Multiple Sclerosis Treatment & Management

Treatment of multiple sclerosis (MS) has 2 aspects: immunomodulatory therapy (IMT) for the underlying immune disorder and therapies to relieve or modify symptoms. IMT is directed toward reducing the frequency of relapses and slowing progression. Currently, most disease-modifying agents have been approved for use only in relapsing forms of MS. Mitoxantrone (see below) is also approved for the treatment of secondary (long-term) progressive and progressive relapsing MS.

Although therapy for clinically isolated syndrome (CIS) (a single episode of neurologic symptoms) with immunomodulatory medications has not yet become standard practice throughout the world, trials such as the TOPIC trial suggest that early intervention may be appropriate. Decisions regarding early treatment of relapsing MS can be guided by using the McDonald diagnostic criteria.

Results from the multicenter TOPIC trial provide evidence that treatment of clinically CIS with the drug teriflunomide delays conversion to MS. ^[88] Patients with CIS have a high likelihood of developing MS.

In the study, 618 patients were treated either with teriflunomide in doses of 14 mg or 7 mg per day or placebo. ^[88] Patients were included if they experienced a first acute or subacute well-defined neurologic event consistent with demyelination, onset of MS symptoms within 90 days of randomization, and MRI showing 2 or more characteristics of MS. During 2 years of treatment, patients receiving 14 mg of teriflunomide experienced a 43% reduction in the risk for conversion to clinically definite MS compared with placebo. Patients who received 7 mg of the drug per day had a 37% reduction in the risk for conversion vs placebo. ^[88]

Given the wide spectrum of clinical manifestations that MS can produce, patients may require consultations with a variety of specialists. Indeed, patients with MS are often best served by a multidisciplinary approach.

Medical management goals that are sometimes achievable in the emergency department are to relieve symptoms and to ameliorate risk factors associated with an acute exacerbation. In patients with fulminant MS or disseminating acute encephalitis, management involves the following:

• Stabilize acute life-threatening conditions

• Initiate supportive care and seizure precautions

• Monitor for increasing intracranial pressure

Consider intravenous steroids, IV immunoglobulin (IVIG), or emergent plasmapheresis. One study suggested that plasmapheresis may be superior to IV steroids in patients with acute fulminant MS. ^[89] The 2011 American Academy of Neurology (AAN) plasmapheresis guideline update states that plasmapheresis is possibly effective and may be considered in acute fulminant demyelinating CNS disease. ^[5]

Identification and control of known precipitants of MS exacerbation include the following:

• Aggressively treat infections with antibiotics

• In patients with a fever, normalize the body temperature with antipyretics, as even small increases in temperature can strongly affect conduction through partially demyelinated fibers

• Provide urinary drainage and skin care, as appropriate

Preoperative considerations for emergency surgery in patients with fulminant MS are as follows:

• Gastric emptying may be delayed secondary to autonomic GI dysfunction

• Lability of the autonomic nervous system may precipitate hypotension during anesthesia and surgery

• Spontaneous ventilation may be disrupted

Methylprednisolone (Solu-Medrol) can hasten recovery from an acute exacerbation of MS. There is no clear evidence that it changes the overall disease progression.

Plasma exchange (plasmapheresis) can be used short term for severe attacks if steroids are contraindicated or ineffective. The 2011 AAN guideline for plasmapheresis in neurological diseases categorizes plasmapheresis as “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids. ^[5]

Texts commonly describe anti-inflammatory treatment as an option for acute transverse myelitis and acute disseminated encephalitis; however, not many supporting data are given. Dexamethasone is commonly used. Anti-inflammatory treatment for ON is very controversial.

Disease-modifying therapies have shown beneficial effects in patients with relapsing MS, including reduced frequency and severity of clinical attacks. These agents appear to slow the progression of disability and the reduce accumulation of lesions within the brain and spinal cord. The disease-modifying agents for MS (DMAMS) currently approved for use by the US Food and Drug Administration (FDA) include the following:

• Interferons (eg, IFN beta-1a, IFN beta-1b, peginterferon beta-1a) ^{[6, 7, 8]}  
• Sphingosine 1-phosphate (S1P) receptor modulators (eg, siponimod, fingolimod, ozanimod) ^{[9, 10, 11, 12]}  
• Monoclonal antibodies (eg, natalizumab, alemtuzumab, ocrelizumab, ublituximab) ^{[13, 14, 15, 16, 17, 18, 19, 20]}  
• Miscellaneous immunomodulators (eg, glatiramer, mitoxantrone, teriflunomide, dimethyl fumarate, monomethyl fumarate, cladribine) ^{[21, 22, 23, 24, 25, 26, 27, 28, 29]}  

Fingolimod, siponimod, ozanimod, cladribine, teriflunomide, dimethyl fumarate, and monomethyl fumarate are administered orally; natalizumab, ocrelizumab, and mitoxantrone are administered by intravenous infusion; interferon beta-1a (Avonex) is administered intramuscularly; and interferon beta-1a (Rebif), interferon beta-1b, and glatiramer acetate are administered by subcutaneous injection. 

Note that in January 2013, the FDA approved a single-use autoinjector (Rebidose, EMD Serono Inc./Pfizer Inc) for self-injection of interferon beta-1a (Rebif) in patients with relapsing forms of MS. ^[30] The ease of use, patient satisfaction and acceptability, and functional reliability of the Rebidose are supported by data from a 12-week open-label, single-group study in 109 patients. The autoinjector is available in a monthly pack in 22 and 44 μg doses and in a titration pack. ^[30]

Patient lifestyle, patient tolerance, and adverse effects of injections should be considered in the choice of DMAMS. To a certain extent, health-care-provider preference and experience with the medications also play a role in determining which drug is appropriate in a particular situation.

