiotoxicity, this drug can only be used up to a lifetime maximum of 140 mg/m2 (about 11 doses). The pivotal mitoxantrone in MS (MIMS) trial entered 194 patients who had relapsing and secondary progressive MS with or without relapses, but participants were randomized to 1 of 3 treatment arms,[31] and thus, no statement about statistical significance of treatment is possible with regard to the group of patients with secondary progressive MS without relapses.

    Treatment of Primary Progressive MS

    There is no proven treatment for primary progressive MS. The recent phase 3 trial of glatiramer acetate (GA), the PROMISE trial, did not find a treatment benefit on progression. Although the drug was well tolerated, neither placebo- nor GA-treated patients deteriorated at the rate predicted from natural history studies. Two phase 2 trials of IFN beta in primary progressive MS have proved disappointing; 1 suggested modest benefits on secondary outcomes, the other was almost uniformly negative.[32,33] An ongoing phase 2 trial of mitoxantrone has not yet reported any results.

    Thus, based on available evidence, use of DMT cannot be endorsed for patients with either secondary progressive MS without relapses or those with primary progressive MS, who together may account for 25% of all patients with MS. At the same time, a case can be made for treatment benefit in patients who have secondary progressive MS with Gd+ activity on MRI, who have worsened by greater than 1 EDSS point in the previous 2 years, or who are temporally close to their relapsing phase. In addition, a benefit of DMT, especially over the long term, has not been disproven for primary progressive MS.

    How Early Should DMT Be Started?

    The National MS Society consensus statement endorses consideration of therapy in selected first-attack/high-risk patients. This is based on 2 phase 3 trials, the Controlled High-risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) and Early Treatment Of MS (ETOMS). In both studies, patients randomized to DMT were significantly less likely to experience a second attack or to develop new brain MRI lesions during the study period than if they received placebo treatment.

    CHAMPS enrolled patients between the ages of 18 and 50 years who had a clinically isolated syndrome (unilateral optic neuritis, incomplete transverse myelitis, isolated brainstem/cerebellar syndrome), abnormal brain MRI, and no better diagnosis for their neurologic attack.[34] Brain MRI had to show at least 2 unrelated T2 lesions >/= 3mm in size, at least 1 of which had to be ovoid in shape or periventricular in location (both these lesion features are suggestive of MS). Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or placebo for 18 months. In a recent analysis of the placebo arm of the CHAMPS trial, 2 or more Gd+ lesions at presentation predicted that 52% of patients would experience a second clinical attack within 18 months, 92% would have an attack or demonstrate 2 or more new or enlarging T2 brain lesions, and 96% would have a clinical attack or at least 1 new or enlarging MRI lesion.[35] The presence of >/= 2 Gd+ lesions was the best predictive marker for development of clinically definite MS.

    The ETOMS study entered 308 first-attack patients, ages 18 to 40 years, with unifocal or multifocal (39%) CNS presentations and abnormal brain MRI.[36] The MRI was required to show 4 T2 white matter lesions, or 3 T2 white matter lesions if 1 was enhancing or infratentorial. Patients were assigned to receive IFN beta-1a 22 mcg SC weekly or placebo, and were followed for 2 years. In both the CHAMPS and ETOMS studies, conversion to clinically definite MS (a second relapse) within the next 18 to 24 months occurred significantly less frequently in the IFN beta-treated groups.

    The number of new/enlarging MRI lesions and lesion burden were also significantly less with treatment. In the ETOMS study, which used a very low dose of IFN beta-1a, 84% of treated patients had either a clinical relapse or new MRI lesions, as did 94% of those who received placebo. Patients with a multifocal presentation experienced an approximately 2-fold higher conversion to clinically definite MS. ETOMS suggests that MS is easier to treat early, since the dose of SC IFN beta-1a used in that trial failed to treat established relapsing MS in the Once Weekly Interferon for MS (OWIMS) trial.[37] In view of these data, which support therapy as soon as possible in the disease process, it would seem prudent to treat first-attack patients who fall into a high-risk group for MS. CHAMPS had the least stringent MRI entry requirements, yet was quite successful in identifying first-attack MS patients. Suggested criteria for offering DMT to first-attack patients are outlined in Table 10.

