People with MS want to have hope and talk more about real remyelinating therapies. When is this going to come out? When will we be able to start taking it? When might we have some repair treatments?

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Prof G’s response

This is a big topic. I have therefore taken a SciSpace search and tried to distil it down to the most important points. I hope this addresses your question.

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Executive Summary

This report systematically examines whether having a family history of autoimmune diseases other than multiple sclerosis (MS) increases the risk of developing MS. Based on analysis of 30 highly relevant studies from a comprehensive literature search across multiple databases, the evidence indicates that family history of non-MS autoimmune diseases is associated with a modest but statistically significant increase in MS risk. The most robust evidence comes from large population-based cohort studies, particularly from Scandinavian registries, which demonstrate elevated risks for MS among first-degree relatives of patients with various autoimmune conditions. Specific autoimmune diseases showing the strongest associations include type 1 diabetes, inflammatory bowel diseases (particularly Crohn’s disease), thyroid disorders, rheumatoid arthritis, and psoriasis. The overall odds ratio for family history of any autoimmune disease ranges from 1.4 to 2.0 across studies, suggesting shared genetic susceptibility and potentially common environmental triggers. These findings have important implications for MS risk stratification, early detection strategies, and understanding the broader autoimmune disease spectrum.

As a result of this review, I have added a family history of autoimmune disease to the calculator and now include a version number and update date so you can keep track as the calculator evolves over time.

This is the actual link to the calculator: https://claude.ai/public/artifacts/1c09d603-6acf-4abf-8fcf-3f24f30363b4

Some of you have asked why this risk calculator is not being used. The reasons are simple. It has not been validated, and at present, we have no data to support an intervention to lower the risk of developing MS. From an individual perspective, someone at high risk could modify certain lifestyle factors and exposures and take vitamin D supplements. However, we cannot be sure at present if these interventions lower the risk of getting MS.

Could the calculator be used to decide who should have further investigations, i.e. for example, be examined by a neurologist or an AI-empowered automaton (robotic neurologist) or have an MRI scan, or require further studies? But this is exactly the question the FIND-MS initiative is trying to answer, but in a cost-effective way?

If one of your family members, for example, one of your children, had a high chance of developing MS, would you want them to be screened for asymptomatic MS? If they had asymptomatic MS, they may be eligible for a clinical trial or treatment. I say treatment because a large number of neurologists are now offering people with RIS (radiologically-isolated syndrome) or asymptomatic MS treatment. At present, the NHS England guidelines don’t allow us to treat people diagnosed with RIS. This is why I was arguing for doing a clinical trial of cladribine in RIS. The good thing about cladribine is that it is relatively safe, and it could potentially be a one-off treatment. The other maintenance DMTs must be administered indefinitely, and many are associated with chronic immunosuppression. I can’t imagine many people with asymptomatic MS will sign up for lifelong therapy with side effects that accumulate.

Please note that we are far away from implementing any MS at-risk screening programme. The following are the UK National Screening Committee (UK NSC) criteria for appraising the viability, effectiveness and appropriateness of a population screening programme. As you can see, the MS-Selfie MS-risk calculator will not fulfil these criteria.

The condition

1. The condition should be an important health problem as judged by its frequency and/or severity. The epidemiology, incidence, prevalence, and natural history of the condition should be understood, including the progression from latent to declared disease, and/or there should be robust evidence of an association between the risk or disease marker and serious or treatable disease.

2. All the cost-effective primary prevention interventions should have been implemented as far as practicable.

3. If carriers of a mutation or persons at risk are identified through screening, the natural history of people with this status should be understood, including its psychological implications.

The test

1. There should be a simple, safe, precise and validated screening test or tool.

2. The distribution of test values in the target population should be known, and a suitable cut-off level should be defined and agreed upon.

3. The test, from sample collection to delivery of results, should be acceptable to the target population.

4. There should be an agreed policy on further diagnostic investigation for individuals with a positive test result and on the choices available to them.

5. If the test is for a particular mutation or set of genetic variants, the method for their selection and the means through which these will be kept under review in the programme should be clearly set out.

The intervention

1. There should be an effective intervention for patients identified through screening, with evidence that pre-symptomatic intervention leads to better outcomes for the screened individual compared with usual care. Evidence on wider benefits of screening, for example, those affecting family members, should be taken into account where available. However, where there is no prospect of benefit for the individual screened, then the screening programme should not be further considered.

2. There should be agreed-upon, evidence-based policies specifying which individuals should be offered interventions and which interventions are appropriate.

The screening programme

1. There should be evidence from high-quality randomised controlled trials that the screening programme is effective in reducing mortality or morbidity. Where screening is aimed solely at providing information to allow the person being screened to make an ‘informed choice’ (such as Down syndrome or cystic fibrosis carrier screening), there must be evidence from high-quality trials that the test accurately measures risk. The information provided about the test and its outcome must be valuable and readily understood by the individual being screened.

2. There should be evidence that the complete screening programme (tests, diagnostic procedures, treatment/intervention) is clinically, socially, and ethically acceptable to health professionals and the public.

3. The benefit gained by individuals from the screening programme should outweigh any harms, such as overdiagnosis, overtreatment, false positives, false reassurance, uncertain findings, and complications.

4. The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training, and quality assurance) should be economically balanced relative to total medical care expenditure (value for money). Assessment against this criterion should have regard to evidence from cost-benefit and/or cost-effectiveness analyses and have regard to the effective use of available resources.

Implementation criteria

1. Clinical management of the condition and patient outcomes should be optimised in all health care providers prior to participation in a screening programme.

2. All other options for managing the condition should have been considered (such as improving treatment or providing other services), to ensure that no more cost-effective intervention could be introduced or current interventions increased within the resources available.

3. There should be a plan to manage and monitor the screening programme, along with an agreed set of quality assurance standards.

4. Adequate staffing and facilities for testing, diagnosis, treatment and programme management should be available prior to the commencement of the screening programme.

5. Evidence-based information explaining the purpose and potential consequences of screening, investigation, and preventive intervention or treatment should be made available to potential participants to assist them in making an informed choice.

6. Public pressure to broaden eligibility criteria to reduce the screening interval and increase the sensitivity of the testing process should be anticipated. Decisions about these parameters should be scientifically justifiable to the public.

I hope you found the SciSpace review helpful. Please feel free to ask questions.

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For those of you concerned about my reference to an AI-empowered automaton (a robotic neurologist), I urge you to read my three-part short story on the future of neurology.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

Here is a breakdown of what we found and what it could mean for you.

The research is based on the Phase 3 EXPAND study, a large clinical trial focused on patients with SPMS. Specifically, we wanted to know whether taking siponimod could delay progression to an Expanded Disability Status Scale (EDSS) score of 7.0 or higher. In clinical terms, an EDSS score of 7.0 means a person is essentially restricted to a wheelchair for about 12 hours a day and cannot walk more than 5 meters, even with an aid.

Key findings

The results of the study strongly suggest that siponimod is effective at slowing down the physical decline associated with SPMS. Here are the key takeaways:

• A 40% overall reduction in risk: In the overall SPMS population studied, patients taking siponimod had a 40% lower risk of progressing to wheelchair dependence than those taking a placebo.

• Even better results for “active” SPMS: The benefits were most pronounced for individuals with “active” SPMS—meaning they had experienced a recent relapse or had active inflammatory lesions visible on an MRI. For this group, siponimod reduced the risk of needing a wheelchair by 51%.

• Results for non-active SPMS: The risk was reduced by 22% compared with placebo. While this specific number wasn’t statistically significant within the study’s primary timeframe, we noted that non-active SPMS tends to progress much more slowly overall, so it may take a longer observation period to see the full benefit.

• Valuable time for those most at risk: We also examined a subgroup of patients who entered the trial already needing two walking aids (an EDSS score of 6.5). For these individuals who were closest to transitioning to a wheelchair, taking siponimod delayed that transition by about one full year.

The future

Because clinical trials typically last only a few years, we used advanced statistical modelling (a multi-state Markov model) to predict how siponimod would affect patients over a much longer period.

The long-term predictions are incredibly hopeful:

• Overall, siponimod is estimated to delay the median time to needing a wheelchair by 5.8 years compared to a placebo.

• For those with active SPMS, the estimated delay is even greater, giving patients a projected 7.9 additional years before needing a wheelchair.

We know that transitioning to a wheelchair is linked to a decline in quality of life and increased healthcare costs, making it a crucial event to delay for as long as possible. This study provides strong evidence that taking disease-modifying therapies like siponimod can give people living with SPMS more time on their feet and more years of independence. Furthermore, the study suggests that initiating treatment earlier rather than waiting offers the greatest benefit.

If you are living with SPMS—especially if you have recently experienced relapses or new MRI activity—these findings are a critical starting point for a conversation with your neurologist. Together, you can discuss whether siponimod or other DMTs are the right choice to help protect your mobility for the future.

Many of the killjoys have in the past made disparaging remarks about the treatment effects of DMTs in SPMS. I would like you to think again about what these results actually mean for pwSPMS. Does it not provide some hope that we are doing something positive for pwSPMS? Please be aware that Siponimod crosses the blood-brain barrier and has CNS effects on glial cells. I suspect it has effects on smouldering MS, which is something that is underappreciated.

I would be interested to hear whether any of you on siponimod have noticed any change in the trajectory of your worsening. I have had several patients who have done exceptionally well on siponimod.

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Vermersch et al. Progression to Wheelchair in Secondary Progressive Multiple Sclerosis and Impact of Siponimod: Post Hoc Analyses From the EXPAND Study. Eur J Neurol. 2026 Jun;33(6):e70659.

Background: Delaying time to requiring a wheelchair in people living with MS is an important treatment goal to maintain quality of life and guard against increased healthcare costs. In this post hoc analysis, the effects of siponimod versus placebo on time to sustained Expanded Disability Status Scale (EDSS) ≥ 7.0 over the core part of the Phase 3 EXPAND study were assessed.

Methods: The time to sustained EDSS ≥ 7.0 (time to requiring a wheelchair) was analysed for participants with secondary progressive multiple sclerosis (SPMS). Analyses were based on a While on Treatment (WOT) set that censored participants if entering open-label treatment. Subgroup analyses were conducted in participants with active versus non-active SPMS (defined based on pre-study/baseline criteria), and in participants with baseline EDSS 6.5.

Results: In the overall EXPAND population, siponimod reduced the risk of reaching sustained EDSS ≥ 7.0 (requiring a wheelchair) by 40% (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41-0.88; p = 0.009) versus placebo; the reduction in risk was 51% (HR, 0.49; 95% CI, 0.29-0.81; p = 0.005) versus placebo in participants with active SPMS and 22% (HR, 0.78; 95% CI, 0.42-1.45; p = 0.437) in non-active SPMS.

Conclusion: Siponimod reduced the risk of requiring a wheelchair in participants with SPMS versus participants receiving a placebo, with a greater effect in those with active disease. Time to requiring a wheelchair is a highly relevant treatment goal and an important indicator of treatment effect in patients with SPMS.

Keywords: Markov model; multi‐state model; secondary progressive multiple sclerosis; siponimod; sustained EDSS ≥ 7.0; wheelchair.

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

Over two days, clinicians, biomarker scientists, data scientists, epidemiologists, ethicists and people living with MS gathered around a single question: can we identify those who already have MS, or who are destined to develop it, early enough to change the long-term outcome?

We mapped the current landscape of risk-assessment tools and early-detection biomarkers, and then argued about three candidate pathways: an easy, low-cost, real-time risk tool; a moderate-cost, biomarker-based tool; and, finally, an in silico risk classifier. The idea behind the latter is to use an AI tool that automatically assesses your medical records and, when it spots something that may be prodromal MS, flags the person for further investigations that may lead to an early MS diagnosis.

My own contribution concerned the risk factor I have spent much of my career discussing and working on, the Epstein-Barr virus or EBV.

EBV: necessary but insufficient

The evidence that EBV is not merely associated with MS but is a necessary cause has become hard to argue against. The landmark longitudinal study of US military personnel by Bjornevik and colleagues showed that the risk of MS rose roughly 32-fold after EBV infection, and that elevated neurofilament light — a marker of nerve injury — appeared only after EBV seroconversion. This temporal sequence is an important part of proving causation. People who remain EBV-negative almost never develop MS, and when you re-test the rare “EBV-negative” patients with sensitive assays, most turn out to be positive. Prior infection with cytomegalovirus, intriguingly, appears to confer slight protection, possibly due to cross-reactive protective immunity.

