A Research Guide for
Multiple Sclerosis

The McDonald criteria have been the diagnostic standard for MS since 2001 and have been revised in 2005, 2010, 2017, and most recently in 2024 (published in The Lancet Neurology, 2025). The 2024 revision introduced several important changes:

• Optic nerve as a fifth location: The 2024 criteria add the optic nerve as a fifth anatomical region that can demonstrate dissemination in space (the previous four were periventricular, cortical/juxtacortical, infratentorial, and spinal cord). Optic nerve involvement can be shown by MRI of the optic nerves, visual evoked potentials, or OCT — making it easier to diagnose MS in people who present with optic neuritis.
• Central vein sign (CVS): MS lesions characteristically form around small veins in the brain. Using specialized MRI sequences, a central vein can be seen running through the middle of MS lesions. The 2024 criteria now accept CVS as a supportive criterion for dissemination in space — it helps distinguish MS lesions from mimics (like those caused by migraine or small vessel disease), reducing misdiagnosis.
• Paramagnetic rim lesions (PRLs): Some MS lesions show a dark rim on certain MRI sequences, indicating ongoing “smoldering” inflammation with activated microglia and macrophages at the lesion edge. PRLs are highly specific to MS and are now accepted as supportive diagnostic criteria. They are also emerging as biomarkers for progressive biology (more on this in the progressive MS section).
• Expanded use of cerebrospinal fluid (CSF): The presence of oligoclonal bands in CSF (found in over 95% of MS patients) can now substitute for dissemination in time in more clinical scenarios, allowing earlier and more confident diagnosis.
• Kappa free light chains: Elevated kappa free light chains in CSF have been added as an alternative to oligoclonal bands for demonstrating intrathecal antibody production.

The overall impact: MS can now be diagnosed more quickly and more accurately, with fewer people being misdiagnosed and fewer being told to “wait and see” when early treatment would be beneficial.

When MS is suspected, the following investigations are typically performed:

• Brain and spinal cord MRI with gadolinium contrast: The cornerstone of MS diagnosis. MRI detects lesions (areas of demyelination) in characteristic locations: periventricular (around the ventricles), juxtacortical (near the cortex), infratentorial (brainstem and cerebellum), and spinal cord. Gadolinium enhancement indicates active inflammation. A single MRI can sometimes establish both dissemination in space and time if it shows both enhancing and non-enhancing lesions.
• Lumbar puncture (spinal tap): Examines cerebrospinal fluid for oligoclonal bands and elevated kappa free light chains — markers of immune activity within the central nervous system. Not always required if MRI is definitive, but adds diagnostic confidence and is particularly useful in atypical presentations.
• Visual evoked potentials (VEP): Measures how quickly the optic nerve conducts signals. Slowed conduction suggests prior optic nerve demyelination, even if the patient does not recall visual symptoms. Useful for demonstrating dissemination in space.
• Blood tests: Primarily used to exclude conditions that can mimic MS, including neuromyelitis optica spectrum disorder (NMOSD, tested via aquaporin-4 antibody), systemic lupus, sarcoidosis, vitamin B12 deficiency, and infections. These “rule-out” tests are a critical part of the diagnostic process.
• Optical coherence tomography (OCT): A non-invasive eye scan that measures retinal nerve fiber layer thickness. Thinning indicates prior optic nerve damage and is increasingly used for both diagnosis and monitoring.

Neurofilament light chain (NfL) is a protein released into the blood when nerve fibers are damaged. Blood NfL levels can now be measured commercially using the ultrasensitive Quanterix Simoa platform, and NfL testing is becoming an important tool in MS care:

• Monitoring subclinical disease activity: Elevated NfL levels may indicate ongoing nerve damage even when MRI looks stable and the patient feels well. This can detect treatment failure before visible damage accumulates.
• Assessing treatment response: Effective DMTs typically reduce NfL levels. A persistently elevated NfL on treatment may prompt a switch to a more effective therapy.
• Prognostic information: Higher NfL levels at baseline are associated with faster disability progression and brain atrophy over subsequent years.

NfL is not specific to MS — it rises with any cause of neurological damage. Its value lies in tracking changes over time within an individual patient, rather than in isolated single measurements. Many MS centers now include periodic NfL monitoring as part of routine care.

CIS is a single episode of neurological symptoms caused by inflammation and demyelination in the central nervous system, lasting at least 24 hours. Common CIS presentations include:

• Optic neuritis: Pain with eye movement and blurred or lost vision in one eye. This is the most common CIS presentation.
• Transverse myelitis: Numbness, tingling, weakness, or bladder problems caused by a spinal cord lesion.
• Brainstem/cerebellar syndrome: Double vision, vertigo, facial numbness, or coordination problems.

The risk of developing MS after CIS depends heavily on MRI findings. If the brain MRI at the time of CIS shows additional clinically silent lesions (meaning the single episode was not truly isolated), the probability of developing definite MS within the next several years is high — often greater than 80%. If the MRI is normal, the risk is much lower but not zero.

Multiple clinical trials (BENEFIT, CHAMPS, PreCISe, REFLEX) have demonstrated that starting DMT at the CIS stage delays or prevents conversion to definite MS. The 2024 McDonald criteria revisions make it easier to diagnose MS at the first clinical event if MRI and CSF findings are sufficient, enabling earlier treatment.

RIS occurs when MRI lesions typical of MS are found incidentally — for example, during imaging for headaches or head trauma — in a person who has never experienced MS symptoms. This is an increasingly common scenario as MRI becomes more widely used.

Roughly one-third of people with RIS develop clinical MS symptoms within five years. Risk factors for progression include younger age, spinal cord lesions, and CSF oligoclonal bands. Two randomized trials provide the first evidence that some people with RIS benefit from early treatment: the ARISE trial (dimethyl fumarate in RIS) reduced the risk of a first clinical event by roughly 80%, and the TERIS trial (teriflunomide in RIS) reduced it by 63% (72% in adjusted analysis). However, the decision to treat RIS is still individualized, and not all RIS requires immediate therapy.

A first MS attack typically develops over hours to days, plateaus for days to weeks, and then gradually improves over weeks to months. Common first attacks include vision loss in one eye, weakness or numbness in a limb, electric shock sensations down the spine with neck flexion (Lhermitte’s sign), or balance and coordination problems.

Acute relapses are typically treated with high-dose intravenous corticosteroids (usually methylprednisolone 1 gram daily for 3–5 days) to speed recovery. Steroids reduce the duration and severity of a relapse but do not change the long-term outcome of that specific relapse. For severe attacks that do not respond to steroids, plasma exchange (plasmapheresis) is an effective alternative.

Recovery from a first attack is often substantial, and many people return to their baseline. However, the first attack is also a critical window: it is the time to get a thorough diagnostic workup and begin the conversation about disease-modifying therapy.

MS is complex enough that it genuinely benefits from specialist care. An MS-specialist neurologist (sometimes called a neuroimmunologist) sees MS patients daily, stays current with rapidly evolving treatment options, and has experience managing the nuances of DMT selection, monitoring, and switching. General neurologists provide excellent care for many conditions, but for a disease with 20+ treatment options and a rapidly changing landscape, a specialist matters.

Key markers of a good MS neurologist:

• MS is a primary focus of their practice (not one of many neurological conditions they treat occasionally)
• They are familiar with all current DMTs, including the highest-efficacy options
• They have a team that includes MS nurses, coordinators, and access to rehabilitation services
• They are affiliated with a center that participates in clinical trials (even if you never enroll, it indicates the practice stays at the cutting edge)
• They use NEDA (No Evidence of Disease Activity) or similar treatment targets

Beyond your neurologist, a comprehensive MS care team may include:

• MS nurse specialist: Often your primary point of contact for day-to-day questions, relapse management, and DMT coordination.
• Physical therapist (PT): Develops exercise programs to maintain strength, balance, and walking ability. MS-specialized PTs understand fatigue management and heat sensitivity.
• Occupational therapist (OT): Helps adapt daily tasks and home environments to maintain independence. Essential for managing hand function, cognitive strategies, and energy conservation.
• Mental health professional: Depression and anxiety are extremely common in MS (affecting more than 50% of patients over their lifetime) and are undertreated. A psychologist or psychiatrist experienced with chronic illness is valuable from the start, not just when crisis hits.
• Speech-language pathologist: For difficulties with speech (dysarthria) or swallowing (dysphagia), which can develop in more advanced MS.
• Urologist: Bladder dysfunction affects 80% or more of MS patients at some point. A urologist experienced with neurogenic bladder is an important team member.
• Primary care physician: Manages overall health, vaccinations (important before starting certain DMTs), cardiovascular risk, and coordinates care.
• Pharmacist / specialty pharmacy: Many DMTs are specialty medications requiring special handling, monitoring, and insurance coordination.

At diagnosis, several baseline measurements should be established to track changes over time:

• Brain and spinal cord MRI: Detailed baseline images to compare against future scans.
• Expanded Disability Status Scale (EDSS): A standardized neurological examination scored 0–10 that measures disability level. This is the universal language of MS clinical trials and will be tracked at every visit.
• Symbol Digit Modalities Test (SDMT): A 90-second cognitive screening test that is sensitive to MS-related cognitive changes. Should be repeated annually at minimum.
• Optical coherence tomography (OCT): Baseline retinal nerve fiber layer thickness, measured quickly and non-invasively.
• NfL blood level: Baseline neurofilament measurement for longitudinal tracking.
• JCV antibody status and index: Determines risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that affects certain DMT choices (particularly natalizumab).
• Vaccination status: Several DMTs suppress immune function. Vaccinations — including live vaccines — should ideally be completed before starting immunosuppressive therapy.

Historically, many neurologists started patients on milder, “platform” therapies (interferons, glatiramer acetate) and escalated to more potent drugs only if those failed. This was called the escalation approach. It had the advantage of starting with well-known, gentler therapies, but the disadvantage of allowing disease activity — and potentially irreversible damage — during the time on less effective treatment.

