I have been told by my neurologist that I can breastfeed my newborn (4 weeks) through my ocrelizumab infusion. I am trying to find out if that is what the literature says. I also wanted to know whether to delay breastfeeding due to the premeds (steroids and antihistamines).

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Prof G’s response

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Prof G, what do you make of the BMJ article published yesterday claiming that ocrelizumab (Ocrevus) is ineffective in primary progressive multiple sclerosis (PPMS) and that its license should be revoked? The article claims ocrelizumab is ineffective in women with PPMS and that it causes breast cancer. Should women with progressive MS on ocrelizumab stop the drug ocrelizumab?

Peter Doshi. Multiple sclerosis: Could Roche’s bestselling drug Ocrevus be doing more harm than good in women with primary progressive MS? BMJ 2026;393:s666 (Published 15 April 2026)

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Prof G’s response

The BMJ published this news article yesterday about a petition submitted to the FDA challenging its approval of ocrelizumab for treating primary progressive MS, in particular, women with PPMS.

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In response to yesterday’s Q&A post on ‘Hypertensive Crises” (4-April-2026), I received the following question.

“I was wondering if my heart rate may be affected by MS - it is quite low resting rate in the high 50s (normal for me for years was about 65). Regular rhythm. Is it likely an MS effect or unrelated?”

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Prof G’s response

MS can affect both heart rate and the heart’s overall autonomic control.

The heart’s functions, including resting heart rate, heart rate variability, and blood pressure, are largely regulated by the autonomic nervous system (ANS). The ANS is a part of the nervous system that controls involuntary, automatic processes. Crucially, major centres for autonomic regulation and the pathways that carry these crucial signals reside within the brainstem and spinal cord – areas frequently affected by MS lesions.

Damage in these specific regions can lead to autonomic dysfunction or cardiovascular dysautonomia, which can manifest in relation to heart rate:

• Reduced heart rate variability (HRV): One of the most common findings, often present even in early MS or in individuals without apparent symptoms. HRV refers to the variation in time between heartbeats, and higher HRV is generally indicative of a healthy, adaptable autonomic nervous system that balances sympathetic (accelerating) and parasympathetic (slowing) inputs. In MS, impaired regulation means this balance is less effective, leading to a more rigid or less varied heart rate pattern.

• Resting heart rate & arrhythmias: Lesions may affect specific autonomic centres or pathways, potentially leading to changes in resting heart rate (inappropriate tachycardia or bradycardia) or increasing susceptibility to arrhythmias (irregular heart rhythms).

• Altered baroreflex sensitivity: The baroreflex is a mechanism that helps maintain stable blood pressure and can also affect heart rate. MS-related autonomic dysfunction can reduce baroreflex sensitivity, impairing the cardiovascular system’s ability to quickly and accurately adjust heart rate and blood pressure, for example, when standing up quickly (which can then lead to dramatic changes in heart rate compensation).

• Exercise response: The normal increase in heart rate during physical activity may be altered or blunted in some people with MS, making it harder for the body to respond appropriately to exercise demands.

Autonomic issues are relatively common in MS, though their presence and severity can vary significantly from person to person. Clinical assessments, like electrocardiograms (ECGs) and specific autonomic tests (including HRV analysis), can detect these subtle changes even before significant symptoms are apparent.

While these are indirect neurological effects rather than a direct disease of the heart muscle itself, they do impact cardiac function and control. If you or someone you know with MS experiences heart-related symptoms, such as persistent fast/slow heart rate, palpitations, dizziness, or fainting, it’s recommended to discuss these with your neurologist.

Can you self-assess and monitor your own heart rate variability (HRV)?

Yes. Many modern smartwatches and fitness trackers are equipped to monitor HRV.

Most smartwatches use a technology called photoplethysmography (PPG). They shine a green or red LED light into your skin to detect changes in blood volume as your heart pumps. By tracking these tiny changes, the watch can calculate the exact milliseconds between each pulse.

Because movement can easily disrupt these optical sensors, most smartwatches (like the Apple Watch, Garmin, and Fitbit) take their most accurate HRV readings while you are asleep or during guided breathing sessions when you are completely still.

Popular devices that track HRV:

• Apple Watch: Tracks HRV in the background, especially during sleep and when using the Mindfulness app. Data is stored in the Apple Health app.

• Garmin: Highly focused on HRV. Many Garmin watches use it to calculate features like “Body Battery,” “Stress Level,” and “Training Readiness” to help you decide whether to work out hard or take a rest day.