How you are infected with EBV matters. Being infected as a young child, usually silently, carries a lower risk than being infected as a teenager or young adult, when it often presents as glandular fever (infectious mononucleosis). Glandular fever is itself an immunopathology and manifests clinically as a dysregulated CD8 T-cell response, in which up to half of your circulating cytotoxic (killer) T-cells can be EBV-specific. Having glandular fever or infectious mononucleosis pushes MS risk higher still.

EBV sits as part of a chain of dominoes, which includes genes, female sex and other environmental factors such as low vitamin D, month of birth, smoking, obesity, organic solvents, air pollution and latitude that together tip a person toward developing MS. Knock out the EBV domino and, in principle, the rest cannot fall. That is the logic behind the EBV vaccine and potentially antiviral therapies to treat IM.

Early detection of an MS endophenotype

What makes early detection plausible is that these processes leave fingerprints. Antibody seroreactivity against EBV shifts on average a decade before the preclinical neuroaxonal damage that characterises MS begins. High anti-EBNA1 titres, a broader EBV-specific T-cell repertoire, and specific EBNA-1 antibody signatures all track with risk. More recently, autoantibody signatures detectable years before diagnosis have been described that flag the people who go on to be diagnosed with MS.

I find it helpful to borrow a framework from type 1 diabetes, which now has a formal presymptomatic staging system: Stage 1 (islet autoantibodies, normal glucose), Stage 2 (autoantibodies plus dysglycaemia) and Stage 3 (clinical onset). Could we create a similar staging system for MS? Staging is not an academic exercise; in diabetes, it created the opening for teplizumab (anti-CD3), a therapy that delays the clinical onset of diabetes by roughly two years. In MS, we are not there yet, but the parallel is the point: if we can identify the presymptomatic phase, we can potentially create the space to intervene to prevent clinically manifest MS and prevent the subsequent disability associated with the disease.

An MS risk calculator

To make some of this more tangible, I built an MS risk calculator with help from Claude's Vibe coding capabilities. I thought we needed something tangible for the meeting. You can try it here.

It is built in two separate parts. The first tab handles susceptibility — the upstream factors that shape whether someone sits at elevated risk of MS in the general population. It combines published effect sizes for genetics (polygenic risk score and HLA status), family history, EBV markers, and the modifiable exposures: smoking, obesity, vitamin D, sun exposure, solvents, air pollution, and others. CMV is included as a protective factor.

The second tab is a different animal. It deals with the early-disease phase — people who already have an incidental MRI finding (radiologically isolated syndrome) or a first clinical event — and estimates the risk of conversion to definite MS, anchored to published cohort data. Here, neurofilament is entered as an age-adjusted percentile rather than a raw value, because age and body mass affect the absolute number.

Throughout, the tool tries to be honest about what we do not yet know. Effect sizes are combined on a log scale with their confidence intervals; the output carries an uncertainty band; risk is capped rather than allowed to run to absurd certainty; and the calculator flags when two inputs — say, genetics and family history, or vitamin D and latitude — are partly measuring the same thing and risk being double-counted. Please be aware that false precision is the enemy of tools like this.

I am interested in hearing your thoughts on using this tool. Would you recommend it to your siblings, children or relatives? Please note that it is not yet in its final form and will need to be validated. The problem with risk prediction for MS is that we don’t yet have anything proven to prevent it. As an individual, you can modify your environmental risk factors and may, in the near future, have regular blood tests and/or MRI scans to detect when you develop asymptomatic MS that may trigger early treatment.

Where next

The FIND-MS meeting did not solve early detection, and it was never going to. But it did something valuable: it forced a community that usually works in silos, such as virology, genetics, imaging, retinal scanning, health economics, and lived experience, to converge on a shared goal and a small set of concrete pathways. The destination is a future in which we identify people in the presymptomatic, prodromal phase of MS and offer them something to prevent clinically manifest MS. We are not there yet. But for the first time, it feels like this problem can be solved.

I would like to conclude by thanking the NMSS and the Valhalla Foundation for inviting me to contribute to this meeting. I sincerely hope the meeting will catalyse a new wave of research into FINDING-MS early. We want MS to be like diabetes.

Please feel free to make comments and feed back on the risk calculator. You can also download my presentation for your reference. Please feel free to use the presentation or hack it to promote the science of EBV as the likely cause of MS.

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Subscriptions and donations

MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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Questions

If you have questions unrelated to the newsletters or podcasts, please email them to ms-selfie@giovannoni.net. Prof. G will try to answer them as quickly as possible.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

Having felt that my MS was under reasonable control over the last few years, I now feel that I am at a crossroads and have no clear way forward for either drug treatment or other remediations (exercise, supplementation, brain training exercises, etc.) to help with an increased level of fatigue and reduced mobility. It seems like the start of a slippery slope to further disability with little in the way of treatment options, except perhaps some of the newer drugs that aren’t yet available. For the first time dealing with MS for 15 years, I feel lost, and am not sure what way to help myself and regain some level of control – can you help?

I am a 64-year-old woman, and I was diagnosed with MS in 2011 after developing symptoms of tingling and discomfort in my hips/legs during walking. I was then in my late 40’s, post-menopausal, and had already noticed some balance symptoms and a degree of hearing loss. Since 2011, I have been treated with a number of DMTs (Dimethyl fumarate, Tecfidera; interferon-beta-1a, Avonex; fingolimod, Gilenya; natalizumab, Tysabri and then cladribine, Mavenclad). My treatment with cladribine was nearly 4 years ago. Of these medications, a number had to be changed due to issues such as low lymphocyte levels, raised liver enzymes and high levels of JCV after being on Tysabri successfully for 5 years.

I have had stable cervical and brain MRI’s for as long as I can remember. My last relapse (and most severe one) was at the start of 2017 due to a rebound after withdrawal of Gilenya. This impacted my left leg function and has affected it since, despite a degree of recovery. Hearing loss continues to deteriorate slowly, and I rely on hearing aids most of the time.

Co-morbidities include hypothyroidism (stable for over 20 years on Eltroxin), interstitial cystitis associated with frequent UTI’s, and, more recently, osteoporosis (on Prolia). I supplement with Vitamin D, calcium, and flaxseed oil, and have a mostly plant-based diet except for chicken and fish, trying to keep my saturated fat intake low. I exercise most days with a mix of stretching, weight-bearing exercise, and swimming.

Over the last 6-10 months, I have noticed a significant increase in my fatigue, which affects my ability to walk (from 45-60 minutes to 30 minutes). My consultant has offered me treatment with Fampiridine to mitigate this, but I have not yet decided to start this due to the consideration of very common side effects. I have also noticed increasing cognitive fatigue and a reduction in the ability to concentrate over time, with an increase in short-term memory loss.

I have found that in dealing with my MS, I have to consider any effects on my co-morbidities, e.g., interstitial cystitis is particularly sensitive to anything that affects the acidity of my urine, and some medication I tried for osteoporosis caused an exacerbation of very unpleasant symptoms. Intermittent catheterisation, in particular, has made life extremely uncomfortable, and only now is it mostly stable after treatment with GAG.

I would value your insight on my situation. Thank you.

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

Feeling at a crossroads, given your history, is an understandable and valid response to the changes you are experiencing. It must be frustrating to feel that despite doing everything “right”—staying active, eating well, and cycling through highly effective therapies—the ground appears to be shifting beneath your feet. What you are describing is a well-recognised phase of the disease, and you will not be alone in feeling this way and experiencing worsening.

Here is an explanation of what is likely happening and how to approach your problems to help you regain control.

Read more

Having a diagnosis of MS and living with MS means having to navigate a complex landscape of sensory changes, numbness, and altered central sensory processing. For many women with MS, this can directly impact sexual function and intimacy. Understanding your own body is a tool to help understand the impact MS has on sexual pleasure.

A newly uploaded anatomical study has completely changed our understanding of the clitoris and its neural pathways. For women with MS and their partners, these new insights into how the clitoris and vulva are wired may offer new possibilities for intimacy, the use of sex aids, and making informed healthcare choices.

Mapping the clitoris in 3D

For a long time, medical illustrations often depicted the clitoral glans (the visible “head” of the clitoris) as having a sparse nerve supply. Because the nerves are largely embedded deep inside the body, standard anatomical dissections struggled to trace them. However, researchers recently used highly advanced, micron-scale 3D imaging technology to map the female pelvis. What they found will rewrite anatomy textbooks:

• A “Tree-Like” network: The primary sensory nerve—the dorsal nerve of the clitoris (DNC)—does not just gradually diminish as it reaches the glans. Instead, it forms a highly complex, tree-like branching pattern with nerve trunks projecting outward toward the surface. Against the current dogma, this supports what many women know, that the clitoris is well endowed when it comes to sensory nerves and hence sensory inputs. In fact, it may be the most richly endowed sense organ in the female body.

• Beyond the glans: The sensory wiring extends much further than previously known. Branches of the dorsal nerve of the clitoris actually travel upward to innervate the clitoral hood and the mons pubis.

• Surrounding support: The posterior labial nerve, which is known to supply the labia, was also discovered to innervate the surrounding areas of the clitoral body.

What this may mean for sexual function and MS

Because MS damages the myelin sheath covering the central nerves, you might experience areas of numbness, hypersensitivity, or altered sensation in your genital region. This new anatomical map provides practical information:

• Expanding the erogenous map: If the clitoral glans itself is overly sensitive or numb due to MS nerve lesions, you and your partner can broaden your focus beyond the glans. Since we now know that sensory nerve branches extend extensively into the clitoral hood, the mons pubis, and the lateral aspects of the clitoral body, these areas can also be stimulated to achieve sexual pleasure.

• Optimising sex aids: Understanding that the nerve network is spread out like a canopy—reaching into the mons pubis and labial structures—means that sex toys and vibrators with wider bases or those designed to lie flat against the vulva can stimulate a much larger cluster of nerve endings than previously thought. You don’t have to rely solely on pinpoint stimulation. It would be an interesting study to survey women with MS and controls to see which sex aids work best in women with MS who have sensory problems affecting the vulva.

Impact on vulvar surgery

If you ever need to undergo gynaecological procedures or elect for vulvar surgeries, this research will allow surgeons to be more careful in how they operate so as not to damage the nerve supply to the clitoris and surrounding erogenous areas. Operations around the vulva, such as labiaplasty, have dramatically increased in popularity. These procedures often involve making incisions in the clitoral hood. Previously, surgeons operated with a defined “danger zone” to avoid nerve damage. However, because this new study proves that sensory nerve branches extend beyond this traditional danger zone into the mons pubis, surgeons will now have to update their techniques to prevent accidental nerve damage and loss of sensation. This comprehensive map is also critically important for reconstructive surgery, such as that performed for survivors of female genital mutilation (FGM) or those having gender reassigment procedures.

The gender gap in anatomical science

I doubt it will shock you to learn that in 2026, we are just now mapping the nerve pathways of the clitoris when we have had this information for the penis for more than 30 years. Why did it take so long? The clitoris has historically been one of the least studied organs in the human body. For centuries, scientific investigation was blocked by cultural taboos surrounding female sexuality. In fact, the clitoris was completely excluded from standard anatomy textbooks until the 20th century, and when it was finally added, it was inaccurately dismissed as just “a small version of the penis”.

While the exact innervation and nerve density of the penile glans have been well-documented for decades, the study of the clitoral glans has heavily lagged behind. This neglect has had real-world consequences for women’s health, leading to surgical risks and a fundamental misunderstanding of female pleasure. By shedding light on the true complexity of the clitoris and its innervation, science is taking an important step forward and addressing the gender imbalance in anatomy research.

For women with MS, this isn’t just anatomical trivia—it can potentially lead to better sexual health, safer medical care, and a deeper connection with your own body.

If you are a woman with MS and have sexual dysfunction due to altered sensation, is the information useful? Do you use sex aids such as vibrators? If yes, is there a particular design that works better than others? Please share this information with others.

Leave a comment

Paper

Lee et al. Neuroanatomy of the clitoris. bioRxiv preprint doi: https://doi.org/10.64898/2026.03.18.712572

The clitoris is one of the least studied organs of the human body. The detailed anatomy of the clitoris is challenging to address through a gross dissection, as most of its parts are embedded internally, surrounded by pubic bone and several pelvic organs. While clinical imaging methods such as magnetic resonance imaging can capture the gross 3D morphology, they lack the spatial resolution required to resolve the detailed structures. In this study, we generated micron-scale computed tomography images of the female pelvises, leveraging a synchrotron radiation X-ray source. This unique data revealed the complex trajectory of the dorsal nerve of the clitoris, the main sensory nerve of the clitoris. Notably, the nerve trunks within the clitoral glans were revealed, with the maximum diameter ranging from 0.2 to 0.7 mm. They showed a tree-like branching pattern projecting towards the surface of the glans. We also revealed that some branches of the dorsal nerve of the clitoris ramify to innervate the clitoral hood and mons pubis. Finally, the posterior labial nerve, a branch of the perineal nerves, was shown to innervate the surroundings of the clitoris and the labial structures. These findings have an immediate impact on operations performed around the vulva area, such as gender-affirmation surgery andreconstruction surgery after genital mutilation.

