MS-Selfie

This Swedish study below explains why I keep repeating myself, i.e. ‘flip the pyramid’ and ‘smouldering MS is the real MS’.The Swedes have investigated how different intensities of initial MS treatments impact long-term physical disability. They compared high-efficacy therapies with standard platform treatments in over 2,500 pwMS to distinguish worsening caused by relapses (relapse-associated worsening, or RAW) from progression that occurs independently of relapses (PIRA). They show that high-efficacy drugs significantly reduced the risk of relapse-associated worsening (RAW) and delayed reaching major disability milestones. However, neither treatment type showed a superior advantage in slowing progression independent of relapse activity (PIRA). This suggests that RAW and PIRA likely stem from different biological processes.These findings indicate that while modern DMTs excel at controlling inflammation (NEIDA), additional neuroprotective strategies are necessary to halt the disease’s gradual decline associated with SAW. The results of this study advocate for aggressive early intervention (hit-hard-and-early) and the development of therapies that target smouldering processes within the CNS and repair mechanisms.The findings of this study are not new and are in keeping with other published data. Sadly, however, there are likely too few patients treated with alemtuzumab and cladribine in this cohort and none treated with AHSCT. It is well known that the majority of pwMS on high efficacy treatments in Sweden are on off-label rituximab. I am told that Swedish neurologists now rarely use alemtuzumab, and the uptake of cladribine has also been slow. It would, however, be interesting to see if IRTs (immune reconstitution therapies), in particular alemtuzumab and AHSCT, made a difference in SAW. I say this because alemtuzumab and AHSCT are the most effective treatments we have for MS and have a profound impact on the end-organ in terms of reducing the rate of brain volume loss or brain atrophy. These two treatments do impact SAW, provided they are used early.It is becoming increasingly difficult to justify a low-efficacy platform DMTs approach when it is clear that pwMS treated with high-efficacy therapies first-line do so much better. Do you agree?A more interesting question for the next generation of neurologists to answer will be whether an induction-maintenance approach is superior to continued long-term immunosuppression, such as long-term anti-CD20 therapy. I note the Swedes are starting to test rituximab induction followed by cladribine as an exit strategy.The HIt HArd and hiT Early in Multiple Sclerosis Trial (HiHat) - ClinicalTrials.gov ID NCT07517185, Sponsor Uppsala UniversityI have been advocating this approach for several years, as it reduces the risks associated with long-term immunosuppression, allows you to recover your naive B-cell population for vaccinations, and, as cladribine is CNS-penetrant, targets CNS-resident B-cells and plasmablasts that are responsible for at least one component of smouldering MS. I have little doubt that this trial will work. Sadly, it is underpowered for efficacy, but who knows if the majority of subjects go into long-term remission, it may affect how both rituximab and cladribine are used in Sweden.If you are on long-term anti-CD20 therapy, would you consider switching to cladribine? Would you participate in a trial to test the safety and efficacy of anti-CD20 induction followed by an exit via cladribine?Guo et al. Long-term disability after initiation of platform versus high-efficacy disease-modifying therapy in relapsing-onset multiple sclerosis. J Neurol. 2026 Apr 1;273(4):240.Background: Several observational studies have compared high-efficacy and platform disease-modifying therapies (DMTs) with respect to long-term disability in relapsing-onset multiple sclerosis (MS), yet it remains unclear whether observed differences reflect relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), or both.Methods: We included 2,563 DMT-naïve individuals with relapsing-onset MS enrolled in a population-based study linked to the Swedish MS registry (40 clinics, 2005-2019). The exposure was an initial DMT efficacy class (platform versus high-efficacy therapy), with platform as the reference. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for RAW, PIRA, and time to EDSS 3 and 4. EDSS trajectories were modelled using mixed-effects models. Follow-up started at DMT initiation and was censored at treatment switch, discontinuation, death, drop-out, or study end.Results: At treatment initiation, 1,987 participants started a platform DMT and 576 a high-efficacy DMT. High-efficacy therapy was associated with a lower risk of RAW (HR 0.60, 95% CI 0.38-0.92), while the risk of PIRA did not differ between treatment groups (HR 1.05, 95% CI 0.79-1.39). Risks of reaching EDSS 3 and EDSS 4 were also lower with high-efficacy DMT (EDSS 3: HR 0.26, 95% CI 0.17-0.38; EDSS 4: HR 0.32, 95% CI 0.18-0.54). EDSS trajectories increased more steeply among participants treated with the platform, with partial convergence toward the high-efficacy group over time.Conclusions: Our findings suggest that inflammatory and relapse-independent components of MS disability respond differently to current therapies and highlight the need for complementary neuroprotective strategies.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. 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If you don’t have advanced MS, you may find the contents of this newsletter upsetting. It is not for everyone. Only read on if you want to know about managing advanced MS.QuestionI am at EDSS 8 and need to get my affairs in order. I cannot do anything really anymore, so is this the beginning of the final stages? I know you won’t sugarcoat the reply, so? I can no longer go to the toilet on my own and need to use the Peristeen system with my partner’s help. My partner uses a hoist to move me to and from bed/chair, etc. I have just had pneumonia, and the doctors said if I had a heart attack, they would not step in on medical grounds, even though I protested. What would you advise?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 ([email protected]) to request a complimentary subscription.Prof G’s responseThank you for your questions and for being so honest about what you are going through. I get the sense that you are exhausted and anxious. I am sorry you are having to navigate such a heavy burden, especially after battling pneumonia and having such a distressing conversation with your doctors about end-of-life care. These conversations are best conducted well in advance, not during an acute crisis. This is why I urge all of you to complete an advance directive early on in your disease course and make sure your family knows about it and has a copy.You asked me not to sugarcoat things, so I will give it to you straight. Reaching EDSS 8 is a significant and difficult reality. It represents the advanced stages of physical disability in MS, which is why you are facing the loss of independence, needing the hoist, relying on the Peristeen system and your wife’s support. However, being in this advanced stage of disability does not necessarily mean you are in the final weeks or months of your life. Many people live for years and decades with an EDSS of 8. However, it does mean you are more vulnerable to complications, as evidenced by the flu.Given that vulnerability, you are right to get your affairs in order. Doing so is not a sign that you are giving up or that the end is near. It is simply about taking back some control, ensuring your exact wishes are legally documented, and giving you and your wife some peace of mind so you don’t have to worry about the administrative side later.Regarding the doctors telling you they would not step in if you had a heart attack or, by implication, another life-threatening event, I can only imagine how surprising or jarring and angering that was, especially as you protested. In the UK medical system, doctors can legally place a “Do Not Attempt Cardiopulmonary Resuscitation” decision on your file if they clinically believe the severe physical trauma of CPR would not be successful or would cause you more suffering due to your body’s current frailty and only if you and your family consent to it happening. However, your voice still matters. You are entirely within your rights to ask for a second medical opinion regarding this decision, to complete an advanced directive contrary to their advice and to demand a clearer conversation about your ongoing care plan going forward.Please try to be mindful of yourself. Your feelings and frustrations are valid, but anger will not help. Your neurological team should be there to support you through this. I would also recommend that they refer you to the palliative care team that has access to community services that can help you. For example, you would benefit from some form of counselling.As you are aware, from a treatment perspective, we don’t have any therapies to stop your disability from worsening or to reverse it. We think treatments such as cladribine may slow the rate of worsening, which is why we are conducting the CHARIOT-MS trial in advanced MS. We also know that comorbidities such as recurrent infections, pressure sores, poor metabolic health, poor sleep hygiene, low mood, etc., worsen MS. This is why you, your GP, and your local MS service need to focus on optimising the small things.I have looked after many people with advanced MS who have done this, and when the small things are looked after, they often notice an improvement in their quality of life.I hope this helps.I now realise the information I have given you is quite superficial. I have therefore produced a longer newsletter that covers topics you and others with more advanced MS may find helpful.Advanced MSAs you know, the EDSS ranges from 0.0, indicating a normal neurological examination, to 10.0, indicating death due to MS. The transition to an EDSS score of 8.0 represents a watershed in the clinical trajectory. At an EDSS of 8.0, the pwMS is usually restricted to a bed or a chair, or requires assistance in a wheelchair for mobility. While they may be out of bed for much of the day, their independent ambulatory capacity is usually curtailed, unless they have an electronically controlled wheelchair. At EDSS 8.0, pwMS generally retain effective use of their arms, with some preservation of many self-care functions. This clinical profile distinguishes them from pwMS at EDSS 8.5, who are restricted to bed for much of the day with only some effective arm use, and those at EDSS 9.0 or 9.5, who are totally confined to bed and face severe bulbar dysfunction, including problems with communication and swallowing.Because pwMS at EDSS 8.0 retain upper-extremity function and cognitive awareness, preserving their autonomy is a clinical priority and the reason we launched our #ThinkHand campaign almost a decade ago. We don’t think pwMS who are wheelchair users should be ignored. As part of the #ThinkHand campaign, we have been involved in designing and starting the O’HAND (ocrelizumab in PPMS), CHARIOT-MS (cladribine in advanced MS) and OCTOPUS trials. All these trials use the 9-hole peg test as the primary outcome measure or part of the composite endpoint.When you lose the use of your legs, your arms and hands function are essential for mobility, and explain why pwMS with advanced MS prioritise upper extremity function over lower limb function.At this stage of advanced MS, care must focus on supporting daily living and preventing complications (preventive neurology). The philosophy I promote relies heavily on the aggregation of marginal gains—the understanding that meticulous attention to seemingly “small things” yields improvements in the pwMS’s dignity, survival, and psychological well-being. Furthermore, the relationship between the pwMS and their carer(s) becomes a central focus of care. The psychological resilience, physical safety, and emotional well-being of the carer are inextricably linked to pwMS outcomes, necessitating support, respite strategies, and environmental adaptations to mitigate the burden of providing chronic care.ComorbiditiesThe management of a wheelchair-bound or bedbound pwMS does not occur in a vacuum. People living with advanced MS exhibit a higher incidence of comorbidities compared to the general population. The most prevalent conditions are high blood pressure, diabetes, heart disease, fibromyalgia, chronic lung disease, and mood disorders such as depression and anxiety.The presence of these comorbidities has been clinically linked to a faster worsening of disability, reduced overall quality of life, more frequent hospital admissions, and a regrettable shorter lifespan. Clinical studies indicate that pwMS who also suffer from vascular disease tend to require assistance with walking much sooner than those without vascular comorbidities. Therefore, the active management of metabolic syndrome and vascular health should not be peripheral to MS care, but a central part of it.Because a pwMS with EDSS 8.0 is often entirely sedentary, their risk for developing metabolic syndrome—a constellation of high blood pressure, elevated blood glucose, excess body fat around the waist, and abnormal cholesterol levels—increases due to a forced sedentary lifestyle. Maintaining a good relationship with your general practice or a primary care provider is, therefore, essential as most MS services don’t have the resources and expertise to manage these comorbidities.Respiratory functionRespiratory complications are recognised as one of the leading causes of death in pwMS, accounting for approximately 50% of all deaths in longitudinal studies. Emergency, unplanned, or non-elective admissions for respiratory crises in pwMS cost an average of £216,000 annually per NHS Clinical Commissioning Group (CCG), with £75,000 attributed to admissions for aspiration pneumonia. Prior to their dissolution, there were 106 CCGs in England; therefore, the cost to NHS England was ~£23M annually for this problem alone.The decline in respiratory function in MS is typically insidious and begins long before the pwMS reaches an EDSS of 8.0. Pulmonary function is affected even in the early stages of disability, primarily through weakening of core stabiliser muscles. This reduction in core strength translates into impaired pulmonary mechanics, diminished health-related quality of life, and worsening fatigue. However, the transition to a wheelchair-bound or bedbound state precipitates a much sharper decline in respiratory function. This manifests clinically as a weak and ineffective cough. When the expiratory muscles fail to generate sufficient force to clear the airway, and the inspiratory muscles are too weak to provide adequate ventilation, the pwMS becomes susceptible to respiratory failure. This is compounded by upper-airway (glottic) muscle weakness, which results in progressive dysphagia (difficulty swallowing). When a pwMS cannot swallow effectively, the risk of aspiration pneumonia—where food, liquid, or saliva is inhaled into the lower respiratory tract and becomes infected—becomes a daily, and often life-threatening reality. Evaluations of pwMS with an EDSS score of 8.0 or higher, 61% report significant symptoms of respiratory dysfunction, including hypophonia (weak voice), shortness of breath, orthopnea (difficulty breathing while lying down), retained chest secretions, and sleep apnea.Mitigating this risk requires meticulous, proactive respiratory pathways and daily low-tech interventions. Respiratory muscle training (RMT) has emerged as an effective, non-pharmacological intervention. Systematic evaluations demonstrate that RMT significantly improves maximum inspiratory pressure (MIP) by an average of 4.74 cmH2O and maximum expiratory pressure (MEP) by 8.50 cmH2O, while simultaneously delivering a substantial reduction in systemic fatigue. Integrating simple breathing exercises, such as the 4-7-8 breathing technique, into your daily wellness routine strengthens the diaphragmatic and intercostal musculature, supporting lung capacity.The 4-7-8 breathing technique is a stress-reducing, rhythmic, and meditative practice that helps calm you, improve sleep, and manage anxiety. Developed by Dr Andrew Weil, it involves inhaling through the nose for 4 seconds, holding for 7 seconds, and exhaling loudly through the mouth for 8 seconds. How to Practice the 4-7-8 technique:* Prepare: Sit comfortably with a straight back or lie down.* Position: Place the tip of your tongue against the ridge behind your upper front teeth and keep it there.* Exhale: Empty your lungs of air completely through your mouth.* Inhale (4): Close your mouth and inhale quietly through your nose for a count of 4.* Hold (7): Hold your breath for a count of 7.* Exhale (8): Exhale completely through your mouth, making a “whoosh” sound (pursed lips) for a count of 8.* Repeat: Repeat this cycle 4 times.The long exhale acts as a natural tranquilliser for the nervous system, activating the parasympathetic (”rest and digest”) nervous system. It is effective for falling asleep, managing panic attacks, or reducing daily stress. If you feel lightheaded initially, start with only 4 cycles. With practice, you can increase to 8 cycles. For best results, practice at least twice a day.Another thing you can do, which is a variation of the 4-7-8 technique, is to stack your lungs. Please see my previous newsletter on this topic.* Do you know how to stack your lungs? (Oct 25, 2021)Furthermore, reviewing your medications is important. Many medications routinely prescribed for MS symptom management possess CNS depressant properties that can dangerously slow a pwMS’s breathing. Anti-anxiety medications (such as benzodiazepines), skeletal muscle relaxants used for spasticity, and opioid pain relievers must be used with caution. For a pwMS with a history of breathing issues or swallowing difficulties at EDSS 8.0 or higher, combining these medications is typically contraindicated and requires monitoring.When your cough strength falls below the threshold required to clear retained secretions, technological intervention becomes necessary. Mechanical insufflation-exsufflation (MI-E) devices, colloquially known as “cough assists,” are helpful for some pwMS. These devices deliver positive pressure to the airway to simulate a deep breath, followed by a rapid, forceful shift to negative pressure to simulate a natural cough, thereby drawing secretions from the lungs. The utilisation of MI-E devices, combined with regular assessments by speech and language therapists (SLTs) for swallowing integrity and dietary modifications, can reduce respiratory complications in pwMS.Tissue viabilityFor an individual confined entirely to a bed or wheelchair, preserving skin integrity is a relentless, round-the-clock challenge. The formation of pressure ulcers (also known as pressure injuries, decubitus ulcers, or bedsores) represents a failure of tissue viability, resulting from localised injury to the skin and underlying soft tissue. These injuries invariably occur over bony prominences—such as the ischial tuberosities, sacrum, heels, and greater trochanters—and are driven by the unrelenting forces of direct pressure, friction, and shear. For more detailed information on this, please read my prior newsletter.* Pressure sores (Feb 23, 2026)An effective daily skincare routine for a bedbound pwMS must focus on gentle cleansing, barrier protection, and intensive hydration to prevent minor irritations from progressing to full-thickness wounds. Harsh alkaline soaps must be avoided; instead, caregivers should utilise mild, pH-balanced, hypoallergenic, and fragrance-free cleansers. Physical exfoliants and rough washcloths must be avoided, as they can cause micro-tears in the skin, providing entry points for bacteria. The generous application of ceramide-rich or hyaluronic acid-based moisturisers helps repair the skin barrier, preventing the skin from becoming brittle and prone to shearing forces during transfers. By preventing these minor skin irritations, caregivers eliminate sources of infection and pain that can impact a pwMS’s QoL and exacerbate other problems such as spasticity.Oral hygieneOral health is an important part of advanced MS management. For pwMS with EDSS 8.0 or higher, the physical symptoms of the disease—including fatigue, weakness, intention tremor, loss of fine motor coordination, and altered sensation—make standard, independent toothbrushing difficult. Furthermore, MS itself and the pharmacological side effects of many MS medications frequently induce xerostomia (chronic dry mouth). Saliva is the mouth’s defence mechanism; it physically washes away food debris, neutralises plaque acids, and provides remineralising ions to the enamel. The absence of adequate saliva allows decay-causing bacteria to proliferate, leading to rapid and often catastrophic tooth loss and severe periodontal disease. When oral bacterial overgrowth is combined with dysphagia (swallowing difficulties) and a high-calorie, high-sugar diet required to prevent the weight loss common in advanced MS, the risks associated with periodontal disease become dangerous.Poor oral hygiene in a pwMS with dysphagia creates a direct, pathogenic pathway from the oral cavity to the lungs. The aspiration of bacteria-rich saliva is a primary driver of aspiration pneumonia. Therefore, oral care becomes important. Implementing “small things” in oral care yields significant improvements in safety. The use of electric toothbrushes with built-up, wide, or angled handles, or the simple application of a weighted glove to dampen intention tremor, can help pwMS maintain a degree of autonomy in their oral care. For those suffering from MS-induced trigeminal neuralgia—a condition where the mere friction of brushing can trigger agonising, electric-shock-like facial pain—careful, ultra-soft brushing techniques, avoidance of extreme water temperatures, and timed medication dosing may be necessary to maintain hygiene without inducing pain.Caregivers must remain vigilant regarding the sugar content of liquid medications and high-calorie nutritional supplements. Substituting sugar-laden medicinal syrups with sugar-free alternatives, utilising mouth-moistening sprays or sugar-free lemon drops to stimulate salivation, and maintaining high ambient humidity in the room are helpful micro-interventions. Regular oral and dental assessments to identify oral thrush (candidiasis) are important, as it typically requires antifungal medications. Upgrading wheelchair accessibility at dental clinics and providing specialised training for dental staff to manage pwMS in wheelchairs are well-described barriers. My personal dentist, for example, is based in an old Victorian building that is not wheelchair-accessible. In the past, I have referred pwMS to our dental school for dental care. The dental school has large, open-plan consulting areas that are wheelchair-accessible.Wheelchair managementFor an individual with an EDSS of 8.0 or above, their wheelchair is more than a mobility device; it becomes their support system for their skeletal and muscular structure. Because the pwMS is non-ambulatory, prolonged sitting places pressure on the ischial tuberosities (the sitting bones of the pelvis). To prevent pressure sores, modern advanced electric-powered indoor/outdoor wheelchairs (EPIOCs) come equipped with dynamic tilt-in-space and recline functions. A tilt-in-space system alters the seat’s orientation relative to the ground while maintaining a fixed seat-to-back angle. Conversely, a recline system opens the seat-to-back angle itself, extending the hip joint. Studies demonstrate that minor tilt adjustments (between 15 and 25 degrees) are effective for managing fatigue, improving visual orientation to the environment, and enhancing the pwMS’s ability to engage in social interactions. Minor angles are insufficient for true pressure relief. To achieve optimal hemodynamic redistribution and significant offloading of pressure from the ischial tuberosities to the broader back surface, a posterior tilt of at least 45 degrees, combined with a recline of 15 to 30 degrees, is required.Elevating leg rests are also used with recline features to prevent shear forces that could slide the pwMS pelvis forward, thereby completely negating the pressure-relieving benefits. Integrating these advanced seating systems with specialised, pressure-relieving cushions reduces the effects of spasticity, accommodates postural asymmetries, and helps prevent pressure ulcers. Because pwMS with an EDSS of 8.0 generally retain some effective use of their arms and hands, they can exert some control over these positional changes through advanced joystick configurations.The biomechanics of seating adjustments require precise calibration, which is why you have to be referred to a wheelchair service. Sadly, the NHS only covers relatively basic wheelchairs and those with all the bells and whistles need to be paid for privately.Hoist systemsAs the disease progresses and the pwMS loses the bilateral lower-extremity strength needed to bear weight during pivot transfers, hoists become a daily, unavoidable necessity. The choice between mobile (floor-based) hoists and overhead ceiling-track hoists affects not only the pwMS’s physical comfort and dignity but also the caregiver’s safety.Mobile hoists offer versatility across multiple unadapted rooms and are generally more cost-effective as an initial investment, making them common in budget-constrained or temporary care settings. However, their operational demands are significant, with repetitive manual exertion on the caregiver. The carer must physically push, drag, and steer heavy steel equipment across varying floor surfaces, often with the added weight of the pwMS suspended in the sling. Furthermore, mobile hoists require a large spatial footprint, which often restricts their use in standard bedrooms and bathrooms. Manual handling is a leading cause of musculoskeletal injuries among caregivers, accounting for burnout, sick leave, and physical incapacitation.In comparison, ceiling track hoists represent a superior investment in the long-term quality of life and safety of the pwMS and their carers. Fixed directly to the ceiling’s structural framework, the automated motor unit glides effortlessly along a track, eliminating frictional resistance and physical strain associated with a floor-based steering system.Smooth, dignified, and precise transfers from the bed to the wheelchair or commode, ceiling hoists reduce the anxiety, physical trauma, and spasticity triggers associated with moving. More importantly, they preserve the carer’s physical health, allowing them to redirect their energy toward companionship and active caregiving. So please think about your caregivers when making a decision about hoists.Circadian rhythmspwMS with advanced MS frequently suffer from maladaptive sensory processing disorders, manifesting clinically as either hypersensitivity (a low neurological threshold) or severe hyposensitivity. This means that people with advanced MS may be unable to effectively register or modulate sensory input from their daily environment, regardless of their cognitive status. Consequently, chaotic, loud, or visually harsh environments can induce fatigue, agitation, and an impact behaviour.Optimising the pwMS’s room may have a profound effect on their overall well-being. Bedbound pwMS are often deprived of natural, dynamic sunlight, leading to circadian rhythm desynchronisation. This may exacerbate existing sleep disorders, increase daytime cognitive fog, and cause behavioural and psychological distress. Tunable, dimmable LED lighting systems that emulate the natural solar cycle can help prevent circadian rhythm desynchronisation. Exposing the pwMS to bright, cool light in the morning helps suppress melatonin and entrain the circadian clock, while transitioning to warm, dim, multi-zoned lighting in the evening promotes sleep and reduces nocturnal awakenings.Further sensory modulation can include targeted aromatherapy to bypass degraded neural pathways and engage the limbic system directly. Scents such as lavender, chamomile, and vanilla possess validated properties that reduce autonomic arousal and create a calming atmosphere. Integrating nature sounds or soft, familiar music therapy masks jarring household noises, providing comfort and positive distraction. When hyposensitivity dominates the clinical picture, structured tactile stimulation—such as contrast baths, graded textured cloths, therapy putties, or targeted vibration therapy—can improve limb awareness, provide comfort, and reduce fatigue.Assistive technologyAt an EDSS of 8.0, the inability to perform basic fine-motor tasks—such as turning off an overhead light, adjusting a thermostat, locking a door, or changing a television channel—can be challenging and can induce a sense of helplessness and dependency. The integration of Smart Home Technology and Voice-Activated Systems (such as Amazon Alexa, Google Home, and Apple HomePod) serves as a digital prosthesis, bridging the gap between the pwMS’s cognitive intent and their physical inability to perform tasks.Using environmental control units (ECUs), pwMS can independently manipulate their physical surroundings using only their voice. A simple voice command can activate motorised window blinds, modulate the ambient room temperature, or adjust the articulation of a specialised hospital bed, without necessarily requiring a carer’s presence. This technology fundamentally redefines the concept of independence for the bedbound pwMS.Advanced systems like the “HomeSmart Assistant” interface seamlessly with home security networks, allowing the pwMS to lock doors, answer the front door remotely, or view external camera feeds. This replaces a sense of physical vulnerability with a restored sense of safety and security. For the caregiver, this means fewer nighttime interruptions for tasks (e.g., turning on a ceiling fan for a heat-intolerant pwMS), thereby preserving sleep for both parties and preventing or reducing caregiver burnout. To overcome the decline in motor speech intelligibility common in MS, these voice-activated devices can be physically modified to sit closer to the person’s head, or their listening duration software can be extended to accommodate slower, more laboured speech patterns.Alternative communicationAs MS advances, some pwMS develop severe dysarthria characterised by progressive muscular incoordination, spasticity, laboured articulation, impaired volume control, and unpredictable articulatory breakdowns. When verbal communication decays, psychological isolation rapidly ensues; the pwMS becomes trapped in an unresponsive body, unable to express complex thoughts, direct their own medical care, or connect emotionally with their family.For pwMS who retain full cognitive function but lose their motor and speech capabilities, eye-gaze communication devices (such as the Tobii Dynavox I-Series or the Eyegaze Edge) are transformative. These high-tech augmentative and alternative communication (AAC) devices utilise advanced infrared cameras to track the micro-movements of the pwMS’s pupils, allowing them to navigate a Windows-based interface or a bespoke communication grid. By simply fixing their gaze on a digital keyboard letter or a pre-programmed phrase for a fraction of a second, the pwMS can generate synthesised speech.Because eye-gaze technology bypasses the descending spinal motor pathways entirely and relies on the relatively well-preserved oculomotor nuclei, it requires minimal physical exertion. This compensates for the debilitating fatigue that is typical of people with advanced MS. The calibration process takes mere seconds, and the technology allows individuals with severe motor deficits to stay connected to the world, browse the internet, and maintain their relationships. Restoring the pwMS’s voice is not merely a convenience; it is the cornerstone of preserving psychological dignity, allowing the individual to remain an active participant in their own life rather than a passive recipient of care.Clothing and thermoregulationClothing is deeply intertwined with personal identity, self-expression, and dignity. Yet standard retail apparel can be physically restrictive, immensely frustrating, and potentially hazardous for a pwMS with EDSS 8.0 or above. The seemingly trivial act of changing clothes can consume a pwMS’s entire daily energy reserve and cause pain by triggering severe muscle spasms.Adaptive clothing reimagines fashion through a lens of functionality and accessibility. Garments utilising hidden magnetic closures or Velcro bypass the need for fine motor dexterity, eliminating the frustration of manipulating small buttons, laces, and zippers. For individuals who spend 15 hours a day seated in a wheelchair, the structural design of trousers is a critical medical issue; traditional rigid seams, rivets, and heavy back pockets create focal pressure points that can cause pressure sores. Adaptive trousers feature a higher-cut back to comfortably accommodate a seated posture, a lower-cut front to prevent fabric bunching and respiratory restriction, and seamless, pocket-free seats to maintain skin integrity. Open-back tops allow for dressing from a seated or prone position without requiring the pwMS to lift their arms above their head or contort their shoulders.Furthermore, extreme heat intolerance is a hallmark of MS. Slight elevations in core body temperature slow neurological conduction across demyelinated axons, causing an acute, temporary worsening of MS symptoms. The strategic use of specialised cooling garments—such as moisture-wicking bamboo fabrics, phase-change cooling vests, and temperature-regulating neck wraps—keeps pwMS below the threshold for symptom exacerbation. Allowing a pwMS to dress efficiently, comfortably, and stylishly not only prevents physical injury and overheating but also preserves their fundamental self-image and dignity amid progressive physical decline.Nutrition, exercise, and cognitive therapyWhile an EDSS score of 8.0 precludes ambulation, the complete cessation of movement is detrimental to the pwMS’s physiological and psychological health. Disuse atrophy, severe joint contractures, decreased bone density, and worsening spasticity rapidly follow immobility. Physio/pr physical therapy at this advanced stage focuses on passive range-of-motion exercises, targeted stretching protocols, and the use of motorised continuous passive motion (CPM) devices to loosen tight muscles and maintain joint mobility. Even minor upper-body aerobic exercise, such as utilising a modified arm ergometer, promotes cardiovascular fitness, aids in sluggish bowel motility, and stimulates the release of endorphins that combat clinical depression and anxiety.A tailored diet emphasising lower saturated animal fats, high dietary fibre, and vegetables may help mitigate the risk of comorbid vascular diseases (such as hypertension and diabetes), which accelerate MS worsening and increase mortality. Ensuring adequate hydration and high-fibre intake is an important defence against chronic constipation that plagues bedbound pwMS.Cognitive behavioural therapy (CBT), mindfulness-based stress reduction (MBSR), and targeted education remain effective at this stage of MS for addressing the grief of lost physical function, managing chronic pain, and restructuring negative thought patterns. Brief, group-based CBT interventions, often delivered via telehealth to overcome mobility barriers, have been shown to significantly reduce symptoms of depression, anxiety, and fatigue, providing the pwMS with critical coping mechanisms.The caregiverThe comprehensive management of a bedbound or wheelchair-bound pwMS requires a daily effort from family carers, whose reality may be defined by physical labour and emotional exhaustion from a chronic and unrelenting state of hypervigilance. I have seen this scenario play out over and over again in my own clinical practice. The progressive, chronic nature of MS dictates that caregiving is not a short-term acute crisis, but a marathon that typically lasts decades. Caregivers routinely sacrifice their own careers, social networks, and physical health, leading to isolation, high incidences of clinical depression, and musculoskeletal injuries from manual handling. Surveys of MS caregivers reveal that 80% experience severe financial problems due to their caring tasks, 55% struggle to combine care with daily activities, and over 50% suffer a decline in their own physical health.Resilience in caregivers must be actively cultivated and supported by the healthcare system. Clinical research indicates that higher caregiver resilience is directly associated with a significantly reduced care burden and vastly improved pwMS quality of life. However, sustaining this resilience requires more than mere endurance; it demands implementing daily habits, cognitive-behavioural coping strategies, and structured psychoeducational training. Caregivers must be educated to view self-care—such as maintaining a proper diet, securing uninterrupted sleep, exercising, and utilising stress-reduction techniques like yoga or meditation—not as a selfish luxury, but as necessary to prevent collapse.The unpredictability of MS symptoms demands that caregivers design structured yet flexible daily routines. Attempting to accomplish too many tasks in a single day inevitably precipitates both fatigue and emotional frustration. Dividing the day into manageable micro-segments with predetermined “empty time slots” prevents task saturation and ensures periods of cognitive rest.Respite care serves as a safety valve for the caregiver. Respite is restorative and must be utilised proactively, well before the carer reaches exhaustion and burnout. Ideal respite involves regular blocks of time—ideally up to two days per week—where the carer completely disengages from medical duties to pursue personal, joy-inducing activities, rather than simply using the time to catch up on household chores. Many organisations exist to facilitate replacement care, “sitting services,” or temporary residential stays to allow the caregiver these crucial periods of psychological and physical reset.If you are a person with MS and have a carer, please consider their well-being as well. If you are a carer for someone with MS, I suggest you read ‘The Selfish Pig’s Guide To Caring: How to cope with the emotional and practical aspects of caring for someone’ (by Hugh Marriot, 2009). I have multiple copies that I used to loan to pwMS and their carers. It is full of very useful information for carers.Navigating the systemThe financial burden associated with advanced MS is staggering. The necessity of purchasing specialised equipment (hoists, advanced wheelchairs, AAC devices), funding major home adaptations, and absorbing the loss of dual household incomes drastically erodes the family’s economic stability. In the UK, navigating the bureaucratic labyrinth of health and social care to secure funding is frequently cited as a distinct, secondary source of trauma for families. Caregivers frequently report profound frustration and powerlessness when dealing with local welfare agencies, citing extensive delays in the provision of equipment, humiliating assessment processes, and a general lack of transparent, proactive information about their rights.Statutory pathways and charitable lifelines do exist, and optimising them is a core component of managing advanced MS. Unpaid carers have a legal right to a formal Carer’s Assessment (administered via their local council in England and Wales, the Health and Social Care Trust in Northern Ireland, or via an Adult Carer Support Plan in Scotland). This assessment evaluates their specific needs and can unlock vital funding for replacement care, stress-reduction therapies, or practical assistance.To fund critical, high-cost home modifications—such as widening doorways to accommodate an electric wheelchair, installing accessible wet rooms, or mounting essential ceiling track hoists—households can apply for Disabled Facilities Grants (DFGs) through their local council. While these grants are means-tested and may require the family to contribute to costs, they are the primary mechanism for funding structural adaptations. While the national MS Society grants program has closed due to broader financial constraints, localised MS Society branches, home improvement agencies (HIAs), and specific charities like the MS Research and Relief Fund continue to provide micro-grants for specialised equipment, health and wellbeing items, and caregiver breaks. Utilising online resources such as the Mobilise platform or the MS Carers Club UK Facebook group provides caregivers with peer-to-peer information to help them navigate these complex bureaucratic systems.Advanced MS ChampionsRecognising the severe fragmentation of care for pwMS with complex, advanced needs, the MS Trust pioneered the Advanced MS Champions Programme. Serving a function similar to that of “Admiral Nurses” in dementia care or Macmillan Nurses in oncology, an Advanced MS Champion is a highly specialised, dedicated clinical coordinator focused exclusively on pwMS with advanced disease (typically EDSS 7.0 and above).Historically, pwMS at EDSS 8.0 fall off the radar of standard hospital neurology clinics. The sheer logistical difficulty, pain, and exhaustion involved in transporting a bedbound pwMS to an outpatient clinic appointment mean that they simply stop attending, losing contact with specialist services just when their symptoms become most complex and life-threatening. The Advanced MS Champion actively bridges this gap, operating fluidly across the rigid boundaries of the NHS and local social care systems. Their multifaceted role involves proactive, individualised care planning, complex symptom triage, and the rapid mobilisation of community multidisciplinary teams—including physiotherapists, dietitians, and occupational therapists—bringing the clinic directly into the pwMS’s home. Sadly, as a neurologist, I have made very few home visits for pwMS; in fact, I can count them on one hand. The current NHS secondary care model in neurology does not include home visits.The financial impact of this specialised Advanced MS Champion role is profound. Pilot data from six initial hospital sites reveals that a single Advanced MS Champion saves an average of 52 hospital admissions and 403 emergency bed days per site annually. This translates to a staggering NHS cost saving of over £465,000 per year per site. By identifying and treating complications—such as urinary tract infections, impending pressure sores, or high-risk aspiration problems—in the community before they rapidly escalate into life-threatening sepsis or pneumonia necessitating emergency hospitalisation, the Advanced MS Champion drastically improves the pwMS’s QoL. Crucially, they also provide an invaluable, easily accessible safety net and point of contact for the exhausted family carer, reducing the psychological burden of managing complex medical conditions in isolation.Other MS-Selfie newsletters, if you have advanced MS, you will find helpful, as they complement this information, are the following.* Q&A 103 - Advanced MS - what can be done? (Aug 04, 2025)* The shrinking world phenomenon (Nov 04, 2025)* Planning for death (Aug 11, 2025)* Infection (Jun 29, 2021)* Getting worse (Jul 02, 2021)ConclusionThe comprehensive management of a person living with MS at an EDSS score of 8.0 or above represents complex and demanding challenges in neuro-palliative and rehabilitative medicine. At this advanced stage, the utility of disease-modifying therapies has, in the past, receded, replaced by a holistic, multidisciplinary approach to managing the myriad physiological, environmental, and psychological consequences of immobility. The clinical reality is that severe disability is not a static endpoint to be accepted, but a dynamic state requiring continuous, proactive, and thoughtful interventions.The clinical evidence definitively underscores that the pwMS’s quality of life is not preserved through grand, episodic medical gestures, but through the obsessive, daily optimisation of “small things”. For example, it is the precise 45-degree posterior tilt of a specialised wheelchair that relieves pain and discomfort and prevents pressure sores. It is the seamless, pocket-free design of an adaptive trouser that averts the cascade that can lead to a pressure sore. It is the structural installation of a ceiling track hoist that saves a dedicated carer’s spine from permanent injury. It is the deployment of an infrared eye-gaze tracker that returns a lost voice to a trapped mind, and the simple utilisation of an electric, angled toothbrush that guards against aspiration pneumonia.Ultimately, caring for someone with advanced MS requires an unwavering commitment to human dignity, ensuring that despite physical limitations, the individual remains autonomous, comfortable, and firmly connected to the world around them.I assume I have left out a lot of the issues relevant to managing someone with advanced MS. If you have any additional questions, please ask or feel free to comment.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. 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I am sure many of you won’t want to know about the underbelly of living with advanced MS. As pwMS become more disabled, complications of being immobilised start to appear. The one that worries all HCPs working with patients who have MS is pressure sores or ulcers.Pressure ulcers remain a devastating clinical challenge encountered in the management of people with advanced MS. Pressure ulcers, pressure sores, bedsores, decubitus ulcers, or pressure injuries, are localised areas of cellular necrosis and tissue damage occurring in the skin and underlying soft tissues. They almost exclusively develop over bony prominences such as the sacrum, ischial tuberosities (hips), heels, and occiput (back of head). The following image from Wikipedia illustrates the most common sites for pressure ulcers. MS does not intrinsically or directly cause skin breakdown; however, motor and sensory loss, autonomic dysfunction, spasticity, and cognitive impairment associated with advanced MS are risk factors for pressure sores.The economic burden of pressure sores is very high and continues to escalate globally. In the UK, pressure ulcers rank among the top 10 harms in the NHS, affecting hundreds of thousands of patients annually. In 2004, pressure ulcers were estimated to cost the NHS between £1.4 billion and £2.4 billion per year, representing approximately 4% of total NHS expenditure at the time. More recent estimates indicate that the management of pressure ulcers costs the NHS over £3.8 million every single day. At an individual level, pressure ulcers diminish a patient’s health-related quality of life. The condition frequently confines individuals to strict bed rest, exacerbates social isolation, causes pain, and introduces the risk of life-threatening complications such as osteomyelitis and septicemia.I recall when I was a very junior neurology trainee looking after a young woman with MS and a large cavitation pressure ulcer over her sacrum. She spent more than 6 months on the ward having the pressure sore managed. Sadly, shortly after discharge, she developed recurrent septicaemia and passed away from infection. Whenever I see a patient with a pressure sore, I have flashbacks to my experience with this patient.The management of pressure ulcers within the MS population is complex and requires a multidisciplinary team to manage spasticity, pain and frequently immobility. Care pathways have shifted away from reactive wound care toward highly proactive, multidisciplinary prevention strategies integrated within frameworks like the National Wound Care Strategy Programme (NWCSP). The intersection of clinical care, patient safety, and legal accountability in the UK has transformed the reporting and management of severe pressure ulcers. Regulatory bodies, such as the Care Quality Commission (CQC), alongside legislative frameworks such as the Care Act 2014, have established notification and safeguarding protocols. These legal mechanisms are designed to determine whether severe tissue damage represents an unavoidable consequence of terminal clinical decline or a physical manifestation of systemic neglect and institutional failure. Yes, pressure sores are a notifiable condition under the NHS and must be investigated.Mechanisms of tissue failureThe aetiology of pressure ulcers in pwMS is multifactorial. The injury involves prolonged mechanical loading on soft tissues compressed between an external support surface—such as a mattress, wheelchair seat, or orthotic device—and an internal skeletal structure. The continuous pressure, friction, and shear forces are responsible for tissue injury. Under normal conditions, capillary closure pressure is approximately 32 mmHg. When external mechanical pressure exceeds this threshold for a sustained period, localised tissue perfusion is severely compromised. This results in hypoxia, the accumulation of metabolic waste products, and subsequent cellular necrosis. Vulnerable individuals lacking the capacity for spontaneous movement, irreversible ischaemic damage can commence in as little as 20 minutes.Shear forces represent a particularly insidious and destructive mechanism. Shearing occurs when the epidermal layer remains stationary against a support surface, anchored by friction, while the underlying skeletal structures and deep fascial layers shift or slide. This dynamic is frequently observed when a patient with poor core control slides down the incline of a hospital bed or assumes a slumped posture within a wheelchair. This parallel, opposing force severely distorts, stretches, and ultimately ruptures deep fascial blood vessels, initiating ischaemia from the deep muscle tissues outward toward the skin. This mechanism frequently results in suspected deep tissue injuries that cause massive subdermal necrosis while initially presenting only as intact, discoloured skin on the epidermal surface. Friction, conversely, acts directly on the epidermal layer. Functioning like sandpaper, friction physically strips away the protective stratum corneum during transfers or spasms, drastically lowering the tissue’s threshold for pressure-induced necrosis and exposing deeper layers to bacterial colonisation.While these mechanical forces are the direct forerunners of ulceration, the intrinsic neurological deficits imposed by MS render the tissues susceptible to injury, stripping away the body’s natural defensive mechanisms. Advanced MS is usually associated with paraparesis or quadriparesis, which is associated with a lack of spontaneous micro-movements and weight-shifting behaviours that healthy individuals continuously utilise to redistribute weight and permit capillary reperfusion during sitting or sleeping. At the same time, damage to the ascending sensory pathways results in significant hypoaesthesia or complete anaesthesia. The loss of protective pain feedback, which would normally alert the brain to impending tissue ischaemia and a change in posture, is reduced or lost in advanced MS.Spasticity (hypertonia), muscle spasms, and joint contractures alter resting posture, often forcing limbs into unnatural and asymmetrical positions, and create friction and shear forces as the patient’s body rubs against support surfaces during movement of spasms.Comorbid bladder and bowel dysfunction leads to frequent urinary and faecal incontinence. Prolonged exposure to moisture, along with bacterial and fungal overgrowth, macerates the epidermis. Moisture accelerates frictional damage and introduces the complicating factor of moisture-associated skin damage (MASD), which frequently co-occurs with pressure ulceration.Advanced MS is often accompanied by dysphagia, fatigue, and severe depression, all of which contribute to reduced caloric and protein intake. This leads to malnutrition and low albumin levels. Skin integrity is intrinsically linked to nutritional status; malnourished, hypoalbuminaemic tissues lack the amino acid substrates required for repair, collagen synthesis, and maintenance of interstitial oncotic pressure, resulting in oedema and diminished resistance to hypoxic stress.EpidemiologyPressure ulcers are a pervasive, escalating global health crisis, exacerbated by ageing populations, increasingly fragmented care networks, and the rising prevalence of complex chronic diseases. In the Global Burden of Disease (GBD) Study, report that the incident cases of pressure ulcers more than doubled from 1,142,594.8 in 1990 to 2,468,317.5 in 2021, and the resultant mortality attributed to pressure ulcers rose from 16,741.1 to 37,032.7 globally, and DALYs surged from 408,887.0 to 803,747.4 over the same period.Despite these increases in absolute burden driven by population growth and ageing, the age-standardised incidence rate (ASIR) decreased slightly, indicating that, while the total number of patients suffering is higher, the per-capita risk, when adjusted for age, has stabilised or marginally improved due to preventive measures.Sadly, the burden of pressure ulcers correlates with the socio-demographic index (SDI), with significantly higher burdens observed in elderly females and a rising incidence in elderly males. In a prospective cohort study of 185 pwMS without existing skin breakdown, the incidence rate of developing a new pressure ulcer was documented at 10.8% (20 patients) (see paper below). The development of pressure ulcers was not random; predictors of tissue failure included a history of previous stroke, being bed- or chair-bound, poor nutrition and urinary or faecal incontinence.In the UK, pressure ulcer prevalence in highly dependent populations ranges from 11 to 13%. However, when looking strictly at wheelchair users—who constitute a large and vulnerable proportion of patients with advanced MS—registry studies indicate varying prevalence rates heavily dependent on the underlying neurological pathology. Among young wheelchair users overall, 55% experience at least one pressure ulcer a decade post-injury or disease onset. Specifically within the MS sub-population of chronic wheelchair users, the cross-sectional prevalence of current pressure ulcers is estimated at 4%.Within intensive care units (ICUs) and orthopaedic surgical wards where MS patients may be admitted during severe disease relapses or for unrelated acute pathologies, incidence rates peak dramatically. General ICU prevalence averages 6.8%, with an incidence rate of 3.8%. Orthopaedic surgery wards have alarmingly high incidence rates of 18.5%, emphasising the danger of prolonged surgical immobilisation. The sacrum is overwhelmingly the most affected area, accounting for up to 68% of ulcers, followed closely by the heels, left and right trochanters, and ankles. When analysing severity across generalised hospital populations, stage 1 and stage 2 ulcers account for the vast majority (45% each), while severe stage 3 and stage 4 ulcers occur at 4% each.Clinical classification and staging systemsThe management and reporting of pressure ulcers in the UK rely on internationally validated classification frameworks. The clinical staging system is based on the depth of visible tissue destruction:* Stage 1: Non-blanchable erythema of intact skin. The skin remains unbroken, but localised discolouration, warmth, oedema, or induration is present. In darkly pigmented skin, this may appear as a distinct alteration in colour or tissue consistency rather than classic redness.* Stage 2: Partial-thickness skin loss involving the epidermis, dermis, or both. This presents clinically as a shallow, open ulcer with a red-pink wound bed, devoid of slough, or as an intact or ruptured serum-filled blister.* Stage 3: Full-thickness skin loss involving damage to or necrosis of subcutaneous fat. Bone, tendon, and muscle are not exposed. Slough may be present, but it does not obscure the depth of tissue loss. Undermining and tunnelling may occur.* Stage 4: Extensive, full-thickness tissue loss with exposed or directly palpable bone, cartilage, tendon, or muscle. Slough or eschar may be present on some parts of the wound bed, and osteomyelitis is a frequent complication.* Unstageable: Full-thickness tissue loss in which the base of the ulcer is completely covered by slough (yellow, tan, grey, green, or brown) or eschar (tan, brown, or black) in the wound bed. The true depth cannot be determined until the eschar is surgically or autolytically debrided.* Suspected deep tissue injury (DTI): A purple or maroon localised area of discoloured intact skin or a blood-filled blister due to damage of underlying soft tissue from pressure and shear. The area may be preceded by tissue that is painful, firm, mushy, boggy, or warmer or cooler than adjacent tissue. These injuries can progress rapidly, exposing additional layers of tissue, even with optimal treatment.Screening and risk stratification protocolsGiven the rapid onset of ischaemic tissue damage—and the consequences of progression—rigorous, routine screening protocols are important. The National Institute for Health and Care Excellence (NICE) provides guidelines (specifically NG220 for Multiple Sclerosis and CG179 for Pressure Ulcers) mandating aggressive risk assessment and proactive intervention for adults living with MS.NICE guideline NG220 explicitly dictates that healthcare providers must check patients with MS who have severely reduced mobility at every single clinical contact for areas at risk of pressure ulcers. Furthermore, any person with MS who utilises a wheelchair requires a formal clinical assessment specifically targeting pressure ulcer risk. This assessment must lead to the development and documentation of a personalised risk minimisation action plan, and the individual must be thoroughly informed of their risk status. Whenever a patient with MS is admitted to a hospital, secondary care facility, or tertiary care environment—regardless of the primary reason for their admission—their immediate need for pressure-relieving devices and procedures must be evaluated.Comprehensive screening goes beyond mere skin examination. The baseline assessment tools linked to NICE NG220 demand a holistic review utilising functional scales that quantify the total level of disability, such as the EDSS, the MSFC, the Cambridge MS basic score (CAMBS), or the functional assessment of MS (FAMS). Clinicians must also assess for factors that worsen spasticity, evaluate cognitive functions that might impair a patient’s ability to self-monitor, and review personal and social care needs, including the availability of community caregivers.Limitations of standardised scalesIn general clinical practice, standardised risk assessment tools such as the Norton Scale, Waterlow Scoring System, and the Braden Scale are utilised to quantify a patient’s vulnerability. These instruments aggregate sub-scores across domains, including sensory perception, skin moisture, physical activity, mobility, nutritional status, and friction and shear. However, clinical evidence and UK consensus guidelines caution against relying solely on these numeric scores for patients with MS. These standardised scales were primarily validated in geriatric populations and place heavy weight on chronological age. Consequently, a younger patient in their thirties or forties with advanced SPMS might automatically score as “low risk” due to their youth, despite possessing profound paraplegia, severe unrelenting spasticity, and complete pelvic sensory loss. Furthermore, tools such as the Waterlow score often omit or inadequately quantify the violent, repetitive shear forces generated by neurogenic spasms. Therefore, UK clinical guidelines expressly state that the assessment must be a holistic clinical evaluation that specifically takes into account the unique features of MS, rather than simply recording and relying on a generalised pressure ulcer risk score.Education and self-monitoringSecondary prevention through patient self-monitoring is important. Teaching pwMS or their caregivers to perform rigorous daily visual and tactile skin inspections is critical. Patients are instructed to routinely check pressure points—heels, knees, hips, buttocks, and elbows—for the primary clinical marker of impending tissue necrosis: non-blanchable erythema. They should be taught that reddened areas of skin over bony prominences should fade within minutes after pressure is removed; if the redness does not dissipate, irreversible ischemic injury may have commenced, requiring immediate intervention by a district nurse. Specific diagnostic screening questions used by community nurses and caregivers assess for sudden changes in mobility, reductions in fluid or caloric intake, recent acute illnesses (such as influenza), significant weight fluctuations, and critical changes in the level of muscle spasms, which often serve as an early warning sign of impending skin breakdown.Prevention and managementThe management of pressure ulcers in MS necessitates a coordinated, multidisciplinary team approach. Because the variables contributing to ulceration cross multiple physiological systems, isolated nursing care is insufficient. Effective management comprises MS specialist nurses, tissue viability nurses (TVNs), general practitioners, neurophysiotherapists, occupational therapists, dietitians, and dedicated wheelchair/seating specialists. The national wound care strategy programme (NWCSP) outlines clinical pathways requiring early risk identification to ensure rapid access to these varied specialities, optimising individual outcomes and preventing the costs associated with worsening pressure sore severity.Pressure ulcers cannot heal, regardless of topical interventions or surgical reconstruction, if the inciting physical forces remain present. It is therefore changing your posture. For seated patients with upper-body mobility, shifting weight slightly—such as rolling from cheek to cheek—every 20 minutes is strongly recommended to facilitate vital capillary reperfusion. Immobile patients confined to bed require strict turning schedules, traditionally executed every two hours, meticulously alternating between lateral, supine, and prone positions to redistribute mechanical load.Occupational therapists and tissue viability nurses can prescribe pressure-relieving equipment. This includes alternating pressure air mattresses, profiling beds, and customised gel-filled or customised moulded wheelchair cushions that expand the surface area over which the patient’s weight is distributed. The use of traditional “ring” or “doughnut” cushions is not recommended as they create a tourniquet effect, concentrating mechanical pressure on the surrounding tissues, occluding blood vessels, and paradoxically causing the exact pressure damage they are intended to prevent.Neurophysiotherapists will teach formal and informal caregivers how to transfer patients safely and, if necessary, how to use mechanical hoists, slide sheets, and transfer boards. Poor transfer techniques—such as manually dragging a patient across a bed—generate extreme friction and shear forces that rapidly strip the epidermal barrier and rupture deep vessels.Wound healing is a catabolic process demanding energy, amino acids, and micronutrients. Dietitians frequently prescribe high-protein supplements, zinc, and vitamin C to bolster collagen synthesis and immune function. Clinical vigilance is especially required during acute infections, influenza, or MS relapses, as the basal metabolic rate increases, often accompanied by frequent drops in appetite, which elevates the risk of rapid skin failure.Active wound careWhen a pressure ulcer develops despite preventative measures, treatment algorithms escalate concurrently with the stage of the ulcer:* Conservative management: For stage 1 and 2 ulcers, the clinical focus relies on offloading, optimising the wound microenvironment using advanced dressings (hydrocolloids, alginates, or foams), managing incontinence to prevent MASD, and preventing secondary bacterial colonisation.* Advanced therapeutic modalities: For complex, highly exudative stage 3 and 4 wounds, negative-pressure wound therapy (NPWT) is frequently used. NPWT applies controlled sub-atmospheric pressure to the wound bed via a sealed vacuum system. This continuously extracts infectious exudate, reduces localised interstitial oedema, physically draws the wound edges together, and subjects the tissue to micro-deformation, which potently stimulates angiogenesis and fibroblastic migration. Other advanced adjunctive therapies, including hyperbaric oxygen therapy (HBOT) to reverse tissue hypoxia and electrical stimulation to accelerate cellular proliferation, are also utilised in refractory cases.* Surgical reconstruction: In severe cases involving extensive necrosis, exposed bone, or confirmed osteomyelitis, surgical intervention becomes mandatory. This process requires radical excisional debridement of all non-viable and infected tissue, frequently including an ostectomy of the underlying bony prominence (e.g., an ischiectomy to remove the mechanical focal point), followed by defect closure using highly vascularized myocutaneous flaps (e.g., gluteus maximus, gracilis, or VY hamstring advancement flaps). However, surgical intervention in elderly or medically fragile MS patients carries substantial morbidity and mortality risks, including severe blood loss and flap failure.Spasticity managementThe definitive treatment and surgical closure of pressure ulcers in patients with MS is virtually impossible without the rigorous control of spasticity. Spasticity and pressure ulcers often exist in a self-perpetuating positive feedback loop. A developing pressure ulcer acts as an intense, continuous nociceptive stimulus. Because the descending inhibitory pathways from the brain are damaged in MS, this peripheral noxious stimulus triggers severe, exaggerated spinal reflex arcs, exacerbating hypertonia and precipitating violent muscle spasms. These uncontrolled spasms, in turn, generate massive friction and shear forces against the support surface, physically tearing newly formed healing granulation tissue and driving the ulcer deeper into the muscle bed.Surgical reconstruction of a pressure ulcer is destined for failure if post-operative spasticity is not aggressively managed. Muscle spasms make proper positioning of the limb to relieve tension on the suture line impossible. Uncontrolled hypertonia will rapidly cause mechanical tension across the surgical site, resulting in complete wound dehiscence, flap necrosis, and severe haemorrhage. Therefore, managing spasticity is not merely an adjunctive comfort measure; it is an absolute prerequisite to wound healing and surgical intervention.The management of MS-related spasticity follows a stepped-care approach:* Physical and non-pharmacological interventions: Daily stretching routines, hydrotherapy, cryotherapy (cooling), and the use of specialised orthotics are the first lines of defence to maintain viscoelastic properties of connective tissue and prevent permanent joint contractures.* Oral antispasmodics: Pharmacological therapy typically begins with muscle relaxants. Baclofen (a GABA-B receptor agonist) and tizanidine (a central alpha-2 adrenergic agonist) are the mainstays of treatment. Clonazepam, diazepam, dantrolene, and gabapentin are also used, though their systemic side effects—particularly severe sedation, cognitive blunting, and hepatotoxicity— limit their utility in fragile patients.* Focal chemodenervation: For localised, severe spasticity affecting specific muscle groups—such as severe hip adductor spasms that prevent perineal hygiene and drive shear forces on the medial femoral condyles—targeted injections of botulinum toxin type A (e.g., Botox, Dysport) can be used.* Intrathecal therapy: In severe, generalised spasticity that is completely refractory to maximum tolerated doses of oral medications, the surgical implantation of an intrathecal baclofen (ITB) pump can be life-changing. By delivering micro-doses of baclofen directly into the cerebrospinal fluid of the intrathecal space, the therapy bypasses the blood-brain barrier.* Surgical and chemical denervation (rhizotomy and intrathecal phenol) and tenotomy.Chemodenervation with Botox has largely replaced the need for rhizotomy or tenotomy for managing focal spasticity. Rhizotomy, or selective dorsal rhizotomy, manages focal spasticity by surgically disrupting the abnormal nerve signals that cause spasticity. During a selective dorsal rhizotomy, the surgeon leaves the so-called ventral (motor) roots intact so the patient does not lose the ability to move the muscle. Instead, they cut the dorsal (sensory) roots. The surgeon selectively cuts (sections) only the abnormal rootlets—often severing between 30% to 60% of them in the targeted area. The healthy rootlets are left alone. By reducing the amount of sensory input travelling from the muscle to the spinal cord, the reflex arc is dampened. The spinal cord stops sending excessive contraction commands to the muscle, effectively reducing the focal spasticity while preserving motor function and sensation.Because selective dorsal rhizotomy permanently removes the faulty sensory pathways, it is one of the few treatments that can offer a permanent reduction in spasticity. It often leads to improved range of motion, easier positioning, better gait (walking), and reduced painful muscle spasms.Another strategy is chemical rhizotomy using phenol. Intrathecal phenol can manage focal spasticity through chemical neurolysis (also called a chemical rhizotomy). Instead of surgically cutting the nerves, this procedure uses a strong chemical agent to intentionally damage and disable the specific spinal nerves causing the severe muscle tightness. Phenol is a chemical neurotoxin. When injected into the intrathecal space (the fluid-filled sac surrounding the spinal cord), it acts rapidly to denature (break down) the proteins in the nerve fibres. It strips away myelin and damages nerve axons. By chemically destroying the nerve roots that communicate with the spastic muscles, phenol completely blocks the hyperactive signals from firing, thereby relaxing the muscle.You might wonder how an injection into the spinal fluid targets a focal (specific) area rather than paralysing the entire body. The secret lies in gravity and physics. Phenol is typically mixed with glycerin. This makes the solution “hyperbaric,” meaning it is heavier and denser than the surrounding cerebrospinal fluid (CSF). Because the solution is heavy, it sinks. During the procedure, the doctor places the patient on an X-ray or fluoroscopy table and tilts the patient’s body to very specific angles. Gravity causes the heavy phenol to flow downward and pool exactly over the targeted nerve roots (usually those controlling the legs or pelvis). The doctor leaves the patient in this tilted position for about 30 to 45 minutes to allow the phenol to “fix” to those specific nerves without spreading to healthy ones.It is important to note that intrathecal phenol is a highly destructive and non-selective procedure. While selective dorsal rhizotomy carefully cuts only the sensory nerves to preserve the patient’s ability to move the muscle, phenol generally destroys both sensory and motor nerves in the area it touches. As a result, intrathecal phenol causes muscle weakness or paralysis and loss of sensation in the targeted area. Because it causes paralysis in the targeted muscles, intrathecal phenol is almost exclusively reserved for non-ambulatory patients (those who cannot walk) who have lost bowel and bladder function. In these cases, preserving motor function is no longer the primary goal. Instead, the phenol injection is used to relieve pain from chronic muscle spasms, prevent severe joint contractures, and improve the patient’s quality of life by making nursing care, hygiene, dressing, and wheelchair positioning significantly easier and more comfortable. The effects of phenol are often long-lasting (several months to years), though spasticity can sometimes return as the damaged nerves slowly regenerate.Finally, tenotomy (tendon release) is an effective tool for managing the severe physical consequences of focal spasticity. Unlike a rhizotomy or phenol injection, which try to turn off the misfiring nerve signals, a tenotomy completely ignores the nervous system. It accepts that the muscle will continue to spasm and instead removes its ability to pull on the bones. During the procedure, a surgeon makes an incision and completely severs the tendon that attaches the spastic, contracted muscle to the bone. Because the tendon is under immense tension from the spastic muscle, severing it causes the two ends of the cut tendon to immediately snap apart, instantly releasing the tension on the joint. The muscle may still receive hyperactive signals from the damaged nervous system, leading it to continue contracting and spasm. However, because its mechanical anchor to the bone has been severed, that muscle no longer moves the joint or causes painful stretching. While tendon lengthening tries to preserve the patient’s ability to use the muscle, a complete tenotomy sacrifices the function of that specific muscle-tendon unit. Therefore, it is typically chosen when restoring normal movement is not the primary goal.Tenotomy is recommended for severe, fixed contractures when a joint has been locked in place for so long that tendon lengthening is no longer physically possible. It is also done to prevent joint dislocation: Severe spasticity in the inner thigh muscles (adductors) can slowly pull the hip bone completely out of its socket. An adductor tenotomy releases this pull, keeping the hip joint safely in place. For non-ambulatory patients, severe spasticity can cause constant pain and make dressing, bathing, and sitting in a wheelchair incredibly difficult. Releasing the tendons allows the limbs to lie flat and relaxed, drastically improving daily comfort and care.By sacrificing the mechanical connection of a problematic muscle, a tenotomy can prevent permanent joint damage and provide immediate relief to a localised area.Pain managementPain management in MS is often complex due to the presence of overlapping pain aetiologies. PwMS suffering from pressure ulcers routinely experience interacting neuropathic and nociceptive pain mechanisms, requiring targeted, multidimensional pharmacological strategies. Central neuropathic pain arises directly from damage to the brain and spinal cord; this pain is independent of external tissue damage. It is classically described as burning, shooting, tingling, or electric-shock-like. Because the neural pathways themselves are physically damaged or malfunctioning, this pain tends to be chronic, frequently worsens at night, and responds poorly to traditional nociceptive analgesics like NSAIDs or paracetamol. In comparison, nociceptive pain tends to be acute, arising directly from non-neuronal tissue destruction, such as the ischemic necrosis of the pressure ulcer itself, or the severe musculoskeletal strain and joint subluxation caused by unrelenting spasticity. It is mediated by intact, functioning peripheral nociceptors communicating the presence of tissue damage to the CNS.Finally, nociplastic pain or hyperpathia is characterised by altered, amplified pain processing and central sensitisation in the absence of demonstrable new tissue damage. This diffuse, chronic pain amplifies the perception of both neuropathic and nociceptive stimuli, making routine preventative interventions—such as physical therapy, exercise, or simple repositioning by nursing staff—excruciatingly painful and difficult to tolerate.Because a pressure ulcer serves as a continuous nociceptive driver that can amplify both central neuropathic pain and spasticity, silencing these pain signals is crucial for psychological well-being. However, conventional opioid narcotics are highly controversial, and their use is generally minimised. While opioids offer short-term nociceptive relief, they carry high risks of severe sedation, respiratory depression, and constipation. Opioid-induced constipation exacerbates neurogenic bowel dysfunction, increasing the risk of faecal impaction, overflow incontinence, and the subsequent bacterial contamination of the pressure ulcer. Instead, clinical management relies heavily on adjuvant analgesics that directly modulate nerve transmission. These include gabapentin, pregabalin and carbamazepine or oxcarbazepine, which are preferred for sharp, paroxysmal neuralgic-type pain.Antidepressants, in particular tricyclic antidepressants (TCAs) like amitriptyline, or serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine, can be effective. They enhance the descending inhibitory pain pathways by increasing synaptic concentrations of serotonin and noradrenaline, providing dual relief for chronic neuropathic pain and can help with comorbid depression that frequently accompanies chronic pressure sores.Occasionally, cannabinoid receptor agonists (THC and nabilone) can be tried not only for their analgesic properties against treatment-resistant neuropathic pain but also for their adjunctive anti-spasticity effects, offering a dual-mechanism approach to the pain-spasm cycle.Non-pharmacological treatments, including transcutaneous electrical nerve stimulation (TENS), targeted physiotherapy, massage, and psychological interventions (such as cognitive-behavioural therapy), are used concurrently to help counteract psychological distress, fear, and anxiety associated with chronic pain and tissue loss.UK regulationUnder the Health and Social Care Act 2008 (Regulated Activities) Regulations 2014, service providers and registered managers are legally bound to notify the Care Quality Commission of specific adverse events that threaten patient safety. Regulation 18 explicitly targets the development of severe pressure ulcers. Under this regulation, providers must formally report the development of any pressure sore of Grade 3 or above that develops after the patient has been admitted to the facility or has started utilising the provider’s service.The regulatory rationale classifies a Grade 3 or Grade 4 ulcer as a “serious injury.” To meet the threshold of a legally notifiable injury under this specific regulation, a healthcare professional must reasonably opine that the ulcer has resulted in:* Changes to the fundamental structure of the service user’s body.* An impairment of sensory, motor, or intellectual functions that is not likely to be temporary (defined explicitly as lasting, or likely to last, for a continuous period of more than 28 days).* The service user is experiencing prolonged pain or prolonged psychological harm (again, defined as lasting for at least 28 days).* A direct shortening of the life expectancy of the service user.Crucially, the Care Quality Commission views compliance with these notifications as foundational to good governance. The CQC holds the statutory authority to move directly to criminal prosecution for breaches of these regulations if a provider fails to notify the commission “without delay,” or if the provider fails to demonstrate safe care and treatment (Regulation 12) resulting in avoidable harm.In parallel with statutory CQC notifications, NHS England requires the meticulous, continuous logging of patient safety events through the National Reporting and Learning System (NRLS) and its successor, the Learn from Patient Safety Events (LFPSE) service. This framework mandates that pressure ulcers must be recorded regardless of their origin of acquisition. If a pwMS is admitted to an acute hospital with a pressure ulcer acquired in a community nursing home setting, the admitting hospital must still log the incident, clearly noting that it was present on admission, and transfer “ownership” of the record to the previous provider. This ensures unbroken epidemiological tracking across the entire health system and prevents critical incidents from falling through the gaps between community and acute care transfers.The classification of harm within these systems has evolved significantly. Categories of pressure ulcers are no longer rigidly linked to preset degrees of harm (i.e., automatically categorising all Category 3 ulcers as “severe harm”). Instead, the actual clinical harm experienced by the patient dictates the classification, which ranges from no harm to death.Historically, the UK utilised the Serious Incident (SI) Framework, under which organisations often automatically reported and investigated all Category 3 and Category 4 pressure ulcers via exhaustive root cause analysis (RCA). However, this automatic, reactive escalation proved administratively burdensome and counterproductive to patient care. The immense burden of conducting deep, time-consuming investigations into every severe ulcer—especially in patients with advanced MS where skin failure may physiologically occur despite perfect, flawless preventative care—diverted specialised tissue viability nurses away from active clinical management and into bureaucratic investigation roles.In response, NHS England introduced the Patient Safety Incident Response Framework (PSIRF) in 2022. PSIRF represents a massive cultural and operational paradigm shift from mandatory, exhaustive investigations based on arbitrary harm thresholds to a highly proportionate, systems-based approach. Under PSIRF, organisations are no longer required to conduct extensive RCAs for all Category 3 and 4 ulcers if routine preventive measures and risk assessments are clearly documented. Instead, resources are strategically focused on analysing systemic clusters of incidents, explicit failures in the clinical pathway, or novel equipment failures, thereby accelerating actual systemic learning without overwhelming the frontline clinical workforce.While clinical reporting mechanisms like LFPSE and PSIRF focus on systemic improvement and learning, the UK legal framework recognises a darker reality: the presence of a severe pressure ulcer can also be a physical manifestation of abuse, neglect, or profound institutional failure. Under the Care Act 2014, safeguarding adults is a statutory duty designed to help and protect individuals with care and support needs who are experiencing, or are at risk of, abuse and neglect, and are unable to protect themselves due to those specific needs.In the context of tissue viability, neglect is defined as the deliberate withholding or the unintentional failure of a caregiver (whether a paid professional or an unpaid family member) to provide appropriate and adequate care. This encompasses a wide range of omissions, including ignoring clear physical care needs, failing to execute a mandated turning schedule for an immobile patient, withholding necessary pressure-relieving equipment, or failing to seek medical escalation when a Grade 1 ulcer is first noted, allowing it to deteriorate into a necrotic Category 4 wound. However, the Care Act 2014 explicitly clarifies that concerns regarding the general quality of a clinical service are not automatically safeguarding concerns under Section 42 of the Act. Historically, treating all severe ulcers as immediate safeguarding alerts resulted in a massive, unmanageable influx of referrals—with retrospective analysis showing that only approximately 20% actually required a full safeguarding investigation—threatening to completely paralyse local authority safeguarding teams and damaging relationships with clinical providers.To rationally navigate the complex interface between clinical complications and true abuse, the Department of Health and Social Care, in partnership with the National Wound Care Strategy Programme, implemented a standardised National Safeguarding Protocol for pressure ulcers. When a severe pressure ulcer is identified, and neglect is suspected, an independent, practising registered nurse with specific wound care expertise—who was not directly involved in the patient’s immediate care at the time the ulcer developed—must complete the Adult Safeguarding Decision Guide within 48 hours of the ulcer’s identification.This rigorous decision guide utilises a weighted scoring system based on six critical assessment domains 12:* Clinical deterioration: Tracking the speed of tissue breakdown, specifically if the skin deteriorated rapidly from healthy tissue to Category 3 or 4 since the last clinical visit.* Clinical condition: Evaluating whether recent systemic changes (e.g., severe MS relapse, acute systemic infection, end-of-life status) logically contributed to unavoidable tissue damage.* Care planning: Assessing whether a documented, appropriate risk assessment and prevention care plan was actively in place and adhered to.* Carer conduct: Identifying if an informal or formal caregiver willfully ignored needs, prevented access to health services, or refused to allow community nurses entry into the home.* Consistency: Determining if the severity and location of the tissue damage are disproportionate or inconsistent with the patient’s previously assessed risk status.* Consent and mental capacity: Investigating if a patient with full mental capacity actively refused life-saving interventions (such as turning or hoisting), or if care was delivered appropriately in the “best interests” of a patient lacking capacity under the Mental Capacity Act 2005.A cumulative score of 15 or above on this guide, or severe overriding concerns raised through the independent nurse’s professional judgment, automatically triggers a formal safeguarding concern referral to the local authority’s adult safeguarding team. Accompanying this referral must be a detailed Body Map recording the exact anatomical site, dimensions (length, width, depth), and tissue typing of the ulcer, alongside photographic evidence obtained with appropriate sensitivity and legal consent.Crucially, modern safeguarding protocols mandate a physiological distinction between systemic neglect and terminal, inevitable physiological decline. In advanced, end-stage MS, as the body begins to shut down, patients may experience Skin Changes at Life’s End (SCALE).14 SCALE recognises that during the active dying process, profound multi-organ hypoperfusion occurs. Blood is shunted away from the skin to preserve vital organs, making the skin and subcutaneous tissues inherently unstable and highly susceptible to ischemic death. In these specific physiological conditions, pressure ulcers become physiologically unavoidable despite optimal, flawless, intensive nursing care and the use of the highest specification support surfaces. If a post-incident review utilising the safeguarding framework determines that absolutely no omissions in care occurred and the rapid tissue damage is consistent with SCALE, the tissue damage is removed from punitive incident reporting systems. This vital distinction acknowledges that in the final stages of a devastating neurological disease, the clinical focus must shift entirely to palliative comfort, pain reduction, and dignity, rather than aggressive, medically futile preventative interventions that cause the patient distress.SummaryWhen I started working in neurology over 30 years ago, I recall always having at least one or two patients on the neurology ward with pressure ulcers. Thankfully, this is now uncommon and typically occurs in the terminal phases of the disease. It has become rare because we now manage people with advanced MS much better than we used to in the past. This has been aided by technological innovations to prevent pressure sores (better chairs, mattresses, and beds) and by legislation protecting people with disabilities. The legislation has made nursing staff much more aware of the problem and the need for preventing pressure sores. I want to stress that patient education and self-monitoring have also played an important role.I would be interested to know whether any of you have developed pressure ulcers and, if so, the context in which they occurred. How were they managed, and did they require surgical intervention?If you think you are at risk of pressure sores and want more information, please contact your HCPs and get advice. Preventing pressure sores is far better than managing them.Apologies for the length of the newsletter, but I need to balance the need to provide information with creating a comprehensive resource for pwMS. This newsletter will be transferred to the MS-Selfie microsite and will form a chapter in the MS-Selfie self-management guide. Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