• Fitbit: Premium models track HRV during sleep to contribute to a “Daily Readiness Score.”

• Whoop & Oura Ring: While not traditional smartwatches, these wearables emphasise HRV to dictate sleep and recovery metrics.

Smartwatches are generally good at establishing your baseline and tracking trends over time. However, they are not flawless. Optical sensors (PPG) on your wrist are not as clinically accurate as an ECG used in medical settings. If you need highly precise, beat-by-beat medical data, a chest strap (like a Polar H10) is superior to a smartwatch.

Do any of you track your HRV? If so, how does it affect your behaviour? Have you reported it to your GP or MS Team?

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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 73 and living with multiple sclerosis (and have done so for over 30 years).

I have been experiencing significant and repeated spikes in my blood pressure, which, as I understand, may be related to my MS. These episodes are concerning, both in their severity and frequency, and they do not currently appear to be well-controlled.

I am worried about the potential risks associated with these spikes.

What is difficult is that, despite the seriousness of these symptoms, the situation does not seem to be receiving urgent treatment. This is adding to my anxiety. I have been passed between the cardiac / GP / A&E / MS teams. The MS team are not proactive and did not even come and see me when I was last admitted.

I would be very grateful for a recommendation:

• Do I need an urgent review of my symptoms and current management plan

• Guidance on whether further investigations or monitoring are needed

• Advice on treatment options to better control these blood pressure fluctuations

• Consideration of whether specialist input (e.g. autonomic dysfunction related to MS) may be appropriate

I am increasingly frightened by these episodes, and we are very keen to ensure I receive the appropriate care and reassurance before the situation escalates further.

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Prof G’s response

I am sorry to hear what you are going through. It is understandable that you and your family are frightened and anxious. Severe blood pressure spikes are scary enough on their own, but feeling like you are being bounced between departments—without any single team taking ownership of your care—can be exhausting and frustrating.

The assumption that hypertensive crises are always due to MS-related autonomic dysfunction needs to be challenged. It could be due to another comorbid disease. It is always a good practice to ask whether this is not MS-related and to think laterally.

I hope you find the following helpful.

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I am a 62-year-old woman who was diagnosed with MS in my late thirties. I was initially treated with interferon-beta, but switched to rituximab 12 years ago. I have been told that my MS is stable in that I have not had any relapses since starting rituximab and that my MRI scans show that there are no new lesions. However, I am seeing a gradual deterioration in my mobility, and I am now using a walking stick outdoors and using the furniture for support indoors. I can manage to walk about 400m on a flat surface at best, for example, when I go shopping. I have been told my EDSS is 6.0. In the last few years, I have been having recurrent respiratory tract and urinary tract infections. I have had several falls at home in the last year, thankfully with no serious injuries. I am seeing my neurologist in a few weeks’ time and feel something needs to change. What would you recommend?

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Prof G’s response

The clinical problems this person faces when she sees her neurologist are as follows:

1. No evident inflammatory disease activity (NEIDA) with smouldering associated worsening (SAW)

2. Chronic immunosuppression due to anti-CD20 therapy

3. Recurrent infections

4. Falls

5. Ageing

Does she need to continue her rituximab therapy? Can she simply stop her treatment, or does she need to switch to another treatment and if so, which DMT?

This woman is one of thousands of people with MS across the world and contributes to the increasing number of people living with MS. Unfortunately, I would need more information to make an assessment and give her sound advice. I would need to know if her latest MRI showed brain volume loss, slowly expanding lesions or evidence of small vessel disease. I would also want to image her spinal cord to make sure there are no new spinal cord lesions or another pathology, for example, spinal cord compression from a disc prolapse that could be contributing to her worsening symptoms.

I would need to know her blood results. Does she have hypogammaglobulinaemia and/or a lymphopaenia contributing to her immunosuppression? What about comorbidities? Does she live alone? Is she socially isolated or lonely? Is she depressed? Does she have a sleep disorder? Does she have other comorbidities, and what concomitant medications is she taking? All these issues impact her management.

This is why she needs to make the most of her follow-up appointment so that all her problems are addressed. Please read my newsletter, ‘The annual MS follow-up consultation’ (Jun 26, 2023), in which I make the case that more than 15 minutes are needed.