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Is there anything I am missing that interests you? Do you still find the Q&A posts helpful?

Please remember the purpose of MS-Selfie must remain a tool to help people with MS self-manage, or at least to empower them to ask the right questions to get the most out of their MS service.

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• Abi Rimmer. PCOS name change to PMOS must be managed to avoid confusing patients, says expert. BMJ 2026; 393: s955 (Published 15 May 2026)

• Rachel Morman. PMOS: What’s in a name? Everything. BMJ 2026; 393: e079749 (Published 20 May 2026)

• Pensée et al. Improving awareness and care in polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome). BMJ 2026; 393: s893 (Published 15 May 2026)

As the majority of people with MS (pwMS) are women, I thought I would cover this topic briefly in a newsletter. It is relevant to clinical practice, as I have managed many women with MS who have also had PCOS, now called PMOS. In the past, I simply documented the diagnosis in the clinical notes, but didn’t really consider whether or not it was more common in women with MS and whether or not MS treatments interacted wth PMOS. On reflection, this is odd for me, as I am usually quite inquisitive about anything related to MS.

The following is a brief summary of information I found from a SciSpace search on PMOS and MS. I hope you find it helpful.

Why rename PCOS?

PCOS actively caused harm by inaccurately implying that pathological ovarian cysts were the defining feature of the condition. This misconception is still held by 85% of patients and 62% of healthcare professionals as recently as 2023. In reality, PMOS is a complex, lifelong multisystem disorder with diverse endocrine and metabolic features. The old name obscured these features, contributing to severe diagnostic delays, stigma, and fragmented care. The medical community is rolling out the new PMOS terminology over a three-year transition period to accurately reflect the condition’s pathology and spur better research and clinical outcomes.

Is PMOS more common in women with MS?

Globally, PMOS is highly prevalent, affecting 1 in 8 women. However, population data do not show a markedly increased prevalence of PMOS among women with MS. A nationwide Swedish cohort study of over 1.3 million women found a PMOS prevalence of approximately 2% in the MS study population. Furthermore, genetic and cross-trait analyses confirm that PMOS does not causally increase the risk of developing MS. While there are shared genetic signals involving sex hormone-binding globulin (SHBG) and testosterone, these biological associations do not indicate a causal relationship between the two conditions.

Should PMOS be screened for and treated in MS populations?

Globally, up to 70% of people with PMOS remain undiagnosed, and diagnosis is exceptionally challenging for women with MS due to clinical overlap. Menstrual irregularities may increase after the onset of MS, but these symptoms are often wrongly attributed to the neurological disease, stress, or MS medications. As a result, the overlapping endocrine symptoms (like oligo/anovulation) are rarely investigated as a separate PMOS diagnosis in neurology clinics, leading to under- or misdiagnosis.

While experts do not explicitly recommend universal asymptomatic screening for all women with MS, they strongly emphasise the need for an endocrine assessment whenever reproductive or menstrual symptoms occur. Proper diagnosis and treatment are critical because untreated PMOS carries an increased risk of several comorbidities, including type 2 diabetes, cardiovascular disease, fatty liver disease, endometrial cancer, and depression. By recognising PMOS as a distinct metabolic and endocrine condition rather than an MS-related gynaecological inconvenience, clinicians can ensure women receive vital proactive, preventative management.

Who is best suited to manage the condition?

Currently, PMOS management suffers from a lack of “joined-up thinking,” with women bouncing between primary care, endocrinology, dermatology, gynaecology, and fertility services. Because PMOS is a chronic multisystem condition—much like diabetes—it requires cross-speciality care delivery models.

Experts and parliamentary reports recommend that PMOS be best managed through integrated, community-based pathways within women’s health hubs. These hubs are designed to provide a clear primary care diagnostic and referral protocol, anchoring the patient’s care in the community while coordinating with necessary specialists. Due to significant racial and socioeconomic inequities in PMOS severity and care, management must be highly patient-centred, culturally sensitive, and rooted in an understanding of the patient’s lived realities.

Are there any diagnostic challenges in MS?

Overlap of menstrual, reproductive, and endocrine symptoms in women with MS can complicate recognition of PMOS and lead to misclassification. Studies report increased menstrual irregularities after MS onset and note that standard PMOS definitions rely on combinations of oligo/anovulation, hyperandrogenism, and ovarian morphology. These features may be documented to varying degrees in neurology clinics.

• Symptom overlap: Menstrual irregularities are reported to increase after MS onset and may be attributed to neurological disease, medications, or stress rather than investigated as PMOS.

• Diagnostic criteria: Rotterdam criteria require at least two of oligo/anovulation, clinical/biochemical hyperandrogenism, and polycystic ovarian morphology. An incomplete endocrine workup or attribution of symptoms to MS will produce under‑ or misdiagnosis.

• Ovarian reserve considerations: Diminished ovarian parameters and other reproductive changes have been evaluated in MS cohorts, which complicates the interpretation of amenorrhea or oligomenorrhea without targeted endocrine assessment.

• Evidence gap: There is insufficient evidence to define how disease‑modifying therapies for MS specifically alter PCOS diagnostic accuracy or to quantify rates of misdiagnosis due to MS treatments. If there is an HCP reading this who is interested in conducting research, I would suggest considering setting up a study to answer this question.

Are there any shared mechanisms and hormonal dysfunction between MS and PMOS?

Available data point to hormonal, metabolic, genetic, and immune intersections between PMOS and MS, but do not demonstrate a simple causal link. A cross‑trait genomic analysis identified shared genetic regions and pleiotropic SNPs involving sex hormone‑binding globulin (SHBG) and testosterone with MS, while Mendelian randomisation found no causal effect of genetically predicted PMOS, SHBG, or testosterone on MS risk.

• Genetic overlap: Pleiotropic loci (in which a single gene, mutation, or factor produces multiple, seemingly unrelated effects or traits) linking SHBG/testosterone and MS were identified, suggesting biological intersections at the genomic level, with no evidence of directional causality from PMOS to MS.

• Hormonal biology: Hyperandrogenism and insulin resistance are central to PMOS pathophysiology and drive metabolic and inflammatory changes that could plausibly intersect with immune processes relevant to MS.

• Autoimmunity signal: Higher autoimmune incidence has been observed in large PCOS cohorts (eg, increased rates of type 1 diabetes and thyroid disease), which raises the possibility of shared immune‑related susceptibility factors, though direct mechanistic links to MS remain unproven.

• Metabolic inflammation: Metabolic syndrome and low SHBG commonly co‑occur with PMOS and reflect insulin resistance and pro‑inflammatory states that could modify clinical risk or outcomes in patients with both conditions.

Is there any clinical overlap between PMOS and MS?

A small set of studies has examined fertility, comorbidities, and symptom overlap between PMOS and MS, but direct investigations of treatment interactions are lacking. Registry and cohort analyses indicate similar infertility rates and mixed signals about the use of assisted reproduction.

• Fertility and assisted reproduction: Infertility prevalence in one large MS cohort was similar to that of age‑matched controls, and assisted reproduction use (IVF, controlled ovarian hyperstimulation) did not differ significantly between MS patients and controls.

• Medically-assisted reproduction (MAR) cohorts: Slightly higher MS prevalence was observed among women undergoing medically assisted reproduction in one register study, but female infertility per se was not associated with increased incident MS on follow‑up.

• Comorbidity reporting: PMOS appears among recorded comorbidities in administrative MS datasets, indicating coexistence in routine care records, though population frequencies vary across data sources.

• Symptom overlap: Menstrual irregularities and ovarian reserve changes have been documented in systematic reviews of reproductive parameters in MS, emphasising the need for integrated assessment when reproductive symptoms occur in women with MS. I am sure most MS Centres don’t do this. However, I suspect this may occur in centres focused on women’s health.

• Treatment interactions: To the best of my knowledge, there are no studies that directly evaluate interactions between MS disease‑modifying therapies and PMOS pathophysiology or PMOS-directed treatments; therefore, evidence on drug‑drug or treatment‑outcome interactions is insufficient to comment on.

How do you treat PMOS?

No single drug has ever been developed specifically for PMOS. However, a recent parliamentary report advocates improving access to care by ensuring that key existing medicines are explicitly licensed for the condition. The specific treatments being called on for PMOS licensing include metformin and glucagon-like peptide (GLP-1) receptor agonists. Additionally, the report recommends reinstating NHS funding for laser hair removal.

Currently, many of these medical and cosmetic treatments are either unlicensed for PMOS or unavailable for routine NHS funding. This lack of access disproportionately impacts patients from lower socioeconomic backgrounds and certain ethnic minority groups, who often face higher PMOS prevalence and greater metabolic burdens but are least able to afford out-of-pocket costs. The renaming to PMOS, alongside upcoming NICE guidelines, will strengthen the clinical case for officially licensing and funding these treatments, ensuring equitable access for all women and gender-diverse people affected.

I would be interested to know if any of you have PMOS and if the diagnosis was delayed because of your MS. Did the treatment of MS interfere with your management of PMOS? And have your PMOS problems been satisfactorily resolved?

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As I move closer to preventive healthcare, the concept of Women’s and Men’s health hubs as a proposed solution to gender-related problems is very appealing. By establishing integrated community-based pathways, these hubs aim to reduce diagnostic delays by providing clear protocols for primary care diagnostics and referrals. I just wonder if MS is on the list of diseases these hubs will consider?

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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For Jaz*, a woman living with multiple sclerosis (MS), it was years before she realised her husband was abusing her.

The coercion and control unfolded slowly, stealthily.

There was the isolation: “Your parents don’t care about you,” her (now-ex) husband would tell her. “I’m the only one that’s here for you.” The degradation: “The words started to get more aggressive. ‘If you come with me, there’s no toilet, so you’re going to piss yourself.” The impairment-linked abuse: “He unplugged my mobility scooter so I couldn’t pick my son up from school.” The chipping away at her sense of self. “He took over most of the roles in the house, even though I was capable of doing them. The finances, too.”

Sadly, Jaz’s story is not unique.

Domestic violence and abuse (DVA) is a pattern of behaviour that commonly uses a variety of forms of abuse – such as physical, sexual, psychological - along with controlling and coercive behaviour to control another person. It is most often perpetrated by men against women.

Disabled people are more than twice as likely to be victim-survivors of DVA - be it by their (ex) partner, a family member or the person they have trusted to care for them. The abuse also lasts longer, is more frequent and severe compared to the general population.

And women with MS are at the greatest risk - due to a convergence of factors rarely observed in other patient groups.

Risk factors

MS predominantly affects women, is often diagnosed during the reproductive years (pregnancy and young age are known drivers) and can lead to physical, cognitive and mental disabilities: all established risk factors for DVA.

Women with MS are also at risk of isolation driven by disease-induced job loss, poverty, decreased motivation, communication barriers, cognitive change and difficulty maintaining social networks. MS symptoms - including pain, fatigue, bladder and mobility problems, depression - can also cause them to socially withdraw.

These factors, coupled with an increasing need to rely on an informal carer, can inherently lead to greater vulnerability as the person with MS becomes dependent on another for physical needs. This power imbalance increases the risk of abuse.

Recent studies back this up. It is estimated that between 38% to 63% of women with the disease have experienced domestic violence.** Some abuse fits within the traditional definitions, while others are MS-specific.

These include perpetrators weaponising bodily functions (refusing to take them to the toilet), withholding access to communication (hiding mobile phone) and mobility aids (taking away wheelchair), medical tampering (denying pain relief) and using the victim-survivor’s inability to physically resist to carry out bodily, sexual and financial abuse (stealing debit cards).

What to do?

MS health care professionals (HCPs) are uniquely positioned to play a vital role in identifying and responding to DVA. Because MS requires frequent, long-term care, patients often form trusting, long-term relationships with their MS clinical team (which includes neurologists, nurses, occupational and physiotherapists and others).

This, however, requires appropriate training, awareness, and protocols so HCPs can ask sensitive questions with confidence, identify subtle signs of abuse and offer safe opportunities for disclosure. As part of that, consultations should also include time alone with the patient – separate from their carer to ensure honest communication.