If you have multiple sclerosis (MS) and are on chronic immunosuppression, you need to check your medical records to make sure you have had the measles vaccine as a child. Due to vaccine hesitancy, MMR (measles, mumps, and rubella) vaccine uptake has dropped considerably since the late 90’s and noughties. As a result, many countries now have both endemic and epidemic levels of measles infections. This is clearly very worrying. The bad news is that the World Health Organisation (WHO) has stated that the UK is no longer considered to have eliminated measles. The WHO has said measles transmission was re-established in the UK in 2024, following a plateau in vaccination coverage and a surge in cases. A total of 3681 measles cases were recorded in England in 2024. This will underestimate the true incidence of measles, as these figures rely on accurate diagnoses and on cases being reported to the Health Security Agency. Now, let's say you are a person with MS who did not have the MMR vaccine because your parents were worried about the safety of the MMR vaccine. You would now be vulnerable to getting infected as an adult. In the past, you could have relied on herd immunity, i.e. all the people around you who had the vaccine and are immune to measles would prevent the virus from spreading in the community and protect you. Unfortunately, herd immunity is simply not good enough. The latest figures from the UK’s Health Security Agency for England show that in 2024-2025, 91.9% of five-year-olds had received one dose of the MMR vaccine, which is largely unchanged from 2023-2024 and the lowest level since 2010-2011. Just 83.7% of 5-year-olds had received both MMR doses, down year-on-year from 83.9% and the lowest level since 2009-2010. The WHO recommends that at least 95% of children receive each vaccine to achieve herd immunity.My worry is that people with MS will get measles, and because they are on an immunosuppressive therapy, will get complications, in particular encephalitis.Measles encephalitisMeasles encephalitis is a serious complication of the measles virus infection that often leads to permanent brain damage or death. While measles is often thought of as a respiratory illness with a rash, the virus can infect the central nervous system. This complication occurs in approximately 1 in every 1,000 people who get measles, but it is much more common in people who are immunocompromised.Acute measles encephalitis usually occurs during or shortly after the initial infection (often whilst the rash is still present). It is often caused by the immune system attacking the brain (an autoimmune reaction) rather than the virus directly attacking brain tissue, though direct viral invasion also happens. It is associated with a high fever, headache, stiff neck, vomiting, drowsiness, seizures, and coma. It typically begins about 6 days after the rash onset. The mortality rate is approximately 10–15%. Among survivors, about 25% suffer permanent neurological damage, such as intellectual disability, seizures, or deafness.Subacute Sclerosing Panencephalitis (SSPE) is a rare, chronic, and fatal form of measles encephalitis. It is caused by a persistent measles virus infection in the brain that reactivates years later. It typically develops 7 to 10 years after the person has recovered from the initial measles infection. It starts with subtle behavioural changes and memory loss, progressing to muscle spasms (myoclonus), seizures, and eventually a vegetative state. It occurs in roughly 1 in 10,000 to 1 in 100,000 people who had measles, but the risk is higher for those infected with measles before the age of two.Measles inclusion body encephalitis (MIBE) is a specific form found in people with compromised immune systems (e.g., those with HIV, organ transplants or on immunosuppressive treatments). It usually occurs a few months after the initial measles infection. It is usually fatal, with death often occurring within weeks of symptom onset.There is no specific antiviral treatment for these forms of measles encephalitis once they have begun; healthcare professionals can only provide supportive care (hydration, seizure management, etc.) to help the body fight the infection. Therefore, the only effective protection is prevention via the MMR vaccine. The vaccine prevents the initial measles infection, thereby eliminating the risk of these neurological complications.It is only a matter of time before a person with MS who has not received the MMR vaccine gets measles and one of the forms of measles encephalitis. I am particularly concerned about pwMS on natalizumab who will get a subacute infectious syndrome that may mimic PML or a prion disease such as Creutzfeldt-Jakob disease. PwMS on anti-CD20 therapies and S1P modulators are also at risk. PwMS treated with immune reconstitution therapies and have reconstituted their immune systems should be okay, as they can mount an immune response to the virus.Measles hyperimmune immunoglobulin (or human normal immunoglobulin - HNIG) is used as post-exposure prophylaxis (PEP) for susceptible individuals at high risk of severe complications from measles. It provides immediate, temporary antibodies and is recommended when the MMR vaccine cannot be used or when exposure has occurred in highly vulnerable people. The eligible groups for immunoglobulin (HNIG/IVIG) are individuals who have had significant exposure to a confirmed case of measles, are not immune (no history of 2 doses of vaccine or measles disease), and are within the 6-day exposure window. This includes infants under 1 year of age, pregnant women and immunocompromised individuals (e.g., bone marrow transplant recipients, HIV/AIDS patients, those on high-dose immunosuppressive therapy). IVIG is usually recommended for immunosuppressed individuals, while intramuscular HNIG is used for pregnant women and infants. For maximum effectiveness, immunoglobulin should be administered as soon as possible after exposure, ideally within 72 hours, but it can be given up to 6 days after exposure. It is typically administered via intramuscular injection or intravenously.HNIG/IVIG is not a replacement for vaccination. Individuals who receive HNIG/IVIG must still receive the MMR vaccine once they are no longer immunocompromised, ideally at least 6–8 months after the immunoglobulin injection. The latter is to wait for the anti-measles IgG from HNIG/IVIG to be cleared from the body, so it won’t neutralise the vaccine.Please note that, on the NHS, approval for measles immunoglobulin treatment is generally provided by a consultant in health protection or a virologist, not by a neurologist. The latter can delay things. I speak from personal experience as I have had one patient on anti-CD20 therapy who has a large family, and none of his children have had the MMR vaccine. The reasons for not vaccinating his children are complex and related to religion and vaccine scepticism. However, when one of his children developed measles, we had to activate this pathway. Thankfully, urgent MMR serology showed he must have had the vaccine as a child. He was not born in the UK and had no documentation of his vaccine status.Please note that it is now part of our standard practice to check all patients’ MMR status before starting chronic immunosuppressive therapy. Since starting this practice, we have identified a small number of people who have been MMR negative who have then had to have the MMR vaccine prior to initiating treatment. The problem is that once you are on an immunosuppressive therapy, you can’t have the vaccine, as it is a live vaccine. This is one of the arguments in favour of IRTs (immune reconstitution therapies) for treating MS. Once your immune system has reconstituted after cladribine, alemtuzumab or AHSCT, live vaccines are relatively safe and not contraindicated.Do you know your MMR status? If not, you may want to know particularly if you are about to start an immunosuppressive therapy. At the same time, please be vigilant for measles in your area, and if you come into contact with someone with measles, let your HCP know.Have any of you not had the MMR vaccine? Have you recently come into contact with someone with measles?Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

In response to comments from yesterday’s podcast and newsletter, I have prepared a more detailed analysis of the issues supporting gender-specific MS services. I hope this clarifies things better. Historically, the clinical and epidemiological descriptions of MS have stressed differences between women and men with MS. This is often referred to as sexual dimorphism. MS is a disease that disproportionately affects women, with current prevalence estimates indicating a female-to-male ratio of approximately 3:1. This ratio has widened over the past century, largely attributed to environmental shifts—such as smoking, obesity, and vitamin D deficiency—that appear to impact female susceptibility more than male susceptibility. However, these changes in risk factors only explain a small proportion of the increased incidence and prevalence of MS in women. Consequently, the “typical” MS patient is often conceptualised as a young woman of childbearing age. This ‘heuristic’ has fundamentally shaped the design of clinical services, support networks, and therapeutic monitoring protocols in clinical practice.However, this statistical predominance masks clinical reality: while women are more susceptible to acquiring the disease, men often experience a more severe, rapid, and neurodegenerative course. The “male paradox” in MS—lower susceptibility but higher severity—challenges the uniform application of clinical guidelines. Standardised care pathways, such as those outlined by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Academy of Neurology (AAN), largely advocate a generalised approach to pharmacological management and symptom monitoring, with sex-based differentiation primarily in reproductive safety.I think it is time to challenge the “one-size-fits-all” model. There is data on genetic, hormonal, and immunological differences that warrant this. Alongside clinical registry data and emerging clinical pilots suggest that the care of women and men with MS differs sufficiently to warrant distinct service based on gender. Biological sex is not merely a demographic variable but a biological determinant of disease pathology, necessitating a shift from gender-neutral to gender-responsive care. This could be part of precision medicine, i.e., tailoring care to the individual.Biological determinantsTo determine whether clinical care pathways should diverge, one must first establish whether the underlying biological substrates of the disease differ significantly between the sexes.While the HLA complex remains the main genetic risk locus for both sexes, sex-specific genetic factors modulate this risk. The “Four Core Genotypes” (FCG) mouse model aims to disentangle the effects of sex chromosomes from those of sex hormones. Utilising this model indicates that the sex chromosome exerts an independent effect on neurodegeneration; i.e., the presence of an XY chromosomal complement is associated with greater clinical severity and increased neuropathology compared to an XX complement, even when hormonal environments are controlled. This indicates that males may possess an intrinsic genetic vulnerability to neurodegenerative processes.Specific gene polymorphisms exhibit sex-dependent risk profiles. An example is the galanin gene (GAL), which codes for a neuropeptide widely expressed in the brain and spinal cord. Variants in the GAL gene have been associated with MS susceptibility and delayed onset specifically in men, whereas in women these variants appear to influence disease progression rather than susceptibility. This implies that the genetic “motor” driving disease onset in men may differ from that in women. Whether different therapeutic targets are needed in men remains to be determined.Neuroendocrine factors: oestrogens vs. androgensSex hormones—oestrogens and progestogens in females, and androgens in males—are immunomodulators that influence the blood-brain barrier (BBB) permeability, immune cell differentiation, and remyelination efficiency. Women possess a more robust adaptive immune system than men, characterised by stronger humoral (antibody-mediated) and Th1 (pro-inflammatory) responses. This evolutionary trait, while beneficial for fighting infection, may lower the threshold for developing autoimmune disease. Oestrogens typically enhance immune reactivity, which may contribute to the higher incidence of relapsing-remitting MS (RRMS) in women.However, the role of oestrogens is biphasic and dose-dependent. At physiological levels present during the menstrual cycle, oestrogens may facilitate inflammation. Conversely, at the high concentrations observed during pregnancy (particularly oestriol), they exert immunosuppressive and neuroprotective effects, which are believed to be responsible for inducing temporary remission. In comparison, the postpartum period represents a withdrawal of this protection, leading to a rebound in relapse rates. The cessation of ovarian function at menopause is associated with an acceleration of disability accumulation, suggesting that oestrogens provide a “neuroprotective buffer” that delays the onset of secondary progression.Testosterone acts as a natural immunosuppressant, suppressing Th1 differentiation and promoting a shift toward the anti-inflammatory Th2 phenotype. This mechanism may protect many men from developing MS. However, once the disease is established, men face a more rapid decline, which may be due to a failure of androgen-mediated repair.Men with MS frequently exhibit lower testosterone levels than age-matched healthy controls. This hypogonadal state is not merely a comorbidity but appears to be a driver of pathology. Testosterone is essential for maintaining muscle mass, cognitive function, and synaptic plasticity. In the context of MS, low testosterone correlates with increased cognitive fatigue, reduced grey matter volume, and poorer functional outcomes. The vulnerability of male oligodendrocytes to oxidative stress and excitotoxicity, combined with lower levels of neuroprotective androgens, creates an environment for rapid neurodegeneration.NeuropathologyWhile women tend to exhibit a disease course dominated by peripheral inflammation (relapses and gadolinium-enhancing lesions) during their reproductive years, men exhibit a predominance of neurodegenerative markers earlier in the disease course. Male patients accumulate “smouldering” or chronic active lesions—characterised by iron-laden rims of activated microglia—at a higher rate than women.MRI studies demonstrate that men exhibit more rapid whole-brain and grey-matter atrophy, particularly in deep grey-matter structures such as the thalamus and cortex. This correlates with the faster cognitive decline observed in male cohorts.Animal models suggest that remyelination efficiency is superior in females, potentially due to oestrogen’s influence on oligodendrocyte precursor cells. Male oligodendrocytes appear more vulnerable to metabolic stress, leading to permanent axonal loss rather than repair.Prognostic disparitiesMen are typically diagnosed at a later age than women and are significantly more likely to present with primary progressive MS (PPMS). Registry data indicate that while relapsing-remitting MS (RRMS) is the most common form for both sexes, the proportion of men with PPMS is significantly higher (approximately 22% vs. 8% in women). Even among those with relapse-onset disease, men convert to secondary progressive MS (SPMS) at a younger age and after a shorter disease duration than women.4This diagnostic latency in men is multifactorial. Biologically, the higher threshold for inflammatory symptoms (relapses) in men may mask the disease until structural damage reaches a critical threshold. The perception of MS as a “woman’s disease” may delay clinical suspicion in men presenting with non-specific motor or cognitive symptoms, leading to diagnostic delays. Natural history studies confirm that male sex is an independent predictor of poor prognosis. Interestingly, the sex difference in relapse rates disappears after age 50—roughly the age of menopause.ComorbiditiesThe comorbidity profile also differs, with some comorbidities affecting survival and disability differently. Men with MS have higher rates of cardiovascular and metabolic comorbidities, including diabetes, hypertension, and ischemic heart disease. These conditions act synergistically with MS pathology. Hypertension and diabetes impair microvascular perfusion in the CNS, reducing the metabolic reserve of neurons already under attack by the immune system. This double hit accelerates brain atrophy and disability worsening in men. Conversely, women with MS report higher rates of other autoimmune conditions (e.g., thyroid disease, psoriasis) and anxiety/depression. While these impact quality of life, they do not typically accelerate neurodegeneration at the same rate as vascular comorbidities.Mortality and suicide riskMortality risks also differ significantly. While MS reduces life expectancy for all patients, the standardised mortality ratio (SMR) and suicide risk show profound gender imbalance. Men with MS have a higher rate of completed suicide compared to women, despite women reporting higher rates of suicidal ideation and attempts. This is likely due to the suicide methods chosen by men and the psychological strain of physical dependency, which conflicts with traditional masculine roles. The loss of physical autonomy strikes at the core of the male provider/protector role, creating a distinct psychological crisis for men that general depression screenings may not capture.CaregiversThe experience of MS is not merely biological; it is also sociological. Gender norms influence how patients perceive their illness, how they seek help, and how their caregivers are burdened. Men with MS often face a crisis of masculinity. Traditional gender norms prioritise strength, independence, and emotional stoicism. MS, by its nature, enforces dependency and physical frailty. Research indicates that men are less likely to seek help, report symptoms later, and are less apt to adhere to treatment regimens compared to women. Men often minimise symptoms during clinical consultations to appear “strong” or to reassure their clinicians. This behaviour leads to the under-recognition of invisible symptoms like fatigue, depression, and sexual dysfunction. Men are significantly less likely to attend traditional support groups, which are often dominated by women and focus on emotional sharing. Studies suggest that men prefer action-oriented interventions—such as mentoring, physical reconditioning, or educational workshops—that allow them to retain a sense of agency and masculinity.The burden of MS caregiving also splits along gender lines, creating distinct support needs for the partners of people with MS. Men caring for female partners often adopt a “stoic” approach, focusing on instrumental tasks (finances, logistics) while suppressing emotional distress. They are less likely to seek social support and may mask their burden until burnout occurs. Their mental health is strongly tied to their perception of “burden,” yet they receive few targeted interventions.Women caring for male partners report lower mental health scores and higher overall burdens. This is partially explained by the intensity of care: female caregivers provide nearly twice as many hours of care per week (approx. 79 hours vs. 48 hours for men) and continue caregiving for longer durations. The physical demands of caring for a male partner (who may be larger and heavier) add physical strain, necessitating different support equipment and respite care services.The gender-blind care modelDespite the overwhelming evidence of biological and clinical differences, current clinical practice guidelines remain largely gender-neutral regarding disease-modifying therapy (DMT) selection, monitoring, and holistic support.The ECTRIMS/EAN and AAN guidelines provide recommendations for DMT usage based on disease activity (relapses and MRI activity). However, they do not stratify treatment algorithms by sex, except in the specific context of pregnancy and breastfeeding. The “Optimal Clinical Care Pathway” developed by the National Neurosciences Advisory Group (NNAG) emphasises timely diagnosis (within 12 weeks) and multidisciplinary team (MDT) access but does not specify distinct monitoring intervals or therapeutic targets for men versus women.This neutrality assumes that DMTs work equally well in both sexes. However, post-hoc analyses of clinical trials suggest nuances. For instance, some data indicate that the efficacy of Interferon-beta may be linked to different cytokine pathways in men (IFN-gamma) versus women (IL-6). Furthermore, adherence patterns differ significantly, with men often exhibiting lower adherence to injectable therapies and a higher discontinuation rate due to perceived lack of efficacy or side effects.Gaps in integrated care modelsThe current integrated care model focuses on coordinating services across neurology, rehabilitation, and primary care. While effective for general management, it fails to address gender-specific needs, resulting in significant gaps. Routine MS care rarely screens for hypogonadism (low testosterone) or prioritises erectile dysfunction (ED) as a primary medical concern, often delegating it to quality of life issues rather than viewing it as a symptom of neurogenic failure.While pregnancy is well-managed, the menopausal transition is often overlooked. Symptoms of menopause (hot flashes, brain fog, fatigue) overlap with MS, leading to diagnostic confusion and potential mismanagement of DMTs during this window. There is often a lack of clarity on the safety of hormone replacement therapy (HRT) in women with MS.Men are significantly less adherent to DMTs, often due to forgetfulness or a lack of perceived benefit. Women, conversely, are more proactive but face challenges with polypharmacy and side effect management. Uniform education strategies fail to address these distinct behavioural differences.Women-specific care pathwaysThe argument for separate services for women is more advanced, driven by the sheer volume of female patients, the management of reproductive issues and the menopause. However, evidence suggests this pathway needs to expand beyond obstetrics and gynaecology to encompass the full life course.This is the only area where a distinct pathway currently exists. Pre-conception counselling, DMT washout periods, and postpartum monitoring are standard practice. However, data indicate that even this is inconsistent, with variations in washout protocols and breastfeeding support. A formalised “Women’s Health in MS” pathway would try to standardise these protocols, ensuring that women on high-efficacy therapies can time pregnancies safely without risking rebound relapses.Emerging evidence identifies menopause as a critical window of vulnerabilityfor women with MS. The decline in oestrogen is associated with increased disability progression and subjective worsening of symptoms. Studies show that after menopause, women experience a measurable decline in walking speed and dexterity, alongside increases in neurofilament light chain (NfL) levels, a biomarker of neuroaxonal damage.Pilot clinics integrating gynaecological and neurological care have shown promise. These clinics help differentiate between hypo-oestrogenic symptoms and MS relapse, optimising the use of hormone replacement therapy (HRT), which is not contraindicated and may offer neuroprotective benefits. For example, a dedicated pathway would include routine screening for perimenopausal symptoms starting at age 45 to distinguish “brain fog” from MS cognitive decline. Frequent monitoring of bone density using DEXA scans, given the compounded risk of osteoporosis from corticosteroids, mobility loss, and menopause. The latter would include expert guidance on the interaction between HRT and DMTs.Women with MS have altered risks for cervical and breast cancers, partly due to immunosuppressive therapies and lifestyle factors. Integrated pathways could ensure that cancer screening is accessible, particularly for women with physical disabilities who find standard gynaecological tables inaccessible—a significant barrier to care often ignored in general practice.Men-specific care pathwaysThe evidence to support a male-specific pathway is grounded in the need for aggressive management of neurodegeneration, specific symptom control (sexual/urological), and culturally sensitive psychosocial support.A pioneering pilot study at the National Hospital for Neurology and Neurosurgery (UCLH) tested a dedicated “Men’s Health” MS clinic. This service integrated neurology, urology, and psychology to address the specific needs of men. The clinic successfully captured symptoms that were underreported in standard reviews. The most frequent concerns were erectile dysfunction (ED), fatigue, mood management, and reduced libido. Notably, 67% of these concerns had been raised in previous general reviews but remained unaddressed. Following assessment, 56% of participants required referrals to specialist teams (andrology, vocational rehab) that they had not previously accessed, and 38% received direct symptom-management education. Post-clinic surveys indicated high satisfaction (54% found it helpful), suggesting that men are more willing to engage with healthcare when the environment is tailored to their specific concerns rather than a general “wellness” model.Sexual dysfunction (SD) affects up to 90% of men with MS, compared to 80% of women, but the mechanics and implications differ. In men, ED is a direct marker of spinal cord pathology and often co-occurs with bladder dysfunction. Meta-analyses show a 3-fold higher risk of ED in men with MS compared to controls. This dysfunction is strongly linked to reduced quality of life and depression. Despite its prevalence, only about 20% of patients are asked about SD by their providers.A separate pathway would prioritise early urological intervention, utilising phosphodiesterase inhibitors or intracavernosal injections not just for sexual satisfaction, but to improve adherence and mental health. Furthermore, men have higher rates of obstructive bladder symptoms (due to prostate enlargement overlapping with neurogenic bladder), necessitating specific urological surveillance to prevent renal damage.One of the strongest arguments for a biological separation of care is the potential for sex-specific pharmacological intervention. Clinical trials have investigated testosterone replacement therapy (TRT) as a neuroprotective strategy in men with MS. A pilot study at UCLA involving men with RRMS demonstrated that daily testosterone gel treatment for 12 months improved cognitive performance and slowed brain atrophy by 67% compared with the pre-treatment phase. Testosterone appears to promote remyelination and reduce grey matter atrophy, addressing the specific “neurodegenerative disadvantage” men face. While not yet a standard of care, phase 2 trials of TRT are ongoing. If validated, this would necessitate a care pathway for men that includes routine gonadal profiling and TRT administration.Lifestyle factorsMen with MS often exhibit different lifestyle risk profiles that require different targeted interventions. Programs like the “Pit Stop” initiatives in Australia have shown that men engage better with health screening when it is framed as mechanical maintenance, analogous to a car service, rather than medical care. Integrating this philosophy into MS care could improve engagement. Men incur higher indirect costs due to “presenteeism” (working while sick) and early retirement. Vocational rehabilitation tailored to male-dominated industries (which may be more physically demanding) is a critical component of a male-specific pathway to preserve economic independence.Economic implicationsThe implementation of stratified pathways has economic implications. The cost of MS is driven largely by disability progression and lost productivity, both of which manifest differently by sex. Women generally incur higher direct medical costs due to longer life expectancy and higher utilisation of ambulatory care and complementary medicine. In comparison, men incur higher indirect costs related to productivity loss. Because men progress to disability milestones faster, their withdrawal from the workforce occurs earlier relative to their healthy peers, which represents a large economic loss.A stratified approach that aggressively treats male neurodegeneration (perhaps with earlier high-efficacy therapies or in the future TRT) could delay workforce exit, yielding high economic returns. Similarly, optimising menopausal management in women could prevent the late-stage disability acceleration that drives long-term care costs in women.Implementing separate pathways does not necessarily require the construction of new facilities. It implies a restructuring of existing resources—allocating “Men’s Health” clinic days or assigning specialised nurse practitioners to gender-specific comorbidities. The success of the UCLH pilot demonstrates that such interventions can be delivered within existing hospital infrastructure, thereby improving patient satisfaction. It will be important to assess if these results lead to better outcomes for men with MS.Final thoughtsI have tried to make the case for gender-specific interventions based on biological, cultural, social and economic factors. Do you think the case is strong enough to set up gender-specific care pathways for people with MS? I do think that by having one gender-neutral MS service, the issues that women have seem to dominate. I have set up a short online survey to assess how gender-specific issues are being managed in current MS management and to explore the need for gender-specific interventions or care pathways.If you have time, could you please take 3-4 minutes to complete the following short survey? Thank you.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Last week, a colleague sent me the publication below (van Laar et al., 2024).The publication highlights that while gender equality efforts traditionally focus on women, including men is essential for achieving lasting social progress. The authors argue that restrictive gender roles significantly damage men’s physical and mental health by discouraging help-seeking and rewarding risky behaviours. Do you agree? Furthermore, men often perceive diversity and inclusion initiatives as a zero-sum threat to their status, leading to resistance or psychological blindness toward their own privilege. Again, do you agree? In the workplace, masculinity contests create competitive environments that harm well-being for all employees and prevent men from engaging in care-oriented roles. To move forward, the authors suggest mobilising men as allies by raising awareness of how equality benefits them personally. Ultimately, true freedom from gender stereotypes requires a holistic approach that allows every individual to reach their potential regardless of traditional norms.Call to actionMy colleague suggested doing two things for men with MS. Firstly, improving care and counselling across gender/sex concordance in MS care. In practice, that would be offering men with MS male doctors and women with MS female doctors. This is easier said than done, particularly in healthcare systems with few resources. I am aware of many centres in the UK where the neurology consultants covering the MS service are of the same sex.Another suggestion is to improve benchmarks and guidelines for comprehensive, lifespan care for men. For example, young men with MS tend to have evolving mental health needs different to those of young women. In midlife, men with MS may need more support for sexual dysfunction, fertility and family planning. And finally, in older men with MS, ageing mechanisms are different, as well as the mix of comorbidities. Men don’t have a biological menopause that is defined and managed by the medical system. There is no male HRT. Men are susceptible to prostatism that needs to be investigated and managed differently from bladder dysfunction in women.Some obvious questions come to mind:* Are men with MS managed and treated differently from women with MS in your centre or country?* The epidemiology of MS differs between men and women. Do we need to explain this to men?* What male-specific issues in MS management differ compared to women?* Do men with MS need a different management pathway, counselling, treatments, etc.?* Are there cultural issues around how men with MS interact and use healthcare that can affect their management and outcomes?* What male-related research priorities need addressing?* Is there any evidence that males with MS are neglected relative to their female counterparts?I would be interested in your take on the issues raised in this paper and the questions I have proposed. I have suggested branding MS a pink-ribbon disease in the past. Maybe we shouldn’t forget that it is also a light-blue ribbon disease.PaperVan Laar C, Van Rossum A, Kosakowska-Berezecka N, Bongiorno R, Block K. MANdatory - why men need (and are needed for) gender equality progress. Front Psychol. 2024 Mar 1;15:1263313.Some criticisms of the paperI found it interesting that all the authors on the paper were women. They identify several limitations to their approach and highlight potential criticisms of men's involvement in gender equality efforts. These criticisms generally fall into categories regarding the scope of the research, the potential for “backfire” effects when involving men, and the risks of performative support.Their review relies heavily on a “western binary view of gender,” where individuals are defined strictly as men or women. The authors admit this approach excludes the experiences of non-binary and gender-fluid individuals and does not reflect how a growing number of people define themselves, though they argue this focus is necessary to understand how to remove the specific power of traditional gender stereotypes. I know this is a woke issue, but it needs to be said.The majority of the research reviewed comes from “WEIRD” countries (Western, Educated, Independent, Rich, and Democratic). Consequently, the findings will not fully account for cultural, ethnic, religious, or national differences in how men experience gender roles. They discuss men as a single group, which risks overlooking their heterogeneity. I make the point regularly that fathers with daughters are different to men without daughters; we simply have a different worldview of women.Many men (due to ethnicity, social class, physical ability, or sexual orientation) do not possess the same levels of privilege usually associated with men in WEIRD countries.Engaging with men can potentially reproduce dominance or paternalistic relationships. For example, men may dominate interactions in gender-equality groups or claim “expert knowledge in areas they know little about”. Furthermore, specific forms of protest, such as men walking in high heels, can sometimes be derisive and reinforce rather than challenge gender inequalities. A criticism of involving men is that they often receive more recognition for their advocacy than women do. Men may be perceived as more credible and less self-interested, which can generate resentment among women and highlight the very inequality the movement seeks to dismantle.Strategies to include men can sometimes decrease women’s engagement. The authors cite research showing that explicitly inviting men to participate in gender-parity task forces led to fewer women volunteering. Additionally, when men take leadership roles in protests (rather than supportive roles), it can reduce women’s identification with the movement. There is also a risk of “performative allyship” or “lip service,” in which men engage in easy, costless actions to boost their reputations without a genuine commitment to change. This appearance of change can ultimately cost the movement by replacing actual progress.While the paper advocates appealing to men’s group-based interests (e.g., better health, better relationships), the authors note that this strategy can be counter-productive. It risks normalising the idea that men should only engage when they stand to “visibly benefit,” potentially hindering progress in areas where achieving equality requires men to give up power or privilege.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