A case-control study from the MSBase longitudinal cohort found that MS patients who are well controlled on injectable drugs but switch to oral therapies aren't at greater risk of early relapse. This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. Results showed there were no differences in the rate of first relapse or disability progression over the first 6 months. ^[90]

Interferon beta-1b therapy

The first medication approved by the FDA for MS, in 1993, was interferon beta-1b (Betaseron, Extavia). It is indicated for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. It has shown efficacy in patients who have experienced a first clinical episode of MS and have MRI features consistent with MS. ^[7]

In a double-blind, placebo-controlled trial of 372 patients with relapsing-remitting MS, interferon beta-1b (8 million IU every other day) decreased the frequency of relapses by 34% after 2 years. In treated patients, the MRI T2 lesion burden increased 3.6% over 5 years, compared with 30.2% in the placebo group. At 5 year follow-up, the incidence of disease progression was lower in the interferon beta-1b group compared with the placebo group (35% versus 45%). ^[91]

Interferon beta-1b is administered every other day subcutaneously by self-injection. The most frequently reported adverse reactions include asthenia, depression, flu-like symptoms, hypertonia, increased liver enzymes, injection site reactions, leukopenia, and myasthenia. Interferon beta-1b can be coadministered with analgesics or antipyretics to help with the occurrence of flu-like symptoms. ^[7]

Interferon beta-1a (Avonex or Rebif) therapy

In a study of 301 patients with relapsing-remitting disease who were given weekly intramuscular injections (6 million U [30 µg]) of interferon beta-1a (Avonex), the annual exacerbation rate decreased 29%. ^[92] Over 2 years, disease progression occurred in 21.9% of patients in the interferon beta-1a group and 34.9% of those in the placebo group. In addition, MRI data showed a decrease in the mean lesion volume and number of enhancing lesions in the interferon beta-1a group.

In Europe and Canada, higher doses of subcutaneous interferon beta-1a (Rebif) were studied in the Prevention of Relapse and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) Study. ^[93] The dose-comparison study of interferon beta-1a reported a 27% reduction in the relapse rate in patients receiving 66 µg/wk and a 33% reduction in those receiving 132 µg/wk. This study, of 560 patients with relapsing-remitting disease, also demonstrated a significant reduction in accrual of disability and MRI lesion burden with the higher dose. ^[93]

In 2002, the FDA approved interferon beta-1a (Rebif) in 22 µg and 44 µg formulations given 3 times per week.

In the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial, which compared 2 preparations of interferon beta-1a (Rebif and Avonex), relapse occurred less frequently with 44 µg 3 times weekly (Rebif) than with 30 µg once weekly (Avonex) (25% vs 37%). ^[94] In addition, the mean number of active unique MRI lesions per patient per scan was lower in the Rebif than in the Avonex group (0.17 vs 0.33). Patients on Rebif experienced fewer flulike symptoms, but more injection site reactions, hepatic function disorders, and white blood cell disorders. Rebif-treated patients had a higher incidence of neutralizing antibodies (Nabs). A reduced MRI effect was noted for Nab-positive patients on Rebif compared with Nab-negative patients on Rebif. However, Nab-positive Rebif patients had better clinical and comparable MRI results to Avonex patients. ^[94]

In a subsequent crossover phase of the EVIDENCE trial, patients who were originally randomized to low-dose weekly treatment were switched to the high-dose 3-times-weekly regimen for an additional 8 months. These patients demonstrated significant reductions in mean relapse rates compared with the last 6 months on Avonex (P< .001). ^[95]

In patients with uncontrolled depression, interferons should be used with caution. Glatiramer may be an appropriate choice in such cases.

Peginterferon beta-1a

Peginterferon beta-1a (Plegridy) was approved by the FDA in August 2014 for treatment of relapsing forms of MS. It is the first pegylated interferon approved for MS and can be self-administered by SC injection every 2 weeks. ^[8]

Approval was based on results from the ADVANCE trial of >1,500 patients with MS over a 2-year period. In the first year of the trial, peginterferon beta-1a dosed every 2 weeks significantly reduced annualized relapse rate (ARR) at 1 year by 36% compared with placebo (P = 0.0007). Risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale, was also reduced with peginterferon beta-1a by 38% (P = 0.0383) compared with placebo. Peginterferon beta-1a also significantly reduced the number of new gadolinium-enhanced [Gd+] lesions by 86% (P< 0.0001) and reduced new or newly enlarging T2-hyperintense lesions by 67% (P< 0.0001) compared with placebo. ^[8]

Glatiramer acetate

Glatiramer acetate (Copaxone) is a synthetic polypeptide approved for the reduction of the frequency of relapses in patients with relapsing-remitting MS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Glatiramer acetate’s mechanism of action is unknown, but this agent could theoretically modify some of the immune processes thought to be involved in the pathogenesis of MS. ^[21]

In a double-blind trial that included 251 patients with relapsing-remitting MS (RRMS), treatment with glatiramer acetate 20 mg SC once daily resulted in a 29% reduction in the relapse rate over 2 years; a positive effect on disability was suggested but this effect was not shown on predetermined disability measures in this trial. ^[96] For this reason, glatiramer acetate is not approved by the FDA for slowing disability progression in MS. A follow-up open-label study demonstrated continued efficacy of glatiramer over 6 years. ^[97]

In January 2014, a higher dose and lower-frequency dosage regimen of glatiramer was approved. The 20-mg/mL SC injection is specific for the original once-daily regimen, whereas the new 40-mg/mL SC injection is specific for the 3-times-per-week dosage regimen. Approval for the new regimen was based on the phase 3 Glatiramer Acetate Low-Frequency Administration (GALA) study. The GALA trial included 1,404 patients and showed that treatment with 40 mg SC 3 times/wk reduced mean annualized relapse rates by 34% compared with placebo (0.331 vs 0.505; P< .0001) at 12 months. ^[98]

Natalizumab

Natalizumab (Tysabri) is a humanized monoclonal antibody that binds to the adhesion molecule alpha-4 integrin, inhibiting its adherence to its receptors. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of MS, to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. It is generally used in patients who have not responded to a first-line disease-modifying therapy or who have very active disease. ^[14]

In a placebo-controlled clinical trial, the use of natalizumab reduced the relapse rate (68%) and progression of disability (42%) over a period of 2 years. ^[99] Natalizumab is given as a 300 mg IV infusion over 1 hour every 4 weeks.

Natalizumab has been associated with progressive multifocal leukocephalopathy (PML), an opportunistic infection of the brain that can lead to death or severe disability. The risk of PML seems to increase with a history of previous immunosuppression, duration of exposure to natalizumab beyond 2 years, and JC virus antibody positivity.

Three cases of PML associated with natalizumab use prompted its temporary withdrawal from the market in 2005; however, it was reapproved in 2006 by the FDA for commercialization under a special restricted distribution program known as Tysabri Outreach Unified Commitment to Health (TOUCH). Use of natalizumab is limited to patients, physicians, and infusion centers that are registered with the TOUCH program.