Experts in DVA say this is essential. In our society, caregivers*** are seen as self-sacrificing heroes – a bias known as the ‘halo effect.’ This can lead friends, family and even clinicians to implicitly believe the word of the carer vs the victim-survivor, and ignore any inconsistencies and red flags.

At the moment, there is no MS-specific guidance about screening for violence and abuse in MS patients. That said, an MS clinical care team at an NHS trust carried out a three-month feasibility study to implement a routine DVA enquiry with their MS patients from October 2024 to January 2025. They discovered that routine screening can be successful if training and support from safeguarding teams are available.

Looking ahead

DVA is a critical public health concern, and we know it is commonly experienced by people with MS. Yet it remains under-detected and under-reported – leaving MS victim-survivors underserved in research and health-system responses.

Raising awareness is a key first step. It’s also imperative that we address knowledge gaps. For example, little is known about the experience/prevalence of DVA among MS men, in culturally-diverse groups or how abuse links to social determinants of health. As for how DVA affects MS outcomes, evidence is limited. It’s also important that HCPs learn how best to safely and timely address DVA among their MS patients. This is very challenging work, and they also need support.

I hope this article helps stimulate discussion and break the silence on a complex issue. Addressing domestic violence and abuse is everyone’s job.

*Jaz is a real person, though this is not her real name. She is a 45 to 54-year-old UK woman who identifies as British Indian. She currently volunteers at a local MS organisation.

** These studies are limited by small sample sizes as well as different terms/definitions of DVA, time frames, collection measures and the absence of healthy control comparison groups.

***This does not imply all caregivers are abusive. Most do not make huge, unrecognised, vital contributions.

My interest

In 2021, concerned at the increase in DVA being experienced by their MS patients, MS neurologists Prof Helen Ford, Prof Nikos Evangelou, and I decided to create the MS Domestic Violence and Abuse Research Initiative at the University of Leeds. Funding came from my family foundation. Its aim was not only to raise awareness of this issue but also to create a toolkit to equip HCPs with the knowledge and practical guidance needed to safely identify, assess, and support people with MS experiencing DVA.

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Rachel Horne, London, 30th May 2026

Rachel Horne is a journalist with MS. She has written about the disease from a patient’s point of view for The BMJ, Nature Reviews Neurology, Annals of Neurology and the MS-Blog.

She is an Honorary Research Fellow at the Wolfson Institute of Population Health at Queen Mary University of London (QMUL) and is co-chair of the Patient and Public Involvement and Engagement Group for the NIHR Policy Research Unit in Dementia and Neurodegeneration at QMUL, launched in 2024.

She is also the founder of the Rachel Horne Prize for Women’s Research in MS, an annual international award of US$40,000 that recognises a woman scientist for her outstanding contribution to women’s health-related research in MS.

Rachel started her journalistic career in China and covered the Tiananmen Square demonstrations and massacre. She later worked as a financial news producer for CNN in London. Her writing has appeared in the Financial Times, The Economist and the Wall Street Journal.

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

Your EDSS can be stable, and you can still be getting worse. In short, the EDSS has multiple blind spots, one of which involves upper-limb and hand function.

Today marks the publication of the ORATORIO-HAND study in The Lancet, which challenges the EDSS’s supremacy as the primary outcome for assessing the effects of DMTs on progressive MS.

Summary of results

ORATORIO-HAND is a positive phase 3b trial of ocrelizumab in primary progressive MS (PPMS). In 1,013 pwMS randomised to ocrelizumab or placebo, ocrelizumab reduced the risk of 12-week composite confirmed disability progression (cCDP) on the EDSS or the nine-hole peg test (9HPT) by 30% (HR 0.70, 95% CI 0.57–0.86, p=0.0007). In pwMS with baseline MRI activity, the risk reduction was 55%.

Ocrelizumab treated subjects also showed a significant reduction in the risk of disability progression in each individual component with a 41% risk reduction (p=0·0002) in 12-week disability progression in 9HPT, corresponding to progression rates of 17% with ocrelizumab and 25% with placebo (Table 1); and 33% risk reduction (p=0·0013) in 12-week CDP in EDSS, corresponding to progression rates of 23% with ocrelizumab and 31% with placebo.

Among pwMS still ambulatory at baseline, the risk of requiring a wheelchair fell by 52%. All the results, including the relative and absolute risk reductions and the number needed to treat, are summarised in the paper and are not too bad at all. I suspect ocrelizumab will be a cost-effective treatment for pwPPM who are using a wheelchair. Don’t forget that once you lose your hand function, you lose your independence and need 24-hour-a-day care. Being EDSS 8.5 and above is very expensive.

Please note that the safety profile of ocrelizumab in ORATORIO-HAND was similar to that observed in other pivotal phase 3 studies and in a decade of post-marketing experience and surveillance.

Importantly, the ORATORIO-HAND study is not merely a confirmatory trial of the original phase 3 ORATORIO PPMS study. It is the first randomised, placebo-controlled evidence in MS that a disease-modifying therapy (DMT) can preserve hand function in people with advanced PPMS, i.e. in subjects aged up to 65 years of age, with an EDSS score between 6.5 and 8.0, who are wheelchair-dependent, using a composite endpoint of confirmed disability progression on either the EDSS or the 9HPT. This treatment effect in the more advanced subjects would have been missed if the EDSS alone had been used. Each of these findings overturns the MS orthodoxy that has, for too long, restricted who gets recruited into clinical trials and, subsequently, who gets treated, when, and on what evidence.

Background theory

We have proposed that progressive MS would be best understood as a length-dependent central axonopathy. The argument, drawing on a model originally hinted at by Kurtzke himself, is relatively straightforward. If MS lesions occur randomly throughout the central nervous system, then the neuronal pathways with the longest central axons will, on average, accumulate the most lesions. The corticospinal tract, which supplies the legs, is the longest pathway in the central nervous system. The corticospinal projections to the arms and hands are considerably shorter. Visual and brainstem pathways are shorter still. Based on this basic anatomy, two predictions followed from the length-dependent central axonopathy hypothesis. First, clinically apparent progression should emerge first in the legs, then later (or in some pwMS, never) in the arms, hands, and other systems with shorter axons. These predictions are what we see clinically: progressive MS typically declares itself as progressive weakness in the lower limbs, with hand involvement following years later. The second prediction that has driven much of the subsequent debate is that neuronal pathways with preserved functional reserve should remain more responsive to anti-inflammatory DMT, even when longer pathways have already exhausted their reserve and entered the apparently treatment-refractory progressive phase. We referred to this as the asynchronous progressive MS hypothesis, and it carries an important corollary: the therapeutic lag to measurable benefit will be shorter and more pronounced in neuronal systems supplied by shorter neuronal pathways. This was noted and ignored in many earlier studies, including the original phase 3 ORATORIO trial, where the treatment effect on hand function, as measured by the 9-HPT, was almost double that seen on predominantly lower-limb function with the EDSS.

These observations underpinned the ORATORIO-HAND study, which used a population enriched for advanced PPMS: 16% of participants had baseline EDSS scores above 6.5, and 27% were aged over 55. Ocrelizumab produced its most striking effects on hand function. The 41% relative reduction in 9HPT progression exceeded the 33% reduction in EDSS progression. In the subgroup with EDSS scores above 6.5 (participants who were wheelchair-dependent and whose lower-limb corticospinal system had effectively exhausted its reserve), ocrelizumab still reduced 12-week cCDP by 49% and 9HPT progression by 41%. The treatment effect on patient-reported upper-limb function (the Neuro-QoL-UE) was significant: MRI-active pwMS improved on ocrelizumab, whereas placebo-treated pwMS deteriorated.

This observation of greater or preserved responsiveness in shorter neuronal pathways, even when longer pathways are no longer salvageable, is consistent with the length-dependent axonopathy hypothesis. The ORATORIO-HAND data support it as a working model for trial design and future clinical decision-making.

The people with MS behind O’HAND

When we discuss ORATORIO-HAND, it is important to acknowledge the patient community that helped make it possible. The #ThinkHand campaign, which we launched in 2016, has been well described on MS-Selfie. It began from an observation that trials of DMTs routinely excluded people with MS who used wheelchairs, on the assumption that nothing could be done for them; the so-called unsalvageables. The justification led to a circular argument. Because trials measured benefit predominantly through ambulation, and because wheelchair users could not walk, they were deemed ineligible. Because they were ineligible, no class 1 trial evidence was generated from wheelchair users. Without evidence of the effectiveness of DMTs in wheelchair users, the assumption that nothing could be done was perpetuated.

The ThinkHand campaign challenged this circular argument from multiple angles. The campaign’s surveys, conducted through The MS Research Blog, found that 92% of people with MS placed greater importance on their upper-limb function than their lower-limb function, and 95% felt that wheelchair users should not be excluded from DMT trials. In a contemporary survey, 75% of UK MS neurologists routinely stopped prescribing DMTs once pwMS needed a wheelchair, though 61% believed the drugs were probably still effective. The campaign developed a low-cost cardboard 9HPT distributed to 12,000 delegates at ECTRIMS, co-designed the Under & Over upper limb and hand rehabilitation tool with people living with advanced MS, and catalysed three clinical trials with upper-limb function as part of the primary endpoint: ChariotMS, which focuses specifically on wheelchair users, the ORATORIO-HAND study, which deliberately broke the EDSS 6.5 ceiling that had constrained the original ORATORIO trial and the OCTOPUS multi-arm platform study.

The decision in ORATORIO-HAND to enrol pwMS with EDSS scores up to 8.0, to use a composite primary endpoint anchored on the 9HPT, and to power the trial specifically to detect benefit in hand function did not simply emerge from the laboratory, animal house, clinic, sponsor, or regulators. It emerged from people with MS telling us, loudly, repeatedly, and with the moral authority of lived experience, that we had been measuring the wrong thing. ORATORIO-HAND is, in a very real sense, their trial. The 41% reduction in the risk of worsening hand function, as measured by the 9HPT, is their victory. The sponsor, regulators, healthcare systems, payers, and HCPs now need to deliver on the ORATORIO-HAND results and ensure that people with advanced PPMS can receive ocrelizumab.

Label change

ORATORIO-HAND should prompt a formal revision of the ocrelizumab prescribing label. The current European and US labels for PPMS reflect the eligibility criteria of the original ORATORIO trial, which enrolled pwMS aged 18–55 years with EDSS scores of 3.0–6.5. The current label is based on data from 2017. ORATORIO-HAND has now demonstrated efficacy in pwMS aged up to 65 and with EDSS scores up to 8.0, and on the clinically relevant endpoint of hand function. Importantly, the safety profile, despite an older and more disabled population, was consistent with the drug’s established profile, with no new signals once the impact of the COVID-19 pandemic on respiratory infections is accounted for.

Three specific label revisions for ocrelizumab are needed. First, the upper age limit should be raised, or, more appropriately, removed, given that the data do not support a sudden biological change at 55. In addition, observational cohorts have shown continued benefit from ocrelizumab treatment beyond this age. Second, the EDSS ceiling should be raised from 6.5 to 8.0 to reflect the population in which efficacy has now been demonstrated. Third, the indication should explicitly include preservation of upper-limb function as a treatment goal, recognising the 9HPT as a validated outcome and aligning the label with what pwMS consider clinically meaningful. Without these changes, the ocrelizumab label will continue to function as a barrier, preventing reimbursement, restricting prescribing, and denying treatment to pwMS for whom we now have strong evidence of benefit.

The question I have for Roche is, would it be ethical not to push for a label change, given the results and the sacrifices pwMS have made to participate in this trial? They may never forgive you if you didn’t.

Stopping criteria

The implications of ORATORIO-HAND extend beyond the regulatory label to the local commissioning policies and stopping rules that govern day-to-day prescribing. In England, for example, the NHS England commissioning policy for DMTs in MS requires discontinuation of treatment when a patient reaches an EDSS score of 7.0 or becomes wheelchair-dependent. Similar stopping rules operate, formally or informally, in many other healthcare systems. These rules were never grounded in evidence but rather in a lack thereof. ORATORIO-HAND replaces this absence with data.

I predict it will be an uphill battle to get NHS England to change its stopping criteria for ocrelizumab. Any ideas on how we can make this happen?

What about SPMS?

The lessons of ORATORIO-HAND do not stop at PPMS. The asynchronous progressive MS hypothesis predicts that the same length-dependent logic should apply to secondary progressive MS, in which many pwMS still retain useful upper-limb function long after walking is lost. The ongoing investigator-led trials, such as ChariotMS, will test whether this prediction holds. If it does, and the biology gives every reason to expect that it will, then the entire stopping-rule architecture for DMTs in MS will need to be rebuilt around upper-limb function rather than ambulation.