    Table 10. Proposed Criteria for Treatment of First-attack/High-risk Patients
     
    • Appropriate age

    • - 10 to 50 years
       

    • Suggestive clinical syndrome

    • - Unilateral optic neuritis with pain and without macular abnormality

      - Incomplete transverse myelitis

      - Isolated brainstem/cerebellar syndrome (eg, internuclear ophthalmoplegia, trigeminal neuralgia)

      - Paroxysmal attacks

      - Lhermitte sign

      - Multifocal white matter syndrome (not suggestive of acute disseminated encephalomyelitis)
       

    • Abnormal brain MRI*

    • - Lesions unrelated to clinical attack

      - Lesions >/= 3 mm

      - >/= 2 contrast lesions, or >/= 2 T2 lesions (1 periventricular or ovoid)
       

    • Other diagnoses ruled out
    *Minimal MRI criteria are adapted from the CHAMPS study.

    T2 MRI has a very high sensitivity for detecting tissue changes, and many disorders can produce brain MRI lesions. However, there are recognized lesion features that have high predictive value for MS (Table 11; Figure). These can be used to increase confidence of the MS diagnosis.

    Figure 1. MRI changes in multiple sclerosis. This composite shows some of the changes captured by serial MRI that are characteristic of the dynamic nature of the underlying pathologic disease activity in multiple sclerosis. The patient was evaluated serially by high-resolution MRI, and the images were quantified automatically. The patient had no clinically defined change in his neurologic symptoms or findings during this 7-month interval despite the significant activity demonstrated by MRI. Source: Lindsey JW, Wolinsky, JS. Section IX: Demyelinating Diseases. Chapter 11: Neurology. In: Dale DC, Federman DD, eds.WebMD Scientific American® Medicine Online. New York, NY: WebMD Corp; 2001. Reproduced with permission of publisher.

    Table 11. Brain MRI Features That Increase Likelihood of Further Disease
     
    • High number of T2 lesions

    •  
    • High volume of T2 lesions

    •  
    • Gd+ lesions

    •  
    • Juxtacortical, infratentorial, corpus callosum lesions

    •  
    • Large T2 lesions

    In summary, immunomodulator DMT should be initiated as soon as there is a confident diagnosis of a relapsing form of MS. It can also be offered to first-attack/high-risk patients who meet criteria that indicate high likelihood of MS (Table 10).

    How Do You Select the Appropriate Disease-modifying Therapy?

    It is not appropriate to let patients choose their DMT in isolation. Multiple factors must be considered, and the treating neurologist should provide an informed perspective and guide the optimal choice (Table 12).

    Table 12. Factors in Choosing an Immunomodulator DMT
     
    • MS Factors

    • - Clinical subtype

      - Disease duration

      - Prognostic profile

      - Clinical disease severity (relapse rate, type of relapse, extent of
      recovery, disability)

      - MRI disease severity
       

    • Patient Factors

    • - Comorbidity

      - Lifestyle preferences

      - History of drug tolerance

      - Ability to inject

      - Compliance
       

    • Drug Factors

    • - Efficacy

      - Side-effect profile

      - Convenience

      - Expense

      - Route of delivery

    Disease/Patient Factors

    Disease considerations involved in the choice of treatment include clinical subtype, duration of MS, prognostic profile, and a variety of disease severity measures. Although the formal trials in first-attack patients were carried out with IFN beta-1a, it is reasonable to conclude that any immunomodulator that works for patients with relapsing MS will work for first-attack patients.