A retrospective review of 906 patients from 5 clinical trials by Cadavid et al found that after treatment with natalizumab, disabled patients with relapsing-remitting MS were more likely to complete a timed 25-foot walk significantly faster; responders took an average of 24–44% less time to walk 25 ft than nonresponders. Natalizumab also appeared to have some efficacy in disabled patients with SPMS. ^[100]

Sphingosine 1-phosphate receptor modulators

Fingolimod

Fingolimod (Gilenya) is the first oral disease-modifying treatment for relapsing forms of MS approved by the FDA. Like other disease-modifying agents for MS, fingolimod can reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. The recommended dosage for fingolimod is 0.5 mg once a day. ^[9]

Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate receptors, which are a subset of a larger family of cell-surface, G protein–coupled receptors that mediate the effects of bioactive lipids known as lysophospholipids. Lysophospholipids are membrane-derived bioactive lipid mediators that can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis.

The mechanism of action of fingolimod is incompletely understood but appears to be fundamentally different from other MS medications. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Fingolimod promotes sequestration of lymphocytes within the lymph nodes, which may reduce lymphocyte migration into the central nervous system. ^[101]

Fingolimod can be associated with macular edema, pulmonary dysfunction, and cardiac adverse effects.

In 2012, the FDA determined that new label changes are required for fingolimod. Within an hour of administering fingolimod, heart rate decreases are noted. The nadir in heart rate typically occurs at 6 hours, but it can be observed up to 24 hours after the first dose in some patients. Because of its cardiac adverse effects, the first dose of fingolimod should be administered in a setting in which resources are available to appropriately manage symptomatic bradycardia. Therefore, all patients started on fingolimod must be monitored for at least 6 hours following the first dose. Additionally, an ECG should be performed prior to dosing fingolimod, blood pressure and pulse should be monitored hourly, and an ECG should be performed at the end of the observation period.

Additional observation beyond 6 hours should be instituted if bradycardia occurs and until the finding has resolved in the following situations: the heart rate 6 hours post dose is less than 45 beats per minute, the heart rate 6 hours post dose is the lowest value observed post dose, or the ECG 6 hours post dose shows new-onset second-degree or higher (atrioventricular) AV block.

Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy (described above) should be repeated after the second dose of fingolimod.

Fingolimod is now contraindicated in patients with recent myocardial infarction, unstable angina, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III/IV heart failure; history or presence of Mobitz type II second- or third-degree AV block or sick-sinus syndrome, unless the patient has a functioning pacemaker; baseline QTc interval greater than or equal to 500 ms; or treatment with class Ia or class III antiarrhythmic drugs.

The following are recommendations for the use of fingolimod in patients with preexisting cardiovascular conditions:

• Patients with some preexisting conditions (eg, ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, and sinoatrial heart block) may poorly tolerate the fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose of fingolimod.

• Prior to treatment, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such an evaluation, and, if treated with fingolimod, should be monitored overnight with continuous ECG in a medical facility after the first dose.

• Since initiation of fingolimod treatment results in decreased heart rate and may prolong the QT interval, overnight continuous ECG monitoring is recommended in patients who have prolonged QTc interval before or during the 6-hour observation (>450 ms males, >470 ms females), are at higher risk for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome), are on concurrent therapy with drugs that prolong the QT interval, and have a known risk of torsades de pointes. The list of drugs associated with risk of torsades de pointes can be found at AzCERT (CredibleMeds).

The following are recommendations for the use of fingolimod with concomitant medications that slow the heart rate or AV conduction:

• Experience is limited when coadministered with drugs that slow the heart rate or AV conduction (eg, beta-blockers, heart rate–lowering calcium channel blockers such as diltiazem, verapamil, or digoxin).

• Because the initiation of fingolimod treatment is also associated with slowing of the heart rate, coadministration of other drugs that cause bradycardia may be associated with severe bradycardia or heart block.

• The possibility to switch to drugs that do not slow the heart rate or AV conduction should be evaluated by the prescribing physician before initiating fingolimod. In patients who cannot switch, overnight continuous ECG monitoring is recommended after the first dose.

The reduction of peripheral lymphocyte count by fingolimod can possibly lead to an increased risk of infection. Reversible, asymptomatic elevations of liver enzymes may also occur. Other adverse reactions that have been commonly reported include headache, diarrhea, ALT/AST elevations and back pain.

If an MS patient is being switched from natalizumab to fingolimod oral therapy, a washout period of 8 weeks or less is advisable. In an observational cohort study involving 350 such patients, those with a washout time longer than 2 months had a higher risk of relapse; in a second study involving 142 patients, shorter washout periods of 8 or 12 weeks were associated with fewer active lesions and less disease recurrence than was a washout period of 16 weeks. ^{[102, 103, 104]}

Siponimod

Siponimod (Mayzent) is an oral S1p receptor modulator that was approved by the FDA in 2019. It is indicated for treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Approval was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3–6.5 to siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval [CI], 0.65 - 0.95; relative risk reduction, 21%; P = .013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression. ^[10]

Ozanimod

The S1P receptor modulator ozanimod was approved for relapsing forms of multiple sclerosis in March 2020. Approval of ozanimod by the FDA was based on two phase 3 clinical trials (SUNBEAM, RADIANCE). ^{[11, 12]}  

The SUNBEAM trial (n=1346) was a conducted at 152 academic medical centers and clinical practices in 20 countries. Patients were randomly assigned to ozanimod 1 mg (n=447), ozanimod 0.5 mg (n=451), or interferon beta-1a (n=448). The primary endpoint was the annualized relapse rate (ARR). Patients treated for at least 12 months had a significantly lower relapse rate compared with interferon beta-1A. Adjusted ARRs were 0.35 for interferon beta-1a, 0.18 for ozanimod 1 mg (p< 0.0001), and 0.24 for ozanimod 0.5 mg (p=0.0013). ^[11]  

The RADIANCE trial (n=1320) analyzed ozanimod data at 24 months of duration. Ozanimod was associated with significantly lower rates of clinical relapses compared with interferon beta-1a. Adjusted ARRs were 0.17 with ozanimod 1 mg, 0.22 with ozanimod 0.5 mg, and 0.28 with interferon beta-1a, with rate ratios versus interferon beta-1a of 0.62 (p< 0·0001) for ozanimod 1.0 mg and 0.79 (p=0·0167) for ozanimod 0.5 mg. ^[12]

Cladribine

Cladribine gained FDA approval in 2019 for relapsing forms of MS, to include relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, use is generally recommended for patients with inadequate response to, or inability to tolerate, an alternate MS drug therapy. 

