Lab Lessons – Prof G's MS Blog Archive

HPV vaccination reduces cervical cancer by up to 90%

Barts-MS rose-tinted-odometer: ★★★★★
(Cancer Pink Thursday #ffbfc3)

News, news, news!

In fact, great news (see Lancet paper below)! HPV vaccine cuts cervical cancer rates by close to 90%, using the new polyvalent HPV vaccine (Gardasil-9), which clovers 9 HPV strains. This stunning bit of innovation doesn’t address the other benefits of preventing HPV infection, which include preventing penile, anal, nasopharyngeal and oesophageal cancers not to mention the simple wart.

So what to advise pwMS about the HPV vaccine?

The HPV vaccine prevents infection with the sexually transmitted human papillomavirus (HPV) which is known to cause cervical cancer and several other cancers.

Cervical Cancer: Screening, Recognition, and Treatment — Cervical cancer: image Medscape.

If you decide to go onto an immunosuppressive therapy, in particular, potent immunosuppressive therapies. The suppression of your immune system allows viruses to escape and to start replicating. This is a particular problem with alemtuzumab and potentially HSCT. So there is a strong augment to get yourself vaccinated, or to upgrade your immunity from the quadrivalent to the polyvalent vaccine, before starting a potent IRT and other immunosuppressive therapy.

HPV is not only a problem for women. HPV is a well-established cause of penile and anal cancer and causes a small proportion of throat and oesophageal cancers. Therefore it makes sense for males to be vaccinated against HPV as well.

The epidemiology of HPV infection is also changing. People are becoming infected later in life and are spreading the virus. Social media and dating apps have revolutionised the dating world and many older people are becoming promiscuous and are having unsafe sex later in life. As a result of this, there has been a large increase in the incidence of sexually transmitted diseases in older people, including HPV infections. This has prompted some commentators to suggest that public health officials extend the HPV vaccine to all women and possibly all men. Why wouldn’t you want to reduce your risk of getting cervical cancer? Isn’t prevention better than having to treat HPV infection and its downstream effects, i.e. premalignant cervical lesions or cervical cancer?

Warts and all – The MS-Blog — Cutaneous warts

Question 1: If I have been vaccinated with the older quadrivalent vaccine could I receive the new vaccine to cover the other strains of the virus?

Yes, there is data that shows that the previous vaccination against HPV doesn’t stop your immune system from responding to the components that cover the new strains.

Question 2: As I am on a DMT can I have the HPV vaccine?

This all depends on the DMT you are on. For the non-immunosuppressive immunomodulators such as interferon-beta, glatiramer acetate and teriflunomide vaccination is unlikely to be a problem. Similarly for the fumarates, natalizumab, cladribine and alemtuzumab the level of immunosuppression and the window of vaccination are unlikely to affect vaccine responses. However, based on the COVID-19 vaccine studies if you are on an S1P modulator (fingolimod, siponimod, ozanimod or ponesimod) or an anti-CD20 (ocrelizumab, ofatumumab, rituximab) the response to the HPV vaccine is likely to be blunted.

Question 3: I need to start a DMT, but I want to have the HPV vaccine or extend my cover with the new polyvalent vaccine, how long will I need to wait before I can start treatment?

The polyvalent vaccine at the moment requires 2 or 3 doses with the last dose given at 5 or 6 months. Ideally, to give your immune system a chance to respond to the vaccine you will need to wait until 4 weeks after the final booster, i.e. 6 or 7 months.

Question 4: 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 untreated MS. In relation to the IRTs, 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 potentially get depleted and depending on the intensity of the immunodepletion may not recover. For maintenance DMTs, in particular, the S1P modulators and anti-CD20 therapies you should probably delay starting treatment to have the vaccine.

Question 5: If I want the new polyvalent vaccine will the NHS cover it?

At present, the answer is no. The UK is in the process of switching from the quadrivalent (Gardasil-4) to the polyvalent vaccine (Gardasil-9) under the national vaccine programme. At present, if you want to be vaccinated against HPV you will have to cover the costs of the vaccine yourself. This is not too dissimilar to what happens with travel vaccines.

