Management of multiple sclerosis
The management of multiple sclerosis (MS) is a multifaceted, patient-centered approach designed to slow disease progression, mitigate relapses, alleviate debilitating symptoms, and improve quality of life for adults with this chronic autoimmune disorder.[1] Central to this strategy are disease-modifying therapies (DMTs), which target the underlying inflammatory processes; acute relapse treatments; symptomatic pharmacotherapies; rehabilitation services; and lifestyle interventions tailored to individual needs and disease subtype, such as relapsing-remitting, primary progressive, or secondary progressive MS.[2] This comprehensive framework emphasizes early intervention, regular monitoring, and shared decision-making to minimize disability and enhance long-term outcomes.[3] Disease-modifying therapies form the cornerstone of MS management, particularly for relapsing forms, where they reduce the frequency of relapses by approximately 30-70%, slow the accumulation of brain lesions visible on MRI, and delay disability progression.[1] Over 20 FDA-approved DMTs are available, categorized by administration route and mechanism: injectable options like interferon beta-1a and glatiramer acetate modulate immune responses; oral agents such as fingolimod and teriflunomide inhibit lymphocyte migration; and infused monoclonal antibodies like ocrelizumab and natalizumab deplete specific immune cells.[1] The American Academy of Neurology (AAN) recommends initiating DMTs in patients with relapsing MS who experience recent clinical relapses or active MRI findings, with selection guided by disease severity, patient preferences, comorbidities, and risks such as infections or progressive multifocal leukoencephalopathy (PML).[3] For primary progressive MS, ocrelizumab is the only approved DMT shown to alter progression in ambulatory patients.[3] Acute relapses, characterized by new or worsening neurological symptoms lasting over 24 hours, are managed primarily with high-dose corticosteroids to accelerate recovery and reduce inflammation, such as oral methylprednisolone (500 mg daily for 5 days) or intravenous methylprednisolone (1 g daily for 3-5 days) for severe cases.[2] If steroids fail, plasma exchange (plasmapheresis) may be considered for non-responders.[1] Symptom management addresses prevalent issues like fatigue (treated with amantadine or modafinil), spasticity (first-line baclofen or gabapentin), bladder dysfunction (anticholinergics or catheterization), and mobility impairments (dalfampridine or physical therapy), often requiring multidisciplinary input from neurologists, therapists, and specialists.[2][1] Rehabilitation and supportive care play a vital role, with physical and occupational therapies improving strength, coordination, and daily function, while exercise programs like yoga or swimming help combat fatigue and heat sensitivity.[1] Lifestyle modifications, including a Mediterranean diet and stress reduction techniques, are encouraged to potentially lower disability risk.[1] Ongoing annual assessments by MS specialists ensure treatment optimization, adherence monitoring, and comorbidity management, with patient education on driving restrictions and support services essential for holistic care.[2][3]Acute Exacerbation Management
Pharmacological Interventions
High-dose corticosteroids represent the first-line pharmacological intervention for managing acute exacerbations in multiple sclerosis (MS), aimed at suppressing the inflammatory response and accelerating symptom recovery. These agents, primarily methylprednisolone, work by inducing lymphocytopenia, reducing the number of IgG-producing cells, and stabilizing the blood-brain barrier to decrease edema and inflammation in the central nervous system. The standard protocol involves administering 1 g of intravenous methylprednisolone daily for 3 to 5 days, followed optionally by an oral taper of prednisone at 1 mg/kg/day for 5 to 10 days to minimize rebound; oral methylprednisolone at 500 mg/day for 5 days is an equivalent alternative with comparable efficacy and fewer logistical challenges. Randomized controlled trials demonstrate that this therapy significantly improves neurological function compared to placebo, with one early study showing 12 of 13 treated patients achieving marked recovery versus 4 of 10 in the placebo group. Overall, corticosteroids hasten recovery time by approximately 50%, though they do not alter the long-term prognosis or prevent residual deficits. For relapses refractory to corticosteroids—defined as lack of substantial improvement within 5 to 7 days—therapeutic plasma exchange (plasmapheresis) serves as the primary escalation therapy, particularly in severe cases affecting motor or visual