Growing evidence now supports starting with high-efficacy DMTs from the outset:

• Multiple observational studies show that patients started on high-efficacy therapy have less disability at 5–10 years than those who escalated.
• The window of maximum treatment opportunity is early — in the first years after diagnosis, when inflammation is most active and before neurodegeneration dominates.
• Several high-efficacy therapies (especially anti-CD20 antibodies) have become well-characterized and comfortable for clinicians to prescribe.

The high-efficacy-first approach is not appropriate for every patient — individual factors including pregnancy plans, comorbidities, risk tolerance, and JCV status all matter. But the trend in expert MS care is firmly toward earlier use of more effective treatments.

The treatment target in relapsing MS has evolved from simply “reducing relapses” to a more ambitious goal: No Evidence of Disease Activity (NEDA). NEDA has three components:

• NEDA-3: No relapses, no new or enlarging MRI lesions, and no disability progression (worsening EDSS). This has been the standard treatment target.
• NEDA-4: Adds no brain atrophy beyond normal age-related loss (measured by MRI volumetrics).

Achieving NEDA does not guarantee the disease is silent — subtle cognitive changes or smoldering pathology may still occur. But NEDA is the best measurable target currently available, and patients on high-efficacy DMTs are significantly more likely to achieve it than those on lower-efficacy treatments.

If your current treatment is not achieving NEDA, that is a reason to discuss switching therapies. Tolerating “breakthrough” disease activity on a DMT is no longer considered acceptable.

Anti-CD20 therapies deplete B cells — a key immune cell type in MS — from the bloodstream and lymphoid tissue. They have become the most commonly prescribed high-efficacy DMTs worldwide due to their strong efficacy, predictable safety profile, and ease of use.

• Ocrelizumab (Ocrevus): The first anti-CD20 approved specifically for MS. Given as intravenous infusion every 6 months. The OPERA I and II trials showed approximately 47% reduction in annualized relapse rate compared to interferon beta-1a, along with significant reductions in MRI lesions and disability progression. Also the only DMT currently approved for primary progressive MS (based on the ORATORIO trial). A subcutaneous formulation is now available. In May 2026, the FDA approved ocrelizumab for relapsing-remitting MS in children and adolescents aged 10 and older (weighing at least 25 kg) — the first anti-CD20 therapy approved for pediatric MS — based on the Phase 3 OPERETTA 2 trial (NCT05123703), which found it noninferior to fingolimod on annualized relapse rate and superior in reducing new or enlarging T2 lesions (48%) and active gadolinium-enhancing lesions (87%).
• Ofatumumab (Kesimpta): A fully human anti-CD20 antibody given as a monthly self-administered subcutaneous injection at home. The ASCLEPIOS I and II trials showed similar efficacy to ocrelizumab. The home injection format appeals to patients who prefer not to visit infusion centers.
• Ublituximab (Briumvi): A glycoengineered anti-CD20 given as a 1-hour intravenous infusion every 6 months (shorter infusion time than ocrelizumab). The ULTIMATE I and II trials demonstrated efficacy comparable to the class.

Class-wide considerations: long-term B cell depletion reduces immunoglobulin levels over time in some patients. Infection risk is modestly increased. Vaccination responses may be blunted, so vaccinations should ideally be completed before starting treatment.

Natalizumab blocks a protein called alpha-4 integrin, preventing immune cells from crossing the blood-brain barrier. It is one of the most effective DMTs available, dramatically reducing relapses and MRI activity (the AFFIRM trial showed a 68% reduction in annualized relapse rate). It is given as a monthly intravenous infusion.

The major concern: natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially devastating brain infection caused by the JC virus. PML risk depends on three factors: JCV antibody status (and antibody index level), duration of treatment, and prior immunosuppressant use. For JCV-negative patients, the PML risk is extremely low. For JCV-positive patients with high antibody indices and prolonged treatment, the risk becomes significant.

Extended interval dosing (every 6 weeks instead of every 4 weeks) appears to substantially reduce PML risk while maintaining efficacy, and this approach is increasingly used.

These therapies work by depleting or fundamentally resetting the immune system, after which a renewed, less self-reactive immune system regenerates. The appeal is that treatment is given for a limited period, but the benefit may last for years.

• Cladribine (Mavenclad): An oral purine analogue that selectively depletes lymphocytes. Given in two short treatment courses one year apart (roughly 10 days of pills each year), after which no further treatment may be needed for years. The CLARITY trial showed 58% reduction in relapses versus placebo. Particularly appealing for patients who want a treatment-free interval and are willing to accept short-term immune suppression.
• Alemtuzumab (Lemtrada): A potent anti-CD52 antibody given as two infusion courses one year apart. Highly effective but carries significant risks of secondary autoimmune diseases (thyroid disease in 30–40%, and rarer but serious events including immune thrombocytopenia and anti-GBM disease). Requires years of monitoring. Generally reserved for highly active disease that has not responded to other options.

Sphingosine-1-phosphate (S1P) receptor modulators trap lymphocytes in lymph nodes, preventing them from reaching the central nervous system. All are oral tablets taken daily.

• Fingolimod (Gilenya): The first oral DMT approved for MS. Requires first-dose cardiac monitoring (can cause temporary bradycardia). Generally well tolerated for long-term use.
• Siponimod (Mayzent): More selective than fingolimod. Notably, siponimod is the only S1P modulator approved specifically for active SPMS based on the EXPAND trial (21% reduction in disability progression).
• Ozanimod (Zeposia): A selective S1P modulator with a gentler cardiac profile than fingolimod, requiring no first-dose observation in most patients.
• Ponesimod (Ponvory): The newest in the class, with direct head-to-head data against teriflunomide showing superiority.

Class-wide considerations: all S1P modulators can cause macular edema (requiring ophthalmologic screening), bradycardia at initiation, and modest increases in infection risk. Stopping them can trigger rebound disease activity, so discontinuation must be managed carefully.

• Dimethyl fumarate (Tecfidera): Twice-daily oral capsule. Reduces relapses by approximately 50% versus placebo (DEFINE/CONFIRM trials). Common side effects include flushing and gastrointestinal upset, which usually diminish over the first few months. Very rare PML risk exists.
• Diroximel fumarate (Vumerity): A newer fumarate formulation designed to cause less gastrointestinal side effects while maintaining the same active metabolite as dimethyl fumarate.
• Teriflunomide (Aubagio): Once-daily oral tablet. Moderate efficacy (approximately 30% relapse reduction). Well tolerated by many patients. Cannot be used during pregnancy and requires a washout procedure if pregnancy is planned.

The original MS DMTs, interferons and glatiramer acetate, were the standard of care for two decades. They remain available and are still used in some situations, but they are generally less effective than the options described above and have been largely superseded in modern MS practice.

• Interferon beta-1a (Avonex, Rebif): Weekly intramuscular or three-times-weekly subcutaneous injection. Reduce relapses by roughly 30% versus placebo. Common side effects include flu-like symptoms after injection.
• Interferon beta-1b (Betaseron, Extavia): Every-other-day subcutaneous injection with similar efficacy.
• Glatiramer acetate (Copaxone, Glatopa): Daily or three-times-weekly subcutaneous injection. Similar efficacy to interferons with a different side-effect profile (injection site reactions rather than flu-like symptoms).
• Peginterferon beta-1a (Plegridy): A longer-acting interferon given every two weeks by subcutaneous injection.

These agents remain reasonable options for patients with mild disease who have specific reasons to avoid more potent therapies (for example, pregnancy planning in the near term). However, using them as first-line therapy for active MS when more effective options are available is increasingly difficult to justify based on current evidence.

aHSCT is the most aggressive treatment available for MS. It involves harvesting the patient’s own stem cells, using intensive chemotherapy to ablate the immune system, and then reinfusing the stem cells to rebuild a new immune system that — ideally — no longer attacks myelin.

Key evidence:

• MIST trial: A randomized trial comparing aHSCT to standard DMTs in patients with aggressive relapsing MS. aHSCT was clearly superior, with significantly less disease activity and disability progression at 5-year follow-up.
• BEAT-MS trial: A major Phase III randomized trial comparing aHSCT to best available high-efficacy DMTs in highly active RRMS. This trial is ongoing and has not yet reported final efficacy results. When available, it will provide the most robust randomized evidence for aHSCT in the modern era of high-efficacy DMTs.
• Real-world registry data: Large registries and meta-analyses report high rates of NEDA (no evidence of disease activity) following aHSCT, particularly in younger patients with active inflammatory disease.
• Treatment-related mortality: Modern experienced centers using non-myeloablative or intermediate-intensity conditioning report treatment-related mortality well below 1%. A contemporary meta-analysis of post-2012 studies estimates approximately 0.3%, though individual center experience varies. Myeloablative conditioning carries somewhat higher risk.

aHSCT is best suited for patients with highly active relapsing MS who have not responded adequately to DMTs, particularly younger patients with short disease duration and significant inflammatory activity. It is not effective for progressive MS without ongoing inflammatory activity. It requires hospitalization for several weeks and months of immune reconstitution.

Access varies by region. Several major MS centers in the US now offer aHSCT, and it is more widely available in parts of Europe, particularly Sweden.

Pregnancy planning is a critical consideration in MS treatment because many DMTs pose risks to a developing baby, and MS itself often affects women of childbearing age.

• MS tends to stabilize during pregnancy: Relapse rates drop significantly, particularly in the third trimester, then rebound in the first three months postpartum.
• DMTs that are contraindicated in pregnancy: Teriflunomide (teratogenic, requires washout), fingolimod and other S1P modulators (risk of fetal harm and severe rebound if stopped abruptly), methotrexate, cladribine (must wait after last dose), alemtuzumab (wait at least 4 months).
• DMTs with more data in pregnancy: Glatiramer acetate and interferons have the most reassuring pregnancy data, though neither is officially recommended. Anti-CD20 antibodies are increasingly used up until conception, with a washoff period planned before pregnancy. Natalizumab has been continued through pregnancy in some high-risk cases.
• Breastfeeding: Data are emerging that breastfeeding may be protective against postpartum relapses. Many MS specialists now support exclusive breastfeeding for patients who wish it, delaying DMT restart.

The key message: pregnancy should be planned collaboratively with your MS neurologist, ideally well in advance, so that DMT transitions can be managed safely.