QuestionProf G, could you do an article on what is going on with tolebrutinib in the States? Having a hard time processing the FDA rejection letter. Not sure what this means for the field.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 ([email protected]) to request a complimentary subscription.Prof G’s responseYou can download the FDA response here. This is the informing Genzyme Corporation (Sanofi) that its application for the tolebrutinib cannot be approved in its current form. The primary obstacle to authorisation is a significant risk of severe liver injury, which the FDA believes outweighs the potential clinical benefits.Despite Sanofi’s attempts to manage this toxicity through intensive monitoring, the FDA identified several “life-threatening cases” during clinical trials. Additionally, the FDA noted substantial uncertainty regarding the drug’s effectiveness across multiple sclerosis subpopulations, particularly in those with inactive disease. To move forward, Sanofi must provide more robust safety data and potentially identify a specific patient group or groups where the therapeutic advantages clearly justify the high risks.The most critical factor in the FDA’s decision was the risk of severe drug-induced liver injury (DILI). The FDA characterised this risk as “substantial and unusually high” for drug development programmes in general, and specifically for MS therapies. In the Phase 3 development programme, there were 6 cases meeting Hy’s Law criteria (indicators of severe hepatotoxicity) out of approximately 2,700 subjects, including one patient who required a liver transplant and subsequently died.The FDA noted that even a single Hy’s Law case is a signal of high hepatotoxicity, and most drugs withdrawn from the market for this reason have rates of severe injury far lower than what was observed with tolebrutinib. While DILI is a known class effect of BTK inhibitors, tolebrutinib’s risk of fatal DILI appears to be “among the highest in the class” and exceeds the risk observed with all other approved MS therapies.The FDA concluded that the proposed Risk Evaluation and Mitigation Strategy (REMS) was insufficient. Although Sanofi implemented weekly liver monitoring, severe liver injury cases continued to occur even under this strict protocol. Consequently, the Agency determined that the benefit-risk assessment must assume severe and potentially fatal DILI cases would occur in a postmarketing setting regardless of monitoring requirements.The FDA identified significant issues with the efficacy data supporting the proposed indication for non-relapsing secondary progressive MS (nrSPMS). The study population was heterogeneous, containing both “active” and “non-active” SPMS patients, which complicated the assessment of benefit. The treatment effect was largely driven by a small subgroup (13% of enrolled subjects) with baseline gadolinium-enhancing lesions, indicating active SPMS. While the drug showed efficacy here, there are already approved therapies for active SPMS that do not carry the same magnitude of liver risk. Therefore, the benefits in this group were not anticipated to outweigh the severe DILI risk.For patients without baseline enhancing lesions—the population with the greatest unmet need—the treatment effect was significantly smaller and uncertain. The FDA stated that therapies with greater risks require a “greater magnitude and certainty of benefit” to support approval. The potential benefit in this population was deemed inadequate to justify the severe liver risks.Their analysis of the data showed that the treatment effect was substantially diminished in patients who had previously tried two or more prior MS therapies. The FDA rejected Sanofi’s claim regarding “slowing disability accumulation independent of relapse activity”. The Agency cited several reasons for this rejection. The concept lacks widely accepted criteria and relies on post hoc analyses. There is limited understanding of whether BTK inhibitors address the underlying pathophysiology of progression. They also highlighted a separate study in primary progressive MS that has recently failed to demonstrate a benefit on its primary endpoint of confirmed disability progression, further undermining the mechanistic rationale for this claim (see Tolebrutinib PPMS trial is negative, 15-Dec-2025). I would counter the latter argument that the PPM population in the Perseus trial differs significantly from the nrSPMS population in the Hercules trial. Ultimately, the FDA could not identify a clinically identifiable population for whom the benefits of tolebrutinib outweighed the “serious and unusually high risk of severe DILI”.My initial thoughtsThis is not the first or last time this has happened with MS DMTs and the FDA. They did the same with natalizumab (Tysabri), alemtuzumab (Lemtrada), and cladribine (Mavenclad) based on PML, secondary autoimmunity & other adverse events (infusion reactions, infections, …) and cancer risk with each DMT, respectively. All these drugs eventually got to market. I am confident there is a way forward.Defining a more responsive subgroupThe FDA is clearly worried about giving tolebrutinib a wide label for smouldering MS. This is because when you look for it using sensitive measures, for example, cognitive and other neurological stress tests, the majority of people with MS have smouldering disease. This means that the use of tolebrutinib would likely spread like wildfire to most subgroups of MS, and hence, the risk of life-threatening liver toxicity would increase. The FDA determined that, in its present form, a favourable benefit-risk profile could not be established for any patient subpopulation. The challenge for Sanofi is to identify a subgroup that would benefit most from the drug.Interestingly, in a post-hoc analysis, subjects with early-relapsing MS who had paramagnetic rim lesions (PRLs) responded better to tolebrutinib than those without PRLs. We have yet to see the same data for the PPMS cohort. But if PRLs serve as a prognostic marker in this population, it would make a compelling case for using this biomarker.Please see the MS-Selfie newsletter on ACTRIMS 2025 Highlights (3-Mar-2026), which covers this analysis.As you are aware, PRLs are one biomarker of smouldering MS lesions, and their presence is associated with poorer outcomes. PRLs are considered a “red flag” in MS because they represent chronic, smouldering inflammation that actively destroys brain tissue long after the initial attack has passed. While a typical MS lesion stabilises and “heals”, PRLs behave like a slow-burning fire that continues to expand outward, causing progressive damage.The defining feature of a PRL is a dark ring seen on specific MRI scans (susceptibility-weighted imaging). This ring corresponds to a dense accumulation of iron-laden microglia at the edge of the lesion. Instead of clearing debris and promoting repair, these immune cells remain chronically activated. Iron accumulation causes oxidative stress, which is toxic to neurons and oligodendrocytes (myelin-producing cells). This “toxic rim” slowly eats away at the healthy tissue surrounding the lesion. A proportion of PRLs are also slowly expanding lesions (SELs).Because these lesions do not shut down as standard lesions do, they are a primary driver of neurodegeneration (brain shrinkage). The ongoing inflammation at the rim severs nerve fibres or axons. Once an axon is lost, it generally cannot be replaced. Patients with multiple PRLs typically show accelerated brain atrophy (shrinkage), particularly in the deep grey matter, which is strongly correlated with physical and cognitive disability.PRLs are a major biological cause of smouldering MS and PIRA (Progression Independent of Relapse Activity). Traditionally, disability was thought to accumulate via acute relapses (attacks). PRLs cause disability to worsen between attacks. A person with MS may not have a new relapse for years, yet their walking or cognition slowly deteriorates because these smouldering lesions are quietly destroying tissue in the background.PRLs are associated with poor outcomes because they are difficult to treat. The inflammation in a PRL is trapped behind the blood-brain barrier (BBB). Most standard DMTs work by stopping immune cells from entering the brain from the blood. Since the immune cells in a PRL are already inside the brain and self-perpetuating, these drugs are less effective at stopping smouldering inflammation. Tolebrutinib is the first DMT to show an effect in smouldering MS, presumably by targeting PRLs and other intrathecal processes driving smouldering MS, which is why this FDA response is so devastating for people with MS.The FDA are also behind the curve when it comes to smouldering MS and are questing whether or not it is a real entity. I suggest they ask people with MS what smouldering MS is. If they read some of the comments on MS-Selfie, they would recognise that this is clearly the unmet need in treating MS and most people with MS, particularly those with advanced MS who identify as having smouldering MS. Clearly, we need a public engagement campaign to highlight what a problem smouldering MS is for people with MS. The FDA does listen to the patient community. I am told it was patient testimonies that won the day for getting natalizumab licensed. Any ideas in this regard are welcome?Could the FDA license tolebrutinib for the subgroup of people with MS with smouldering MS and PRLs?I suspect not. In clinical practice today, measuring, identifying and quantifying paramagnetic rim lesions (PRLs) is moderately difficult. It is not yet a “push-button” result like measuring blood sugar, but it is becoming increasingly feasible in most MS centres with the right equipment and protocols. You cannot see paramagnetic rims on a standard “routine” MRI sequence (like T1 or T2/FLAIR) used for general MS monitoring. To see the iron rim, the radiologist must run a specific sequence called SWI (Susceptibility-Weighted Imaging) or T2*-weighted imaging. Most modern MRI scanners (specifically 3 Tesla machines found in major hospitals) can run this sequence, but they often do not turn it on automatically because it adds an extra 4–5 minutes to the scan time. Time is money in the neuroradiology unit. It is significantly easier to spot these rims on a powerful 3T MRI scanner. On older, standard 1.5T scanners, the rims can be faint or indistinguishable from noise.Once the image is taken, a human (a radiologist) must find the rims. This is currently the biggest bottleneck. The “rim” is sometimes a subtle shadow rather than a distinct black ring. Distinguishing a true iron rim from a vein or a normal lesion edge requires a trained eye. In a patient with 50+ MS lesions, a neuroradiologist must manually check each lesion on the SWI scan to determine whether it has a rim. In a busy clinical workflow, they may simply report “multiple lesions” without characterising the rims unless specifically asked to do so. Let’s hope AI changes this. Until recently, there was no universal rule for “how thick” or “how dark” the rim must be to count. New guidelines (such as those from the NAIMS cooperative) are addressing this, but not all local neuroradiologists have yet adopted them.While saying “Patient X has 3 rim lesions” is doable, measuring exactly how much those lesions have expanded (e.g., “The lesion grew 1.2mm this year”) is extremely difficult in routine practice. Most hospital software is designed to show new bright spots, not the subtle expansion of old dark spots. Research centres use AI algorithms (like “RimNet”) to automatically detect and measure these, but these tools are rarely integrated into the standard computer systems neuroradiologists use daily.Would you be interested in knowing your PRL status? I suspect not unless something can be done about it, for example, switching from your current DMT to tolebrutinib.Because of these issues, I would be surprised if the FDA licenses tolebrutinib for patients with baseline PRLs. I hope I am wrong.Can we derisk the liver injury?Based on the FDA response, the short answer is likely no—at least not effectively enough to satisfy the FDA. While we attempted to “derisk” tolebrutinib during clinical trials using strict exclusion criteria and frequent monitoring, the FDA has concluded that these mitigation strategies are insufficient to prevent severe liver injury. The primary hurdle is that tolebrutinib-induced liver injury appears to be idiosyncratic, meaning it is unpredictable. It is not strictly dose-dependent (meaning you can’t just lower the dose to fix it) and does not have clear biomarkers that predict who will get it before they start. It typically occurs within the first 90 days of treatment. In the clinical trials, the rate of severe liver injury (Hy’s Law cases) was significantly higher than in other MS therapies. There was one fatality following a liver transplant, which is a massive red flag for FDA approval.What “derisking” strategies failed?Sanofi implemented aggressive safety protocols during the Phase 3 trials after the initial safety signals appeared (leading to the 2022 clinical hold). These included excluding anyone with pre-existing liver risk factors or complications. Increasing liver function testing (LFT) frequency to weekly or bi-weekly during the first 3 months.According to the FDA, even with these strict protocols, new cases of severe liver injury continued to occur. The FDA noted that while monitoring can catch injuries earlier, injuries can progress so rapidly that monitoring alone does not guarantee safety.Very worrying for the field is that the FDA states that DILI is a known “class effect” of BTK inhibitors (the family of drugs tolebrutinib belongs to). However, the FDA noted that tolebrutinib’s risk profile appeared “unusually high” compared to others in the class and existing MS treatments. The question we all have is, will this affect the chances of fenebrutinib, remibrutinib and other follow-on BTKi? I suspect yes.Other MS drugs (like alemtuzumab or natalizumab) carry high risks (autoimmunity, PML), and these risks can be effectively managed with REMS (Risk Evaluation and Mitigation Strategies) programs. I am not sure why the FDA thinks DILI from tolebrutinib is any different. I envisage a future in which people with MS who start tolebrutinib will have home liver function tests that they do daily for the first three months, so a rise in LFTs can be detected very early and addressed. This technology already exists in the form of lateral flow tests. I can’t see why the FDA can’t see beyond the trial protocol.Paternalistic MedicineThe question I have asked in the past and do so again: “Who is taking the risk when someone with MS decides to start a treatment with a known severe adverse event profile?” The regulator, the healthcare system, the prescribing physician or the patient themselves? At the end of the day, if we are transparent, surely it is the patient who makes the decision, with support from their team and the healthcare system. Provided we have a responsive system to manage DILI, I see no difference between tolebrutinib’s DILI risk and the PML risk with natalizumab, or the secondary autoimmune risk with alemtuzumab.I wish the FDA would come and sit in a clinic with me to see how common smouldering MS is and how large the unmet need is for treating smouldering MS. I am aware this news is devastating for people with MS living in the US. Interestingly, tolebrutinib is already licensed in the United Arab Emirates, and hopefully, the EMA and MHRA will take a different approach to the FDA. I also have concerns for fenebrutinib and the other BTKi.As a person with MS, are you not tired of regulators, payers, healthcare providers and HCPs deciding on what is too risky or not for you? I think the MS community should push back on this decision and find a path forward to get tolebrutinib to market for people with smouldering MS. Do you agree?Abstract of interestOh et al. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. ACTRIMS 2025 LB1.1.Background: Tolebrutinib is a brain-penetrant Bruton’s tyrosine kinase inhibitor (BTKi) that, in phase 3 pivotal trials, led to a 31% and 29% reduction in disability accumulation relative to placebo and teriflunomide in nrSPMS and RMS, respectively. MRI paramagnetic rim lesions (PRLs) are chronic active lesions associated with inflammation, demyelination, and axonal transection in the white matter and are correlated with disability accumulation and resistant to currently approved therapies. Because BTKi can modulate neuroinflammation driven by disease-associated microglia and B cells, we asked, in a post-hoc analysis, whether PRLs were associated with response to tolebrutinib.Objectives: To evaluate PRLs observed at baseline as a prognostic and predictive biomarker for disability accumulation and treatment response in HERCULES and GEMINI.Methods: HERCULES (NCT04411641), GEMINI 1 (NCT04410978), and GEMINI 2 (NCT04410991) were phase 3, double-blind trials of 60 mg tolebrutinib once daily. In HERCULES, participants were randomized 2:1 to receive tolebrutinib or placebo. In GEMINI, participants were randomized 1:1 to receive tolebrutinib or teriflunomide (14 mg once daily), each with matching placebo. 437 (39%) of the 1131 HERCULES participants and 631 (34%) of the 1873 GEMINI participants were from sites with imaging capabilities allowing evaluation of PRLs. Following prior studies, we analyzed the effect of tolebrutinib on time to onset of 6-month confirmed disability worsening (6-mo CDW) in participants with 0, 1-3, or ≥4 PRLs at baseline. PRLs were manually identified on SWI images generated from 3D-gradient echo phase images (6 echoes ranging from 4.9 to 41 ms, 0.8-mm isotropic resolution).Results: Across both trials, 653 participants (61%) had PRLs, consistent with data from observational studies with high-sensitivity MRI sequences. In HERCULES, the proportion of participants with 0, 1-3, or ≥4 PRLs at baseline was 40%, 36%, and 24%, respectively, with similar proportions in GEMINI. In both HERCULES and GEMINI, the risk of 6-mo CDW increased as a function of baseline PRLs in the placebo and teriflunomide comparator groups, respectively. In HERCULES, tolebrutinib appeared to mitigate the risk of 6-mo CDW with greater effect in participants with more baseline PRLs, reducing the risk by 54% in participants with ≥4 PRLs. In GEMINI, a similar risk mitigation was observed with a 46% and 49% risk reduction in participants with 1-3 and ≥4 PRLs, respectively. In tolebrutinib-treated participants with PRLs in both HERCULES and GEMINI, the risk of 6-mo CDW was numerically similar to the corresponding risk in participants without PRLs.Conclusions: This post-hoc analysis suggests that the impact of tolebrutinib treatment may be greater in those with higher number of PRLs, consistent with the CNS bioactive mechanism of action of tolebrutinib.Specific conflict of interestI sit on the tolebrutinib phase 3 trials steering committee. Therefore, you may want to take anything I say on this topic with a pinch of salt. Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I keep getting pushback from people, including many colleagues, when I claim that the Epstein-Barr virus (EBV) is the cause of MS. This claim is based on a large body of epidemiological studies over the last 20 years and on applying causation theory. The most important observation supporting my claim is that people who are EBV-seronegative are protected from getting MS. In other words, EBV is necessary to get MS, but is clearly insufficient as not all people who are infected with EBV develop MS, i.e. other factors must contribute to causing MS in addition to EBV.The phrase “necessary but insufficient” describes a condition or factor that must be present for a specific outcome to happen, but cannot make that outcome happen on its own. Think of it as a “required ingredient” rather than a “guarantee.”The Breakdown* Necessary: You absolutely cannot develop MS without EBV. If EBV is missing, MS is impossible.* Insufficient: Having EBV alone does not guarantee you will get MS. Other factors are then required for someone to develop MS.Other examples1. Oxygen and Fire* Necessary: Oxygen is required for a fire to burn. You cannot have fire without it.* Insufficient: Just having oxygen isn’t enough to start a fire. You also need fuel and heat.* Therefore, oxygen is necessary but insufficient for fire.2. A Lottery Ticket* Necessary: You cannot win the lottery if you don’t buy a ticket.* Insufficient: Buying a ticket doesn’t guarantee you will win. You also need luck (the right numbers).3. In a Medical Context (Revalidation)* Necessary: Attending your annual appraisal is necessary to keep your license to practice.* Insufficient: Merely showing up is insufficient to successfully complete your appraisal. You must also demonstrate quality improvement, gather feedback, and show you are up to date.A Simple FormulaFactor A + [Other Factors] = Success* Factor A is “necessary but insufficient.”* If you remove Factor A, the equation fails.* If you only have Factor A, the equation is incomplete.Why is this distinction important?In logic and critical thinking, confusing these two helps avoid errors in judgment. For example, a politician might argue, “We increased police funding, so crime will drop.”A critic might reply: “Funding is necessary for a good police force, but insufficient to solve crime on its own—you also need social programs and economic stability.”EBV-negative MSThe counter-argument a lot of people make is that they have MS, but are EBV-negative. I counter this by saying that they may not be EBV-negative. All assays have false-negative and false-positive rates. To illustrate this in an International Clinically Isolated Syndrome (CIS) study, we found that 41 (3.9%) of 1,047 subjects with CIS were EBV-negative using screening serology. When we tested them with more sensitive assays, only one remained EBV-negative.EBV (true-positive) + [Other Factors] = multiple sclerosisThe other issue is whether we are sure the person who is EBV-negative (true negative) has MS or another disease. We know that at least 1 in 20 people diagnosed with MS in life turn out to have another disease. This is why I think EBV-seronegativity is an important clinical flag and should make one reconsider the diagnosis of MS.I am firmly in the camp that EBV-seronegative MS is likely not to exist, i.e. if you are truly EBV-negative, then you have another disease. Please be aware that the McDonald criteria for diagnosing MS completely ignore this, and there is no mention of EBV serology as a diagnostic aid in helping make the diagnosis of MS or in not making a diagnosis of MS.The futureGetting naysayers to understand and accept “EBV is necessary, but insufficient to develop MS” is important, as they often review and reject grant applications. And this statement underpins using an EBV vaccine to prevent MS. My domino model of MS attempts to illustrate this. Is it clear enough, or do I need to simplify it to illustrate the point? Do any of you have any suggestions to make it easier to grasp?If you are interested in learning more, you can watch my lecture on EBV and MS, which I recently gave at the Nobel Symposium in Stockholm.I would be interested in hearing your thoughts on the concepts in this newsletter. Do you agree with me, or not? If you don’t, can you let me know why?Paper of interestDobson R, Kuhle J, Middeldorp J, Giovannoni G. Epstein-Barr-negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm. 2017 Feb 3;4(2):e318. doi: 10.1212/NXI.0000000000000318.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Several subscribers have asked me to comment on the new classification system for multiple sclerosis (MS) published last month in the journal Brain, which uses MRI and serum neurofilament levels. One person asked whether this means MS is now two diseases rather than one. Other commentators have hinted that this will change how we diagnose, treat and manage MS.In short, none of these claims are supported by the research findings presented in this paper (Willard et al. Combined magnetic resonance imaging and serum analysis reveals distinct multiple sclerosis types. Brain. 2025 Dec 4;148(12):4578-4591). The article introduces a new machine learning model that integrates MRI data with serum neurofilament light chain (sNfL) levels to supposedly categorise MS based on ‘biology’ rather than ‘MS-related symptoms’. The assumption that MS-related symptoms are not biological is incorrect. The fact that humans, and by inference, people with MS, are biological machines means their symptoms are biological.The Oxford dictionary defines biology as ‘the study of living organisms, divided into many specialised fields that cover their morphology, physiology, anatomy, behaviour, origin, and distribution.’ Symptoms of a disease are hence biological.The study combined fluid biomarkers (sNFL) with brain imaging, which then identified two distinct disease subtypes: early-sNfL and late-sNfL. The early-sNfL group is characterised by higher levels of inflammatory activity, significant lesion accrual, and faster brain atrophy, whereas the late-sNfL group exhibits more gradual neurodegeneration. The authors claim the multimodal approach, including sNFL, proved superior to MRI-only models in correlating with patient disability and predicting how individuals respond to therapeutic interventions. They claim the findings may provide a prognostic framework to support personalised medicine by identifying more aggressive disease states earlier in the clinical course, which are more likely to predict treatment response.LimitationsPlease note that the authors have identified several limitations and flaws in their study, which can be categorised into issues with the study population, methodology, and challenges related to clinical implementation. The study utilised data drawn from clinical trial cohorts, which means the participants do not fully represent the broader MS population. Due to strict eligibility criteria in the source trials, the study lacks data on underrepresented ethnic groups and patients with co-morbidities. While the model was trained on a cohort including both relapsing–remitting and secondary progressive MS, the external validation was conducted only on a cohort of newly diagnosed patients (early MS). Consequently, the model’s accuracy for late-stage disease remains to be validated.The external test dataset had a limited range of EDSS scores, which likely contributed to lower correlation coefficients between the model stages and disability measures in the test set than in the training set. Although the study aimed to use unsupervised machine learning, the pipeline was “not entirely unsupervised” because the initial feature selection step relied on correlations with the EDSS. The researchers noted that the decision to narrow the selection to exactly five variables was an “arbitrary decision” guided by the dataset’s size and resources. The SuStaIn algorithm assumes that disease progression follows a “monotonic sequence,” in which subtypes accumulate abnormalities in a fixed order. This assumption facilitates modelling but may limit the model’s sensitivity to fluctuating disease trajectories. In the longitudinal analysis, sNfL levels decreased in untreated control subjects. The authors attribute this to “regression to the mean,” as patients were recruited during active phases of inflammation (a requirement for trial entry), which naturally subsided, complicating the assessment of actual therapeutic effects.The authors acknowledge that few hospitals currently possess the necessary infrastructure to convert routine MRI scans into the precise quantitative measures required by their model. Quantitative MRI measures are sensitive to differences in scanners and acquisition parameters. While the study used harmonisation (the ComBat algorithm) to mitigate this, such harmonisation poses practical challenges for widespread clinical adoption. The correlations between the model-derived stages and the EDSS were weak. The authors argue this is expected because EDSS is weighted toward motor function, while MRI/sNfL changes often precede clinical symptoms. Still, it highlights a gap between the biological staging and current clinical disability measures. To ensure the model remained accessible for potential clinical translation, the study excluded more advanced imaging modalities (such as myelin-sensitive MRI sequences), which might have provided more comprehensive insights.I am clearly not on the same page as the authors.My initial thoughtsThe title refers to distinct MS subtypes. Use of the term “distinct" is a misnomer, as some subjects switched from one subtype to the other.“Given that 7% of patients switched from one subtype to another in the training dataset, and 23% switched in the testing dataset, these subtypes are likely to represent a continuum of underlying pathology.”The title is therefore misleading and argues against two distinct subtypes of MS.Please note that the training dataset was derived from a phase 2 Evobrutinib clinical trial conducted between March 2017 and July 2018. The study subjects were selected using well-defined inclusion and exclusion criteria. All trial subjects had to have one or more documented relapses within the 2 years before screening, with either one relapse which occurred within the last year before randomisation or the presence of at least one T1 gadolinium-enhancing lesion within 6 months before randomisation—about a quarter of study subjects had been exposed to DMTs in the past.Therefore, the cohort used for training and model development had established active MS, as defined by relapses and/or Gd-enhancing lesions on MRI. Another issue is that they were diagnosed using the 2011 McDonald criteria. This creates problems, as subjects with active MS tend to become less active over time due to regression to the mean. In addition, the consequences of having active MS will then unfold over time as part of the natural history of MS. I would be interested to know how the model would have been developed if it included pwMS who did not have active MS as defined by the trial inclusion criteria. I suspect very differently.Is the model simply measuring baseline MS disease activity, including raised sNFL as an activity marker, and then predicting the consequences of this period of MS disease activity on the end organ, i.e., brain volume loss or end-organ damage? In comparison, those without activity at baseline, i.e. a normal sNFL, will not have the same trajectory in terms of the pathology in the end-organ as measured by MRI, but are likely to regress to the mean in the opposite direction; i.e. have a delayed rise in sNFL as part of the fluctuation in MS disease activity over time. I think any model of MS, a dynamic disease, needs more than a few limited MRI metrics and sNFL to capture its behaviour.In comparison to the training dataset, the testing dataset was from the phase 3 REFLEX trial that compared two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis or CIS. These subjects were diagnosed using the older 2005 McDonald criteria, were younger and were naive to DMTs. The subjects in this study had CIS rather than established MS. I know that a subsequent analysis of the REFLEX clinical trial population, retrospectively applying the McDonald 2017 MS diagnostic criteria, estimated that about 50% of these subjects would have been classified as having MS. This means that 50% didn’t fulfill the requirements for MS and are more likely to have benign MS. Validating the model developed on established active MS using an early, much younger group of subjects naive to DMTs diagnosed with different diagnostic criteria makes little sense to me, i.e. it is flawed from a scientific perspective, and is likely to introduce bias. For example, the validation using subjects very early in the course of their disease, who were much younger and hence had a greater ability to recover function and repair damage, introduces a biological variable not measured by the model. How does neurological reserve and recovery of function impact the model?An essential aspect of clinical outcomes and various biomarkers in MS is that they evolve at different rates. In other words, the temporal sequence of how they change over time is out of sequence with each other. I have referred to this phenomenon in the past as lag. Let me give you some examples. Demyelination develops along a specific pathway before loss of function and before a Gd-enhancing lesion is seen. Changes in the magnetisation transfer ratio (MTR) on MRI can occur in normal-appearing white matter (NAWM) several months before an MS lesion becomes visible with Gd-enhancement. This indicates that MTR changes are earlier and more sensitive markers of pre-lesional tissue damage than Gd enhancement. At some point, axonal injury occurs, leading to NFL release. Based on serial sampling studies, we suspect this process may precede the onset of clinical relapse symptoms and the detection of Gd enhancement on MRI. However, these latter processes are likely to cluster into a relatively narrow window that lasts days to weeks. We know that Gd enhancement of a lesion typically lasts 2-3 weeks before resolving, whereas NFL levels remain elevated for months. The latter occurs because of Wallerian degeneration, which takes a long time to unfold: it can take months to clear the debris from transected axons. The proximal axonal degeneration above the lesion may take even longer and play out over years. Similarly, repaired or remyelinated axons may be programmed to die off in the future. We think they are vulnerable to early ageing, energy failure and delayed excitotoxicity. This delayed neurodegeneration may happen over decades. I try to illustrate these time changes in this cartoon that I made more than a decade ago.The loss of tissue from an acute lesion, i.e., the subsequent atrophy, can take months to years to occur. In optic neuritis and the optic nerve model, atrophy is seen after 3 months and reaches a plateau at about 6 months. Therefore, the inflammation detected now, as evidenced by Gd-enhancing lesions and/or elevated NFL levels, will result in whole-brain or regional atrophy six or more months later. With longer axons than those in the optic nerve, it will take longer than 6 months to reach a plateau. The point I am making is that I don’t know how this model accounts for the lag in changes in these biomarkers. The study utilises five specific MRI-derived measures, three of which are volume measures (limbic cortex, deep grey matter, and parietal cortex volume), all of which are likely to be impacted by lag.The other two MRI metrics are the total T2 lesion volume and the corpus callosum white matter T1-weighted/T2-weighted ratio. I am aware that the T2 lesion volume changes with time at an individual lesion level in response to treatment. In general, the T2 lesion volume of an acute MS lesion is large and decreases as the Gd-enhancement disappears, i.e., the lesion shrinks in size. Most MRI analyses show a reduction in T2 volumes with treatment. Therefore, this component of the model would be affected by treatment.The T1-weighted/T2-weighted (T1w/T2w) ratio in the white matter of the corpus callosum changes significantly over time as a function of age. After middle age, the T1w/T2w ratio in the white matter and corpus callosum generally begins to decline. This decrease is thought to be associated with age-related microstructural changes, including myelin degeneration and loss of white matter integrity. How do the significant age differences between the training and validation datasets affect this component of the model?Therefore, these MRI metrics are not static and change over time. How these dynamic changes affect the model is unknown. The changes may not be that important at a group level. However, I suspect they will create a lot of noise or variability in individual datasets, which may make it difficult to use for decision-making at a patient level.SummaryA crucial point made by the authors in the discussion is that few centres have the infrastructure to reliably analyse the scans and generate the metrics required as inputs into this model. Therefore, it isn't easy to see how this model will impact precision medicine. In comparison, sNFL and CSF NFL levels are beginning to enter routine clinical practice and are increasingly being used to aid in clinical decision-making. To be blunt, I am not sure how this paper changes my thinking about MS and its management. Our therapeutic strategies remain the same: early, effective treatment is the best way to protect the end organ. Our treatment targets remain no evident inflammatory disease activity (NEIDA) and no evident smouldering disease activity (NESDA), regardless of what proposed subtype of MS you have. We have very effective treatments for NEIDA and less effective treatments for NESDA; it would take a brave neurologist not to treat a person with a low-sNFL phenotype with an anti-inflammatory. Similarly, it would not make sense to ignore smouldering MS in a person with a high sNFL phenotype. The challenge from now on for the MS community is developing treatments for smouldering MS to achieve stable MS and long-term remission regardless of putative subtypes.Does my response to this paper make sense? I am prepared to answer further questions.PaperWillard et al. Combined magnetic resonance imaging and serum analysis reveals distinct multiple sclerosis types. Brain. 2025 Dec 4;148(12):4578-4591.Multiple sclerosis (MS) is a highly heterogeneous disease in its clinical manifestation and progression. Predicting individual disease courses is key for aligning treatments with underlying pathobiology. We developed an unsupervised machine learning model integrating MRI-derived measures with serum neurofilament light chain (sNfL) levels to identify biologically informed MS subtypes and stages. Using a training cohort of patients with relapsing-remitting and secondary progressive MS (n = 189), with validation on a newly diagnosed population (n = 445), we discovered two distinct subtypes defined by the timing of sNfL elevation and MRI abnormalities (early- and late-sNfL types). In comparison to MRI-only models, incorporating sNfL with MRI improved correlations of data-derived stages with the Expanded Disability Status Scale in the training (Spearman’s ρ = 0.420 versus MRI-only ρ = 0.231, P = 0.001) and external test sets (ρ = 0.163 for MRI-sNfL, versus ρ = 0.067 for MRI-only). The early-sNfL subtype showed elevated sNfL, corpus callosum injury and early lesion accrual, reflecting more active inflammation and neurodegeneration, whereas the late-sNfL group showed early volume loss in the cortical and deep grey matter volumes, with later sNfL elevation. Cross-sectional subtyping predicted longitudinal radiological activity: the early-sNfL group showed a 144% increased risk of new lesion formation (hazard ratio = 2.44, 95% confidence interval 1.38-4.30, P Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Sylvia found us, and that is the primary learning point of this case study.Sylvia was diagnosed with MS two months into an internship with an investment bank in London. She probably had an episode of optic neuritis when she was 17, whilst studying for her A-levels. She had transient blurring of vision in her right eye, accompanied by a mild headache behind the eye. Her vision was minimally affected and was back to normal within a week or two. Her general practitioner diagnosed her as having migraine. However, she has the telltale signs of prior optic neuritis when you examine her vision: abnormal colour vision, optic disc pallor, and slowed conduction velocity in that eye on visual evoked potential testing. Sylvia was then well until she developed weakness in her right foot during her final exams at University. She had difficulty lifting her right foot, and it would catch when she walked, causing her to trip several times. In addition, her left leg felt odd with reduced sensation that was more pronounced in the lower leg. As Sylvia was studying for her exams, she put off seeing the campus GP and waited until she returned home. At this point, the weakness had almost resolved. At her mother’s insistence, Sylvia saw the family GP, who advised her to see a specialist.By the time Sylvia saw a neurologist at a central London teaching hospital, the weakness had resolved. However, when the neurologist examined her, he detected persistent weakness in her right foot and some altered sensation in her left foot. He didn’t tell Sylvia what he was thinking, but said she needed an MRI of the brain and spinal cord. Sylvia did not question the neurologist at this stage, as she was excited about her summer ahead. She had a holiday planned with her boyfriend and was due to start a prestigious paid internship at a large international investment bank. Life was good.Two weeks later, she was called by the hospital’s neuroradiology department, saying they had a cancellation and were offering her the slot if she was free. The problem is that she needed to come in that afternoon for her MRI. As Sylvia had yet go on holiday, she was able to postpone seeing her friends that afternoon and attend the hospital for her MRI. Things changed dramatically two weeks later, when she was on holiday in Greece, she received a call from the consultant neurologist saying her MRI had shown some evidence of inflammation in the spinal cord and brain and that he wanted her to have some additional tests. At no point did he mention the cause of the inflammation.A week later, on Monday morning, Sylvia was escorted into the daycase ward at the hospital for blood tests and a lumbar puncture. Sylvia had to wait about an hour as the trainee doctor needed some of the blood results before doing the lumbar puncture. The lumbar puncture was uneventful. She remembers feeling a cold sensation on her lower back, some pressure, and then, three minutes later, the young trainee doctors saying it was all done. Sylvia then had to go to another building that housed the neurophysiology department for electrical tests, including a complete set of evoked potentials and central motor conduction times.You would be wrong to think that Sylvia was a passive recipient of healthcare at this point. Sylvia had immediately Googled spinal cord inflammation, and as a result, she had decided that she likely had multiple sclerosis, and these tests were being done to exclude other conditions and to confirm the diagnosis. Sylvia was a knowledgeable university graduate who had just won one of the most competitive internships in the country. She was an exceptionally bright and capable young lady.To cut a long story short, when Sylvia saw the neurologist three weeks later, she was surprisingly clear-headed and well prepared when he said she had multiple sclerosis. Sylvia had spent the last three weeks reading up on the condition and was ready for what was coming next. He said she had the relapsing-remitting subtype of MS. He said the visual blurring she had had when she was an A-level student was her first attack, which was supported by the abnormal visual evoked potentials showing slow conduction in the right optic nerve.Sylvia wanted to cut to the chase and wanted to ask about treatment. He said she would be eligible for several treatments available on the NHS, but wanted her first to go away and understand what MS was before she could discuss with the MS nurse specific therapies. This was not good enough. Sylvia then begged him for a list of the treatments she could have so she could research them. Reluctantly, he provided her with four options: interferon beta, glatiramer acetate, teriflunomide and dimethyl fumarate. He said that his recommendation would be for dimethyl fumarate. When Sylvia asked him about Tysabri and Lemtrada, he said that she would not be eligible for Tysabri as she had only had one MS attack in the last 12 months and that Lemtrada was too dangerous to use first-line and that he personally did not prescribe alemtuzumab. The issue Sylvia had was that after doing her own research, she had decided she wanted to be treated with Lemtrada or alemtuzumab. Who was this neurologist deciding that alemtuzumab was too dangerous to be used as a first-line treatment? It was at this stage that I received a call from Sylvia’s GP asking if we would be prepared to see Sylvia at the Royal London Hospital for treatment.When I met Sylvia, she was level-headed, intelligent, and street-smart. She knew about all things MS, having spent several hours a day for months reading and learning about MS. She had read our MS Blog and knew all the arguments for and against treating MS aggressively from the start. She had her whole adult life ahead of her and wanted the best chance of living a normal life despite having MS. Contrary to what the neurologist from St Elsewhere had told her, Sylvia fulfilled the NHS criteria for being treated with alemtuzumab, and she went ahead with two courses of treatment in 2015 and 2016.What was not mentioned is that Sylvia had a high lesion load on her MRI and had several gadolinium-enhancing lesions on her initial diagnostic scan, including some subtle enhancement of a lesion in her upper thoracic cord—all the more reason for treating her MS aggressively. From an MS perspective, Sylvia has done well. She has not had any further relapses or new lesions on her MRI, and her brain volume seems to be stable.Sylvia is now married and has two young daughters. She is a senior analyst in the investment bank where she did her internship. She is the primary breadwinner at home. With annual bonuses, she earns over a million pounds per year. The press and media often call upon her to discuss economic issues. She is an ultra-successful young woman, a super-mum. You would not think she had MS.This year marked the tenth anniversary of her MS diagnosis and initial course of alemtuzumab. The question is whether she has been cured of having MS. This is where definitions matter and how we define an MS cure. Although Sylvia has no evident inflammatory MS disease activity (NEIDA), she does have fatigable weakness in her right foot. Sylvia runs half marathons and notices that toward the end of her races and at the end of long training sessions, her right foot begins to drop. Over the last three to four years, the foot drop has started to happen earlier in the race. When Sylvia first began running half-marathons, the foot drop used to occur in the last quarter of the race. She is now noticing it happening from the halfway mark. Is this the first sign of smouldering MS? Or is this simply premature ageing? I don’t know. But if you include ageing or early ageing as part of your definition of smouldering MS, you would say she has smouldering MS. We don’t usually do repeat MRI scans of the spine to monitor MS disease activity. However, I arranged for Sylvia to have an MRI of her spine, and it is clear that the lesion in her upper thoracic spine had gotten longer, and there is evident cord atrophy at the site of the lesion and in the lower cervical cord. So, based on my current thinking of MS, I would say Sylvia has smouldering MS in an existing lesion in the spinal cord. She is aware of this and expects her right foot weakness to worsen gradually. The question Sylvia asks me whenever I see her is: What can be done to slow or stop this process? She is clearly interested in tolebrutinib.I am deliberately using Sylvia as an example of alemtuzumab’s ability to do what it can, i.e., stop new lesion formation and prevent end-organ damage. But what it can’t do is stop smouldering MS that is already established in a small number of lesions before treatment. I have many other examples of people with MS who have no evident inflammatory disease activity nor smouldering associated worsening 15 years or more after being treated with alemtuzumab. I think these people have been cured of having MS. I am aware of similar examples in patients treated with AHSCT. I suspect that in time, we will also see some cures after treatment with cladribine. For a more detailed discussion on defining an MS cure, please see my previous newsletter, ‘To cure or not to cure MS, that is the question’ (24-Aug-2023).I have little doubt that if Sylvia had lived in a different era and had not been promptly treated with alemtuzumab, she would be much worse off than she is now. The counterfactual here would be very different. The only reason Sylvia has done so well and will do well long term is that she is an educated, determined, and self-confident individual who was not prepared to take no for an answer. She knew her rights and made sure she got her MS treated the way she wanted it to be treated.Sylvia’s case is an example of what we glibly call a ‘social determinant of health’. Usually, we discuss social determinants in a negative sense, i.e. low levels of education are associated with poor outcomes. In this case, high levels of education and self-agency are associated with a good result. Imagine thousands of Sylvias or not-Sylvias across the NHS, and you begin to understand how crucial social determinants of health are. This is why HCPs are so important in counteracting the impact of social determinants of health. If a patient lacks a high level of self-agency, they are relying on us to do what is best for them.I refer to colleagues who are not prepared to offer and use alemtuzumab and HSCT as the ‘refuseniks’. They are putting themselves and their institutions at risk from legal challenge. When NICE (National Institute for Health and Care Excellence) was created, it was done so through an Act of Parliament. NICE’s primary aim was to eliminate postcode prescribing and variable access to treatments. Therefore, if a therapy has been NICE-approved, the NHS has a legal obligation to offer eligible people that treatment. Thus, in the case of Sylvia, her previous consultant, by denying her access to alemtuzumab, was breaking the law and putting not only themselves at risk of a legal challenge but also their relevant NHS Trust at risk.You may be asking why neurologists are so paternalistic. Not allowing patients to choose their own treatment is against one of the central tenets of modern medicine. In reality, it is not the neurologist or the institution where the neurologist works who is taking a risk when someone is treated with alemtuzumab; it is the patient who is taking the risk. Don’t they understand this? I think that if you are not using alemtuzumab or HSCT in a proportion of your patients with highly active MS, then you and your centre are not managing MS the way it should be handled in 2025.Many people with MS who come to me later on the course of their disease, when they are disabled, were never offered high-efficacy therapies, never mind immune reconstitution therapies, early in the course of their disease. Things have changed since Sylvia was diagnosed with MS in 2015, in that most people with MS in high-income countries are now at least being offered anti-CD20 therapies as a first-line therapy. But many are not being offered alternatives to anti-CD20 therapies. It is as if the broader MS community thinks anti-CD20 therapies are the panacea for treating MS. This is clearly not the case, as the majority of people with MS on an anti-CD20 therapy, given sufficient time, will present with smouldering MS.Therefore, as we approach 2026, several problems persist in MS despite improved overall outcomes for people with MS. These are paternalistic medicine, therapeutic inertia, accepting NEIDA as a therapeutic target, not asking what an MS cure looks like, ignoring smouldering MS, and gaslighting people with MS who bring up the issue of smouldering disease. I sincerely hope things will change in 2026.Do you agree? How many of you were offered alemtuzumab early in the course of your MS? Do you think we can cure MS? Do you think smouldering MS is a significant unmet need in the treatment of MS? How many of you have smouldering MS? Have you been gaslit when you brought up the issue of smouldering MS? P.S. Many people were upset by my post about Mary and her condition on Christmas Eve (see Christmas 2025, 24-Dec-2025). I apologise for disturbing you. My timing was deliberate. For me, Christmas and the Christmas holidays are a time of reflection and charity. Putting our heads in the sand or wearing rose-tinted glasses does not stop the suffering of those less fortunate. Relieving others of suffering is part of the Christmas message. In addition, we need to understand how bad MS can be to inform risk-benefit analyses of high-risk treatments early in the disease course. Sylvia knew about the Mary’s of the world when she was deciding on which treatment she wanted. Her decision to be treated with alemtuzumab was to prevent her from becoming a Mary herself.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

24th December 2025, Byfield, NorthamptonshireMary lives alone. Her husband has long departed; he filed for a divorce and left the marital home more than a decade ago when Mary had to stop working. Mary has two daughters who have both fledged. Charlotte, her oldest, works in London and is living with her boyfriend. Elizabeth, the youngest, is currently living and working in Sydney, Australia, after finishing University. Charlotte, who calls Mary every day, would now only be visiting on the 28th of December. She informed her mother weeks ago that she would be spending Christmas with her boyfriend’s family in Dorset this year. Mary’s parents are both deceased, and her brother and sister live in Scotland. As a result, Mary would be spending Christmas alone again this year - almost alone.Carolotta, her Italian carer, will visit twice on Christmas Day. The first visit will start at 8.30 am on Christmas morning to help Mary get out of bed, empty her catheter bag, and wash and dress her. Carolotta will then push Mary in her wheelchair from the bathroom to the kitchen for breakfast. Breakfast would likely be a bowl of Quaker Oats So Simple from a sachet, mixed with milk and heated in the microwave oven.After breakfast, Mary will take her medications under Carolotta’s watchful eye, who will then push Mary in her wheelchair into the lounge and help transfer her into her reclining chair in front of the TV. Mary spends most of the day watching daytime TV or listening to the radio. She frequently complains about the poor quality of TV on the BBC, claiming that there are too many repeats. Mary had to recently cancel her Netflix subscription because she couldn’t afford it on her meagre living allowance. Maybe one of her daughters will renew the subscription as a Christmas present.Mary has persistent double vision from a neurological episode that happened more than a decade ago. If she watches TV, she has to cover one eye with a frosted lens using her reading glasses. She finds this tiring, and now prefers listening to the radio. She finds reading difficult, but has adapted by listening to audiobooks. Saying that she finds it difficult to find and download free audiobooks onto her mobile phone. Charlotte helps whenever she visits. As Charlotte hasn’t been to see her for several months, Mary has run out of audiobooks.Carlotta brought her daughter to visit last Saturday to decorate Mary’s artificial Christmas tree. Sadly, there are no presents under the tree this year. Mary is not expecting any family or friends this Christmas. On the table next to the Christmas tree are six Christmas cards. In the past, when her daughters were young, and Mary was still working as a teacher in the local primary school, they used to get over 100 cards every Christmas. All Mary’s pupils and colleagues would give her a card. Mary recalls how she used to string the cards above the fireplace in multiple rows. A boast about how socially connected she was by the sheer volume she had on display. How times have changed.Mary is only just able transfer herself back into the wheelchair from her reclining chair using a monkey rope attached to the wall. She only does this if she wants to have lunch or go to the bathroom. As she finds it exhausting getting up by herself, she tends to miss lunch. Her kitchen has been adapted so she can access the fridge and countertops from her wheelchair. These days, when she eats, she mainly eats ready meals warmed in the microwave. Carolotta kindly fills a flask with tea each morning and puts it on the table next to Mary. This allows Mary to have warm tea without risking using the kettle and pouring boiling water over herself. Mary has noticed increasing weakness in her dominant right hand, with worsening coordination and tremor. As a result, she finds the kettle too heavy to lift.Carlotta will visit on Christmas Day at about 4.30 pm to make sure Mary has a light dinner. Carolotta will then take Mary to her bedroom, undress her and get her ready for bed. Carolotta’s evening visit will be rushed and short. She is on call for the agency she works for and has three other residents in the village to see as cover for her colleagues who have Christmas off this year. Carlotta will want to get back home to spend the evening with her family. Despite this, the rushed evening visit on Christmas Day will be slightly different to other evening visits. Carlotta will bring Mary a serving of Christmas pudding with brandy butter, the same as last year. A kind gesture that someone cares and a simple reminder that Christmas Day is special and different from the other 364 days of the year.You have probably realised by now that Mary has MS. She was diagnosed 34 years ago. She is now in her late fifties and lives alone. She has a paraparesis with worsening hand and arm function. She is socially isolated, lonely, and vulnerable. People in her village look out for her; she is known as the woman with MS. The owner of the local Co-op delivers groceries once a week, but sadly, she has no friends or other visitors from the village. The few friends she has are mainly colleagues from when she still worked, who live some distance from her. They rarely visit, and they call her infrequently. On top of being alone, Mary is finding it increasingly difficult to make ends meet on her meagre allowance. Mary is beginning to realise that it won’t be long before she will have to move into a nursing home. May be Christmas’ are merrier in care homes - at least Mary will have company and have the luxury of eating a Christmas meal.Some of you may recognise Mary’s predicament. Many people with MS live alone and will be lonely this Christmas. An MS Society national survey that was done several years ago showed that three out of five people with MS self-report as being lonely. This figure is staggering when you consider the fact that loneliness kills. This is why the NHS has a “Better Lives: Every Mind Matters” loneliness resource to help people who feel lonely. It covers feeling lonely, advice for loneliness, support for loneliness, and finding support.Having MS makes loneliness worse. MS is a very stigmatising disease that, given sufficient time, at least in the pre-disease-modifying therapy era, causes most pwMS to become disabled. Associated with this disability are the well-documented complications of unemployment, the breakdown of personal relationships, depression, anxiety, cognitive impairment, fatigue, loss of quality of life and, tragically, an increased suicide risk. As a result of these factors, pwMS are at a high risk of becoming socially isolated and lonely.Numerous studies have shown that loneliness can be explained by employment status, marital status, upper extremity function, social disability and physical disability. Mary is a typical example with all these risk factors. Not surprisingly, other correlates of loneliness included depression, cognitive fatigue, psychosocial fatigue, poor quality of life and suicidal ideation and suicide. We can only wonder if Mary has any of these other cofactors.Loneliness is a modifiable social determinant of health and is associated with poorer health outcomes. It therefore needs to be identified and managed as part of the holistic management of MS. This is part of my marginal gains philosophy for managing MS.“If we break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together.”I suspect Mary has many modifiable factors to improve her quality of life. What can we do about it? The NHS’s “Better Lives: Every Mind Matters” resources, NHS link workers, social prescribing, and self-management are just some of the tools to tackle loneliness and social isolation. We, Barts-MS, unsuccessfully tried to secure funding to set up a programme we provisionally called ‘Teaching people with MS how to Fish’. The choice of title was based on Lao Tzu’s teachings, the Chinese philosopher and founder of Taoism, who said, “Give a man a fish, and you feed him for a day. Teach him how to fish, and you feed him for a lifetime.”Connecting people increases their social capital, i.e. the size of their social network, which improves health outcomes. If you are spending Christmas alone, there are things you can do. If you are religious, reconnect with the true meaning of Christmas and try to attend a Church service, either in person or via TV, radio, or online. Pick up the phone and call people; friends, family or one of the many charitable organisations that provide telephone companions. Watch Christmas TV. Listen to Christmas carols. Have a Zoom lunch, dinner or drink with someone who is also alone. If you can practice mindfulness, please do. Get out if you can for exercise and fresh air. Make sure you fill your day with as many activities as you can.I was impressed and grateful to receive an email from an MS-Selfie subscriber explaining that, during lockdown, she took part in a poetry-writing initiative started by someone with MS. The poems are about the lived experience of MS. The book is available online and will be in print shortly. The poetry project aims to help HCPs and others to understand the experiences of people living with MS. Please download the book, read it and share the link with others. These are the kinds of things pwMS and the wider community can do to build communities to counteract the curse of loneliness.If you know someone who is alone this Christmas, please take some time out on Christmas Day to call them. Make sure they know someone cares for them and that they are not alone in the world. If you have any suggestions to help people who are alone this Christmas, please share them with us. This is the power of community, albeit a digital online community.I hope you are all doing well and holding up under very trying global and national circumstances. I want to wish you all a Merry Christmas or Happy Holidays. The following is a poem from one of my favourite poets that reminds me of yuletide.Stopping by Woods on a Snowy EveningBy Robert FrostWhose woods these are I think I know.His house is in the village though;He will not see me stopping hereTo watch his woods fill up with snow.My little horse must think it queerTo stop without a farmhouse nearBetween the woods and frozen lakeThe darkest evening of the year.He gives his harness bells a shakeTo ask if there is some mistake.The only other sound’s the sweepOf easy wind and downy flake.The woods are lovely, dark and deep.But I have promises to keep,And miles to go before I sleep,And miles to go before I sleep.I sincerely hope Mary gets plenty of calls on Christmas Day. Do you?Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

If you are a regular MS-Selfie reader, you will know that I am a proponent of the Epstein-Barr virus (EBV) theory of multiple sclerosis (MS). I am convinced that EBV is the cause of MS. EBV is necessary but insufficient for the development of MS. Put simply, people who are EBV negative don’t get MS. This observation underlies the hypothesis that an EBV vaccine can prevent MS. I am happy to report that several vaccine companies are developing EBV vaccines, so this question about primary MS prevention will hopefully be answered in the next 10-20 years.It is now time for the next experiment on the EBV-related prevention strategy.As you know, I have taken partial retirement to focus on MS prevention. The second hypothesis is based on the observation that a history of symptomatic EBV infection or infectious mononucleosis (mono) is a more substantial risk factor for MS than asymptomatic EBV infection. People with a history of mono have, on average, double the risk of getting MS compared to people without a history of mono. This is why we need to focus on what is happening to the immune system during mono to determine which changes lead to MS.Please note the case for targeting mono with a vaccine goes beyond MS prevention.Mono is often described in medical texts as a benign, self-limiting viral infection. However, as with most infections, mono can be severe and associated with significant morbidity and mortality in addition to the potential delayed complication of developing. A minority of people with acute mono have to be admitted to a hospital with complications. These include pharyngeal and/or upper airway obstruction, difficulty swallowing and dehydration. Other complications include meningoencephalitis, haemolytic anaemia, thrombocytopaenia, neutropaenia, haemophagocytic syndrome, myocarditis, hepatitis, pancreatitis, pericarditis, pneumonitis, conjunctivitis, splenic rupture, Guillain-Barré syndrome, cranial neuritis, transverse myelitis, brachial neuritis and chronic fatigue syndrome (CFS). Approximately 3-5% of patients diagnosed with chronic fatigue syndrome have a history of recent mono, and about 10% of patients with documented mono develop CFS.Children typically miss 1 to 3 weeks of school due to mono and its sequelae. Most children are too ill to attend school during the first week of mono. They begin to feel better in the second week and may be able to return to school with some restrictions; however, they remain contagious and should avoid close contact with other students for the first two weeks. By the third week, most school children are no longer infectious and can return to school without restrictions. However, many children experience lingering fatigue for several weeks or months after the initial infection, which impacts school performance. Participation in contact sports is not recommended for at least three weeks after mono due to the potential risk of splenic rupture. Approximately 30% of university students experience mono, and about 1 in 8 must retake a year of studies. Persistent fatigue after mono impacts university performance.The risk of splenic rupture post-mono prevents students and athletes from playing contact sports and military recruits from participating in physical training. In the U.S. military, mono has been shown to reduce operational readiness, as each patient with mono is unable to perform duties for at least 2 weeks following infection.Therefore, from a medical and socioeconomic perspective, it could be argued that preventing or treating acute mono represents an unmet medical need. Preventing mono with a vaccine or treating it with effective antivirals to reduce the duration and severity of mono would reduce the acute and chronic complications of mono itself and, potentially, EBV-associated autoimmunity and malignancy.Immunologists currently favour molecular mimicry to explain how EBV may cause MS. Arguably, the most well-documented infectious agent to trigger autoimmunity is group A beta-haemolytic streptococcus (strep) or Streptococcus pyogenes. It is the established cause of acute rheumatic fever (acute rheumatic fever), Sydenham’s chorea, glomerulonephritis, arthritis and vasculitis. We therefore hypothesise that EBV drives MS disease activity, as strep infection drives attacks of acute rheumatic fever.The first attack of MS is asymptomatic in the majority of people who develop MS and is likely to occur relatively soon after primary EBV exposure. MS manifests later, when a subsequent attack or lesion forms in a pathway that results in neurological symptoms. This explains why most people who develop MS have pre-existing old white matter lesions on their brain MRI when presenting with their first clinical attack. EBV differs from strep because it establishes a latent infection that reactivates intermittently. This intermittent asymptomatic reactivation of EBV (latent-lytic cycling) likely drives MS disease activity.In contrast, strep tends to cause repeated symptomatic infections. However, asymptomatic colonisation with strep is associated with elevated anti-streptolysin (ASO) titres (antibodies against a strep protein) and other serological markers of strep infection. Similarly, people with MS have increased titres and responsiveness to a broader array of EBV epitopes in their antibody and T-cell repertoires compared to healthy controls, supporting the latent-lytic cycling hypothesis as the driver of MS disease activity. It is the latent-lytic cycle that acts as a booster, increasing antibody levels and the number and diversity of T cells.The emergence of antibiotics to treat strep pharyngitis or tonsillitis was associated with a rapid decline in the incidence of acute rheumatic fever. Observational data, rather than randomised controlled trial data, demonstrated the primary link between strep infection and acute rheumatic fever. Randomised controlled trials were only conducted much later to prove that secondary antibiotic prophylaxis in patients with a prior episode of acute rheumatic fever could prevent recurrent attacks and the chronic sequelae of rheumatic fever.If EBV infection triggers MS attacks in a similar way to how strep causes attacks of acute rheumatic fever, then treating acute mono with effective antiviral therapies may prevent MS and other EBV-associated conditions. An effective antiviral treatment for mono would be considered a primary prevention measure. With acute rheumatic fever as the analogy, this concept could be further extended to the treatment of established MS. Treating patients with MS continuously or prophylactically with EBV antivirals over the long term may prevent further attacks and the chronic sequelae of MS, i.e., EBV antivirals could be used as a secondary prevention measure. Arguably, this is how currently licensed MS disease-modifying therapies and some experimental therapies work, by targeting memory B-cells where latent EBV resides.We hypothesise that treating mono with an effective antiviral will reduce EBV viral loads and the aberrant immune response induced by EBV during mono. This may prevent the immunological events that lead to MS, analogous to treating pharyngitis due to strep with penicillin or other antibiotics to prevent acute rheumatic fever.To test the EBV-mono/MS hypothesis, we need to develop effective treatments for mono. Once antiviral therapies are licensed for treating mono, and they are widely adopted in clinical practice, we could use population registries to track the impact of this treatment intervention on the incidence of MS and other EBV-related disorders.Studying mono is proving more difficult than I thought. This is based on changes to medical practice induced by COVID. Many people presenting with a sore throat are not seen face-to-face by doctors, and very few receive tests to diagnose the specific cause. Many patients are now managed remotely, and many see their local pharmacist. This means that many people who have mono are not being treated appropriately; they are inappropriately prescribed antibiotics to cover strep. Antibiotics are prescribed to cover strep and prevent the development of post-streptococcal-associated autoimmune disease. The good news is that we will change this practice and have put in place a pathway to diagnose both strep sore throats and mono, in the hope of studying them to see if we can find an immunological signature associated with autoimmunity, and then try to prevent this signature with an antiviral that targets EBV.If this study is successful, we hope to secure funding for a large, multicentre randomised controlled trial to develop a treatment for mono. If anyone from the pharma industry is reading this newsletter, can I urge you to consider creating new antiviral drugs to target EBV? There is a large market, and there is a good chance that such a treatment will profoundly impact post-mono autoimmunity. If such a therapy gets licensed, it will provide a reason for primary care HCPs to diagnose and treat mono. If our hypothesis is correct, we would then see a gradual decline in the incidence of new cases of MS and other EBV-associated autoimmune diseases. Wouldn’t that be amazing?Now that we have the diagnostic pathway set up for strep sore throats and acute mono, we would be interested in whether you would be willing to participate in the studies we propose. If you have time, we would greatly appreciate it if you could watch this short video that explains our studies and then complete a brief online survey. This would take about 2-3 minutes to complete. The survey results will then be used to support our ethics application for the proposed studies. Thank you for being so supportive; we would be able to do this kind of research without your help.Have any of you had mono? If yes, was it severe? Can you imagine a counterfactual of taking a 7-day course of antivirals to treat your mono and never having developed MS? This thought has consumed thousands of hours of my time. Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