There is also a broader methodological point. ORATORIO-HAND is the first MS trial designed from the outset to take upper-limb function seriously, and it succeeded where its predecessors, particularly in more advanced populations, had failed. The lesson for trialists is clear: in progressive MS, an endpoint that does not include the 9HPT, on the available evidence, asks the wrong question.

ORATORIO-HAND is, in the end, a study about listening. It is about listening to pwMS who told us that their hand function mattered more than ambulation. It is about listening to the data that told us that wheelchair users were being denied therapies that might still help them. It is about listening to a hypothesis, that progressive MS is a length-dependent central axonopathy, which predicted, ahead of the evidence, what a trial like this would find. The work now is to act on what we have heard, to rewrite the ocrelizumab label, to revise the starting and stopping criteria, and to design the next generation of trials around the functional domain that pwMS have been telling us matters most for years.

Thank you

I would like to thank Roche for believing in the science and agreeing to fund the extension of this study into wheelchair users. Other Pharma companies would have said no. I am aware that several staff members at Roche went above and beyond their duties to secure funding for this study. I won’t forget who you are; you are now part of MS history. Don’t forget the unsalvageable are now salvageable.

I would like to thank the pwMS for participating in this study at a time when ocrelizumab was already licensed for treating active PPMS. If it wasn’t for your altruism, the next generation of pwPPMS with more advanced disability may have remained unsalvageable. Thank you, thank you, thank you,....

Then to all the sites across the world for helping make this trial a success, and to my colleagues on the steering committee. To the best of my knowledge, this was the first steering committee in which we sought to advance gender equality; possibly another milestone for the field of MS.

I assume a lot of what is discussed in this newsletter may be too scientific. Don’t be shy and ask questions.

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Paper

Giovannoni et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study. The Lancet, 407(10544):2195-2207.

Background: The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly with respect to hand function preservation.

Methods: ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18–65 years and Expanded Disability Status Scale (EDSS) score of 3·0–8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting.

Findings: Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57–0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups.

Interpretation: Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile.

Funding: F Hoffmann-La Roche.

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If you have questions unrelated to the newsletters or podcasts, please email them to ms-selfie@giovannoni.net. Prof. G will try to answer them as quickly as possible.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

Can I please ask what your take is on the precautions for blood transfusions post-cladribine? I received this response from my MS centre.

“Yes, this is correct for patients who have received oral cladribine. They should receive irradiated blood products if they ever need a blood transfusion, and this requirement is considered indefinite. I cannot see the same irradiated blood transfusion advice specifically stipulated for subcutaneous cladribine; this is probably why it wasn’t mentioned to you previously. If you’re happy to err on the side of caution, you can carry an irradiated blood card and make healthcare professionals aware if you ever require a blood transfusion.”

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

This question similarly arose with alemtuzumab and was addressed via the MHRA. It is time to do the same with cladribine.

I suggest we rethink a precaution when it no longer fits the evidence.

If you have been treated with cladribine (Mavenclad) or alemtuzumab (Lemtrada), you may have been told you must carry a card stating that any future blood transfusion has to be irradiated, possibly for life. This recommendation is intended to prevent a rare but devastating complication called transfusion-associated graft-versus-host disease (TA-GvHD). But does the evidence still support it? My colleague Professor Klaus Schmierer recently pulled together the data, and the answer is increasingly: probably not, at least not in the way the current guidance implies.

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The MS International Federation (MSIF) has two initiatives I would like you to note. One is aimed at people with MS (pwMS) and the other at healthcare professionals (HCPs) who may not be MS specialists but may benefit from a better understanding of MS diagnosis.

1. ‎Support people with MS to contribute to global MS diagnosis research

Last year, pwMS were able to share their diagnostic experience visually through the World MS Day poster maker. Over 3500 people from 100+ countries participated last year. The MISF is now turning to using the exercise for research this year. They have all the necessary consent/ethics in place and want to collect a substantial amount of data from people living in regions of the world that don’t usually have the chance to have their voices heard in research.

You can access the poster maker here: https://worldmsday.org/poster-maker/.

The MSIF would greatly appreciate your support in helping us reach as many people with MS around the world as possible.

Please note: the poster maker is currently only available in English, and participation in the research is voluntary.

2. Online course to improve MS Diagnosis

Following last year’s success, the Multiple Sclerosis Symptoms and Diagnosis online course is back in 2026.  With over 1,500 participants across 116 countries in 2025, including a strong healthcare audience, this course is helping to improve understanding and support earlier diagnosis worldwide.

The course has now been updated with new information on the McDonald Criteria, and a certificate of completion is available to participants. Please share this resource widely within your networks, particularly with any healthcare professionals (GPs, nurses, physiotherapists, psychiatrists, medical students) who may not be MS specialists.

Course dates: 1 May – 15 June 2026

Register here: https://worldmsday.org/online-course/

As someone with MS, how do you feel about having an International Day dedicated to you and the disease you have to live with every day?

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

I was diagnosed with MS 5 years ago. I am 43 years old. There has been significant diagnostic uncertainty amongst different neurologists about whether I have primary progressive MS (PPMS) or secondary-progressive MS (SPMS). I am aware that the difference between the two subtypes is debated.

I started with progressive weakness in my right leg with exercise-induced fatigue that has now progressed to weakness and fatigue, which is present at baseline. This started 10 years ago. However, in my left leg, I have had two episodes that some argue are relapses. I developed sudden onset weakness in the left leg and was unable to stand on that leg. This weakness lasted 2 months with complete resolution of symptoms. I then had a second similar episode in Sept 2025, and symptoms have not completely resolved. These symptoms finally led to the diagnosis.

I have also developed right-hand weakness in the last 3 years. I have been on ocrelizumab (Ocrevus) for 5 years. My MRI show cervical and thoracic lesions, but no brain lesions. My MRI is stable despite new symptoms. I have never had Gd-enhancing lesions.

I have recently sought a second opinion on whether to switch to cladribine, undergo HSCT, or participate in a clinical trial for CAR T-cell therapy. One group has suggested switching to cladribine because I am still progressing on ocrelizumab, with the long-term plan to eventually do HSCT or CAR T cell when it is available in my country. My primary neurologist has recommended that I stay on ocrelizumab. My question for you is, what is your opinion on the treatment options discussed above?

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

Q: PPMS or SPMS?

I wish the issue of how to classify your MS were academic, but unfortunately, the way you classify someone as having PPMS or SPMS has an impact on what treatment they are eligible for in most healthcare systems, including yours.

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Book review

If you are caring for someone with MS — a partner, a parent, a sibling, a friend — this is a book you ought to know about. It has an irreverent title and the rare quality of saying out loud the things most carers only think in private. The Selfish Pig’s Guide to Caring, in my view, is one of the most useful books for a carer. It does not purport to cure anything or complete the endless number of benefit forms. But it does something valuable: it will make you feel less alone.

Why this book exists

Marriott did not set out to be an author on caring. He became a carer when his wife, Cathie, was diagnosed with Huntington’s disease, and he very quickly discovered what millions of others know: that the role of being a carer arrives without training, without a manual, and almost always without warning. There are an estimated six million unpaid carers in the UK alone, and yet the practical and emotional reality of what you do is barely acknowledged, let alone discussed honestly. Marriott wrote the book he wished someone had handed him at the beginning of his journey.

The premise is captured in the title. Carers, by definition, are the opposite of selfish pigs. They give up sleep, careers, friendships, holidays, hobbies, and often their own health, for someone they love. And yet — and here is the catch — they are forever guilty about not doing enough. Marriott’s central, liberating argument is that you must, occasionally, be a Selfish Pig. Not because you are one, but because the only way to keep caring sustainably is to look after yourself first. A burnt-out carer helps no one. The aeroplane oxygen mask analogy applies to caring, too.

What he is willing to say

What sets this book apart from the well-meaning leaflets in the GP or neurology outpatient waiting room is that Marriott refuses to be polite about the hard bits. Like me, he does not pull his punches or wear rose-tinted glasses. He talks about the feelings that no one will admit to: resentment, exhaustion, sexual frustration, the terrible fleeting thought that life would be easier if the person you love simply weren’t there any more. He calls these the things that “come in the night”, and he is absolutely right that almost every long-term carer has had them, and almost every long-term carer believes, wrongly, that they are alone in having them.

Marriott’s matter-of-fact discussion of these feelings is, for many carers, the first time anyone has given them permission to be human. That permission is worth the cover price on its own.

He covers, with the same directness:

• The grief of watching the person you love change, while everyone around you insists they are “still the same person”.

• The peculiar invisibility of carers — to friends, to neighbours, to officialdom, sometimes to the cared-for person themselves.

• Sex and intimacy, which most books on caring step around as if it were radioactive.

• The exhausting choreography of dealing with Social Services, benefits, hospitals, and the legions of professionals who descend on your life with clipboards.

• The need, occasionally, to laugh — at the absurdity, at yourself, at the situation. Marriott’s gentle humour is itself a form of resistance.

He also brilliantly gives the cared-for person a name. Rather than the clinical “service user” or the saccharine “loved one”, he coins PIGLET — Person I Give Love and Endless Therapy to. It is funny, affectionate, and slightly subversive, and it captures the essence of the relationship better than any official terminology.

Why this matters for MS

Caring for someone with MS rarely arrives in a single dramatic moment; it accumulates. A little more help with the stairs. Then with the shopping. Then with dressing. Then with continence. Then with cognition. Each step is small enough that the carer slides into the role without ever quite noticing they are now doing it full-time. Many MS carers I have spoken with describe a kind of bewilderment — how did this become my life? — combined with the absolute certainty that they would not have it any other way.

Marriott understands this. He understands that caring for someone with a progressive neurological condition is not a sprint or even a marathon; it is something more like a very long, unpredictable walk in weather you cannot forecast. You need different equipment for that. You need pacing. You need to enjoy the views. You need to know where the rest stops are. And you need company.

The motivational core

I want the carers reading this newsletter to hear, above everything else, this: the feelings you are having are normal. The exhaustion is normal. The flashes of resentment are normal. The grief — anticipatory, real, complicated, sometimes a relief — is normal. The guilt about feeling any of these things is also, sadly, normal, but it is the bit that Marriott most wants you to put down.

You are not failing. You are doing one of the hardest jobs in the world, with no training, no salary, and very little recognition. Millions of other people are doing it alongside you, right now, in flats and houses up and down the country, feeling the same things you are feeling. That is not a sad fact. It is a quietly hopeful one. It means there is a vast, mostly invisible community of people who would understand you immediately if you spoke up.

And here is the bit that the title is really getting at: looking after yourself is not a betrayal of the person you care for. It is the single most important thing you can do for them. The hour you spend on a walk, in a café with a friend, at a yoga class, asleep in the afternoon — that hour buys you the energy for the next week. Refusing to take it does not make you a better carer. It makes you more exhausted. Marriott gives you permission on every page to take the hour.

What the book is not

It is fair to say what this book is not, so you know what to expect. It is not a benefits guide; you will need the Carers UK or MS Society websites for that. It is not a clinical primer on MS; you have other resources for that, including this newsletter. It is not relentlessly cheerful in the way some self-help books are; Marriott is far too honest for that. And it is not, very deliberately, politically correct. He uses the language carers actually use when they are talking among themselves, and some readers will occasionally wince. That, I think, is the point.

What it is is a companion. The sort of book you keep on the bedside table and dip into when things are particularly bleak at three in the morning. The sort of book that makes you laugh out loud, and then makes you cry, and then makes you feel, for the first time in a long while, properly understood.

Practical suggestions for using it

A few thoughts on how to get the most from it:

• Read it slowly. A chapter a week, even a chapter a month, is plenty.

• Lend it to the person you care for, if they would like to read it. Many people with MS find it useful to understand what the caring role actually looks like from the inside — it can shift the conversation in your household.

• Lend it to your friends and family who don’t understand. Marriott is much better at explaining the carer’s experience than most carers have the energy to be.

• Underline the bits that resonate. When the dark days come — and they will come — flick back to them and remember you are not the first person to feel this way.

A final word to carers

If you take only one thing from this newsletter, take this: caring is not a competition, and it is not a measure of your worth. You are not required to be a saint. You are required only to be a person — a tired, fallible, real person — doing your best for someone you love. You are doing extraordinary work. You are not alone. And, in the sense Marriott means it, being a Selfish Pig now and again is not a character flaw — it is a survival skill. Use it.