She also needs to prepare for the annual follow-up appointment. There are many online resources available to you. For this newsletter, I have put together a spreadsheet of factors to consider and document before your annual follow-up assessment. This is in the form of a Google sheet, but can be downloaded as an Excel spreadsheet. The spreadsheet has four tabs or sheets. The ‘About’ tab tells you about the tool. The ‘Annual Review’ records your information and adds it to the ‘History’ tab. The ‘Trend’ tab plots the changes in your outcomes over time. Finally, the ‘Scale Guide’ provides information about the PROMS (patient-related outcome measures) I have included in the tool.

The first time you use the tool, it will take a bit of time to complete all the required information. However, each subsequent time you use it will be much quicker. You can print out a summary sheet from the annual review to take with you to your consultation, or at least send it to your MS team a week or two before you are seen. Please note that the spreadsheet is in its beta form and can be downloaded, hacked and changed to meet your personal needs. I would be interested to know whether I have missed anything on the sheet or if it should be expanded to include more PROMS?

Now for her specific questions:

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I started Ocrelizumab (Ocrevus) in Nov 2023 and have been mostly stable on it. Unfortunately, my immunity status was not checked before starting. I just had the blood test, and despite having two rounds of the MMR vaccine when I was a child, I do not have full immunity. I do have immunity to mumps and rubella. I am curious if you have suggestions for what I should do? Should I just try to do the COVID lockdown? My understanding is that the BTK inhibitor data is not looking good, so it’s not like I could switch to that for a bit to get the vaccine and then go back on Ocrevus? I’m getting everyone who is in contact with me to have their immunity checked. There are current cases of measles in my city, and unsure what I can do both now and in the future.

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Prof G’s response

I am sorry to hear about the surge in measles cases in your city. This is the tragic consequence of the anti-vaxx movement and the fall-off in childhood vaccine uptake. The reasons why the anti-vaxx movement has thrived are well-rehearsed, and I won’t review them here.

Don’t despair. If you are sure you have had the MMR vaccine and are seropositive for at least one of the three viruses, there is a high chance that you still have good memory T-cell responses to measles. However, measles T-cell responses are not measured in routine clinical practice in the same way as they can be assessed against TB, for example, with the TB Quatiferon or Elispot assays.

It is understandable that you are concerned about your immune status. Living with MS whilst on a continuous immunosuppressive therapy generates anxiety and a state of hypervigilance. It is natural to want to understand exactly how protected you are, especially with a highly contagious virus like measles circulating in the community.

Anti-CD20 therapies (such as ocrelizumab, rituximab, ofatumumab or ublituximab) work by depleting B cells, which produce antibodies. Over time, anti-CD20 therapies can reduce your circulating antibodies, causing hypogammaglobulinaemia. This may explain why you are currently seronegative for measles, despite having had two MMR doses as a child. Your antibody levels have simply waned below the detectable threshold.

What about your T-cells?

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I was diagnosed nearly 3 years ago, but have had symptoms for about 6. I was initially diagnosed with radiologically-isolated syndrome (RIS), which was changed to relapsing-remitting MS (RRMS) after a positive CSF examination and after changing neurologists for the third time.

Typical brain lesions were found after having an MRI for strange head pains/crawling sensations, and numbness on the side of my face. I had had pains in my legs and tingling in my feet for about a year, but put it down to going through the menopause, even after being put on HRT. I have multiple brain lesions and a posterior fossa lesion, which wasn’t picked up at first. There were no lesions in my spine at that time.

I haven’t been put on a DMT as my MRIs have remained stable until late last year, when a possible new small lesion in my thoracic spine was noted. It is behind a calcified disc, so my Consultant has advised monitoring after 6 months to see if it has changed.

I have also had a new episode of trigeminal neuralgia lasting 3 days in January. It has left my cheek slightly numb with aching pain in the temple area, and my lips and tongue tingling. Since Christmas, I’ve also had continuous tinnitus with occasional stabbing pain with no ear infection. I’ve had twitching in my eyes intermittently for a few years, too. I had an MRI in early February, which was stable.

I recently saw my Consultant, who was on the fence again about starting treatment. I said that in the light of a relapse of TN and already having a brainstem lesion, and a possible new lesion in the spine, I was really worried about not being on a DMT. He said that if I felt really strongly about starting, I would be eligible for ofatumumab (Kesimpta) or ocelizumab (Ocrevus). I pushed for cladribine as it won’t leave me immunocompromised for too long. He left it with me to decide which one.