function. This procedure involves 5 to 7 exchanges of 1 to 1.5 plasma volumes every other day over 10 to 14 days, removing autoantibodies and inflammatory mediators from the blood to interrupt ongoing demyelination. Evidence from a pivotal randomized, sham-controlled trial indicates moderate to marked improvement in 42% of treated patients with severe, steroid-unresponsive relapses, compared to 6% in the sham group, supporting its use in relapsing-remitting MS with debilitating symptoms. The American Academy of Neurology guidelines recommend plasma exchange for such fulminant attacks, emphasizing patient selection based on rapid progression and significant disability risk. Adrenocorticotropic hormone (ACTH), administered as repository corticotropin injection (e.g., H.P. Acthar Gel) at 80 to 120 units intramuscularly or subcutaneously daily for 5 to 15 days, offers an adjunctive option for rare cases of non-response to corticosteroids or in patients intolerant to steroids. Historically introduced in the 1950s and FDA-approved for MS exacerbations since 1978, ACTH exerts anti-inflammatory and immunomodulatory effects through melanocortin receptor activation, independent of its steroidogenic properties, and shows efficacy comparable to high-dose methylprednisolone in older trials. Its modern use remains limited due to the availability of synthetic corticosteroids, reserved primarily for specific non-responders. Common risks associated with these interventions include steroid-induced complications such as gastrointestinal irritation, hyperglycemia, psychiatric disturbances (e.g., mood changes or psychosis in up to 33% of cases), osteoporosis with repeated courses, and increased infection susceptibility due to immunosuppression. Mitigation strategies encompass prophylactic proton pump inhibitors (e.g., omeprazole) for gastrointestinal protection, blood glucose monitoring with insulin if needed, psychiatric evaluation for severe mood alterations, and bone density assessments with calcium and vitamin D supplementation for long-term courses; plasma exchange carries procedural risks like hypotension or citrate toxicity, managed through careful monitoring and hydration. Following relapse resolution, transition to disease-modifying therapies is often recommended to prevent future episodes.Supportive Measures
Supportive measures during acute multiple sclerosis (MS) relapses focus on ensuring patient safety, promoting comfort, and preventing complications through non-pharmacological and basic interventions. Hospitalization is indicated for severe relapses that cause significant functional impairment, such as inability to walk unaided or vision loss exceeding 20/200 acuity, particularly when home-based care cannot meet medical or social needs.[4][5] In such cases, close monitoring for complications like urinary retention and deep vein thrombosis (DVT) is essential, as immobility and inflammation increase DVT risk, with studies showing up to a twofold higher incidence of venous thromboembolism in MS patients during exacerbations.[4][6] Hydration, rest, and symptomatic pain relief form the cornerstone of supportive care to facilitate recovery and reduce the need for prolonged hospitalization. Adequate fluid intake prevents dehydration, which can exacerbate symptoms, while enforced rest minimizes fatigue and supports neurological stabilization, with guidelines noting that most relapses can be managed outpatient with these measures, potentially shortening hospital stays by enabling early discharge.[7][8] Pain, often musculoskeletal or neuropathic during relapses, is typically addressed with non-steroidal anti-inflammatory drugs (NSAIDs) alongside these supportive strategies, as recommended in nursing guidelines for acute MS care.[9] These measures are employed in conjunction with corticosteroids to optimize outcomes.[4] Bladder dysfunction, common in acute relapses due to spinal cord involvement, requires prompt management to avoid urinary retention and secondary complications. Intermittent self-catheterization is the preferred method for incomplete emptying, with protocols emphasizing regular assessment and hygiene to prevent urinary tract infections, which can mimic or worsen relapses.[4][10] The American Academy of Neurology (AAN) and National Institute for Health and Care Excellence (NICE) guidelines advocate screening for bladder issues and timely urology referral if needed, reducing infection rates through proactive protocols.[10][4] Patient education plays a critical role in supportive care by empowering individuals to recognize relapses—defined as new or worsening neurological symptoms lasting over 24 hours, excluding infection or fever—and seek timely medical attention. Education includes guidance on distinguishing true relapses from pseudo-relapses triggered by heat or stress, with emphasis on early intervention to limit disability accrual.[4] The 2025 Best Practices Update underscores the importance of provider-patient communication on relapse signs and prompt care-seeking to improve long-term prognosis and quality of life.[11]Disease-Modifying Therapies