I cannot recommend this book highly enough.

The Selfish Pig’s Guide to Caring by Hugh Marriott is widely available in paperback and e-book.

If you are a carer and reading this, please also know that the MS Society and Carers UK both run carer support services, peer groups, and helplines. Reach out. The community is bigger than you think.

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If you have been forwarded this email and are not an MS-Selfie subscriber, please consider subscribing and helping MS-Selfie expand its resources for the broader MS community. MS-Selfie relies on subscriptions to fund its curated MS-Selfie microsite, MS-Selfie books, MS-Selfie Infocards, and other activities that extend beyond the MS-Selfie Substack newsletters.

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Subscriptions and donations

MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

Give a gift subscription

Questions

If you have questions unrelated to the newsletters or podcasts, please email them to ms-selfie@giovannoni.net. Prof. G will try to answer them as quickly as possible.

Important Links

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💾 Prof. G’s MS Blog Archive

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🔗 LinkedIn

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

The answer, it turns out, depends on what kind of caring you do. Looking after a parent for a few hours a week outside the household appears to preserve executive function. But caring for a partner or spouse at home for 50+ hours a week is associated with a faster cog than in matched non-carers. Memory showed the same pattern, but more weakly. Neither sex nor wealth lessened the effect. The finding lands awkwardly for neurology and multiple sclerosis (MS): the carers we depend on most—the spouses of people with MS, Parkinson’s disease, motor neurone disease (MND), Huntington’s disease and dementia—sit in this high-risk category.

I will try to summarise what we know about the scale of this burden, what it does to the carer’s mental and physical health, the under-recognised risk of domestic violence and abuse running in both directions, and the resources—patchy, underfunded, but real—that exist to help people who are carers.

Scale of the problem

Around 8% of the UK population—roughly 5–6 million people—are providing unpaid care at any one time, and approximately 1.5 million of them provide 50 or more hours of care per week. Over a lifetime, around two in three UK adults will spend some period as an unpaid carer. The economic value of this work has been estimated at over £160–180 billion a year, comparable to the total NHS budget. Carers UK polling in 2024 found that 62% of current and former carers said they had no choice but to take on the role, driven by the absence of any viable alternative.

Neurodegenerative disease is one of the principal drivers. Around 150,000 people live with MS in the UK, and roughly 69% of people with MS receive informal care, with spouses providing up to 70% of that care. The pattern is mirrored across Parkinson’s, MND, Huntington’s, atypical Parkinsonian syndromes, and the dementias. Because these conditions are progressive, fluctuating and often span decades from diagnosis, the carer’s role rarely shrinks, but accumulates. A carer who started by occasionally fetching a coat ends up, ten years later, managing catheters, hoists, medication schedules, financial affairs, and increasingly the cognitive and behavioural symptoms of the disease.

This is precisely the configuration—high-intensity, in-household, spousal, long-duration—that Xue and colleagues identify as the highest-risk profile for accelerated cognitive decline in the carer themselves. We are, i.e. society, in effect, generating a second group of brain-vulnerable people in the slipstream of every neurodegenerative diagnosis.

Impact on mental health

The mental health toll on informal carers is large, consistent across conditions, and disproportionately concentrated in spousal carers. A 2025 review of 18 meta-analyses reported median pooled prevalences of 33% for depression, 35% for anxiety, and 49% for caregiver burden across informal carers globally. Carers of people with dementia, stroke and progressive neurological disease consistently sit at the higher end of these ranges. In MS specifically, qualitative work has documented a recurring constellation: sense of loss, emotional exhaustion, social isolation, anticipatory grief, and chronic anxiety about disease unpredictability.

Spousal carers fare worse than other carer types. They are older, more isolated, less likely to share the load, and locked into the relationship in a way an adult child caring for a parent is not. They also lose the partner as a source of emotional support at the same time as the demands of care escalate—what Aneshensel and Pearlin called the “unexpected career” of caregiving. The Lacey et al. (Lancet Public Health, 2024) propensity-matched UK analysis showed that transitioning into intensive unpaid care produces a measurable worsening of mental and physical health that persists for years.

The finding of cognitive decline from Xue et al. should be read in this context. Chronic stress, sleep disruption, social withdrawal and depression are themselves established risk factors for cognitive impairment; the carer’s accelerated executive-function decline is not a mystery—it is the predictable downstream signature of grinding chronic stress with no exit.

Impact on physical health

Carers are more likely than non-carers to report poor general health, to attend A&E, and to be admitted to hospital, even after adjustment for age and socioeconomic status (ONS, 2024). Around 43% of current or former UK carers report that a mental or physical health condition has developed or worsened since taking on the caring role (Carers Week 2025). Female carers report disadvantage more often than male carers (64% vs 52%).

Mechanisms are multiple and overlapping: musculoskeletal injury from lifting and transferring; chronic sleep fragmentation from night-time care; missed or postponed health appointments for the carer themselves; reduced physical activity; deteriorating diet; increased smoking and alcohol use; and—on the biological side—sustained sympathetic and HPA-axis activation with the inflammatory and metabolic consequences that follow. A landmark US longitudinal study found that carers reporting emotional or mental strain had a 63% higher mortality risk than matched non-carers.

For spousal carers of people with MS or other progressive neurological disease, the trajectory often involves the carer themselves entering older age with their own emerging morbidities, just as the care recipient becomes most dependent. Two frail people, one home, no slack, no resilience.

Domestic violence and abuse

Domestic violence and abuse (DVA) in the context of neurodegenerative disease is a hidden, under-reported and under-researched problem—and it runs in both directions.

Women with MS face an elevated risk of being abused by their partners. A cross-sectional Iranian study of 275 married women with MS reported domestic violence prevalences of 53% psychological, 63% economic, 34% physical, and 20% sexual. UK clinicians have begun to describe similar patterns: partners removing walking aids, withholding medication, removing wheelchair batteries, and intercepting communication. A 2026 JAMA Neurology Viewpoint specifically called for routine, trauma-informed safeguarding in MS care, noting that disability, cognitive impairment, fatigue, financial dependence and isolation create unusual vulnerability to coercive control. The COVID-19 lockdowns made the problem visible to many of us, i.e. MS HCPs, for the first time.

The opposite direction is also real. Around 20% of people with newly diagnosed dementia have behaved aggressively towards a caregiver, and Australian police-record analysis identified dementia-related domestic violence events in which spouses were the most common victims (51%), with physical assault present in over 80% of events. Disinhibition, frontal-lobe dysfunction, misidentification syndromes, agitation in the context of pain or delirium, and—less commonly—pre-existing patterns of abuse that re-emerge as inhibition weakens, all contribute. Similar issues arise with the behavioural and psychiatric features of MS, late-stage Parkinson’s, Huntington’s disease, frontotemporal dementia and traumatic brain injury, although these have been studied less.

Compounding both directions: research from the US has shown that, in many couples where abuse occurs in the context of dementia caregiving, abuse was already present in the relationship long before the diagnosis. The illness amplifies and shifts an existing dynamic rather than creating one from nothing.

The implication for neurology and MS is uncomfortable but unavoidable: asking about safety at home should be part of routine reviews for MS, Parkinson’s, MND, and dementia, with the carer and the patient seen separately at least intermittently. HCPs need to know their local safeguarding pathway and—crucially—be aware that the carer is also a potential victim, not just a potential reporter.

UK resources and support

Statutory framework

Under the Care Act 2014 (England), Social Services (Scotland) Act 2013, and equivalent legislation in Wales and Northern Ireland, any adult providing regular unpaid care is entitled to a Carer’s Assessment (Adult Carer Support Plan in Scotland) from their local authority. This is the legal gateway to most other statutory support, including respite, direct payments and equipment. Uptake is poor: Carers UK report that around 39% of those who haven’t had one cite simply not knowing it exists. Please note that employees in England, Scotland and Wales (not yet Northern Ireland) are entitled to five days of unpaid Carer’s Leave per year under the Carer’s Leave Act 2023, taken as half-days, full days or a block.

Potential financial support for carers

• Carer’s Allowance (England, Wales, NI) — £86.45/week from April 2026 for those providing 35+ hours of care to someone receiving qualifying disability benefits (PIP daily living, Attendance Allowance, DLA care component middle/higher rate). Earnings cap £204/week net. Notoriously low, with a hard cliff-edge at the earnings threshold. The DWP is currently reassessing overpayment debts accrued between 2015 and 2025 following the Sayce Review.

• Carer Support Payment — Scotland’s replacement for Carer’s Allowance, paid at the same rate but with a more carer-friendly administration.

• Carer’s Credit — National Insurance credit for those caring 20+ hours/week but not eligible for Carer’s Allowance.

• Carer Element of Universal Credit — additional monthly payment for those caring 35+ hours; usually a better-off route than Carer’s Allowance for working-age carers.

• Council Tax discounts, Pension Credit Carer Addition, Housing Benefit Carer Premium — frequently missed top-ups; a Turn2Us or Citizens Advice benefits check is usually worth doing.

• Discretionary grants from the MS Society, Parkinson’s UK, the MND Association, the Alzheimer’s Society, Independence at Home, and the Royal British Legion (for veterans’ families) — particularly useful for one-off costs such as equipment or short breaks.

Respite and replacement care

Respite—or what Brimblecombe and colleagues have argued should more honestly be called “replacement care”—is the single most consistently requested form of support across UK carer surveys, and the single most rationed. It ranges from a few hours of sitting service through to one- or two-week residential placements for the person being cared for. Funding is variable, often means-tested via the local authority, and frequently rationed below what carers need to sustain the role. Charitable sources (MS Society respite grants, Carers Trust local network breaks, Revitalise short breaks) plug some of the gap. The evidence from Lacey, Brimblecombe, and colleagues strongly suggests that adequately resourced replacement care is the single most cost-effective intervention available.

Information, peer support and training

• Carers UK — 0808 808 7777 helpline, online Carers Connect forum, benefits and rights guidance, and employer programmes.

• Carers Trust — 0300 772 9600; a network of around 130 local carer services across the UK offering one-to-one support, training and group activities.

• Mobilise — online peer community, daily virtual cuppa (45-minute video calls with other carers), financial checklists; founded by carers from an MS-affected family.

• Condition-specific carer support — MS Society, MS Trust, MS-UK, Parkinson’s UK, MND Association, Alzheimer’s Society, Huntington’s Disease Association. All run carer-focused information lines, local groups and information resources.

• Young Carers services — through Carers Trust, Action for Children and Barnardo’s. Important for families where a parent has young-onset MS, Huntington’s or familial dementia.

• Psychological support — IAPT/NHS Talking Therapies accept carer self-referral in most areas; some MS centres and memory services offer in-house carer counselling; Mind has specific resources on caring while coping with mental health difficulties.

Safeguarding

Where DVA is suspected—in either direction—the relevant routes are the local authority safeguarding adults team (statutory duty under the Care Act), the National Domestic Abuse Helpline (0808 2000 247, Refuge), Galop (LGBTQ+ victims), Hourglass (older victims, 0808 808 8141), and SafeLives (training and frameworks for professionals). The Domestic Abuse Act 2021 introduced new protective orders and statutory definitions that explicitly cover coercive control.

Recently, the Horne Family Charitable Fund initiated a project to gather information about DVA in pwMS. The initiative has improved our understanding of DVA’s impact on people with MS and its implications for MS clinical practice. The study was conducted as a partnership between the University of Leeds and Nottingham, and they have now developed a toolkit for MS HCPs to equip them with the knowledge to safely identify and respond to signs of DVA in clinical settings. A version of their resource ‘A Toolkit for Multiple Sclerosis Healthcare Professionals‘ was launched at the recent MS Trust Annual Conference. Please read it and share any feedback and insights with the group to make sure it is fit for purpose.

I have asked Rachel Horne to write a guest MS-Selfie newsletter on DVA and the project she so kindly funded. I think the issue of DVA needs a lot more attention than we have given it in the past.

International picture

The pattern is broadly similar across high-income countries, with national variation in the extent to which the burden is offset by formal services. The Netherlands, the Nordic countries, and Germany generally provide better statutory respite and direct payments than the UK does. The US relies more heavily on private long-term care insurance and Medicaid waivers, with significant geographical variation. Australia’s National Disability Insurance Scheme funds care for younger people with MS and other progressive conditions, but excludes those who acquire disability after age 65. The 2024 European Eurocare report found that across Europe, women provide more intense and prolonged care than men, with the gap narrowing—but not closing—in later life.