I’m now questioning if this is a good choice after reading about all the risks. My EDSS is 2.0. I have no other comorbidities.

Last question, if I do go on it and my trigeminal neuralgia flares up, can I take carbamazepine when on cladribine?

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Prof G’s response

You raise many issues in your short description of your MS journey. Let me give it a go.

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I have been on natalizumab for 16 years and have just been diagnosed with renal cancer. It is slow-growing and 5 cm in size. I am about to have the affected kidney removed and may not need any further treatment. My MS team want to talk to me about potentially stopping natalizumab. Can you offer any medical insights as to being on natalizumab with one kidney? I haven’t found anything online saying otherwise. I just wondered if you have any views on this.

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Prof G’s response

Yes, you are right.

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Clinical history

2002, 2010, & 2019: My relapsing remitting MS diagnosis was confirmed by three separate lumbar punctures, all of which were positive for oligoclonal IgG bands (OCB) in the CSF.

2020 – 2024: Treated with ocrelizumab. During this period, I was stable and able to walk 200-300m independently (EDSS ~3.5-4.0).

Early 2024: MS therapy was paused due to a tonsil tumour (successfully treated with chemo and radiation). Oncologists have now cleared me for MS therapy restart.

The Current Crisis

During the 12-month treatment gap, I suffered a massive clinical and radiological decline:

Clinical: My mobility has drastically decreased. I am currently only able to walk up to 500 meters, strictly with walking aids.

Radiological: The latest MRI shows 20-50 new T2/FLAIR lesions in the brain and cervical spine.

The Paradox: A follow-up lumbar puncture performed recently (after 4 years of ocrelizumab and recent chemotherapy) was reported as OCB negative. I must note that the hospital refused to provide me with the original laboratory report; the “negative” result was only communicated verbally and noted in my discharge summary.

The Conflict

My national MS centre is now using this single negative OCB result to revoke my 23-year MS diagnosis, claiming I have a “Functional Neurological Disorder” (FND). This is despite three previously positive OCB tests and the clear radiological explosion of new inflammatory lesions. Consequently, they are refusing to restart my DMT or offer me another therapy.

Local MS experts strongly disagree with this revision. They maintain that the latest negative OCB is a direct result of long-term B-cell depletion and that up to 20-50 new lesions prove I have had an MS rebound.

My questions to you are

Is it medically sound to dismiss a 23-year history of confirmed MS (with 3 positive OCB tests) based on one negative result following long-term Ocrelizumab treatment?

Can an “FND” (Functional Disorder) explain up to 20-50 new inflammatory lesions appearing immediately after stopping a high-efficacy DMT?

In your experience, how should a patient with this level of radiological activity be treated to prevent further permanent disability?

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Prof G’s response

Q1. Is it medically sound to dismiss a 23-year history based on one negative OCB result?

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You may have seen this study: “GA Depot, a long-acting glatiramer acetate, vs placebo in patients with relapsing MS: a randomized phase 3 clinical trial”.

Over 52 weeks, a total of 1,016 were treated with GA Depot - the other half placebo. Those on GA Depot significantly reduced number of contrast-enhancing lesions vs placebo.

Am I right in thinking this is unethical? I am surprised by some of the study sites in the US.

The referenced abstract

Miller et al. GA Depot, a long-acting glatiramer acetate, vs placebo in patients with relapsing multiple sclerosis: A randomized phase 3 clinical trial. Mult Scler. 2026 Feb;32(2):202-213.

Background: GA Depot is a long-acting glatiramer acetate (GA)-based formulation designed to provide significantly extended dosing intervals compared to currently available GA formulations.

Objective: To assess GA Depot efficacy, safety, and tolerability compared to placebo in patients with relapsing multiple sclerosis (RMS).

Methods: A 52-week multi-center, double-blind, placebo-controlled phase 3 trial in RMS. Patients aged 18-55 with an Expanded Disability Status Scale (EDSS) score ⩽ 5.5 were enrolled and randomized (1:1) to intramuscular (IM) GA Depot 40 mg or matching placebo every 4 weeks. The primary endpoint was annualized relapse rate (ARR) at 52 weeks.

Results: A total of 1016 patients were treated with GA Depot (n = 508) or placebo (n = 508). Adjusted ARR was lower in patients treated with GA Depot compared to placebo (0.18, 95% confidence interval [CI] = 0.14 to 0.3 vs 0.26, 95% CI = 0.21 to 0.32, 30.1% relative risk reduction, p = 0.0066). GA Depot significantly reduced the number of contrast-enhancing lesions (p = 0.0083). The most common adverse events were injection site reactions (46.1% with GA Depot vs 28.7% with placebo), primarily mild and self-limited.

