eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Multiple Sclerosis: Treatment & Medication

Author: Fernando Dangond, MD, Senior Director of Medical Affairs, Neurology, EMD Serono, Inc
Contributor Information and Disclosures

Updated: Sep 11, 2009

Treatment

Medical Care

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

• Patients with more advanced forms of the disease who have lost all family support, are separated from their spouses, require constant psychiatric and nursing assistance, and are unable to walk are not rare. These patients create a challenge for the physician who is not trained in handling these demanding (administrative or ancillary) aspects of medical care. A social worker specialist can be instrumental in helping address these issues.
• The physician should not underestimate the impact of fatigue symptoms on the patient's daily activities. Treatment with amantadine (Symmetrel) or modafinil (Provigil) is often attempted when no contraindications exist. Pemoline, a drug that was gaining attention by MS clinicians for the treatment of fatigue is no longer being used due to reports of rare fatal liver damage events during its use. The United States Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all companies that produced generic versions of pemoline also agreed to stop sales and marketing of pemoline.
• Patients who have progressed beyond EDSS scores of 5.5-6 tend to respond poorly to the current treatments.
  • The impact of this disease on quality of life is reflected in the high suicide rate (7.5 times higher than in the general population). As already stated, however, reactive depression by itself does not fully account for this higher suicide incidence. Many believe that the accumulation of lesions in the brain eventually has an impact on mood.
  • Thus, preventing disease progression by using available medications is imperative in MS treatment, especially for patients who have been diagnosed early and probably will respond to treatment.
• Prevent relapses or disease progression by using the ABCR immunomodulatory drugs (ie, interferon beta-1a IM [Avonex], interferon beta-1b SC [Betaseron], glatiramer acetate SC [Copaxone], or interferon beta-1a SC [Rebif]). These 4 medications have been approved by the FDA and are currently used widely in the United States for MS. As a rule of thumb, the ABCR medications tend to decrease the rate of MS relapses by approximately one third, with the highest efficacy demonstrated in clinical trials for the high-dose, high-frequency (HDHF) beta interferons (ie, Betaseron [34%], Rebif [33%], Copaxone [29%]). In contrast, low-dose, low-frequency (LDLF) beta interferon (Avonex) decreased relapse rate by only 18%. However, trial comparisons do not necessarily reflect true differences and, therefore, head-to-head trials are carried out to answer questions on relative efficacy.
• Evidence for clinical superiority of HDHF to LDLF beta interferons has been provided by 2 head-to-head clinical trials (see INCOMIN and EVIDENCE below). Recent head-to-head trials failed to show superiority of HDHF interferons (Betaseron in the BEYOND study and Rebif in the REGARD study) to Copaxone in reducing relapse rates, although HDHF interferons better helped some MRI measures in these trials. The BECOME study, which also compared HDHF Betaseron with Copaxone, showed no significant difference in the primary outcome (an MRI-based outcome consisting of reduction in combined unique active lesions) and showed no difference in relapse reduction by these 2 agents, but showed superiority of HDHF in other MRI measures (ie, reduction in black holes).
  