The OECD has repeatedly flagged informal carers as an unrecognised pillar of national health systems whose collapse would be unaffordable. No country has fully solved the problem; some have simply chosen to subsidise it more honestly.

What neurologists should actually do?

Carer health is not a soft add-on to MS, Parkinson’s, MND or dementia care—it is part of the clinical pathway, because carer collapse is one of the commonest reasons that home-based care fails, and the patient is admitted, placed, or worse. Practical steps:

• Identify the principal carer at every annual review and document them in the record. Ask their name.

• Ask, briefly, how the carer is doing. The single question “How are you coping?” picks up more than any poorly used structured tool.

• Signpost actively to a Carer’s Assessment. Most carers do not know they are entitled to one.

• Where intensity is escalating—night care, incontinence, falls, behavioural symptoms—escalate to social work, community neurology nurses, palliative care or specialist nurses early, not at crisis point.

• Ask about safety. Seeing the patient and carer separately at least once a year creates the opportunity to disclose abuse in either direction.

• Recognise that spousal carers of people with MS, dementia, or other neurodegenerative disease are themselves a high-risk cohort for cognitive decline, depression and premature mortality. Treat them as such.

Conclusion

The Xue et al. analysis confirms what carers, charities and a generation of social-care researchers have been saying: caring at moderate intensity, with autonomy and support, can be a good thing—it keeps the brain busy and the social network alive. Caring at high intensity, inside the home, for a partner with progressive disease, with no exit and no respite, is corrosive to mental health, physical health and cognition.

Spousal carers of people with MS and other neurodegenerative diseases sit on the wrong side of that line by definition. They are the human infrastructure on which we run our services, and we currently fund their support at a fraction of what we save by their unpaid labour. The case for adequately resourced replacement care, financial parity with the minimum wage for those caring 35+ hours, routine carer assessment, accessible psychological support, and active safeguarding is neither sentimental nor radical—it is the basic precondition for keeping people with progressive neurological disease at home for as long as they want to be there. We owe carers more than gratitude. We owe them a plan.

Questions

I would be interested in hearing your thoughts on the issues raised in this newsletter. How many of you are carers or are being cared for by a partner? Have you been given any support? Have you experienced any abuse? Have you discussed this with your HCP or social services?

I am aware that a large proportion of pwMS and their carers don’t want to discuss these issues, but unless we do, the problems they cause will not be addressed. Part of the holistic care of pwMS includes looking after their carers’ health. Do you agree?

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Paper of interest

Xue et al. Association between becoming a carer in later life and changes in the trajectory of cognitive function: results from the English longitudinal study of ageing. Age Ageing. 2026 May 4;55(5):afag132.

The influence of becoming a carer on cognitive function presents a complex picture. Variations in intensity, recipients and locations of caring may influence cognition differently. Using waves 2 to 10 (2004/2005 to 2021/2023) of the English Longitudinal Study of Ageing, we examined cognitive changes before and after transitioning into caring and explored whether these effects depend on care characteristics. We integrated the strengths of both ‘matching’ and ‘before and after’ methods. Using propensity score matching, we paired 2765 carers aged 50+ with 2765 non-carers. Using piecewise growth curve modelling, we modelled the changes in cognitive trajectories-memory and executive function-before and after transitioning into caring. Analyses also examined variations by care hours, location, recipient, number of people caring for, duration, sex and wealth. Carers were on average 60 years old, and 56% were women. We found that transition into lower-intensity caring responsibilities (5-9 hours/week), caring outside the household and caring for parents/parents-in-law exhibited a slower decline in executive function than non-carers. Those providing very intensive care (50+ hours/week), caring within the household or caring for a spouse/partner showed a more rapid decline. Memory changes followed a similar but much weaker pattern than for executive function. No evidence was found that sex or wealth moderated these effects. This suggests that the influence of caring on cognitive function is likely to be shaped by care-related characteristics. Our findings underscore the importance of preventing carer overload. While caring may help preserve cognitive function, excessive caring demands appear to accelerate cognitive decline.

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Other key references

• Xue B, McMunn A, Lacey R, et al. Association between becoming a carer in later life and changes in the trajectory of cognitive function: results from the English Longitudinal Study of Ageing. Age Ageing 2026;55:afag132.

• Lacey RE, Xue B, Di Gessa G, et al. Mental and physical health changes around transitions into unpaid caregiving in the UK: a longitudinal, propensity score analysis. Lancet Public Health 2024;9:e16–25.

• Carers UK. State of Caring 2024 / 2025; Facts About Carers (December 2024).

• Office for National Statistics. Unpaid care expectancy and health outcomes of unpaid carers, England: April 2024.

• Topcu G, et al. Informal carers’ experiences of caring for someone with multiple sclerosis: a photovoice investigation. Br J Health Psychol 2021;26:478–501.

• Hutchison K, Ford H, et al. JAMA Neurology Viewpoint, 2026: Safeguarding people with multiple sclerosis from domestic violence.

• Brimblecombe N, Fernández JL, Knapp M, et al. Review of the international evidence on support for unpaid carers. J Long Term Care 2018:25–40.

• Livingston G, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet 2024;404:572–628.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

I am a 60-year-old woman with relapsing-remitting MS. I was diagnosed in 2016 and started on dimethyl fumarate (Tecfidera). I was then switched to ocrelizumab (Ocrevus) in 2021. My MS is now stable. I have a low EDSS score, and I am fully mobile. I was very careful during the pandemic. I received all the vaccines and did not contract COVID-19, influenza, or any other infection until about 3 weeks ago, when I developed severe nausea, and my GP said it was likely a gastrointestinal virus. I have not felt so sick in years. I had terrible foot and leg pain that prevented me from sleeping, and pain in the lower back. As I started to feel better a week after, I was hit with a respiratory virus and a bad cough. I also noticed numbness in what I now know is called the saddle region.

The numbness persisted; I became incontinent with urine and have no sensation in the bowel area - I’m unable to poop. On Saturday, I came to the local hospital ER and was admitted. They did a spine-only MRI with contrast, which showed no activity. I have had a brain MRI with contrast and a lumbar puncture. The current diagnosis is that I have Guillain-Barré Syndrome (GBS). I tried to search MS-Selfie for any posts you’ve made on the site re GBS. Is GBS common in people with multiple sclerosis (pwMS)?

Do you know whether having MS makes it more or less likely for a full recovery from GBS? I have no interest in living with incontinence and significant bowel issues - it’s quite terrible. I am hoping it will eventually resolve. Has that been the case with any of your patients?

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

Q: What is Guillain-Barré Syndrome (GBS)?

Read more

Prof G, what experiment(s) would you conduct to prove that EBV causes multiple sclerosis?

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

From a personal perspective, as I enter the twilight of my research career in multiple sclerosis (MS), I am interested in conducting only three experiments. All are designed to prove that Epstein-Barr virus (EBV) is the cause of MS.

Read more

The “three bus analogy” is a popular British expression referring to waiting for a bus for a long time, only to have three buses arrive at once. It is often used to describe any scenario in which a resource is scarce and then suddenly abundant. I am not sure if people with MS (pwMS) and the other MS stakeholders realise what the implications of three recent ocrelizumab-related PPMS trials and one tolebrutinib PPMS trial mean for the field.

Bus 1 - GAVOTTE Study

First, there was the news that the high-dose versus standard-dose ocrelizumab PPMS study, or GAVOTTE study, was negative, i.e. there was no difference in disability outcomes between the two arms. However, the active group of subjects with PPMS, i.e., those with baseline Gd-enhancing lesions, did better with higher doses than with standard doses. I am aware that we must always be careful when looking at post-hoc analyses, as they are often underpowered and part of a data-torturing exercise. However, a similar observation was seen in the relapsing or MUSETTE study. These observations will not affect the license or how Ocrelizumab is used, but it does inform how we think about the biology of MS in relation to B-cell targeted therapies. This onservation of a better response in relation to smoudlering MS in relation to baseline disease activity is supported by the observation that high-dose rituximab and standard-dose ocrelizumab are superior at preventing disability worsening in subjects with active PPMS, as defined by the presence of Gd-enhancing lesions at baseline. Is this because Gd-enhancing lesions are an indicator or message from the immune system that whatever is causing MS is active and modifiable by anti-CD20 therapy? Could this be related to EBV? I have argued in the past that rebound on natalizumab withdrawal is likely to be due to CNS EBV reactivation and is blocked by anti-CD20 therapy. Could Gd-enhancing lesions in any siuation, not just post-natalizumab, indicate the same pathology?

The fact that pwMS with active MS do better with higher doses of anti-CD20 therapy suggests that the dose-response curve is complex and that higher doses may be needed for more active patients, i.e., that standard-dose ocrelizumab is not on the shoulder of the dose-response curve (see figure below). It is for this reason why I think higher doses of ocrelizumab are better than lower doses. I think this is due to deeper B-cell depletion and possibly greater CNS effects with higher doses. This is not a trivial issue and applies to other diseases such as lupus nephritis. In general, rituximab has only a modest or no effect on lupus nephritis. However, the recent approval of Gazyva (obinutuzumab) for active lupus nephritis illustrates this. Obinutuzumab is one of the most effective deep-tissue-depleting anti-CD20 monoclonal antibodies on the market, underscoring the importance of achieving deep tissue depletion for treating B-cell-mediated autoimmune disease or EBV-driven autoimmunity. I am sure the same lessons apply to MS and makes a strong case for CD19-targeting CAR T-cells as a treatment for lupus, MS and other autoimmune diseases.

Bus 2 - O’HAND Study

The O’HAND study, which I have discussed in detail in previous newsletters is the second bus or trial of importance. In short, O’HAND has shown that the original ORATORIO study was not a false-positive result, i.e. ocrelizumab is effective as a treatment for active PPMS, and there was also a treatment effect, albeit lower, in inactive PPMS. However, more importantly, pwPPMS who are wheelchair users benefited from ocrelizumab. This trial is a game-changer: we now know that even people with advanced MS will benefit from DMTs, and the primary outcome in progressive MS trials will likely change to include the 9-hole peg test. I have mentioned that the O’HAND will hopefully impact the stopping criteria for ocrelizumab as well. At present, we are being forced to stop ocrelizumab in pwPPMS who become wheelchair users. This will now be unethical, given that O’HAND shows that ocrelizumab slows the loss of hand and upper-limb function.

Please see:

• O’HAND Study - recognised by AAN (Apr 17, 2026)

• Q&A 158 - Should Ocrelizumab’s license for treating PPMS be revoked? (Apr 16, 2026)

Bus 3 - FENTREPID Study

The FENTREPID study has shown that fenebrutinib is non-inferior to ocrelizumab for the treatment of PPMS. However, across the piste of outcome measures, fenebrutinib looks better or superior to ocrelizumab. Interestingly, if the primary outcome in this trial was the same as that used in the O’HAND study, fenebrutinib would have been shown to be superior to ocrelizumab. This is because including the timed-25-foot walk (T25FW) in the composite for the primary outcome introduced noise. This is a sad state of affairs as we have known for some time, in fact, since the EXPAND siponimod SPMS trial, that the T25FW is too noisy and not a good outcome measure for MS. The good news is that Maria Pia-Sormani and colleagues have done a meta-analysis across numerous phase 3 studies showing the poor performance of the T25FW. I hope regulators will take this analysis into consideration when assessing the efficacy of fenebrutinib for PPMS.

I am currently presenting both the O’HAND and FETREPID results at the Association of British Neurology annual meeting in Birmingham (click here to download ABN posters). Despite my enthusiasm for these studies the response from my colleagues was underwhelming. I think they have been worn down by the riches of DMT data presented over the last 30 years for treating relapse-onset MS. What is not being noticed is that things are also changing for PPMS, a previously neglected group of pwPPMS.

Bus 4 - PERSEUS study

Sadly, bus 4 or the PERSEUS trial (NCT04458051) designed to answer whether tolebrutinib could alter the course of PPMS was negative. This study did not meet its primary endpoint of delaying the time to onset of 6-month composite confirmed disability progression compared to placebo. This failure is in contrast to the HERCULES trial, where tolebrutinib successfully delayed disability progression in non-relapsing Secondary Progressive MS (nrSPMS). This discordance—success in secondary progression but failure in primary progression— has triggered debate regarding the biological distinctions between these two forms of progressive disease. It suggests that, while they share features of smouldering inflammation, the specific drivers or the timing of required therapeutic intervention may differ fundamentally. I don’t agree with this and think the differences are due to bad luck; when we look at the PERSEUS trial in more detail, we see a treatment signal similar to that seen in the HERCULES trial. This supports other data that there are no differences between the biology of nrSPMS and PPMS.