Conclusion: GA Depot effectively reduced clinical and radiological activity compared to placebo in RMS patients, recapitulating the favorable profile of subcutaneous GA products with significantly less frequent injections.

Trial registration: ClinicalTrials.gov Identifier: NCT04121221 (https://clinicaltrials.gov/study/NCT04121221).

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Prof G’s response

I am not sure if you are aware that this is not the only placebo-controlled phase 3 trial.

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Everything has gone very quiet regarding the BTK inhibitors and the regulators. Will the BTKi’s get to market?

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Prof G’s response

I suspect this question is from a business or market analyst. It is not necessarily the kind of question my patients would ask, except for those working in financial/investment industries or the pharmaceutical industry.

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Hello Prof G

As you are interested in general brain and physical health as part of the management of MS, I wondered what your opinion is on brain training apps - do they actually work? By this, I mean: do they cause physical changes in the brain that increase neural resilience and, hence, better outcomes for those of us with MS?

I have been using PEAK for two weeks now. I do quite enjoy it and am making progress, but is it doing anything more than just training me to play these particular games?

I can see that if I suddenly started to get worse at something, it might indicate a new lesion, but I’m more interested in whether I am gaining skills that will help me function better in daily life in the future.

Also, are these sorts of games used to assess cognitive ability in a clinical setting? If so, I wonder if it is taken into account whether someone practises them daily? I am sure my current progress reflects only my understanding of how the games work, coupled with my total lack of experience with any sort of computer game beforehand. I do play quite complex games quite often, but these are tabletop games with real people, so it seems to me that the apps are training in very specific skills.

Thank you as ever. Obviously, this isn’t an important question, but it just struck me that I have never seen you recommend this sort of thing, and maybe I am wasting my time, not to mention the £27 I paid for the app.

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Prof G’s response

What a wonderful set of questions. I have spent the last 2 days researching this topic, i.e., computerised cognitive training and will answer your questions at the end of the newsletter.

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“I took a look at the reported ALT elevations for fenebrutinib in FENtrepid and tolebrutinib in PERSEUS side-by-side (table below), and I wanted to understand how the superior safety profile of fenebrutinib was confirmed?”

I responded: “Based on Hy’s law. It’s the bilirubin levels that count. That is what makes regulators and hepatologists take notice.”

I got back the following: “I understand that Hy’s Law is a red flag, though ALT levels >8x ULN may also be a concern to my knowledge.”

I responded: “You are right, there are no differences. I have made corrections to the text to reflect this. We really need to wait until all the Fenebrutinib data are presented, i.e. the relapsing data. The FDA have already said it is a class effect, so I suspect the black box warning will be the same. I will do a separate newsletter on DILI to make these points.”

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Prof G’s response

Correction, I was wrong.

When you actually do the stats on the table, you will see that, for transaminitis defined as a rise in ALT greater than 3x the upper limit of normal or greater than 10x the upper limit of normal, the incidence of transaminitis is actually lower with tolebrutinib than fenebrutinib.

However, what is not captured are the dynamics, i.e., how quickly the ALT rises on therapy and falls on stopping therapy. And more importantly, can you prevent subjects with raised ALT getting worse and developing more severe DILI as defined by Hy’s law, when you detect raised ALT and stop the drug? The point I made about Hy’s law is also moot, as it clearly depends on the case definition of Hy’s law (biochemical versus clinically-confirmed).

The following is a more general response to the topic of drug-induced liver injury (DILI) for people with MS and HCPs.

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Prof G, what do you think of the PERSEUS and FENtrepid results presented on Saturday at ACTRIMS?

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Prof G’s response

ACTRIMS = Americas Committee for Treatment and Research in Multiple Sclerosis

This meeting, which took place last week from the 5th to the 7th Februrary in San Diego, California, was organised under the theme “MS at a Crossroads”. This theme was prescient, particularly in relation to the therapeutic landscape for Primary Progressive Multiple Sclerosis (PPMS). For over a decade, the management of PPMS has been characterised by a paucity of effective disease-modifying therapies (DMTs), with the anti-CD20 monoclonal antibody ocrelizumab (Ocrevus) standing as the only approved therapy. While ocrelizumab represented a leap forward, demonstrating the ability to slow disability progression, it does not represent a cure, nor does it fully arrest the insidious, “smouldering” neuroinflammation believed to drive the degenerative phase of PPMS.