People with MS can report alterations of consciousness, self-perception, and reality testing. Among these neuropsychiatric phenomena, dissociative states—ranging from transient feelings of unreality to chronic depersonalisation-derealization disorder (DPDR) and non-epileptic seizures (NES) - can occur in pwMS and are often undiagnosed.PwMS have an elevated risk of experiencing dissociative phenomena arising from lesions in the temporal and parietal lobes, which can disrupt neural networks responsible for embodied self-awareness (organic dissociation). Psychogenic dissociative states can also occur as a result of the psychological trauma of diagnosis and the high prevalence of comorbid post-traumatic stress disorder (PTSD) in pwMS. Finally, dissociated states can be induced by pharmacological interventions, particularly high-dose corticosteroids and psychoactive symptomatic treatments (iatrogenic dissociation).As you know, the prevalence of psychiatric comorbidities in MS is high, with depression and anxiety affecting up to 50% of pwMS. Dissociation is typically defined as a disruption in the integration of consciousness, memory, identity, emotion, perception, body representation, motor control, and behaviour. The most frequently reported dissociative symptoms in the MS population fall under the spectrum of depersonalization-derealisation.Depersonalisation (the fragmentation of self)Depersonalization is characterised by a persistent or recurring feeling of being detached from one’s own body or mental processes. PwMS describe this as feeling like an “outside observer” of their life, or as if they are an automaton or “robot” with no control over their speech or actions. In MS, depersonalisation is associated with parietal lobe lesions or spinal cord damage, which disrupts joint position and proprioceptive feedback. PwMS may experience their limbs as “alien” or not belonging to them. Please note that this is not a delusion, as reality testing remains intact, but rather a sensory failure in which the “body schema” (the brain’s internal map of your body) no longer matches the physical body. A patient may see their hand move and intellectually know it is theirs, but lack the subjective feeling of agency or ownership over the movement.Derealisation (the distortion of the world)Derealisation involves a subjective sense of detachment from the surroundings. The external world may appear foggy, dreamlike, lifeless, colourless, or artificially two-dimensional. Objects may appear distorted in size or shape; macropsia is when things appear prominent, and micropsia is when they are small. With derealisation, sounds may seem muted or distant. For pwMS, derealisation is frequently exacerbated by sensory deficits. Optic neuritis, a common initial presentation of MS, causes visual blurring, colour desaturation, and visual field defects. When the brain receives degraded visual input, it struggles to construct a vivid, “real-feeling” model of the environment, which can lead to a secondary sense of derealisation. It never ceases to amaze me how often pwMS who have optic neuritis complain of weird visual symptoms. I am sure many of you can relate to this.Vestibular dysfunction (vertigo) is often associated with derealisation, as a mismatch between visual and vestibular signals can cause pwMS to feel disoriented.Non-epileptic seizures (NES)NES, also referred to as dissociative seizures, represents one behavioural manifestation of dissociation. These events resemble epileptic seizures — involving convulsive movements, apparent loss of consciousness, and stiffening of the body — but are not caused by abnormal neuronal discharges on EEG. Instead, these non-epileptiform attacks are psychological and are thought to be a mechanism for managing distress or trauma. The relationship between MS and PNES is complicated by the fact that MS patients are also at a higher risk for epilepsy due to cortical pathology. MRI studies suggest that lesions in the right hemisphere and the frontal lobes may predispose the brain to the generation of non-epileptic seizures.Dissociative amnesia and brain fogDissociative amnesia is the inability to recall important personal information, usually of a traumatic or stressful nature, that is inconsistent with ordinary forgetting. In MS, this poses a diagnostic challenge due to the high prevalence of cognitive dysfunction that affects processing speed and working memory. In a study differentiating organic memory loss from dissociative amnesia in MS, it was found that self-reported memory problems were significantly associated with high levels of dissociation and emotional distress (anxiety), but not with objective performance on neuropsychological tests (see paper below). This implies that what many pwMS experience as “memory loss” is often a failure of attention due to a mild dissociative state or emotional preoccupation, rather than a structural deficit in memory formation or hippocampal function.Dissociative identity disorder (DID)While rare, cases of DID, characterised by the presence of two or more distinct personality states, have been documented in pwMS. These cases typically have childhood trauma, which predisposes the individual to develop dissociation, with the onset of MS acting as a further stressor that may destabilise the identity systems. Other symptoms of DID can include functional weakness and sensory loss, which can mimic MS relapses, leading to potential misdiagnoses.MechanismsUnlike dissociative disorders in the general psychiatric population, which are primarily conceptualised as psychogenic, dissociation in MS often has a neuroanatomical correlate. The MS disease processes of demyelination, axonal transection, and grey matter involvement disrupt brain functional connectivity, leading to disconnection syndromes in which the disruption of white matter tracts isolates cortical regions from one another, preventing the integration of sensation, emotion, and cognition into a conscious experience.The temporal lobes play a central role in memory encoding, emotional processing, and the integration of auditory and visual inputs. Lesions in these areas are associated with psychiatric manifestations in MS, including psychosis and dissociation. The temporal lobe also houses the amygdala (emotion) and the hippocampus (memory). Demyelination in the white matter tracts connecting these limbic structures to the frontal cortex (uncinate fasciculus) or to sensory cortices can disrupt the emotional content of an experience.When a pwMS perceives a familiar object or person, the visual cortex sends data to the limbic system to retrieve the associated emotional resonance (e.g., warmth, recognition). If MS lesions sever this connection, the pwMS perceives the object accurately but feels no emotional familiarity with it. This mismatch, i.e. recognition without feeling, is the core of derealisation and the “jamais vu” phenomenon (the strange feeling that a familiar situation, word, or place is suddenly unfamiliar and new) often reported in temporal lobe disorders.Temporal lobe epilepsy (TLE)MS plaques in the temporal cortex can act as epileptogenic foci. Even in the absence of overt convulsions, erratic electrical activity in the temporal lobes can induce “dreamy states,” profound déjà vu, or feelings of unreality that mimic the aura of TLE. Symptoms of depersonalisation disorder overlap with those experienced in TLE, particularly regarding anomalous body experiences and memory distortions. A case report of a pwMS detailed first-episode psychosis and paranoia directly linked to acute lesions in the temporal lobe. His symptoms, including auditory hallucinations and persecutory delusions (”they are out to get me”), abated with treatment of the MS flare, confirming the organic origin of the dissociative state (Yadav & Zigmond. Temporal lobe lesions and psychosis in multiple sclerosis. BMJ Case Rep. 2010 Oct 12;2010:bcr0120102651).Parietal lobeThe parietal lobe is responsible for integrating sensory information to form a single perception (cognition) and constructing a spatial coordinate system to represent the world around us. The brain maintains an internal model of the body, or “body schema,” constantly updated by sensory inputs from the spinal cord. MS lesions in the parietal lobe or the posterior columns of the spinal cord deprive the brain of this data.When the brain ceases to receive reliable input from a limb, it may “dissociate” that body part from the self-image. This can manifest as asomatognosia (the inability to recognise parts of one’s own body), somatoparaphrenia (the delusion that a limb belongs to someone else) and/or depersonalisation (a generalised feeling that one’s physical form is merely a vessel or a machine, distinct from the observing self).The temporoparietal junction (TPJ) is a hub for integrating vestibular (balance), visual, and somatosensory signals to locate the self in space. Electrical stimulation of the TPJ has been shown to induce out-of-body experiences. In MS, lesions affecting the TPJ or the brainstem vestibular pathways can trigger these dissociative events. The pwMS may feel they are floating above their body or viewing themselves from a third-person perspective. This is often precipitated by vestibular dysfunction; studies indicate a correlation between vestibular disease and derealisation, as the brain attempts to reconcile conflicting spatial data.Occipital lobeLesions in the occipital lobes or the optic radiations can lead to complex visual distortions that can trigger derealisation. Alice in Wonderland Syndrome is a perceptual distortion in which objects appear much smaller (micropsia) or much larger (macropsia) than they actually are. This can occur in MS when lesions involve the visual association areas. PwMS can experience two-dimensional vision; they report that the world appears “flat,” like a painted backdrop. This loss of depth perception contributes to the feeling of living in a movie or a simulation, a feature of derealisation.Clinico-radiological paradoxThe clinico-radiological paradox refers to the discrepancy between the number and volume of MS lesions seen on MRI and a patient’s level of physical disability. Some pwMS possess a massive burden of brain lesions yet maintain relatively preserved motor function (low EDSS scores). While these patients may appear physically “fine,” the “silent” lesions in associative cortices (frontal, parietal, temporal) may disrupt high-order cognitive and emotional networks. This group may be at high risk for subjective dissociation—feeling internally fragmented or cognitively detached—while objective observers (and disability scales) fail to register any deficit. These hidden symptoms can further exacerbate the patient’s sense of isolation and unreality.Trauma-related aetiologiesWhile focal MS lesions provide the “hardware failure” that enables dissociation, psychological factors often provide the “software trigger.” MS is an inherently traumatic, chronic, and unpredictable condition that requires psychological adjustment. Receiving a diagnosis of MS should be classified as a medical trauma. Many pwMS fulfil the diagnostic criteria for having PTSD explicitly related to their MS diagnosis and prognosis. I have discussed this issue before on MS-Selfie (please see, ‘How common is post-traumatic stress disorder in people with MS?’, 4-Sept-2021). The onset of a chronic, incurable, and potentially disabling neurological condition affects one’s fundamental assumptions of invulnerability and future planning. In the face of this existential threat, dissociation serves as an adaptive defence mechanism — a “mental flight” when physical flight is impossible. By detaching from the reality of the diagnosis, the pwMS attempt to shield themselves from overwhelming anxiety and grief. I know this sounds dramatic, but it represents one model for why pwMS develop dissociative disorders.We know that the diagnostic MS journey often involves invasive procedures (lumbar punctures), frightening MRI experiences (claustrophobia), and hospitalisations. These repeated exposures to threat and a feeling of helplessness can induce a state of chronic hyperarousal and subsequent dissociation, consistent with the dissociative subtype of PTSD.Question: I would be interested to know if any of you have been diagnosed with the dissociative subtype of PTSD?Childhood traumaResearch has demonstrated the relationship between childhood trauma, dissociation, and possibly the development of MS. Severe stress, neglect, or abuse in childhood permanently dysregulates the hypothalamic-pituitary-adrenal (HPA) axis. This results in a chronic pro-inflammatory state and altered cortisol responses, which may increase biological susceptibility to developing MS later in life. Large-scale cohort studies indicate that women who experienced childhood abuse are significantly more likely to develop MS in the future (see Rehan et al. Association of adverse childhood experiences with adulthood multiple sclerosis: A systematic review of observational studies. Brain Behav. 2023 Jun;13(6):e3024).Iatrogenic causesThe management of MS involves disease-modifying therapies (DMTs) and corticosteroids for acute relapse management. Many of these agents have significant neuropsychiatric side effects that can mimic, induce, or exacerbate dissociative states. High-dose intravenous methylprednisolone (IVMP) (e.g., 1000mg daily for 3-5 days) is the standard of care for speeding up the recovery from acute MS relapses. It is well-documented to cause acute psychiatric disturbances. Psychiatric adverse effects occur in a large number of patients treated with corticosteroids and are typically dependent on dose. Symptoms often begin with insomnia and euphoria but can progress to severe mood lability, anxiety, and frank dissociation and delirium. Patients may experience a “steroid high” followed by a crash into depression, or develop acute psychosis with hallucinations and confusion. Corticosteroids enhance dopamine activity. They may cause acute, reversible reductions in hippocampal volume. The effect of corticosteroids on the brain presumably decouples the patient from reality, leading to a temporary dissociative or psychotic state that resolves upon tapering the medication.Interferon-beta has a longstanding association with depression and anxiety. Interferons are cytokines that induce a pro-inflammatory response similar to “sickness behaviour,” which includes social withdrawal, fatigue, and anhedonia. They may also decrease serotonin levels in the brain. While direct dissociation is less common, the severe anxiety and depression induced by interferons presumably lower the threshold for stress-induced depersonalization.Natalizumab is a highly effective monoclonal antibody, but it carries specific risks. The “crap gap” often reported as a “wearing off” effect in the week preceding the next infusion can be characterised by intensifying fatigue, cognitive fog, and mood instability, which can manifest as a feeling of detachment or unreality. The most severe risk associated with natalizumab is progressive multifocal leukoencephalopathy (PML). PML causes extensive, rapid demyelination that can lead to confusion, personality changes, and cognitive decline. These symptoms can be misinterpreted as psychiatric dissociation or dementia in the early stages.Fingolimod, an S1P modulator, has been associated with posterior reversible encephalopathy syndrome (PRES). This condition involves vasogenic oedema in the posterior brain regions (parietal/occipital lobes). It presents with acute confusion, visual changes, headaches, and altered consciousness—a constellation of symptoms that could mimic derealisation and dissociation.Abrupt withdrawal of baclofen and tizanidine, which are used for spasticity, can cause severe delirium, hallucinations, and dissociation. Similarly, gabapentin and pregabalin, which are often used in pwMS to manage neuropathic pain, can cause sedation and cognitive clouding (”zombie-like” feeling) that contributes to depersonalisation.DiagnosisDiagnosing a dissociative state in an MS patient requires the exclusion of organic mimics before attributing symptoms to a purely psychogenic cause. A diagnostic algorithm should do the following:* Rule out an MS relapse: any new onset of psychiatric or dissociative symptoms warrants an MRI with gadolinium. New lesions in the temporal, parietal, or frontal lobes can directly cause these symptoms.* Rule out infection (delirium): Urinary Tract Infections (UTIs) are extremely common in MS and are the leading cause of acute confusional states (delirium) that can mimic dissociation. A urinalysis and work-up for other infections is mandatory.* Medication review: assess for recent steroid use, anticholinergic burden (bladder meds), or withdrawal from muscle relaxants (baclofen and tizanidine).48* Neuro-otological examination: assess for nystagmus and vestibular dysfunction. Treating vertigo may resolve the derealisation.* Psychological screening: Your HCP can use the Dissociative Experiences Scale (DES) or the Dissociative Disorders Interview Schedule (DDIS) to quantify symptom severity. PwMS generally score in the normal range on the DES unless they have comorbid DID or PTSD, but helping to differentiate organic from psychiatric dissociation is difficult. It may require a referral to a neuropsychiatrist. MS-related cog-fog or cognitive impairment is characterised by slowed processing speed, word-finding difficulties, and fatigue. Patients try to engage but fail.* In comparison, dissociation is characterised by a subjective sense of detachment (”I am not here”). Patients may have preserved processing speed but feel emotionally disconnected. As noted above, MS cog-fog often contains a dissociative component driven by anxiety. Treating the anxiety usually clears the “cog-fog” more effectively than cognitive rehabilitation alone.ManagementManaging dissociative states in MS requires a dual approach: treating MS, i.e. a biological approach, and using psychological strategies.Pharmacological ManagementThe primary prevention of organic dissociation is preventing new lesion formation. High-efficacy DMTs are the best way to preserve brain volume and connectivity. Psychotropics such as SSRIs (e.g., fluoxetine, sertraline) can help manage the anxiety and depression that underlie DPDR. They may also help with MS-related fatigue. Antipsychotics (e.g., quetiapine, olanzapine) may be rarely indicated for managing steroid-induced psychosis or organic paranoia related to temporal lobe lesions. Lamotrigine and other anticonvulsants can be used for both seizures and depersonalization; they are particularly beneficial in patients with temporal lobe pathology.Psychotherapeutic interventionsCognitive behavioural therapy (CBT) is the gold standard for treating DPDR. It helps patients reframe the terrifying sensation of “going crazy” or “disappearing” as a harmless, albeit distressing, symptom of anxiety or the disease. This reduces the catastrophic thinking that perpetuates the dissociation.Eye Movement desensitisation and reprocessing (EMDR) can be effective for MS-related PTSD (medical trauma) or childhood trauma. However, standard EMDR can be overwhelming for patients with dissociation. I have read that protocols can be modified (e.g., “titrated” EMDR) to prevent flooding the patient with traumatic memories before they have stabilisation skills. I have no personal experience with EMDR, but it is available via some NHS psychiatric services.Grounding and mindfulness are techniques that anchor the patient in the present moment (e.g., holding an ice cube, describing the environment) and help manage acute episodes of derealisation. Mindfulness-based stress reduction (MBSR) has shown efficacy in improving quality of life and reducing depressive symptoms in people with multiple sclerosis (pwMS.Vestibular rehabilitation should be offered to pwMS where derealization is driven by vertigo, and physical therapy to improve balance and gaze stability can directly reduce the feeling of unreality.I am writing this newsletter as this is one of the stops on my MS-Selfie Self-Management tube map (version 9.0) that I have not covered before.This newsletter will form one of the sections in the chapter on psychiatric manifestations of MS, with a link to one of the hidden symptoms of MS. This is yet another MS-related group of symptoms that is probably neglected in routine MS neurological practice and may fall through the cracks.Questions: Have any of you experienced dissociative symptoms? Did you bring this up with your HCPs? How was it handled? I.e., were you investigated, diagnosed appropriately, and offered treatment for your symptoms? Or is this issue new to you, i.e. is this the first time you have heard about dissociative symptoms being linked to having MS?PaperBruce et al. Self-reported memory problems in multiple sclerosis: influence of psychiatric status and normative dissociative experiences. Arch Clin Neuropsychol. 2010 Feb;25(1):39-48.Multiple sclerosis (MS) patients’ self-reported cognitive difficulties do not typically correlate well with objective neuropsychological assessment. The relationship between self-reported memory, dissociation, emotional problems, and objective cognitive functioning was examined in 79 MS patients. Increased self-reported memory problems were significantly associated with higher levels of normative dissociation. Self-reported memory problems were also associated with more reports of depression, anxiety, and neuroticism. Consistent with expectations, self-reported memory was not significantly associated with performance on any of the neuropsychological variables. The present study then evaluated a theoretical causal model with normative dissociation mediating the relationship between emotional problems and perceived cognitive problems. Increased depression, anxiety, and neuroticism were all significantly correlated with more dissociative cognitive failures, which, in turn, were strongly associated with perceived memory problems. Findings have significant theoretical implications for understanding the relationship between perceived and objective cognitive difficulties. Findings are also clinically relevant and suggest that dissociative experiences should be evaluated when MS patients report memory problems.Accidental readersIf 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.Subscriptions and donationsMS-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 ([email protected]).QuestionsIf you have questions unrelated to the newsletters or podcasts, please email them to [email protected]. Prof. G will try to answer them as quickly as possible.Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumThanks for reading MS-Selfie! This post is public, so feel free to share it.General DisclaimerPlease 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. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I just received a howler of an email from an MS-Selfie reader accusing me of neglecting people with primary progressive MS (pwPPMS) and of being a charlatan for running a subscription model. They concluded by asking me to unsubscribe them from MS-Selfie to stop receiving future emails.So the questions I have for you are, do you think I am neglecting people with primary progressive MS? What additional information do you need me to cover? And do you think the two-tiered funding model of MS-Selfie needs changing? The regular funding from subscriptions supports the development of the MS-Selfie microsite, MS-Selfie infocards, the MS-Selfie Self-Management Guides and future MS-Selfie initiatives that are planned. Without funding, the development of these would have to stop.In response to this person’s email, I have prepared the following for people who have recently been diagnosed with PPMS. It may also be helpful to read some older MS-Selfie Newsletters:* Diagnosing MS: what to expect? (10-03-2023)* The annual MS follow-up consultation (26-06-2023)* What to do about MS follow-up consultations that are too short? (07-08-2024)Receiving a diagnosis of MS and PPMS in particular is a life-changing event, and it is entirely normal to feel overwhelmed. I would therefore suggest going into your neurology appointments prepared with questions, which can help you feel more in control, understand your condition, and partner with your healthcare team to make informed decisions.Here is a list of questions to ask your neurologist or healthcare professional, organised by category. You don't need to ask all of them at once; pick the ones that are most important to you for your next appointment. Tips for your appointment* Take someone with you: A family member or trusted friend can provide support, help you remember what was said, and ask questions you might not have thought of.* Write down the answers: Or ask if you can record the audio of the consultation on your phone to review later.* Prioritise your questions: Star or highlight the 3-5 questions that are most important for you to have answered during this specific visit.* Be honest: Be open about your symptoms, fears, and what you hope to achieve.Category 1: Understanding Your DiagnosisThese questions help clarify the specifics of your situation.* Certainty of diagnosis: How certain are you that I have PPMS and not another form of MS or a different condition? What in my MRI, spinal fluid (lumbar puncture), or other tests points specifically to PPMS?* Meaning of PPMS: Can you explain in simple terms what "primary progressive" means and how it's different from relapsing-remitting MS?* Current status: Based on my scans and symptoms, what is the current state of my MS? Can you show me the lesions on my MRI and explain what they mean?* Cause: Do we know what might have caused my MS? Is there anything I did to cause this? (The answer is almost always no, but it can be reassuring to hear.)Category 2: Prognosis and ProgressionThese questions are about the future, but remember that a neurologist cannot predict the future with certainty. They can only speak about general patterns.* Typical progression: What does a typical course of PPMS look like? Since progression is a key feature, how will we monitor it?* Personal factors: Are there any factors in my specific case (e.g., age, location of lesions, initial symptoms) that give you an idea of how my MS might progress over time?* Key indicators: What are the key signs or symptoms I should watch for that would indicate a significant change or progression?* Life expectancy: Does PPMS affect life expectancy?Category 3: Treatment and disease managementThis is a critical area, mainly since treatment options for PPMS have recently emerged.* Disease-modifying therapies (DMTs): What disease-modifying therapies are approved for PPMS? Am I a candidate for them (e.g., Ocrelizumab/Ocrevus)?* Treatment goals: What is the primary goal of this treatment? Is it to slow progression, manage symptoms, or both? What level of success can I realistically expect?* Risks and benefits: What are the potential short-term and long-term side effects and risks of this treatment? How do these weigh against the possible benefits for me? What can be done to derisk these issues?* Administration and monitoring: How is the treatment given (e.g., infusion, injection)? How often? What kind of monitoring (blood tests, MRIs) will I need while on this therapy?* Alternative options: If I am not a candidate for a DMT, or if I choose not to take one, what is our plan?* Clinical trials: Are there any clinical trials I could consider?Category 4: Symptom managementThis focuses on your day-to-day quality of life.* Specific Symptoms: I am currently experiencing [list your symptoms: e.g., fatigue, leg stiffness, balance issues, bladder urgency, pain]. What can we do to manage these?* Mobility: What can I do to maintain my mobility and balance for as long as possible? Would physiotherapy be helpful?* Fatigue: My fatigue is a significant issue. What are the best strategies for managing MS-related fatigue?* Pain and spasticity: What medications or therapies are available for nerve pain, muscle stiffness (spasticity), or spasms?* Bladder, bowel and sexual dysfunction: Are bladder and bowel issues common? Who can I talk to if these become a problem? What can be done for my sexual problems?* Cognitive and Mood Changes: Should I be aware of potential cognitive changes ("brain fog") or mood changes like depression and anxiety? What support is available for this?Category 5: Lifestyle and wellnessThese are questions about what you can do to help yourself.* Exercise: What type and amount of exercise is safe and beneficial for me? Is there a type I should avoid?* Diet and nutrition: Is there a specific diet you recommend for people with MS? Are there any foods I should avoid?* Supplements: Should I be taking any vitamins or supplements, such as Vitamin D? If so, at what dosage?* Stress and work: How does stress impact PPMS? Do you have any advice on managing my condition at work?Category 6: Your healthcare team and supportA team best manages MS.* MS Team: Besides you, who else should be on my healthcare team? (e.g., MS Specialist Nurse, Physiotherapist, Occupational Therapist, Psychologist). How do I get referrals?* Communication: Who is my main point of contact between appointments if I have a question or a new symptom? What is the best way to contact them?* Urgent issues: What symptoms would you consider an emergency that requires immediate medical attention?* Support resources: Can you recommend any reliable resources for information and support, such as the MS Society, the MS Trust, or local support groups?Category 7: MS research* Is there any research into PPMS that I need to know about?* Is there anything I can do to help participate in research?Choosing the right questions for you will help you turn a daunting appointment into a productive conversation about your health and future. You are your own best advocate.An alternative view of PPMSI have made the argument over and over again that MS is one, not two, three or four diseases. You either have MS or you don’t. PPMS is simply MS, and people who are diagnosed with PPMS miss out on having relapses. About a quarter of pwPPMS will subsequently go on to have relapses and are referred to as having progressive relapsing MS. As we move to a biological definition of MS, the clinical descriptors are likely to be relevant in terms of treatment targets, i.e. we want to render pwMS NEIDA (no evident inflammatory disease activity) and NESDA (no evident smouldering disease activity).How many of you use the search function on the MS-Selfie Substack website? When I put in the search term ‘primary progressive’, I get back a pretty large number of newsletters dedicated to PPMS. In addition, there is the MS-Selfie microsite you can use. A helpful section is the one on ‘What type of MS do I have?’.I have hypothesised that the real MS is smouldering MS, and the immune response to what is causing MS is what drives focal inflammation (relapses and MRI activity). The clinically-apparent progressive phase of MS is simply a manifestation of a loss of reserve in that particular part of the nervous system, and the reason why progressive MS tends to affect the motor system in the lower limbs relates to the length of the axons subserving lower limb function. The longer the axons, the more likely they are to have multiple hits and the more likely they are to degenerate early. I, therefore, refer to MS as a length-dependent axonopathy.So if you are newly diagnosed with MS and are an MS-Selfie newbie, I would spend time on the MS-Selfie microsite and then cover the following old MS-Selfie Newsletters.* Is your MS salvageable? (03-11-2022)* Relapses versus Progression (16-12-2024)* Getting worse (02-07-2021)* Is primary progressive MS a different disease? (20-09-2022)Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have just returned from a lecture tour of Canada, which included four cities in four days and 12 speaking arrangements. My host's hospitality and kindness were exceptional. Thank you, thank you. I felt appreciated. I have previously done lecture tours of Canada, Australia, and India. People, including my wife, often ask why I accept these invitations, as they are gruelling. I suspect it is flattery, i.e., it is nice that people still want to hear you talk even when you are in the twilight of your career and dodging bullets in snipers' alley. Yes, I have just had my second melanoma excised, and I am waiting for the histology report. The period of not knowing a result that could have significant implications for your management is what you must go through every year you have a monitoring MRI. It is anxiety-inducing. The other side of travel and lecture tours is thinking and feedback time. When you get away from the Toads, you have time to test new ideas and revisit old ideas and concepts with a critical audience. The Canadian audiences asked difficult questions. All of this helps refine your thinking. Please note that Toads references the late Philip Larkin’s poem about work (it is one of my favourites). Whilst away, you also get time to read new literature and listen to new things without being distracted by Toads.Toads, by Philip Larkin (March 1954)Why should I let the toad workSquat on my life?Can't I use my wit as a pitchforkAnd drive the brute off?Six days of the week it soilsWith its sickening poison -Just for paying a few bills!That's out of proportion.Lots of folk live on their wits:Lecturers, lispers,Losers, loblolly-men, louts-They don't end as paupers;Lots of folk live up lanesWith fires in a bucket,Eat windfalls and tinned sardines-They seem to like it.Their nippers have got bare feet,Their unspeakable wivesAre skinny as whippets - and yetNo one actually _starves_.Ah, were I courageous enoughTo shout, Stuff your pension!But I know, all too well, that's the stuffThat dreams are made on:For something sufficiently toad-likeSquats in me, too;Its hunkers are heavy as hard luck,And cold as snow,And will never allow me to blarneyMy way of gettingThe fame and the girl and the moneyAll at one sitting.I don't say, one bodies the otherOne's spiritual truth;But I do say it's hard to lose either,When you have both.CanadaBefore I started the tour, Canadian neurologists were asked what they wanted to hear me speak about. The themes were:* The new MS McDonald criteria: what I thought of them and how their implementation would change MS practice.* Emerging challenges in the management of MS: I focused on making MS one disease and targeting smouldering MS.* Ageing and MS: Does late-onset MS differ from young-onset MS, and how does age affect MS management? Interestingly, this is the one talk I never delivered.* EBV and MS prevention: This is closest to my current research interest.You can download them from my file-sharing site to read, hack, and use the slides in your talks. Many years ago, I realised that my job as an academic is creating and disseminating knowledge. Knowledge creation is your research output, and dissemination is communicating your findings via conferences, publications, lectures, blogs, podcasts, patents or teaching. To help disseminate knowledge, I share my slides with anyone who wants to read and learn from them. I don’t mind people hacking my slides for their talks; please proceed. And if you disagree with them, let me know! EBV immunotherapiesMany Canadian neurologists asked about using EBV-targeted immunotherapy to treat MS. The discussion revolved around the recent failure of Atara Bio's allogeneic cytotoxic T-cell therapy, Moderna’s EBV therapeutic vaccine trial, which will be starting soon, and B-cell and EBV-targeted CAR T-cell therapies.In MS, the T-cell response to EBV is exhausted, particularly the CD8+ cytotoxic T-cells (CTL) response, which leads to poor virus control. This is why, in pwMS, EBV is often found to be cycling through its latent and lytic infection cycles. This latent-lytic-cycling is at the core of the driver hypothesis of how EBV causes MS. We and others have proposed to use EBV-targeted immunotherapy as a treatment for MS. The adoptive transfer of in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was shown to work in a proof-of-concept study by Michael Pender’s group. This approach was then explored using the adoptive transfer of partially MHC-matched allogenic EBV-specific T-cells (Atara Bio). However, the phase 2 EMBOLD trial of ATA188 in non-active progressive multiple sclerosis was negative. I have discussed this trial on many occasions on MS-Selfie. Whether this trial failed because of the poor survival of these allogeneic cells is unknown. Other possibilities include poor trial design, i.e. targeting people with too advanced MS and severe disability, and expecting a read-out within 12 months was unrealistic. Another factor is the product itself. How good was it compared to freshly prepared autologous cells?Moderna’s approach will use an EBV RNA vaccine to boost the immune responses to EBV. Many centres in Canada are participating in this trial, and our centre at Barts Health has also put up its hand. My problem with the Moderna approach is that if the immune system of pwMS sees EBV all the time, i.e., from latent-lytic cycling, why will a vaccine work? Will the vaccine sufficiently wake the EBV-specific T-cells from their senescing slumber? I have hypothesised that the vaccine will not be potent enough to achieve its aims. What is needed is to reverse the T-cell exhaustion or senescence that characterises MS-associated T-cell responses. Agents that do this in cancer are called immune checkpoint inhibitors (ICI). A therapeutic EBV vaccine may need an ICI to boost T-cell responses, which will then control EBV and MS disease activity. Moderna know about this strategy as their latest therapeutic melanoma vaccine is being tested with pembrolizumab (Keytruda), the biggest selling ICI.In support of this is the observation that IRT (immune reconstitution therapies) such as autologous haematopoietic stem cell transplantation (AHSCT) or alemtuzumab may be working like this already. The depletion cycle of both AHSCT and alemtuzumab has a paradoxical effect, resulting in EBV reactivation as T-cell and NK-cell function is impaired. However, when NK-cells and T-cells repopulate, they are rejuvenated and provide an effective EBV-specific T-cell response, which enables them to control EBV. Notably, almost all MS patients undergoing AHSCT have EBV viraemia detected in the peripheral blood, which supports this mechanism.Many Canadian neurologists queried my suggestion about using an ICI in pwMS. However, contrary to current dogma, pwMS with comorbid cancer seem to tolerate ICIs without obvious recrudescence of MS disease activity. This observation is a powerful argument against MS being a T-cell-mediated autoimmune disease. The CNS demyelination cases triggered by ICIs appear to be ADEM and not MS, which makes sense as ADEM is a T-cell-mediated disease. ADEM is the human equivalent of EAE (experimental allergic encephalomyelitis), the main animal model of MS, which is primarily driven by T-cells.The obvious question from these observations is whether ICIs could be used as a monotherapy to treat MS. Do we need an EBV therapeutic vaccine at all; can’t we rely on endogenous EBV to trigger autoimmunity? I suggest Moderna take a step back and do a small proof-of-concept study looking at the EBV-specific immune responses that their vaccine induces in a small number of pwMS. If they don’t overcome the T-cell exhaustion, they could test their vaccine in combination with an ICI to ensure it works immunologically before doing a costly phase 2 trial. But who am I to pontificate about what will and won’t work in MS in relation to the EBV hypothesis?Another thing that resurfaced in my consciousness is that if EBV causes MS, it has to explain everything about the disease. For example, AHSCT and alemtuzumab have such a dramatic effect on stopping the end-organ damage that is occurring in MS, as neither of these treatments has direct CNS effects. The T-cell rejuvenation and EBV autovaccine hypothesis addresses this conjecture to some extent, as activated EBV-specific T-cells will traffic to the CNS and inhibit the impact of EBV infection.Further reading* Atara Bio's EMBOLD study is negative, 9-Nov-2023* Q&A 74: AHSCT with ATG vs AHSCT with rituximab vs alemtuzumab, 14-Feb-2025Paper of interestGelibter et al. Do immune checkpoint inhibitors affect the course of multiple sclerosis? A systematic review and meta-analysis. Eur J Neurol. 2025 Jan;32(1):e16547.Background and purpose: Elderly people with multiple sclerosis (pwMS) present higher probability of malignancies. Immune checkpoint inhibitors (ICIs) improve cancer prognosis but pose risk of disease flares in people with pre-existing autoimmune conditions, including MS. Data addressing the impact of ICIs on MS are scarce. This systematic review and meta-analysis evaluates the effects of ICIs on MS disease activity.Methods: A systematic literature search in Google Scholar and PubMed, following PRISMA 2020 guidelines, identified five observational studies. Data on clinical and neuroradiological outcomes were analyzed using random-effects models.Results: The clinical activity meta-analysis included 90 pwMS undergoing ICI therapy (median follow-up = 0.62-1.85 years, 103.74 patient-years). The pooled relapse rate was 5.45 per 100 patient-years (95% confidence interval [CI] = 1.86-14.92). Median time to relapse was 1 month after the ICI start (range = 0.4-6 months). No relapse occurred after 58 years. The neuroradiological activity meta-analysis was conducted on 36 pwMS (median magnetic resonance imaging [MRI] follow-up = 0.75-1.85 years, 41.94 patient-years). The pooled new MRI lesion rate was 24.9 per 100 patient-years (95% CI = 10.9-47.3), with median time to new MRI lesions of 3 months (range = 1-6 months). In 80% of cases, disease-modifying treatment (DMT) was suspended at ICI initiation.Conclusions: We found a low relapse rate in pwMS following ICI treatment, with no events in older pwMS. The risk of neuroradiological activity appears higher, but mainly occurs in pwMS who discontinued DMT. All events occurred within the first 6 months of ICI therapy. These conclusions are based on small observational studies, highlighting the urgent need for further research on this topic.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Do we need to challenge the dogma that traditional MRI is good enough to monitor MS?Our current treatment target in MS is no evident inflammatory disease activity or NEIDA. In other words, there should be no relapses or focal MRI activity (new or expanding T2 lesions or Gd-enhancing T1 lesions).Question: Is the NEIDA treatment target appropriate?I don’t think so for several reasons.Not all relapses are relapsesIf you have MS, you are likely to attribute new neurological symptoms, particularly if they persist, to a relapse. Can you be sure it is a relapse and not a pseudorelapse?Differentiating pseudorelapses from relapses can be challenging, as pwMS are often unaware of preexisting deficits in the particular neuronal pathway from which the new symptoms arise. The recurrence of old symptoms, such as blurred vision in an eye previously affected by optic neuritis, is easy to understand. However, new symptoms in a pathway affected by smouldering MS are typically interpreted as a relapse. Smouldering MS gradually reduces the neurological reserve in a path that then becomes exposed when you have a pseudorelapse (see figure below).Before the physical (exercise), cognitive (exam) or systemic insult (infection or pyrexia) that caused the pseudorelapse, the pwMS would say this pathway was unaffected by MS. It is only when it is stressed that the pwMS develop symptoms. The stressor acts as a neurological stress test to expose pre-existing damage, albeit in a neurological path not previously affected by a symptomatic relapse (please note that I refer to new Gd-enhancing lesions without symptoms as asymptomatic relapses).In the future, we will distinguish between biochemically confirmed relapses (new focal inflammatory activity) and pseudorelapses by measuring blood neurofilament levels. A new lesion will likely cause new damage, transecting axons and releasing neurofilaments into the blood. In comparison, pseudorelapses are caused by a temporary conduction block in a previously damaged pathway and will not be associated with a neurofilament spike. Relapses will be classified as “biochemically confirmed” or “biochemically unconfirmed” relapses, with the former being much more severe.Please be aware that only three of four relapses (75%), confirmed by a neurologist, are associated with new MRI activity (new or Gd-enhancing lesions), i.e. only 75% of relapses are MRI-confirmed. I am aware that many of these MRI unconfirmed relapses are associated with raised neurofilament levels, which may be more sensitive in detecting or confirming ‘true relapses’. This indicates that many MRI unconfirmed relapses are likely to be due to small lesions below the detection threshold of the MRI or stress-induced symptoms and signs due to loss of reserve from smouldering MS.This is why we must challenge the current dogma and definition of a relapse; patient-reported and physician-determined relapses are not good enough to document relapse disease activity.What about Gd-enhancing lesions?The detection of Gd-enhancing lesions depends on how frequently you are scanned, the dose of gadolinium administered, how long the radiographer waits before repeating the T1 scan to detect enhancement and the neuroradiologist who reads the scan. You should wait at least 10 minutes after the IV administration of gadolinium before repeating the T1 scan. I know many patients have their repeat scan done earlier than 10 minutes. The reason is that radiographers are impatient in completing the scan before moving on to the next patient. In healthcare, time is money, so the quicker you process patients, the more time you have to scan additional patients. If, on the other hand, you are prepared to wait 20 minutes after the administration of Gd before repeating the T1 scan, you are much more likely to find gadolinium-enhancing lesions. A similar story is true for triple-dose versus single-dose gadolinium. Finally, I have also seen many MRI reports being changed from non-enhancing lesions to enhancing lesions after a second opinion. I am sorry to disappoint you. Nothing is black and white regarding whether or not Gd-enhancing lesions are detected on MRI.Will enlarging T2 lesions be better?Labelling an enlarging T2 lesion as enlarging due to focal inflammation secondary to an adaptive immune response (B & T cells) from the periphery may also be a wrong call or dogma. Chronic active lesions, either PRLs (paramagnetic rim lesions) or SELs (slowly expanding lesions), become more prominent with time due to what we think is from innate immune activity and not necessarily from the influx of adaptive immune cells such as T and B lymphocytes. Can we, therefore, expect peripherally acting anti-inflammatory treatments to affect PRLs and/or SELs? This will come to a head when the T2 lesion data from the tolebrutinib study is analysed differently. Does it have a more significant effect on new T2 or enlarging T2 lesions? I predict the latter, as the data from the relapsing tolebrutinib trials, the Gemini 1&2 studies, suggest that tolebrutinib impacts how T2 lesions evolve, i.e., how much innate immune activation remains after a new Gd-enhancing lesion.Another curved ball for the MS community was the recent MS-Base study referenced below, which showed that high-efficacy DMTs were superior to low-efficacy DMTs in suppressing new lesion activity on brain MRI but not on new spinal cord lesions. The data from this study suggest that the biology of spinal cord lesions differs from that of brain lesions. Despite these patients being primarily NEIDA, spinal cord lesions appeared over time. Could these new T2 spinal cord lesions be SELs that evolve from microscopic lesions and don’t have a Gd-enhancing or relapsing phase? I say this as the current dogma states that new spinal cord lesions are more likely to be symptomatic, and this is the main reason we don’t do annual or regular spinal cord monitoring MRI scans.In the past, I was told that spinal cord activity and brain activity cluster, i.e., if you develop new lesions in the spinal cord, you are also likely to develop new brain lesions in parallel. This is another reason why brain MRI monitoring is meant to be sufficient to detect MS disease activity. Again, this dogma needs to be challenged.We may have to revisit this position as we seem to be missing important MS disease activity, albeit smouldering disease activity, that is not seen on brain MRI but on spinal cord imaging.What about new T2 lesions?Whether new and expanding T2 lesions can emerge spontaneously without going through a Gd-enhancing phase has become a critical question for the field of MS. Based on my worldview of MS, I would say yes. The MS-Base paper on the spontaneous appearance of new T2 spinal cord lesions is evidence of this. These lesions have emerged as largely asymptomatic lesions in pwMS on DMTs who are relapse-free. This implies they are emerging from the spinal cord and are independent of relapse or focal inflammatory disease activity, hence representing smouldering MS.A counterargument is that DMTs are ineffective in suppressing all focal inflammatory lesions, particularly those that are microscopic below the scanning resolution of current MRI scanners. It is vital to note that using high-efficacy DMT in patients with PIRA reduces the likelihood of long-term persistence and further PIRA events compared to lower-efficacy DMTs (see Zhu et al. below).The late Professor Giancarlo Comi always pointed out that just because you are not detecting focal inflammatory lesions clinically as relapses and/or on MRI does not mean that focal inflammation is not occurring. Sorting this out is critical for the future treatment of MS, as some people with apparent SAW may need to switch DMTs to suppress microscopic focal inflammation, and others may need a combination approach to add-on treatments to address SAW (smouldering-associated worsening).The following is a figure I have been working on to try and explain the evolution of MS lesions on MRI. Does it make sense to you? IM-SMOULDERING TrialThis is why we are proposing to test an induction maintenance strategy in patients with smouldering MS followed by an add-on CNS penetrant therapy to target smouldering MS. To be eligible for the trial, you have to have smouldering MS as detected by a PIRA event (progression-independent of relapse activity) and PRLs on your baseline scan. The latter is to enrich the study for pwMS, who are more likely to worsen in the future, i.e. having further PIRA events.We want to use AHSCT as the induction therapy as it is the most effective therapy we have and puts a large number of people with MS into remission. Do you agree with this? We need feedback from the MS community for our grant application. So, if you can spare two minutes, I would appreciate it if you could complete this short survey. Thank you.Paper 1Kreiter et al. Effectiveness of Disease-Modifying Treatment on Spinal Cord Lesion Formation in Relapse-Onset Multiple Sclerosis: An MSBase Registry Study. CNS Drugs. 2024 Nov;38(11):921-930.Background: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs.Methods: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses.Results: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p Conclusion: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.Paper 2Zhu et al. Risk factors associated with persistent progression independent of relapse activity (PIRA), and the association of persistent PIRA with disability progression in multiple sclerosis. ECTRIMS 2024 Scientific Session 5: New phenotypes O055/605.Introduction: Some patients with relapsing-remitting multiple sclerosis (RRMS) experience sustained disability progression independent of relapse activity (PIRA), which can be a sign of early secondary progressive MS (SPMS). However, PIRA events may regress over time. Persistent PIRA indicates ongoing sustained disability or progression of disability without improvement, so understanding the factors that would predict this is crucial.Objectives/Aims: To examine risk factors for persistent PIRA (defined as persisting to the end of follow-up) and the risk differences in long-term disability worsening between patients with persistent and non-persistent PIRA.Methods: This cohort study used data collected from patients enrolled in the MSBase registry between April 16, 1995 and Jan 10, 2024. The median follow-up was 6.8 years.The baseline was set at the time of PIRA occurrence. The primary outcome was time to 6-month confirmed non-persistent PIRA. The secondary outcomes were time to 6-month confirmed EDSS 6 and time to SPMS (following Lorscheider criteria). A stratified Cox regression model was used to identify the risk factors associated with non-persistent PIRA. We matched persistent PIRA patients with non-persistent PIRA patients in a 1:1 ratio (1164 patients in each group) using their propensity scores, and then compared the risk of reaching EDSS 6 using the Cox regression model. We re-matched patients with complete Kurtzke Functional Systems Scores (733 patients in each group) to compare the risk of reaching SPMS.Results: We included 3536 RRMS patients with PIRA (mean [SD] age, 42.41 [9.77]). Use of high-efficacy disease-modifying therapies (DMT) at baseline (hazard ratio [HR], 1.37; 95% CI, 1.20-1.56; pConclusion: Persistent PIRA risk was higher in older patients, with longer disease duration or worse disability at baseline. Use of high-efficacy DMT during PIRA events markedly reduced the likelihood of long-term persistence. Patients with persistent PIRA were at a substantially higher risk of reaching EDSS 6 and SPMS.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

A fact worth knowingDid you know that people with MS who have a vascular comorbidity (smoking, obesity, hypercholesterolemia, hyperlipidemia, hypertension and/or established vascular disease) need to use a walking stick about six years earlier than people who don’t have a vascular comorbidity? Now that you know this, you can’t unlearn it, so you need to do something about it. The holistic management of MSI have been pushing the concept of the holistic management of MS with a focus on both MS-specific and non-MS factors for over a decade. It is clear that factors that are poor for brain health reduce brain reserve or resilience and are associated with worse MS outcomes.A major contributor to poor MS outcomes is co-existing vascular comorbidities (smoking, obesity, hypercholesterolemia, hyperlipidemia, hypertension and established vascular disease), and people with MS are at increased risk of developing vascular comorbidities (see Marrie et al., below). This study from Canada showed that pwMS with vascular comorbidity reached EDSS 6.0 (needing a walking stick) on average 6 years earlier than pwMS without vascular comorbidities (~12 years versus ~18 years). This difference of 6 years is more significant than the treatment effect of interferon beta on slowing down the acquisition of disability progression. This is why we, as an MS community, need to be aggressive about the prevention and treatment of vascular comorbidities.The good news is, at least for pwMS in the UK, that when diagnosed with hypertension and treated, they are more likely to reach the treatment target regarding their blood pressure (see Palladino et al. below). I suspect this is because pwMS have more contact with HCPs and may understand the importance of adhering to their medication.Self-monitoring your BPAs you know, MS-Selfie stands for MS self-management and self-monitoring. I always encourage my patients to measure their blood pressure. My mistake is that I have assumed incorrectly that you know how to measure their blood pressure, which prompted me to write this newsletter.I subscribe to Journal Watch, an NEJM publication that I read weekly. It is my way of keeping up with developments in general medicine. This week, I was surprised to read a summary of the article by Clapham and colleagues that home blood pressure measurements (HBPM) are not performed according to guideline recommendations, and adults who received ad hoc education did not perform high-quality HBPM. These findings highlight a need for effective teaching to support HBPM for clinical decision-making. This is why I have posted the American Medical Association guide on HBPM so you can refresh your memory.In general, you should have your blood pressure checked at least annually and more frequently if you have risk factors for high blood pressure, a history of high blood pressure readings or have been diagnosed with hypertension.I would be interested to know how many of you self-monitor your blood pressure and how many of you have self-diagnosed yourself as having hypertension.Are these non-MS self-help newsletters helpful or simply clogging up your email inboxes?Abstracts of interestClapham et al. Home Blood Pressure Measurements Are Not Performed According to Guidelines and Standardized Education Is Urgently Needed. Hypertension. 2025 Jan;82(1):149-159.Background: Patient education is needed to perform home blood pressure measurement (HBPM) according to blood pressure (BP) guidelines. It is not known how BP is measured at home and what education is provided, which was the aim of the study.Methods: Mixed-methods study among Australian adults who perform HBPM (June to December 2023). Participants completed a 30-item online survey on whether they followed guideline recommendations and the education they received for HBPM. Phone interviews were conducted among a purposive sample to further explore survey topics.Results: Participants (n=350) were middle-aged (58±16 years; 54% women), and most (n=250, 71%) had hypertension. Guideline recommendations for HBPM were not always followed by survey participants. Most participants measured BP seated (n=316, 90%) with the cuff fitted to a bare arm (n=269, 77%). Only 15% measured BP in the morning and evening (n=54) and 26% averaged the BP readings over 7 days (n=90). Interview participants (n=34) described measuring BP at "different times of the day after doing different things." One-third of participants (n=112, 37%) received education for HBPM, which interview participants described as vague verbal instructions from health care practitioners. Participants who received education did not perform high-quality HBPM. Participants who did not receive education mimicked BP measurement methods of health care practitioners, "I do it the way I've seen them do it."Conclusions: HBPM is not performed according to guideline recommendations, and adults who received ad hoc education did not perform high-quality HBPM. These findings highlight a need for effective education to support HBPM for clinical decision-making.Marrie et al. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology. 2010 Mar 30;74(13):1041-7.Background: Vascular comorbidity adversely influences health outcomes in several chronic conditions. Vascular comorbidities are common in multiple sclerosis (MS), but their impact on disease severity is unknown. Vascular comorbidities may contribute to the poorly understood heterogeneity in MS disease severity. Treatment of vascular comorbidities may represent an avenue for treating MS.Methods: A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study. Time from symptom onset or diagnosis until ambulatory disability was compared for patients with or without vascular comorbidities to determine their impact on MS severity. Multivariable proportional hazards models were adjusted for sex, race, age at symptom onset, year of symptom onset, socioeconomic status, and region of residence.Results: Participants reporting one or more vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41-1.61). Vascular comorbidity at any time during the disease course also increased the risk of ambulatory disability (adjusted HR for unilateral walking assistance 1.54; 95% CI 1.44-1.65). The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular comorbidities.Conclusions: Vascular comorbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple sclerosis. The impact of treating vascular comorbidities on disease progression deserves investigation.Palladino et al. Trajectories and management of vascular risk following the diagnosis of multiple sclerosis: A population-based matched cohort study between 1987 and 2018 in England. Mult Scler. 2024 Nov;30(13):1653-1663.Background: People with multiple sclerosis (PwMS) have an increased cardiovascular and cerebrovascular disease burden, but this could be mitigated by vascular risk factor management.Objectives: We compared the trajectories of vascular risk factors, vascular comorbidities and clinical management in PwMS against the general population post-MS diagnosis while controlling for frailty.Methods: Retrospective longitudinal analysis using English data from the Clinical Practice Research Datalink between 1987 and 2018 comprising PwMS matched with up to six controls without MS by age, sex and general practice.Results: We compared 12,251 PwMS with 72,572 matched controls; 3.8% of PwMS had mild-moderate frailty, 1.2% more than matched controls. Compared to controls, PwMS had an elevated incidence of Type 2 diabetes (HR 1.18, 95% CI (1.04, 1.34)), and starting antihypertensive medications (HR 1.40, 95% CI (1.33, 1.47)). Among those with hypertension at baseline, blood pressure trajectories did not differ between PwMS and controls. PwMS had increased rates of meeting targets for hypertension management (HR 1.25, 95% CI (1.12, 1.41)).Conclusion: The observation that PwMS with hypertension are more likely to meet treatment targets than matched controls is encouraging, but the elevated rates of vascular comorbidities suggest that tighter vascular management may be needed in this population.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

The current dogma that is emerging in the field of immunology and multiple sclerosis (MS) is that a prophylactic EBV vaccine will create an older population of individuals susceptible to later wild-type EBV infection as vaccine immunity wanes. Therefore, instead of reducing the risk of MS, the vaccine will increase the risk. I don’t necessarily agree with this position. The arguments supporting their claims are very nuanced and, at present, are not evidence-based. Yes, we need to have concerns and be prepared to address them once an EBV vaccine gets approved and adopted for general use. We cannot let a theoretical concern stop an essential experiment designed to prove or disprove that EBV is the cause of MS, other autoimmune diseases and several human cancers. Do you agree?For more information on the EBV vaccine experiment, please read my newsletter, ‘Preventing multiple sclerosis by vaccination’ (22-Jan-2025).The theoryThe theoretical consideration that waning immunity to an EBV vaccine may increase the risk of MS is based on the observation that delayed EBV, particularly symptomatic EBV in the form of infectious mononucleosis (IM), is the main EBV-associated risk factor for developing MS. Delayed EBV infection remains a risk factor lifelong and doesn’t disappear after adolescence or early adulthood.In the UK, the Health Improvement Network (THIN) Database uses data from the NHS as part of routine care. A recent analysis commissioned by the MS Society estimated that the lifetime risk of developing MS in the UK is approximately 1 in 330.These risks could be refined further with better prediction calculators, including a history of IM, antibody titres to the ENBA complex or EBNA-1, other risk factors, and polygenic risk scores. However, EBV and IM are the most significant modifiable MS risk factors at a population level. We know that for EBV-negative individuals (5% of the adult population), the risk of developing MS is close to zero. For people who have EBV-associated IM, the lifetime risk of MS is approximately 1 in 100. For people who seroconvert to becoming EBV-positive without a history of IM, the risk is approximately 1 in 800. Therefore, in addition to preventing infection with EBV, preventing IM and potentially treating IM need to be explored as preventive MS strategies.We don’t know how EBV causes MS and why the risks are higher in people who have symptomatic infection or IM compared to those who seroconvert asymptomatically. The hypothesis is that something happens from an immunological perspective during IM that triggers MS. Many immunologists think the overzealous immune response during IM dysregulates immune function, which leads to autoimmunity later on. Others feel that because of the poor control of the virus during IM, the immune system reacts to many more EBV antigens, making molecular mimicry more likely to occur. Another theory is that autoimmunity is bad luck due to rogue B-cells. During IM, more B-cells are infected with EBV due to higher and more prolonged EBV viral loads. This increases the chances of a B-cell being self-reactive, which then causes MS. The latter is a random event, and the chances are much higher in people with IM, which may explain why IM is associated with several autoimmune diseases. Finally, some think that IM is an epiphenomenon and that what predisposes someone to IM is the same phenomenon that increases one's risk of getting MS, i.e. IM is simply an association and is not in the causal pathway of MS. The latter hypothesis doesn’t explain why EBV seronegative people don’t get MS, nor does it explain the temporal sequence of needing to be infected with EBV before you develop MS. I rejected the last hypothesis years ago, however, what seems obvious to me doesn’t seem obvious to others. I often have to point out to colleagues that causation theory has eliminated that hypothesis.The reason I am spending so much time explaining all of this to you is that if an EBV vaccine reduces your risk of getting IM, it may reduce your risk of getting MS. In other words, the vaccine doesn’t have to be sterilising. This is why it is essential to see if an EBV vaccine that reduces the incidence of IM but not necessarily wild-type EBV infection reduces the risk of getting MS. Unless we do the vaccine experiment, we will never know the answer.The only EBV vaccine with efficacy data concerning IM is a monovalent (gp350) GSK EBV vaccine. This vaccine was shown to prevent IM in young adults (78% efficacy) but was found to be non-sterilising, as it did not prevent wild-type EBV infection. Subsequently, GSK licensed this vaccine to MedImmune, which sadly did not advance its development. Based on this experience and other early human studies, it is widely assumed that a component EBV vaccine is unlikely to create long-lasting sterilising immunity.As with most vaccines, immunity fades with time, so vaccinated subjects may be at risk of delayed late wild-type infection. An argument against this is the experience with the prophylactic VZV childhood vaccine, which protects against delayed chickenpox or primary VZV infection. This protection is maintained and is not short-lived. A caveat is that the prophylactic VZV vaccine is a live-attenuated vaccine that is more likely to provide life-long sterilising immunity than a component vaccine. It is important to note that the live-attenuated VZV strain (Oka) can establish latent infection and reactivate to cause shingles in some individuals. However, this risk is substantially lower than with wild chickenpox infection. Similar experiences have been with other live-attenuated viral vaccines, i.e., smallpox, MMR and yellow fever.One could argue for using a live-attenuated EBV vaccine. However, I am unaware of any efforts to develop one. I suspect this is due to the complexity of EBV and the difficulty of proving that an attenuated virus will not be oncogenic and induce delayed autoimmunity. Current EBV vaccines under development include subunit component and mRNA vaccines. To my knowledge, a viral vector vaccine using the modified vaccinia virus Ankara (MVA) has not been developed.People don’t live in bubbles, so if you have some immunity to EBV from a vaccine, you will likely get exposed to wild-type EBV from day-to-day interactions with other people. Based on trial data, these exposures will likely cause asymptomatic EBV infection, which will give you lifelong protection against EBV infection unless you become immunocompromised. Therefore. I don’t think a non-sterilizing component EBV vaccine will create a large population of older adults susceptible to IM. I suspect most older people will become infected asymptomatically. We can test this in registry studies as we follow up cohorts of people vaccinated with an EBV vaccine to prevent IM.Evolutionary biologySome commentators feel that as more people are vaccinated against EBV, the vaccine will eventually eliminate EBV from the human population, which may have consequences for human biology. The theory is that EBV plays an essential positive role in human immunity. Again, this is theoretical and not evidence-based. When you study EBV-seronegative older adults, they don’t seem to have any problems with their immune function and general biology. Granted, older EBV-negative adults may benefit from the herd, i.e. they are protected by the surrounding EBV-seropositive subjects. We can potentially look at this by studying EBV seronegative older adults to see if they have some problems because they don’t have EBV. These people are hard to find, and recent data suggest that some seronegative subjects have T-cell responses to EBV and, hence, may not be genuinely EBV-negative.Conversely, we could look for benefits that EBV may offer humans. We haven’t found any noticeable benefits of having EBV, only the abovementioned negatives. Is EBV a symbiont (positive benefits for itself and the host), or is it a parasite? I suspect EBV is a symbiont, and its benefits likely related to B-cell immunity will emerge with future research. I am incubating some ideas around this research theme. This, however, is not a reason not to do the necessary experiment and test an EBV vaccine to prevent IM and downstream events.So, my message to the EBV vaccine naysayers or killjoys is that unless you can produce data, you should support the EBV vaccine experiments and consider what experiments you want to conduct to prove your point.I know this newsletter is hardgoing. Please ask questions if you have any doubts.The survey to explore your attitude toward an EBV vaccine is still open. If you have two minutes, please complete it. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