    Clinical disease severity is measured by relapse criteria, including number, severity (motor, cerebellar, and sphincter involvement indicate a more severe attack), and degree of recovery, and by development of disability/progression. More severe clinical disease clearly warrants more effective DMT. When seen early in relapsing MS, certain factors suggest a more rapid onset of progressive disease and disability (Table 13). The patient's prognostic profile is also an important factor when choosing therapy. Patient-specific factors include comorbidity (psychiatric disorders, hepatic disease, psoriasis), which may influence choice of drug, as well as practical issues such as ability to self-inject or availability of a partner to do so (Table 13).

    Table 13. Factors Indicating Worse Prognosis in Relapsing MS
     
    • Early high relapse rate

    • - > 2 in yr 1
       

    • Late  in relapse rate

    •  
    • Poor relapse recovery

    • - EDSS >/= 3 by yr 3

      - moderate pyramidal involvement 
       

    • IgG index (> 1.0) at diagnosis 

    •  
    • Late age at onset

    •  
    • EDSS > 3.5 

    •  
    • Polyregional onset

    • - especially sphincter, motor involvement
       

    • Sphincter, motor relapses

    Drug Factors

    Among drug factors, efficacy and side-effect profile are probably the 2 most important considerations. Good data now exist to show that the 3 IFN beta DMTs are not equally effective. Two randomized, prospective, multicenter phase 3 trials have compared the different IFN betas head-to-head. The Independent Comparison of Interferon (INCOMIN) study was funded by the Italian government and the Italian MS Society.[38] The 2-year study enrolled 188 patients with mild (EDSS 1.0-3.5) active relapsing disease. Patients were randomized to receive IFN beta-1a 30 mcg IM once weekly or IFN beta-1b 8 MIU SC every other day. At the end of 2 years, the group receiving IFN beta-1b included a higher proportion of relapse-free patients (51% vs 36%, P = .035), fewer patients with sustained EDSS worsening (14% vs 30%, P = .04), and a greater proportion of patients with no new T2 lesion activity on brain MRI (55% vs 26%, P = .0003) compared with the IFN beta-1a group. Although treating physicians and patients were not blinded, MRIs were read blinded at a central site.

    The European-North American Comparative Efficacy (EVIDENCE) study was funded by Serono, the makers of the SC formulation of IFN beta-1a.[39]This 48-week study entered 677 patients with active relapsing MS. Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or IFN beta-1a 44 mcg SC 3 times weekly. Participants underwent monthly MRI scans for 24 weeks, then a final scan at 48 weeks. The critical primary and secondary outcomes, judged at 24 weeks, were proportion of relapse-free patients and combined unique MRI lesions (Gd+ plus T2 lesions, not double counted). Although patients and treating physicians were aware of their therapy, evaluating physicians (who judged relapses) were blinded, and MRIs were read blinded at a central site.

    At 24 weeks, the proportion of relapse-free patients was higher in the SC IFN beta-1a compared with the IM regimen arm (75% vs 63%, P = .0005), and combined unique MRI lesions were fewer compared with the IM arm (0.8 vs 1.2, P < .0001). In addition, the group receiving the higher, more frequent IFN beta-1a dose experienced a lower relapse rate (P = .022), fewer treated relapses (P = .004), longer time to relapse (P = .001), lower rate of active MRI scans (P < .0001), and included more patients without any MRI activity (P < .0001).

    The 48-week data continued to show a statistically significant difference in favor of the higher, more frequent dose regimen of IFN beta-1a. The proportion of relapse-free patients was 62% vs 52% (P = .009) in the SC vs IM dose regimen, and the number of mean T2 active lesions was lower (0.9 vs 1.4, P < .001), as were proportions of active scans per patient (27% vs 43%, P < .001). The higher, more frequent regimen group was also more likely to have shown no MRI activity (63% vs 45%, P < .001).