The “Crossroads” at ACTRIMS 2026 was defined by the long-awaited readout of two pivotal Phase 3 clinical trials investigating Bruton’s Tyrosine Kinase (BTK) inhibitors in PPMS. Sanofi’s PERSEUS trial evaluating tolebrutinib, and Roche/Genentech’s FENtrepid trial evaluating fenebrutinib. These agents were designed to cross the blood-brain barrier (BBB) to target not only peripheral B cells but also the compartmentalised inflammation within the central nervous system (CNS), specifically the innate immune cells, microglia, and CNS-resident B cells.

The outcomes of these trials were presented back-to-back in the late-breaking session. In short, the PERSEUS trial failed to meet its primary endpoint. Conversely, the FENtrepid trial met its primary endpoint of non-inferiority relative to ocrelizumab as the active comparator and demonstrated signals of superiority in preserving upper limb function, a critical domain for maintaining independence in pwMS.

I provide a more detailed analysis here.

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Prof G, what do you think are the most exciting out-of-the-box theories about the cause of MS circulating at present? Do you think a toxin may be involved in causing the MS lesions?

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Prof G’s response

Most people still think the aetiology of MS is multifactorial, involving an interplay between genetic susceptibility and environmental triggers. I disagree and think EBV is the cause of MS, as EBV is necessary but insufficient to develop MS. People who are not infected with EBV don’t get MS.

The problem is, we don’t really know how EBV causes MS. I have spent the last few years writing what are essentially hypothesis papers about how EBV causes MS based on the so-called ‘hit-and-run’ and ‘driver’ hypotheses. One hypothesis I have spent less time discussing is the so-called ‘dual-hit’ hypothesis, i.e. EBV sets the stage for another factor to then trigger the disease.

Yes, the secondary environmental hit could be a toxin. For a detailed discussion on the dual-hit hypothesis and role of a toxin in the pathogenesis of MS, please read on …..

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I’m a 45-year-old male, diagnosed with RRMS in 2021 after an inner-ear MRI for BPPV (benign paroxysmal positioning vertigo) that picked up lesions compatible with demyelinating disease or MS. My first incident was in 2019, tingling in my leg and arm that sent me to the ER, thinking it was a stroke. Since then, my symptoms have stayed pretty mild: mostly tingling and abnormal sensations, no real disability. I have minimal brain lesions (maybe one), with the rest in my spine. I never had a lumbar puncture; I actually passed out during the consent discussion and cancelled it.

I’ve been on rituximab since December 2021. Earlier this year (around Feb 2025), I developed a stubborn ear infection, went through multiple antibiotics, caught COVID in the middle of it, and ended up with fully inflamed sinuses. This led to endoscopic sinus surgery, septoplasty, and turbinate reduction. I’ve also been doing off-label compounded antibiotic nasal rinses and dealing with eustachian tube dysfunction. I recently had a balloon dilation.

My July infusion was pushed to August. My B cells were still at zero, but I went ahead anyway because I just wanted it done. Throughout this year, I’ve had chronic rhinitis; looking back, it might have been brewing longer. The deviated septum wasn’t really noticeable until the infections and inflammation piled on. My ENT is still working with me and is in touch with my neurologist.

My main question for you is: Would it make sense to delay my next infusion to let my B cells repopulate a bit so my body has a better shot at resolving these sinus issues? And second, are there any other avenues I should be exploring?

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

I am assuming your diagnosis of MS is correct. I say this because you have one brain lesion and have not had a lumbar puncture and spinal fluid analysis to exclude MS mimics and help make a diagnosis of MS.

What is the cause of your sinusitis? The knee-jerk response will assume it is bacterial and related to your chronic immunosuppression due to rituximab. However, this may not be the case.

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I am seeking your guidance on the feasibility of a future clinical trial evaluating anti-BCMA CAR-T therapy for primary progressive multiple sclerosis (PPMS). I was diagnosed with PPMS in 2018, though my first symptoms appeared in 2012. Despite continuous treatment with ocrelizumab since 2019, my disease has progressed significantly over the past year. My current EDSS is 6.5, with marked lower-limb spasticity and mobility impairment.