Established Treatments for Relapsing MS
Established disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) focus on immunomodulation to reduce relapse rates, slow disability progression, and limit new lesion formation on MRI. These therapies are categorized by administration route and mechanism, with selection guided by disease activity, patient preferences, and risk profiles. Injectable, oral, and infusion options form the backbone of treatment, with high-efficacy agents increasingly recommended for aggressive disease to achieve no evidence of disease activity (NEDA). Injectable therapies include interferon beta formulations, such as intramuscular Avonex or subcutaneous Betaseron, which exert immunomodulatory effects by reducing pro-inflammatory cytokine production and enhancing anti-inflammatory responses. These agents reduce annualized relapse rates (ARR) by approximately 30%, based on pivotal phase III trials like the Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) study for subcutaneous interferon beta-1a. Glatiramer acetate (Copaxone), administered subcutaneously daily or three times weekly, mimics myelin basic protein to promote regulatory T-cell responses and shift immune profiles toward tolerance, achieving a 29-33% relapse reduction in the U.S. Pivotal and European/Canadian Glatiramer Acetate Study (REGARDS). Both classes are self-administered weekly or more frequently, with common side effects including injection-site reactions and flu-like symptoms for interferons. Oral therapies offer convenience for patients preferring non-injectable options. Fingolimod (Gilenya), a sphingosine-1-phosphate receptor modulator, sequesters lymphocytes in lymph nodes to prevent central nervous system infiltration, reducing ARR by 48% compared to interferon beta in the Trial Assessing Injectable Interferon Versus Fingolimod for Relapses and Disability (TRANSFORMS). Dimethyl fumarate (Tecfidera), which activates the Nrf2 pathway to induce antioxidant enzymes and modulate immune cells, demonstrated a 53% ARR reduction versus placebo in the Define study. Teriflunomide (Aubagio), an inhibitor of dihydroorotate dehydrogenase that limits pyrimidine synthesis in proliferating lymphocytes, yields 31-36% relapse reductions in trials like TEMSO. Overall, these orals achieve 40-50% efficacy in relapse prevention across meta-analyses. Monitoring is essential, particularly for fingolimod, which requires baseline lymphocyte counts, ECG for bradycardia risk, and periodic ophthalmologic exams due to macular edema potential. Infusion therapies target highly active disease. Natalizumab (Tysabri), a monoclonal antibody blocking alpha-4 integrin to inhibit leukocyte migration across the blood-brain barrier, reduces ARR by 68% in the AFFIRM trial for RRMS patients. It is administered intravenously every four weeks but carries a risk of progressive multifocal leukoencephalopathy (PML) due to JC virus (JCV) reactivation, necessitating stratified risk assessment via JCV antibody index testing, prior immunosuppressant exposure, and treatment duration. Extended-interval dosing (every six weeks) further mitigates PML incidence while preserving efficacy, as supported by real-world data. High-efficacy options, particularly anti-CD20 monoclonal antibodies, deplete B cells to suppress autoimmune responses and are favored for rapid control in early or aggressive RRMS. Ocrelizumab (Ocrevus), administered intravenously every six months, reduces ARR by 46-47% versus interferon beta in OPERA I/II trials, with broader placebo-adjusted reductions of 60-70% in lesion activity. Ofatumumab (Kesimpta), a fully human anti-CD20 antibody given subcutaneously monthly at home, achieves 50-59% ARR reductions compared to teriflunomide in ASCLEPIOS trials, offering convenience over infusions. Ublituximab (Briumvi), another glycoengineered anti-CD20 infused every six months after initial doses, demonstrated 59% ARR reduction versus teriflunomide in ULTIMATE I/II studies. As of 2025, subcutaneous formulations like ofatumumab and ocrelizumab (Ocrevus ZUNOVO, approved 2024) expand access and improve patient adherence.[12] Treatment escalation strategies, per guidelines from the American Academy of Neurology (2018, reaffirmed 2021) and ECTRIMS/EAN (2018), advocate initiating high-efficacy DMTs early in patients with aggressive disease—defined by ≥2 relapses in the prior year, ≥1 gadolinium-enhancing lesion, or significant T2 burden—to minimize long-term disability accumulation. This approach outperforms moderate-efficacy starters in reducing confirmed disability progression by 20-30% over five years, based on comparative effectiveness studies.[13]Therapies for Progressive MS