    In summary, these randomized, prospective comparison trials indicate that, for a broad spectrum of patients with MS, IFN beta has greater efficacy when it is given several times a week (vs once a week) and at higher doses. This is consistent with data showing that a sustained level of IFN beta (with a greater area under the curve drug concentration) is better than brief periods of IFN beta exposure. Dosing frequency may be more important than dosing amount, since a recent study of IM IFN beta-1a given at 30 vs 60 mcg once a week showed similar clinical and MRI effects for both dosing schedules.[40]

    Side effects are another important factor in drug selection. Among the DMTs, GA has the best side-effect profile. Since this DMT also has good long-term efficacy data, it is an attractive choice when overall tolerability is a major issue.

    How Do You Determine Suboptimal Response/Treatment Failure?

    Response to DMT spans a wide spectrum. Patients may be super responders, partial responders, or even biologic nonresponders. Response may also change over time. Criteria used to judge poor treatment outcome include clinical and MRI criteria (Table 14).

    Table 14. Criteria to Determine Suboptimal Response/Treatment Failure
     
    • Clinical Criteria

    • - Intolerable side effects

      - Relapse rate
       

      • failure to show  relapse rate

      •  
      • of < 33%

      •  
      • > 1 mild relapse/yr

      •  
      - Transition from relapsing to SP MS

      - Progression rate on therapy is unchanged or accelerated
       

    • MRI Criteria

    • - Gd+ lesion activity continues unchanged, only mildly , or  (high-dose IFN beta suppresses by 70% to 90%, low-dose IFN beta by 50%, GA by 35%)

      T2, T1 burden of disease

      - Marked  in CNS atrophy

    In general, patients doing well on DMT should show little disease activity, as measured by relapses or disease progression. Patients should be receiving drug for a finite period of time (generally 6 months) before judging therapeutic response. The most valuable laboratory assessment for evaluating suboptimal response is contrast brain MRI. Although the value of a single MRI scan has been questioned, a recent expert consensus group of neurologists and neuroradiologists endorsed performing MRI on patients with MS who were receiving treatment but in whom there was a concern about response to therapy.[41]

    The role of neutralizing antibodies (NAbs) to IFNbeta and judging treatment response is unclear. To date, there is no agreed upon assay, cutoff value, or recommended time frame to evaluate NAbs. Although persistently high levels probably interfere with the drug's efficacy in most patients, this is not an absolute. The recent National MS Society Consensus Guidelines did not endorse changing therapy for patients with elevated levels of NAb who were otherwise doing well.[26]

    How Do You Approach Suboptimal Response/Treatment Failure?

    There are several options when a patient on DMT is not responding appropriately (Table 15).

    Table 15. Treatment Options When Faced With a DMT Poor Responder
    • Increase IFN beta dose, frequency

    •  
    • Change class of DMT

    •  
    • Administer intensive induction therapy, with temporary discontinuation of DMT

    •  
    • Administer combination therapy

    •  
    • Discontinue therapy

    The comparison IFN beta trials support the concept that suboptimal responders on once-weekly IFN beta can be switched to greater efficacy IFN beta regimens, either IFN beta-1a 44 mcg SC thrice weekly or IFN beta-1b 8 MIU SC every other day.

    With any drug treatment, there are patients who are biologic nonresponders. In this situation, it is reasonable to consider a switch in the class of immunomodulator, for example, from IFN beta to GA, or vice versa. Characteristically, a biologic nonresponder experiences no period of therapeutic response, as opposed to responding for a period of time and then showing breakthrough disease activity.

    Induction Therapy

    Induction therapy is appealing in the presence of rapid deterioration despite reasonable immunomodulator therapy. There is precedent for a short course of immunosuppression to restore the patient's response to the primary DMT. For patients with rapid deterioration despite therapy with an effective DMT, it may be reasonable to temporarily discontinue the drug and treat with several months of IV mitoxantrone or cyclophosphamide. After a period of time (6 months or more), as soon as the disease process is controlled, the immunomodulator can be resumed.

    The abnormal immunologic cascade in MS involves multiple levels, with multiple potential damage factors. Small-scale studies suggest that patients who are failing monotherapy may respond to combination therapy. There are a number of proposed combination treatments for MS (Table 16), all of which await large-scale clinical trials to compare their efficacy and safety against the existing single-drug regimens.