I predict that HPV vaccination is going to be one of those factors that have to be put in the mix when deciding which is the correct DMT for you. It is not a major factor but is an important factor nevertheless. I have only just started to routinely discuss this topic with my patients. It clearly has future health implications.

What is your view on this? Do you think MS healthcare professionals should be obliged to discuss issues around HPV vaccination before pwMS start a DMT?

Falcaro et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. The Lancet 2021:November 03.

Background: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12–13 years with a catch-up programme for females aged 14–18 years in 2008–10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations.

Methods: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20–64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders.

Findings: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25–41) for age 16–18 years (school year 12–13), 62% (52–71) for age 14–16 years (school year 10–11), and 87% (72–94) for age 12–13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36–41) for those offered at age 16–18 years, 75% (72–77) for age 14–16 years, and 97% (96–98) for age 12–13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339–556) fewer than expected cervical cancers and 17 235 (15 919–18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England.

Interpretation: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12–13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

EBV: is it time to pluck the black swan?

Barts-MS rose-tinted-odometer: ★★★★★
London Gray & Raining #666677 #C4D3DF

SEPSEPIEN a commentator this morning said: “Would have been more rewarding to find a DMT that successfully addresses the causes of MS”. I agree and I really think we have found the cause of MS. It is Epstein Bar Virus (EBV). The epidemiology is pretty convincing that EBV acts in the MS causal pathway and all of our effective i.e. licensed DMTs work on memory B-cell where the latent EBV virus resides.

The piece on my #1 ECTRIMS-2021 highlight, i.e. the MRI changes in relation to treatment with Atara Bio’s anti-EBNA1 allogeneic CTLs (cytotoxic T-cells), has resulted in at least ten emails from business analysts wanting to speak to me about the product. I think it is my reference to a ‘Black Swan’ that piqued their interest. What they don’t realise is that when you pluck a black swan it looks just like a plucked white swan.

So if Atara Bio gets their product to market they will get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents. What do I mean?

Rituximab (anti-CD20) is licensed to treat EBV-associated lymphoproliferative disorders. Peripheral EBV viral loads plummet when you administer anti-CD20 therapies. In other words, anti-CD20 therapies are anti-EBV drugs so why would you need to use an expensive cellular therapy? To get into the CNS. Step up the CNS penetrant BTK inhibitors.

Ibrutinib the first licensed BTKi is a potent anti-EBV drug and works very well against EBV-associated lymphomas including CNS lymphomas. EBV in fact uses BTK as a signalling molecule to bypass B-cell receptor-mediated cell cervical signals.

MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery with the exception of natalizumab that blocks trafficking of memory B-cells into the CNS.

So all it will take for Big Pharma to pluck Atara Bios black swan is for them to produce data showing how their DMTs impact EBV viral infection in the periphery and potentially in the CNS. The frustrating thing for me is I have been trying to get Pharma to do these studies for decades. Just maybe with a black swan soaring up above they may start to listen. I suspect some of the companies have data on this already.

The good thing that Atara Bio has done is to move EBV centre stage. So maybe now we will get some momentum behind our EBV vaccination study off the ground.

For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study. It is almost too good to be true, which is why I referred to it as the Lazarus effect.

Plucked Swan | monsieurpolk — A plucked swan; was it a black or white swan?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50.

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

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#ECTRIMS2021: no loss of effectiveness with 6-weekly natalizumab

Barts-MS rose-tinted-odometer: ★★★★★
Lime green and purple Thursday, #32cd32 & #6a0dad

If you are on natalizumab and are JC virus seropositive, you are at increased risk of developing PML (progressive multifocal leukoencephalopathy). If you transfer from 4-weekly infusions or standard interval dosing (SID) to 6-weekly or extended interval dosing (EID) you reduce the risk of getting PML by close to 90%.

Does shifting from SID to EID affect the efficacy of natalizumab? In short NO.

The following data was presented at ECTRIMS 2021 and should reassure both patients and HCPs

The NOVA trial was designed to estimate the difference in efficacy between EID and

SID dosing in a population that was clinically stable on SID dosing.