  The long-term significance of the differences seen in MRI measures on these head-to-head trials (BEYOND, REGARD, and BECOME) remains unclear. Controversy also exists regarding the impact on the statistical power of such few on-drug relapse rates experienced by the cohorts entering these studies (particularly REGARD), compared with the higher on-drug relapse rates seen in the pivotal MS studies. Other compounds approved by the FDA for use in MS include mitoxantrone (Novantrone) and natalizumab (Tysabri). Tysabri showed a reduction in relapse rate of 67% and slowing in disability progression of 42%.¹⁴ These drugs carry black box warnings on their label but are not necessarily contraindicated in patients with MS who are naive to therapy (see Medication section for details).
• Interferon beta-1b (Betaseron) at 8 MIU SC every other day was shown in a 2-year, double-blind, placebo-controlled trial of 372 patients with RRMS to decrease the frequency of relapses from 1.27 per year to 0.84 per year, a 34% reduction in the relapse rate compared with placebo.¹⁵ Five-year follow-up data show that disease progression rate was 35% in the interferon beta-1b group and 46% in the placebo group. A 30% decrease in the yearly exacerbation rate in the treated group over 5 years also was demonstrated. While the placebo group had a median MRI lesion burden of 30.2% over 5 years, no significant increase (3.6%) was detected in the patients treated with interferon beta-1b.¹⁶ Interferon beta-1b was found to delay disability in European patients with SPMS.¹⁷ However, these results on disability were not replicated in a study on North American patients with SPMS. At the time of this report, Betaseron was not approved by the FDA for slowing disability progression.
• Interferon beta-1a (Avonex) was studied in a double-blind placebo-controlled study in 301 patients with RRMS receiving weekly intramuscular (IM) injections of 6 million units (30 mcg). Over 2 years, the annual exacerbation (ie, relapse) rate was 0.90 in the placebo group and 0.61 in the Avonex-treated group, a 29% reduction. At 2 years, the mean MRI lesion volume was 122.4 in the placebo group and 74.1 in the Avonex-treated group. The mean number of MRI enhancing lesions over 2 years was 1.65 in the placebo group and 0.80 in the Avonex-treated group. By the end of 104 weeks, the proportion of patients progressing was 34.9% in the placebo group and 21.9% in the Avonex group.¹⁸
• Interferon beta-1a (Rebif) was evaluated in a randomized, double-blind, placebo-controlled study in patients with MS for at least a year and EDSS scores ranging from 0 to 5. Patients received SC injections of placebo, Rebif 22 mcg, or Rebif 44 mcg 3 times per week (tiw) for 2 years. Rebif significantly reduced the number of clinical exacerbations (the primary endpoint) and the number and area of brain active lesions by MRI. Rebif-treated patients also had a significantly longer time to reach sustained disability progression than placebo-treated patients.
• Controversy has also existed regarding the eventual clinical impact of raising the dose of these medications to higher or maximally tolerated levels—a study (BEYOND trial) failed to show superiority of Betaseron 500 mcg to both Betaseron 250 mcg (currently approved dose) and Copaxone in reducing relapses.
• Other head-to-head studies have directly addressed the issue of clinical and MRI superiority of HDHF beta-interferons (Betaseron and Rebif) to LDLF beta-interferon (Avonex). The INCOMIN trial, which compared the effects of interferon beta-1b (Betaseron) administered subcutaneously and interferon beta-1a (Avonex) administered intramuscularly, suggested that higher and more frequent doses delivered by Betaseron correlate with higher (clinical and MRI) efficacy.¹⁹ The EVIDENCE trial, which compared interferon beta-1a SC (Rebif) to interferon beta-1a IM, also found that higher dosing and more frequent administration led to higher (clinical and MRI) efficacy.²⁰ Studies of combinations of beta interferons with other drugs such as glatiramer acetate are also underway.
• Glatiramer acetate (Copaxone) showed positive effects in a large randomized double-blind trial in 251 patients with RRMS. Patients on Copaxone had a 2-year relapse rate of 1.19, while patients on placebo had a rate of 1.68. The relapse rate reduction was 29% over 2 years for patients on Copaxone.²¹ Extension data show that over 140 weeks, 21.6% of patients treated with Copaxone worsened, while 41% of those on placebo worsened.²² Results of an 18-month study examining the impact of Copaxone on MRI outcome show a 35% reduction in the number of new T2 lesions.
• The safety and efficacy of mitoxantrone (Novantrone) was evaluated in 2 multicenter, randomized clinical trials.
  • Study 1 was conducted in patients with SPMS or RPMS. These patients had experienced a mean deterioration of the EDSS of about 1.6 points over the 18 months prior to study entry. Patients on mitoxantrone had a mean change in the EDSS of -0.13 compared with placebo (0.23), an ambulation index mean change of 0.30 (placebo, 0.77), and a mean number of relapses requiring steroids of 0.40 (placebo, 1.20). The number of patients with new gadolinium-enhancing lesions on mitoxantrone was 0 out of 31, compared with placebo (5 [16%] of 32).
  • Study 2 lasted 6 months and evaluated mitoxantrone in combination with methylprednisolone in patients with SPMS or worsening RRMS. The average deterioration in EDSS was 2.2 points in the previous 12 months. Of patients who only received methylprednisolone in this study, 31% were without new gadolinium-enhancing lesions versus patients on mitoxantrone plus methylprednisolone (90% without new gadolinium-enhancing lesions) (primary endpoint of the study). The annualized relapse rate was 3 for methylprednisolone patients and 0.7 for methylprednisolone plus mitoxantrone patients. The percentage of patients without relapses was 33% for the methylprednisolone group and 67% for the methylprednisolone-mitoxantrone combination.
• Two large studies assessing the efficacy of natalizumab (Tysabri) have been conducted.
  • Study 1, Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM), was a randomized, placebo-controlled trial in RRMS patients. Patients were randomized to receive natalizumab (n = 627) or placebo (n = 315). The primary endpoints were the rate of clinical relapse at 1 year and the rate of sustained EDSS progression at 2 years. Natalizumab reduced the rate of clinical relapse at 1 year by 68%. The cumulative probability of progression was 17% in the natalizumab patient group versus 29% in the placebo group. Natalizumab also showed MRI efficacy, demonstrating a reduction in the accumulation of new or enlarging T2 lesions by 83% over 2 years and a 92% reduction in number of gadolinium-enhancing lesions in the natalizumab group at 1 and 2 years.¹⁴
    