Given the pace of my progression and the emerging evidence that B-cell–directed CAR-T therapies may induce more durable immune rebalancing than anti-CD20 therapies, I am highly motivated to explore every opportunity to participate in a trial or expanded access programme, if and when such studies begin.

I would be extremely grateful for any information you may have on:

1. Whether anti-BCMA CAR-T therapy (or related CAR-T approaches) is expected to enter clinical testing for MS in the near future?

2. Are you aware of any trial centres, collaborators, or timelines under consideration?

3. What recommendations do you have for someone in my situation who wishes to be considered for early-phase CAR-T studies?

I fully understand the experimental nature and risks of CAR-T therapy, including lymphodepletion. Nonetheless, given my current trajectory, I am willing to pursue innovative therapeutic options with appropriate medical oversight.

Thank you very much for your time and for your ongoing contributions to the MS field. Any guidance you can provide would be greatly appreciated.

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

I searched SciSpace, which highlighted 9 CAR T-cell trials in MS. However, when I searched on clinicaltrials.gov, I found 18 studies, and as this is a US-based search engine, I am sure there are more studies underway globally.

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I am a 29-year-old male, diagnosed with MS for 1.5 years, but have probably had MS for 5-7 years. I was started on ofatumumab (Kesimpta), but failed with many new lesions, then switched to ublituximab (Briumvi). I have now been stable for 10 months, but I now have a new lesion. I didn’t start on ocrelizumab (Ocrevus) due to a perception of lower efficacy with high BMI; I was 300lbs at diagnosis. I’m now 180lbs - all through diet and lifestyle.

Since I’m JCV negative, my neuro suggested natalizumab (Tysabri). I am also eligible for CAR-T and AHSCT clinical trials. I am risk-averse, but like the idea of immune reconstitution, so I was interested in cladribine (Mavenclad). My neurologist said Mavenclad would be a step back, and Tysabri or Ocrevus would be far superior.

I really want a DMT that penetrates the CNS, clears EBV-infected cells and pathogenetic plasma cells. Could Cladribine or another DMT theoretically do this? Tysabri is potent at stopping peripheral inflammation, but likely doesn’t address smouldering MS or halt progression.

My Briumvi infusion is next week, I was thinking of still taking it, then follow with a course of Cladribine. If I relapse, then go to Ocrevus (now that I’ve lost weight). Is this wise, or would you advise something different? I suggest skipping the Briumvi infusion and going with Tysabri. I am patiently waiting/hopeful for BTK Inhibitors.

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 answer

These are my thoughts.

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This newsletter is the final chapter of a trilogy describing my journey through a new NHS that has adopted AI-assistants. I am using this story to convey to you how neurological management will change in the future. Before reading this newsletter, you should read chapters 1 and 2, which provide the necessary context.

Q&A 120a - AI and its impact on the practice of neurology (20-Nov-2025)

Q&A 120b - The automated neurological examination (27-Nov-2025)

The final chapter raises questions about how AI will affect the workforce in terms of skills and its potential to replace humans. It also raises questions about the role of AI in diagnosing and managing common medical problems. I want to remind readers that this story is science fiction and hence may not come to pass. Many of the issues raised will spark discussion about this critical topic. We are entering a brave new world, and there is very little we can do about it. You may disagree. If you do, please leave a comment.

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 dystopian view

Chapter 3 - The neurology follow-up appointment

Thursday, 25th October 2035

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I have been asked to switch from IV ocrelizumab (Ocrevus) to SC ocrelizumab (Zunova). Reading the information leaflet provided suggests that there is no difference, apart from the mode of administration and a higher dose, to account for the differences in the modes of administration and the way the body absorbs the drug. Is this really a case of saving time and money for the same outcome? Why is it an option and not something I am being told I need to switch to? Or is that the letter I received after? Would you agree? Or am I missing something?

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 answer

Yes, this is really about saving time and money for the same outcome. However, if that were their real motivation, they should have also offered you ofatumumab or ublituximab.

Q: Reading the information leaflet provided suggests that there is no difference, apart from the mode of administration and a higher dose, to account for the differences in the modes of administration and the way the body absorbs the drug.

Would you agree? Or am I missing something?

Is this really a case of saving time and money for the same outcome? Why is it an option and not something I am being told I need to switch to? Or is that the letter I received after?

Yes, you are correct. The main advantage of subcutaneous (SC) ocrelizumab compared to the traditional intravenous (IV) infusion is significantly reduced treatment time, offering convenience while maintaining the same level of efficacy.

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