My prediction is that we will prevent multiple sclerosis (MS) by accident, i.e. as a secondary outcome to a broader public health intervention.Many stakeholders think we can run a randomised controlled EBV vaccination trial in a high-risk cohort to prevent MS. This is not feasible. Firstly, the incidence of MS is relatively low; therefore, you would need a large study (approximately 10,000 EBV-negative subjects) to capture enough events, i.e. people developing MS, in a relatively short period (People at high risk of MSPolygenic risk scores and other biomarkers of MS risk are not sensitive and specific enough to enrich clinical trials. A pragmatic way to identify a high-risk cohort is to recruit first and second-degree relatives who are approximately 10 times more likely to develop MS than the general population. However, these high-risk subjects would need to be recruited early, that is, as infants, before EBV exposure to maximise the power of the trials. We have shown that by 10 years of age, over three-quarters of children in the UK are already EBV seropostive. In addition, the average onset of MS is close to 30 years of age, with less than 3% of people developing MS before the age of 16, the age of consent for clinical trials. Therefore, an EBV vaccine trial in a high-risk cohort will take decades. I will be long gone, i.e. deceased, by the time this sort of trial reads out. I want to see MS prevented in my lifetime.Similar arguments can be made for other delayed EBV-associated diseases. These include other autoimmune diseases (systemic lupus erythematosus or SLE, rheumatoid arthritis, Sjogren’s syndrome, primary biliary cirrhosis, and inflammatory bowel disease) and EBV-associated cancers (Hodgkin, diffuse B-cell, Burkitt, CNS and other lymphomas, nasopharyngeal carcinoma and gastric cancer). Dare I suggest we design a basket study to catch all these diseases?Targeting infectious mononucleosisYears ago, I realised that we need to get an EBV vaccine licensed to prevent infectious mononucleosis (IM), which needs to be adopted as a public health intervention at a population level. We can then collect real-world data via a registry to see what happens to the incidence of a basket of diseases in people who have been vaccinated and those who choose not to. To address safety concerns, we have suggested doing this study on 12 to 13-year-old adolescents before the peak in the incidence of IM. This occurs at 12-13 in girls and 15-17 in boys. This three-year gap in the peak of IM between girls and boys is because girls mature earlier than boys and start kissing earlier. EBV is mainly transmitted via saliva; hence, it is called the kissing disease. The target age of 12-13 is the same age that HPV vaccination is given; therefore, it will be easier to implement an EBV vaccine nationally by piggybacking the EBV vaccine onto the HPV vaccine. Once an EBV vaccine is shown to be relatively safe in adolescents, it could be moved to an earlier age group to try and vaccinate the majority of children before EBV exposure.I am aware that about 80% of adolescents aged 12-13 are already EBV seropositive and hence may not need the vaccine. However, as latent-lytic cycling of EBV may underlie the pathogenesis of MS, boosting immunity to EBV with a vaccine may reduce lytic infection and hence reduce the incidence of MS or EBV-associated diseases. A good analogy here is Shingrex, a varicella-zoster virus vaccine given to adults likely to be VZV seropositive from having chickenpox in childhood to minimise the risk of getting shingles.Did you know that recent data has shown that adults who have had the Shingrex vaccine may be at lower risk of developing dementia? The mechanism behind this is unknown, but if this finding is causal, i.e., if Shingrex reduces the incidence of Alzheimer’s disease (AZD), it will tell us something about the pathogenesis and cause of AZD. There is a literature linking herpes viral infection to AZD.The good news is that a gold rush is happening with several big pharma companies developing EBV vaccines to prevent IM. Let us assume one of the companies can get regulatory approval and marketing authorisation for their EBV vaccine to reduce the incidence and potential severity of IM. Will public health officials and governments adopt the vaccine nationally, find the resources to pay for the vaccine, and set up real-world registry studies to see if downstream diseases such as MS, SLE and Hodgkin's disease are prevented? I am not sure. Vaccine uptake by governments is generally slow and, potentially, even slower considering the backlash after the rapid rollout of the COVID-19 vaccine, the rise in the influence of the anti-vaccine lobby and the recent problems with the respiratory syncytial virus (RSV) and rotavirus vaccines.Governments and individuals, in particular parents, will need convincing. We should start by challenging the medical dogma that IM is a benign self-limiting disease. IM is an unpleasant disease associated with significant short and long-term morbidity and mortality. Using NHS hospital statistics for England, the incidence of acute IM needing admission is estimated to be 108 per 100,000 of the population annually. In other words, over 60,000 patients with acute IM are admitted to NHS hospitals in England each year and spend, on average, 3-4 days in the hospital. Assuming this applies to the UK, we estimate that IM consumes over 250,000 NHS inpatient days annually. This is likely underestimated, as IM follows a latitudinal gradient and is more common in Scotland and Northern Ireland than in England. Hence, extrapolating English figures to the country's north will underestimate NHS admission rates.Complicated IMPeople with IM are typically admitted with complications, in particular, throat and upper airway obstruction, difficulty swallowing and dehydration. Then, there are the acute complications associated with IM that often need admission. These include meningoencephalitis, haemolytic anaemia, thrombocytopaenia, neutropaenia, haemophagocytic syndrome, myocarditis, hepatitis, pancreatitis, pericarditis, pneumonitis, conjunctivitis, splenic rupture, Guillain-Barre syndrome, cranial neuritis, transverse myelitis, brachial neuritis and chronic fatigue syndrome (CFS). Yes, about 3-5% of patients diagnosed with CFS have had recent IM.Schoolchildren typically lose 1-4 weeks of schooling due to IM and its sequelae. Up to 30% of University students get IM, and about 1 in 8 must re-do a year of studies. A similar story plays out in the military. Between 2002 and 2018, there were 23,861 cases of IM in the US military, which is an incidence of 104.2/1,000 patient-years. This worked out to 44,606 total medical encounters, 4,189 hospital bed days and 2,797 weeks/yr of lost duty time. Military recruits who have IM are forbidden from doing any physical exercise for 8 weeks to prevent splenic rupture. In some countries, this period of inactivity is increased to 12 weeks. Then, there are the elite athletes who can’t compete for months and rarely years after IM. Outbreaks of IM amongst athletes often occur in sports camps. I hope you understand that IM is not a pleasant disease.The case for an EBV vaccine to prevent IM is a no-brainer. Do you agree? However, the vaccine needs to be shown to be cost-effective, and the rub is herein. A national EBV vaccine programme is particularly compelling if it may reduce the long-term sequelae of EBV. I anticipate big pharma companies trying to price the latter into their products. The price based on a cost-benefit analysis to prevent IM alone will be relatively low compared to a vaccine that prevents MS, other autoimmune diseases, and potentially several cancers.United Kingdom and the NHSThe UK should take the lead on this. Despite having the NHS and its record-keeping systems to do these studies, we are not large enough as a country. Some preliminary power calculations suggest we need between 210,000 and 300,000 EBV-negative adolescents to answer the question on MS prevention. If only 20% of adolescents are EBV-negative, then we will need 1.0-1.5 million adolescents to be enrolled in the study to answer the question in 5-7 years. This is why MS prevention is so hard; it needs to be a global effort.What needs to be done? We need to hold a multi-disease stakeholder meeting around EBV-associated disease prevention, not just MS prevention but all of the potential diseases I have mentioned above. Let us assume we get a vaccine licensed to prevent IM. What needs to be done to get public health officials to adopt the vaccine as a public health intervention? Do we need a preemptive policy initiative, including economic modelling, to convince public health officials to adopt an EBV vaccine? How do we get a licensed EBV vaccine rolled out nationally and collect high-quality data to show that the vaccine is reducing the incidence of a basket of EBV-associated cancers and autoimmune diseases? In addition, an effective EBV vaccine may reduce the incidence of post-transplant and immunosuppressive lymphoproliferative diseases. Is there a national register for these diseases? Can we use the same registries or reporting structures that are in place for cancer surveillance for autoimmune diseases? Or can we clone these cancer surveillance systems for autoimmune diseases? What funding do we need? Who will fund such a meeting? I estimate that it will cost about £40,000 to hold this meeting. Is anyone willing to fund or part-fund this meeting?In addition to preparing for the post-licensing studies, many other fundamental questions concerning EBV and its role in human biology need to be answered. These will need to be done in parallel. For example, what will the impact of remaining EBV-negative be as we get older? Will an adolescent EBV vaccine create an older population that is susceptible to IM as vaccine immunity wanes? EBV is one of the viruses that has co-evolved with humans and may play an essential role in human biology. Will eliminating EBV from the human population have adverse effects? As you can see, ‘I have many miles to go before I sleep’.Attitudes to an EBV vaccineI would like to know how many people with MS would let their children be vaccinated with a new EBV vaccine. When I asked my patients this question, they overwhelmingly said no. They would only agree to vaccinate their children if the EBV vaccine was shown to be relatively safe for adults and adolescents. This attitude toward new vaccines is not unique to emerging EBV vaccines but has been noted with other vaccines and explains why the COVID-19 vaccine was never given to infants and young children.To explore your attitude toward an EBV vaccine, please spare two minutes to complete this survey. Would you allow your children, grandchildren, or other young relatives to be vaccinated, and at what age do you think they should be vaccinated?Thank you for your participation.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have written about uncertainty and how it affects the minds of people with chronic diseases such as MS (please see ‘Uncertainty associated with MS: are you comfortable with it?’, 20-Apr-2024).Uncertainty has a dark underbelly, and unless you can come to terms with it, it will paralyse you with rumination and intrusive thoughts about what life would be like if only this or that happened. I have seen too many of my patients succumb to this problem whilst others come to terms with what has happened to them and get on with their lives. I urge you to try and embrace the latter. For example, the following are some questions you may have about your MS:* Why did it take so long for my general practitioner or neurologist to take my symptoms seriously?* Why did it take so long to be diagnosed with MS?* Would an earlier diagnosis of MS have made a difference to my outcome?* Why are there no reliable prognostic calculators for people with MS to know what is going to happen in the future?* Will I have benign MS and not have any disabilities when I am older?* Will I become disabled and need a wheelchair in the next 15 years?* Will MS affect my cognition and prevent me from being able to work?* If I start on a low-efficacy DMT, will it mean I won’t do as well if I switch to a high-efficacy treatment in 5-10 years?* If I have AHSCT, will I be cured?* If I start on an anti-CD20 therapy, will I recover function?* I have smouldering MS; if I start tolebrutinib, will my physical functioning improve?* …….Uncertainty underlies the potential answers to all of these questions. Although uncertainty surrounds us, the human brain deals poorly with it. A field of science deals with uncertainty, which some call the ‘science of uncertainty’ and deals with different concepts depending on the context. The following are some of the issues around uncertainty and the practice of medicine. I suspect many of you have been ‘victims’ of uncertainty without necessarily knowing about it.Uncertainty as a core component of the scientific and medical process1. Measurement Uncertainty:All measurements in neurology and medicine have inherent uncertainty due to the limitations of the neurological examination and our diagnostic tests. In addition, there is human error and variability in the measured neurological phenomena. Clinicians rarely quantify this uncertainty and report it alongside their findings. How confident are they that the neurological examination is normal, and is that white matter abnormality on MRI non-specific, or could it be the first sign of multiple sclerosis? If your initial MRI was passed off as normal despite having non-specific white matter lesions, you may not realise that you fell into this grey zone of diagnostic uncertainty.2. Statistical Uncertainty:When analysing data, we use statistical methods to estimate the range of possible values for a quantity and the confidence level associated with that estimate. There is always a chance that a so-called positive finding is a false positive, and sometimes a normal or negative finding is a false negative. This is why the sensitivity and specificity of tests are so important and give us confidence that what we are measuring is likely to be correct. No neurologist can be 100% sure about a diagnosis of MS or saying you don’t have MS, i.e. not diagnosing MS. They rarely tell you about their uncertainty, and it is even rarer for them to provide figures of how likely they are to make a diagnostic error.3. Natural Variability:Many natural phenomena are inherently variable, making it difficult to predict their exact behaviour. This can apply to neuroradiological findings. Many aspects of neurological function, its measurement and the impact of disease on these attributes are fundamentally uncertain, meaning their outcomes cannot be predicted with certainty. This explains why decisions in medicine can seem so variable and depend on who you see and may even depend on their cultural background. For example, if you have MS in Sweden, you are likely to get a different decision about the treatment of your MS compared to if you live in Denmark. This variability even happens at a local level. For example, one MS centre in London may have a very different way of treating MS compared to another. Even within centres, one neurologist may give you different advice than their colleague working in the same centre. The general public rarely gets exposed to this side of medical practice. This variability also applies to diagnosis. One neurologist may be prepared to diagnose MS when the diagnostic certainty is 70%, and another would prefer to wait until something happens to improve their diagnostic certainty to above 90%. I know many of you find this variability in medicine unacceptable.Decision theoryDecision theory is the field that studies how to make optimal decisions in the face of uncertainty. Sadly, decision theory is not taught in medical school—at least not in my medical school, and I am not aware of it being taught in my current medical school where I work. I think this is a mistake.Clinicians need the skills to do clinical risk assessments in near real-time. If they make a premature diagnosis of MS based on insufficient data, what are the consequences for the patient and their reputation? The general population think the diagnosis of MS is black and white. It is not. It is rather grey and may get greyer when the new MS diagnostic criteria are implemented. In general, neurologists prefer to err on not making a diagnosis of MS when they are not sure. If you are diagnosed with MS in the future, it is because, with time, the diagnosis of MS declares itself. This does not mean the neurologist was negligent; he or she was likely to be uncertain when you first presented.Could diagnostic uncertainty or diagnostic dithering be considered medical gaslighting? Yes, this would have been gaslighting if the correct interpretation of symptoms or ignoring a patient’s questions had led to further investigations and an earlier diagnosis. And possibly not if interpreting and investigating those symptoms would not have changed the diagnosis in terms of fulfilling the MS criteria for dissemination in time and space. Gaslighting can be subtle; if, for example, the neurologist didn’t acknowledge and validate a patient's symptoms, then this is a form of gaslighting. The ‘science of uncertainty’ encompasses understanding and managing uncertainty in clinical practice, medical research, and medical decision-making. It involves quantifying uncertainty, analysing its sources, and developing strategies to cope with it and communicate it to people with diseases. Much needs to be done concerning the latter. Many of you email me with issues that could be avoided with a better understanding of uncertainty.Some think AI and large-language models (LLMs) will resolve diagnostic uncertainty. I doubt it will. While AI may make diagnostic algorithms more efficient and include more data, uncertainty will always exist. An example that is relevant to MS is MS prognosis.Prognostic profilingHow many of you want to know your prognosis, e.g. what are my chances of needing a walking stick in 10 years, given my current state? For the pre-DMT era, I could give you an answer based on natural history data. The average time needed for a walking stick from symptom onset was about 17 years, which means 50% of pwMS needed a walking stick in less time than this, and in the other 50%, it took longer than 17 years or not at all. Don’t forget that about 15% of pwMS in this pre-DMT era never needed a walking stick.A question worth asking is, “How many people who don’t have MS end up needing a walking stick due to ageing?” Data from the 2011-2012 National Health and Aging Trends Study estimated that 15.9% of people aged 70-74 used a cane. This number increased with age, reaching 50.1% for those aged 85-89 and 70.6% for those 90 and older. Therefore, ageing and its effects on physical functioning must be considered when predicting MS outcomes. I have given many talks about MS prognosis and include the following poor prognostic factors on the list. You can add up how many you have on the list. The question is whether this will help you manage your MS.* Age of onset >40 years* Male sex* Ancestry - Afro-American, Afro-Caribbean, African, South Asian, Asian* Multifocal disease onset* Motor involvement* Cerebellar involement* Bladder dysfunction* Bowel dysfunction* Cognitive involvement* Residual disability after your first attack* Progressive worsening* Diagnosis of primary or progressive MS* Ability to improve cognition (learning on the PASAT test)* Partial or no recovery from any relapses* More than two relapses in the first 2 years* An EDSS ≥ 3.0 within 5 years of diagnosis* High baseline MRI ≥ 9 T2 lesions* Gd-enhancing lesions on baseline MRI scan* Posterior fossa lesions (brain stem or cerebellum)* Spinal cord lesions* Two or more paramagnetic rim lesions or PRLs* Brain atrophy on MRI* Advanced brain age* Retinal thinning on OCT* Locally synthesised OCBs (oligoclonal IgG bands) in your spinal fluid* Raised neurofilament levels in your spinal fluid or blood* Low vitamin D levels* Smoker* Diabetes or prediabetes* Hypertension* Hypercholesterolaemia* Obesity* Failed a platform or low-efficacy DMT* Failed a high-efficacy DMT* Social isolation* Depression* Falls* Low income, i.e. you can’t come out financially each month* Unemployed* Genetic risk (not available yet)When you think about this list, you will note that many of these poor prognostic factors are a consequence of having MS, i.e. they are indicators of past damage. They don’t necessarily represent MS biology. This is why we need to understand the biology of MS and use dynamic biological factors in prognostic models, particularly in the current DMT era. For example, a first attack may damage the spinal cord and leave some with mobility problems (motor involvement) and bladder and bowel problems. But why should they be used to predict future outcomes regarding a potential response to a treatment? These prognostic factors are based on data in largely untreated populations. If we treat MS early and effectively, most of these predictive factors will likely be irrelevant if you respond well to a treatment.Uncertainty surveyI want to thank you for completing the recent survey on uncertainty in pwMS (please see ‘MS and uncertainty: how big is the problem?’, 21-Dec-2024 ). The survey is still open. The preliminary results indicated that uncertainty in pwMS is a more significant issue than I realised and needs to be addressed to maximise health outcomes in MS. Effective management strategies exist; healthcare professionals can help individuals with MS manage uncertainty through education, support, and coping strategies. If you or someone you know is struggling with the uncertainty of MS, it is crucial to seek professional help. Remember, you are not alone. With psychological support and the implementation of coping mechanisms, there is no reason why you can’t live a whole and meaningful life with MS, even in the face of uncertainty. You don’t have to be blighted by past and future events.Please let each of you know if past events have affected your functioning and how you have overcome them so you can focus on maximising living in the present and an uncertain future.Thank you.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Stopping by Woods on a Snowy Eveningby Robert Frost, 1923Whose woods these are I think I know.His house is in the village though;He will not see me stopping hereTo watch his woods fill up with snow.My little horse must think it queerTo stop without a farmhouse nearBetween the woods and frozen lakeThe darkest evening of the year.He gives his harness bells a shakeTo ask if there is some mistake.The only other sound’s the sweepOf easy wind and downy flake.The woods are lovely, dark and deep,But I have promises to keep,And miles to go before I sleep,And miles to go before I sleep.This is one of my favourite poems, which always reminds me of Christmas. So I hope you don’t mind me sharing it with you. The miles to go before I sleep is about a life unfinished; in my case MS research to be completed.I studied this poem in high school with a teacher who, in retrospect, was a very inspiring woman. She made me curious about things other than science and encouraged me to look for deeper meanings and hidden gems. She wasn’t focused on outputs, such as exam results, and got joy from hearing about how much we enjoyed reading a particular book. She gave me extra-curricular reading lists, which I devoured during holidays and weekends. One of our set books was The Great Gatsby. We spent a week of lessons with her just studying and debating the final two paragraphs. The haunting beauty of reading Fitzgerald’s prose is nostalgia at its best.“Gatsby believed in the green light, the orgastic future that year by year recedes before us. It eluded us then, but that’s no matter—tomorrow we will run faster, stretch out our arms farther. . . . And one fine morning——So we beat on, boats against the current, borne back ceaselessly into the past.“Are these closing paragraphs about hope and resilience or giving up? For me it is about the fight to make a difference, to be heard and to hope for a better future. A future free of multiple sclerosis?I heard on BBC Radio 4 this morning that more people in Britain will be spending Christmas alone this year than in any year in the past. This surprised me as I thought Christmas 2020 would have been the worst because of lockdown. That is the year I started calling patients of mine who I knew would alone to wish them a merry Christmas. So if you know someone spending Christmas alone, please take some time out to call them and make sure they know that someone cares.And if you are spending Christmas alone and feel lonely, you can do some things to help yourself. If you are religious, try and get to a Church service in person or one of the TV, radio or online Christmas services. Pick up the phone and call people, such as friends, family, or one of the many charitable organisations that provide telephone companions. Watch Christmas TV. Listen to Christmas carols. Have a Zoom lunch, dinner or drink with someone alone. Connect! If you can practice mindfulness, please do. Get out if you can for exercise and fresh air. Make sure you fill your day with as many activities as you can.If you have any suggestions for helping people who are socially isolated, lonely and alone this Christmas, please share them with us.I wish you a Merry Christmas or Happy Holidays and thank you for your support.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important Links📋 MS-Selfie microsite💰 Donations to MS-Selfie👈 Prof. G’s Backstory and CV💾 Prof. G’s MS Blog Archive❓ Conflicts of Interest🦋 BlueSky Social🔗 LinkedIn🖋 MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I attended a meeting last week where a KOL (key opinion leader) in the field of multiple sclerosis (MS) made the point that relapses and focal MRI activity (Gd-enhancing and new or enlarging T2 lesions) are MS, i.e. they are the disease and that suppressing relapses and MRI activity is what we aim to achieve with our disease-modifying therapies (DMTs). Do you agree?I have spent the better part of a decade coming to the opposite conclusion that relapses and focal MRI activity are not the disease. They represent the immune system’s response to what is causing MS and that the real MS is smouldering MS.If relapses and focal MRI activity were MS, then:* Baseline relapse rates and MRI activity should be predictive of outcome* Changes in disease activity over time are predictive of outcome* Changes in disease activity due to DMTs should predict the outcomeThese three criteria are called the Prentice criteria and are philosophical approaches to defining a surrogate outcome measure. Unfortunately, relapses and focal MRI activity don’t fulfil the Prentice criteria; therefore, they can’t be the disease by definition.1. Baseline relapse rates and MRI activity should be predictive of outcomeIn relapse-onset MS, the relapse rate and MRI activity in the first 2-5 years do predict the outcome. However, this does not hold up for people with primary progressive MS (pwPPMS). It could be argued that people with pwPPMS have had the disease longer by the time they present and get diagnosed; hence, the rule still holds that early activity is the disease and predicts the outcome. Unfortunately, we don’t have long-term follow-up data on very early PPMS or RIS-PPMS.2. Changes in disease activity over time are predictive of outcomeOutside the initial 5-year window, the data on relapse rates and MRI activity predicting clinical outcomes is weak. This is one of the paradoxes in the field of MS and has been referred to in the past as the MRI-clinical paradox. If MRI activity was MS, it should predict the outcome regardless of where you are in the course of the disease.3. Changes in disease activity due to DMTs should predict the outcomeThis is where evidence against MS disease activity being MS is most substantial. It is clear from clinical trials that if you are on a DMT, then MS disease activity on therapy is a poor prognostic sign. However, the outcome is not predicted if you are on a placebo or no treatment. If MS is focal inflammatory disease activity, then it should predict outcome regardless of what treatment you are on. From a philosophical perspective, this point is critical and tells us that focal inflammation (relapses and MRI activity) cannot be MS. It is remarkable how many people don’t appreciate this point and ignore it.Here are some examples to illustrate this point. Ocrelizumab exposureThe observation that pwMS with increasing ocrelizumab exposure do better despite a ceiling effect on relapses and MRI activity tells us that something is happening beyond focal inflammation. It has been shown that following the administration of ocrelizumab 600 mg every 6 months, serum concentrations of the drug are higher among subjects weighing 90 kg, compared to subjects weighing 60-90 kg. This dose effect can be seen in levels of B-cell depletion but is not reflected in the reduction of relapses or focal lesions on MRI, as all levels of ocrelizumab exposures were associated with almost complete suppression of focal inflammatory disease activity. However, a dose effect is observed, with more significant prevention of disability progression in people with both relapsing and PPMS with higher levels of peripheral B-cell depletion. This tells us that there is a disconnect between the pathological processes driving focal inflammation and those responsible for non-relapsing disability progression or smouldering MS. Based on these observations, we are now testing high-dose ocrelizumab (1200 mg or 1800 mg vs. 600 mg every 6 months) in two clinical trials (ClinicalTrials.gov Identifiers: NCT04117529 and NCT04548999). The hypothesis is that higher ocrelizumab exposure can target peripheral deep-tissue B-cells and CNS-resident B-cells, which drive smouldering MS beyond focal inflammatory events.Ofatumumab vs. TeriflunomideOfatumumab, a fully humanised monoclonal anti-CD20 therapy, is superior to teriflunomide in suppressing relapses and focal inflammatory MRI activity but is no better than teriflunomide at slowing the rate of brain atrophy over 2 years. Despite its relatively modest impact on focal inflammation, teriflunomide’s effect on end-organ damage or smouldering MS is the same as that of ofatumumab. Tolebrutinib vs. Teriflunomide or PlaceboMore recently are the lessons from the Tolebrutinib phase 3 trials. Tolebrutinib is a second-generation BTK inhibitor (BTKi) with a dual mode of action. It inhibits BTK in B-cells and is an anti-inflammatory therapy. In both the relapsing and non-relapsing progressive MS trials, it had a relatively modest impact on relapses and focal MRI activity. In the relapsing trials (Gemini 1 & 2), tolebrutinib was not superior to teriflunomide in suppressing relapse activity, i.e. the relapse rates were similar, and it was inferior to teriflunomide in suppressing Gd-enhancing lesions.Teriflunomide was superior to tolebrutinib in suppressing Gd-enhancing lesions but had a similar effect on new T2 lesions. This could be referred to as a Gd-enhancing-T1/T2-lesion paradox, implying that new Gd-enhancing lesions are less likely to form chronic T2 lesions in subjects treated with tolebrutinib. This indicates that tolebrutinib is changing the biology of how MS lesions evolve; i.e. it is doing something to the acute Gd-enhancing lesions that makes it less likely to leave a scar or new T2 lesion. Based on these preliminary observations, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse MS outcomes.However, despite being inferior to teriflunomide in suppressing focal inflammatory activity, tolebrutinib was superior to it when it came to disability progression., i.e. it has an impact on smouldering MS-associated worsening (SAW) but not relapses.Tolebrutinib, therefore, dissociates relapses from disability progression and ‘proves’, yes proves, that these two processes are likely to be independent of each other with the caveat that relapses can be associated with some disability progression called relapse-associated worsening or RAW.This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib.Based on these observations, I don’t know how anyone can claim that focal MS disease activity is MS. My interpretation is that focal MRI activity is simply the immune system’s response to the cause of the disease. The real MS is in the tissue against which the immune system may or may not react. I call this the field hypothesis of MS.The field hypothesisIf you have an MS relapse or attack in one particular area of the brain or spinal cord, you are more likely to have subsequent attacks in this area. Something locally in a specific anatomical area triggers recurrent attacks in the same site.What underlies the field effect? One explanation is that the area damaged by the initial attack is more likely to trigger autoimmune responses in the future due to the local up-regulation of so-called second, or danger, signals. The latter occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated, they need an antigen-specific signal via the T-cell receptor and an additional signal via co-stimulation.The obvious question is what triggers relapses in the field or CNS. Possibly a virus, like an isolated seed or flower in a wheat field? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine that stimulates immune responses, they relapsed. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was fundamental and was telling us something important about MS.Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab, the field (brain and spinal cord) becomes more abnormal. When you let these cells back in, they detect the abnormal field and run amok, trying to clear the field of the offending agent. This happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out, the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post-natalizumab is a form of IRIS in response to the virus that causes MS.Another observation comes from serial MRI studies showing subtle changes in the normal-appearing white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology in the nervous system takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. The best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this, we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. The viral load is likely to be higher in the absence of inflammation. This is why it is so crucial for pwMS to donate their brains for medical research.MS clinical phenotype is determined by the immune responseI have argued that MS is one disease, not two, three, or four, and the immune response to the cause determines the clinical phenotype. Inflammation-driven clinical phenotypes are not a new concept and have been well-studied in infectious diseases such as leprosy, TB, hepatitis B, and leishmaniasis… This is why I often use the leprosy analogy when I refer to MS.Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems’ responses to antigens. Depending on the immune response, you get a different clinical picture. If you have a brisk inflammatory response, you get tuberculoid leprosy, which presents with inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy, which is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone called borderline subtypes. Interestingly, people can convert from having lepromatous to tuberculoid leprosy if they shift their immune response to a so-called type 1 immune response driven by interferon-gamma. The following is a diagram I drew over 20 years ago describing this hypothesis. Primary progressive MS is lepromatous MS, and relapsing-remitting MS is tuberculoid MS. SPMS is in the middle and is borderline MS. Interestingly, gamma interferon seems to have the same effect on MS as on leprosy, driving lepromatous MS (PPMS) to become tuberculoid or relapsing MS.The only way to prove the leprosy theory of MS is to have the organism that causes MS in hand and study the immune response to the agent using immunological techniques applied to leprosy.ConclusionsI know many of the issues discussed above are repetitions, but the concepts, which I think are relatively straightforward, don’t seem to be getting through. When a colleague says that relapses and MRI activity are MS, my heart sinks. Do these concepts make sense to you?If you need hard-core science, I suggest you read our two papers on smouldering MS below.Paper 1 - relapses tend to occur in the same siteWillis et al. Site-specific clinical disease onset in multiple sclerosis. Eur J Neurol. 2015 Apr;22(4):732-5.BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.Paper 2 - International consensus on smouldering MSScalfari et al. Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann Neurol. 2024 Jul 25. doi: 10.1002/ana.27034.Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.Paper 3 - Smouldering MS, the ‘Real MS’Giovannoni et al. Smouldering multiple sclerosis: the 'real MS'. Ther Adv Neurol Disord. 2022 Jan 25:15:17562864211066751Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestBlueSky Social / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I was referred to a patient from another centre as he had relocated to East London. He had had multiple sclerosis (MS) for over 20 years and was interferon-beta-1a (Avonex). He was pretty disabled (EDSS 5.5), with an unsteady gait, lower leg weakness, slurred speech and cognitive impairment. He needed a walking aid but was determined to get by without one. He was divorced and lived alone. He had a teenage son who he rarely saw. He was unkempt and needed help. I was concerned about falls and his ability to look after himself. We arranged for a community nurse to do a home visit. She reported that his tiny one-bedroom apartment was overflowing with items, such as old packaging and items this patient had been collecting. She described narrow corridors between the piles of rubbish, which were at head height. His chair in front of the television, the TV, his bed, and his bathroom were connected by corridors walled with piles of clutter. His kitchen was so full of items that he could barely use it to prepare food. As a result of this, he mainly ate out or got takeaways. This pwMS had a hoarding disorder (HD), which I suspect was related to his MS.Hoarding disorder (HD)Hoarding is abnormal. People with HD are classified as having a mental health condition characterised by persistent difficulty discarding possessions that are not related to their value. Individuals with HD form an emotional attachment to their possessions. They often describe the items they have hoarded as having sentimental value, providing a sense of security, or they serve as reminders of past events.Beyond the emotional components associated with hoarding, HD is also related to other cognitive difficulties, which include emotional dysregulation, poor executive functioning and problems with impulse control, attention, organisation and problem-solving. These mental issues contribute to the excessive accumulation of clutter, a defining feature of HD. While HD can theoretically affect anyone, it is particularly prevalent among older adults. It is estimated that more than one in 20 people over the age of 70 has HD. On reflection, I have seen many people with MS display some features with HD. I know about it as community teams often do home visits and have to clear the homes of disabled people before adjustments can be made so they can cope with their disabilities. I have never thought much of it, but I suspect it may be more common than expected in pwMS. I would like to know if you are a hoarder or have HD.People with HD tend to be older and have physical limitations, which may hinder their ability to manage clutter. Clutter creates safety issues related to tripping and falling, poses a fire hazard, and can obstruct access in an emergency. In one of my patients, another older man, the paramedics couldn’t get a stretcher into a home because of the clutter.A recent US Senate report highlights a crisis stemming from the rising prevalence of hoarding disorder (HD), particularly amongst the ageing population and, in my experience, pwMS and other neurodegenerative disorders. The US HD report stresses the significant health and safety risks, including increased fire hazards, and advocates for a coordinated national response.HD is classified as one of the obsessive-compulsive disorders (OCD) and is more common in people with OCD. As with most psychiatric diagnoses, the primary symptom or sign, as in the case of hoarding, typically represents the tip of an iceberg with many hidden symptoms (see figure below).At present, effective treatments for HD are limited, primarily focusing on cognitive behavioural therapy (CBT). Some new approaches, such as virtual reality and cognitive rehabilitation, may help.The following are the diagnostic criteria for primary HD under DSM-5.Disorder Class: Obsessive-Compulsive and Related Disorders* Persistent difficulty discarding or parting with possessions, regardless of their actual value.* This difficulty is due to a perceived need to save the items and the distress associated with discarding them.* The difficulty of discarding possessions results in the accumulation of possessions that congest and clutter active living areas and substantially compromise their intended use. If living areas are uncluttered, it is only because of the interventions of third parties (e.g., family members, cleaners, or the authorities).* The hoarding causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (including maintaining a safe environment for oneself or others).* The hoarding is not attributable to another medical condition (e.g., brain injury, cerebrovascular disease, Prader-Willi syndrome).* The hoarding is not better explained by the symptoms of another mental disorder (e.g., obsessions in obsessive-compulsive disorder, decreased energy in major depressive disorder, delusions in schizophrenia or another psychotic disorder, cognitive defects in major neurocognitive disorder, restricted interests in autism spectrum disorder).Specify if:* With excessive acquisition: If difficulty discarding possessions is accompanied by excessive acquisition of items that are not needed or for which there is no available space. (Approximately 80 to 90 percent of individuals with hoarding disorder display this trait.)Specify if:* With good or fair insight: The individual recognises that hoarding-related beliefs and behaviours (pertaining to difficulty discarding items, clutter, or excessive acquisition) are problematic.* With poor insight: The individual is mostly convinced that hoarding-related beliefs and behaviours (pertaining to difficulty discarding items, clutter, or excessive acquisition) are not problematic despite evidence to the contrary.* With absent insight/delusional beliefs: The individual is completely convinced that hoarding-related beliefs and behaviours (pertaining to difficulty discarding items, clutter, or excessive acquisition) are not problematic despite evidence to the contrary.SurveyI would be interested to know if any of you were aware of the possible association between hoarding and MS and if any of you display some of the traits of HD or have been diagnosed and treated for HD. I would therefore appreciate it if you could complete this short survey on MS and hoarding. It will take you less than 5 minutes. Thanks.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestBlueSky / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

This is a free preview of a paid episode. To hear more, visit gavingiovannoni.substack.comCaseI am a 27-year-old female student with relapsing-remitting MS treated with oral cladribine four years ago. I recently graduated from university with a BSc. I am currently studying for a master's. I have remained stable on MRI scans but continue to have difficulty walking. I understand that cladribine is an induction therapy, meaning that further treatment is not usually required after two courses. How effective is a third course of cladribine (Mavenclad) in halting disease progression?NOTE: General substack newsletters and microsite are free; only Q&A sessions are restricted to paying subscribers. I can't run and maintain the MS-Selfie microsite, hence the need to pay people to help me do the work. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they either need to become paying subscribers or email ([email protected]) to request a complimentary subscription.Prof G’s answer

There are too many ECTRIMS 2024 highlights to cover in one newsletter. However, the top of the list of highlights was the positive tolebrutinib results in non-relapsing (inactive) secondary progressive MS. At the bottom was the negative, but not unexpected, simvastatin trial in SPMS.Tolebrutinib Tolebrutinib, a second-generation BTK inhibitor (BTKi), has a dual mode of action in MS. It inhibits BTK in B-cells and is an anti-inflammatory therapy. In both the relapsing and non-relapsing progressive MS trials, it had a relatively modest impact on relapses and focal MRI activity and more or less matched the anti-inflammatory effects of evobrutinib, the first BTKi (see paper below). Both tolebrutinib and evobrutinib were not shown to be superior to teriflunomide in suppressing relapse and focal Gd-enhanced MRI activity. Teriflunomide, however, was superior to tolebrutinib in suppressing Gd-enhancing lesions but not new T2 lesions. This would indicate that new Gd-enhancing lesions are less likely to form chronic T2 lesions in subjects treated with tolebrutinib. This suggests that tolebrutinib is changing the biology of how MS lesions evolve; i.e. it is doing something to the acute Gd-enhancing lesions that makes it less likely to leave a scar or new T2 lesion. Based on this preliminary observation, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse outcomes. These data have yet to be analysed. It will be interesting to see if these MRI findings also apply to blood neurofilament levels, i.e. if new Gd-enhancing lesions are less likely to form new T2 lesions on tolebrutinib subjects on tolebrutinib should have lower NFL levels associated with Gd-enhancing scans than those occurring in patients on teriflunomide or placebo. However, despite being inferior to teriflunomide in suppressing focal inflammatory activity, tolebrutinib was superior to it when it came to disability progression., i.e. it has a robust impact on smouldering MS-associated worsening (SAW) but not relapses. Tolebrutinib, therefore, dissociates relapses from disability progression and proves that these two processes are likely to be independent of each other with the caveat that relapses can be associated with some disability progression called relapse-associated worsening or RAW. This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib. I hope biomarker data can support the recovery of function data. How do you explain tolebrutinib’s effect on smouldering MS and its moderate impact on focal inflammatory activity?  Tolebrutinib is a CNS penetrant BTKi and will inhibit CNS resident B-cells and plasmablasts. In addition, it downregulates and inhibits microglia and macrophages via the so-called Fc-gamma III receptor. So, this agent tackles some CNS processes that drive smouldering MS and may switch microglia into a regulatory phenotype that promotes remyelination and recovery of function.  Notably, the data on reduced disability progression and recovery of function on tolebrutinib was not associated with a significant impact on brain volume loss. This needs to be explained. Brain volume is a complex measure, and a shrinking in the volume of microglia may confound any protection of volume by reduced neuroaxonal loss. Therefore, we will have to wait for more detailed analyses of regional brain volume and other MRI metrics from these studies to interpret this data. What is clear is that simply using brain volume alone as a biomarker does not explain what is happening at the tissue level. Please note that tolebrutinib and the other BTKIs are associated with liver toxicity. Hence, if they get to the clinic, they will require frequent blood monitoring for the first 3-6 months to prevent severe drug-induced liver injury (DILI).  What about other BTK’s?The phase 2 extension data of fenebrutinib, another BTKi in phase 3, was presented as an ePoster. Compared to tolebrutinib, fenebrutinib is much more effective at suppressing Gd-enhancing lesions. Based on this data, I would give fenebrutinib a ~87.5% (range 75-95%) of being superior to teriflunomide in suppressing relapses and focal MRI activity. The billion-dollar question is whether or not it will have an impact on smouldering MS pathology to a similar degree to tolebrutinib. I raised this question with a pharmacologist and got the following response. ‘Fenebrutinib differs from tolebrutinib in that fenebrutinib is a non-covalent reversible inhibitor that targets the “open” conformation of the enzyme and acts to trap BTK in an inactive conformation. Fenebrutinib is reasonably potent, more so than evobrutinib, but about 9-fold less potent than tolebrutinib. From a PK perspective, tolebrutinib has a very short half-life (~90 min), while fenebrutinib is ~4-6 hrs. Because tolebrutinib is covalent, the PD actions are long-lasting, and enzyme activity recovers after the last dose within 5-7 days as new enzyme is synthesized (protein turnover). Fenebrutinib is a classical competitive inhibitor, so to maintain “coverage” in vivo, relatively high doses are needed, given twice daily. Fenebrutinib has a “long residency time”, meaning that the off-rate is slow. The consequence of nanomolar potency with slow dissociation means that the steady-state is defined by the off-rate. When measured in a model system, occupancy of BTK within cells is driven primarily by C trough, with estimates being that fenebrutinib is likely to have modest occupancy within the CNS. Interestingly, remibrutinib is also a hybrid covalent inhibitor that targets the same open conformation as fenebrutinib but also reacts with the C481 residue to form a thioether adduct like tolebrutinib evobrutinib, ibrutinib, etc.’The proof will be in the trial results. You may be interested in knowing that fenebrutinib is being compared to ocrelizumab in a primary progressive trial. Ocrelizumab is setting a high bar, and if fenebrutinib is superior to ocrelizumab in PPMS, this will further prove the need to target CNS mechanisms to slow down SAW. After deep thinking about this data this weekend, I will be optimistic and give fenebrutinib a 40% chance (range 30-50%) of being superior to ocrelizumab in PPMS. The latter is based on its superior anti-inflammatory effect to tolebrutinib and the fact that it does get into the CNS at a level likely to inhibit BTK in both B-cells and microglia. If I am proven correct about fenebrutinib, this would be great news for pwPPMS. The dark horse is remibrutinib. We have no detailed PK and PD data on its CNS effects. However, the news on the ECTRIMS grapevine is that remibrutinib does not have a clear liver toxicity signal. If that is the case and it is as effective as tolebrutinib and fenebrutinib, it may just win the battle of the BTKi’s on safety. How will the BTKi’s be used in clinical practice? It is too early to speculate. But if the regulators’ license tolebrutinib to reduce SAW in non-active SPMS, it will be used as a monotherapy in more advanced MS. However, as SAW or PIRA occurs very early in the course of MS I suspect we will be identifying SAW early and switching patients early from other DMTs onto tolebrutinib in early MS. In other words, the diagnosis of SPMS will move to an earlier time in the course of MS. Going forward, tolebrutinib may be best used as part of an induction-maintenance protocol after an anti-CD20 or immune reconstitution therapy. You can download my ECTRIMS slides from here. Papers of interestTurner et al. Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. Drugs R D. 2024 Jun;24(2):263-274.Background and objectives: Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS.Results: In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a Ki value of 4.7 nM and slow off-rate (1.54 x 10-5 s-1), also had an association rate 1760-fold slower (0.00245 μM-1 * s-1). Estimates of cellular potency were largely consistent with the in vitro kinase assays, with an estimated IC50 of 0.7 nM for tolebrutinib against 33.5 nM for evobrutinib and 2.9 nM for fenebrutinib. We then observed that evobrutinib, fenebrutinib, and tolebrutinib achieved similar levels of exposure in non-human primate CSF after oral doses of 10 mg/kg. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp,uu CSF=0.40) exceeded the IC90 (the estimated concentration inhibiting 90% of kinase activity) value, while evobrutinib (3.2 ng/mL) (kp,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the estimated IC90 values.Conclusions: Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates.Montalban et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med . 2019 Jun 20;380(25):2406-2417.Background: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.Methods: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).Results: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.Conclusions: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).Additional readingThese studies’ results support my claim that relapses are not MS and that the real MS is smouldering MS. I have been saying this for some time. I suggest you read the following MS-Selfie Newsletters and papers to learn about some of the issues these trial results raise and support. * Getting worse (02-Jul-2021)* Do you have smouldering MS? (27-Jan-2022)If you use the search function on MS-Selfie and search for the term "smouldering", you will find many more newsletters, podcasts, and case studies on this topic, which becomes very pertinent now that we have emerging treatments that work on smouldering MS. I sincerely hope we have given the PPMS Tolebrutinib study enough power to deliver a positive result as well. Giovannoni et al. Smouldering multiple sclerosis: the 'real MS'. Ther Adv Neurol Disord. 2022 Jan 25:15:17562864211066751. Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.Scalfari et al. Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann Neurol . 2024 Jul 25. Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.Post-script: If you are an analyst and want more information on BTKi’s and MS, you cannot talk to me. I have too many conflicts of interest, so please don’t contact me. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

How many of you have disturbed sleep? How many of you suffer from insomnia? In my MS practice, insomnia is the most common sleep disorder I encounter, and it generally goes untreated. The reason is simply because most people with MS accept it as part of living with MS, and it is not prioritised by HCPs (healthcare professionals) who tend to focus on other MS-related problems. InsomniaInsomnia is defined as difficulty initiating or maintaining sleep and can be a symptom or a disorder. If a disorder, insomnia is associated with a feeling of distress about poor sleep, and it disrupts social or occupational functioning.In the general population, ~10% of adults have insomnia disorder and another 15-20% report occasional insomnia, i.e. the symptom. In comparison, 40-50% of people with MS have insomnia. Insomnia is more common in women and is associated with mental health and other medical problems. The most common MS-associated symptoms that are linked to insomnia are pain, neurogenic bladder, spasticity, restless legs, periodic limb movements, alcohol and stimulant misuse, menopausal symptoms, poor sleep hygiene (daytime napping), deconditioning (lack of exercise), anxiety and depression. All these MS-related problems can interfere with sleep initiation, maintenance, or perception.Insomnia can be episodic or situational and tends to follow a persistent course in most people. Chronic insomnia in itself can cause depression and is associated in the general population with the development of hypertension and dementia. I suspect this applies to pwMS as well. Insomnia assessment, diagnosis, and management require a careful history to document its course, concomitant comorbidities, and potential contributing factors. I suspect many of you have never had your insomnia formally assessed. A 24-hour history of sleep-wake behaviours can help identify additional behavioural and environmental factors for intervention. Patient-reported outcome measures and sleep diaries provide valuable information about the nature and severity of insomnia, help screen for other sleep disorders, and monitor treatment progress.A sleep diary should collect information on your sleep cycle (bedtime, arising time, napping) and estimates of your sleep-wake characteristics, i.e. sleep latency (how long it takes to fall asleep), number and duration of awakenings, and an estimated sleep time. Useful PROMS included the Insomnia Severity Index, Pittsburgh Sleep Quality Index, STOP–Bang questionnaire for evaluating the risk of sleep apnoea and the International Restless Legs Syndrome Rating Scale. ManagementIf you have any MS-related symptoms that can affect sleep, these need to be managed accordingly. How can you treat insomnia if your sleep is interrupted by anxiety-related rumination, nocturia, pain, leg spasms, restless legs, inability to roll over in bed, vasomotor menopausal symptoms and poor sleep hygiene? I would start with the following simple self-help guide to improve your sleep hygiene:* Ensure you spend an appropriate amount of time asleep, at least 6 hours in bed. Some people need more than this to feel refreshed. * Limit daytime naps to 30 minutes. Please note that napping does not make up for inadequate nighttime sleep. * Avoid stimulants such as caffeine, modafinil and nicotine close to bedtime. * Only drink alcohol in moderation. Alcohol is well-known to help you fall asleep faster, but too much disrupts sleep.* Exercise helps improve sleep quality. As little as 10 minutes of aerobic exercise daily can enhance sleep quality. * Don’t eat before going to bed. Heavy foods and fizzy drinks can trigger indigestion or heartburn/reflux, which can disrupt sleep.* Ensure you get adequate exposure to natural light; sunlight during the day and darkness at night help maintain a regular sleep-wake cycle. * Establish a regular relaxing bedtime routine, which helps the body recognise it is bedtime. This could include taking a shower or bath or reading. However, avoid reading or watching emotionally upsetting content before attempting to sleep.* Make sure that your sleep environment is pleasant. Your mattress and pillows should be comfortable. The bedroom should be cool for optimal sleep (16-20°C). The bright light from lamps, smartphones and television screens can make it difficult to fall asleep, so turn those lights off or adjust them when possible. Use the blue filter mode on your smartphone and other devices to reduce the inhibition of melatonin from light. Consider using blackout curtains, eyeshades, earplugs, white noise machines and other devices to make the bedroom more relaxing.If this should fail, other current treatment options include prescribed and over-the-counter (OTC) medications, cognitive behavioural therapy for insomnia (CBTI), and complementary and alternative therapies. I would avoid over-the-counter sedatives, as these tend to be first-generation antihistamines with potent centrally acting anticholinergic effects that affect cognitive function and long-term brain health (please see ‘Your anticholinergic burden’, 08-Jul-2021). Some pwMS self-medicate with OTC melatonin, CBD (cannabidiol) and THC (tetrahydrocannabinol) preparations. Please be aware that melatonin has a U-response curve for some people; therefore, lower doses may be better than higher doses. In general, I can’t recommend the use of CBD and THC for insomnia. However, if my patients find these work, who am I to say stop taking them? If you do buy CBD and THC, please try and use a reputable supplier and preferably pharmaceutical-grade products. Medicinal cannabis cannot be prescribed on the NHS but can be obtained via several private clinics. I know it is available online; many patients purchase it this way. As a doctor, I can’t recommend buying it this way. Please be aware that CBD is a drug and is associated with liver toxicity. CBD may interact with your other medications. If you raise the issue with your HCP, they often reach for the prescription pad. Before accepting a sedative, please ensure you have optimised all of the above and know its limitations. Sedatives are only a short-term solution; they work well for about 4-5 days before you develop tachyphylaxis and need higher doses. Tachyphylaxis refers to the rapidly diminishing response to successive doses of a drug, rendering it less effective. Once you build tachyphylaxis and stop taking sedatives, you may have rebound insomnia. Benzodiazepines (e.g. diazepam) are pretty addictive, and in general, most doctors avoid using them for insomnia. However, there is still a role for them when insomnia is part of acute anxiety. The goto sedatives are the so-called z-drugs (zolpidem, zopiclone, zaleplon and eszopiclone). Zopiclone and eszopiclone have a longer half-life and work for 5-6 hours. In comparison, zolpidem and zaleplon act for a much shorter period (1-3 hours). Many neurologists still use tricyclic antidepressants, such as amitriptyline, as sedatives. I have largely stopped this practice unless there is another reason for using a tricyclic, for example, to help with pain management. I have primarily replaced amitriptyline with duloxetine in my clinical practice for pain management.  Duloxetine is a serotonin-noradrenaline reuptake inhibitor and has much fewer anticholinergic side effects than tricyclics. For those of you taking amitriptyline or another tricyclic, please read my newsletter ‘Amitriptyline: the neurologist's dirty little secret’ (29-Sept-2021). Please be aware that antispasticity agents such as baclofen and gabapentinoids (gabapentin and pregabalin) also help sleep. However, these agents should only used for insomnia if you have spasticity or, in the case of the gabapentinoids, spasticity and/or pain that needs to be managed.  Psychiatrists and some neurologists use sedating antipsychotics to help with insomnia. This practice is widespread and has been heavily criticised, but there is a role for it in patients with cognitive issues or significant psychiatric problems. The older generation antipsychotics, for example, haloperidol, have now been replaced by safer drugs such as quetiapine and olanzapine. Sadly, as a neurologist, I have seen too many severe adverse events because of the liberal use of antipsychotics as sedatives. In my opinion, there needs to be a good reason for someone to be prescribed an antipsychotic, and insomnia in isolation is not one of them. The good news is that there is a new class of sedatives on the market in some countries. These are the dual orexin receptor antagonists (ORAs); suvorexant, lemborexant and daridorexant. Daridorexant is NICE-approved for use in the NHS. Daridorexant is recommended for treating insomnia in adults with symptoms lasting for three nights or more per week for at least three months and whose daytime functioning is considerably affected and only if CBTi has been tried but not worked, or CBTi is not available or is unsuitable. I have no experience prescribing ORAs, but they are at least something new to help insomniacs. Cognitive Behavioural Therapy for Insomnia (CBTI)Only some patients receive CBTI due to a lack of adequately trained therapists. CBTI aims to change your behaviour and psychological factors (e.g., anxieties and unhelpful beliefs about sleep) that contribute to insomnia. At the core of CBTI are behavioural and sleep-scheduling strategies (sleep restriction and stimulus control instructions), relaxation methods, psychological and/or cognitive interventions to change unhelpful beliefs and excessive worrying about insomnia, and sleep hygiene education. The following are the components of CBTISleep restriction: Limit the time you spend in bed to match your sleep time as closely as possible. After the initial restriction, the sleep window can be gradually adjusted upward or downward every week as a function of sleep efficiency (time asleep÷time spent in bed×100) until an appropriate sleep duration is established.Stimulus control: You need to follow a set of instructions designed to reinforce the association between bedtime and bedroom stimuli with sleep and to reestablish a consistent sleep-wake schedule:* Go to bed only when you feel sleepy* Get out of bed when you are unable to sleep* Use the bed and bedroom for sleep and sex only; do not use your bed for reading, watching television, etc.* Try and get up at the same time every morning* Avoid nappingRelaxation training: Try using different procedures to reduce arousal, muscle tension, and intrusive thoughts that interfere with sleep, such as progressive muscle relaxation and imagery training. Relaxation procedures need to be practised daily over a few weeks. Cognitive therapy: This is a psychological approach to revising many common misconceptions about sleep and reframing unhelpful beliefs about insomnia and its daytime consequences. This method also reduces excessive worrying about sleep difficulties and their daytime consequences. Additional cognitive strategies include paradoxical intention (willingly trying to stay awake rather than trying to fall asleep) to alleviate the performance anxiety triggered by attempting to force sleep.Sleep hygiene education: These are the general guidelines about health practices mentioned above and in many other MS-Selfie newsletters. For example, diet, exercise, substance use, and optimising environmental factors (e.g., light level, noise, and excessive temperature) that may promote or interfere with sleep are included (see above). Acceptance and commitment therapy (ACT): ACT is a form of psychotherapy that aims to educate people to stay focused on the present moment and accept life experiences, thoughts, and feelings (even negative ones) without trying to change them. ACT involves using different methods (e.g., acceptance, defusion, mindfulness, and committed action) and processes to increase psychological flexibility.Mindfulness: This meditation method involves observing one’s thoughts and feelings and letting go of the need to change or ruminate. Originally designed to reduce stress and anxiety, mindfulness has been adapted for the management of insomnia and can be included as one component of ACT.Brief behavioural treatments for insomnia: This abbreviated version of CBT-I emphasises behavioural components and is typically implemented in fewer sessions. It involves education about sleep regulation, factors that promote or interfere with sleep, and a tailored behavioural prescription based on stimulus control and sleep restriction therapy.Please note that CBTI is focused on sleep and oriented toward problem-solving. A psychologist typically guides you through CBTI over roughly six consultations. There are several variants in the methods for implementing CBTI, including shorter formats, group therapy, using other providers such as counsellors and specialist nurses, and using telehealth digital platforms, including smartphone applications. eCBTIDigital CBTI (eCBTI) is becoming increasingly popular. The Sleepio application, recommended and covered by the NHS, has a positive effect on several sleep outcomes and is said to be as effective as medication. NICE recommends Sleepio as a cost-saving option for treating insomnia and insomnia symptoms in primary care for people who would otherwise be offered sleep hygiene or sleeping pills. A medical assessment should be done before referral to Sleepio for people who may be at higher risk of other sleep disorder conditions, such as during pregnancy or in people with comorbidities. These are other eCBTI applications that some of you may have tried. I would be interested to hear if you found any of them helpful. To explore how common sleep problems are in pwMS with a focus on insomnia, I would appreciate it if you could complete the short MS-Selfie survey. The results of these surveys have, in the past, led to MS service changes and developments, which is why completing them makes a difference and has an impact. For example, the medical gaslighting survey has led to publications and educational programmes. As always, I am very keen to hear your stories about living with insomnia and how you have managed to self-manage this often disabling symptom. Thank you. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have often been asked if I could go back in time and change my career, what would I change? I probably wouldn’t change my decision to go to medical school. Discovering biology, biochemistry, human physiology, evolutionary medicine, neuroscience, and neurology has been and remains exhilarating. I am an addicted learner and consumer of news related to biology and medicine. However, knowing what I know now, I would probably not become a neurologist. I would study epidemiology to do global and public health. Why? As a jobbing neurologist, you are focused on diagnosing and treating individuals with disease; your impact is relatively small. In comparison, as a public health doctor, you think about population health and preventive medicine, where your influence is potentially much more significant. To be blunt, I would prefer to prevent people from getting multiple sclerosis (MS) rather than diagnosing and managing their MS. I was quite an unusual medical student in that I gave up attending lectures midway through medical school, preferring to teach myself in the library. I must have been the only student in my class who read the rather lengthy public health textbook we had been recommended. As a consequence of this, I unexpectedly won the public health prize in my fourth year. In my end-of-year viva, I went off-piste and discussed many topics not covered in the rigid lectures and curriculum. I remember the external examiner and me heatedly debating the Cuban barefoot doctor programme and why it was such a good model for Africa. As a result of my unexpected success, the head of the department was super-impressed and thought I would follow him into a public health career after my house job, but I didn’t. Was this a mistake? My next exposure to public health was during my year of national service. I was conscripted into the South African military for one year. After my officer’s course, I was posted to head up the medical epidemiology unit at the South African Medical Service headquarters. I had to teach myself epidemiology. I also taught myself how to code and became an expert user of Epi-info, the databasing and analysis program run by the CDC in the US. I did some extraordinary things during my year in the military. For example, I did a ‘top-secret’ HIV surveillance study and modelled the South African HIV epidemic. I set up a national register for South African veterans disabled in war. It was called the Curamus database. I studied many sexually transmitted and other infectious disease outbreaks in the SA military. I introduced a weekly report of notifiable diseases and coded a live dashboard to spot emerging disease outbreaks very early. I met the top generals and had a weekly audience with the Surgeon General (please see addendum below). Upon completing my military service, I got a commendation and medal from the Surgeon General for my services to the military. I have always played this part of my career down because of the reputation the South African military has in maintaining the apartheid state. However, on reflection, my time in the military has been very informative, at least from a public health perspective. I have always remembered the lessons I learned from teaching myself epidemiology, computer coding, and report writing. At that stage of my career, I should have realised that public health was for me. Instead of thinking deeply, I left the military and enrolled as a neurology trainee in the Johannesburg General rotation program; the rest is history. At the age of sixty, it is only now that I have finally reversed course and am following my instinct to do public health. I did my last official NHS clinic on Tuesday - apart from our MS nurse and visiting fellow, nobody noticed. I will now be spending my last few active years trying to prevent MS. As far as I am concerned, EBV is the cause of MS, and we now need to prove it. People who are EBV-negative are protected from getting MS underpinning using a sterilising EBV vaccine to prevent MS. A sterilising EBV vaccine, however, has yet to be developed and remains a challenge due to the complexity of EBV biology. The mechanism of how EBV causes MS is unknown. Most people think it is due to molecular mimicry; I am not convinced as there is emerging evidence that people with MS have a different and possibly aberrant immune response to EBV. This new data supports the case for testing immunotherapies, including therapeutic EBV vaccines, as potential treatments for MS. The possibility that intermittent lytic EBV infection, either peripherally and/or within the central nervous system, is driving MS disease activity makes a case for testing EBV antiviral therapies in MS. EBV vaccine studies, be they prevention or treatment trials, and testing EBV antivirals will happen regardless of whether or not I am involved. This is why I plan to focus on symptomatic EBV infection or infectious mononucleosis (IM). IM increases one’s risk of getting MS. However, the mechanism of IM increasing MS risk is unknown. Treating IM with EBV antivirals may reduce this risk and is a strategy that needs to be explored. My central hypothesis is that treatments to shorten the period of illness and severity of IM will reduce the risk of MS. Whatever immunological process that occurs during IM may be prevented with an effective antiviral therapy. This theory is analogous to using antibiotics to treat streptococcal pharyngitis to prevent the development of rheumatic fever and other post-streptococcal autoimmune diseases. So, I am retraining to become an infectious disease expert to set up a diagnostic and treatment pathway for purulent pharyngitis. By doing this, I hope to capture a new cohort of patients with IM for study and, more importantly, to test antivirals to treat IM. If I can get this working locally in East London, it could be scaled up nationally and internationally.  How many of you had IM? How many of you had complicated IM, such as prolonged fatigue or another complication?  Imagine if your IM was promptly diagnosed and treated with an effective antiviral. Maybe you would not have developed MS. Wouldn’t that be a fantastic story to tell? Addendum added 14-April-2025“Dear Gavin, I note your reference to the Surgeon General as a mensch. I am not sure if you are aware of his role or potential role in South Africa’s covert biological and chemical war program. I hope all is well in retirement.“I received this email from a friend and colleague in my medical school class. No, I was not aware of Surgeon General Knobel’s role in South Africa’s biological weapons programme, but I should be aware. It is rather upsetting that the Surgeon General could not give complete and honest evidence to the South African Truth and Reconciliation Commission (TRC) on his role in the biological and chemical war program for what appears to be spurious legal reasons. On reviewing the history via the archives of the TRC, it is hard to believe that he didn’t know what Dr Basson, who took the ultimate blame as a lone wolf for the biological and chemical war program, was doing. I assume the decision to set up a programme would have been political. Dr Basson, who ran it, was a South African Medical Service (SAMS) member and reported to the Surgeon General. It is therefore hard to believe he would not have known about the programme. After reading Timothy Snyder’s books on Tyranny and Freedom, it gives you insight into how living and working for a tyrannical government affects your norms and behavior. It would not have been easy for him as a cog in the machine not to follow orders. I used the term mensch in its Yiddish or colloquial sense, meaning a good person. Whenever I met the Suregon General to discuss epidemiological data and potential interventions about the data, he was respectful, a listener and appeared to care deeply about the role of the South African Medical Service (SAMS) in the health of the defence force and the nation. The only recommendations he didn’t act on were those to combat the emerging HIV epidemic. I am aware my HIV report went up the command change, but nothing happened. The dying National Party apartheid government did not have the mandate to change much. When the ANC party came into power, their initial response to the HIV epidemic was also woeful. The history of HIV and its management in South Africa needs its own TRC, and I would be willing to give evidence.I sincerely hope that Surgeon General Knobel has come to terms with his role in maintaining the apartheid state. I can't say I have. Chemical and biological weapons are a no-no for any medical practitioner who takes the Hippocratic oath. Cearly he was not a mensch. * For more information on Surgeon General Knobel, please see https://en.wikipedia.org/wiki/Daniel_Knobel * For more information on Dr Basson, please see https://en.wikipedia.org/wiki/Wouter_Basson * For more information on South Africa's biological and chemical weapons programme, please see https://www.nonproliferation.org/wp-content/uploads/npr/73gould.pdfSubscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Because I refer to smouldering MS as the ‘real MS, and play down the importance of relapses and focal MRI activity in driving MS disability, I am increasingly being asked if everyone with MS has smouldering MS. The answer is NO. And does everyone with smouldering MS end up in a wheelchair? Again the answer is NO.  Once you have been identified with smouldering MS do you get relentlessly worse. NO. No, no and no needs repeating. I was asked some of these questions by one of my patients in clinic yesterday. He has been successfully treated with alemtuzumab in 2018 and 2019. Despite having no relapses and no new MS disease activity on MRI, he is aware of worsening lower limb function and is having increasing problems with his bladder, bowel and sexual function. Over the last two years, his mobility has decreased to about 10 minutes or 400-500m walking time. Whenever he walks, his right leg begins to drag, and he develops a drop in his right foot. The latter has resulted in him stumbling and having several falls. Last year, he fractured a metatarsal or foot bone as a result of a fall. This patient missed out on being treated early with alemtuzumab and was only treated several years after diagnosis. He had a delayed diagnosis and spent several years on glatiramer acetate before being able to access alemtuzumab. His consultation was longer than usual. The outcome of the consultation will lead to several interventions: * He needs an appointment in the walking clinic for a trial of fampridine and possibly a functional electrical nerve stimulator (FES). If he can't tolerate a FES, he will need a bespoke ankle foot orthosis (AFO). In the interim, I recommended that he purchase and use a foot-up device. * I triggered a community physiotherapy assessment for rehabilitation or exercise programmes for his lower limb function. He needs to start using a walking stick to help him prevent any further falls. * He has to have a DEXA or bone density scan to see if he is osteopaenic or osteoporotic. The orthopaedic surgeon managing his metatarsal fracture did not consider MS-related osteoporosis. I suspect this oversight was because he is relatively young, and osteoporosis is uncommon in men. * I referred him to the continence service for a postmicturition volume assessment. This will tell us if he needs to start intermittent self-catheterisation (ISC) to deal with urinary urgency and hesitancy. I started a trial of Mirabegron for his urinary frequency and nocturia. The recommended starting dose was 25mg, which could be increased to 50mg if there was a poor response to the 25mg dose. I also gave instructions to his family doctor about a trial of DDAVP (Desmotabs or Desmospray) for his nocturia. For his hesitancy I suggest trying a lower abdominal vibrator and running water. These can sometimes lead to relaxation of the bladder sphincter. * I spent a lot of time advising on his MS-related constipation and bowel urgency. We are going to start with atrial of senna, 1-2 tablets at night, in combination of lactulose (15-30mL) and a glycerine suppository each morning to have a bowel action. If the glycerine suppository should fail, he will try Microlax mini-enemas and as a back-up we have the option of using anorectal irrigation (e.g. Peristeen system). This patient had had a few episodes of faecal urge incontinence and wants to avoid this happening in the future, hence the proactive approach to managing his bowel function.  * The next issue was sexual dysfunction. As a start, he will have a trial of tadalafil (Cialis), and if this fails, to add on top of the tadalafil a small dose of sildenafil (Viagra). Yes, the combination of these two drugs works better than either drug alone. Failing this he will need to go to the sexual dysfunction clinic. * Another issue was his poor sleep. He complained of interrupted sleep and not feeling refreshed on awakening in the morning. I suspect his sleep problem is due to his bladder dysfunction and will improve on Mirabegron and/or DDAVP. However, as he is a heavy snorer, I have asked for him to have a sleep study to exclude obstructive sleep apnoea (OSA). As you are aware, OSA is common in pwMS. He wanted to know why he was getting worse and whether or not I could predict if and when he would need a wheelchair.  He wanted to know if there were any other treatments I could give him to slow down his worsening lower limb function. These question triggered my usual explanation about why pwMS worsen despite being NEIDA (no evident inflammatory disease activity). I referred him to the MS-Selfie Newsletter ‘Getting Worse’ (02-Jul-2021) and have also referred him for screening for the SIZOMUS trial, an add-on study to assess the safety and efficacy of Ixazomib in patients with MS. This treatment aims to target CNS resident plasma and B-cells one of the many drivers of smouldering MS. I also mentioned to him the concept of burnt-out MS, i.e. that worsening MS continues for a time until all the nerve fibres destined to degenerate from previous damage die off, leaving behind a pool of surviving nerve fibres that maintain function at a similar level for decades until ageing mechanisms start to impact function later in life. Professor WI (Ian) McDonald, one of my clinical mentors when I started in the field of MS,  pointed out that in his experience, a minority of patients with worsening MS would continue to worsen for several years. Then, they would stop getting worse as if their disease burnt itself out. He used to tell his patients this in his clinic, claiming that about 1 in 10 patients or 10%, would develop this. He referred to this as a burnt-out MS (BOMS).Burnt-out MS is a controversial topic not covered in the literature. Many commentators mix up the concept of BOMS with benign MS. By definition, ‘benign MS’ is having MS for an extended period with little or no disability. In comparison, BOMS is flat-lining regarding disability worsening after a period of smouldering-associated worsening (SAW). As I enter the twilight of my career, I agree with Prof. McDonald’s observation with the one proviso that many patients with BOMS, who may be stable for decades, often come back when they get older, with deterioration in function likely to be age-related. The flatlining after a period of SAW represents therapeutic lag, i.e., it takes time for the anti-inflammatory effect of treatment to manifest, just as it takes time for the damage from past activity to manifest itself fully. In addition, some of the pathologies that underpin smouldering MS may also burn out with time. For example, paramagnetic iron-rimmed lesions on MRI (PRLs), which are thought to expand slowly over time, may stop expanding after several years. I then had to break the news to this patient that I was partially retiring and that he would have to be seen by one of my colleagues in the future. This generated a lot of discussion about my career plans going forward. If my retirement is news to you please read my recent newsletter ‘Prof G is retiring’ (21-Jun-2024).Several other problems this patient had that we could not sort out during this visit were chronic lower back pain, which is common in people with more advanced MS, nocturnal limb jerks, low mood and anxiety. In addition, his autoimmune thyroid disease post-alemtuzumab was not being well managed. His last thyroid function tests showed he was still hyperthyroid. Instead of managing this myself, I asked him to contact the endocrine team. He also had on his list of questions for me regarding supplements (which ones to take), exercise (how to do HIIT with weak legs), AHSCT (should he go abroad for AHSCT) and news about remyelination trials. I didn’t have time to answer these questions and referred him to MS-Selfie for answers. Other aspect of marginal gains approach to the management of MS I could not address included metabolic and social health, diet and alcohol consumption, comorbidities and a detailed review of his current medications. For example, he takes regular antihistamines for hay fever and I want to discuss with him the impact these could be having on his brain health. Sadly, I didn’t have time for this. The NHS expects us to do MS follow-up consultations in 10-15 minutes. This consultation took over 35 minutes and could have lasted an hour. Thankfully, he had done his self-monitoring (web-EDSS, T25FW, 9HPT and online SDMT), so I did not have to do a neurological examination and formal EDSS. We didn’t even have time to discuss his self-monitoring results. This patient expected more from his follow-up consultation than I could offer him. What is the solution? What would you recommend to address the problem of needing more time for follow-up consultations? If he had been an MS-Selfie subscriber and read all the self-help newsletters, he could have sorted out many of his problems. Is this a realistic expectation? Or do people with more advanced MS need an annual MOT? Is MS self-management a pipedream? For non-British people, an MOT refers to the annual requirement of the UK’s Ministry of Transport (MOT) for motor vehicles to have a service and certificate of roadworthiness before being driven on public roads. In an MOT, the motor vehicle is checked and has preventative maintenance done to prevent breakdowns in the future and, importantly, to ensure the car is safe to drive. All I can say is this person with MS had an incomplete and rather shoddy MOT. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