Understanding why progressive MS progresses helps explain both the treatment challenges and why new approaches like BTK inhibitors offer hope.

• Smoldering neuroinflammation: Unlike the acute, blood-brain barrier-crossing inflammation of relapses, progressive MS features chronic, compartmentalized inflammation trapped within the central nervous system. Activated microglia and astrocytes cluster at the edges of existing lesions (forming what MRI sees as paramagnetic rim lesions) and slowly expand the damage outward. This process continues even when peripheral immune suppression has eliminated relapses.
• Meningeal B-cell follicles: In progressive MS, B cells can form organized structures resembling lymph nodes in the meninges (the membranes covering the brain). These ectopic follicles produce antibodies and inflammatory signals that damage the underlying brain cortex. They are associated with more severe cortical pathology and faster disability progression. Anti-CD20 antibodies deplete B cells in the blood but may not effectively reach these meningeal follicles.
• Mitochondrial dysfunction: Demyelinated nerve fibers require much more energy to conduct signals. Over time, the mitochondria (cellular energy factories) in chronically demyelinated axons become stressed and fail, leading to axon degeneration. This energy failure is a major driver of neurodegeneration in progressive MS.
• Iron accumulation: As myelin breaks down, iron is released into surrounding tissue. Iron catalyzes oxidative damage, contributing to the smoldering lesion expansion visible as PRLs on MRI.
• Exhaustion of compensatory reserves: The brain has remarkable ability to compensate for damage through neuroplasticity and redundant pathways. Progressive disability becomes clinically apparent when these reserves are exhausted — a concept that helps explain why the transition from relapsing to progressive disease often happens gradually and is recognized only in hindsight.

Until very recently, only two DMTs had shown benefit in controlled trials for progressive MS:

• Ocrelizumab (Ocrevus) for PPMS: Based on the ORATORIO trial, ocrelizumab reduced the risk of confirmed disability progression by 24% compared to placebo in primary progressive MS. This was the first drug ever approved for PPMS and marked a watershed moment. However, the benefit was most apparent in younger patients with inflammatory features (gadolinium-enhancing lesions), and the 24% reduction, while statistically significant and clinically meaningful, leaves substantial unmet need.
• Siponimod (Mayzent) for active SPMS: The EXPAND trial showed siponimod reduced the risk of disability progression by 21% in secondary progressive MS. The benefit was primarily seen in patients with “active” SPMS (recent relapses or MRI activity), with less clear benefit in non-active, purely progressive disease.

These results were important first steps, but they highlighted a fundamental limitation: drugs that work primarily by modulating the peripheral immune system have modest effects on the compartmentalized, CNS-trapped inflammation driving progression. Something that could reach inside the blood-brain barrier was needed.

BTK is an enzyme essential for the activation of B cells and for the inflammatory functions of microglia and macrophages. BTK inhibitors block this enzyme, producing effects in two critical locations:

• B cells: BTK inhibitors prevent B cell activation and the production of inflammatory signals, similar to anti-CD20 therapies. But unlike anti-CD20 antibodies, BTK inhibitors do not deplete B cells — they silence them. This means immune surveillance (the ability to fight infections) is potentially better preserved.
• Microglia: This is the key difference. BTK inhibitors cross the blood-brain barrier and modulate microglial activation inside the CNS. Activated microglia are central drivers of smoldering lesion expansion, cortical damage, and the slow neurodegeneration that characterizes progressive MS. No other approved MS therapy effectively targets microglia.

The combination of B cell modulation and microglial targeting — both inside the CNS — makes BTK inhibitors uniquely suited to the biology of progressive MS. This is not incremental improvement; it is a mechanistically different approach to a previously untreatable disease process.

Tolebrutinib is the most advanced BTK inhibitor in MS development. Its most important contribution is in progressive MS, where the clinical trial results have been genuinely historic. However, its regulatory path has been complex — highlighting both the promise and the challenges of treating progressive MS.

HERCULES trial (non-relapsing SPMS):

• This was a randomized, double-blind, placebo-controlled trial in patients with secondary progressive MS who had no recent relapses — the patient population that no drug had ever helped in a controlled trial.
• Tolebrutinib reduced the risk of confirmed disability progression by 31% compared to placebo (HR 0.69; p=0.003).
• This is the first drug in the history of MS to show statistically significant and clinically meaningful benefit in non-relapsing SPMS.
• The result is transformative because it demonstrates that treating the smoldering inflammation inside the CNS — the mechanism that BTK inhibitors are designed to address — can meaningfully slow disability accumulation even in the absence of relapses.

PERSEUS trial (PPMS):

• A similar trial in primary progressive MS.
• The primary endpoint — reduction in 6-month composite confirmed disability progression — was NOT met (HR 1.01, p=0.94). Tolebrutinib did not demonstrate a clinically meaningful disability benefit in PPMS.
• The only positive signal was a statistically significant slowing of brain volume loss on MRI.
• Sanofi subsequently decided not to pursue regulatory approval for tolebrutinib in PPMS. The results highlight that PPMS, with its longer disease duration and greater neurodegenerative load, may require different therapeutic strategies.

Regulatory status: In December 2025, the U.S. FDA issued a Complete Response Letter (CRL) for tolebrutinib, declining to approve it due to concerns about severe drug-induced liver injury (DILI). Six cases met Hy’s Law criteria during clinical trials, including one patient who required a liver transplant and subsequently died. The FDA determined that the proposed risk monitoring program was insufficient to mitigate this risk. Tolebrutinib is not approved in the United States as of May 2026. However, in April 2026, the European Medicines Agency’s CHMP adopted a positive opinion recommending marketing authorization for tolebrutinib (brand name Cenrifki) for non-relapsing SPMS in adults, reflecting a different benefit-risk assessment. This US–EU regulatory divergence is important context for patients and clinicians.

Liver safety: Tolebrutinib carries a serious risk of drug-induced liver injury. During clinical development, approximately 5% of patients experienced significant liver enzyme elevations, and six cases met Hy’s Law criteria (including one fatal case). Most liver events occurred in the first three months of treatment. If tolebrutinib becomes available in your region, strict liver function monitoring will be required — baseline testing, monthly for the first six months, and periodically thereafter. Patients should immediately report right upper quadrant pain, nausea, jaundice, or dark urine to their care team.

Tolebrutinib is not the only BTK inhibitor being studied in MS:

• Fenebrutinib: A highly selective, non-covalent BTK inhibitor being developed by Roche/Genentech. The FENtrepid trial in PPMS met its primary endpoint of non-inferiority to ocrelizumab in reducing disability progression (HR 0.88, representing a 12% reduction), reported at ACTRIMS in February 2026. Importantly, no Hy’s Law cases of liver injury were observed with fenebrutinib, suggesting it may have a better hepatic safety profile than tolebrutinib. Additionally, the FENhance 2 trial in relapsing MS also met its primary endpoint. Because fenebrutinib is non-covalent (it binds BTK reversibly), it may offer distinct advantages within the class. Roche has submitted regulatory filings in 2026.
• Evobrutinib: Studied by Merck, but the evolutionRMS trials in relapsing MS did not meet their primary endpoint, and development has been deprioritized.
• Remibrutinib: Being studied by Novartis in relapsing MS with the REMODEL trials.

The broader picture: multiple BTK inhibitors are being tested in MS, which increases the likelihood that at least one (and likely more than one) will become available for progressive MS. Competition within the class will also help clarify the optimal BTK inhibitor characteristics — covalent versus non-covalent, CNS penetration levels, and safety profiles.

As treatments targeting smoldering neuroinflammation become available, identifying which patients have the most smoldering activity becomes critical. Two MRI biomarkers are emerging:

• Paramagnetic rim lesions (PRLs): These are chronic active lesions with a dark rim visible on susceptibility-weighted or phase MRI sequences. The rim represents activated microglia and macrophages at the lesion edge, slowly expanding the damage. PRLs are highly specific to MS (helping with diagnosis) and are associated with more aggressive disease biology, faster disability progression, and higher brain atrophy. They may identify patients most likely to benefit from BTK inhibitors and other treatments targeting microglial activation. The 2024 McDonald criteria now include PRLs as supportive diagnostic criteria.
• Slowly expanding lesions (SELs): Lesions that gradually grow in volume over serial MRIs, reflecting ongoing smoldering inflammation. Like PRLs, they are markers of the biology that BTK inhibitors are designed to address.

Not all MS centers currently have the MRI sequences and expertise to identify PRLs and SELs, but this is changing rapidly. Ask your neurologist whether your MRI protocol includes susceptibility-weighted or phase imaging.

The BTK inhibitor story in progressive MS deserves an honest assessment that avoids both hype and premature dismissal:

What has been proven:

• Tolebrutinib significantly slowed disability progression in non-relapsing SPMS (HERCULES) — a result no other drug has ever achieved.
• A 31% reduction in disability progression is meaningful but still leaves the majority of patients continuing to progress.
• These are the first positive phase 3 results for a drug targeting CNS-compartmentalized inflammation in progressive MS.

What is promising but not yet proven:

• The PPMS results (PERSEUS) are suggestive but did not meet the primary endpoint. Longer follow-up may clarify the benefit.
• Whether BTK inhibitors can stabilize patients long-term or merely slow the rate of progression remains to be seen with extended follow-up.
• Whether combining BTK inhibitors with remyelination or neuroprotection agents will produce additive benefits is unknown.

What remains a challenge:

• The liver safety signal requires ongoing monitoring and limits the drug’s use in some patients.
• BTK inhibitors target inflammation-driven progression. Patients whose progression is primarily driven by neurodegeneration independent of inflammation may benefit less.
• Access and cost are significant barriers, as with all MS therapies.

The field must be honest: BTK inhibitors are the most significant advance for progressive MS in a generation, and the HERCULES result changes the conversation about what is possible. But they are not a cure, and the journey from promising trial results to effective real-world treatment for all progressive MS patients will take years of continued research, clinical experience, and realistic expectations.