The ORACLE MS trial (n=903) demonstrated that cladribine significantly delayed MS diagnosis compared with placebo (p < 0.0001) when initiated in patients following a first clinical demyelinating event. ^[28]  In the CLARITY study, cladribine treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. ^[29]

Teriflunomide

Teriflunomide (Aubagio) was approved by the FDA in September 2012 for the treatment of patients with relapsing forms of MS (approved tablet forms are 7 mg and 14 mg). The prescribing information contains a black box warning for the risks of hepatotoxicity and teratogenicity (pregnancy category X). It is an oral pyrimidine synthesis inhibitor for treatment of relapsing forms of MS. Approval was based on a randomized trial (TEMSO) of 1088 patients with a minimum of 1 relapse in the previous year or 2 relapses in the last 2 years. Teriflunomide was shown to significantly reduce annualized relapse rates (31% relative risk reduction compared with placebo [P< .001]). It was also shown in the TEMSO trial to reduce disability progression at doses of 14 mg/day. ^[105] However, the FDA has not approved the use of teriflunomide to slow disability progression.

Phase III of the TEMSO study found that teriflunomide significantly slowed brain volume loss compared with placebo over 2 years in patients with relapsing MS. Data obtained from MRI were used to assess patients treated with 14 mg or 7 mg of the drug, or placebo. By month 12, median percent reduction from baseline in brain volume was 0.39, 0.40, and 0.61 for teriflunomide 14 mg, 7 mg, and placebo, respectively. ^[106]

The most common adverse reactions of teriflunomide are headache, alopecia, diarrhea, nausea, increased ALT, influenza, and paresthesias.

Teriflunomide can predispose to infections (due to a decrease in the white blood cell count that remains throughout treatment) and increases in blood pressure. To assess safety, it is recommended to obtain transaminase levels, bilirubin levels, and a CBC count within 6 months before initiation; screen for latent tuberculosis infection with a tuberculin skin test; and check the blood pressure before the first dose and periodically thereafter.

Teriflunomide is contraindicated in patients with severe hepatic impairment, patients who are pregnant or women of childbearing potential not using reliable contraception, or patients on current treatment with leflunomide. If liver injury occurs, teriflunomide should be immediately discontinued and an accelerated elimination procedure using either activated charcoal or cholestyramine should be initiated. Monitor liver tests weekly until normalized.

Upon discontinuing teriflunomide and based on the teratogenicity risk, it is recommended that all women of child-bearing potential undergo the accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to pose minimal risk. Without an accelerated elimination procedure, it takes teriflunomide on average of 8 months (and up to 2 y) to reach plasma concentrations less than 0.02 mg/L.

Teriflunomide or its parent compound, leflunomide, can also be associated with peripheral neuropathy and acute renal failure, hyperkalemia, hypophosphatemia, serious skin reactions, and interstitial lung disease.

Other trials for teriflunomide (TOWER) are completed (not yet published) or ongoing. Results from the TENERE study (n= 324) observed similar efficacy and safety between teriflunomide and interferon beta-1a for relapsing forms of MS. ^[107] Another study of teriflunomide added to beta interferon therapy is currently ongoing. ^[108]

Dimethyl fumarate and monomethyl fumarate

Dimethyl fumarate (DMF) is an oral Nrf2 pathway activator indicated for relapsing forms of MS. The active metabolite, monomethyl fumarate (MMF), activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a transcription factor encoded by the NFE2L2 gene.

FDA approval for DMF in adults with relapsing forms of multiple sclerosis ^{[24, 25]} was based on data from 2 phase 3 studies, the DEFINE ^[26] and CONFIRM ^[27] studies, that involved more than 2600 patients. An ongoing extension study (ENDORSE) includes some patients that have been followed for longer than 4 years.

In the DEFINE trial, dimethyl fumarate significantly reduced ^[26] : (1) the proportion of patients who relapsed by 49%, (2) the annualized relapse rate by 53%, and (3) the 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), by 38% relative to placebo at 2 years. In the CONFIRM study, dimethyl fumarate significantly reduced the annualized relapse rate by 44% and the proportion of patients who relapsed by 34% compared with placebo at 2 years. ^[27] Although not statistically significant, dimethyl fumarate also showed a 21% reduction in the CONFIRM trial's 12-week confirmed disability progression. ^[27] Both studies also showed that dimethyl fumarate significantly reduced lesions in the brain relative to placebo, as measured by magnetic resonance imaging. ^{[26, 27]}

Monomethyl fumarate (MMF) is the active metabolite of the prodrug dimethyl fumarate. Following oral administration, 190 mg of MMF is bioequivalent to 240 mg of DMF.

Alemtuzumab

Alemtuzumab (Lemtrada) was approved by the FDA in November 2014 for relapsing forms of multiple sclerosis. Because of the risk for severe autoimmune adverse effects, it is reserved for use in patients who have an inadequate response to 2 or more other drugs for MS. Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This action promotes antibody-dependent cell lysis.

Approval was based on 2 randomized Phase III open-label rater-blinded studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). In CARE-MS I, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance. ^[15] In CARE-MS II, alemtuzumab was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was also significantly slowed. ^[16] The clinical development program for alemtuzumab use in MS involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up. ^[17]

In a single-arm, open-label study in 45 patients with MS that was refractory to treatment with interferon, alemtuzumab effectively reduced relapse rates and improved clinical scores. ^[109]

In subsequent subgroup analysis of 101 MS patients with multiple recent relapses and MRI-detected gadolinium-enhancing lesions, researchers found alemtuzumab to be more effective than interferon. ^[110] The study showed that after 2 years, almost a quarter of patients had achieved a disease activity–free state, whereas none of those treated with interferon and reached such a state.

In this study, disease activity–free was defined as no relapse, no sustained accumulation of disability (SAD) as measured by the Expanded Disability Status Scale (EDSS), and no new gadolinium-enhancing lesions or new or enlarging T2-hyperintense lesions. ^[110] Relapses occurred in 35.8% of the alemtuzumab group and 60.0% of the interferon group. Respective percentages for SAD were 7.4% and 17.5%; for gadolinium-enhancing lesion activity, 22.1% and 52.5%; and for T2 lesion activity, 60.0% and 92.5%.