    Table 16. Proposed Combination Therapies for MS
     
    • IFN beta + GA

    •  
    • DMT + immunosuppressive

    • - oral (azathioprine, methotrexate)

      - IV (cyclophosphamide, mitoxantrone)
       

    • DMT + pulse therapy

    • - glucocorticoids

      - intravenous immune globulin

      - anti-adhesion molecule monoclonal antibody
       

    • DMT + adjuvant/neuroprotective agent

    Which Treatments Look Promising?

    Table 17 lists a select group of recently proposed novel therapeutic approaches to MS.

    Table 17. Potential MS Therapies
     
    • Natalizumab

    •  
    • Bone marrow transplantation

    •  
    • Statins

    •  
    • Minocycline

    •  
    • Sex hormones (estriol, progesterone, testosterone patch)

    •  
    • Peroxisome proliferation-activated receptor ligands

    •  
    • Antiglutamate agents

    •  
    • CNS repair strategies

    • - neurotrophins

      - cell transplantation

      - immune modulation

      - gene transfer

      - modulation of axonal signals/molecule expression

    Natalizumab

    Natalizumab, a humanized monoclonal antibody directed against alpha 4 integrins, blocks lymphocyte binding to endothelium and cell migration into the CNS. There are 2 ongoing phase 3 trials in relapsing MS. One of these is a 2-year monotherapy study evaluating monthly IV infusions of natalizumab vs placebo. The other is a 2-year combination therapy study evaluating IV natalizumab with weekly IM IFN beta-1a. These studies are based on a multicenter phase 2 trial of 213 patients with relapsing or secondary progressive MS. The 3-arm study involved monthly IV placebo, or monthly natalizumab at doses of 3 mg/kg or 6 mg/kg[42] for a duration of only 6 months. The mean number of new contrast brain MRI lesions was 9.6 in the placebo group, compared with 1.1 in the higher-dose and 0.7 lesions in the lower-dose treatment arms. Placebo patients experienced 27 relapses, compared with 14 in the higher-dose and 13 in the lower-dose natalizumab arms.

    Bone Marrow Transplantation

    At least 3 different groups are evaluating bone marrow transplantation to treat severe MS. Radiation and chemotherapy are used to ablate the host immune system, and then stem cells are infused to reconstitute a new healthy immune system. To minimize morbidity and mortality rates, autologous stem cells from the MS patient are harvested before treatment and later infused back. Although in theory allogenic healthy control stem cells are preferable, they involve the risk of graft vs host disease, with greater morbidity and mortality. Even autologous bone marrow transplantation carries a risk of death. To be considered successful, transplantation will have to stabilize patients for very prolonged periods and provide much better results than intensive drug immunosuppression.

    Statins

    Statins are oral lipid-lowering agents with pleiotropic immunomodulatory actions. They inhibit MHC class II expression and costimulatory molecule expression and affect T-cell regulation. Atorvastatin reduced disease severity, and even prevented disease, in 3 different models of relapsing or progressive experimental allergic/autoimmune encephalomyelitis (EAE), an animal model of MS.[43] A small safety study of simvastatin in relapsing MS has just been completed, and results should be reported at the American Academy of Neurology meeting in April 2003. If proven beneficial, statins would be a convenient oral add-on therapy.

    Minocycline

    Another attractive, well-tolerated oral agent is minocycline. This oxytetracycline also has a number of immune effects that would be expected to benefit MS, including inhibition of matrix metalloproteinases, inducible nitric oxide synthase, caspases, tumor necrosis factor, and microglial activation, as well as induction of T helper 1 to T helper 2 immune deviation. Minocycline treatment lessens clinical and pathologic severity of EAE, with less CNS inflammation, demyelination, and microglial activation.[44] Preliminary studies are ongoing in relapsing MS.