Progressive multiple sclerosis (MS), encompassing primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive relapsing MS, presents unique therapeutic challenges due to its predominant neurodegenerative pathology over inflammatory processes, limiting the efficacy of many disease-modifying therapies (DMTs) designed for relapsing forms.[14] Unlike relapsing MS, where inflammation drives relapses, progressive MS involves compartmentalized central nervous system inflammation and axonal degeneration, resulting in fewer approved options and a focus on slowing disability progression rather than preventing relapses.[15] Current strategies emphasize early intervention with targeted immunomodulators, though evidence remains modest, with ongoing research highlighting the need for neuroprotective agents.[16] Ocrelizumab, a monoclonal antibody that depletes CD20-positive B cells, was the first DMT approved by the FDA in 2017 specifically for PPMS, based on the phase 3 ORATORIO trial demonstrating a 24% relative reduction in the risk of 12-week confirmed disability progression (CDP) compared to placebo, alongside slower brain volume loss. Administered as intravenous infusions every six months, it targets B-cell mediated inflammation implicated in progressive disease, though its impact on neurodegeneration is indirect. Recent 2025 data from Genentech's analysis of advanced PPMS patients showed a 30% reduction in the risk of 12-week composite CDP, with long-term real-world studies confirming sustained disability stabilization over five years in up to 76% of treated patients, underscoring its role as the cornerstone therapy for PPMS.[17][18] For active SPMS—characterized by ongoing relapses or MRI activity—siponimod (Mayzent), a selective sphingosine-1-phosphate (S1P) receptor modulator targeting S1P1 and S1P5 receptors, is FDA-approved since 2019, following the EXPAND trial which reported a 21% reduction in 6-month CDP risk versus placebo, particularly in patients with inflammatory features. Oral once-daily dosing traps lymphocytes in lymph nodes to reduce CNS infiltration, but requires CYP2C9 genotyping for dose adjustment and first-dose cardiac monitoring in patients with preexisting conditions like bradycardia or atrioventricular block to mitigate risks of transient heart rate reduction, unlike broader S1P modulators.[19] Long-term extensions up to five years affirm its safety profile, with no increased infection risk beyond placebo.[20] Options for non-active SPMS, lacking relapses or new lesions, are more restricted due to the dominance of neurodegeneration. Mitoxantrone, an anthracenedione chemotherapy agent approved in 2000 for worsening relapsing-remitting MS, progressive-relapsing MS, and SPMS, is occasionally used off-label here at 12 mg/m² intravenously every three months, with a strict lifetime cumulative dose limit of 140 mg/m² to prevent irreversible cardiotoxicity, including heart failure in up to 2.9% of patients.[21] Its immunosuppressive effects via DNA intercalation offer modest slowing of progression, but risks of myelosuppression, secondary malignancies (0.25% leukemia incidence), and poor tolerability have led to rare use in modern practice.[22] The 2018 American Academy of Neurology (AAN) guidelines (reaffirmed 2021), with no major updates as of 2025, endorse ocrelizumab for PPMS and siponimod for active SPMS (Level B recommendations), while suggesting mitoxantrone for worsening SPMS (Level C); off-label use of high-efficacy relapsing DMTs, such as natalizumab or fingolimod, may be considered in early progressive disease with evidence of activity, based on trials showing modest 15-20% reductions in progression rates, though AAN emphasizes shared decision-making due to limited prospective data.[13] High-efficacy relapsing therapies can serve as bridging options in select progressive cases to delay transition to non-active phases.[3]| Therapy | Indication | Key Efficacy | Mechanism | Major Risks/Monitoring |
|---|---|---|---|---|
| Ocrelizumab | PPMS | 24% reduction in 12-week CDP (ORATORIO); 30% in advanced (2025 data) | B-cell depletion | Infusion reactions; infections; PML risk |
| Siponimod | Active SPMS | 21% reduction in 6-month CDP (EXPAND) | S1P1/5 modulation | Cardiac effects (first-dose monitoring if preexisting); macular edema |
| Mitoxantrone | Non-active/worsening SPMS | Modest progression delay | DNA intercalation, immunosuppression | Cardiotoxicity (cumulative 140 mg/m²); leukemia; myelosuppression |