    A retrospective, post-hoc analysis of the AFFIRM trial has shown that over 2 years, natalizumab treatment was associated with a 37% proportion of patients with relapsing MS who were free of combined (MRI and clinical) disease activity, compared with 7% for the placebo group (p<0.0001). In this analysis, absence of MRI disease activity was defined as no gadolinium-enhancing lesions and no new or enlarging T2 hyperintense lesions in MRI; absence of clinical disease activity was defined as no relapses and no sustained disability progression.²³
  • Study 2, Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL), evaluated patients on Avonex and placebo (n = 582) versus Avonex and natalizumab (n = 589). The primary endpoints were the rate of clinical relapse at 1 year and the cumulative probability of sustained EDSS progression at 2 years. The patient group on Avonex plus natalizumab had a 24% reduction in the relative risk of sustained EDSS progression and a lower annualized relapse rate (0.34) versus Avonex plus placebo (0.75). As shown in study 1, fewer new or enlarging T2 lesions developed in the Avonex plus natalizumab group (0.9) than in the Avonex plus placebo group (5.4).
• Four studies have examined the efficacy of ABCR drugs in reducing conversion of clinically isolated syndrome (CIS) to clinically definite MS (CDMS): Interferon beta-1a was shown by the CHAMPS trial¹⁸ (for Avonex, given as 30 mcg IM once a week) and ETOMS trial (for Rebif, given as 22 mcg SC once a week) to delay the onset of CDMS in patients with CIS, when compared with placebo. The BENEFIT trial (for Betaseron) demonstrated the efficacy of Betaseron in reducing conversion from CIS to CDMS and to McDonald MS (ie, using MRI-based criteria). The PRECISE trial (for Copaxone) also showed that this drug is efficacious in reducing conversion to CDMS in patients with CIS.
• Considerable controversy exists regarding whether the delay in onset of new attacks by these drugs ultimately has a long-term impact on neurodegeneration and disability; these issues need to be addressed in future trials.
• Acute exacerbations
  • No highly effective treatment is currently available to counteract MS attacks after their onset. The most widely used treatment is intravenous (IV) methylprednisolone, 1 g IV qd for 3-5 days. This medication may help expedite the timing of recovery but will not affect the actual degree of recovery.
  • High-dose IV steroids may work more effectively than oral steroids for the acute attack, and home IV therapy is recommended if the patient does not require hospitalization. Alternatively, high-dose oral methylprednisolone should be used, when feasible.
• Secondary progressive forms
  • Patients with SPMS who are still experiencing relapses may be treated with Betaseron, especially when the clinical course reflects an early phase of progression (EDSS score <6).
  • Mitoxantrone is approved in North America and Europe for use in patients with MS. Patients on mitoxantrone need to be monitored with echocardiograms prior to and during treatment, as the drug carries a risk of cardiomyopathy (the drug carries a black box warning regarding this potential toxicity). Because of this risk, mitoxantrone is typically reserved for patients with aggressive clinical presentations of MS (ie, worsening MS) or in whom immunomodulatory drug therapy has failed.
  • Head-to-head studies are underway to compare the efficacy of mitoxantrone versus cyclophosphamide (Cytoxan) in large numbers of patients. When studied individually in adult populations, mitoxantrone seems effective for all age ranges tested. The data on cyclophosphamide, in contrast, indicate that the benefits of this drug may be restricted to male patients younger than 40 years. Controversy exists whether patients with dramatic and rapid progression of disease (regardless of the type and timing of MS) should be treated earlier with immunosuppressive agents to try and arrest the ongoing inflammatory cascade. Cytoxan is not approved by the FDA for use in MS.
  • Azathioprine and methotrexate have also been used as immunosuppressive oral treatments for MS, but these drugs should not substitute for ABCR drugs as first-line agents in newly diagnosed RRMS. They are not FDA indicated for MS. They are considered less suppressive than mitoxantrone or cyclophosphamide and are being considered increasingly as potential combination partners for the ABCR drugs.