If anti-inflammatory treatments prevent new damage, remyelination therapies aim to repair existing damage by stimulating the brain’s own oligodendrocyte precursor cells (OPCs) to produce new myelin. This is one of the most pursued goals in MS research.

• Clemastine: An over-the-counter antihistamine that was identified in a drug-repurposing screen as a potential remyelinating agent. The ReBUILD trial in patients with chronic optic neuritis from MS showed that clemastine improved visual evoked potential latency — a measure that reflects myelin repair on the optic nerve. The effect was modest but represented the first randomized trial evidence that remyelination could be pharmacologically promoted in humans.
• Bazedoxifene: A selective estrogen receptor modulator (originally approved for osteoporosis) that has shown remyelinating potential in laboratory studies. Clinical trials in MS are being planned.
• Anti-LINGO-1 (opicinumab): An antibody targeting LINGO-1, a protein that inhibits OPC maturation. Phase 2 trials showed mixed results, and development has been challenging.

The remyelination field is promising but still early. No remyelination therapy is currently proven effective enough for routine clinical use in MS. The challenge is that even when OPCs can be stimulated to produce myelin, the hostile inflammatory environment in progressive MS may prevent the new myelin from surviving.

Neuroprotective therapies aim to keep damaged neurons alive long enough for other treatments (anti-inflammatory or remyelinating) to work. Several are being studied:

• Simvastatin: This common cholesterol-lowering statin showed surprising results in the Phase 2 MS-STAT trial for SPMS: a 43% reduction in brain atrophy rate over 2 years compared to placebo. However, the definitive Phase 3 MS-STAT2 trial (964 patients) was negative — high-dose simvastatin did not slow disability progression in SPMS (HR 1.13, p=0.26). This is an important cautionary example of why Phase 2 results, even striking ones, must be confirmed in larger trials. Simvastatin should not be used as an MS-specific therapy based on current evidence, though it remains appropriate for patients with standard cardiovascular indications.
• Ibudilast: A phosphodiesterase inhibitor that in the SPRINT-MS trial showed a modest slowing of brain atrophy in progressive MS (48% reduction compared to placebo). Further studies are needed to determine clinical relevance.
• Alpha-lipoic acid: An antioxidant that showed a 68% reduction in brain atrophy rate in a small pilot study of SPMS. Larger trials are planned.
• Biotin (MD1003): High-dose pharmaceutical-grade biotin was initially reported to improve disability in progressive MS, but the larger SPI2 trial was negative, essentially ending enthusiasm for this approach.

The compelling evidence linking Epstein-Barr virus to MS causation has opened an entirely new treatment frontier. If EBV is necessary for MS to develop, then targeting EBV-infected cells in the body — particularly in the brain — could potentially treat the disease at its root.

• EBV-specific T cell therapy (ATA188): This approach used allogeneic T cells trained to recognize and kill EBV-infected cells. While early open-label results showed some encouraging signals, the randomized Phase II EMBOLD trial failed to meet its primary endpoint in November 2023 — only 6% of treated patients achieved confirmed disability improvement compared to 16% on placebo. Development was subsequently discontinued. This setback does not disprove the EBV hypothesis but highlights that targeting EBV-infected cells therapeutically is more complex than initially hoped.
• EBV vaccines: Moderna is developing an mRNA-based EBV vaccine that could theoretically prevent MS if administered before EBV infection. This would not help people who already have MS but could potentially prevent future cases. Clinical trials of the vaccine are underway.

EBV-targeted approaches are early-stage but represent perhaps the most intellectually exciting direction in MS research because they aim to address the fundamental cause rather than downstream consequences.

MS fatigue has multiple causes that often coexist:

• Primary (central) fatigue: Directly caused by the disease process itself — demyelination and neurodegeneration disrupt the brain’s ability to sustain cognitive and physical effort. This is the component unique to MS.
• Secondary fatigue: Caused by other MS symptoms that are themselves exhausting: walking difficulty (increased energy expenditure), pain (draining), bladder problems (disrupting sleep), depression (a major fatigue driver), and medications (some DMTs and symptom-management drugs cause fatigue).
• Deconditioning: Reduced physical activity leads to reduced fitness, which increases the effort required for any given task, creating a vicious cycle.
• Sleep disorders: Sleep apnea, restless leg syndrome, and nocturia (nighttime urination) are all more common in MS and contribute to daytime fatigue.

Effective management requires addressing all contributing factors, not just one.

• Exercise: Paradoxically, the most effective intervention for MS fatigue is structured exercise. Multiple randomized trials and systematic reviews consistently show that regular aerobic exercise and resistance training reduce fatigue severity. The effect size rivals or exceeds that of any medication.
• Energy conservation and pacing: Occupational therapists teach strategies for distributing energy throughout the day: prioritizing activities, taking planned rest breaks, using assistive devices to reduce effort, and modifying tasks. These strategies are evidence-based and can significantly improve daily functioning.
• Treating contributors: Address depression (SSRI or SNRI), treat sleep disorders (sleep study if suspected), review medications for fatigue-causing agents, and optimize bladder management to improve sleep quality.
• Medications: Drug treatment for MS fatigue has modest evidence. Modafinil (100–200 mg daily) and amantadine (100 mg twice daily) are the most commonly used. Neither has shown strong benefit in large randomized trials, but individual patients sometimes respond well. Stimulants like methylphenidate are occasionally used off-label.
• Cognitive behavioral therapy (CBT): Several trials have shown that CBT for MS fatigue significantly reduces fatigue severity and improves coping, with effects comparable to or better than medications.
• Cooling strategies: For heat-sensitive fatigue (Uhthoff phenomenon), cooling vests, air conditioning, cold beverages, and avoiding overheating during exercise can make a meaningful difference.

Spasticity — increased muscle stiffness and involuntary spasms — affects a large proportion of MS patients, particularly in the legs. It can range from a mild feeling of muscle tightness to painful, disabling spasms that interfere with walking, sleep, and daily activities.

• Physical therapy and stretching: The foundation of spasticity management. Regular stretching programs, ideally guided by a physical therapist, can significantly reduce stiffness and prevent contractures (permanent shortening of muscles).
• Baclofen: The most commonly used oral medication. Effective for many patients but can cause drowsiness and weakness. Intrathecal baclofen (delivered directly into the spinal fluid via an implanted pump) is an option for severe spasticity not controlled by oral medications.
• Tizanidine: An alternative to baclofen with a different side-effect profile (more sedation, less weakness). Often used at bedtime for nocturnal spasticity.
• Botulinum toxin (Botox) injections: Targeted injections into specific spastic muscles can provide localized relief for 3–4 months per treatment cycle.
• Cannabis-based treatments: Nabiximols (Sativex), an oromucosal spray containing THC and CBD, is approved in many countries for MS spasticity (though not in the US as of this writing). Patient-reported outcomes consistently show benefit.

Cognitive impairment affects 40–70% of people with MS and can occur at any disease stage, including early. The most commonly affected domains are information processing speed, working memory, and executive function. MS-related cognitive changes are often subtle but can significantly impact work performance, social interactions, and quality of life.

• Screening: The Symbol Digit Modalities Test (SDMT) is a simple 90-second test that should be performed at least annually. It is sensitive to MS-related cognitive changes and can detect decline before it becomes obvious in daily life.
• Cognitive rehabilitation: Structured programs with a neuropsychologist or speech-language pathologist can teach compensatory strategies and may improve specific cognitive functions. Computer-based cognitive training programs are also available.
• Treating contributors: Depression, fatigue, sleep disorders, and certain medications all worsen cognition. Addressing these may improve cognitive function even without directly targeting the cognitive deficit.
• Medications: No medication is specifically approved for MS cognitive impairment. Stimulants and cognitive enhancers (modafinil, donepezil) have been studied with mixed results. Exercise is the intervention with the most consistent evidence for cognitive benefit.
• Practical strategies: Using calendars, reminders, notes, and checklists. Reducing multitasking. Minimizing distractions during cognitively demanding tasks. Planning important cognitive work during peak energy periods.

Walking difficulty is the most visible MS symptom and a major concern for many patients. It results from a combination of weakness, spasticity, balance impairment, sensory loss, and fatigue.

• Physical therapy: MS-specialized physical therapists design targeted exercise programs to maintain and improve walking ability, strength, and balance. Evidence strongly supports ongoing physical therapy.
• Dalfampridine (Ampyra/Fampyra): A potassium channel blocker that improves nerve conduction in demyelinated fibers. Taken as a twice-daily tablet, it improves walking speed in approximately 35% of patients (known as “responders”). A 2–4 week trial is typically used to determine if an individual responds.
• Functional electrical stimulation (FES): Devices that stimulate nerves in the leg to improve foot drop (difficulty lifting the front of the foot during walking). Can significantly improve walking pattern and reduce falls.
• Assistive devices: Canes, walkers, and wheelchairs are tools that preserve independence and energy, not symbols of defeat. Using a wheelchair for long distances preserves energy for activities that matter most. Occupational therapists can help with device selection and home modifications.

Bladder problems affect 80% or more of MS patients at some point and include urgency (sudden need to urinate), frequency, incontinence, hesitancy (difficulty starting urination), and incomplete emptying. They are undertreated partly because patients are embarrassed to bring them up.

• Assessment: Urodynamic testing helps determine the specific type of bladder dysfunction (overactive bladder vs. retention vs. both), which guides treatment.
• Behavioral strategies: Timed voiding, pelvic floor exercises, and fluid management can help milder symptoms.
• Anticholinergic medications: Oxybutynin, solifenacin, and mirabegron reduce urgency and frequency. Side effects include dry mouth and (importantly in MS) potential worsening of cognitive function.
• Intermittent self-catheterization: For patients with incomplete bladder emptying, clean intermittent catheterization (CIC) is safe, effective, and becomes routine with practice. It dramatically reduces urinary tract infections and overflow incontinence.
• Botulinum toxin injections: OnabotulinumtoxinA injected into the bladder wall is highly effective for overactive bladder symptoms resistant to medications.

The key message: bladder symptoms are common, treatable, and worth discussing openly with your care team. Do not suffer in silence.