Ocrelizumab

Ocrelizumab (Ocrevus) was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for RRMS was based on the OPERA 1 and 2 phase 3 trials that included about 800 patients with RMS who received intravenous ocrelizumab or subcutaneous interferon-beta1a. Results showed the annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P < 0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P < 0.001). The percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; P< 0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; P = 0.003). The mean number of gadolinium-enhancing lesions per T1-weighted MRI was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P < 0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P < 0.001). ^[18]

Further analysis of participants from the OPERA studies in October 2017 showed that ocrelizumab may improve visual outcomes in adult patients with RMS. Patients who received the drug intravenously had significantly greater improvement on low-contrast letter acuity (LCLA) tests compared with those who received subcutaneous interferon β-1a. Within the visually impaired subgroup, significantly more patients receiving ocrelizumab showed at least a 7-letter improvement at 12 weeks compared to the interferon group. ^[111]

Ofatumumab

Kesimpta (ofatumumab SC), a CD20-directed cytolytic monoclonal antibody, is the first B-cell therapy for SC administration. In August 2020, FDA approved ofatumumab SC for relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Approval was based on results from the phase 3 ASCLEPIOS I and II trials that compared ofatumumab with teriflunomide in patients (n = 1882) with RMS. Ofatumumab SC significantly lowered the annualized relapse rate (primary end point) compared with teriflunomide. Additionally, ofatumumab significantly reduced the risk of 3-month confirmed disability progression compare to teriflunomide, as well as the number of T1 gadolinium-enhancing lesions and the rate of new or enlarging T2 lesions. ^[112]  

Ublituximab

Another CD20-directed monoclonal antibody, ublituximab (Briumvi), was approved by the FDA in December 2022 for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. 

Approval was supported by results from the ULTIMATE I (n = 549) and ULTIMATE II (n = 545) trials. Compared with teriflunomide, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (P < 0.001); the ULTIMATE II trial showed annualized relapse rates of 0.09 and 0.18, respectively (P = 0.002). ^[20]

High-dose cyclophosphamide (Cytoxan) has been used for induction therapy to stabilize aggressive MS. In a retrospective study of 32 patients, Harrison et al reported that induction with cyclophosphamide (200 mg/kg IV infusion over 4 days) followed by long-term maintenance therapy with glatiramer was well tolerated and appeared to be effective in reducing the risk of relapse, disability progression, and new MRI lesions. ^[113] Adverse effects of cyclophosphamide include leukemia, lymphoma, infection, and hemorrhagic cystitis.

Mitoxantrone is an immunosuppressive agent approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS. Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.

Mitoxantrone has a black-box warning for cardiotoxicity. The risk of cardiotoxicity increases with cumulative mitoxantrone dose and can occur whether or not cardiac risk factors are present. Mitoxantrone therapy in MS patients and in patients with cancer increases the risk of developing secondary acute myeloid leukemia (AML). Mitoxantrone also has a black-box warning for secondary leukemia. Mitoxantrone treatment in MS patients and in patients with cancer increases the risk of developing secondary AML.

Few treatments are available for primary progressive MS (PPMS). Ocrelizumab was approved in March 2017 for adults with relapsing or primary progressive forms of multiple sclerosis. Approval for PPMS was based on results from the ORATORIO phase 3 trial that included 732 patients with PPMS who received the treatment or matching placebo. Ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04). The total volume of brain lesions on T2-weighted MRI decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P< 0.001), while the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). ^[19]

Siponimod was approved by the FDA in 2019 for adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Siponimod approval was based on results of the phase 3 EXPAND trial, which randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3–6.5 to siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events. At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79; 95% confidence interval [CI], 0.65 - 0.95; relative risk reduction, 21%; P = .013). Siponimod also meaningfully delayed the risk of 6-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression. ^[10]

Cladribine

Cladribine gained FDA approval in 2019 for relapsing forms of MS, to include relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, use is generally recommended for patients with inadequate response to, or unable to tolerate, an alternate MS drug therapy. 

The ORACLE MS trial (n=903) demonstrated that cladribine significantly delayed MS diagnosis compared with placebo (p < 0.0001) when initiated in patients following a first clinical demyelinating event. ^[28]  In the CLARITY study, cladribine treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. ^[29]

A literature review by Rojas et al. indicated that interferon beta could not be linked to reduced disability progression in patients with PPMS. ^[114] The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

Patients with secondary progressive MS (SPMS) who experience relapses are sometimes started on a DMAMS approved for relapsing-remitting MS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with SPMS. ^[115] }

In a European study of SPMS, patients receiving interferon beta-1b showed a highly significant delay in time to disease progression. FDA approval has not been granted yet for this indication, however. ^{[116, 117, 118]}

Mitoxantrone is another treatment option for progressive MS. It is approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing remitting MS, but not for primary progressive MS.

More oral agents are under development (eg, laquinimod). ^{[119, 120]}

In a randomized, double-blind trial involving 30 patients with relapsing-remitting MS, a skin patch delivering a mixture of 3 myelin peptides (MBP85-99, PLP139-151, and MOG35-55) significantly reduced the number of gadolinium-enhanced (Gd+) lesions on MRI, as well as reduced the annual relapse rate in patients wearing the patch for 1 year. ^{[121, 122]} The most common adverse effect in those receiving myelin peptides was local reaction in the area of the skin patch, followed by redness and moderate itching.

Autologous hematopoietic stem cell transplantation (AHSCT) may be effective for slowing the course of MS and for repairing damage to the nervous system.

One retrospective study evaluated 281 patients with MS who underwent AHSCT between 1995 and 2006. Almost half of the patients (46%) remained free from neurological progression for 5 years after transplant. However, 8 deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. 

It is important to note that patients with a relapsing form of MS fared better than those with progressive MS. This suggests that AHSCT may not necessarily treat a neurodegenerative component of the disease that is operative in the later stages of the disease. ^[123]

In a trial of 110 patients with relapsing-remitting disease, stem cell therapy helped control MS. After 1 year, just one stem cell recipient had experienced a relapse, versus 39 relapses in drug therapy recipients. Additionally, during a mean follow-up of 3 years, treatment failure occurred in just 6% of stem cell patients, compared with 60% of those on drug therapy. ^[124]

Confavreux et al found that the frequency of MS relapses decreases during pregnancy, particularly in the third trimester, when it drops by as much as 70%. ^[125] In the first 3 months post partum, however, the frequency of relapses returns to the prepregnancy rate, probably as a result of postpregnancy hormone loss. Overall, pregnancy does not have a negative effect on the course of MS. Initial data suggested that breast-feeding reduced MS relapses, but the most recent study found no significant benefit. ^[126]

Few negative outcomes have been reported with exposure to interferon beta or glatiramer during pregnancy, which suggests the possibility of offering treatment until conception. ^[126] However, the absence of conclusive data should not encourage physicians to treat patients who are pregnant with these agents; the use of disease-modifying treatments in women planning to become pregnant should be considered on a case-by-case basis, weighing the risks of drug exposure against risks of relapses. Agents with known teratogenicity risks, such as teriflunomide (Aubagio), are clearly contraindicated in this setting.