The MS community has painted itself into a corner with how we classify MS. Neurologists in the UK and the United Arab Emirates (UAE) have just published new treatment guidelines based on the old and arguably outdated classification system that MS can be divided into different clinical categories, i.e. clinically-isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS). Layered on top of this is whether MS is active or inactive and whether the predicted prognosis is good or bad. The UAE guidelines have also included radiologically isolated syndrome (RIS) or asymptomatic MS in their treatment algorithm. I assume the inclusion of RIS into their treatment algorithm is to pre-empt the new MS diagnostic criteria that will be published later this year. The problem with these classifiers is that they are all flawed and not underpinned by biology. MS was divided into multiple subtypes by the pharmaceutical industry to allow interferon-beta-1b to be licensed by the FDA as a treatment for RRMS under the Orphan Drug Act in the US. The Orphan Drug Act incentivises drug development in rare and neglected diseases. To be considered an orphan disease, there have to be fewer than 200,000 people with the disease in the USA. MS could only fulfil the 200,000 rule by being divided into three diseases (RRMS, SPMS and PPMS); later, a fourth category, CIS, was added. This is folly as MS is MS, i.e. it is one disease. From a biological perspective, there are no differences in these four categories. For that matter, RIS, a fifth category that is about to be added as a diagnostic category, is also MS. The FDA has tried to row back on this classification system and now licenses MS DMTs under the categories relapsing forms of MS and PPMS. The same cannot be said for the MHRA and EMA in Europe. Just so you know, the FDA was complicit with the MS three-or-four disease paradigm when they met with Berlex and MS experts in 1989 to classify MS as an orphan disease. Sadly, we are still suffering the consequences of that flawed decision. The next issue of active versus inactive MS is driven by a clinico-radiological worldview of MS. MS is active if there have been relapses or MRI activity (Gd-enhancing lesions or new or enlarging T2 lesions) in the last 12-36 months. Please note the exact period of time for defining what constitutes active MS is debatable; some use 12 months and others 24 and 36 months to define active MS. In the UK, the definition of active SPMS has even been extended to ‘inactive’ MS if someone is on an existing DMT. The assumption is that the current DMT is suppressing relapses and MRI activity but not helping with the so-called SPMS phase of the disease. This fudge allows us to at least switch patients with smouldering MS on existing DMTs to siponimod (Mayzent), which is licensed in Europe for treating active SPMS.  Have you ever tried telling someone with MS who has NEIDA (no evident inflammatory disease activity) who is getting worse because of smouldering disease that they have inactive MS? The standard response is how can I have inactive MS if I am getting worse. This is one of the reasons why I have had to develop a narrative to explain to pwMS why they are getting worse despite having no focal inflammatory disease activity (please see ‘Getting Worse’; 02-Jul-2021). I have argued before that superimposed focal inflammatory activity (relapses or new lesions on MRI) is likely to be the immune system’s response to what is causing MS and not MS itself. Relapses and focal MRI activity don’t fulfil contemporary criteria for being a surrogate outcome and are poor predictors of MS disease outcomes. Therefore, they can’t be the primary pathology driving MS. I think the real MS is smouldering MS that may or may not trigger a focal inflammatory event. Please note I am not saying relapses and focal MRI activity don’t matter. Focal inflammation contributes to the underlying damage that occurs in MS, but it is not the primary driver of MS. This is why you use focal inflammation as a treatment target in MS and switch or escalate treatment based on relapses and focal MRI activity. However, a large proportion of people who have NEIDA will still get worse from smouldering MS. Does this mean all pwMS will have smouldering disease?Clearly not, as many people found to have pathologically-confirmed MS at post-mortem were never diagnosed as having MS in life; either they didn’t have symptoms or their symptoms were mild and/or atypical and didn’t warrant a diagnostic work-up. Similarly, about 10% of siblings of pwMS have lesions on MRI that look suspicious of MS. However, only 2.5% or a quarter of them go on to develop MS. Similarly, a relatively large proportion of people with RIS never have an MS-defining attack. Presumably, these people diagnosed with RIS during life but don’t develop MS represent those people who are found to have incidental MS at post-mortem and didn’t have smouldering MS in life. Can you prevent or prevent smouldering MS from developing?It is also notable that a small percentage of people with MS treated early with immune reconstitution therapies, such as alemtuzumab or AHSCT, go into long-term remission and don’t develop smouldering MS. I have argued in the past that I think some of these people may be cured of their MS. I keep repeating these points because you can have MS and not develop smouldering disease. I suspect what is happening in this situation is that your immune system finds and eliminates the cause of MS, which prevents the subsequent development of smouldering disease. I think that smouldering MS represents active MS, which is why the term inactive MS is a misnomer. A counterfactualAs a counterfactual, I would prefer people to have MS or not have MS using a biological definition of MS. Then we can add on descriptors such as recent evident focal inflammatory activity (EIDA) or no recent evident focal inflammatory disease activity (NEIDA) and recent evident smouldering worsening (SAW) or no recent evident smouldering worsening (NSAW). This construct will at least frame future MS drug development, focusing on what to do about SAW. Will switching someone who is NEIDA/SAW from a platform therapy to one of the high-efficiency DMT make a difference? I suspect it may, but we don’t yet have the evidence. We need new treatment strategies, such as combination treatments targeting both EIDA and SAW, to address the unmet need. There is one caveat to this counterfactual classification system is that some pwMS who have had MS for decades and have lost a lot of brain and neuronal reserve may be present with delay worsening as a result of superimposed ageing. At the moment, we don’t have a reliable way of identifying or diagnosing this ageing-associated worsening, which will likely require a different therapeutic approach. I would like to know if you understand the semantics and arguments in this newsletter and whether this has relevance to you as someone with MS. I sincerely hope we will be able to sort out the diagnosis and classification of MS so that we can start trials in people with smouldering MS to tackle the problem of SAW. Paper 1 - UKRashid et al. Association of British Neurologists guidance for use of disease-modifying treatments  in multiple sclerosis. ABN June 2024. Paper 2 - UAEJacob et al. Disease-modifying treatment guidelines for multiple sclerosis in the United Arab Emirates. Mult Scler Relat Disord. 2024 Jun 9:88:105703.The newly constituted National Multiple Sclerosis (MS) Society (NMSS)of the United Arab Emirates (UAE), set up a scientific committee to create a MS disease modifying treatment (DMT) guideline for UAE. The committee considered several unique features of the MS community in UAE including large number of expatriate population, wide variations in health insurance coverage, physician and patient preferences for DMT. The overall goal of the treatment guideline is to facilitate the most appropriate DMT to the widest number of patients. To this end it has adapted recommendations from various health systems and regulatory authorities into a pragmatic amalgamation of best practices from across the world. Importantly where data is unavailable or controversial, a common sense approach is taken rather than leave physicians and patients in limbo. The committee classifies MS into subcategories and suggests appropriate treatment choices. It recommends treatment of RIS and CIS with poor prognostic factors. It largely equates the efficacy and safety of DMT with similar mechanisms of action or drug classes e.g. ocrelizumab is similar to rituximab. It allows early switching of treatment for unambiguous disease activity and those with progression independent of relapses. Autologous hematopoietic stem cell transplantation can be offered to patients who fail one high efficacy DMT. Pragmatic guidance on switching and stopping DMT, DMT choices in pregnancy, lactation and pediatric MS have been included. It is expected that these guidelines will be updated periodically as new data becomes available.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Survey resultsI recently did an MS-Selfie Q&A newsletter on the impact of having MS on taste and included a survey (please see: Q&A-33 multiple sclerosis and taste; 4-May-20204)In short, two-thirds of readers were unaware that MS could impact taste. So, this newsletter addressed an unmet need. Almost two-thirds of respondents stated that they had or may have experienced and alteration in taste that could be MS-related. This figure is much higher than I expected, but not surprising. The most commonly reported change in taste was reduced (hypogeusia) or altered taste (dysgeusia). However, eight respondents described ageusia or loss of taste. Many respondents also described other changes in their taste, such as heightened or intermittent metallic tastes. Not surprisingly, changes in taste often occur as part of an MS relapse, indicating that MS disease activity can impact taste function. The majority of you who reported MS-related alterations in taste had yet to have them investigated or treated by your MS HCPs. Is this a problem? Taste and MSIt is well known that MS can lead to changes in taste perception, resulting in a range of symptoms. Taste is a sensory modality not studied in depth in people with multiple sclerosis (pwMS). In a small study (see below), the taste identification scores for sucrose, citric acid, caffeine, and salt were significantly lower in pwMS. In 15-32% of subjects with MS, taste identification scores fell below the 5th percentile of controls for the different substances. These scores were inversely correlated with MRI MS lesion volume. Interestingly, women outperformed men in terms of taste. A large proportion of pwMS exhibit taste deficits that are associated with MS-related pathology throughout the brain. Altered taste function is yet another hidden symptom of having MS. Understanding altered taste in MSDysgeusia is a persistent, unpleasant taste in the mouth, manifesting as a metallic, bitter, or salty flavour. MS typically causes hypogeusia or diminished ability to taste flavours, reducing the perception of sweet, sour, salty, or bitter tastes as described above. Ageusia is a complete loss of taste perception, which rarely occurs in MS and significantly impacts an individual's ability to enjoy food. I have only seen one patient in my career who had a reversible loss of taste due to a brain stem relapse. Altered taste sensation has implications for nutritional intake. Changes in taste perception may lead to a decreased appetite, aversion to certain foods, and difficulty enjoying meals. This could lead to poor dietary choices and inadequate nutritional intake. The new GLP1 agonists (e.g. semaglutide (Ozempic/Wegovy) or tirzepatide (Zepbound/Mounjaro)) are thought to modulate taste perception and cause food to taste bland. This is part of their action mode and why they cause weight loss. The MS lesions that can affect taste are typically located in the areas associated with taste processing. These areas include the brainstem, thalamus, and cerebral cortex, which are involved in taste (gustatory) perception. When lesions form in these regions due to MS, they disrupt the transmission of taste signals and lead to alterations in taste perception. Please be aware that if you have altered taste, don’t assume it is MS. Altered taste can be caused by a variety of factors, including:* Infections: Respiratory infections, sinus infections, and other illnesses can temporarily affect the taste buds, leading to a distorted taste perception. This was particularly common with SARS-CoV-2 during the COVID-19 pandemic. * Medications: Certain medications, such as antibiotics, antihistamines, and chemotherapy drugs, can cause taste disturbances as a side effect.* Dental issues: Oral conditions like gum disease, dental infections, or injuries to the mouth can impact taste sensation.* Other neurological conditions: Apart from multiple sclerosis, other diseases affecting the nervous system, such as Parkinson's disease or Bell's palsy, can lead to altered taste perception.* Chemical exposure: Certain chemicals or environmental toxins can change taste perception.* Nutritional deficiencies: Deficiencies in certain nutrients, such as zinc, vitamin B12, or folate, can lead to taste abnormalities.* Smoking: Smoking can reduce one's ability to perceive flavours.Identifying the underlying cause of altered taste is important for determining the appropriate treatment and management strategies. Having MS may increase one's susceptibility to the effects of other diseases and medications that affect taste. Managing taste disturbances in MS can be challenging, but there are strategies that pwMS can employ to improve their eating experience. If loss or altered taste is due to a relapse, a course of high-dose steroids may help. If reduced or altered taste persists, you can try experimenting with flavours by exploring different seasonings, herbs, and spices, enhancing the taste of foods and making meals more enjoyable. Adapting foods' texture, such as creamy or crunchy elements, can provide a more satisfying eating experience, even if the taste perception is altered. If you can’t get on top of troubling taste symptoms, you may need to see a dietician and/or oral medicine expert. A dietician can help you develop a personalised diet plan to meet your nutritional needs despite taste disturbances.By understanding these challenges and implementing appropriate coping strategies, individuals with MS should be able to work towards maintaining a balanced diet, which hopefully is enjoyable. Calorie-sensingThere is more to taste than its perception. The human body has a sophisticated calorie-sensing system for detecting and managing calorie intake. This system helps maintain energy balance and, hence, impacts metabolic health. However, while artificial sweeteners are beneficial in reducing sugar intake, they have raised concerns about their impact on the physiological function of calorie-sensing.  Calorie sensing involves multiple physiological mechanisms that enable the body to gauge calorie intake and energy expenditure. This process is vital for maintaining homeostasis and preventing both undernutrition and overnutrition.* Sensory input: The taste buds and gut cells have receptors that respond to the caloric content of food, sending signals to the brain.* Hormonal responses: Hormones such as insulin, leptin, and ghrelin play pivotal roles in hunger regulation and energy storage.*  Metabolic adjustments: The body adjusts its metabolic rate based on perceived calorie intake to maintain energy balance.Artificial sweeteners are widely used as substitutes for sugar, offering sweetness without the calories. Examples include aspartame, sucralose, and saccharine. While artificial sweeteners are advantageous for reducing caloric intake, they challenge the body's natural calorie-sensing mechanisms. Artificial sweeteners provide intense sweetness with little to no calories. This discrepancy can trick the body into expecting energy that isn't delivered, potentially leading to increased appetite and overeating. Several studies have shown that artificial sweeteners can alter gut microbiota, impacting metabolism and energy utilisation. The sweet taste of artificial sweeteners triggers insulin release in anticipation of glucose. However, when artificial sweeteners are consumed regularly, this response can become disjointed, potentially leading to insulin resistance over time.If you use artificial sweeteners, you must be aware of their impact on your health. There is now overwhelming evidence that artificial sweeteners are associated with cardiovascular disease (see paper 2 below). As vascular disease is linked to worse MS outcomes, will the regular consumption of artificial sweeteners lead to worse MS outcomes? From an evolutionary medicine perspective, it is best to avoid artificial sweeteners. Why would we hijack a physiological system (calorie-sensing) to try and reduce sugar consumption?  Do you agree?For those of you who are not paying subscribers, I would like to hear if you have noticed problems with taste, either as part of a relapse or as a complication of smouldering or more advanced MS. If you have time, please complete the taste survey. I would also be interested in your thoughts about artificial sweeteners and MS-related health outcomes. Should we ignore the emerging science or avoid artificial sweeteners to optimise our metabolic health? Paper 1Doty et al. Taste dysfunction in multiple sclerosis. J Neurol . 2016 Apr;263(4):677-88. Empirical studies of taste function in multiple sclerosis (MS) are rare. Moreover, a detailed assessment of whether quantitative measures of taste function correlate with the punctate and patchy myelin-related lesions found throughout the CNS of MS patients has not been made. We administered a 96-trial test of sweet (sucrose), sour (citric acid), bitter (caffeine) and salty (NaCl) taste perception to the left and right anterior (CN VII) and posterior (CN IX) tongue regions of 73 MS patients and 73 matched controls. The number and volume of lesions were assessed using quantitative MRI in 52 brain regions of 63 of the MS patients. Taste identification scores were significantly lower in the MS patients for sucrose (p = 0.0002), citric acid (p = 0.0001), caffeine (p = 0.0372) and NaCl (p = 0.0004) and were present in both anterior and posterior tongue regions. The percent of MS patients with identification scores falling below the 5th percentile of controls was 15.07 % for caffeine, 21.9 % for citric acid, 24.66 % for sucrose, and 31.50 % for NaCl. Such scores were inversely correlated with lesion volumes in the temporal, medial frontal, and superior frontal lobes, and with the number of lesions in the left and right superior frontal lobes, right anterior cingulate gyrus, and left parietal operculum. Regardless of the subject group, women outperformed men on the taste measures. These findings indicate that a sizable number of MS patients exhibit taste deficits that are associated with MS-related lesions throughout the brain.Paper 2Debras et al. Artificial sweeteners and risk of cardiovascular diseases: results from the prospective NutriNet-Santé cohort. BMJ 2022 Sep 7:378:e071204. Objectives: To study the associations between artificial sweeteners from all dietary sources (beverages, but also table top sweeteners, dairy products, etc), overall and by molecule (aspartame, acesulfame potassium, and sucralose), and risk of cardiovascular diseases (overall, coronary heart disease, and cerebrovascular disease).Design: Population based prospective cohort study (2009-21).Setting: France, primary prevention research.Participants: 103 388 participants of the web based NutriNet-Santé cohort (mean age 42.2±14.4, 79.8% female, 904 206 person years). Dietary intakes and consumption of artificial sweeteners were assessed by repeated 24 h dietary records, including brand names of industrial products.Main outcomes measures: Associations between sweeteners (coded as a continuous variable, log10 transformed) and cardiovascular disease risk, assessed by multivariable adjusted Cox hazard models.Results: Total artificial sweetener intake was associated with increased risk of cardiovascular diseases (1502 events, hazard ratio 1.09, 95% confidence interval 1.01 to 1.18, P=0.03); absolute incidence rate in higher consumers (above the sex specific median) and non-consumers was 346 and 314 per 100 000 person years, respectively. Artificial sweeteners were more particularly associated with cerebrovascular disease risk (777 events, 1.18, 1.06 to 1.31, P=0.002; incidence rates 195 and 150 per 100 000 person years in higher and non-consumers, respectively). Aspartame intake was associated with increased risk of cerebrovascular events (1.17, 1.03 to 1.33, P=0.02; incidence rates 186 and 151 per 100 000 person years in higher and non-consumers, respectively), and acesulfame potassium and sucralose were associated with increased coronary heart disease risk (730 events; acesulfame potassium: 1.40, 1.06 to 1.84, P=0.02; incidence rates 167 and 164; sucralose: 1.31, 1.00 to 1.71, P=0.05; incidence rates 271 and 161).Conclusions: The findings from this large scale prospective cohort study suggest a potential direct association between higher artificial sweetener consumption (especially aspartame, acesulfame potassium, and sucralose) and increased cardiovascular disease risk. Artificial sweeteners are present in thousands of food and beverage brands worldwide, however they remain a controversial topic and are currently being re-evaluated by the European Food Safety Authority, the World Health Organization, and other health agencies.Trial registration: ClinicalTrials.gov NCT03335644.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Anyone who lives in London will tell you that buses come in threes. What you are not told is which bus to catch and which buses to miss. I have just turned 60, and I have the option of choosing between three buses. I need to decide which one to catch. I suspect it is quicker to catch the second bus as the first one is usually packed and stops frequently and longer to allow passengers to get on-and-off. This may enable the second bus to overtake it as it doesn’t have to stop at each bus stop. The third bus may be the emptiest, so it catches up quickly to the first two but is unlikely to overtake the second bus that is now in front.The first bus is to continue doing what I do now, and I hope I survive trying to run an increasingly busy NHS MS practice, conduct clinical trials, maintain MS-Selfie, and set up a new line of research around EBV and MS prevention.  The second option is to step back from clinical practice and use the time to focus on MS prevention. The third and final option is to throw in the towel and retire early to focus on my family and interests outside of medicine. Many of my colleagues are taking up the third option; burnt out and exhausted, they want something different. I have been told things happen for a reason, so I have had to make a tough decision. My accident and its lingering effects on my day-to-day functioning, the threat of melanoma metastases, clinical burnout and increasing administrative demands have led to me to the decision to take partial retirement. So, starting on the 1st of September 2024, I will stop NHS clinical practice and work four days a week. The latter is a requirement of the NHS partial retirement scheme. I will continue to do MS clinical trials and see potential study subjects. Clinical trials are vital as each trial is an experiment and, if designed and done well, allows you to formulate, reject or advance a research hypothesis. I am particularly interested in exploring EBV antivirals and immunotherapies as potential treatments for MS. I recently gave an invited talk at the Medical Society of London entitled “Multiple Sclerosis—a road less travelled, with miles to go before I Sleep”. The lecture was part of the Mansell Competition for young researchers, which our brilliant Dr Ben Jacobs won. He summarised his PhD work on the genetic analysis of MS risk in diverse ancestral populations. In my talk, I discussed what still needs to be done to prove that EBV is the cause of MS. I presented the obvious MS prevention trials that need to be undertaken. I am involved with most of the EBV MS prevention strategies to a greater or lesser extent, but the one most neglected is infectious mononucleosis (IM). The hypothesis is simple. IM or symptomatic EBV infection is the predominant risk factor for the development of MS. People who have IM are about 2.0-2.5 times more likely to develop MS. Why? I suspect the aberrant immune response during IM is the substrate that sets the stage for autoimmunity in the future. If we can diagnose and treat IM with effective antiviral drugs and prevent this immune response, we can avoid the development of MS and other EBV-related autoimmune diseases. The analogy is streptococcal infections and post-streptococcal autoimmunity, for example, rheumatic fever. Rapidly diagnosing and treating streptococcal pharyngitis and impetigo have virtually eliminated rheumatic fever in high-income countries. Could treating infectious mononucleosis do the same for MS? I have been awarded a grant from the Horne Family Foundation to set up a pilot study to see if we can create a rapid diagnosis and treatment pathway for purulent pharyngitis, which will include IM. This will allow us to study the immunology of IM and conduct randomised controlled trials in patients with acute IM. If we can get a licensed therapy for acute IM, we will then set up population-based registers to see if treating IM reduces the incidence of MS and other EBV-related disorders. This is not dissimilar to what we want to achieve with a prophylactic EBV vaccine. My partial retirement is a misnomer. I will use the time freed from stopping clinical work to do something completely different: MS prevention. How will this affect my patients? People with MS who are from out of the area and are not being treated at Barts Health will need to be followed up and managed by their local MS team. I have stopped taking new referrals. My colleagues at Barts Health have kindly agreed to take over some of my patients, and a close colleague of mine will be taking over my general neurology and MS clinic later this year.  In the interim, I will continue to run and contribute to MS-Selfie, but I will be looking for someone to help me with a view of a timely succession. I still plan to complete the MS-Selfie microsite and launch the MS-Selfie self-management course and guide. People are surprised that despite my commitment to neurology and multiple sclerosis, I do have outside interests. I intend to allocate more time to these pursuits. Having had two life-threatening events in short succession focuses the mind on one's mortality. I have many miles to go before I sleep and promises to keep ….. You can download my slides from my Medical Society of London talk here and watch a recorded version on my YouTube channel. If you have any comments or questions about my London bus choice, please let me know. Finally, I have recently been asked to start a series of online webinars and live Q&A sessions. For example, I could do the first one on the issues discussed in this newsletter. Is there an appetite for live sessions? P.S. For patients under my care, please don't panic. We will process your cases individually and then set up a follow-up plan. Either a referral back to your local team, a transfer to one of my colleagues, or you will stay in my clinic, which will be taken over later this year by a close colleague. I am not physically leaving and will still see trial subjects at the Royal London Hospital and will be participating in the multidisciplinary team meetings (MDTs). Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Sometimes, things need repeating. Exercise, exercise, exercise, ………I have previously stated exercise is the most underrated and under-utilised multiple sclerosis disease-modifying therapy (DMT) we have. So why is regular exercise not part of the standard MS care package?Please see: * Exercise, exercise, exercise ... how important is it? (MAR 09, 2022)* Exercise: how important is it? (NOV 23, 2021)I am always surprised how people with MS (pwMS) often think that they get enough exercise by simply walking their dogs a few times a week. Similarly, some pwMS believe that doing a session of weight training a few times a week is sufficient exercise. A patient criticised me for suggesting she do HIIT (high-intensity interval training). She registered for a HIIT session at her local gym and had to stop after 3 minutes. She said my recommendation was ridiculous, considering her physical state. The problem is she was doing a HIIT class with a group of very fit people. HIIT is not about an exercise class but the type of exercise and the physiological stimulus it gives to the body that results in metabolic reprogramming. In other words, HIIT has to be personalised. Simply climbing a flight of stairs may be HIIT for one person. What is HIIT?HIIT is an exercise alternating between short bursts of intense activity and fixed periods of less intense or complete rest. It is a cardiovascular exercise strategy that combines short, intense bursts of anaerobic exercise with less intense recovery periods. It has been shown to improve metabolic health and cardiovascular fitness faster than traditional steady-state workouts.The key features of HIIT are:* Short Duration: workouts usually last between 10 to 30 minutes. E.g. 3 x 5 minutes ( 1 minute high-intensity & 4 minutes of low intensity exercise) = 15 minutes* High Intensity: exercise periods involve maximal or close to maximal effort.* Variable Intervals: alternating between high-intensity periods and low-intensity recovery periods.* Versatility: can incorporate running, cycling, rowing, or body-weight exercises.A sports physiologist told me that you need to raise your heart rate to above 90% of the predicted maximum heart rate to be confident that the intensity of HIIT is sufficient. In comparison, with moderate-intensity exercise, your heart rate is typically 60-80% of the predicted maximal heart rate and with low-intensity exercise, it is below 60% HRmax. You can use the following formula to calculate your predicted maximal heart rate. The age-predicted maximum heart rate (HRmax) =  220 - age (yrs)There is evidence in pwMS that HIIT is superior to moderate-intensity aerobic exercise (see paper 1 below), which is why I recommend it. However, HIIT is not enough. You should also make the time for weight training. Weight training helps prevent the loss of muscle mass, is good for bone health, and has other health benefits in the future. I was impressed with the results of a study that has just been published in well-functioning older adults at retirement age (paper 2 below). One year of heavy resistance training may induce long-lasting beneficial effects by preserving muscle function. These results will likely apply to pwMS regardless of age. If you have the time and physical capacity, try to do low—to moderate-intensity exercise as well. For me, it provides an opportunity to switch off, i.e., a form of mindfulness. If I don’t get regular aerobic exercise (3-4 times a week), my mood drops, I start to feel lethargic, and I don’t sleep as well. Many people with MS tell me that they are simply too tired to exercise. My response is that lack of exercise tends to worsen fatigue due to deconditioning, which is why most MS fatigue management programs include graded exercise. If exercise exhausts you, try to do it last thing in the day. When it comes to low to moderate-intensity exercise, there is no point in reinventing the wheel I simply recommend the WHO or American Heart Association Recommendations for Physical Activity in Adults and Kids. Below are the levels of physical activity that WHO recommends for people of different ages to undertake. Children and adolescents aged 5-17 years* Should do at least 60 minutes of moderate to vigorous-intensity physical activity daily.* Physical activity of amounts more than 60 minutes daily provides additional health benefits.* It should include activities that strengthen muscles and bones at least three times per week.Adults aged 18–64 years* Should do at least 150 minutes of moderate-intensity physical activity throughout the week, or do at least 75 minutes of vigorous-intensity physical activity, or an equivalent combination of both.* Adults should increase their moderate-intensity physical activity to 300 minutes per week or equivalent for additional health benefits.* Muscle-strengthening activities should be done involving major muscle groups on two or more days a week.Adults aged 65 years and above* Should do at least 150 minutes of moderate-intensity physical activity throughout the week, or at least 75 minutes of vigorous-intensity physical activity, or an equivalent combination of both.* For additional health benefits, they should increase moderate-intensity physical activity to 300 minutes per week or equivalent.* Those with poor mobility should perform physical activity three or more days per week to enhance balance and prevent falls.* Muscle-strengthening activities should involve major muscle groups two or more days a week.Social HealthExercise can also address social health, which is another unmet need in pwMS. If you join a gym or an exercise group, you can meet other people and interact with them. I have little doubt this is one of the other benefits of exercise: It gets pwMS to interact with other people and addresses the problems of loneliness and social isolation. Case studyRecently, I did a telephone follow-up consultation with a patient who is a wheelchair user (EDSS 7.0). He opened the consultation by stating that he feels rejuvenated since a local charity had bought him an arm bike. He now does 30-60 minutes of upper limb aerobic exercise 5-6 times per week, and it has improved almost all of his MS problems. He has lost weight, improved his mood, and is sleeping better. Remarkably, he has managed to dispose of his CPAP mask for his obstructive sleep apnoea. He also enrolled in an online course on ancient Greece, something he had wanted to do for many years, even before he developed MS. He is also arranging a late summer cruise in the Mediterranean with his wife with the aim of visiting several historical sites in Greece and the Greek islands. This man has regained his joie de vivre because of the magic of exercise. If exercise has transformed your life, please let us know. If you are not exercising, you need to start. If you need help figuring out how to start, please ask to be referred to a physiotherapist who can design a bespoke programme for you. In conclusion, exercise is the most underrated and under-utilised MS disease-modifying therapy, which is why everybody who has MS should be doing it. Paper 1Joisten et al. Exercise Diminishes Plasma Neurofilament Light Chain and Reroutes the Kynurenine Pathway in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021 Mar 29;8(3):e982.Objective: To examine acute (single-bout) and training effects of high-intensity interval training (HIIT) vs standard exercise therapy (moderate continuous training [MCT]) on plasma neurofilament light chain (pNfL) and kynurenine (KYN) pathway of tryptophan degradation metabolites in persons with multiple sclerosis (pwMS).Methods: Sixty-nine pwMS (Expanded Disability Status Scale score 3.0-6.0) were randomly assigned to a HIIT or an MCT group. Changes in pNfL and KYN pathway metabolites measured in blood plasma were assessed before, after, and 3 hours after the first training session as well as after the 3-week training intervention.Results: Acute exercise reduced pNfL and increased the KYN pathway flux toward the neuroprotective kynurenic acid (KA). Changes in pNfL correlated positively with changes in KA and negatively with the quinolinic acid-to-KA ratio. HIIT consistently led to greater effects than MCT. Following the 3-week training intervention, the KYN pathway was activated in HIIT compared with MCT.Conclusion: Future studies and clinical assessments of pNfL should consider acute exercise as confounding factor for measurement reliability. Moreover, exercise-induced KYN pathway rerouting might mediate neuroprotection, potentially underlying the benefits in rehabilitation for pwMS.Classification of evidence: This study provides Class II evidence that acute HIIT diminishes pNfL and increases KA levels, and 3 weeks of HIIT activate the KYN pathway in pwMS.Trial registration information: Clinical trial registration number: NCT03652519.Paper 2Bloch-Ibenfeldt et al. Heavy resistance training at retirement age induces 4-year lasting beneficial effects in muscle strength: a long-term follow-up of an RCTBMJ Open Sport & Exercise Medicine 2024;10:e001899.Objectives: Muscle function and size decline with age, but long-term effects of resistance training in older adults are largely unknown. Here, we explored the long-lasting (3 years) effects of 1 year of supervised resistance training with heavy loads.Methods: The LIve active Successful Ageing (LISA) study was a parallel group randomised controlled trial at a university hospital in Denmark. Older adults (n=451) at retirement age were randomised to 1 year of heavy resistance training (HRT), moderate-intensity training (MIT) or a non-exercising control group (CON). Primary outcome measure was leg extensor power. Secondary outcomes included maximal isometric quadriceps torque (isometric leg strength) and body composition (dual-energy X-ray absorptiometry (DXA)). Participants completed test procedures at baseline, following the 1-year intervention, and 2 and 4 years post study start.Results: At the 4-year assessment, 369 participants attended (mean age=71 years, 61% women). The main finding was that across all four time points, there was a significant group×time interaction in isometric leg strength (F6,1049=8.607, pConclusion: In well-functioning older adults at retirement age, 1 year of HRT may induce long-lasting beneficial effects by preserving muscle function.Trial registration number NCT02123641.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. If people want to ask questions unrelated to the Newsletters or Podcasts, you must be a paying subscriber. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

MS-Selfie rose-tinted-odometer = ★★★☆☆A few readers have recently found some of my newsletters so unsettling and dark that one of them unsubscribed. Therefore, I have reinstated my rose-tinted-odometer, a simple 5-star rating of the type of content the Newsletter contains. The rating will allow you, the reader or listener, to make a call on whether or not you want to be exposed to content that is not so rose-tinted. Another criticism is that the content of the MS-Selfie podcast and newsletters are not sufficiently curated to allow people with MS and their families to self-manage their condition, and they are written in a way that is too scientific or highbrow, i.e. the content is for HCPs and not pwMS. I’m afraid I have to disagree with the latter criticisms. I have deliberately positioned MS-Selfie at a high level. Firstly, it is my understanding that pwMS want something more than what the MS charities provide. For example, the MS Society’s content is written for a reading age of 12. Am I correct in this assumption? Secondly, as many pwMS become more health literate, they are often as well-informed and, in some cases, better informed than their HCPs. This is why the content on MS-Selfie is for both pwMS, their families and HCPs. With the democratisation of knowledge, everybody has access to similar levels of information and having a platform that potentially caters to both patients and HCPs is an advantage. Or maybe I am being naïve?  One of the main aims of MS-Selfie is health literacy, which gives people with MS (pwMS) agency and the confidence to make decisions about their MS care or to at least ask the questions that will lead to better management of their MS. Health literacy is even being identified by the World Health Organisation as an agent or change. The WHO has stated that “improving health literacy provides the foundation on which citizens can play an active role in improving their own health, engage successfully with community action for health, and push governments to meet their responsibilities in addressing health and health equity. Promoting health literacy in all but in particularly marginalised societies is crucial in accelerating progress in reducing health inequities and advancing broader social, economic, and environmental goals outlined in the 2030 Agenda for Sustainable Development”.I want to repurpose what the WHO says about population health literacy in managing MS. “Improving health literacy provides the foundation for pwMS to play an active role in improving their health, engaging successfully with their HCPs, and pushing payers, third-party providers and their governments to meet their responsibilities in addressing health and health equity in managing MS.” PwMS interacts with its healthcare professionals (HCPs) at different points in their MS journey. The diagnostic and initial treatment phase tends to take precedence over the rest of the MS journey. However, in reality, the ongoing day-to-day management of MS is much more critical in the life of someone with MS.  As the NHS and other healthcare systems come under increasing pressure due to unsustainable funding models, demographic changes, and economic and political pressures, it is clear that people with chronic diseases need to do more to self-manage the impact of their disease(s) on their functioning. MS is no exception. So, ask not what the NHS or your HCP can do for you but what you can do to help yourself.Many, if not most, pwMS are dissatisfied with their 3-monthly, 6-monthly or annual follow-up consultations. Yes, in some healthcare systems, for example, Germany, pwMS get 3-monthly follow-up appointments. Short and incomplete follow-up assessments are part of a broader problem in the NHS related to understaffing, an increasing number of pwMS, i.e. both the incidence and prevalence of MS are increasing, and there is less time for patient contact due to the digitalisation of our practice. About the latter, we now have more administrative duties on the electronic health record that consume time. Another aspect that needs to be addressed is that pwMS are more educated about having MS than they were in the past. Hence, they expect more from their MS services, including more time with their MS neurologist and nurse specialist. Many patients come with lists of questions that could quickly be answered by subscribing to a resource such as MS-Selfie. Many patients know the answers to most of these questions but want the answers validated.   So, I would like to ask you for advice on how you would like MS-Selfie to evolve. Do you want me to ‘dumb down’ the content to make it more understandable to MS newbies? Should the content be sugar-coated or rose-tinted? Should I only focus on MS self-management? Should I avoid research topics and other musings that are arguably quite obtuse? The following is an example of what a typical self-management newsletter could look like. Self-Management 101 - What to expect from your scheduled follow-up appointmentsPreparing for your follow-up appointments is important. Before you arrive at the clinic, collect data and complete a proforma. A well-designed clinic proforma could act as a crib or manifesto for the self-management of MS. Since the NHS adopted a specialist model of MS care to improve the management of people with long-term conditions, you need to remain under your MS service lifelong. Yes, until we prove we can cure you of having MS, MS remains a lifelong condition, and hence, you need lifelong support from a specialist MS service. The Association of British Neurologists recommends follow-up appointments take 15 minutes. From comments on this platform, it is clear that many patients don’t get 15 minutes for their annual appointment. It is also evident that as our treatment goals get more ambitious and we adopt a holistic approach to managing MS, we need more than 15 minutes for follow-up appointments, or we need a new way of doing things.The needs of pwMS change over time. Someone who develops MS typically starts their journey as being at risk of getting MS. They then pass through asymptomatic, prodromal and diagnostic phases. Once diagnosed with MS, they go through the stages of no or minimal disability, moderate disability, severe disability and finally, the terminal stages of having MS. Please note that completing the journey is not inevitable. Many pwMS hop off when treated with high-efficacy DMTs, particularly early on, preventing them from becoming disabled. I have included a dashed grey line that leads to long-term remission and an MS cure. This line is still under construction as we don’t have enough data to claim we can cure MS.As your needs along the MS journey change, the annual follow-up appointments must reflect this. Some HCPs want to create specific care pathways to manage all the problems pwMS complain about. However, care pathways can fragment MS care. For example, we may refer patients to see their local continence team or refer them to the spasticity clinic to consider a baclofen pump. A different team deals with these problems, and they justify a specific, well-defined care pathway. Having separate care pathways for multiple problems often increases healthcare utilisation and costs. This is why MS teams attempt to deal with most MS-related problems themselves or initially before more specialist input is required.  The following typically needs to be done at the annual follow-up appointment in no particular order:Is your MS active?Have you had any relapses in the last 12 months, and has your annual MRI scan shown any new lesions? This is important as it may make you eligible for starting, switching or escalating your disease-modifying therapy (DMT). This section of the follow-up consultation can be difficult if the patient is getting worse, i.e. has smouldering MS or intermittent symptoms that may or may not be due to a relapse. Smouldering MS is very probably the norm in pwMS if it is looked for with neurological stress tests and more sensitive outcome measures. However, neither of these are part of routine clinical practice. The problem is a lack of evidence on how to manage smouldering MS, i.e. at present, we don’t know if escalating treatment in people with smouldering MS or PIRA (progression independent of relapse activity) makes any difference. This is likely to be the reason why clinicians don’t look for it. This will change in the future once we have treatments targeting smouldering MS. Retrospective relapse assessments are also difficult. For example, somebody who had new symptoms since their last assessment but didn’t bring it to our attention then, and their symptoms have now resolved. Part of what defines a relapse are changes on examination, and if you can’t find any new clinical signs, it is very difficult to call a possible relapse a relapse. This may not be important if the monitoring MRI shows new lesions as this provides objective evidence of ongoing inflammatory MS disease activity. However, if the MRI shows no changes, an opportunity has been missed to document MS disease activity. Please be aware that about a quarter of relapses, as defined clinically, are not associated with new lesions on MRI. So, this issue is not trivial and occurs far too commonly in my clinical practice. In the future, when regular blood neurofilament monitoring becomes routine, we may include biochemical evidence of relapse as part of the definition. This will be particularly powerful if we can do remote self-administered NFL measurements. I have predicted that biochemically-defined relapses will become the norm. Are you stable or getting worse?In our centre, we are asking patients to self-monitor to get them to engage with their own MS and to save time. We now expect our patients to complete the online web-EDSS, their own timed 25-foot walk and 9-hole peg test, and the online SDMT (symbol digit modality test). Some patients do more than this; for example, they record their walking or running times and produce activity monitoring data. In the future, this is likely to expand to include neurological stress tests and even home sleep monitoring using wearable technology. Most pwMS have a sleep disorder, which contributes to poor brain health and exacerbates fatigue. Getting people with MS to sleep better will improve many other MS symptoms. Have all your pharmacovigilance and derisking activities been done?This involves ensuring your blood tests are fine, that you have had your annual vaccines, and, if necessary, screening for malignancies. Please note that the blood tests and procedures required are unique to each class of DMTs; for example, if you are on natalizumab, this will include a  6-monthly JC virus antibody index and potentially a 4-monthly PML monitoring MRI.Current medications?Before a detailed symptom review, I like to review a list of current medications. This can be easy if you remember to take a list with you. Often, the medication review forms the basis of the consultation. It is not only the current list that is helpful but also any changes from the last visit and a review of dietary supplements. PwMS are increasingly using supplements on top of their prescribed medications to try and improve their outcome.  It is remarkable how often supplements and alternative therapies hijack the annual visit. It is also incredible how many patients attend their follow-up appointments without an up-to-date list of their medications. Family planningWhere appropriate, I ask patients about their plans to start or extend their families. This is highly relevant as this often interacts with DMTs and medications. This conversation may lead to a discussion about contraception. The family planning detour in itself can take many minutes to complete. Do you have any symptomatic problems? This list of symptoms you ask about and apply here depends on where you are on the MS train journey. There is little point in asking about spasticity and falls if a patient is not disabled and runs marathons. I always start with the bladder and bowel function and then proceed to sexual dysfunction. I then ask about mobility, i.e. walking distance, trips and falls.  Even if a patient is not falling, they may be at risk of falls and need to be referred to a fall prevention programme and to have their bone health assessed. The latter involves having a DEXA or bone density scan and taking vitamin D supplements (4,000U per day). If you are osteopaenic or osteoporotic, you should also have been prescribed calcium. I then move on to fatigue, sleep, nocturnal spasms, restless legs and pain. I then bring up the issue of mood and anxiety, which are common problems in pwMS. I always close this section with an open-ended question about other symptoms. On many occasions, I have to deal with symptoms that are not MS-related, for example, joint pain from arthritis. It is incredible how often non-MS-related symptoms are attributed to MS and are left to the MS team to sort out. Brain HealthI try to address all the issues I have mentioned in the past that can impact brain health, including exercise, diet, comorbidities and other lifestyle factors such as alcohol, smoking and other substances and HRT (hormone replacement therapy). In an ideal world, I would love to be able to screen my patients for hypertension and the state of their metabolic health, but I don’t have time for this, and the management of these problems needs to be done by the general practitioner. It is pretty depressing that many of my patients who have comorbid hypertension or diabetes are not as engaged with managing their comorbidities as much as their MS. If you have hypertension or diabetes, you need to self-monitor your blood pressure and blood sugars and feedback the information to your GP. Social Health and the Social Determinants of HealthMore recently, I have started addressing modifiable social determinants of health. This includes questions about work, whether patients come out each month financially, loneliness and social isolation. We focus on social issues because we can now refer, or ask the GP to refer, patients for help using social prescribing, or we can simply sign-post people to community services. CognitionI don’t specifically ask about cognition because self-reporting cognitive problems is often unhelpful. I am unsure if you know that pwMS who complain of cognitive problems are more likely to be depressed and anxious than have significant cognitive impairment. I prefer to pick up clues from the consultation that cognition is an issue and try to deal with the consequences as best I can. For example, an occupational health assessment may be the most appropriate action if someone is not coping at work. Now that we are monitoring cognition with the online SDMT, it is noteworthy that some people with relatively low scores still manage very well at work. Therefore, bringing up cognitive issues in high-functioning patients is not necessarily appropriate. Activities of Daily LivingIn patients who are disabled, it is essential to ask about activities of daily living. Are they managing their self-care? Can they wash and dress themselves? Brush their teeth? What is the state of the oral hygiene? Do they have caries or gum disease that needs attention? Who is looking after their feet?  Can they cut their toenails? Do they need a referral to a podiatrist?  Can they wash, dry and brush their hair? Can they transfer themselves from the bed to the wheelchair and then to the toilet? If they are battling, do they have the necessary home adaptations? In almost every clinic, one or two of my patients must be seen by the community-based disability team because of these problems. Social CareFor some patients, we need to address other social issues, i.e. Is the care package sufficient, and are they managing to get everything done when their carers come in? Sometimes, their carers are on such a tight schedule that they can’t even wait for their clients to complete a meal. This may result in a truncated feeding time. I have had rare patients who became malnourished as a result.   Bulbar functionBulbar function refers to the functioning of structure innervated by nerves from the lower half of the brainstem (pons and medulla). In pwMS, who are more disabled, I always ask about swallowing problems and choking episodes. This frequently prompts a referral for a speech and language assessment. Similarly, if their speech is affected, they may need help with a communication aid. Advanced DirectivesIn addition to the above, I often remind pwMS of the need to complete an advanced directive (a form or a living will). This needs to be done early in your disease when you have insight and can discuss the issues with your partner and family. Waiting until you have advanced MS is too late for an advanced directive. Question time and trialsOn top of the above, we are expected to give patients time to ask questions. This usually prompts questions about MS research and clinical trials. Discussing clinical trials takes time. Would you be able to do all of the above in 15 minutes? No, which is why we often limit the consultation to a few big-ticket items. I am a big fan of asynchronous consultations using email or a portal that automates some of the above. This is why pwMS need to be more proactive about managing their MS. The MS-Selfie ChallengePlease note that I have covered almost every issue above in earlier newsletters and podcasts. Despite this, I suspect some topics still need to be covered in more detail. This will happen over time, and the information will gradually be transferred to an MS-Selfie microsite and eventually end up in an MS-Selfie Self-Management guide. Please keep in mind that this section on what needs to be done with scheduled follow-up assessments can never be comprehensive but is written to provide an overview of my attempt to manage MS holistically. Have I missed anything that you think needs to be covered in your scheduled follow-up appointments? Please note I have written previously on this subject and the subject of preparing for your annual follow-up appointment, using ‘My MS Piorities’ and ‘Your MS Questionnaire’. This advice still holds (see ‘What are your priorities in relation to 'Your MS'?’; 4-Oct-2021). Providing factual information like this can be tedious, so I prefer using case studies to teach MS self-management strategies. I suspect some of you will disagree with me on this. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

The ethics of placebo-controlled phase 3 disease-modifying therapy (DMT) trials in multiple sclerosis (MS) are well-rehearsed; most ethics committees don’t approve these studies. However, in countries with limited access to licensed therapies due to economic constraints, placebo-controlled trials are still being conducted. Participating in a trial, albeit placebo-controlled, is one way of accessing a potential DMT.  An example of this is the current vidofludimus phase 3 studies. Studies to Evaluate the Efficacy, Safety and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis (ENSURE-1 & 2). (ClinicalTrials.gov ID NCT05134441 &  NCT05201638)Despite my enthusiasm for the drug, based on its modes of action, it would not be possible to recruit patients to this study in our centre as it is placebo-controlled. We said no because we thought it was unethical. Maybe we were wrong? Vidofludimus is a new-generation dihydroorotate dehydrogenase inhibitor (DHODHI), which is much better tolerated than teriflunomide. It has potent antiviral effects, including targeting EBV, hence my interest in the drug. It is much cleaner than teriflunomide. Hence, it is very well tolerated and with few side effects. More recently, it has also been shown that vidofludimus acts as a potent nuclear receptor-related 1 (Nurr1) activator. Nurr1 is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Activation of Nurr1 is likely to be responsible for the drug’s neuroprotective effects. It may explain its potential impact on smouldering MS. Vidofludimus reduces MS-related fatigue, possibly due to its anti-EBV activity, and significantly lowers serum neurofilament levels in progressive MS. These data were presented at the recent ACTRIMS meeting. It is an exciting time for MS, and if vidofludimus is shown to be the first DMT to target smouldering MS, it would have reached patients against the odds. It has also made me question the assumption that placebo-controlled trials are unethical. I am aware that pwMS have the option of deciding not to be treated with DMTs, and many opt for no treatment. Given its novelty as a DMT, is it not patronising for us HCPs not to offer pwMS the option of participating in a placebo-controlled trial of vidofludimus? Phase 2 placebo-controlled trialsThe ethical arguments against placebo-controlled trials are now moving to phase 2 studies. Some HCPs now feel placebo-controlled phase 2 studies are unethical. This is a problem. If we can’t do proof-of-concept phase 2 trials, then MS drug development will stop. Doing phase 2 trials against an active comparator makes if virtually impossible to do proof-of-concept studies. Particularly as most licensed DMTs, which would be the active comparator, may impact the biology you are trying to study. For example, I am working on several proof-of-concept anti-EBV phase 2 trial designs. As most licensed DMTs impact memory B-cells, where EBV resides, comparing a new anti-EBV strategy to an active comparator would make it difficult to know if the drug is working. If we don’t compare new emerging agents to placebo, how will we know if the therapy in question impacts EBV and/or MS biology? Have we lost equipoise in relation to phase 2 placebo-controlled trials? People with MS and the ethics committees may have a different take on this dilemma than HCPs. Equipoise is about transparency and putting in place procedures to protect study subjects from unnecessary harm. With placebo-controlled trials, you could potentially have more subjects randomised to the active treatment than placebo, say, a two-to-one ratio to give study volunteers a greater chance of accessing the potentially effective therapy. You could also include an escape clause so that when a study subject reaches the end-point, i.e. has a relapse or shows multiple new lesions on MRI; they can either come out of the study or be switched to open-label treatment with the new agent. Another option is to reduce the exposure from 6 months, the current standard, to 3 months. Three months is a relatively short period. In many healthcare settings, three months is the time pwMS have to wait to start a DMT because of administrative inertia and waiting times for infusion slots. Using more sensitive outcome measures may also reduce the number of study subjects exposed to a placebo. At present, we tend to base our decisions on the effect of the DMT on Gd-enhancing or new T2 lesions. In the future, using blood neurofilament levels as a more sensitive marker will allow us to test new therapies using fewer subjects. We must not forget that a rich-world worldview doesn’t address the reality on the ground. In many countries, many pwMS can’t afford DMTs or are uninsured. Therefore, participating in clinical trials allows them access to potential DMTs. It is well known that subjects with MS who participate in clinical trials do better than pwMS managed outside clinical trials. The latter observation is probably based on patients' overall better care in clinical trials. Should we deny these people access to a potential treatment because people in high-income countries with universal healthcare systems think randomising them to a placebo is unethical? Let's have a wider discussion and explore some of the options above with pwMS, organisations representing pwMS, statisticians, ethicists, ethics committees and the wider MS community before we take the moral high ground that placebo-controlled phase 2 MS trials are unethical. I need your help with a short (1 minute) survey. Have we lost equipoise? Is it unethical to randomise pwMS to a placebo-controlled phase 2 proof-of-concept trial? Please remember a lot is riding on this issue. If we start saying no to placebo-controlled phase 2 trials, developing the next generation of MS DMTs will become very difficult. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have just returned from a road trip to the Mississippi Delta in the Deep South of the United States as part of my 60th birthday celebrations with my family. We did the Golden Music Triangle (New Orleans-Memphis-Nashville), including a stop in Clarksdale, home of the Dixie Blues. This trip has been on my bucket list for a while. Experiencing the roots of ragtime, blues, jazz, gospel, rock-and-roll, soul and country music first-hand was exhilarating. I have returned refreshed and resolved to explore music even more deeply than in the past. I am doing this with my wife, and we are starting by exploring the musicians of Clarksdale. We hope to listen to the canon of each Clarksdale musician, one at a time, and to learn about them as people. Having quality time to focus on my family and music has been a liberating experience. It has also made me question why I have been so slow to adopt music therapy into my management plans for people with MS (pwMS). I don’t recall actively referring or recommending music therapy to any of my patients despite being aware that music therapy helps pwMS (see review paper below) and is supported by a solid scientific evidence base. I, therefore, want to apologise to all my patients and all the music therapists out there for ignoring you. I will now add music and music therapy to my holistic management of MS, including my holistic management of MS diagram and will actively mention music therapy in future MS educational talks.  Scientific evidenceMusic has clear effects on the brain. It is not just a form of entertainment; it is a universal language that carries the power to evoke emotions and memories and alter moods. Numerous studies have examined its profound effect on the human brain, revealing insights into how music interacts with our cognitive processes, emotional well-being, and neurological health. The cognitive effects include enhanced learning and memory. Music significantly aids in learning and memory retention. Studies have shown that music activates various brain areas, including memory processing. For instance, recalling information is better when it is set to familiar music. Music improves attention and concentration. Background music, especially instrumental and classical music, can enhance concentration on tasks by stimulating the brain's attention centres while providing a calming environment that reduces stress levels.Music has an emotional impact and helps regulate mood. Music directly impacts the limbic system, the part of the brain responsible for emotion and mood regulation. Listening to music can release dopamine, one of the neurotransmitters associated with pleasure and reward, thereby improving mood and potentially reducing stress and anxiety.Music therapy for mental healthMusic therapy has emerged as a valuable tool for treating various psychological conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD). It provides an emotional outlet and a means for self-expression, which can help individuals process emotions and reduce stress.Brain HealthListening to music, and even more, so playing an instrument, can stimulate neurogenesis (the growth of new neurons). Active engagement with music enhances brain plasticity, the brain's ability to reorganise itself by forming new neural connections, which can lead to improved brain function.Some research suggests that music can have neuroprotective effects, potentially lowering the risk of cognitive decline in diseases like Alzheimer's. Musical exposure can engage the brain in a complex cognitive process that helps to maintain cognitive functioning in old age. I suspect music will have the same effect in pwMS. Music involves timing, rhythm, and coordination, affecting the brain's motor regions. Playing an instrument, for example, can improve fine motor skills, coordination, and timing, so physiotherapists often advise doing physical therapy to music.Social HealthMusic is inherently a social experience that fosters community and emotional bonds among people, connecting us through shared experiences and cultural identities. Group musical activities, like choirs or bands, enhance feelings of belonging and social cohesion and contribute to participants' collective joy and emotional upliftment. This may be why patients with MS who belong to choirs or play music in social settings report that music helps their MS. As with most allied medical therapies, their availability could be better across the NHS and other healthcare systems. I am not aware of a music therapist in my NHS trust, nor am I aware of community-based music therapy services outside of psychiatric settings. Therefore, I would like to hear if you have been referred for music therapy in person or online and if your experience is helping your MS symptoms. If you want more information on music therapy, I recommend reading the review article below and visiting the British Association for Music Therapy’s (BAMT) website, which has a lot of useful information. Thank youI want to thank all of you who sent me such kind messages for my Birthday. Your generosity is much appreciated. Review paperWeigel et al. Orchestrating a New Path for Multiple Sclerosis: Achieving Physical, Cognitive, and Emotional Rehabilitation Goals Through Physical and Music Therapy. Int J MS Care. 2023 Jul-Aug;25(4):168-175. Background: Interdisciplinary therapies for the management of people with multiple sclerosis (MS) are underappreciated. There is an urgent need to introduce music therapy (MT), either alone or in combination with physical therapy (PT), into clinical practice to achieve synergy with disease-modifying therapies. A holistic approach to rehabilitation for people with MS may mitigate symptoms and reduce polypharmacy, potentially lowering healthcare costs.Results: As MS progresses, patients experience a range of worsening symptoms, and many develop psychosocial comorbidities. As disease-modifying therapies delay disability progression, nonpharmacologic treatments become increasingly important. The main aim of PT is to improve or maintain patients' functional mobility, strength, and flexibility. Because it targets multiple functions, MT can help improve functional and psychosocial domains and may be a valuable intervention to help patients achieve the physical, cognitive, and emotional goals of PT. Exploratory studies showed that MT, alone or in combination with PT, can lead to functional improvements in mobility, balance, gait, and fatigue. Similar to PT, MT also has benefits in improving fine motor skills, cognition, learning, and memory and in providing emotional support.Conclusions: Both MT and PT have the potential to improve overall well-being and health-related quality of life in physically active patients with MS, and MT can provide added emotional support for those who are less able to engage in physical activity. However, MT is not typically a part of standard of care, and PT visits are limited. Nevertheless, interdisciplinary therapies should be incorporated into clinical practice.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