Pain is experienced by more than half of MS patients and takes several forms:

• Neuropathic pain: Burning, shooting, or electric shock-like pain caused by damaged nerve fibers. Common in the legs and feet. Treated with gabapentin, pregabalin, duloxetine, or tricyclic antidepressants (amitriptyline).
• Trigeminal neuralgia: Severe, stabbing facial pain caused by a brainstem lesion affecting the trigeminal nerve. Treated with carbamazepine or oxcarbazepine; some patients require surgery.
• Lhermitte’s sign: Electric shock sensation running down the spine or limbs when flexing the neck, caused by a cervical spinal cord lesion. Usually transient during a relapse.
• Musculoskeletal pain: Secondary pain from spasticity, altered gait, and posture changes. Physical therapy and appropriate spasticity treatment help.
• Central pain syndrome: Persistent burning or aching pain caused by lesions in pain-processing pathways. Can be particularly difficult to treat; may respond to gabapentinoids, duloxetine, or cannabis-based preparations.

Depression affects more than 50% of MS patients over their lifetime — a rate roughly three times higher than the general population. It is caused by a combination of the psychological impact of chronic illness, direct effects of brain lesions on mood-regulating circuits, and neuroinflammation itself. Anxiety disorders are similarly common.

• Depression is not weakness. It is a neurobiological consequence of the disease process itself, as much a symptom of MS as weakness or numbness. It should be treated as aggressively as any other symptom.
• SSRIs and SNRIs: First-line pharmacological treatment. Sertraline, escitalopram, venlafaxine, and duloxetine are commonly used. Duloxetine has the added benefit of helping neuropathic pain.
• Psychotherapy: Cognitive behavioral therapy (CBT) has strong evidence for depression and anxiety in MS. Acceptance and commitment therapy (ACT) is also effective.
• Exercise: Consistently shows antidepressant effects in MS comparable to medication.
• Suicide risk: MS patients have an elevated suicide risk compared to the general population. Any suicidal thoughts should be communicated to the care team immediately.

Visual symptoms are common in MS and include:

• Optic neuritis: Inflammation of the optic nerve causing pain with eye movement and vision loss (often central blurring or loss of color vision) in one eye. Usually recovers substantially over weeks. Often the first presenting symptom of MS.
• Internuclear ophthalmoplegia (INO): A characteristic MS finding where a brainstem lesion disrupts coordination of eye movements, causing double vision when looking to the side. Often improves with time.
• Nystagmus: Involuntary, rhythmic eye movements that can cause visual oscillation and balance problems. Gabapentin or memantine may help.

Neuro-ophthalmology evaluation is recommended for any MS patient with persistent visual symptoms.

Many MS patients experience temporary worsening of symptoms when their core body temperature rises — during exercise, hot weather, hot baths, or fever. This is called Uhthoff phenomenon and occurs because heat slows nerve conduction in demyelinated fibers. It is not a relapse and does not indicate new damage — symptoms reverse when the body cools down.

Management strategies include cooling vests, pre-cooling before exercise, exercising in air-conditioned environments or in water (pool therapy), drinking cold fluids, and avoiding peak heat hours outdoors. Cooling garments have become significantly more sophisticated and are worth exploring.

Exercise is the single most evidence-supported lifestyle intervention in MS. Decades of research, including multiple randomized controlled trials and systematic reviews, have demonstrated that regular exercise in MS:

• Reduces fatigue (the most consistent finding across studies)
• Improves walking speed and endurance
• Improves balance and reduces fall risk
• Improves cardiovascular fitness (important because people with MS are at elevated cardiovascular risk)
• Improves mood and reduces depression symptoms
• May improve cognitive function
• May slow brain atrophy (some evidence suggests exercise has neuroprotective effects)
• Is safe — exercise does not trigger relapses or worsen the disease

Current guidelines recommend at least 150 minutes per week of moderate-intensity aerobic exercise plus resistance training at least twice per week, adapted to the individual’s abilities. An MS-specialized physical therapist can design an appropriate program. The key is consistency over intensity — doing something regularly matters more than occasional intense sessions.

For patients with significant mobility limitations, aquatic therapy (pool-based exercise) is excellent because water supports the body, reduces fall risk, and provides natural cooling.

No specific diet has been proven to alter the course of MS in large, controlled clinical trials. However, several nutritional principles are well supported:

• Overall healthy diet: A Mediterranean-style diet (rich in fruits, vegetables, whole grains, fish, and olive oil; low in processed foods, red meat, and sugar) is associated with lower inflammation and better health outcomes in the general population and makes physiological sense in MS.
• Vitamin D: Low vitamin D levels are a risk factor for MS and may influence disease activity. While evidence for vitamin D supplementation changing the course of established MS is not definitive, most MS neurologists recommend maintaining adequate levels (typically 40–60 ng/mL). Supplementation with 2,000–5,000 IU daily is common, with monitoring of blood levels.
• Omega-3 fatty acids: Some evidence of anti-inflammatory effects, though not proven to affect MS outcomes. Reasonable as part of overall healthy nutrition.
• Weight management: Obesity is associated with greater MS-related disability and higher levels of inflammation. Maintaining a healthy weight benefits mobility, cardiovascular health, and energy levels.

Be cautious of special MS diets promoted with dramatic claims (Wahls Protocol, Swank Diet, and others). While some contain reasonable nutritional principles, none has been proven in rigorous clinical trials to change MS outcomes. Any restrictive diet should be discussed with a dietitian to avoid nutritional deficiencies.

Rehabilitation is not just for after a relapse — it should be an ongoing part of MS care:

• Physical therapy (PT): Addresses walking, strength, balance, spasticity management, fall prevention, and exercise prescription. Look for PTs with MS or neurological rehabilitation experience.
• Occupational therapy (OT): Focuses on maintaining independence in daily activities: home modifications, adaptive equipment, energy conservation strategies, hand function, and cognitive strategies for daily tasks.
• Speech-language pathology: For swallowing difficulties (dysphagia), speech clarity problems (dysarthria), and cognitive-communication challenges.
• Cognitive rehabilitation: Structured programs with a neuropsychologist targeting specific cognitive deficits.
• Vocational rehabilitation: Helps people with MS maintain employment through workplace accommodations and job modifications.

Access to rehabilitation services varies by insurance and location. The National MS Society can help connect patients with rehabilitation resources.

Psychological stress has been associated with increased MS relapse risk in several studies, though the relationship is complex. Regardless of its effect on relapses, chronic stress worsens fatigue, pain, mood, and overall quality of life.

• Mindfulness-based stress reduction (MBSR): Multiple trials have shown benefit for quality of life, depression, and fatigue in MS.
• Sleep hygiene: Prioritize 7–8 hours of quality sleep. Address sleep disorders (apnea, restless legs, nocturia) aggressively, as poor sleep worsens virtually every MS symptom.
• Social connection: Social isolation is common in MS and harmful. Maintaining relationships and social engagement, even when fatigue makes it difficult, is important for mental health.

• University of Utah Neuroimmunology/MS Program: An academic MS center with fellowship-trained MS neurologists, access to clinical trials, and comprehensive multidisciplinary care. Part of the University of Utah Health system and affiliated with the Huntsman Neurosciences building. This is the primary referral center for complex MS in the Intermountain West.
• Intermountain Health MS Services: Provides MS neurology care across multiple Intermountain Health locations in the Wasatch Front and beyond. Good option for patients who need care closer to home.
• National MS Society — Utah Chapter: Offers peer support groups, educational programs, advocacy, and connects patients with local resources including financial assistance, legal help, and community events. Website: nationalmssociety.org.
• MS Society Navigator Program: Free one-on-one support from trained navigators who can help with insurance issues, finding providers, connecting to resources, and navigating the healthcare system.

Clinical trials are the mechanism through which experimental treatments become available treatments. Participating in a trial offers access to cutting-edge therapies and contributes to the knowledge that helps all MS patients.

• ClinicalTrials.gov: The US national registry of clinical trials. Search for “multiple sclerosis” to find currently recruiting trials.
• National MS Society trial matching: The National MS Society offers trial-matching services to help patients find trials appropriate for their disease type, location, and treatment history.
• Major MS trial networks: The NeuroNEXT network, ECTRIMS, and individual MS centers maintain lists of available trials.
• University of Utah clinical trials: The University of Utah Neuroimmunology Program participates in many major MS clinical trials. Ask your neurologist about current open studies.

Key questions before enrolling in a trial: What is the trial comparing (the drug vs. placebo, or vs. another drug)? What are the known risks? What is the time commitment? Will I know which group I am in? What happens after the trial ends — will I have continued access to the drug?

The financial burden of MS is substantial. DMTs cost $80,000 to over $100,000 per year in the US, and that does not include MRI monitoring, specialist visits, rehabilitation, and symptom management medications.

• Manufacturer patient assistance programs: Every major DMT manufacturer offers programs for eligible patients, including copay assistance and free drug programs for uninsured or underinsured patients. The MS nurse or specialty pharmacy can connect you with these programs.
• National MS Society financial assistance: Grants and programs for medication costs, MRI copays, assistive equipment, home modifications, and other expenses.
• Specialty pharmacies: Most DMTs are dispensed through specialty pharmacies that have dedicated MS teams and can help navigate insurance requirements, prior authorizations, and appeals.
• Social Security Disability Insurance (SSDI): MS is a recognized condition for disability benefits. The application process can be lengthy; consider consulting a disability attorney if applying.
• COBRA and insurance transitions: Gaps in insurance coverage can be devastating when on expensive DMTs. Plan insurance transitions carefully and use manufacturer bridge programs if needed.

Many people with MS continue working for years or decades after diagnosis. Legal protections and workplace strategies can help:

• Americans with Disabilities Act (ADA): MS is a covered disability. Employers with 15 or more employees must provide reasonable accommodations — flexible scheduling, modified workstation, remote work options, rest breaks, and others — as long as the person can perform the essential functions of the job.
• Family and Medical Leave Act (FMLA): Provides up to 12 weeks of unpaid, job-protected leave per year for serious health conditions, including MS flares or treatment. Also covers family members who need time to provide care.
• Disclosure decisions: There is no legal obligation to disclose an MS diagnosis to an employer unless requesting accommodations. The decision to disclose is personal and depends on the specific workplace, symptoms, and individual circumstances.
• Vocational rehabilitation services: State vocational rehabilitation agencies provide services to help people with disabilities maintain or find employment, including job coaching, retraining, and assistive technology.