Treatment of symptoms is an essential part of the management of MS. Pharmacologic and nonpharmacologic measures can be used to address the following:

• Fatigue

• Spasticity

• Bladder problems

• Bowel problems

• Cognitive dysfunction

• Pain

• Paroxysmal symptoms

• Sexual dysfunction

• Tremor

• Heat intolerance

• Optic neuritis

Cognitive dysfunction

Cognitive dysfunction is a major problem that affects quality of life, family and social relationships, and employment. Cognitive dysfunction can impact memory, comprehension, problem solving, and speech. Treatment for cognitive dysfunction in patients with MS should include supportive therapy provided by speech pathologists or occupational therapists. In addition, depression may contribute to cognitive dysfunction and should be treated if it is diagnosed.

Pharmacologic therapy has not been shown to be beneficial for cognitive impairment in MS. For example, a multicenter randomized clinical trial in MS patients with memory impairment found that donepezil (Aricept) was no better than placebo for improving memory. ^[127]

Depression

Selective serotonin reuptake inhibitors are preferred for treating depressive symptoms in patients with MS. Second-line treatment options include the use of tricyclic antidepressants. The anticholinergic side effects of tricyclic antidepressants may be helpful to patients with symptoms of bladder spasticity or chronic pain. For more information, see the Medscape Reference article Depression.

Fatigue

Fatigue is one of the most common and disabling symptom of MS, occurring in approximately 76-92% of MS patients. ^[128] Fatigue can worsen before and during exacerbations and with increased temperatures. There are no FDA-approved drugs for treatment of MS-related fatigue.

Amantadine is perhaps the first-line drug for treatment of fatigue in MS, although this is an off-label use. The usual dosage is 100 mg orally twice a day. Approximately 40% of MS patients experience some fatigue relief with amantadine. Pemoline was found to be effective in some people, but it was removed from the US market in 2005 after the FDA concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. ^[129]

Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine (Prozac). A disadvantage of methylphenidate is that it is a controlled substance, with potential for abuse. Methylphenidate has been recommended at dosages of 10-60 mg/day in 2-3 divided doses, using extreme caution. For patients with concurrent depression, fluoxetine may be tried to manage both problems.

Modafinil (Provigil), a drug approved for the treatment of narcolepsy, has demonstrated some success in MS patients at doses of 200 mg/day. In addition, armodafinil (Nuvigil) has also been suggested as being helpful with fatigue.

Nonpharmacologic treatment of fatigue involves energy conservation, work simplification, scheduled rest periods, and the use of cooling garments (eg, vest, hat, collar). Regular exercise also may help alleviate fatigue.

Medications used in MS management often can contribute to fatigue. These drugs include analgesics, anticonvulsants, antidepressants, muscle relaxants, sedatives, and immune-modulating medications.

Pain

Pain can be a common occurrence in patients with MS, with 30-50% of patients experiencing pain at some time in the course of their illness. Treatment for pain accounts for nearly 30% of the medications used for symptom management in MS patients. ^[130]

Pain in MS may be primary or secondary, and the two may be experienced at the same time. Primary pain is related to the demyelinating process and is often characterized as having a burning, gnawing, or shooting quality. Tricyclic antidepressants are first-line drugs for primary pain. Anticonvulsants, such as carbamazepine, phenytoin, and gabapentin, can be added as second-line agents.

Secondary pain in MS is primarily musculoskeletal in nature, possibly due to poor posture, poor balance, or the abnormal use of muscles or joints as a result of spasticity. Pharmacologic agents for this type of pain include nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics. The use of narcotics is seldom indicated.

Heat intolerance

Steps to manage heat intolerance are as follows:

• Time outside activities for early morning or evening hours to avoid the heat of the day

• Spread activities throughout the course of the day to avoid overheating

• Use air conditioning in homes and cars, cooling garments, light-colored clothes, and wide-brimmed hats

• Avoid exposure to saunas, hot tubs, or even hot showers or baths

• Avoid exposure to excessive humidity; dehumidifiers can help indoors

• Treat fevers aggressively with around-the-clock antipyretics.

Spasticity

Treat spasticity when it interferes with function, mobility, positioning, hygiene, or activities of daily living. Reducing spasticity can give the patient more freedom of movement with less energy expenditure, as well as avoiding complications such as pain, contractures, and decubitus.

Spasticity can be managed through nonpharmacologic means. Pharmacologic treatment of spasticity includes baclofen (Gablofen, Lioresal), which is particularly useful for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity in MS patients with reversible spasticity. Baclofen is effective in most cases, is inexpensive, and is titrated easily from 10-140 mg/day in divided doses. Adverse effects include fatigue and weakness.

Second-line agents include benzodiazepines (eg, diazepam, clonazepam). These agents can be sedating and habit-forming; however, for patients who also have sleep disorders, the sedative effects can be beneficial, allowing the clinician to manage the spasticity and the sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects.

Dantrolene sodium (Dantrium) acts directly on skeletal muscle to decrease spasticity. This agent is used less frequently than baclofen because of its hepatotoxicity at higher doses and numerous drug interactions.

The anticonvulsant drug gabapentin (Neurontin) is particularly useful in patients who experience spasticity and neuropathic pain. It is easily titrated from 300 to 3600 mg/day in divided doses. However, along with being relatively expensive, gabapentin often causes significant sedation, which is effectively dose limiting.

Tizanidine (Zanaflex), a centrally acting alpha-adrenergic agonist, is also used to manage spasticity. Tizanidine has effects similar to those of baclofen, but it produces less weakness and more sedation. This drug is titrated from 2 to 32 mg/day in divided doses.

Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. Because of their greater invasiveness, these treatments are usually reserved for the most difficult cases.

Impaired ambulation

Oral, sustained-release dalfampridine (Ampyra) has been shown to improve walking ability in patients with MS. It is the only medication approved by the FDA for this indication for MS patients.

Fourteen weeks of treatment with dalfampridine was found to improve walking ability in a significant percentage of patients in a randomized, multicenter, double-blind, phase III trial (which was not limited to any specific form of MS). ^[131] The mechanism of action of dalfampridine appears to be restoration of action potential conduction via blockade of an as-yet uncharacterized subset of potassium channels in demyelinated axons.

An increased risk of seizures has been observed in patients taking dalfampridine; therefore, it is contraindicated in patients with a history of seizures. Most seizure events in patients taking dalfampridine occur within days to weeks after starting the recommended dose, and they happen in patients without a history of seizures. Because dalfampridine is eliminated through the kidneys and its blood levels (along with the risk of seizures) can be enhanced in patients with kidney dysfunction, now the FDA has changed the dalfampridine label (July 2012) to recommend that kidney function be checked in patients before starting the drug (moderate-to-severe renal impairment is a contraindication) and monitored at least annually while the treatment continues. Additionally, patients who miss a dose of should not take an extra dose, since an extra dose can increase seizure risks. Dalfampridine should be discontinued permanently if a seizure occurs.