Surgical Care

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

Consultations

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

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

Diet

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

Activity

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

Medication

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

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

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

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

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

Briefly, treatments of choice include the following:

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

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

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

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

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

Immunomodulators

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

Interferon beta-1a (Avonex, Rebif)

Indicated for treatment of patients with relapsing forms of MS to slow the accumulation of physical disability and to decrease the frequency of clinical exacerbations. Patients with MS in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with MS. Safety and efficacy in patients with chronic progressive MS have not been established. Believed to act via ability to counteract cell surface expression of proinflammatory or pro-adhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. Differs from interferon beta-1b (Betaseron, see below) only in that it has amino acid sequence identical to that of natural compound and is glycosylated. Presence of glycosylation is claimed to lead to structural stability and presumably to higher biological potency.
Interferons act through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, leads to activation of interferon-responsive genes. Interferon beta may decrease expression of B7-1 (a proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory molecule) in circulation of patients with MS. Interferon beta-1a is the only ABCR drug administered on a weekly schedule.
Frequency of development of neutralizing antibodies against interferon is higher with interferon beta-1b than with interferon beta-1a, but long-lasting clinical effects of neutralizing antibodies are still unclear and controversial.
Shown to delay relapses in patients who have only manifested one clinical attack but have MRI evidence of MS.

Interferon beta-1b (Betaseron in US, Betaferon in Europe)

Indicated for treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. Efficacy has been demonstrated in patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Acts via ability to counteract cell surface expression of proinflammatory or pro-adhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action. May decrease expression of B7-1 (proinflammatory molecule) on surface of immune cells and increase levels of TGF-beta (anti-inflammatory) in circulation of patients with MS.
Acts through common receptor that activates Jak/Stat pathway of signal transduction molecules, which, in turn, leads to activation of interferon-responsive genes.
Frequency of development of neutralizing antibodies against interferon is higher with interferon beta-1b than with interferon beta-1a, but interferon beta-1b nAbs disappear faster. The long-term clinical significance of nAbs is still unclear and controversial.

Glatiramer acetate (Copaxone)

Mix of amino acids proposed to mimic myelin proteins when presented on surface of antigen-presenting cells. Copaxone is indicated for reduction of the frequency of relapses in patients with RRMS. In theory, lymphocytes reactive against CNS myelin would be diverted to bind to Copaxone in circulation, thus decreasing entry of immune cells across blood-brain barrier. Most mechanisms of action, however, remain unknown, and wider effect on immune system responsiveness may be at play. Has safest systemic side effect profile of ABCRs.