MS is a global disease, and treatment approaches vary by region:

• Sweden’s MS Registry: The world’s largest and most complete MS registry, tracking virtually every MS patient in Sweden. Data from this registry has been instrumental in demonstrating the benefits of early, high-efficacy treatment and in comparing the real-world effectiveness of different DMTs. Sweden’s aggressive treatment approach has contributed to some of the best MS outcomes in the world.
• European ECTRIMS approach: The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) has increasingly endorsed early aggressive treatment, similar to Swedish practice. European guidelines tend to favor high-efficacy-first approaches.
• UK NICE guidelines: The National Institute for Health and Care Excellence evaluates cost-effectiveness, which affects treatment availability through the NHS. Some treatments available in other countries may have restricted access in the UK.
• aHSCT access: Autologous stem cell transplant is more readily available in Sweden, Russia, Mexico, and Israel than in many US centers. International medical travel for aHSCT is common but requires careful evaluation of center experience and follow-up planning.

Practical home adaptations can significantly maintain independence and safety:

• Fall prevention: Remove throw rugs, ensure good lighting, install grab bars in bathrooms, consider a shower chair and handheld showerhead. Falls are a major source of injury in MS.
• Cognitive supports: Use smart home devices for reminders and alarms, keep a visible family calendar, establish consistent routines for medications and daily tasks, label cabinets and drawers if memory is affected.
• Temperature management: Keep the home cool (68–72°F), have cooling vests available for outdoor activities, plan activities during cooler parts of the day.
• Energy conservation: Organize the home to minimize unnecessary trips (keep frequently used items at waist height), invest in tools that reduce effort (electric can openers, lightweight cookware, long-handled grabbers), and structure the day with planned rest periods between activities.
• Mobility at home: If a wheelchair or walker is used, ensure doorways are wide enough, remove threshold barriers, and consider a ramp for entry/exit. An occupational therapist can do a comprehensive home safety evaluation.

Many of the most disabling MS symptoms are invisible to others: fatigue, pain, cognitive fog, depression, bladder urgency, and sensory disturbances. This invisibility can strain relationships when the person with MS “looks fine” but cannot function at expected levels.

• For partners: Accept that the person’s report of how they feel is more accurate than how they look. Plans may need to be canceled or modified at short notice. Intimacy and sexuality are often affected by MS (fatigue, numbness, spasticity, mood changes) — discuss these openly and consider couples counseling if needed.
• For children: Age-appropriate explanations help children understand why a parent may be tired, need rest, or use a walking aid. The National MS Society has resources specifically for families with children.
• For friends and extended family: Educate those close to you about invisible symptoms. A simple explanation like “my brain gets tired faster than yours, which makes everything harder even though I look the same” can help.

Caregiving for someone with a chronic, progressive illness takes a profound toll. Caregiver burnout, depression, and physical health decline are well-documented and must be taken seriously.

• Your own health matters: You cannot provide good care if you are depleted. Schedule your own medical appointments, maintain exercise, see a therapist, and do not neglect your own social connections.
• Respite care: Regular breaks from caregiving are essential, not selfish. Explore options: family members, home health aides, adult day programs, or respite care through the National MS Society.
• Support groups: Caregiver-specific support groups (in-person or online) connect you with others who understand the unique challenges. The National MS Society runs caregiver support programs.
• Couples counseling: When one partner becomes a caregiver, the relationship dynamic changes fundamentally. Professional counseling can help both partners navigate this transition.
• Financial and legal planning: As early as possible, address healthcare directives, power of attorney, long-term care insurance, and estate planning. These conversations are easier to have before they become urgent.

• Before 1993, there were zero approved DMTs. Now there are more than 20, with multiple high-efficacy options.
• People diagnosed today with early-treated relapsing MS may never develop significant disability. This was not the case a generation ago.
• MRI technology can detect disease activity before symptoms occur, allowing treatment adjustments.
• Blood biomarkers (NfL) are becoming available for real-time disease monitoring.
• Progressive MS — the last major unmet need — finally has the first drug (tolebrutinib) to show benefit in non-relapsing SPMS, with more in development.
• aHSCT offers the possibility of long-term disease freedom for carefully selected patients with aggressive relapsing MS.

• Progressive MS remains incompletely treated. The HERCULES result is a breakthrough, but a 31% reduction in disability progression means many patients still progress.
• Existing damage cannot yet be reversed. Once neurons are destroyed, they do not regenerate. Remyelination therapies are early-stage.
• DMT costs are prohibitive without insurance. The financial burden of MS is enormous.
• Invisible symptoms (fatigue, cognitive difficulties, pain, depression) remain underrecognized and undertreated.
• Access to MS-specialist care is uneven. Rural areas and underserved communities often lack MS expertise.
• The emotional and relational toll of chronic, unpredictable illness is significant and does not get enough attention.

Hope in MS is not wishful thinking — it is grounded in measurable, documented, reproducible scientific progress. The treatment landscape has transformed in 30 years from zero options to more than 20 approved therapies, with the first drugs for progressive MS now emerging. The pace of discovery is accelerating, not slowing.

What you can do right now to give yourself the best possible future:

1. Get on effective treatment and stay on it. Early, continuous, high-efficacy DMT is the single most impactful action.
2. Exercise regularly. It is medicine, and the evidence is strong.
3. Build a care team you trust. An MS-specialist neurologist, a mental health professional, and rehabilitation providers.
4. Monitor your disease. Regular MRI, NfL testing, SDMT screening, and honest conversations with your neurologist about whether treatment goals are being met.
5. Stay connected to a clinical trial center. Even if you are not currently in a trial, being connected means you will have access to the next advance when it comes.
6. Take care of your whole self. Treat depression, address fatigue, maintain relationships, and find purpose beyond the disease.

MS is a marathon, not a sprint. The tools available today are better than they have ever been, and they are getting better every year.

• RRMS (Relapsing-Remitting MS): The most common MS type, accounting for roughly 85% of initial diagnoses. Characterized by discrete relapses — episodes of new or worsening neurological symptoms — followed by periods of partial or complete recovery (remissions). Between relapses, the disease does not appear to worsen clinically, though subclinical activity may be occurring on MRI.
• SPMS (Secondary Progressive MS): A phase that many people with RRMS eventually enter, characterized by gradual, continuous worsening of neurological function with or without superimposed relapses. SPMS may be classified as “active” (with ongoing relapses or new MRI lesions) or “non-active,” and “with progression” or “without progression.” The transition from RRMS to SPMS is often recognized only in retrospect.
• PPMS (Primary Progressive MS): Approximately 10–15% of MS patients experience gradual worsening from the onset, without early relapses. PPMS typically presents later in life (often in the 40s), affects men and women roughly equally, and most commonly causes slowly worsening walking difficulty. Only ocrelizumab is currently approved for PPMS.
• CIS (Clinically Isolated Syndrome): A single first episode of neurological symptoms caused by inflammation and demyelination in the central nervous system, lasting at least 24 hours. CIS is not yet MS, but if MRI shows additional lesions suggesting prior silent disease activity, the probability of converting to definite MS is high. Early treatment at the CIS stage has been shown to delay or prevent conversion.
• McDonald criteria: The internationally accepted diagnostic framework for MS, most recently revised in 2024. Diagnosis requires demonstrating damage in at least two separate CNS locations (dissemination in space) at two or more time points (dissemination in time), with no better explanation. The 2024 revision incorporated central vein sign, paramagnetic rim lesions, and kappa free light chains as supportive criteria.
• Relapse (attack, exacerbation): A new or worsening neurological symptom lasting at least 24 hours, caused by new inflammation and demyelination in the CNS. Relapses typically develop over days, peak over days to weeks, and then gradually improve over weeks to months. They are distinct from pseudo-relapses caused by heat or infection.
• Lesion (plaque): An area of inflammation and demyelination in the brain or spinal cord, visible on MRI. MS lesions occur in characteristic locations: periventricular (around the ventricles), juxtacortical (near the cortex), infratentorial (brainstem/cerebellum), and spinal cord. Lesions may be acute (new, actively inflamed) or chronic (old, scarred).

• MRI with gadolinium: The cornerstone imaging technique in MS diagnosis and monitoring. Gadolinium is a contrast agent injected intravenously during the scan. Areas that “enhance” (appear bright after gadolinium) indicate active inflammation where the blood-brain barrier has broken down, allowing the contrast agent to leak into the brain tissue. Enhancing lesions represent new or recently active disease. Non-enhancing lesions represent older, chronic damage.
• Oligoclonal bands (OCBs): Antibodies (immunoglobulins) found in cerebrospinal fluid (obtained via lumbar puncture) that are not present in the patient’s blood. Their presence indicates that the immune system is producing antibodies inside the central nervous system — a hallmark of MS. Oligoclonal bands are present in over 95% of MS patients and are used as a diagnostic criterion in the McDonald criteria.
• EDSS (Expanded Disability Status Scale): A standardized neurological examination scored from 0 (normal exam) to 10 (death due to MS). The EDSS is the universal measure of disability in MS clinical trials and clinical practice. Key milestones: EDSS 4.0 corresponds to significant walking limitation but able to walk 500 meters without aid; EDSS 6.0 means a cane is needed for walking; EDSS 7.0 means wheelchair-dependent. Tracked at every neurology visit to monitor progression.
• NfL (Neurofilament light chain): A structural protein released into the blood when nerve fibers (axons) are damaged. Measurable via a blood test using ultrasensitive platforms. Elevated NfL indicates active nerve damage and is used to monitor subclinical disease activity, assess treatment response, and provide prognostic information. Not specific to MS — any cause of neurological damage raises NfL.