For details on recommendations to patients and physicians, see FDA Drug Safety Communication: Seizure risk for multiple sclerosis patients who take Ampyra (dalfampridine).

Urinary tract infections have been reported more frequently in patients receiving dalfampridine 10 mg twice daily (12%) than in those receiving placebo (8%). ^[132]

Bladder problems

Bladder dysfunction in MS may consist of failure to store, failure to empty, or a combination of the two. Interventions for failure to store include the following ^[133] :

• Scheduled voiding

• Limiting fluid intake in the evening

• Using anticholinergic medications (eg, oxybutynin)

• Eliminating diuretics (eg, caffeine)

• Injecting onabotulinumtoxinA (Botox) into the bladder ^[134]

Failure to empty is characterized by a large, flaccid bladder and an inability of the urinary sphincter to relax. Symptoms include urgency, frequency, hesitancy, nocturia, incontinence, incomplete emptying, and frequent urinary tract infections. Interventions include intermittent catheterization or the use of alpha-blockers (eg, prazosin) and, possibly, the Crede maneuver.

Combined dysfunction is due to incoordination of the detrusor and sphincter (dyssynergia). Symptoms in combined dysfunction are similar to those of failure to empty. Interventions may include anticholinergic medications or intermittent catheterization.

Bladder problems usually can be managed appropriately after a careful history, physical examination, and urinalysis. If initial attempts at symptom management are not effective, more studies, such as renal ultrasonography, voiding cystourethrography, renal scanning, or urodynamic studies, may be indicated to better characterize the problem. Recurrent urinary tract infections are common in MS patients with end-stage bladder disability.

Bowel problems

Constipation, the most common bowel problem in MS patients, may result from neurogenic bowel, immobility, or restricted fluid intake. The first step in management of constipation is to increase fluid intake to 8-10 cups daily and increase dietary fiber to 15 g.

Next, it is essential to establish a consistent bowel program time. A bowel program is most effective if done at least every other day and preferably after a meal, which takes advantage of the body's gastrocolic reflex. Sitting in an upright position, rather than lying in bed, permits gravity to assist in evacuation. The patient should also be involved in an exercise program, consisting of walking or simply performing chair exercises.

Pharmacologic management of constipation includes stool softeners, bulk formers, or laxatives. Stool softeners, such as docusate sodium, work by decreasing surface tension, allowing water to enter the stool. Bulk formers (eg, Metamucil, Per Diem, Citrucel, FiberCon) work by increasing the bulk and weight of the stool. Laxatives act as an irritant to the bowel, increasing peristalsis; they generally work within 8-12 hours. Examples include milk of magnesia and Peri-Colace.

For patients with a neurogenic bowel or with poor abdominal muscle tone, rectal suppositories may be part of an effective bowel program that can help prevent incontinence episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl and glycerin.

Nonpharmacologic techniques of bowel management include proper positioning, abdominal massage, and digital stimulation. Abdominal massage performed in the direction of bowel peristalsis, from ascending toward the descending colon, can be useful. Finally, digital stimulation, in which a lubricated finger is inserted gently into the rectum and moved side to side along the wall of the rectum, can stimulate a bowel movement.

Diarrhea

Diarrhea, if it occurs, typically is not related to MS per se. Rather, it is more likely from fecal impaction, diet, irritation of the bowel, or overuse of laxatives or stool softeners. Diarrhea may also be an adverse effect of medications.

Diarrhea is treated first by eliminating the cause and then, possibly, with bulk formers (eg, psyllium). Drugs that slow the muscles of the bowel, such as Lomotil (diphenoxylate and atropine) are rarely indicated.

Sexual dysfunction

Sexual dysfunction in patients with MS may be associated with other symptoms of the disease, such as fatigue, spasticity, depression and bowel dysfunction. Erectile dysfunction is common in men with MS and may be treated with oral phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra, Staxyn); for more information, see Erectile Dysfunction. Penile prostheses are an alternative for men with erectile dysfunction who do not respond to medical management.

Tremor

Tremor is difficult to manage in MS patients. Several treatments have been used for tremor, with little success. Treatments have included anticonvulsants, isoniazid, primidone, benzodiazepines, propranolol, and ondansetron.

Optic neuritis

In the Optic Neuritis Treatment Trial (ONTT), patients recovered visual function regardless of whether they were treated with oral prednisone, intravenous methylprednisolone (IVMP), or placebo. ^[135] However, patients who received IVMP recovered faster. IVMP also seemed to decrease the incidence of the development of MS over a 2-year period, but this effect was not sustained after year 3. Patients treated with oral prednisone demonstrated an increased incidence of recurrent optic neuritis compared with those who were administered IVMP or placebo.

Patients with MS may benefit from referral to physical therapists, occupational therapists, and speech therapists. Speech therapists assess the patient's speech, language, and swallowing abilities and may work with the patient on compensatory techniques to manage cognitive problems.

Physical therapy

Physical therapists provide assessment of gross motor skills (eg, ambulation) and assessment and training in appropriate assistive devices to improve mobility in patients with MS. They evaluate and train the patient in appropriate exercise programs to decrease spasticity, maintain range of motion, strengthen muscles, and improve coordination. They also provide invaluable input into the prescription of appropriate seating systems for the nonambulatory patient.

Physical therapy for spasticity in patients with MS includes the establishment of a stretching program in which joints are moved slowly to positions that stretch the spastic muscles. Each position is held for at least a minute to allow the stretched muscle to slowly relax. Stretching exercises may be performed in a cool (85°F) pool, which provides buoyancy and cooling. Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.

Nonpharmacologic treatments for primary pain in MS, such as the use of imagery or distraction, can be helpful. Transcutaneous electrical nerve stimulation (TENS) is useful in some patients.

Nonpharmacologic treatment for secondary pain includes moist moderate heat, massage, physical therapy, and exercise (eg, stretching). Devices such as the WalkAide and Bioness use functional electrical stimulation to aid walking and may be helpful to some MS patients.

Occupational therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing activities of daily living, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs. They can provide treatment for cognitive dysfunction.

Treatment approaches for cognitive dysfunction include cognitive retraining and the use of compensatory strategies. Cognitive retraining involves the employment of repetitive drills and mentally stimulating exercises designed to strengthen areas of cognition that are weak.