If you have MS and have been treated with an immunosuppressive disease-modifying therapy (DMT), was HPV (human papillomavirus) infection and/or vaccination discussed with you before starting the DMT? Before we start female patients on an immunosuppressive DMT, we check to see if they had a recent cervical smear or vaginal swab PCR to exclude active HPV (human papillomavirus) infection. This is to prevent them from developing CIN (cervical intraepithelial neoplasia) and cervical cancer. As I write this, I realise we are not extending this concern to men. Yes, men who have sex with men and anal sex are at risk of developing HPV-associated anal and penile cancer. Should we be asking them to have anal HPV screening? A quick search shows there is currently no approved test for HPV in men nor a national screening programme. However, several private sexual health clinics offer this service to men. What happens after initiating immunosuppressive therapy? Unless in a clinical trial, we leave it up to the patient and general practitioners to make sure women continue to have regular HPV screening. The problem is that this may not be enough, as the adherence rates with repeated cervical screening are poor. I am not surprised, as women find the procedure of having a cervical smear unpleasant. If you are one of these women, please take note of the Australian study below that shows women with MS on moderate-to-high efficacy DMTs are 3.8x more likely to have a cervical abnormality detected on cervical screening tests than women not exposed to moderate-to-high efficacy DMTs. The message is clear that chronic immunosuppression increases your risk of chronic HPV infection and, hence, your risk of developing CIN and cervical cancer. I assume this risk will apply to the other HPV-associated cancers that we are currently not screened for, i.e. anal, oropharyngeal, oesophageal, penile and vulvar cancer.Is there anything else that can be done about HPV? Yes, vaccination. I counsel all my patients on HPV vaccination. Since September 2008, the HPV vaccine has been offered to all girls in school year 8 (12-13 years). From September 2019, it has also been offered to year eight boys. The uptake of the HPV vaccine has dropped significantly and is currently at ~80%. This means 1 in 5 eligible people for the vaccine are unvaccinated. If you missed your vaccination at school, try to get it as soon as possible. Contact your GP practice to arrange an appointment. In the UK, you can receive the HPV vaccine on the NHS until your 25th birthday.However, things have changed since the initial rollout of the school HPV vaccination programme, which uses the quadrivalent vaccine Gardasil-4. We now have the polyvalent or Gardasil-9 vaccine, which covers most of the cancer-causing strains of the virus (>95%) compared to only about 67% protection with the older vaccine. If I have been vaccinated with the older quadrivalent vaccine, you can extend your coverage by receiving Gardasil-9. However, you would need to do this privately. Even if you are already on an immunosuppressive DMT, it is worth considering upgrading or having the HPV vaccine. I say this because there has been a surge in older women getting cervical cancer from being exposed to HPV in later life. This is because sexual mores have changed, and older women are now more likely to have multiple sexual partners and unprotected sex than in the past, both risk factors for HPV infection. Dating apps are driving this behaviour change and have been linked to a mini epidemic of sexually transmitted diseases in older people. The UK has moved to a single-dose schedule for the routine adolescent and men who have sex with men programme who come forward before their 25th birthday and a two-dose schedule for people between 25 and 45. However, for those over 45 and immunosuppressed individuals, a three-dose schedule is recommended. For the two-dose schedule, the second dose should ideally be given 6-24 months after the initial dose. For the three-dose schedule, the second dose must be given at least a month after the initial dose and the third between 6 and 12 months.For more detailed information, please see Chapter 18a in the green book on human papillomavirus (HPV). Should I delay starting DMTs to have the vaccine?There is no simple answer to this question. You have to balance the risks and benefits of having the vaccine against the risks of under-treated or untreated MS. If you are starting an immune reconstitution therapy (IRT), i.e. cladribine, alemtuzumab or AHSCT,  I would suggest going ahead and starting the IRT and delaying the vaccine until you have reconstituted your immune system. Delaying starting an IRT to have the vaccine does not make immunological sense in that the memory responses you have just made to the vaccine could get depleted and, depending on the intensity of the immunodepletion, may not recover. For maintenance DMTs, particularly the S1P modulators, fumarates, and anti-CD20s, you should delay starting treatment to get the vaccine or at least the first two doses. Booster vaccine responses have been shown to occur whilst on these therapies. Please note that these vaccine studies have tended to look only at antibody responses and not T-cell responses. It is now clear that even if you don’t mount a good antibody response to, for example, the COVID-19 vaccines on anti-CD20 therapies (rituximab, ocrelizumab, ofatumumab, ublituximab), you still have detectable T-cell responses.  To get an idea of the awareness of HPV infection and vaccination and MS DMTs, I would appreciate it if you could complete this short survey. It will take less than 5 minutes to complete, and the information will let us know if we need to take a more proactive approach to this topic. Thanks.Other cancer screeningPlease be aware that the UK has two other routine cancer screening programmes: bowel and breast cancer screening. The screening programme for prostate cancer was stopped in the UK because the PSA test is not reliable enough. However, men over 50 can request a PSA test via their GP. Depending on individual risk factors, including genetic risks, you may be eligible for lung, skin, ovarian, and other cancer screening in some parts of the UK. If any issues this newsletter raises are relevant, please share your thoughts. Thank you. PaperBridge et al. Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies. Multicenter Study Neurology. 2024 Feb;102(4):e208059. Background and objectives: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs).Methods: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects.Results: We included 248 wwMS. The incidence of abnormal CSTs was lower (p Discussion: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs.Classification of evidence: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have spoken many times on MS-Selfie about the risks associated with chronic immunosuppression. I was, therefore, not surprised to hear about a patient of a colleague of mine who developed molluscum contagiosum on fingolimod. I suggested they stop fingolimod and transition the patient onto teriflunomide, and if the patient was unable to tolerate teriflunomide, start interferon-beta. The logic behind these switch agents is that they are not immunosuppressive and have potential antiviral activity. I was then reminded of this issue when I noted a case report of a child with MS developing disseminated molluscum contagiosum on fingolimod (see Murali et al. Int J Dermatol. 2024 Mar 8. doi: 10.1111/ijd.17128.). What is molluscum contagiosum?Molluscum contagiosum is a common viral skin infection caused by the molluscum contagiosum virus (MCV). This condition primarily affects children, sexually active adults, and individuals with weakened immune systems. Molluscum contagiosum is characterised by the development of small, raised, and usually painless bumps on the skin. These bumps are often flesh-coloured, dome-shaped, and typically have a small indentation in the centre.The virus spreads through direct skin-to-skin contact or sharing personal items, such as towels or clothing, with an infected person. Molluscum contagiosum is typically benign and self-limited and usually resolves independently without treatment. However, in some cases, medical intervention may be necessary to manage the symptoms and prevent the spread of the virus.The diagnosis of molluscum contagiosum is usually based on the appearance of the characteristic lesions. Sometimes, a skin biopsy or PCR on an aspirate of the lesion is done to make the diagnosis. Treatment options for molluscum contagiosum may include cryotherapy (freezing the bumps),  cantharidin topical ointment or minor surgical procedures to remove the lesions.Avoid scratching or picking at the bumps, as this can spread the virus to other parts of the body and increase the risk of secondary bacterial infections. Practising good hygiene and avoiding direct skin contact with affected individuals can help prevent the transmission of molluscum contagiosum.This case reminded me of a patient I had in the alemtuzumab CARE-MS 1 trial who caught molluscum contagious from her daughter. The infection spread all over her body, and when her immune system was reconstituted, she mounted an immune response to the virus, with all the lesions becoming inflamed and forming pustules. At the height of the antiviral response, she looked like she had smallpox. Not only is MCV a problem with immunosuppression, but also HPV, which causes warts, cervical and other cancers, hepatitis B and C, HIV, TB, and the herpes viruses. This is why it is important to be carefully screened for these viruses and bacteria before starting immunosuppression. If you have an active viral or bacterial infection, you must clear the infection or start antiviral or antibacterial therapy before immunosuppression. After starting an immunosuppressive DMT, I would like to know if you have developed any viral or bacterial infections.   Please see the following related MS-Selfie Newsletters:* Warts and HPV vaccination (6-Jul-2021)* Case study: cervical intraepithelial neoplasia (CIN) and ocrelizumab (6-Nov-2021)* MMR vaccine: to vaccinate or not? (8-Aug-2022)* The rationale for derisking DMTs (20-Aug-2022)PaperMurali S, Bhat PI, Prathiba JP, Jithendriya M. Disseminated molluscum contagiosum presenting during fingolimod treatment in a child. Int J Dermatol. 2024 Mar 8. doi: 10.1111/ijd.17128.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Over the years, it has become apparent to me that people with multiple sclerosis (pwMS) seem to accept developing several comorbidities as if it is just part of having multiple sclerosis (MS). It is as if having MS and living with MS is so overwhelming that other medical problems tend to be ignored. Am I correct in my interpretation? Do pwMS suffer from medical inertia when recognising or identifying other medical problems? I suspect medical gaslighting may contribute to this problem in that many healthcare professionals (HCPs) often attribute symptoms to having MS when particular symptoms may be related to comorbidities or other medical problems. One of these comorbidities is rectal bleeding. A few weeks ago, I saw a patient who had had intermittent rectal bleeding. He had been passing fresh blood when going to the toilet for several months. He wasn’t concerned about the bleeding as he had put it down to having haemorrhoids. This was despite no prior history of haemorrhoids and no current history of prolapsed haemorrhoids. He assumed he had haemorrhoids because he suffers from MS-related constipation and has to strain on passing stool. He only mentioned the bleeding to me because I asked him about his bowel habits and whether or not he had noticed any changes. Yes, pwMS are more likely to have anorectal pathology due to chronic MS-related constipation, but you mustn’t assume this is normal and simply a part of having MS. Rectal bleeding is always abnormal, is not due to having MS and always needs to be investigated. Common causes of rectal bleeding in pwMS1. Constipation and haemorrhoids - constipation is one of the most prevalent gastrointestinal (GI) symptoms in pwMS. It is primarily due to decreased intestinal motility, reduced physical activity, pelvic floor dysfunction, poor diet and/or side effects of medications. Straining during bowel movements can lead to the development of haemorrhoids, which are swollen blood vessels in the lower rectum or anus, causing rectal bleeding.2. Anal fissures - anal fissures are another common cause of bleeding related to constipation. These small tears in the lining of the anus can occur when trying to pass hard or large stools, leading to painful bowel movements and rectal bleeding.3. Medication side effects - certain medications used to manage MS symptoms or the disease itself can contribute to GI issues, including rectal bleeding. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief can increase the risk of gastrointestinal complications like ulcers, gastrointestinal bleeding and rarely NSAID-related colitis.4. Inflammatory bowel disease (IBD) - though not directly caused by MS, there is an association between autoimmune diseases like MS and conditions such as Crohn’s disease or ulcerative colitis, which fall under IBD. These conditions can cause inflammation of the gastrointestinal tract, leading to symptoms like diarrhoea, abdominal pain, and rectal bleeding.5. Infections - infections of the GI tract or the anal area, which may be more common in individuals with compromised mobility or those on immunosuppressive treatment for MS, can lead to rectal bleeding. These might include bacterial, viral, or fungal infections affecting the intestines or anal area.6. Polyps and anal cancer - rectal bleeding is often a harbinger of colonic and anorectal cancers. This is why anyone presenting with rectal bleeding needs to be examined. 7. Diverticular disease - colonic diverticular disease is a condition characterised by the formation of diverticula in the colon. Diverticula are small, bulging pouches that can form in the lining of the digestive system. While they can occur anywhere in the intestines, they are most commonly found in the large intestine or colon. The presence of these pouches themselves is known as diverticulosis. The condition is called diverticulitis when one or more pouches become inflamed or infected. The exact cause of diverticular disease is not fully understood, but it is believed to be associated with low-fiber diets. Fibre helps to soften stool and make it easier to pass, reducing pressure inside the digestive system. Without enough fibre, the colon has to exert more pressure to move small, hard stools, which can lead to the formation of diverticula. Other risk factors include ageing, obesity, smoking, lack of exercise, and certain medications like nonsteroidal anti-inflammatory drugs (NSAIDs).8. Colonic telangiectasia - colonic telangiectasia, also known as angiodysplasia of the colon, refers to a condition characterised by the presence of small, dilated blood vessels in the colon. These vascular lesions are typically flat, red and can range in size. They are most commonly found in the right colon but can occur anywhere in the large intestine. Telangiectasias in the colon are a form of vascular ectasia, which means they are part of a group of conditions that involve the dilation of blood vessels. The exact cause of colonic telangiectasia is not completely understood, but it is believed to be related to the ageing process and the degeneration of blood vessels. Several factors may contribute to its development, including ageing, chronic constipation and cardiovascular disorders. 8. Rectal prolapse -  rectal prolapse occurs when the rectum loses its normal attachments allowing it to stretch and protrude out through the anus. This condition can be distressing and often impacts the quality of life, leading to embarrassment and social isolation for those affected. Rectal prolapse is different from haemorrhoids, which are swollen blood vessels that line the anal canal. A partial prolapse (also known as mucosal prolapse) is when only the lining (mucosa) of the rectum protrudes from the anus. In comparison, complete prolapse is when the entire wall of the rectum protrudes from the anus. This prolapse may initially occur during bowel movements and retract afterwards, but over time, it may not. PwMS are at risk of rectal prolapse because several factors contributing to its development are common in pwMS. This includes chronic constipation or straining during bowel movements, which over time weaken the rectum’s support structures in the pelvic floor. Other risk factors included childbirth, ageing and possibly some medications that relax muscles. For example, it seems to commoner in habitual cannabis users. Symptoms of rectal prolapse can vary depending on the severity and include visible prolapse, rectal bleeding and mucus discharge, faecal incontinence, anal leakage, the inability to control bowel movements and the sensation of incomplete evacuation.Identifying the cause of rectal bleeding in pwMS involves a detailed medical history, physical examination, and sometimes diagnostic procedures like colonoscopy or sigmoidoscopy. Treatment depends on the underlying cause and might include dietary management for constipation, medication adjustments, or specific treatments for conditions like haemorrhoids, anal fissures, IBD, etc.It is crucial that if you are experiencing rectal bleeding, you consult a healthcare professional for appropriate diagnosis and management. It is critical to rule out any serious underlying conditions, in particular early cancer. While multiple sclerosis itself does not cause rectal bleeding, its associated symptoms, the indirect effects of its management, and related autoimmune conditions can contribute to GI symptoms, including rectal bleeding. Understanding these connections emphasises the importance of comprehensive care in managing MS, highlighting the need for a multidisciplinary approach that includes monitoring and addressing gastrointestinal health.I would be interested to hear if any of you have had rectal bleeding and how you approached it. Having MS may increase your risks of getting several comorbidities, but all of these comorbidities need to be managed on their own merits and not assumed to be just another part of having MS. And don’t accept being gaslit. If you have symptoms that you think are not related to your MS, make a fuss and get them investigated. The patient I am referring to above was found to have early rectal cancer.  Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Case studyI am 70 years old and have advanced MS with an EDSS of 7. I can’t lift my legs, so I can only walk a few metres backwards with a Zimmer frame, dragging my feet. I’ve got very swollen feet (see photo below) due to spending all but a few minutes of the day seated. I have had Doppler scans of my feet, and there’s no blockage. Also, I have no heart issues. To try and reduce the swelling, I have a lymphatic massage of the lower legs and feet done by a physio, which was successful but is no longer having any effect. In the last few weeks, I’ve been doing 20-30  minute sessions three times a week on a recumbent, Medi motion type exercise machine, but that doesn’t seem to have an effect. I’ve tried compression socks in the past, and they aggravated the swelling.Prof G’s responseThis patient illustrates a problem that people with multiple sclerosis (pwMS) who have reduced mobility commonly experience. It is called dependency oedema and typically causes swelling of the feet, ankles and legs. Dependency oedema is common among pwMS who are less mobile, typically those who have to use wheelchairs. It is characterised by swelling in the lower limbs (feet, ankles and legs) due to fluid accumulation. Dependency oedema resulting from prolonged sitting and lack of leg movements impedes blood and lymph fluid circulation. The veins in the lower limbs have veins that allow one-way blood flow, i.e. away from the legs towards the heart. When standing or sitting, this flow is upwards and against gravity. To achieve flow against gravity, the calf muscles act as a pump; when the calf muscles contract, the veins are compressed, and blood flows upwards. Without calf muscle contraction, the blood and fluid accumulate in the tissues, manifesting as foot and ankle swelling. Dependency oedema is not unique to pwMS limited mobility—people with normal mobility experience it when sitting for long periods, for example, on long-haul flights, other forms of long-distance travel, or just sitting at a desk all day.  Please be aware that foot swelling or pedal oedema (the medical term for foot swelling) is also a sign of heart, renal or kidney disease and can be a sign of deep vein thrombosis. It can be a side effect of specific medications (e.g. anti-hypertensives, steroids, DDAVP, ...) and can be part of a normal physiological state; for example, it is quite common in pregnancy. This is why, without a medical assessment and investigations, it is difficult for someone with MS to exclude these other causes of foot and leg swelling. This is why it is important to have a medical assessment when you first develop foot swelling. All these other causes of foot swelling have additional symptoms that can act as pointers towards a specific cause other than mobility-related dependency oedema. For this discussion, I will assume this patient has been fully investigated, and all of these other causes of foot swelling have been excluded. He has simple dependency oedema due to poor mobility. Managing dependency oedema effectively is part of the holistic management of MS to improve the comfort and quality of life for pwMS with reduced mobility. The following are some simple strategies to manage and mitigate dependency oedema:1. Elevation of legs: elevating the legs above the level of the heart several times a day helps to promote venous return and fluid drainage, thereby reducing swelling. This can be achieved by using a footrest or pillow. Even short periods of elevation can make a significant difference over time. If you are a wheelchair user, some of the more expensive larger wheelchairs have this feature built into them 2. Regular exercise and movement: regular movement and exercise within an individual's capability is important. Leg stretches, foot rotations, and other gentle exercises can help stimulate blood flow and prevent fluid from pooling in the lower extremities. Consulting a physiotherapist to tailor an exercise plan is advisable. You can purchase electrical nerve stimulators that contract the calf muscles. The latter is called electrical muscle stimulation (EMS), which repeatedly contracts and relaxes the lower legs and feet muscles, activating the calf muscle pump to help increase blood flow.3. Compression garments: wearing graduated compression stockings or wraps can aid in preventing fluid accumulation in the legs by applying gentle pressure to promote blood and lymph flow. Getting this via your HCP for the appropriate compression level is important. In the NHS, there are specialist lymphoedema clinics that do this. The ideal pressure is 30-40 mmHg. If the stockings are too tight, they can reduce blood flow to the feet and cause ischaemia, resulting in foot ulceration. As a general rule, stockings should not feel uncomfortable. Put them on and wait 10 minutes to get used to them. If, after 10 minutes, they feel too tight or cause pain or your toes change colour and become blue and/or cold, the stockings are likely too tight. 4. Proper nutrition and hydration: maintaining a good balanced diet and staying well-hydrated can also aid in managing oedema. Reducing salt intake helps prevent fluid retention. Please avoid diuretics. I have seen many patients being prescribed diuretics to treat foot swelling. Diuretics result in dehydration and hypovolaemia (reduced blood volume) and don’t deal with the problem of foot swelling due to fluid in the tissues and not inside blood vessels.5. Positioning and seating adjustments: ensuring your wheelchair and seating are properly fitted and offer adequate support can prevent unnecessary strain contributing to swelling. Adjustments to the wheelchair for optimal leg positioning and specialised cushions can distribute pressure evenly and improve circulation.6. Manual lymphatic drainage: a gentle foot and leg massage can encourage the movement of lymph fluids out of the affected limbs and can be performed by a certified lymphoedema therapist. It is a therapeutic option for reducing swelling and improving comfort. You can also purchase a mechanical massager or compression boot to do this. These are relatively inexpensive, but it is best to ask your HCP for advice on which one to purchase. Things to look out for. PwMS with dependency oedema are at risk of deep vein thrombosis (DVT). If you develop calf pain and leg and foot swelling worsening in the leg with pain, you must seek medical attention urgently. The danger of a DVT is potentially life-threatening pulmonary embolism. When leg swelling becomes extreme, it can cause skin tightness, increasing pressure in the lower leg compartments. This form of compartment syndrome results in reduced blood supply to the skin. If this occurs, you can get ischaemic or venous leg ulcers and break down to the skin with a superimposed infection that can spread and cause cellulitis or lymphangitis (infections in the lymphatics). If this occurs, you will need antibiotics and dressings for the ulcer.  While dependency oedema is a common issue for pwMS who have reduced mobility, adopting a multi-faceted approach to its management can significantly reduce its impact. Incorporating leg elevation, movement and exercise, compression therapy, dietary adjustments, proper seating, lymphatic drainage, and consistent medical oversight can help manage symptoms and improve overall well-being for pwMS with dependency oedema. For this patient, I recommend using a combination of the above, and he may need to purchase an electrical muscle stimulation (EMS) device to help keep his calf muscle pump working. I assume many of you have dependency oedema and have developed your self-management hacks to manage the problem. Please share them with us. Anything that can help this patient beyond what I have said here would be much appreciated. Thank you. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

The phase 2 data of frexalimab in relapsing multiple sclerosis has just been published in the New England Journal of Medicine. This is very big news and has rejuvenated my enthusiasm for the future of MS treatments. CD40 is a critical costimulatory signal that drives T-cell activation and is involved in B-cell and innate immune activation. The phase 2 Frexalimab study results are strikingly positive and are the most exciting to emerge in MS in the last 12-24 months. Firstly, the impact on MRI activity in MS put the therapy in the very high efficacy bracket, but against the odds, considering the duration and size of the study, we saw an effect on blood neurofilament and CXCL13 levels and quality of life outcomes. These results are extraordinary. These results also tell us a lot about the pathogenesis of MS by confirming a critical role for T-cells in the pathogenesis of MS and strongly support MS as being an autoimmune disease. As you are aware, I have taken a very strong position on EBV, and I have been convinced that EBV causes MS and is the driver of MS disease activity. Hence, I push for developing EBV antivirals as a treatment for MS. Therefore, the obvious question is, how are the frexalimab results compatible with EBV being the driver of MS disease activity? From an evolutionary perspective, It should not be surprising that EBV has hijacked CD40 and the CD40-ligand signalling pathways to promote its survival. EBV's latent membrane protein 1 (LMP1) is a CD40 mimic that augments the normal CD40 signalling pathway. This gives EBV-infected B cells a survival advantage. Blocking the normal CD40 pathway with Frexalimab may be enough to remove the pro-survival signal that results in the selective loss of EBV-infected B-cells over time, i.e. they die off because of reduced CD40 signalling. Alternatively, anti-CD40L may be inhibiting the function of EBV-infected B-cells. In a little-known and rarely quoted study, it has been shown that EBV-infected B-cells aberrantly express CD40L (Imadome et al. Proc Natl Acad Sci USA. 2003 Jun 24;100(13):7836-40). Non-infected B-cells don’t express CD40L. This aberrant CD40L expression may augment EBV-infected B-cell's ability to present antigens, even autoantigens, to T-cells. Blocking this aberrantly-expressed CD40L on EBV-infected B-cells will reduce EBV-infected B-cells presenting antigens to T-cells. Even if I am wrong about EBV and Frexalimab, there is no doubt the results of this study are sending a buzz through the MS community, particularly the immunologists and genomics experts who predicted these results two decades ago. Because Frexalimab blocks the co-stimulation of autoreactive T-cells, it may convert a stimulating autoreactive signal into a tolerogenic or anergic signal. So, will Frexalimab put pwMS into long-term remission and mimic the stunning results we see with alemtuzumab or AHSCT? Blocking CD40-CD40L interactions should stop autoimmunity. You can now understand why I am so excited about Frexalimab as a potential treatment for MS.I was asked by a colleague yesterday where I see the MS market in 10 years. Considering the stunning results of anti-CD20 and the potential emergence of BTK inhibitors, he wanted to know whether there is space for Frexalimab in the treatment landscape. I suggested to this colleague that he should read my extensive commentaries on anti-CD20 therapies in MS. It is clear that despite anti-CD20 therapies being very effective at suppressing relapses and focal MRI activity, they don’t stop smouldering MS, i.e. they are not getting to the core pathology that is driving MS worsening. In addition, it is highly unlikely that people with MS (pwMS) will be able to stay on an anti-CD20 therapy life-long. Over time, some people develop hypogammaglobulinaemia, and with ageing, the risk of infection increases. This is why we need an exit strategy from anti-CD20 therapies or an alternative treatment approach. So if the phase 3 Frexalimab study shows it to have a more pronounced effect on the end-organ, i.e. reduced brain volume loss, fewer paramagnetic rims lesions, fewer slow expanding lesions getting larger, a reduction in spinal fluid biomarkers of B and plasma cell activity and less microglial activation, Frexalimab will win hands down. Then there is this tantalising possibility that Frexalimab may re-establish immune tolerance and not need to be given continuously. So, there is a lot to play for when it comes to the future MS market. I also suspect the BTK inhibitors may not be as effective as anti-CD20 therapies and, as a class, will be handcuffed with a major pharmacovigilance burden given the liver toxicity signal with these therapies. So I don’t necessarily see the BTKi’s threatening the anti-CD20’s dominance in the short to medium term. Even if Frexalimab and other anti-CD40L and anti-CD40 therapies fail, we will have induction-maintenance strategies, i.e., using immunodepleting therapies as an induction followed by a safer maintenance therapy. This would also threaten the hegemony of the anti-CD20s in that they will only be used for a short period and replaced by a safer, non-immunosuppressive therapy. The latter could be a fumarate (dimethyl fumarate, diroximel fumarate, …), a dihydroorotate dehydrogenase inhibitor (teriflunomide, vidofludimus, … ), or an EBV antiviral. This is the iTeri study that I proposed several years ago. I have just completed a review article on potential EBV antivirals, and there are a lot of drugs that need to be tested in MS. What we now need are brave Pharmaceutical companies that have little experience in MS to join the party. It is clear to me, and it should be clear to my colleagues, that anti-CD20 therapies have a limited shelf-life as a treatment for MS and will not be the mainstay of MS treatment in 10 years. I am not sure if you are aware that all of the big pharma companies that have a licensed anti-CD20 therapy for MS are not sitting on their hands; they all have deep and very interesting MS development pipelines. This tells us they know that their anti-CD20 products are not good enough and that we must go beyond preventing relapses and suppressing focal MRI activity. The most exciting of these products are CNS penetrant therapies targeting smouldering MS. The latter includes CD19-targeted CAR T-cells and proteasome inhibitors (ixazomib). I know some of the information in this newsletter may be difficult to understand, so please ask questions if you don’t understand anything. Paper 1Vermersch et al. Inhibition of CD40L with Frexalimab in Multiple Sclerosis. N Engl J Med . 2024 Feb 15;390(7):589-600.Background: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.Methods: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.Results: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.Conclusions: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).Paper 2Imadome et al. CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7836-40.Epstein-Barr virus (EBV), implicated in numerous human diseases, including lymphoid malignancies, persistently infects peripheral B cells and transforms them into lymphoblastoid cell lines. Here we found that EBV equally infected B cells from patients with X-linked hyper IgM syndrome and those from healthy donors; however, it hardly transformed X-linked hyper IgM syndrome B cells, because of the dysfunctional gene of CD40 ligand (CD40L) of the patients. Unlike CD40, CD40L is not usually expressed on B cells. However, we found that EBV infection of normal B cells induced CD40L expression as a critical effector in host cell transformation and survival. Moreover, chronic active EBV infection of peripheral T cells, implicated in T cell malignancies, was associated with ectopic expression of CD40, and, in Jurkat T cells, EBV infection induced CD40 expression. These results suggest that EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Dehydration is not a good way to control your bladder symptoms.Almost 30 years ago, while doing my PhD on a urine biomarker of inflammation, I noted that urinary concentration of creatinine, a muscle metabolite excreted in the urine, correlated with disability. I soon worked out that people with MS with worse disability (higher EDSS) were more likely to have bladder dysfunction and were dehydrating themselves to manage urinary frequency, urgency and nocturia. As I asked my study subjects to collect daily urine samples, it became clear that these people with MS (pwMS) were not intermittently dehydrating themselves but were doing it chronically.  We published a small letter in the Annals of Neurology on this issue in response to another paper suggesting urine levels of myelin basic protein-like material (uMBPLM) correlated with disability. It was clear to me that all this group were describing was the correlation of dehydration with disability, i.e. higher levels of uMBPLM were simply a marker of urine concentration and not linked to the biology underpinning disability. Giovannoni et al. Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis. Ann Neurol. 1996 Jul;40(1):128-9.This observation was highlighted again with the chronic cerebrospinal venous insufficiency (CCSVI) debacle. It was clear that many people with advanced MS had collapsed central veins because they were dehydrated, and when rehydrated with intravenous fluids, their veins opened spontaneously (see paper 2). I was vindicated as I had hypothesised this was the underlying problem in CCSVI in an earlier blog post (see ‘CCSVI: could dehydration be a possible confounding variable?’ 25-June-2011).These findings were familiar. Professor Bryan Matthews, a neurologist in Oxford, had described dehydration as a strategy to manage urinary symptoms in the 1960s and highlighted the issue of pwMS dehydrating themselves to manage their bladder problems in his textbook on MS. Therefore, I was interested to read a recent paper from the Southhampton group describing the same findings (see paper 2 below). It is remarkable how the same things in medicine or neurology tend to be rediscovered for people to become aware of them. I am frustrated that despite highlighting the issue of chronic dehydration in pwMS many times over the years, it is clear that it remains a persistent problem. My message is clear: don’t use dehydration to manage your bladder symptoms. The potential consequences of chronic dehydration should be enough to change your habits. Chronic dehydration can have a significant impact on your overall health and well-being and can exacerbate many of your MS symptoms. Here are some of the potential effects of chronic dehydration:1. Impact on Physical Performance: Dehydration can decrease physical endurance, cause muscle cramps, and exacerbate or cause fatigue. This can affect overall physical performance and make everyday tasks more challenging.2. Cognitive Function: Dehydration has been linked to cognitive impairment, including issues with concentration, alertness, and short-term memory. Prolonged dehydration may even contribute to long-term cognitive decline.3. Mood and Mental Health: Studies have shown that dehydration can affect mood and contribute to increased feelings of anxiety and irritability. In severe cases, it can even lead to symptoms resembling depression.4. Kidney Function: Chronic dehydration can put a strain on the kidneys, potentially leading to the formation of kidney stones and urinary tract infections. It can also impair the kidneys' ability to filter waste from the blood effectively. It also makes you more susceptible to side effects of non-steroidal anti-inflammatory medications.5. Digestive Problems: Dehydration can lead to constipation and other digestive issues. It may also contribute to an increased risk of developing peptic ulcers and acid reflux.6. Skin Health: Inadequate hydration can lead to dry, flaky skin and exacerbate conditions such as eczema and psoriasis. Proper hydration is essential for maintaining overall skin health and elasticity.7. Risk of Heat-Related Illnesses: Dehydration reduces your body's ability to regulate temperature, increasing the risk of heat exhaustion and heat stroke, particularly in hot and humid conditions. Please remember that pwMS, in particular people with more advanced MS, may already have a problem with thermoregulation, and dehydration will make things worse. Please note this problem is worsened by drugs that affect sweating, e.g. anticholinergics. A better way of managing urinary symptoms is using a holistic approach, which I have written about many times before on MS-Selfie. Are you doing your pelvic floor exercises? Have you deconditioned your bladder by not training yourself to resist emptying your bladder whenever you get the urge to pass urine? The bladder is a muscle that needs to be trained. Are you avoiding bladder irritants or stimulants, for example, caffeine and nicotine? Have you tried peripherally acting anticholinergics or mirabegron? Have you had a post-micturition bladder scan to see if you are emptying your bladder? You may need to intermittently self-catheterise to increase your functional bladder volume. Do you have a chronic low-grade urinary tract infection? Do you have bladder stones? Have you tried DDAVP (Desmotabs or Desmospray) to help concentrate your urine without dehydrating yourself? DDAVP helps reduce urinary frequency and urgency for a defined period, for example, at night or when travelling. If you are a post-menopausal woman, have you tried HRT? Pelvic floor tone and bladder function often improve on HRT. Please see: * Infection: Managing your bladder to prevent recurrent UTIs - 29-June-2021* Help, I am peeing myself at night - 21-Aug-2021* Is it MS or is it the menopause? - 16-Aug-2021* Why am I so fatigued? - 9-Aug-2021* Your anticholinergic burden - 8-July-2021To find out how many of you use dehydration to manage your bladder problems, I have set up a short MS-Selfie survey. If you have time, please complete it; it will take 2-3 minutes. Thank you. Finally, please share any hacks or tricks you use to manage your bladder symptoms. Paper 1Diaconu et al. Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments. Neurol Clin Pract . 2013 Oct;3(5):386-391. We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30-45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.Paper 2Kaninia et al. Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis. Eur J Neurol. 2023 Dec 20:e16175.Background: Lower urinary tract symptoms (LUTS) are common in persons with progressive multiple sclerosis (pwPMS), who may consequently limit their fluid intake. We aimed to investigate the hypothesis that LUTS associate with objective evidence of inadequate hydration status in pwPMS.Methods: In this prospective study, 55 pwPMS were studied over 2 years. A 6-monthly first-morning urine specimen was analysed for urinary osmolality and sodium as hydration markers. LUTS symptom severity in three categories (urgency, voiding and discomfort) was assessed and quantified using a questionnaire. Correlation between LUTS severity and hydration was assessed within subjects and between subjects, controlling for age.Results: Some 274 urine samples with accompanying LUTS data from 55 participants were analysed. Biochemical data showed the expected loss of urine-concentrating capacity with increasing age. Inadequate hydration was observed in 47% of participants. LUTS were very common (87% reported urgency and 89% voiding symptoms). Voiding and discomfort, but not urgency severity, were correlated with hydration markers, both within and between participants.Conclusions: LUTS are very common in pwPMS, and associate with inadequate hydration. The causes and consequences of inadequate hydration in MS need further study, since (i) this will focus greater attention on LUTS management in pwPMS and (ii) dehydration has been associated with reversible cognitive dysfunction and physical underperformance.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Case studyI am a 54-year-old male with secondary progressive MS. I am not on a disease-modifying therapy at present. I was on fingolimod, but it was stopped two years ago when I started using a wheelchair. I have severe marked spasticity in my legs despite taking baclofen 20 mg three times a day. I take my first dose of baclofen at about 8 am, the second at 3 pm, and the third before bed at night, between 10 and 11 pm.  Despite this, I get severe breakthrough spasms that wake me at about 3-4 am in the morning. I also find the baclofen very sedating during the day. Is there anything I can do to help with the spasms and reduce my sedation? Prof G’s opinionUnfortunately, we don’t have any oral drugs that work on spasticity that don’t have off-target effects that include sedation and, sadly, cognitive slowing. Baclofen is a very old drug that was developed in the 1960s as an anti-seizure drug and repurposed in the 1970s to treat spasticity. Baclofen works by stimulating a receptor called the GABA-B receptor. GABA is the primary inhibitory neurotransmitter in the central nervous system (CNS). Baclofen has a very narrow therapeutic window, i.e. you have to achieve relatively high blood levels to achieve an anti-spastic effect, which is at a similar level that causes sedation and cognitive slowing. Baclofen also has a short half-life that varies between individuals and falls between 2-6 hours. A half-life refers to the time it takes for blood levels to fall by half. The short half-life means baclofen has to be taken frequently; otherwise, you get wearing-off effects, i.e. spasticity returns before the next dose. Some patients have to take baclofen 4-6 times a day. Wearing off is particularly prominent at night when it intersects with the diurnal (day-night) variation in spasticity. Spasticity is naturally worse in the early morning hours (4-6 am), and when this coincides with baclofen levels dropping, spasms become more prominent and uncomfortable. Add-on antispastic agentsOne solution would be to take baclofen as a slow-release formulation to lengthen its half-life. A slow-release formulation has been developed but is unavailable in Europe or the UK. This patient can either increase his baclofen dose and take it four times a day, with an additional dose between 2 and 3 am in the morning or take an add-on antispastic agent with a longer half-life that covers the 4-8 am time window. Many pwMS with frequent waking choose to wake up to take an additional dose of baclofen in the early hours of the morning. If not, I tend to add on clonazepam starting at 0.5 mg at bedtime, increasing by 0.5 mg every few weeks until the patient gets to 2 mg or there is an adequate therapeutic response. Some patients need even higher doses. Please note clonazepam is a benzodiazepine that works on the GABA-A receptor and is associated with a phenomenon called tachyphylaxis. Tachyphylaxis is a diminishing response to successive doses of a drug, rendering it less effective. A 0.5 mg initial dose may stop working after a few days or weeks, and a higher dose may be needed. Please be aware that tachyphylaxis happens with a large number of drugs working on the CNS and can be due to metabolism, i.e. the drug induces the liver to be more effective at breaking down or metabolising the drug, or it downregulates its effects on the receptor in the CNS or the CNS upregulates the number of receptors, therefore, higher doses of the drug are required to have the same effect. The effects of tachyphylaxis are reversed when you have a drug holiday, and that is why if you restart the drug, a period of re-titration is required. A common cause of opioid deaths in people with opioid addiction is because of this phenomenon; i.e. after a period of abstinence, they relapse, and instead of using a lower dose, they go back to the same dose they were using before, which causes CNS suppression and they have a respiratory arrest. The most dangerous time for opioid abusers to overdose is when they resume using the drug after a period of abstinence. If you know someone who uses or abuses opioids, please tell them about this phenomenon.  The compensatory mechanisms resulting from taking antispastic agents mean you can have a severe rebound or augmented spasticity if you stop taking them suddenly. In this situation, the spasticity is much worse than before starting the specific anti-spastic agent. If clonazepam does not work or is poorly tolerated, this patient could try one of the gabapentinoids (gabapentin or pregabalin) or add-on Sativex or THC. Please be aware that all add-on agents with a longer half-life can cause a hang-over effect, i.e. you feel groggy and slow in the morning. In my experience, most people get used to the hangover effect with time. A general principle with anti-spastic agents is gradually increasing the dose slowly over weeks to months. This gradual titration allows you to get used to the sedation and other side effects of the drugs. Anybody who has started taking high doses of anti-spastic agents initially or titrates up the dose too quickly will know what I mean. Ragdoll effectPeople who have a lot of weakness and use their lower limbs as splints to mobilise and sometimes walk often go off their feet when they start anti-spastic agents. This is because they lose tone in their legs, which then collapse. This is why some pwMS prefer to live with their spasticity. Others only take antispastic agents at night, knowing that the ragdoll effect is reversible and accept not being able to walk at night but relying on the drug wearing off so they can mobilise in the morning. If you have a lot of leg weakness, you must be careful when starting antispastic agents. Due to the ragdoll effect, many pwMS have fallen when getting out of bed at night. This can be a problem if you live alone, particularly if you don’t have enough strength to get up. One of my patients had to lie on the floor for 5 hours before his carer came in to help him get off the floor. This is another reason for purchasing and wearing a community alarm at night. Please be aware the ragdoll effect can affect the trunk in wheelchair users and result in pwMS slumping forwards or sideways in the wheelchair. In people with more advanced MS, it can result in the head flopping forwards, backwards, or to the side. Intrathecal baclofenFinally, if all else fails, a baclofen pump may be required. This is when a catheter is inserted into the lumbar sac, and a low but continuous dose of baclofen is infused into the spinal fluid. This is an expensive and invasive procedure, but it can significantly improve the quality of life of a pwMS with severe spasticity. The good thing about intrathecal baclofen is that it works locally at the level of the spine and spares the brain. This means the person benefits from baclofen without the sedation and cognitive slowing. This advantage of intrathecal baclofen can’t be underestimated. Being able to wean high doses of oral antispastic agents often results in patients waking up from a state of perpetual sedation. One of my mentors used to refer to these patients as being baclofen zombies because of their inability to function due to excessive sedation. I suspect many of you on high doses of anti-spastic agents will relate to this. I relate to this. After my accident, when I was on gabapentin and morphine, I was unable to function cognitively. I would have to read something twice or three times to understand it, and even then, my memory was poor. My concentration span was limited to 15 to 20 minutes. It was only after weaning both the gabapentin and morphine that I realised how disabling these drugs can be. Zombification from anti-spastic agents is one of the indications for referral for a baclofen pump. This is particularly relevant for pwMS who need to function cognitively. It is amazing to see how much cognition improves when you do formal cognitive testing before and after the insertion of a baclofen pump insertion and weaning oral antispastic agents (see the research paper below). Other antispastic agentsSome of you may be on tizanidine, another licensed anti-spastic agent. I don’t find this drug to be that effective. It is often needed in very high doses to have an antispastic effect, and again, it is very sedating. I very rarely prescribe it. Dantrolene is an old antispastic agent that works at the level of the muscle and not the CNS. Despite its appealing mode of action, it is associated with many CNS side effects, which include depression, a confusional state, anxiety, hallucinations, disorientation, dizziness, altered taste, seizures and insomnia. It can be hepatotoxic, and liver function needs to be monitored regularly. Due to all these factors, I rarely use it in my clinical practice, but some patients may need it when all else fails. The cannabinoids help spasticity, but we have a problem prescribing them on the NHS. Sativex spray, which contains tetrahydrocannabinol (THC) and cannabidiol (CBD), can be a very effective adjunct to other antispastic agents. Sativex is particularly effective at night and helps with nocturnal spasms and insomnia. Please be aware that there is no actual therapeutic window where you get the anti-spastic effects of THC without the dysphoric or euphoric effects. This is why many pwMS who find Sativex and other cannabinoids effective stop taking them. Other benzodiazepines, including diazepam and clobazam, are sometimes used as antispastic agents. From my experience, these don’t have an advantage over clonazepam.Finally, anti-seizure drugs, including sodium channel blockers, may impact spasticity. I have often started a sodium channel blocker (carbamazepine, oxcarbazepine, lamotrigine, phenytoin)  for pain, and patients have reported that their spasticity has improved or they have noticed the ragdoll effect. I don’t prescribe these drugs for spasticity, but their effect on spasticity is worth noting. Physical therapiesExercise, including both active and passive movements, can help spasticity. This is why seeing a physiotherapist is an essential part of spasticity management. I have many patients who manage their spasticity with exercise and stretching alone. So please don’t underestimate the physiotherapist's role in spasticity management.  Some patients may benefit from botox injections into specific muscles to control spasticity locally. For example, weakening the adductor or thigh muscles that close the legs can allow for better perineal hygiene and intermittent catheterisation. Rarely can you inject phenol into the spinal canal to permanently destroy the sensory nerves, or you can cut the nerves (rhizotomy) to achieve the same effect. Destroying the sensory nerves breaks the feedback loop essential for the spinal reflex and spasticity. Time courseSpasticity often takes time to develop. For example, if you have a severe spinal cord relapse with weakness in the legs, the legs may be initially floppy. Then over months or years, the legs start to become spastic. This delayed ramping up of spasticity over time tells us the central mechanism causing spasticity is due to the remodelling of spinal cord neuronal circuits. I have also seen the opposite, with spasticity improving with time. Again, the mechanisms causing this must be due to CNS plasticity and the rewiring of neuronal circuits. Other factorsPlease be aware that constipation, urinary retention, infections, pressure sores, poor-fitting orthotics, menstruation, menopause, sleep deprivation, high and low ambient temperatures, pain and other factors can worsen spasticity. Most pwMS become aware of these exacerbating factors with time. Some people even use their spasticity as an early warning sign of a urinary tract infection (UTI). I highlight these extraneous factors because the management of spasticity in pwMS is complex and often requires a multidisciplinary team to optimise its management. For example, it is not good to focus on spasticity if the underlying problem is faecal impaction or a urinary tract infection. Too often, spasticity needs to be better managed. Poorly controlled spasticity can have a major impact on your quality of life. If you feel your spasticity is being poorly managed, don’t accept it. Contact your HCP so you can have a spasticity review. Please share your experiences and spasticity management hacks. What do you do to improve your spasticity management? How many of you are baclofen, gabapentin, pregabalin, clonazepam, tizanidine or dantrolene zombies? The study below demonstrates the reversal of this state after the implantation of a baclofen pump. Do you need to be assessed for a baclofen pump?PaperFarrell et al. Evaluation of the cognitive benefits of intrathecal baclofen pump implantation in people with intractable multiple sclerosis-related spasticity. Mult Scler Relat Disord. 2021 May:50:102831. Background: Spasticity is a common problematic symptom in Multiple Sclerosis with over one third of patients failing first line therapies. Intrathecal baclofen is a safe and efficacious option for treatment resistant spasticity. Anecdotally patients report improved concentration/cognitive performance when switching to intrathecal baclofen (ITB) from systemic medications.Aim: To explore whether subjects who proceed with ITB pump implantation for spasticity management and reduce oral anti-spasticity agents will have improved cognitive function.Methods: Subjects were admitted for trial of ITB via lumbar puncture and subsequent pump implantation. Spasticity and cognitive measures before ITB trial and 3 months post implant were recorded. Paired t-test or Wilcoxon Signed Ranks test was used for within subject change and effect sizes (Cohen's dz) were calculated. Subgroup analysis of those on ≥2, or ≤ 1 spasticity medications at baseline was performed.Results: 27 subjects with MS completed per protocol. Mean age 46 years [26 - 56], disease duration 15 years [6 - 26], RRMS = 3, SPMS = 17 and PPMS=7. The majority were on multiple spasticity medications. Spasticity scores significantly improved post pump implant. Mean ITB dose at 3 months was 143 mcg / day and 19 discontinued all other treatments for spasticity. There was no deterioration on any cognitive or mood measure. An improvement of moderate effect size was found in Backwards Digit Span (d=0.41, p=0.059) and HADS - anxiety (d=0.37, p=0.097). Fatigue Severity Scale score decreased substantially (d=0.81, p=0.005). Small improvements in Symbol Digit Modalities Test score (d=0.24) and Sustained Attention to Response Task response time (d=0.23) were non-significant. Performance on other measures did not change. Effect sizes were larger in subgroup on ≥2 oral spasticity medications at baseline, compared to the group on ≤1 medication (SDMT, d=0.42 vs d=0.07; Backwards digit span 0.45 vs 0.28; HADS-anxiety 0.39 vs 0.32; HADS-depression d=0.32 vs 0.05 and FSS, d= 1.14 vs 0.42).Conclusions: In a pilot study exploring the impact of ITB on cognition, spasticity scores improved universally and beneficial effects on some measures of fatigue, anxiety, auditory attention and verbal working memory were found. Improvement of speed of processing in those withdrawing higher doses of oral medication was also demonstrated suggesting that switching to ITB has added cognitive and psychological benefits for people with MS.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Merck’s press release on the Evobrutinib vs Teriflunomide phase 3 EVOLUTION trials says more about teriflunomide than evobrutinib, but they do raise questions about all the other Bruton Tyrosine Kinase Inhibitors (BTKi) in clinical trials in MS and other autoimmune diseases. 05 DEC 2023 | DARMSTADT, GERMANY“Results from the EVOLUTION clinical trials showed evobrutinib did not meet its primary endpoint of annualized relapse rate for up to 156 weeks compared to oral teriflunomide in both studies.Merck, a leading science and technology company, today announced that its two Phase III EVOLUTION clinical trials (evolutionRMS 1 and evolutionRMS 2) investigating the efficacy and safety of evobrutinib did not meet their primary endpoints of reducing annualized relapse rates (ARR) in people with relapsing multiple sclerosis (RMS) compared to oral teriflunomide (0.11 vs. 0.11 in evolutionRMS 1 and 0.15 for evobrutinib vs. 0.14 for teriflunomide in evolutionRMS 2, p=NS in both trials). Of note, teriflunomide ARR values were lower than reported in other recent Phase III studies. The overall safety and tolerability profile was consistent with results from the previously reported Phase II trial. The company will complete a full evaluation of the data from the EVOLUTION clinical trials and will work with investigators on the future presentation and publication of the results.”Teriflunomide clearly performed much better than expected and surprised Merck. Why? I changed my mind about teriflunomide several years ago. I now think teriflunomide is the most underrated DMT in our therapeutic armamentarium. I also predict it will eventually become one of the most used MS DMTs once its alternative mode of action becomes widely known, we understand its efficacy profile, and we change how we use it in MS. There are several reasons for this. Teriflunomide is much more effective as a DMT than we realise As we reinterpret old data and new data emerge, it is clear that when we go beyond focal inflammation (relapses and MRI activity), teriflunomide is much more effective than we would expect based on its impact on relapses and MRI activity. Despite reducing relapses by, on average, a third, teriflunomide has a remarkably robust effect on disability progression and slows the accelerated brain volume loss due to MS. The head-2-head studies of ofatumumab and ublituximab (anti-CD20 therapies) against teriflunomide show that despite both anti-CD20 agents being superior to teriflunomide in suppressing relapses and focal MRI activity, only ofatumumab was more effective than teriflunomide when it came to reduced disability worsening. The latter difference, however, was very small and not clinically significant. The difference was mainly driven by relapse-associated worsening (RAW), as the absolute differences between ofatumumab and teriflunomide on PIRA (progression independent on relapse activity) are small (EAN 2020). Please note that ublituximab was no better than teriflunomide on disability progression (see figures below). When assessing the more objective brain volume loss, an integrator of end-organ damage, teriflunomide, was equivalent to both these agents in slowing MS-related accelerated brain volume loss (BVL) (see figure below). Relapses and focal MRI activity are not MS and are likely to represent the immune system’s response to what is causing MS (see ‘Hot topic AAN 2023: smoldering MS’; 24-April-2023). My position on this is based on many observations, one of which is how teriflunomide dissociates the treatment effect on relapses and focal MRI activity from disability worsening and brain volume loss. Teriflunomide is more effective when used as a switch agent Another interesting observation regarding teriflunomide is that it is more effective when used second or third-line than as a first-line agent in DMT-naive patients. This observation is robust and is the only DMT to do this. What happens to the biology of MS over time that makes teriflunomide more effective? This observation is important because, in contemporary phase 3 clinical trials, more subjects are not naive to DMTs. Therefore, teriflunomide is likely more effective than anticipated from the phase 3 trial of teriflunomide.  For example, in a recent French real-world study no difference in efficacy between dimethyl fumarate and teriflunomide (see paper below). The teriflunomide real-world data and the negative Evobrutinib studies will have all the other Pharma companies with BTKi programmes sitting on tenterhooks.  The relapsing MS BTK inhibitor trials, which are currently running, are all using teriflunomide as the active comparator (ClinicalTrials.gov Identifiers: NCT04338022, NCT04338061, NCT04410991, NCT04410978, NCT04586023,  NCT04586010, NCT05147220, NCT05156281). The only exception is the fenebrutinib primary progressive trial, where the active comparator is ocrelizumab (ClinicalTrials.gov Identifier: NCT04544449). The reason for the latter is that ocrelizumab is the only licensed therapy for PPMS and, hence, is considered the standard of care. The billion-dollar question now arises: Will any of the other BTKi’s be superior to teriflunomide? Before drawing too many negative conclusions, we really need to see the other data in the EVOLUTION trials, in particular the disability progression, brain volume and other end-organ damage markers. However, based on teriflunomide’s ability to impact end-organ damage in MS, I would be surprised if evobrutinib is superior to teriflunomide in protecting the end organ or the brain and spinal cord in pwMS. Teriflunomide is also an outlier in terms of memory B-cells Teriflunomide is an outlier in terms of its impact on memory B-cells. We have made the point in the past that all of our licensed MS DMTs either reduce or stop the trafficking of memory B-cells into the CNS. Teriflunomide doesn’t have a significant effect on memory B-cells. The percentage of circulating memory B cells does not change. However, in some instances, the absolute number of B cells may decrease slightly, but this is likely to be non-specific to memory B-cell and represents the impact of teriflunomide on total lymphocyte counts. Although teriflunomide has been labelled as an immunosuppressive therapy, its profile is not immunosuppressive. In most treated pwMS, it doesn’t cause significant leukopaenia or lymphopaenia; it is not associated with opportunistic infections, or secondary malignancies and vaccine responses are not blunted. Teriflunomide has broad-spectrum antiviral activity, including activity against the herpes viruses, which includes EBV. Our group has shown that teriflunomide reduced salivary shedding of EBV in subjects with MS. I have therefore hypothesised that teriflunomide is working as an antiviral in MS. Please note this observation is not unique to teriflunomide but is relevant to the class of agents that are dihydroorotate dehydrogenase inhibitors (DHODHI), leflunomide, vidofludimus or ASLAN003. I have hypothesised that teriflunomide and the class of DHODHIs will work best as second or third-line agents, particularly maintenance therapies after induction with a B-cell-depleting agent. Underpinning this hypothesis is to allow B-cell reconstitution to occur in the presence of an antiviral agent that targets EBV. This is the foundation of the so-called iTeri study (see ‘EBV immunotherapy for MS’; 11-Jan-2023). The EVOLUTION or Evobrutibib study results will further support the uptake of teriflunomide as the go-to agent for de-escalating pwMS off chronic immunosuppressive therapies when they start encountering problems with infections, hypogammaglobulinaemia or poor vaccine responses. The latter is particularly an issue with older patients on anti-CD20 or other immunosuppressive therapies who are developing immunosenescence. Teriflunomide is a low-cost DMTAnother driver is economics. Teriflunomide is either off-patent or coming off-patent very soon in many countries. As a small molecule, teriflunomide’s price will plummet by more than 90% with the launch of generics. Generic teriflunomide is already the cheapest DMT in the USA. The wholesale cost of generic teriflunomide has been reported to be between $32.40 - $2,058.90 per 30-day supply. In comparison, Aubagio, the innovator formulation of teriflunomide, costs approximately $9,155.25 per month (18 April 2023, National Multiple Sclerosis Society).In countries where teriflunomide is still on-patent or not available, you can use leflunomide instead; 20 mg or 10 mg of leflunomide is metabolised into the equivalent of 14 mg or 7 mg of teriflunomide, respectively. In my opinion, there is not much difference between teriflunomide and leflunomide. Leflunomide is a prodrug converted into teriflunomide in the body, so if you live in a resource-poor environment and are paying for your DMTs, please ask for generic leflunomide instead. Many neurologists in resource-poor settings are reluctant to prescribe leflunomide instead of teriflunomide. Call to armsIf you are a wealthy philanthropist or funder, please consider funding a large phase 3 international iTeri study. I have little doubt that teriflunomide after induction with a depletion therapy (alemtuzumab, mitoxantrone, cladribine, AHSCT or anti-CD20) will revolutionise the management and outcome of pwMS. Paper Laplaud et al. Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis. Neurology. 2019 Aug 13;93(7):e635-e646. Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.Classification of evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Last weekend, I attended the AIMS (Autoimmunity In MS) Charity AHSCT (autologous haemopoietic stem cell transplantation) meeting that was held in Sheffield. All the big guns offering AHSCT to pwMS as a private procedure were there. That was the problem with the meeting; there were no AHSCT naysayers, except my ghost from Christmas past. Applying BBC-like rules to provide both sides of the AHSCT argument would have improved the meeting immensely. Having only YES people at the meeting left me with a slightly bitter aftertaste. Should the aim be to convert the naysayers to your side of the argument?The scientific messages presented at the meeting haven’t changed, i.e. AHSCT is a highly effective treatment for MS, but it comes with risks, which include a relatively high mortality (0.3%-2%) and a high risk of infertility. What was not discussed openly is the failure rate of AHSCT. Yes, it does not work for everyone. It is pretty clear from published data that many people with MS (pwMS) who have AHSCT still have ongoing smouldering disease, i.e. they still get worse despite having no further relapses and focal MRI activity (NEIDA). In the following graph of Paolo Muraro’s paper (paper 1), you can see that over time, more than 60% of treated patients have worsening of their disability (smouldering MS). It was clear from meeting people at the meeting who had had AHSCT that early treatment when young and not when you have more advanced or progressive MS is the secret to AHSCT success. It was clear from the meeting that most people in the AHSCT field are still wedded to the dogma that MS is an autoimmune disease and that AHSCT is working by resetting the immune system, by eliminating the cells that cause autoimmunity, or resetting immune regulatory networks, or both. CAR T-cells - the new kids on the blockYou are probably aware that I am convinced that CD19-targeted CAR T-cells will be the next big experiment in MS. I am convinced that CD19-targeted CAR T-cells may cure MS. The latter is based on the truly stunning results of CAR T-cells in systemic lupus erythematosus (SLE) and the fact that these CAR T-cells work well in EBV-associated CNS B-cell lymphomas (please see ‘CAR T-cells as a treatment for MS‘, 17-Sept-2022). The latter tells us these cells traffick to the CNS, kill tumour cells and reduce EBV viral loads. At the meeting, one talk was dedicated to CAR T-cells in MS and its future promise as an MS treatment (please see ‘Inspiring Change: changing the MS treatment paradigm’ 4-Nov-2023). One international expert, however, dismissed CAR T-cells as a treatment for MS based on the dogma that MS is a T-cell mediated autoimmune disease and that purging B-cells with CAR T-cells would be like using an anti-CD20 therapy and would not stop smouldering MS. What was not mentioned or acknowledged is the fact that anti-CD20 therapies don’t penetrate the CNS to any significant degree (please see ‘Anti-CD20 Kool-Aid’, 11-Sept-2021). In contrast, CAR T-cells will get into the CNS and potentially scrub it clean of  B-cells. This is one of the major distinctions between CAR T-cells and anti-CD20 therapies. There is also a large body of evidence in the scientific literature on CNS B-cells and the antibodies they produce as being pathogenic and one of the drivers of smouldering MS. So it makes sense to go beyond peripheral B-cell depletion to target CNS B-cells and their antibody products. The other big issue that was ignored was the potential causal role of EBV plays in driving MS disease activity (please see ‘More evidence that EBV causes MS’, 6-Sept-2022). If EBV is the driver, CD19-targeted CAR T-cells will purge the body of EBV-infected B-cells, including the CNS and other deep tissue compartments such as the deep cervical lymph nodes. If a specific strain of EBV is causing MS, CD19-targeted CAR T-cells could cure MS by depleting latently EBV-infected B-cells and eliminating the virus from the body. This is why I am so excited about CAR T-cell technology and have spent the best part of 2 years trying to get the pharmaceutical industry to take their CAR T-cell technology into MS. The good news is that a few pharmaceutical companies are progressing with CAR T-cell studies in MS. I hope they will start in the new year. The initial trials will be safety studies and not powered for efficacy. Would you be interested in participating in one of these trials? Or do you consider them too risky?AHSCT reactivates EBV; is this a problem? A specific problem discussed at the meeting was the high incidence of EBV reactivation in pwMS treated with AHSCT. In the London cohort (see paper 2 below), 87 out of 109 AHSCT-treated patients had EBV reactivation, with about 70% developing a transient EBV-associated M-protein or paraproteinaemia.  The paraproteinaemia is due to a monoclonal expansion of a B-cell that produces high levels of a single antibody (a human monoclonal antibody). I am told that this high level of EBV reactivation, in particular the development of paraproteinaemia, is not seen in patients undergoing AHSCT for other autoimmune diseases and is another indication that pwMS seem to control EBV poorly. If AHSCT causes EBV reactivation, a driver of MS disease activity, how does it work as a treatment for MS? PwMS have a problem controlling EBV. A large body of evidence shows that pwMS have increased latent-lytic cycling of EBV. They are more likely to shed EBV in their saliva, have EBV reactivation post-AHSCT, develop lymphoblastoid cell lines when their B-cells are cultured in the laboratory and have higher levels of antibodies and more reactive T-cells to EBV antigens. We also know that pwMS have blunted or exhausted T-cell responses to EBV. The latter is common to a large number of chronic viral infections and is the rationale underpinning the Pender Hypothesis of MS and explains why he developed EBV-reactive cytotoxic T lymphocyte treatments for MS. Sadly, the latter hypothesis has been called into question by the recent negative results of the EMBOLD Atara phase 2 Biotherapeutics ATA188 trial.  However, I have made the case that the negative EMBOLD trial results should be ignored in the context of EBV and MS because of bad science (please see: ‘Atara Bio's EMBOLD study is negative’, 9-Nov-2023). When you study the T-cell repertoire in pwMS, you find it quite restricted. In other words, pwMS have a reduced variety of T-cells in their peripheral blood. This means a fewer number of unique T-cell receptors to respond to foreign proteins or antigens. This reduced or truncated T-cell receptor repertoire is seen with age and is a marker of immunosenescence (ageing immune system). However, when pwMS undergo AHSCT, they widen or rejuvenate their T-cell repertoire. A recent study has shown that this widening T-cell repertoire also occurs in relation to EBV immunity. We hypothesised that AHSCT would do this a few years ago and planned to study this phenomenon in our STAR-MS trial. What does this mean? I hypothesise that AHSCT is depleting the exhausted anti-EBV T-cells, and when immunosuppressed during the depletion phase of AHSCT, EBV reactivates from its latent to its lytic state, and the result is the production of infective virus. The reconstituting immune system then sees the infective EBV virus and stimulates new T-cell responses to control EBV. Importantly, these new T-cell responses are not exhausted and are very effective at killing and keeping EBV under control. These EBV-reactive T-cells are detected as being different from those present before AHSCT; this is what is meant by ‘diversification and widening’ of the EBV-reactive cytotoxic T-cell repertoire. If this hypothesis is correct, AHSCT acts as an EBV immunotherapy. I suspect all immune reconstitution therapies (IRTs) in MS are acting as EBV immunotherapies to a greater or lesser extent. If this is correct, we may be able to design much better treatment strategies to treat MS. Rather than using AHSCT as an immunological sledgehammer, we may be able to use a simple therapeutic vaccine to rejuvenate T-cells and widen the EBV-reactive T-cell repertoire. It may interest you that at least one vaccine company is developing a therapeutic EBV vaccine to treat MS. A simpler strategy may be to simply to use EBV antivirals. I am hedging my bets and urging the MS community to try all strategies., including using AHSCT and CAR T-cells to test the EBV hypothesis of MS. When one delegate at the AIMS meeting in Sheffield told me she had a new immune system after AHSCT, she may have been right, i.e. a new immune system to control EBV. I know this Newsletter is heavy going with a lot of immunology. Please let me know if you need help understanding what I have written. If not, I will try another tactic. Paper 1Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. Importance: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.Objective: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.Design, setting, and participants: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.Exposures: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.Main outcomes and measures: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.Results: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).Conclusions and relevance: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.Paper 2Nicholas et al. Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series. Neurology. 2021 Aug 31;97(9):e890-e901. Objective: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.Methods: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined.Results: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure.Conclusions: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.Classification of evidence: This study is rated Class IV because of the uncontrolled, open-label design.Paper 3Massey et al. Diversification and expansion of the EBV-reactive cytotoxic T lymphocyte repertoire following autologous haematopoietic stem cell transplant for multiple sclerosis.  Clin Immunol. 2023 Sep:254:109709. Both genetic susceptibility and environmental exposures are thought to be involved in multiple sclerosis (MS) pathogenesis. Of all viruses potentially relevant to MS aetiology, Epstein-Barr virus (EBV) is the best-studied. EBV is a B cell lymphotropic virus which is able to evade the immune system by establishing latent infection in memory B cells, and EBV reactivation is restricted by CD8 cytotoxic T cell (CTL) responses in immune competent individuals. Autologous haematopoietic stem cell transplantation (AHSCT) is considered to be the most effective therapy in the treatment of relapsing MS even though chemotherapy-induced lymphopenia can associate with the re-emergence of latent viruses. Despite the increasing interest in EBV and MS pathogenesis the relationship between AHSCT, EBV and viral immunity in people with MS has not been investigated to date. This study analysed immune responses to EBV in a well characterised cohort of 13 individuals with MS by utilising pre-AHSCT, and 6-, 12- and 24-month post AHSCT bio-banked peripheral blood mononuclear cells and plasma samples. It is demonstrated that the infused stem cell product contains latently EBV-infected memory B cells, and that EBV viremia occurs in the immune-compromised recipient post-transplant. High throughput TCR analysis detected expansion and diversification of the CD8 CTL responses reactive with EBV lytic and latent antigens from 6 to 24 months following AHSCT. Increased levels of latent EBV infection found within the B cell pool following treatment, as measured by EBV genomic detection, did not associate with disease relapse. This is the first study of EBV immunity following application of AHSCT in the treatment of MS and not only raises important questions about the role of EBV infection in MS pathogenesis, but is of clinical importance given the expanding clinical trials of adoptive EBV-specific CTLs in MS.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Like me, most of you have probably been following the ups and downs of OpenAI in the press this last week since Sam Altman, its CEO, was fired and now reinstated with essentially a new board. It turns out it was down to a boardroom battle between the AI boomers and AI doomers, and it seems the boomers have won the day. ‘On one side are the “doomers”, who believe that, left unchecked, AI poses an existential risk to humanity and hence advocate stricter regulations. Opposing them are “boomers”, who play down fears of an AI apocalypse and stress its potential to turbocharge progress.’  The Economist, 19-11-2023.This is not a trivial issue. When I previously floated the idea of using AI to improve the management of MS, I got a lot of pushback (please read ‘Has AI come of age?’, 13-April-2023). Despite the pushback, I remain an AI boomer and want to take AI to the next level. In short, I want to create an equivalent of Chat-GPT for MS. Imagine an MS Generative Pre-trained Transformer (MS-GPT), analogous to Chat-GPT,  that you interact with on WhatsApp, a bespoke App, a website or your favourite social media platform. For it to be transformative, it has to fit in with how you acquire and use information. Imagine MS-GPT as a personalised MS guide with which you chat and interact regularly. I envisage you sending MS-GPT text, voice messages, or even photographs, and it responds to you in the format you select. Similarly, if you allow it, MS-GPT can send you spontaneous messages, and you can respond to them. The value is in the two-way dialogue and how it will lead to better management of your MS and better long-term outcomes. Please note we envisage training MS-GPT using well-defined MS-related material from peer-reviewed journals and pre-vetted websites with a reliable reputation. We don’t want to use the whole of the internet as a training resource as this will include debunked theories, quack remedies, etc. Yes, we want MS-GPT to be better trained than the best MS Neurologist on the planet, and we want to build real-life feedback into the platform so that it can learn and improve with time. Some of you who have gotten this far will think this is science fiction and be asking how this will work. Let me explain. If you have just been diagnosed with MS and you register with MS-GPT and select WhatsApp as your preferred platform for communication. WhatsApp's use of encryption may make you feel better about data privacy. However, MS-GPT will ask whether or not you want your chat(s) recorded and analysed for your regular assessment with your neurologist and MS team. If you permit it, it will analyse your data over time and assess whether you are stable, improving or worsening. It can also summarise the issues that need addressing at your next appointment. So, there will be an incentive to record and analyse your interactions with MS-GPT. As a newly diagnosed patient, you may ask the following questions:* What is MS?* What to expect from having MS?* Do I tell my partner I have MS? When you set up your account, you will be asked what level of detail you want to interact with MS-GPT. This will tell MS-GPT to provide short, concise answers or longer, more detailed answers. You can even ask MS-GPT to recommend online resources to read, listen to or watch. Please think of the interaction as being quite personal. In the end, you want a long-term relationship with MS-GPT. Later, you will ask MS-GPT detailed questions about specific disease-modifying therapies, including their relative efficacy, side effects and monitoring requirements. I envisage MS-GPT being intelligent enough to ask you about family planning issues, and it will prompt you to consider this information in your decision-making process. Over time, MS-GPT will learn about how you function. It will ask permission to access your step-counting function from the relevant health applications on your phone. This data will be needed to monitor your mobility. If you give MS-GPT access to your GPS function and microphone, it will start to monitor your toilet habits and detect urinary frequency, nocturia and bowel habits. If you use a sleep monitor, it will be able to track your sleep pattern via the third-party application’s API (application programming interface). This will all be kept in MS-GPT documentation or memory about you, which it will use to produce periodic summaries.  When it detects urinary frequency or nocturia, it could ask you whether you think your bladder function has changed. It could recommend some simple self-help solutions or advise you on this problem, and it will include it in your summary to bring this up with your HCP. You will prompted if you want MS-GPT to remind you about lifestyle changes. For example, if your exercise drops off, as documented in your Strava application or other health app, it can ask you why. You could ignore its advice or apologise to it and get down to the gym. MS-GPT will gently nudge you to improve your lifestyle. In the future, I envisage building an HCP vetting function into MS-GPT. If, for example, MS-GPT recommends a specific class of medication for managing leg spasms at night, you could flag the response as being in need of vetting, and it will then be sent to an HCP for confirmation. A message will then come back from an HCP saying whether or not the advice is correct. In this way, MS-GPT will learn. This latter functionality will have to be costed and paid for in some way; for example, the NHS or your medical insurance may cover the subscription cost. Please note that all MS-GPT represents is AI-driven knowledge curation and communication. It will replace what I am trying to achieve with MS-Selfie Newsletters and Podcasts and with MS-Selfie Microsite. I envisage MS-GPT taking over my job and doing it much better. I will be obsolete. This is what some of the AI-doomers are worried about the hollowing out of the knowledge economy.  I suspect the latter is being overstated because doing a physical examination and ordering diagnostic tests will still require an HCP to be in the loop, at least for the foreseeable future. MS-GPT could go beyond the obvious and detect how you function using outputs from other smartphone applications. I envisage it being able to detect you having a tremor or making typing mistakes due to incoordination. If it does detect these problems, it could ask you to do a formal assessment for these problems, document them, and then advise you on how to manage them. MS-GPT could help you manage your bowel, bladder and sexual problems. It could help with CBT and mindfulness. In short, it will be an indispensable guide on self-managing and self-monitoring your MS. It may sound like science fiction, but if I had access to funding and a group of bright techies, we could build a prototype within two years. My vision would be not to make MS-GPT MS specific but to allow it to acquire general medical knowledge to answer questions beyond the management of MS; it will be much more knowledgeable than your neurologist. It could provide answers to specific questions about HRT (hormone replacement therapy), the management of hypertension, warts, etc. In other words, MS-GPT will be a general medical and lifestyle guide. The naysayers will say I don’t want this; I really want quality time with my neurologist. I suspect it will achieve this because anyone using MS-GPT will realise they have a neurologist of sorts on their smartphone and that when they do see their actual neurologist, they will have a summary of how they are doing and what problems to focus on. The neurologist will find the summary helpful. I predict MS-GPT will be a win-win-win: a win for the person with MS, the neurologist looking after the pwMS and the healthcare system paying for the MS care.  Steve Jobs, who created Apple and turned it into the most valuable company in the world, is famous for saying, “Some people say, ‘Give the customers what they want,’” he said in one of his most-quoted statements. “But that’s not my approach. Our job is to figure out what they’re going to want before they do.” I predict pwMS are going to want and need MS-GPT much sooner than they realise. InnovationInnovation is creating and implementing novel ideas, methods, or products that bring about positive change and improvement. It is the ability to think creatively and find new solutions to existing problems or to address emerging needs and opportunities.Innovation is essential for several reasons. Firstly, it drives progress and advancement in various fields, such as technology, healthcare, and business. Without innovation, we would be stuck in a state of stagnation, unable to evolve and adapt to ever-changing circumstances. Innovation fuels economic growth by fostering the development of new industries, creating job opportunities, and increasing productivity.Furthermore, innovation plays a crucial role in improving the quality of life for individuals and society. By introducing innovative ideas and products, we can find more efficient ways to perform tasks, enhance communication, and solve complex challenges. For example, the invention of the internet revolutionized how we access information, connect with others, and conduct business globally. AI will take this to the next level. Innovation also encourages competitiveness and fosters a culture of continuous improvement—healthcare systems and individuals who fail to innovate risk being left behind in a rapidly evolving world. By embracing innovation, institutions, businesses and individuals can stay ahead of the curve, differentiate themselves from competitors, and meet the ever-changing demands of their members, customers, patients and colleagues.Moreover, innovation can have a positive impact on sustainability and the environment. By developing innovative technologies and practices, we can reduce our carbon footprint, conserve resources, and find alternative energy solutions. This is crucial in addressing the pressing global challenges of climate change and environmental degradation.Innovation is the driving force behind progress, growth, and improvement. It empowers us to think outside the box, challenge existing norms, and solve complex problems creatively. By fostering a culture of innovation, we can create a better future for ourselves and future generations.Please let me know what you think of MS-GPT as a concept and how you would use it if it became available. Innovation ChallengeRoche and Genentech asked me to join an innovation challenge steering committee to drive early detection of MS disease worsening, thus enabling early and effective treatment and improving the monitoring and prediction of the impact of disease on people’s lives, including disability trajectories. If you know anyone with an innovative idea that needs funding, please forward them this email and encourage them to apply. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