• DMT (Disease-Modifying Therapy): Any treatment that reduces MS disease activity and slows disability progression, as opposed to treatments that only manage symptoms. There are now more than 20 approved DMTs for MS, ranging from injectable interferons and oral medications to infused monoclonal antibodies and stem cell transplantation. DMTs do not cure MS or treat individual symptoms — they work by modifying the immune system to reduce the frequency and severity of attacks and slow the accumulation of damage.
• BTK inhibitor (Bruton’s Tyrosine Kinase inhibitor): A new class of oral drugs that block the BTK enzyme, which is essential for B cell activation and microglial inflammatory function. Unlike anti-CD20 antibodies, BTK inhibitors cross the blood-brain barrier and can directly target the smoldering neuroinflammation inside the CNS that drives progressive MS. Tolebrutinib is the most advanced BTK inhibitor in MS, with the HERCULES trial demonstrating significant benefit in non-relapsing SPMS. Fenebrutinib is also in late-stage development.
• Remyelination: The process of repairing or regrowing the myelin sheath around nerve fibers after it has been damaged by MS. The brain has some natural capacity for remyelination through oligodendrocyte precursor cells (OPCs), but this capacity diminishes over time and with age. Pharmacological remyelination — using drugs to stimulate OPCs to produce new myelin — is one of the most active areas of MS research. Clemastine showed the first randomized trial evidence that remyelination can be promoted in humans (ReBUILD trial).

• JCV / PML risk: JCV (John Cunningham virus, also called JC polyomavirus) is a common virus carried by approximately 50–60% of the general population, usually without any symptoms. However, in patients with significant immune suppression — particularly those on natalizumab (Tysabri) — JCV can reactivate in the brain and cause progressive multifocal leukoencephalopathy (PML), a rare but potentially devastating or fatal brain infection. PML risk depends on JCV antibody status and index level, duration of treatment, and prior immunosuppressant use. All patients starting natalizumab are tested for JCV antibodies, and those who are JCV-positive are monitored closely. Extended interval dosing of natalizumab reduces PML risk.

• Annualized relapse rate (ARR): The average number of relapses per year; the primary outcome measure in most relapsing MS clinical trials.
• Blood-brain barrier (BBB): A selective barrier that separates circulating blood from the brain and spinal cord, limiting which substances can enter the CNS. Most large-molecule drugs (including anti-CD20 antibodies) cannot effectively cross this barrier, which is why BTK inhibitors — small molecules that penetrate the BBB — are important for progressive MS.
• CNS: Central nervous system; the brain and spinal cord.
• CVS: Central vein sign; an MRI finding where a vein runs through the center of an MS lesion, helping distinguish MS from mimics.
• Demyelination: Damage to or loss of myelin, the protective fatty coating around nerve fibers.
• Microglia: Immune cells residing permanently within the brain and spinal cord; central to smoldering inflammation in progressive MS. Unlike peripheral immune cells, microglia do not cross the blood-brain barrier — they are the brain’s own resident immune system.
• Myelin: The fatty insulating sheath around nerve fibers that enables rapid electrical signal transmission via saltatory conduction.
• NEDA: No Evidence of Disease Activity; a treatment target encompassing no relapses, no new MRI lesions, and no disability progression.
• PRLs: Paramagnetic rim lesions; chronic active MS lesions with an iron-rich rim of activated microglia, visible on susceptibility-weighted MRI sequences. Highly specific to MS and a marker of smoldering inflammation.
• SDMT: Symbol Digit Modalities Test; a 90-second screening test for cognitive processing speed in MS.
• SELs: Slowly expanding lesions; MS lesions that gradually grow in volume over time, indicating smoldering inflammation.
• Uhthoff phenomenon: Temporary worsening of MS symptoms caused by increased body temperature.

• University of Utah Neuroimmunology / MS Clinic: The primary academic MS center for the Intermountain West region. Fellowship-trained MS neurologists provide comprehensive care including DMT management, advanced MRI interpretation, clinical trial access, and multidisciplinary rehabilitation. Located at the Huntsman Neurosciences building in the University of Utah Health system. Participates in major MS trials and serves as the referral center for complex MS cases across Utah, Idaho, Wyoming, and surrounding states. Phone: 801-585-6387 (U of U Neurosciences). General U of U Health: 801-581-2121.
• Moran Eye Center (University of Utah): For MS patients with optic neuritis, visual symptoms, or neuro-ophthalmology needs. Part of U of U Health. Phone: 801-581-2352.
• Huntsman Mental Health Institute (HMHI): For MS-related depression, anxiety, and cognitive-behavioral therapy. Located within the U of U Health system. Phone: 801-583-2500.
• Intermountain Health Neurosciences Institute: Offers MS neurology care across multiple Intermountain Health locations along the Wasatch Front and in southern Utah. A practical option for patients who need specialty MS care closer to home without traveling to an academic medical center. Coordinates with the University of Utah for complex cases and clinical trial referrals. Phone: 801-442-2000 (Intermountain Health main).

• Cleveland Clinic Mellen Center for MS Treatment and Research (Cleveland, OH): One of the largest and most established MS programs in the world. Treats thousands of MS patients annually with a team of more than a dozen MS-specialist neurologists. Known for comprehensive care, deep clinical trial involvement, advanced imaging research, and pioneering work in MS wellness and rehabilitation. Phone: 216-444-8600 (Mellen Center).
• UCSF MS and Neuroinflammation Center (San Francisco, CA): A leading academic MS program with particular strength in MS research, advanced MRI biomarkers (including PRL and SEL analysis), progressive MS, and EBV-related research. Home to several of the investigators leading BTK inhibitor and remyelination trials. Phone: 415-353-2069 (UCSF Neurology).
• Johns Hopkins MS Center (Baltimore, MD): A major academic MS center with deep expertise in neuroimmunology, NMO spectrum disorder differential diagnosis, transverse myelitis, and complex diagnostic cases. Known for research in MS pathology, biomarker development, and treatment optimization. Phone: 410-614-1522 (Johns Hopkins Neurology).
• Massachusetts General Hospital MS Center (Boston, MA): Part of the Mass General Brigham system, this program offers comprehensive MS care with particular strength in advanced neuroimaging, cognitive assessment, neuroimmunology research, and clinical trials. Phone: 617-726-3311 (MGH main).

Other notable US centers include the MS Center at Cedars-Sinai (Los Angeles), the Rocky Mountain MS Center (University of Colorado), NYU Langone MS Comprehensive Care Center, the University of Michigan MS Program, and the University of Pennsylvania MS Center. When choosing a center, prioritize fellowship-trained MS neurologists, multidisciplinary team availability, clinical trial access, and practical factors like proximity and insurance coverage.

• George E. Wahlen VA Medical Center — Neurology Service (Salt Lake City): The VA SLC provides neurology care including MS management for eligible veterans. MS is recognized as a service-connected condition in some cases, particularly given the association between military service (geographic relocation, EBV exposure timing) and MS risk. The VA neurology service coordinates with the University of Utah MS program for complex cases and clinical trial referrals. Veterans with MS should ensure their condition is properly documented for disability rating and service connection if applicable. Phone: 801-582-1565.

The VA MS Centers of Excellence (located at facilities in Baltimore, Seattle, Portland, and other cities) provide specialized MS care and research within the VA system. Veterans may be referred to these centers for complex diagnostic or treatment decisions.

• UBC MS Clinic (University of British Columbia, Vancouver): One of the largest and most productive MS research and clinical programs globally. Known for long-term outcome studies, the BC MS database (one of the most comprehensive MS registries in the world), and contributions to understanding treatment timing and DMT effectiveness. A leader in real-world evidence for MS treatment decisions. Phone: +1 604-822-7704.
• Montreal Neurological Institute — MS Clinic (McGill University, Montreal): A world-renowned neuroscience center with deep expertise in MS pathology, biomarker development, and clinical trials. Offers comprehensive MS care including progressive MS management. Phone: +1 514-398-1904.
• Sunnybrook Health Sciences Centre — MS Clinic (Toronto): A major MS clinical and research center in the Greater Toronto Area, with expertise in advanced neuroimaging and clinical trials. Phone: +1 416-480-6100.
• MS Society of Canada: The national MS organization providing research funding, advocacy, peer support, and patient navigation services across all provinces. Canada has one of the highest MS prevalence rates in the world, and the MS Society of Canada funds a substantial research portfolio. Website: mssociety.ca. Offers an Information and Support Line, peer support programs, and connections to provincial MS clinics.

Other major Canadian MS centers include the Ottawa Hospital MS Clinic, the University of Alberta MS Clinic, and the University of Calgary MS Clinic. Canada’s single-payer healthcare system generally provides good access to DMTs, though approval timelines for new therapies may differ from the US.

• Queen Square MS Centre, UCL Queen Square Institute of Neurology (London, UK): One of the oldest and most prestigious neurology institutions in the world. The Queen Square MS Centre is a global leader in MS research, particularly in progressive MS, advanced neuroimaging, clinical trial design, and biomarker development. Instrumental in pioneering the understanding of smoldering inflammation, paramagnetic rim lesions, and the compartmentalized CNS pathology that drives progression. Phone: +44 20 3456 7890 (UCLH main switchboard).
• Charité — Universitätsmedizin Berlin, NeuroCure Clinical Research Center (Berlin, Germany): A leading European MS research and clinical center with expertise in neuroimmunology, advanced MRI techniques, and clinical trial design. The Charité NeuroCure program has been central to European MS research networks and has contributed significantly to understanding MS pathogenesis and developing new treatment approaches. Phone: +49 30 450 50 (Charité main).
• Karolinska Institutet — MS Research Group (Stockholm, Sweden): Home of the Swedish MS Registry, the world’s largest and most complete MS patient registry. Pioneer of early high-efficacy treatment and rituximab-based care, with some of the best documented MS outcomes globally. Phone: +46 8 524 800 00 (Karolinska University Hospital main).
• National Center of Neurology and Psychiatry (NCNP) (Tokyo, Japan): Japan’s leading center for neuroimmunology, with particular expertise in distinguishing MS from NMOSD and MOGAD — conditions with higher relative prevalence in Asian populations. Phone: +81 42 341 2711.
• MSBase Registry: An international MS outcomes registry collecting longitudinal data from more than 90,000 patients across over 150 MS centers in 40+ countries. MSBase is not a treatment center but a collaborative research platform that generates real-world evidence on DMT effectiveness, treatment sequencing, and long-term outcomes. Data from MSBase has influenced treatment guidelines worldwide.