I hope you agree with me on the importance of the first three buses, or trials, for the treatment of PPMS. The fourth bus may be empty, but it doesn’t change the message that PPMS is modifiable beyond EDSS 6.5 and that CNS penetrant therapies such as fenebrutinib will change the outlook for pwPPMS.

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Paper - T25FW

Bovis et al. Composite endpoints to detect treatment effects on MS disability progression. Lessons from phase III trial data. MedRxiv preprint doi: https://doi.org/10.64898/2026.04.22.26351458 (April 24, 2026).

Disability worsening is the critical long-term outcome in multiple sclerosis, yet the Expanded Disability Status Scale incompletely captures neurological deterioration and has limited sensitivity in the short time windows of clinical trials. Composite endpoints incorporating functional measures have been proposed to address these limitations, but whether they reliably improve detection of treatment effects has not been established across trials. We conducted a post-hoc analysis of individual patient data from ten phase III randomised controlled trials (ASCEND, BRAVO, CONFIRM, DEFINE, EXPAND, INFORMS, OLYMPUS, OPERA I/II, and ORATORIO; n = 9,369), spanning relapsing-remitting and progressive multiple sclerosis. Confirmed disability worsening was defined using harmonised criteria with the MSprog package and confirmed at 24 weeks. Treatment effects were estimated using Cox proportional hazards models and combined across trials in a one-stage individual patient data framework. Composite endpoints were constructed from the Expanded Disability Status Scale, the timed 25-foot walk test, and the nine-hole peg test using logical unions (OR-type), intersections (AND-type), and majority-vote structures. Sensitivity to treatment effect was quantified using Z-scores (the ratio of the pooled log-hazard ratio to its standard error) and compared to the Expanded Disability Status Scale reference using interaction tests. Event rates varied across components: the timed walk test generated the highest rates (up to 46.8%) while the nine-hole peg test generated the lowest (as low as 2.1%). OR-type composite endpoints showed weaker treatment effects than the Expanded Disability Status Scale alone, with the largest reductions in sensitivity observed for endpoints incorporating the timed walk test ( Δ Z up to +2.26; interaction p = 0.004). These findings were confirmed across disease subtypes and were pronounced in relapsing-remitting trials, where no composite endpoint outperformed the Expanded Disability Status Scale. In progressive multiple sclerosis, the combination of the Expanded Disability Status Scale and the nine-hole peg test showed numerically stronger treatment effects ( Δ Z = −1.65), though interaction tests did not reach statistical significance (p = 0.051). Composite endpoints do not systematically improve treatment effect detection in multiple sclerosis trials. Increased event capture driven by the timed walk test introduces noise that dilutes the treatment signal rather than amplifying it, highlighting that event rate and endpoint quality are not interchangeable. Upper limb function assessed by the nine-hole peg test provides complementary and specific information, particularly in progressive disease. The combination of global disability and upper limb measures represents a promising direction for future endpoint development in progressive multiple sclerosis trials, warranting validation.

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MS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite and other related activities, as I don’t have time to do this myself. You must be a paying subscriber to ask questions unrelated to the newsletters or podcasts. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription (ms-selfie@giovannoni.net).

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If you have questions unrelated to the newsletters or podcasts, please email them to ms-selfie@giovannoni.net. Prof. G will try to answer them as quickly as possible.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

I am a 52-year-old male with MS. My first attack hit when I was 38 and caused numbness and pins & needles down the right side of my body. I have had two attacks since then, but have been stable for a long while (by this I mean MRIs, etc.), up until 12 months ago, when disease activity and new lesions were spotted on two subsequent MRIs. I am about to switch from dimethyl fumarate (Tecfidera) to ofatumumab (Kesimpta).

Your theory of smouldering MS being the real MS resonates with what I feel physically. By this, I mean that I have had occasional feelings down the right side of my body (especially my right leg) over the years, even when my consultant said that I was stable. It seems consistent with the theory that my first attack and its damage were smouldering in the background and not completely stable.

The right leg and facial weakness have been particularly worrisome over the last 2 weeks.

My questions are as follows:

Questions

1. Is there any hope that ofatumumab will help with my smouldering MS? I know that you suggest high-dose B-cell therapy followed by a drop, ideally with ocrelizumab, but I am going for standard dose with ofatumumab.

2. Are there any tests or scans that I can do privately to check on my smouldering MS and brain volume, and what other tests do you recommend in this regard?

3. Why do other consultants not accept the theory of smouldering MS? I mentioned it to a neurologist I saw a while back, and he was quite dismissive and said it would just be scar damage on the lesion from my first attack.

Question added by me:

4. What other treatment options are available for this patient? Is he eligible for tolebrutinib?

NOTE: General Substack newsletters and the microsite are free; only Q&A sessions are restricted to paying subscribers. I can’t run and maintain the MS-Selfie microsite, so I must pay people to assist me. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email (ms-selfie@giovannoni.net) to request a complimentary subscription.

Prof G’s response

Q1. Is there any hope that ofatumumab will help with my smouldering MS? I know that you suggest high-dose B cell therapy followed by a drop, ideally with Ocrelizumab, but I am going for standard dose with ofatumumab.

Read more

Tom A, an MS-Selfie subscriber and commentator, said: ‘Dr G, there might be another book here in the comments.’ Maybe not a book, but at least another look at the subject. I have therefore tried to extract some of the learnings from the comments for further debate. The comments provide a deep and arguably multifaceted look into how people living with MS (pwMS) view suicidal ideation, mental health, and assisted dying.

Suicide as a rational decision vs. a mental health disorder

A significant thread throughout the comments is the belief that contemplating suicide is a logical, rational response to the relentless physical decline caused by MS, rather than a psychiatric illness.

• Rational planning: Ian describes suicide as “sensible planning” to avoid the end-stage reality of becoming a “totally helpless bed patient.” He argues that treating this as a mental health issue is merely a “smokescreen” and an “excuse to dish out a pill”.

• Logical choice: Bottomley echoes this sentiment, asserting that deciding to end a life that has become a “hard daily struggle with absolutely no prospect of anything getting better” is a “factual and straightforward, even logical decision,” and absolutely not a mental health issue.

• Situational distress: Other commenters point out that suicidal thoughts are often a direct result of their horrific circumstances. “Italien” emphasises that the natural sadness accompanying a degrading quality of life and social isolation should not be conflated with clinical depression. Others note that severe, unmanageable symptoms—such as bowel incontinence—or severe social failures like homelessness are the root causes of their suicidal thoughts.

Conversely, there is pushback against dismissing the clinical reality of mental health disorders in MS:

• Validating mental illness: Jenny Powell firmly objects to the notion that mental health issues are a “smokescreen,” noting that her own severe depression and anxiety are effectively managed with medication and are incredibly real.

• Biological basis: I reinforced that depression in MS is not simply a psychological “reaction” to having the disease. It has a biological basis driven by neuroinflammatory and neuroendocrine mechanisms, and may also be due to specific lesion locations in the brain.

• Proactive treatment: Another commenter notes that treating MS early and aggressively can reduce both physical disability and the underlying biological disease that causes clinical depression.

Arguments for assisted suicide

Those advocating for the right to assisted dying focus primarily on bodily autonomy and the prevention of extreme suffering.

• Fear of end-stage MS: Several commenters express a deep fear of the late stages of MS, detailing the horrors of being bed-bound, entirely reliant on carers for feeding and washing, and suffering from repeated bouts of aspiration pneumonia.

• Autonomy and dignity: Commenters express a strong desire for control over their end of life. Ian states, “I alone will decide when the quality of my life is so poor that I want to end it,” expressing a wish for a local dignified method (like a pill or injection) rather than having to travel to Dignitas in Switzerland or use “messy” methods at home.

Arguments against assisted suicide and alternative views

Arguments against legalising assisted dying focus on fears of systemic healthcare degradation, coercion, and procedural concerns.

• Healthcare degradation and “mission creep”: Mark strongly argues that legalising assisted suicide could have severe unintended consequences. He fears that busy doctors might refer high-demand patients to assisted dying services rather than aggressively treating their depression, leading to the defunding of neurology departments and a halt in MS cure research. He also warns of “mission creep,” where the criteria for assisted suicide expand dangerously over time.

• Adaptation to disability: Mark points out that published evidence suggests a person’s tolerance for disability often changes as their condition worsens, meaning a patient’s current fear of future disability might not match their reality when it arrives.

• Procedural horrors: Luke notes he is conflicted about legalisation because he has read that assisted dying procedures can sometimes cause a patient’s lungs to fill with fluid, leading to an “excruciating sense of drowning for an extended period”.

• Existing legal alternatives: Some commenters note that individuals already have the legal right to bodily autonomy without changing the law. Patients can legally refuse a feeding tube or voluntarily stop eating and drinking, which commentators describe as a painless way to die that does not require a doctor to administer poison.

Defining the role of the healthcare system and/or HCP

When looking at the literature, the proposed medical framework focuses entirely on preventing suicide by identifying and treating underlying distress, rather than providing policies to guide pwMS toward assisted suicide. Most articles state that suicide in MS is not inevitable and emphasise aggressive treatment of the drivers of suicidal ideation.

However, it is clear that the patient community, or at least part of it, highlights a desperate need for policies that allow for open, non-judgmental dialogue about end-of-life fears without pwMS immediately losing their autonomy.

There are, therefore, learnings and policies that could be implemented to identify and support these individuals:

Policies for systematic screening and identification

To accurately identify who is experiencing suicidal ideation, HCPs must stop relying on pwMS to spontaneously volunteer this information.

• Mandatory routine screening: Clinics must embed a validated screening tool, such as the Patient Health Questionnaire-9 (PHQ-9), into routine MS reviews.

• Targeted screening at critical junctures: Screenings should occur at least annually and, crucially, at major transition points. These include diagnosis, relapses, major disability milestones (like losing the ability to walk or drive), or when transitioning to secondary progressive MS.

• Structured follow-up questions: If a pwMS screens positive for suicidal ideation, policies must dictate specific follow-up questions to assess imminent risk. Clinicians must ask whether the pwMS has a plan, access to the means, or has made any preparations for suicide.

• Immediate action protocols: The presence of a plan, access to means, or preparatory behaviour must trigger an urgent, ideally same-day, psychiatric referral.

Policies for intervention and support

Once identified, the healthcare system must have pathways to address the physical, psychological, and social drivers of the pwMS’s distress.

• Aggressive treatment of comorbidities: Clinics must reject the dogma that depression is just a “normal” reaction to having MS. Policies should encourage the proactive use of SSRIs, talking therapies, mindfulness, and cognitive behavioural therapy (CBT), which have a good evidence base in MS.

• Holistic symptom management: Because physical symptoms directly drive suicidal ideation, treating pain, fatigue, sleep disturbances, and bladder/bowel/sexual issues must be viewed as an active suicide prevention strategy.

• Mandatory safety planning: For at-risk pwMS, HCPs must collaboratively develop a written safety plan (such as the Stanley-Brown Safety Plan) that outlines warning signs, coping strategies, and crisis contacts.

• Embedded mental health professionals: At a systemic level, it should be a minimum standard—not a luxury—to have a clinical psychologist or neuropsychologist embedded directly within the MS care service.

Policies for managing “rational” end-of-life discussions

While the clinical framework aims to prevent suicide, pwMS advocate for policies that allow them to discuss the realities of severe disability safely.

• Destigmatising the conversation: HCPs should be trained to initiate calm, kindly, and reassuring discussions about general mental health shortly after diagnosis. They should normalise the fact that pwMS may experience fears about mortality or even abstract thoughts of suicide when facing severe disability.

• Protecting patient agency: Policies should ensure that when pwMS express fears about their future or end-of-life scenarios, the medical system does not immediately “swoop in” with aggressive interventions that strip the pwMS of their voice and agency.

• Facilitating frank discussions: The NHS or other healthcare systems and MS support services should facilitate open discussions about life in the later stages of MS, including the associated problems, rather than treating it as a taboo subject. The latter must not be rose-tinted, but realistic.

Implementing these policies requires significant investment and a shift in how chronic illness is managed, ensuring mental health is treated with the same urgency as physical health. Given the clear need for better mental health integration, how do you think the NHS and other healthcare systems can overcome the financial and staffing barriers to embedding psychologists directly into standard MS clinics? Trying to prioritise MS care in a system that is failing feels like rearranging the deck chairs on the Titanic.

People with MS deserve better care. Do agree? Any thoughts on how we can get things changed?

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have any problems, please tell your healthcare professional, who can help you.

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