Compensatory strategies emphasize coping methods or organizational skills to help patients use their strengths to compensate for areas of relative weakness. Such strategies can include the following:

• Maintaining a consistent routine

• Making lists

• Keeping a daily planner

• Organizing the home or work environment

In providing education on MS management to patients with cognitive impairment, it is important to involve family or caregivers in training, provide step-by-step instructions, and present information in a visual and verbal format. New topics should be presented at times when fatigue is less likely to be an issue.

Surgical procedures that relate to MS 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.

Preliminary evidence suggests that persons with high circulating levels of vitamin D are at lower risk of MS ^[42] ; thus, vitamin D supplementation may reduce the risk of developing MS and of conversion from a first clinical event suggestive of MS to clinically definite MS. Vitamin D may also reduce the relapse rate among patients with relapsing-remitting MS. ^[136]

For healthy individuals, serum vitamin D concentrations of 50-125 nmol/L (20-50 ng/mL) are generally considered adequate for bone and overall health, according to the Institute of Medicine. ^[137] Serum vitamin D concentrations of 75-100 nmol/L (30-40 ng/mL) have been proposed as optimal for patients with MS. ^[138]

Achieving these levels may require the use of supplemental vitamin D in doses up to 3000 IU daily; maintaining these levels appears to require doses of 500 to 800 IU daily. ^[138] The safety and effectiveness of vitamin D supplementation among patients with MS remains unclear, however. ^[139]

Early treatment with immunomodulatory drugs has been associated with decreased disability progression and lower secondary relapse rates. Patients with MS must understand, however, that current immunomodulatory drugs are not curative.

The Uhthoff phenomenon is an exacerbation of MS symptoms that is induced by exercise, a hot meal, or a hot bath. The most notable symptoms seen with this phenomenon are transient visual obscurations, dyschromatopsia, and contrast sensitivity changes. The symptoms tend to resolve with restoration of euthermia, typically within 60 minutes to 24 hours. Sunlight by itself is not considered to be deleterious, but excessive exposure may mimic the effects of high temperatures.

On the other hand, the impact of stress on MS exacerbations is thought to be minimal or noncontributory. Likewise, trauma has no demonstrated impact on the disease course.

Patients with MS may require multiple consultations to rule out other causes of their symptoms. A significant number of MS patients will need a multidisciplinary approach to their care. 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.

The following are the most common consultation services involved in referrals from an MS clinic:

• Physical therapy and rehabilitation specialist

• Speech therapist

• Ophthalmologist

• Urologist: Urologic consultation may be warranted to help in the assessment and treatment of incontinence

• Gastroenterologist

• Neuropsychologist: Neuropsychologic consultation is advisable so that a baseline assessment for future reference can be obtained; such consultation is especially important in patients with primary cognitive involvement

• Psychiatrist

• Otolaryngologist

It is not unusual for patients with more advanced MS to lose all family support, become separated from their spouse, lose the ability to walk, and require constant psychiatric and nursing assistance. These patients create a challenge for the physician who is not trained in handling the demanding administrative or ancillary aspects of medical care. A social worker specialist can be instrumental in helping to address these issues.

For the newer oral therapies with specific adverse effects, consultations with specialists may be warranted. Consultation with a cardiologist to evaluate the appropriateness of fingolimod in a patient with a history of nonrecent myocardial infarction, with an ophthalmologist to examine the appropriateness of fingolimod in patients with visual symptoms (to evaluate potential macular edema), or with a nephrologist for MS patients with mild-to-moderate renal insufficiency (for consideration of treatment with dalfampridine or teriflunomide) may be required.

Recommended follow-up is yearly at minimum. Patients receiving therapy with certain agents (eg, natalizumab, fingolimod) require monitoring as often as every 3-4 months. Clinicians who also provide primary care for the patient with MS can perform routine health maintenance at these annual visits. For patients with worsening symptoms, a medical cause, such as infection, should be ruled out first before assuming that the patient is having an exacerbation.

Once a patient/provider relationship is established, a great deal of symptom management can be provided through careful telephone triage. More frequent visits, such as bimonthly or quarterly, may be necessary for patients with difficult symptoms, such as intractable spasticity, or for individuals whose social support system is not as stable as necessary.

Vaccination

MS specialists generally advise against the use of live-attenuated virus vaccines in patients with MS, particularly in patients receiving immunosuppressive therapy. Despite concerns that vaccination may trigger the onset or relapses of MS, almost all killed-virus vaccines studied have been found safe in this regard. ^[51]

The Vaccine Safety Datalink Research Group of the US Centers for Disease Control and Prevention (CDC) found that vaccination against hepatitis B, influenza, tetanus, measles, or rubella did not increase the risk of developing MS or optic neuritis. ^[140] The Vaccines in Multiple Sclerosis Study Group reported that vaccination for tetanus, hepatitis B, or influenza does not increase the short-term risk of relapses. ^[141]

Injectable influenza vaccine has been extensively studied in MS and found to be safe. However, the form of influenza vaccine that is delivered via a nasal spray (FluMist) is a live-virus vaccine and is not recommended for MS patients.

Varicella-zoster vaccine (Zostavax) is also a live-attenuated vaccine. However, in a patient with a definite history of chicken pox or a positive antibody test, this vaccine is likely to be safe and beneficial, although full discussion of the risks and benefits must precede its use. Discussion of risks and benefits is also important before a close family member of an MS patient receives this or any other live-virus vaccine. ^[51]

A study in 7 patients with relapsing-remitting MS who received yellow fever vaccine found a significantly increased risk of MS relapse during the 6 weeks following the vaccination. For MS patients who must travel to areas where yellow fever is endemic, these researchers advise careful weighing of the risk of relapse with the risk of contracting yellow fever, which is a potentially fatal illness. ^[142]

No studies have been published addressing the safety of the following vaccines in MS:

• Pneumonia

• Meningitis

• Typhoid

• Polio

• Hepatitis A

• Human papillomavirus (HPV)

• Pertussis

There are rare reports of demyelination syndromes following administration of the HPV vaccine. Thus, physicians should thoroughly discuss the possible benefits and risks of this vaccine before administering it. ^[51]

Some special considerations for vaccination in MS patients from the National Multiple Sclerosis Society are as follows ^[51] :

• In patients experiencing a serious relapse that affects their ability to carry out activities of daily living, defer vaccination until 4-6 weeks after the onset of the relapse

• Vaccine response may be blunted in patients who have received immune globulin in the past 3 months or who are taking natalizumab or fingolimod.