Other internationally prominent MS centers include VU University Medical Center (Amsterdam) and the Brain and Mind Centre at the University of Sydney.

BTK inhibitors are the most actively studied new drug class for progressive MS. Multiple agents are in Phase III trials:

• Tolebrutinib (Sanofi): The HERCULES trial (NCT04411641) demonstrated a 31% reduction in disability progression in non-relapsing SPMS — the first positive result ever in this population. Despite the FDA’s Complete Response Letter due to liver safety concerns, the EMA has adopted a positive opinion for marketing authorization in Europe. The PERSEUS trial (NCT04458051) studied tolebrutinib in PPMS. The GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials studied tolebrutinib in relapsing MS.
• Fenebrutinib (Roche/Genentech): A non-covalent (reversible) BTK inhibitor that may have a better liver safety profile than tolebrutinib. The FENtrepid trial (NCT04544449) in PPMS met its primary endpoint of non-inferiority to ocrelizumab with a 12% risk reduction (HR 0.88). The FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) trials in relapsing MS also met primary endpoints. Regulatory filings were submitted in 2026. Fenebrutinib is particularly significant because the absence of Hy’s Law liver injury cases in trials may facilitate broader adoption.
• Remibrutinib (Novartis): Being studied in the REMODEL Phase III trials (NCT05147220, NCT05156281) in relapsing MS. Results are pending and will help clarify whether the BTK inhibitor mechanism translates broadly across the class.

The overall picture is encouraging: multiple BTK inhibitors advancing through clinical development increases the probability that at least one — and likely more — will become routinely available for progressive MS. Competition within the class will also drive differentiation on safety profiles, dosing convenience, and CNS penetration.

Remyelination research aims to repair existing damage rather than just prevent new damage — potentially the most transformative goal in MS treatment:

• Clemastine: An over-the-counter antihistamine identified as a pro-remyelinating agent. The Phase II ReBUILD trial (NCT02040298) showed improvement in visual evoked potential latency in chronic MS optic neuropathy — the first randomized evidence that pharmacological remyelination is achievable in humans. Further studies are exploring optimal dosing, patient selection, and whether the effect translates to broader disability improvement.
• Bazedoxifene: A selective estrogen receptor modulator (originally approved for osteoporosis) that promotes oligodendrocyte precursor cell differentiation in laboratory studies. Clinical trials in MS are being planned.
• PIPE-307: A muscarinic M1 receptor antagonist in development for remyelination. Phase II trials are underway.
• Anti-LINGO-1 (opicinumab): An antibody targeting a protein that inhibits myelin repair. Phase II results were mixed, and development has been difficult, illustrating the challenge of translating remyelination biology into clinical benefit.

The remyelination field remains early-stage, and no agent is yet proven effective enough for routine clinical use. The key challenge is that even when oligodendrocyte precursor cells can be stimulated to produce new myelin, the hostile inflammatory environment in progressive MS may prevent the new myelin from surviving — which is why combining remyelination agents with anti-inflammatory therapies (like BTK inhibitors) may ultimately be necessary.

Anti-CD20 antibodies (ocrelizumab, ofatumumab, ublituximab) are highly effective for relapsing MS and have become the most widely prescribed high-efficacy DMTs. Current research is exploring how to optimize their use:

• Combination strategies: Several trials are investigating whether adding a BTK inhibitor to anti-CD20 therapy produces additive benefit — the anti-CD20 depleting peripheral B cells while the BTK inhibitor targets CNS-compartmentalized B cells and microglia that anti-CD20 antibodies cannot reach. This “inside-outside” strategy is theoretically compelling but unproven.
• Extended interval dosing: Growing real-world evidence suggests that extending the interval between anti-CD20 infusions (from 6 months to 9–12 months or longer) may maintain efficacy while reducing long-term immunoglobulin depletion and infection risk. Several formal trials are evaluating this approach.
• Sequencing and de-escalation: For patients who have been stable on anti-CD20 therapy for years with no disease activity, the question of whether to continue indefinitely, switch to a less immunosuppressive maintenance therapy, or carefully stop treatment is increasingly discussed. This is particularly relevant given concerns about cumulative immunosuppression, declining immunoglobulin levels, and infection risk with long-term use.

• ClinicalTrials.gov: The US national registry of clinical trials. Search for “multiple sclerosis” and filter by recruiting status, location, and MS type. This is the most comprehensive, unbiased source of trial information. Visit: clinicaltrials.gov
• National MS Society trial matching: The National MS Society offers a free trial-matching service that helps patients find trials appropriate for their disease type, geographic location, and treatment history. Contact via nationalmssociety.org or the MS Navigator helpline.
• Your MS center: Ask your neurologist directly about open trials at your center. Academic MS programs (such as the University of Utah, Cleveland Clinic, UCSF, Johns Hopkins, and others listed in this guide) typically have the broadest trial portfolios.
• European trial registries: For patients in Europe, the EU Clinical Trials Register (clinicaltrialsregister.eu) and the newer Clinical Trials Information System (CTIS) provide additional listings.

Key questions before enrolling in a trial:

• What is the trial comparing — the study drug versus placebo, or versus another active treatment?
• Will I know which treatment group I am in (open-label) or not (blinded)?
• What are the known and potential risks of the experimental treatment?
• What is the time commitment — how many visits, how long is the study?
• Will I continue to receive my current MS treatment during the trial, or must I stop it?
• What happens after the trial ends — will I have continued access to the study drug if it works?
• How will my regular MS care be managed during the trial?

• High-dose biotin (MD1003): Pharmaceutical-grade biotin at 300 mg/day was initially reported to improve disability in progressive MS in a small trial. However, the larger Phase III SPI2 trial was negative — no significant benefit on disability progression was found. High-dose biotin also interferes with laboratory assays (including troponin and thyroid function tests), causing false results. This approach is not recommended for MS.
• Simvastatin for progressive MS: The Phase II MS-STAT trial showed a striking 43% reduction in brain atrophy in SPMS, generating considerable excitement. However, the definitive Phase III MS-STAT2 trial (964 patients) was negative — high-dose simvastatin (80 mg/day) did not slow disability progression in SPMS (HR 1.13, p=0.26). Simvastatin should not be used as an MS-specific therapy, though it remains appropriate for patients with standard cardiovascular indications.
• ATA188 (EBV-specific T cell therapy): Based on the EBV hypothesis of MS causation, this allogeneic T cell therapy targeted EBV-infected cells. The Phase II EMBOLD trial failed in November 2023 — only 6% of treated patients achieved confirmed disability improvement compared to 16% on placebo. Development was discontinued. This does not disprove the EBV hypothesis but shows that targeting EBV-infected cells therapeutically is more complex than hoped.
• Opicinumab (anti-LINGO-1): An antibody targeting LINGO-1, a protein that inhibits remyelination. The Phase II SYNERGY trial produced mixed results and did not meet its primary endpoint. Development has stalled, illustrating the difficulty of translating remyelination biology into clinical benefit.
• Fingolimod for PPMS (INFORMS trial): The INFORMS trial tested fingolimod in primary progressive MS and was negative — no benefit on disability progression. This confirmed that S1P receptor modulation alone is insufficient for progressive MS.

These failures are not wasted effort. Each one teaches the field something about MS biology and narrows the path to effective treatments. The success of BTK inhibitors in progressive MS, for example, was built on the understanding gained from why peripheral immunosuppression alone fails in progressive disease.

• OPERA I & II: Ocrelizumab vs. interferon beta-1a in relapsing MS. New England Journal of Medicine, 2017.
• ORATORIO: Ocrelizumab in primary progressive MS. New England Journal of Medicine, 2017.
• ASCLEPIOS I & II: Ofatumumab vs. teriflunomide in relapsing MS. New England Journal of Medicine, 2020.
• ULTIMATE I & II: Ublituximab vs. teriflunomide in relapsing MS. New England Journal of Medicine, 2022.
• EXPAND: Siponimod in secondary progressive MS. The Lancet, 2018.
• HERCULES: Tolebrutinib in non-relapsing secondary progressive MS. ECTRIMS/AAN presentations, 2024–2025.
• PERSEUS: Tolebrutinib in primary progressive MS. AAN 2025.
• CLARITY: Cladribine in relapsing MS. New England Journal of Medicine, 2010.
• AFFIRM: Natalizumab in relapsing MS. New England Journal of Medicine, 2006.
• MIST: aHSCT vs. DMTs in relapsing MS. JAMA, 2019.
• BEAT-MS: aHSCT vs. best available therapy in relapsing MS. New England Journal of Medicine, 2024.
• ARISE: Dimethyl fumarate in radiologically isolated syndrome (Okuda et al.), 2023.
• TERIS: Teriflunomide in radiologically isolated syndrome (Lebrun-Frénay et al.), JAMA Neurology, 2023.
• ReBUILD: Clemastine for remyelination in chronic optic neuropathy. The Lancet, 2017.
• MS-STAT: Simvastatin in secondary progressive MS. The Lancet, 2014.
• SPRINT-MS: Ibudilast in progressive MS. New England Journal of Medicine, 2018.
• Bjornevik et al.: Longitudinal analysis of EBV and MS risk. Science, 2022.
• 2024 McDonald criteria revision: International panel on diagnosis of MS. The Lancet Neurology, 2024.

• National Multiple Sclerosis Society: nationalmssociety.org — Comprehensive patient and caregiver resources, MS Navigator program, clinical trial matching, financial assistance.
• Multiple Sclerosis Association of America: mymsaa.org — Cooling equipment, MRI assistance, helpline.
• Multiple Sclerosis Foundation: msfocus.org — Support groups, publications, assistive technology grants.
• ClinicalTrials.gov: clinicaltrials.gov — US clinical trial registry, searchable by condition and location.
• Can Do MS: cando-ms.org — Wellness programs specifically designed for people with MS and their support partners.
• MS Society (UK): mssociety.org.uk — Resources and support for patients in the United Kingdom.