The 7th of November was the third anniversary of my accident when a speeding motorcyclist hit me whilst out jogging. Only three years ago, I was lying in the neurosurgery ward at King’s College Hospital, in a state of morphine-induced torpor, waiting for a rehabilitation bed that didn’t materialise. Thankfully, I have made a reasonable recovery, with minor residual problems that have clipped my quality of life by ~20 percentage points. The latter is nothing compared to the counter-narrative of not being here to reflect on the experience. I am genuinely grateful for being alive. Many people continue to ask me about the accident, which is receding from my memory. My post-traumatic flashbacks, typically triggered by the sound of a speeding motorbike, are now quite rare. However, the one thing that still haunts me is the chronic insomnia I experienced due to the pain and discomfort of not being able to roll over in bed. For about six months, I had to sleep on my back. I was unable to roll over due to the fact I had a fractured pelvis and was wearing a neck brace. As a result of lying on my back, I developed a heat rash that was torture. The rash was itchy, and I developed a burning sensation that made me want to have a cold shower. In retrospect, I suspect the latter was a side effect of the high doses of morphine I was taking to control the pain. Not only did I have pain from my fractured cervical vertebrae and pelvis, but I also had radicular or neuralgic pain radiating down from my neck to my hand. The radicular or neuralgic pain has to be the worst pain I have ever experienced and much worse than the pain I experienced when I had renal colic. Because of my ordeal, I now appreciate what my patients go through when they have neuralgia or complain about insomnia. When I see patients with Parkinson’s disease, I always ask them whether or not they can roll over in bed at night. This is an indication of whether or not their motor symptoms are being adequately managed at night. Since having my accident, I now ask my patients with advanced MS the same question. Once you have experienced the torture of being immobile in bed yourself, you realise how important it is for people with neurological or other conditions as well. This is a personal example of how ‘the lived experience’ impacts medical practice. If you have problems rolling over in bed at night, there are things you can do to help yourself. * Stretching and range of motion exercises: doing gentle stretching and range of motion exercises during the day can help improve flexibility and reduce muscle stiffness, making it easier to roll over in bed at night.* Physical therapy: please see a physio or physical therapist who can provide a personalised exercise programme and teach you techniques to address specific mobility issues and improve overall movement.* Medication: ensure you have been assessed and prescribed appropriate medications to manage muscle spasticity and spasms, and pain during the night.* Use of supportive devices: utilising supportive devices such as bed rails, grab bars, monkey ropes, or specially designed pillows can provide additional assistance and stability when transitioning in bed.* Low-friction bed linen and pyjamas: using satin or low-friction linen and pyjamas can make the difference in being able to roll over in bed or not. * Specialised beds: if all else fails, you may need to purchase a tilting bed that helps automate the process of rolling over in bed. These beds are expensive and, in general, are not covered by NHS budgets. * Maintaining a comfortable sleep environment: creating a comfortable and supportive sleep environment, including using a supportive mattress and pillows, can help reduce discomfort and make it easier to roll over at night.I have previously commented on a short commentary in the BMJ on ‘How to write your own wellbeing prescription’. The top piece of advice was to improve your sleep. Sleep is probably the most essential performance-enhancing agent we know. We know poor sleep is the elephant in the room. Most studies on sleep in MS show that over 70% of pwMS have a sleep disorder—the following results from a survey we did many years ago of our MS-Blog readers illustrates the problem. Only 12% of respondents reported having no problems with sleep. I doubt much has changed.You know what it is like if you wake in the morning and have had a good night’s sleep; you feel energised, your mood is better, and you are prepared to take on the world. In contrast, when you wake from a night of tossing and turning, or not being able to turn, legs jerking, getting up to go to the toilet several times, with a hangover from too much alcohol the night before, etc., you find it challenging to get through the day; you are irritable, and your mood is low. The study below shows that restless legs syndrome, common in pwMS, affects sleep quality and is associated with poor cognition in people with MS. So, if you have RLS, bring it to the attention of your HCP so that you can get it treated. The following is a simple self-help guide to improve your sleep hygiene:* Ensure you spend an appropriate amount of time asleep in bed, at least 6 hours. Some people need more than this to feel refreshed. * Limit daytime naps to 30 minutes. Please note that napping does not make up for inadequate nighttime sleep. * Avoid stimulants such as caffeine, modafinil and nicotine close to bedtime. * Only drink alcohol in moderation. Alcohol is well-known to help you fall asleep faster, but too much disrupts sleep.* Exercise helps improve sleep quality. As little as 10 minutes of aerobic exercise daily can improve sleep quality. * Don’t eat before going to bed. Heavy foods and fizzy drinks can trigger indigestion or heartburn/reflux that disrupts sleep.* Ensure you get adequate exposure to natural light; exposure to sunlight during the day and darkness at night helps maintain a regular sleep-wake cycle. * Establish a regular relaxing bedtime routine, which helps the body recognise it is bedtime. This could include taking a shower or bath or reading. However, avoid reading or watching emotionally upsetting content before attempting to sleep.* Make sure that your sleep environment is pleasant. Your mattress and pillows should be comfortable. The bedroom should be cool for optimal sleep (16-20°C). The bright light from lamps, smartphones and television screens can make it difficult to fall asleep, so turn those lights off or adjust them when possible. Use the blue filter mode on your smartphone and other devices that reduce the inhibition of melatonin from light. Consider using blackout curtains, eyeshades, earplugs, white noise machines and other devices to make the bedroom more relaxing.* And if you have pain, nocturia, restless legs, sleep apnoea, etc., get these adequately managed via your HCP.Please let me know what strategies work for you to improve your sleep.  An essential role of MS-Selfie is to share best practices and alternative practices. I like it when pwMS hack their physiology to develop solutions that work. Don’t forget the current treatment strategy is to maximise your brain health, and part of this philosophy is the holistic management of MS, including sleep.You may find the following MS-Selfie Newsletters helpful:* Are you sleep-deprived? (18 AUG 2021)* Do you suffer from restless legs syndrome? (23 AUG 2023)* Why am I so fatigued? (9 AUG 2021)Research paperCederberg et al. Restless Legs Syndrome, Sleep Quality, and Perceived Cognitive Impairment in Adults With Multiple Sclerosis. Mult Scler Relat Disord. 2020 May 18;43:102176. doi: 10.1016/j.msard.2020.102176. Background: Restless Legs Syndrome (RLS) is a prominent sleep disorder that often worsens sleep quality and perhaps cognitive function in adults with multiple sclerosis (MS). The present study examined the relationships among RLS prevalence and severity, sleep quality, and perceived cognitive impairment in adults with MS.Methods: Participants (N=275) completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group (IRLS) Scale, the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ), the Pittsburgh Sleep Quality Index (PSQI), the Patient Determined Disease Steps (PDDS), and a demographic and clinical characteristics questionnaire.Results: Persons with MS who had RLS (i.e., MS+RLS; n=74) reported significantly worse perceived cognitive impairment compared with those who did not have RLS (n=201; p=0.015). Bivariate correlation analyses within the MS+RLS group indicated that greater RLS severity was significantly associated with more severe perceived cognitive impairment (r=0.274) and sleep quality (r=0.380), and worse perceived cognitive impairment was significantly associated with worse sleep quality (r=0.438). Linear, step-wise regression analyses indicated that RLS severity significantly predicted perceived cognitive impairment (β=0.274), but the inclusion of sleep quality (β=0.391) accounted for the relationship between RLS severity and perceived cognitive impairment (β=0.126).Conclusions: Our results suggest that sleep impairment may be an intermediary factor in the association between RLS severity and cognitive impairment in persons with MS who present with RLS. The diagnosis and treatment of RLS symptoms and other effectors of sleep quality could improve neuropsychological consequences of MS.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. You must be a paying subscriber if people want 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Case studyProf G, I am 63 years of age and have had multiple sclerosis for 27 years. I have recently had to retire as a journalist because of cognitive impairment and fatigue. I do not have the mental energy and cognitive capabilities to perform my job. Since having COVID-19 in 2021, my cognitive function has plummeted. Using your online EDSS calculator, my EDSS is 5.0. I am still taking fingolimod, which seems to be working in that I have had no relapses, and my MRI has not shown any new lesions. I have been told that I do have some brain atrophy. Is there anything I can do about my cognition? My neurologist has told me this is what happens when you have MS and get old. Prof G’s OpinionHow long is a piece of string? This person describes what many of my patients complain about in clinic—worsening cognition despite being on an effective DMT and having no evident inflammatory disease activity or NEIDA. The cognitive impairment in this patient could be due to smouldering MS, superimposed ageing, long COVID or some other disease process. The knee-jerk reaction is to assume their progressive cognitive impairment is MS-related and to tell the patient there is nothing that can be done about their problem. It could be argued that this is a form of medical gaslighting and not how I would necessarily approach the problem. The following is my knee-jerk response to the query. Rule 1: Don’t assume the cognitive impairment is MS-related This patient needs a full medical and neurological assessment, including a neuropsychological referral, to document the cognitive impairment and to define what domains are involved so that the patient can potentially be referred for cognitive rehabilitation. Many pwMS who complain of cognitive impairment are more likely to have depression and anxiety.  Treating depression and anxiety can help. Rule 2: Don’t assume the cognitive impairment is age-relatedI am aware that MS prematurely ages the brain and brings forward age-related cognitive decline. MS does this via several mechanisms. Firstly, by reducing neurological and brain reserve. Having fewer neurons, axons, and synapses reduces your biological resilience. In addition, ongoing smouldering MS-related inflammation will drive ageing mechanisms. Unfortunately, we have very little we can offer patients for age-related cognitive impairment outside of general brain health recommendations, which I have covered in an earlier MS-Selfie Newsletter (Brain Health: how important is it? 6th-Oct-2-22). This patient will need a brain health screen to see if anything can be modified, i.e. all the factors under the so-called non-MS targets below. Don’t underestimate the importance of every one of these factors in helping to improve your general and brain health. The big ones on the list are sleep, diet, exercise and comorbidities, including infections. This patient needs to be seen in the clinic to have a detailed medical history taken and a clinical examination.  In addition, they may need some regular blood tests done to exclude metabolic causes of cognitive decline, for example, hypo- or hyperthyroidism, vitamin B12 deficiency, diabetes, hypercalcaemia, etc…Rule 3: Don’t assume because you haven’t had relapses and your last MRI is stable that, your MS is inactive.This rule is very controversial but is supported by recent observations that clinical and MRI monitoring is very insensitive and does not pick up some ongoing inflammation. We are now offering patients like this patient a lumbar puncture to check to see if they have raised spinal fluid neurofilament levels that would indicate ongoing inflammation. We have shown that approximately 1 in 10 pwMS who are NEIDA have increased neurofilament levels that will guide DMT switching. In our centre, this patient would potentially be offered a switch to siponimod or recruitment into our add-on SIZOMUS trial to try and tackle smouldering MS. A spinal fluid analysis will also allow us to exclude an opportunistic infection that can occur on fingolimod, such as cryptococcal meningitis and to do a dementia screen on the fluid for Alzheimer’s disease. Yes, people with MS are also at risk of getting Alzheimer’s disease (AZD). The problem is very few neurologists think about co-morbid Alzheimer’s disease, mainly because we don’t have treatments for AZD. This will change in time as AZD DMTs emerge. This particular person thinks that COVID-19 accelerated their cognitive decline. This is possible for three reasons. Firstly, they may have long COVID or smouldering COVID-19. The latter is the prolonged shedding of SARS-CoV-2 in immunocompromised patients; in some patients, the shedding has been documented to occur over many months and rarely years. Smouldering COVID-19 is not a trivial medical problem and is likely to be the primary substrate for the emergence of new SARS-CoV-2 variants. As fingolimod is not that immunosuppressive, the chances of this person having smouldering COVID-19 is very small. Nevertheless, they should have a nasal and throat swab sent for SARS-CoV-2 PCR. A second reason for this person having cognitive decline is long COVID. There is now mounting evidence that people with COVID-19 take a hit when it comes to the brain. There are several studies showing brain atrophy and/or cognitive deficits in people who have long COVID compared to controls. There are also pathological studies showing SARS-CoV-2 infection of the brain in people who have had COVID-19. However, before labelling this patient as having long-COVID-19-associated cognitive impairment, I would want to exclude other conditions referred to above. My problem with long COVID is that the definition of the condition and the diagnostic criteria for making the diagnosis are a bit vague and are also non-specific, so that long COVID is a bit of a dumping ground for clinicians. I am not saying that long COVID does not exist, but that a lot of people diagnosed with long COVID may have other causes for their symptoms. The third reason is the impact the COVID-19 pandemic has had on brain health in general. The paper below has just come out, showing how, in older people, the pandemic has affected cognitive function in general. The researchers think the main drivers are reduced exercise, increased alcohol consumption and social isolation. What this study shows us is how susceptible the brain is to minor insults and that we should take brain health more seriously in future. I have been writing and talking about MS brain health for over a decade, and very few MS services include brain health screening and management in routine clinical practice. The problem is bandwidth. We have very little time to manage MS and its problems and even less time to cover brain health. I think we are missing a trick and that if we all adopted the marginal gains approach to managing MS, our patients would have better outcomes and better quality of life. I would like to know if you have had a brain health screening done and/or been advised in your regular MS follow-up assessment on optimising your brain health. Similarly, has the concept of prehabilitation been discussed with you (please see: Prehabilitation the ultimate in self-help, 5-Jul-2021). Research paperCorbett et al. Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data. Lancet Healthy Longev 2023; 4: e591–99.Background: Although the long-term health effects of COVID-19 are increasingly recognised, the societal restrictions during the COVID-19 pandemic hold the potential for considerable detriment to cognitive and mental health, particularly because major dementia risk factors—such as those related to exercise and dietary habits—were affected during this period. We used longitudinal data from the PROTECT study to evaluate the effect of the pandemic on cognition in older adults in the UK. Methods: For this longitudinal analysis, we used computerised neuropsychology data from individuals aged 50 years and older participating in the PROTECT study in the UK. Data were collected from the same participants before the COVID-19 pandemic (March 1, 2019–Feb 29, 2020) and during its first (March 1, 2020–Feb 28, 2021) and second (March 1, 2021–Feb 28, 2022) years. We compared cognition across the three time periods using a linear mixed-effects model. Subgroup analyses were conducted in people with mild cognitive impairment and in people who reported a history of COVID-19, and an exploratory regression analysis identified factors associated with changes in cognitive trajectory. Findings: Pre-pandemic data were included for 3142 participants, of whom 1696 (54·0%) were women and 1446 (46·0%) were men, with a mean age of 67·5 years (SD 9·6, range 50–96). Significant worsening of executive function and working memory was observed in the first year of the pandemic across the whole cohort (effect size 0·15 [95% CI 0·12–0·17] for executive function and 0·51 [0·49–0·53] for working memory), in people with mild cognitive impairment (0·13 [0·07–0·20] and 0·40 [0·36–0·47]), and in people with a history of COVID-19 (0·24 [0·16–0·31] and 0·46 [0·39–0·53]). Worsening of working memory was sustained across the whole cohort in the second year of the pandemic (0·47; 0·44–0·49). Regression analysis indicated that cognitive decline was significantly associated with reduced exercise (p=0·0049; executive function) and increased alcohol use (p=0·049; working memory) across the whole cohort, as well as depression (p=0·011; working memory) in those with a history of COVID-19 and loneliness (p=0·0038; working memory) in those with mild cognitive impairment. In the second year of the pandemic, reduced exercise continued to affect executive function across the whole cohort, and associations were sustained between worsening working memory and increased alcohol use (p=0·0040), loneliness (p=0·042), and depression (p=0·014) in those with mild cognitive impairment, and reduced exercise (p=0·0029), loneliness (p=0·031) and depression (p=0·036) in those with a history of COVID-19. Interpretation: The COVID-19 pandemic resulted in a significant worsening of cognition in older adults, associated with changes in known dementia risk factors. The sustained decline in cognition highlights the need for public health interventions to mitigate the risk of dementia—particularly in people with mild cognitive impairment, in whom conversion to dementia within 5 years is a substantial risk. Long-term intervention for people with a history of COVID-19 should be considered to support cognitive health.Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it myself. If people want to ask questions unrelated to the Newsletters or Podcasts, you must be a paying subscriber. If you can’t afford to become a paying subscriber, please email a request for a complimentary subscription ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestX (Twitter) / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

Case studyDear Professor GiovannoniMy 17-year-old son has just been diagnosed with multiple sclerosis. As you can imagine, as a parent, I am very concerned about his long-term future. His neurologist has recommended he start fingolimod without much discussion about other treatment options. Is there any advice you can give about the underlying principles of treating MS in young people? Prof G’s OpinionAs I have said before, how MS is managed and treated worldwide is variable and depends on local practices and guidelines. I suspect your son has been offered fingolimod because fingolimod is the only DMT that has been appropriately tested in the so-called paediatric population, as it was shown to be superior to interferon-beta (Avonex). I don’t think there is any difference between a 17-year-old (paediatric patient) and an 18+-year-old patient (adult). I would have, therefore, made sure your son was well informed about MS and its management before recommending a treatment. I would almost certainly have recommended multiple treatment options, i.e., I would have offered a choice. I suggest your son asks the following questions before deciding which treatment to start. * What is multiple sclerosis (MS)?* Am I sure that I have MS?* What should I expect from a diagnostic consultation?* What type of MS do I have?* What prognostic group do I fall into? * What are the consequences of not treating MS? * Do I have active MS? * Am I eligible for treatment with a DMT? * How do I want my MS to be treated? What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?* Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?* How can I reduce my chances of adverse events on specific DMTs?* Do I understand the concept of treat-2-target and NEDA?* What are the attributes of the specific DMTs or treatment strategies?* Interferon-beta* Glatiramer acetate* Mitoxantrone* Natalizumab * S1P modulators* Alemtuzumab* Cladribine* Teriflunomide* Fumarates* Anti-CD20 (to be completed)* AHSCT* Off-label DMTs* Will I be able to become a parent? What about pregnancy and breastfeeding? Multiple sclerosis (MS) treatment has evolved rapidly with 11 disease-modifying therapy (DMT) classes. I will provide a brief overview of the different classes of DMTs and a classification system for how we think of them and how this fits in a treatment paradigm for using these DMTs effectively and safely. To address the unmet need for treating more advanced MS, including people with MS using wheelchairs, we need a two-pronged approach. A more proactive approach to early and effective treatment of MS with a defined treatment target of no evident inflammatory disease activity (NEIDA), defined as no relapses and no new or enlarging lesions on MRI. In addition, we need to modify our expectation of what can be achieved in more advanced MS and focus on neuronal systems with reserve capacity, for example, the upper limb, speech and swallowing (bulbar function), visual function and cognition. I also appeal to solving the problem of the slow adoption of innovations and the global problem of untreated or undertreated MS.NEIDA as a treatment targetRelapses and ongoing focal inflammatory activity on MRI (new or enlarging T2-lesions and gadolinium (Gd)-enhancing lesions) are associated with a worse short to intermediate-term prognosis, contradicting natural history studies. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a treatment target in MS.  NEIDA is an essential goal for treating individual pwMS and could be used as an outcome in clinical trials. To adopt NEIDA in day-to-day clinical practice, it is advisable to have a ‘rebaseline’ MRI scan after the onset of action of the DMT has been assessed. The timing of the baseline MRI is based on how quickly the DMT works and when you can potentially redose immune reconstitution therapies. Please note that recommendations for immune reconstitution therapies differ from maintenance or continuous therapies. In the case of an IRT, for example, alemtuzumab or cladribine, which are given as short courses of breakthrough disease activity, can be used as an indicator to retreat rather than necessarily switch therapy. Therefore, the rebaselining MRI should be delayed until after the final initial course of therapy, e.g. two years, or close enough to the time when a third or subsequent course can be administered. The question of how many cycles need to be given before considering that a person has failed an IRT remains a moot point until much-needed long-term evidence emerges to guide us.Compared to IRTs, disease activity on maintenance therapy, provided you have been adherent to treatment, is usually interpreted as a sub-optimal or non-response and a need to escalate or switch therapies to a more effective DMT. In the past, we used NEDA (no evident disease activity) as a treatment target, which included progression or worsening independent of relapse activity (PIRA) or smouldering MS. PIRA may have little to do with ongoing focal inflammatory activity and may represent the dying back of central nerve fibres as a result of preceding focal inflammatory lesions. Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on PIRA or smouldering MS disease activity. Many HCPs remain sceptical of using NEIDA as a treatment target; they remain critical of the zero-tolerance target. Some are concerned that most pwMS would be on ‘more risky’ high-efficacy therapies. A less aggressive approach uses various scoring systems, allowing minimal disease activity (MEDA). MEDA, however, flies in the face of the science of the focal inflammatory lesion being ‘bad’ and is associated with poor short-, intermediate- and long-term outcomes. If the majority of pwMS end up on the so-called risky high-efficacy therapies because of breakthrough disease activity, then this is what they probably need to have their MS actively treated. Achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. pwMS with MS treated-to-target of NEIDA do better than those with breakthrough disease (at a clinical or subclinical/MRI level).  I would, therefore, strongly encourage both pwMS and their HCPs to adopt NEIDA as an initial treatment target for MS. In the future, we must go beyond this to target smouldering MS.  The following figure is an example of implementing a treat-2-target NEIDA strategy.  The important take-home message is that the treatment goals in MS have moved and now require setting goals and actively monitoring outcomes to achieve these goals. From now on, there will be a need to regularly update the definition of NEIDA as new technologies become available and are validated as predictors of treatment response. I envisage the definition of NEIDA changing shortly to include more objective metrics, particularly ones measuring end-organ damage, for example, brain volume loss and the inclusion of patient-related outcome measures (PROMS). Disease-modifying therapiesThe effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a strategy of treat-2-target of NEIDA. Choosing a DMT with a lower efficacy rate, i.e. a lower NEIDA rate, means that a higher proportion of treated pwMS will need to be switched to higher efficacy therapies over time to achieve NEIDA. In comparison, pwMS choosing high-efficacy therapies will have a greater chance of achieving NEIDA with their initial choice of therapy. Data shows that pwMS treated with the step-care approach do worse on average than those offered rapid escalation or high-efficacy DMTs first-line. The latter of the three approaches is now called flipping the pyramid, i.e. choosing high-efficacy therapies first line. In recent trials of alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, pwMS randomised to 2 years of interferon-beta-1a therapy or teriflunomide had poorer outcomes than those receiving highly-active therapy from the outset. Real-world data from registries also support this; groups of pwMS with delayed access to high-efficacy DMTs do worse than those getting onto high-efficacy treatments early. About the conventional step care paradigm, pwMS switching horizontally in terms of efficacy from interferon-beta to glatiramer acetate, or vice-versa, i.e. from one moderate efficacy DMT to another moderate efficacy DMT, do not do as well as pwMS switching vertically to fingolimod a highly-effective DMTs. Similarly, people with MS escalating to natalizumab, a very-high efficacy DMT, do better than pwMS being escalated to the less effective, but still high-efficacy, DMT fingolimod. What determines what efficacy level of a DMT is appropriate depends on individual factors, for example, baseline prognostic profile, family planning, local or national treatment guidelines, socioeconomic factors, patient factors in particular comorbidities, cognitive impairment, risk aversion and lifestyle issues. The adoption rate of the rapid escalation or the flipping of the pyramid over the conventional step-care approach is highly variable worldwide and even within countries. To address the variation in clinical practice and how MS is treated, we launched a policy document, ‘Brain Health: Time Matters in Multiple Sclerosis’, to activate the MS community to be more proactive in managing MS. We need to update this policy document to include the concept of flipping the pyramid.One development worth highlighting is the classification of DMTs into maintenance and immune reconstitution therapies and those that are immunomodulatory compared to those that result in immunosuppression. In addition, immunosuppressive therapies can be further subdivided into those that cause prolonged compared to short-term immunosuppression, the relative attributes of which are compared in the following table. Maintenance vs Immune Reconstitution Therapies (IRTs)There is a divide between the two main treatment philosophies: maintenance-escalation vs. IRTs.  By definition, an IRT is given as a short course, i.e. as a one-off treatment in the case of AHSCT or intermittently as in the case of alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional therapy courses are only given if there is a recurrence of inflammatory activity. IRTs can induce long-term remission and, in some cases, potentially a cure. One could argue that none of our treatments cure MS, but unless we define what constitutes a cure and look for it, we won’t find it. At the recent ECTRIMS/ACTRIMS meeting in Milan, I noted that several speakers raised the issue of needing a definition of an MS cure. None of them had read our Editorial from 2013 doing just this. Banwell B, Giovannoni G, Hawkes C, Lublin F. Editors' welcome and a working definition for a multiple sclerosis cure. Mult Scler Relat Disord. 2013 Apr;2(2):65-7. In comparison, maintenance therapies are, by definition, given continuously without an interruption in dosing. Although maintenance therapies can induce long-term remission, i.e. NEIDA, they cannot, by definition, result in a cure. With maintenance therapies, the recurrence of, or ongoing, inflammatory activity indicates a suboptimal response to treatment and typically results in a treatment switch. Ideally, this switch should be to a more effective class of DMTs, hence the term escalation.  Continuous and intermittent immunosuppressionAnother practical way of classifying DMTs is based on whether or not they are immunosuppressive. An immunosuppressive is any DMT that reduces the activation, or effectiveness, of the immune system. From a regulatory perspective, for a drug to be classified as being immunosuppressive, it should (1) cause significant lymphopaenia (low lymphocyte count) or leukopaenia (low white blood cell count), (2) be associated with opportunistic infections, (3) reduce the antibody response to vaccines and (4) and increase the risk of secondary malignancies. The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself.In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. The following table summarises the main attributes of intermittent and persistent immunosuppression. Please note that live vaccines are generally contraindicated in pwMS on immunosuppressive therapies. In comparison, pwMS on IRTs who have reconstituted their immune systems can tolerate and respond to live vaccines. The decision to administer live vaccines in this situation must be balanced against the risks of the vaccine. Advanced MSI have had several debates with a colleague about therapeutic targets and whether or not they are achievable. In general, many consider NEIDA an unrealistic treatment target as most of our pwMS who achieve NEIDA still have residual problems. Therein lies the problem. NEIDA refers to no evidence of ongoing inflammation. NEIDA does not refer to the reversal of previous damage, nor does it refer to the ongoing consequences of previous damage. You can only do so much with an anti-inflammatory agent, i.e. switch off inflammation, and even then, most anti-inflammatory agents don't switch off innate immune activation within the CNS, for example, activated microglia, nor do they necessarily purge the nervous system of B-cells, plasmablasts, plasma cells and their oligoclonal immunoglobulin products that are considered to plan a major role in worsening disease or smouldering MS. We can only ask so much of our current DMTs, which is why in the future we will need combination therapy strategies to target other pathways.I have previously proposed that we consider rejecting the adjective ‘progressive’ to describe the worsening disability in MS. Progression is a misnomer and means improvement. I prefer the term ‘worsening MS’, which captures the associated disability that comes with the later phases of the disease. As a community, we must accept the pathology that drives neuroaxonal loss or neurodegeneration (the pathological substrate that underlies ‘worsening MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning, long before pwMS become physically disabled. In my opinion, MS is one disease and not two or three diseases. Scientific or philosophical arguments do not back up the division of MS into several diseases. The false division of MS into several diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license in the United States based on the results of one pivotal phase 3 study. Following the abovementioned point, the division between SPMS and PPMS is also false. No pathological, genetic, imaging or other data suggests these are different entities. We, therefore, should be doing trials in both populations simultaneously. Another dogma that needs addressing is the proposal that more advanced MS is ‘non-inflammatory’. There are clinical, imaging and pathological data that show inflammation still plays a big, and probably a major, role in advanced worsening or smouldering MS. Therefore, not targeting more advanced MS with an anti-inflammatory is folly and may explain why so few single therapy neuroprotective trials have been unsuccessful. The fact that ocrelizumab has been licensed for active primary progressive MS and siponimod for active secondary progressive MS implies they will form the platform for future add-on trials. It is essential to acknowledge that reserve capacity in particular neuronal systems plays an integral part in how MS worsens. Neuronal systems with reserve capacity are more likely to recover function and hence show a treatment effect than neuronal systems in which reserve capacity is exhausted. In the latter systems, showing a treatment effect will take longer; I refer to this as therapeutic lag. These observations are explained by the length-dependent axonopathy hypothesis of worsening MS, i.e. progressive MS manifests initially in pathways with the longest axons (bladder and lower limb motor function).  Therefore, we should focus more on the arm-and-hand function as a primary outcome in pwMS who have already lost too much function in their lower limbs (EDSS>=6.0).  Once someone with MS has lost lower limb function and become a wheelchair user, they still have neuronal systems that are potentially modifiable, for example, upper limb, speech, swallowing, visual and cognitive function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. I feel very strongly about this point and have argued for future trials in advanced MS to include wheelchair users with a focus on upper limb function as the primary outcome measure. Their arm and hand function keeps pwMS independent and functioning in society. Another trend beginning to emerge is the need to use combination therapies in advanced MS. This does not necessarily exclude using two classes of anti-inflammatory therapies, provided their mechanisms of action are complementary. There are good arguments for combining agents that target innate immune mechanisms - for example, drugs that target activated glia - with a classic anti-inflammatory targeting adaptive immune mechanisms that are presumably MS-specific, for example, anti-B and anti-T cell-driven autoimmunity. However, a combination of an anti-inflammatory targeting adaptive immune responses and a neuroprotective or remyelination therapy makes the most sense. We also need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain and cognitive reserve drives the worsening of MS in older pwMS is, in my opinion, beyond doubt. What we need is some way of dissecting premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, mainly smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes, social determinants of health and a sedentary lifestyle. Despite the promise of treatments to modify the course of more advanced MS, we need to manage expectations. PwMS expect an effective treatment to restore function or return them to normal. This is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line disability progression, with a combination of anti-inflammatory and neuroprotective strategies. Although it is plausible that neuronal systems and pathways with reserve capacity can show improvement in function, it is unlikely sufficient to make predictions on future outcomes and falsely raise the hopes of pwMS. To get substantial and meaningful improvements in disability, we will need new treatments, including remyelination therapies and therapies that promote neuronal growth (axonal sprouting), new nerve connections (synaptogenesis) and plasticity mechanisms to restore function. For more information on advanced MS, I would suggest reading the MS-Selfie Newsletter ‘Getting Worse’ (2 Jul 2021).ConclusionsOver the last 30 years, the treatment and management of MS has been transformed. Who would have thought we would target NEIDA, and potentially end-organ damage, as a realistic treatment target for pwMS and define a potential MS cure? The MS community is now considering slowing down disability worsening in the more advanced stages of the disease, wheelchair users, and exploring add-on neuroprotective and neurorestorative therapies. Despite all the hype of the future, the biggest single problem we in the MS community face is slow and, in some circumstances, meagre adoption rates of innovations. Far too many pwMS remain untreated or under-treated with DMTs. In many parts of the world, this is simply due to economic factors and the unaffordability of high-cost innovator drugs. We must think of creative ways to get people living in resource-poor environments to access effective DMTs. Including three DMTs in the WHO’s essential medicines list may change this. However, this may involve compassionate-use DMT access programmes or establishing an evidence-based list of essential low-cost, off-label DMTs. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it 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 ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestTwitter / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your own healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I gave the annual Murray Bornstein Multiple Sclerosis Memorial Lecture at Dartmouth College on Friday. Murray B. Bornstein (22 November 1917 - 31 August 1995) was the principal investigator on the original COP-1 trial that eventually led to the licensing of glatiramer acetate (Copaxone) as a treatment for MS. I never met Murray Bornstein, but it is worth noting that the original COP-1 paper was published in August 1987 three months before I graduated from medical school and long before I had decided to become a neurologist. Bornstein et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med. 1987 Aug 13;317(7):408-14. Travelling to the US allowed me to see New England in the fall; New Hampshire and Vermont were beautiful, and the hospitality of my hosts was exceptional. Professor Andrew Pachner, the Bornstein Professor of Neurology, and Selma Bornstein made my stay very special. Thank you. It was both an honour and a privilege to be invited to give the lecture. Memorial lectures are usually the preserve of old farts at the end of their careers. Is this a hint? Preparing for the memorial lecture allowed me to reflect on the history of multiple sclerosis research and the direction of future MS research. My talk allowed me to share my dreams; hence, I chose the title “Preventing and Curing Multiple Sclerosis”. Both topics are dear to my heart. You are welcome to download my presentation from my slideshare folder. Preventing MSI briefly reviewed the epidemiology of EBV and MS, pointing out that EBV is almost certainly the cause of MS. EBV is necessary but insufficient to develop MS. The fact that people who don’t have EBV are protected from developing MS is one simple fact that underpins the primary EBV vaccination programme to prevent MS. I also discussed my EBV driver hypothesis and made the case for testing EBV antiviral strategies in MS. Sadly, I didn’t have time to discuss the importance of infectious mononucleosis (IM) in the pathogenesis of MS and why we need to develop treatments for IM. One hypothesis I am working on is that if we treat IM with effective antivirals and avoid the exuberant and dysfunctional immune response to EBV that occurs during IM, we may also be able to prevent MS. I haven’t discussed this IM hypothesis that widely, but it is why I am trying to shift my research focus away from MS to the virus itself. However, I am having trouble convincing funding agencies why a neurologist needs to get involved in infectious disease research. I need help. I am also asking myself whether I have enough productive years ahead of me to start a new research programme. I am turning sixty next year. Curing MSI used my usual arguments of needing to define an MS cure to be able to look for one. I presented the arguments that alemtuzumab and AHSCT, both highly effective immune reconstitution therapies (IRTs), may already cure a proportion of people with MS. They are the only treatments that prevent early end-organ damage (brain volume loss). Do you agree? I discussed the immunopathogenesis of MS, making the point that the CD40-CD40L is the critical costimulatory pathway in the pathogenesis of MS. I presented the data from the phase 2 frexalimab trial, highlighting that frexalimab may be able to reinduce immune tolerance in an antigen-agnostic way and hence switch off MS-related autoimmunity. This in itself may cure MS. In the past, I have taken flak from several colleagues about using the ‘P’ and ‘C’ words. I have been told any talk about preventing and/or curing MS raises expectations unnecessarily and will ultimately lead to disappointment. Almost all innovations in science and medicine and social and political movements start off as somebody’s dream. Why shouldn’t I have a dream? A dream of a world free of MS. Subscriptions and donationsMS-Selfie newsletters and access to the MS-Selfie microsite are free. In comparison, weekly off-topic Q&A sessions are restricted to paying subscribers. Subscriptions are being used to run and maintain the MS Selfie microsite, as I don’t have time to do it 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 me for a complimentary subscription ([email protected]).Important LinksMS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestTwitter / LinkedIn / MediumGeneral DisclaimerPlease 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 problems, please tell your own healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe

I have just returned from my summer holiday, where I had time to reflect and think about multiple sclerosis research, the practice of neurology and managing multiple sclerosis. We are at a crossroads where things are changing rapidly, mainly driven by developments in information technology. Over the next few weeks, I will cover these issues in more detail, in particular (1) the most exciting current MS research, (2) changes in the practice of neurology that will impact the diagnosis and management of MS, and (3) the unmet need in the management of MS. Catching up with some journal reading this morning, I read a perspective in the New England Journal of Medicine on the management of patients with dementia (Harrison et al. Toward Gerineuropalliative Care for Patients with Dementia. N Engl J Med. 2023 Aug 31;389(9):775-778). I was particularly struck by the following paragraph:“As things stand, Americans with dementia and their care partners face extensive care gaps and fragmentation, even if they are well-resourced and can access clinics associated with Alzheimer’s disease research centers. Specialty memory care clinics provide diagnosis and annual appointments focused on medical management; even when they are available, psychosocial supports are insufficient to address all the needs of patients. In interviews, persons with dementia and their care partners described their need for adaptive support in managing progressive changes in distressing behavioral symptoms, function, and social connections. Interviewees said they wanted prognostic information and anticipatory guidance specific to dementia to inform their treatment decisions, financial planning, home adaptations, and transitions between settings.”This perspective could have been written about multiple sclerosis. The issues people with MS have regarding their long-term management are not too dissimilar to patients with Alzheimer’s or dementia. Yes, people with MS (pwMS) “want prognostic information and anticipatory guidance specific to MS to inform their treatment decisions, financial planning, home adaptations, and transitions between settings”. This paper is a call to arms for the holistic management of dementia. Using MS-Selfie as a platform, I have been calling for something similar for pwMS.  I know that most MS centres primarily focus on diagnosis and MS disease-modifying therapies and have too little time and resources to manage many of the symptoms of MS. MS-related symptomatic problems are numerous and often require additional input from allied healthcare professionals. This often leads to disjointed care. One way of addressing fragmented care pwMS have to deal with is by giving them the knowledge and tools to self-manage their symptoms. However, self-management is easier said than done. Despite writing MS-Selfie Newsletters about many of the symptomatic problems pwMS suffer from, many readers and subscribers still ask questions I have previously covered. In other words, the dissemination of information is not sufficient. To address this, I plan to start an online MS-Selfie self-management course. However, this course will need to do more than disseminate information.  Therefore, I am considering designing self-management flowcharts or algorithms that will allow you to do as much as possible before asking for help from an HCP. Would self-assessment and self-management flowcharts for MS-related symptoms be helpful? Regarding MS, three core symptoms that tend to be poorly managed in clinical practice are insomnia, fatigue and cognitive problems. When these symptoms are systematically assessed, the assessments often cover almost all other MS-related symptoms, so I would want to focus on these problems first. Do you agree?Before embarking on a large body of work to create an MS-Selfie clickthrough self-management algorithm for each of these symptoms, I would appreciate your input on whether or not you think it is worth it. Am I reinventing the wheel? Have you found other resources helpful in this area? If yes, please share them. I would prioritise sleep. Poor sleep is an integrator of many of the symptomatic problems associated with MS. Sorting out MS-related sleep problems will catalyse the holistic management of MS. For example, you can only tackle MS-related fatigue and cognitive problems once you sleep well. Do you agree? For background reading, I suggest my previous MS-Selfie Newsletter on sleep (‘Are you sleep-deprived? 18-Aug-2021).Subscriptions and donationsMS-Selfie newsletters and the microsite are free; only weekly off-topic Q&A sessions are restricted to paying subscribers. I can't run and maintain the MS Selfie microsite myself as I don’t have enough time, hence the need to pay people to help do the work. If people want to ask medical questions unrelated to the Newsletters or Podcasts, they must be paying subscribers. However, if you can’t afford to become a paying subscriber, please email a request for a complimentary subscription ([email protected]).MS-Selfie micrositeDonations to MS-SelfieProf. G’s Backstory and CVProf. G’s MS Blog ArchiveConflicts of InterestTwitter / LinkedIn / MediumGeneral Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit gavingiovannoni.substack.com/subscribe