    Sex Hormones

    Sex hormones are another novel treatment strategy. The most studied in connection with MS are the estrogens. In a single-center safety trial, oral estriol at 8 mg daily was well tolerated (menstrual cycle disruption was the only notable side effect) and appeared to benefit 6 women with relapsing MS. While on treatment, they showed reduced numbers and volume of contrast brain MRI lesions and stable T2 lesion volume. When taken off treatment, MRI activity increased, only to decrease again when estriol was reinstituted.[45] A phase 2 multicenter trial is planned.

    PPAR Ligands

    Peroxisome proliferation-activated receptors (PPARs) are nuclear hormone receptors that regulate adipocyte differentiation and gene transcription. There are alpha, delta, and gamma isotypes. Oral PPAR ligands are being evaluated for treatment of diabetes. These drugs have multiple actions, including anti-inflammatory microglial effects, inhibition of T-cell activation and proliferation, and enhancement of myelin gene expression.[46] The PPAR ligand pioglitazone, as well as other PPAR ligands, have been shown to prevent or reduce severity of EAE.

    Glutamate Receptor Antagonists

    A number of studies suggest that glutamate excitotoxicity is a damage mechanism in MS.[47] In a recent report, riluzole treatment decreased development of cervical spinal cord atrophy and brain T1 hypointense lesions in patients with primary progressive MS.[48] Riluzole and other glutamate receptor antagonists may have a role in treating MS, but further studies are needed to confirm this role.

    CNS Repair

    CNS repair strategies are growing as a therapeutic focus, because they can theoretically restore function and improve fixed damage. As noted, many approaches are under development. One approach is to use neurotrophic factors to boost remyelination, preserve or restore neurons and oligodendrocytes, and protect or regenerate axons. Both ciliary neurotrophic factor and leukemia inhibitory factor can alleviate EAE. They may be helpful to promote oligodendrocyte survival in patients with MS.

    What Is the Role of Steroids in MS?

    Glucocorticoids, most commonly methylprednisolone or prednisone, are typically used for symptomatic treatment of MS relapses. They are said to potentially shorten the time to recovery, but not ultimately change the degree of recovery. Glucocorticoids are not considered DMTs. Rather, they produce a number of beneficial anti-edema and anti-inflammatory effects, including temporarily decreasing blood brain barrier permeability and shutting off production of pro-inflammatory cytokines and other inflammatory and potentially damaging substances.

    Recent studies suggest that glucocorticoids may have an impact on the MS disease process. In a single-center phase 2 trial, patients with relapsing MS were randomized to either receive regular pulses of intravenous steroids or only be treated at the time of relapse. At 5 years, the pulse steroid-treated patients showed less disability, brain atrophy, and T1 brain lesion load compared with those in the control group, who received steroids only for acute relapses.[49] Another small study evaluated brain lesions detected on monthly MRI scans of 4 patients with relapsing MS. Lesions showed the least permanent tissue damage (as measured by magnetic transfer ratio) when patients were treated with steroids.[50] The greatest tissue damage was noted in untreated lesions, while moderate damage was noted in lesions that occurred in IFN beta-treated patients. However, because complications involved with long-term steroid use may be significant, the role of steroids in management of MS needs further study, in terms of both safety and efficacy.

    Summary

    Fundamental changes in our understanding of MS are refining treatment approaches. Current emphasis involves early use of DMT and use of logical combination strategies when the response to monotherapy is suboptimal. Future emphasis will involve axon/neuron strategies, novel therapies, and effective repair mechanisms.

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    Disclosure:

    Patricia K. Coyle, MD, has disclosed that she has received grants for clinical research, served as advisor or consultant and is a member of the Speaker's Bureau for Serono, Teva, Berlex, and Immunex. Dr. Coyle has also received grants for educational activities from Serono. Dr Coyle discusses the following investigational modalities: natalizumab, bone marrow transplantation, statins, minocycline, sex hormones, peroxisome proliferation-activated receptor ligands, antiglutamate agents, CNS repair strategies and steroids in the treatment of multiple sclerosis.
     

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