Natalizumab (Tysabri)

Three cases of progressive multifocal leukoencephalopathy (PML) associated with natalizumab use prompted temporary withdrawal from the market in 2005. Natalizumab was later reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as TOUCH.
The drug now carries a package insert black box warning about potential risks of opportunistic infections. Patients, physicians, and pharmacists must be involved in the TOUCH program in order to receive, prescribe, or dispense (respectively) natalizumab. Indicated as monotherapy for MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Not to be used with other immune system-modifying drugs. Because Tysabri increases risk of PML, it is now generally recommended for patients who have had an inadequate response to, or are unable to tolerate an alternate MS therapy. The safety and efficacy of Tysabri beyond two years are unknown. Additional cases of PML, some of which occurred during monotherapy with Tysabri, have been reported after Tysabri re-introduction into the market.
Recombinant humanized IgG4-_1C monoclonal antibody produced in murine
myeloma cells. Binds to alpha-4 subunits of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on leukocyte surface, which inhibits alpha-4-mediated leukocyte adhesion to their receptors. Clinical effect in MS may be secondary to blocking interaction of alpha-4-beta-1 expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal brain cells. Indicated for relapsing MS and to reduce symptom exacerbation frequency.
There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate Tysabri clearance in a study of 12 patients, although in the majority of patients, alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. There is no evidence that plasma exchange has any benefit in the treatment of opportunistic infections such as PML.

Corticosteroids

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

Methylprednisolone (Solu-Medrol, Depo-Medrol)

For treatment of inflammatory and autoimmune reactions. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. Also may alter expression of some proinflammatory cytokines.

Immunosuppressors

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

Mitoxantrone (Novantrone)

Anthracenedione compound used for SPMS and RPMS. Induces DNA cross-links and strand breaks and leads to apoptosis. Mitoxantrone also interferes with RNA and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. Indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Not indicated in the treatment of patients with primary progressive MS.

Cyclophosphamide (Cytoxan, Neosar)

Metabolized in liver by mixed-function microsomal oxidase system.
Mechanism of action believed to involve DNA cross-linking. Has been used off-label for secondary progressive MS, especially for patients with dramatic, rapid progression. Thought to be more effective if given in early stage of progression.

Azathioprine (Imuran)

This immunosuppressive antimetabolite drug is an imidazolyl derivative of 6-mercaptopurine. Cleaved in vivo to mercaptopurine and converted to 6-thiouric acid by xanthine oxidase. Generally used in treatment of transplant rejection or severe, active, erosive rheumatoid arthritis. Has been used off-label for MS.

Methotrexate (Rheumatrex)

Immunosuppressive metabolite drug used for some neoplasias (including leukemia), psoriasis, and rheumatoid arthritis. Interferes with DNA synthesis, repair, and cellular replication. Inhibits dihydrofolic acid reductase, which participates in synthesis of thymidylate and purine nucleotides. Has been used off-label for MS.

Antiviral, anti-Parkinson agent

This agent is used for treatment of fatigue in MS.

Amantadine hydrochloride (Symmetrel)

Mechanism of counteracting fatigue unclear. May have antiviral effects by inhibiting replication of some viruses, including influenza A.

Central nervous system stimulants

These agents are used for treatment of fatigue without interfering with normal sleep architecture. They promote wakefulness.

Modafinil (Provigil)

Mechanism of action currently unknown. Listed in Schedule IV of the Controlled Substances Act. Patients should be observed for signs of use or abuse, as drug has psychoactive and euphoric effects similar to those seen with other scheduled CNS stimulants (eg, methylphenidate).

• Search for CME/CE on This Topic »

• Multiple Sclerosis (Physical Medicine and Rehabilitation)
• Multiple Sclerosis, Spine (Radiology)
• Multiple Sclerosis (Emergency Medicine)
• Brain, Multiple Sclerosis (Radiology)

• Muscle Disorders Center
• Multiple Sclerosis Symptoms
• Brain and Nervous System Center
• Erectile Dysfunction Center
• Multiple Sclerosis Overview
• Multiple Sclerosis Causes
• Impotence/Erectile Dysfunction Introduction
• Erectile Dysfunction FAQs
• Multiple Sclerosis Treatment

• Interleukin 27 Investigated for Multiple Sclerosis
• Vitamin-D Levels Inversely Correlated With Disability and Disease Progression in Multiple Sclerosis
• Overactive Bladder Symptoms in Patients With Multiple Sclerosis Go Untreated

• Neurogenesis In The Chronic Lesions Of Multiple Sclerosis
• Imaging Outcomes for Neuroprotection and Repair in Multiple Sclerosis Trials
• Escalating Immunotherapy of Multiple Sclerosis

• Multiple Sclerosis (MS) Resource Center