Although a small difference in efficacy between EID and SID dosing was estimated for the primary endpoint (number of new or newly enlarging T2 lesions at week 72) this was driven by two subjects in the EID arm with very high lesion values. The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity. The other subject had 25 lesions at week 72 and was subsequently diagnosed with asymptomatic progressive multifocal leukoencephalopathy (PML). The latter could have been PML lesions and not MS lesions.

When you exclude these 2 patients or outliers there is no difference in the primary endpoint between EID and SID. This study shows that patients who are stable on natalizumab SID dosing can switch to EID dosing without a meaningful loss of efficacy.

I hope you now feel confident enough to switch from SID to EID without worrying about rebound or loss of efficacy.

Foley_NOVA_ECTRIMS2021_P970_Final

Foley et al. Primary results of NOVA: a randomized controlled study of the efficacy of 6‑week dosing of natalizumab versus continued 4-week treatment for multiple sclerosis. ECTRIMS 2021, P970.

Background: Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsingremitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. Real-world data suggest similar effectiveness, but NOVA is the first randomized trial to assess Q6W efficacy.

Objective: Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.

Methods: NOVA is a randomized, contro led, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W arms. The primary endpoint was number of new/newly enlarging T2 (N/NET2) hyperintense lesions analysed by negative binomial regression with baseline (BL) weight, prior natalizumab exposure, and region as covariates. Secondary endpoints included relapses and 24week confirmed disability worsening (CDW). Primary estimand used a l observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.

Results: 195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. BL characteristics were wel balanced. Proportions of patients with N/NET2 lesions among observed data were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. The difference was mainly due to 2 Q6W patients with high values: (1) 30 lesions that occurred 3 months after natalizumab discontinuation and (2) 25 lesions that occurred with asymptomatic PML observed at week 72. The sum of a lother N/NET2 lesions in NOVA was 18 with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were consistent with the known drug profile and similar between groups.

Conclusions: Despite a sma l difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinica ly meaningful loss of efficacy. No conclusions on PML risk can be drawn from NOVA.

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#ECTRIMS2021: Do you have inactive SPMS? How often are you having an MRI?

Barts-MS rose-tinted-odometer: ★★★★

Gray & White MRI Friday #808080

When we interrogated a large number of pwSPMS we discovered that what really determines if you have active vs. inactive SPMS is how frequently you have an MRI scan. The more frequently you get scanned the more likely your team are to find new MRI lesions. If you rely on having a clinical relapse you may wait a long time. For example, after 2 years of no relapse and no MRI activity, disease activity returned in >50% of previously inactive pwSPMS. However, in 4 out of 5 cases this was driven by MRI activity and not by having a relapse.

Based on the observation that many pwSPMS have reduced MRI monitoring this decreases the chances of detecting and potentially treating and preventing disease activity in pwSPMS.

For those of you who have been told you have inactive SPMS and are ineligible for treatment, you need to ask has my MS been looked at in enough detail?

Giovannoni et al. MRI activity versus relapses as markers of disease activity in SPMS: Data from real world and pivotal clinical studies. ECTRIMS2021 P001.

Introduction: Secondary progressive multiple sclerosis (SPMS) is often categorised as active (aSPMS) or non-active (naSPMS) based on the evidence of disease activity (relapses and/or magnetic resonance imaging [MRI] activity).

Objectives: To evaluate the contribution of MRI activity and relapses in defining disease activity in SPMS patients by analysing real-world data from Adelphi real-world MS Disease Specific Programme (Adelphi MS DSP) and to understand whether aSPMS and naSPMS are mutually exclusive groups based on data from the Phase 3 EXPAND study.

Methods: Adelphi MS DSP was a non-interventional, multinational real-world study consisting of 37,318 MS patients that includes 3580 patients with SPMS who were surveyed between 2011–2019. Patients were categorised into aSPMS (≥1 new lesion on the most recent MRI and/or ≥1 relapse in the last 12 months) and naSPMS groups. In the EXPAND study, disease activity (aSPMS) was defined as presence of relapses in the 2 years prior to screening and with/without ≥1 gadolinium-enhancing (Gd+) T1 lesion at baseline. Demographics, MRI and relapse status were analysed descriptively.

Results: Patients with SPMS from the Adelphi MS DSP were categorised as aSPMS (n=1889) and naSPMS (n=665). Disease activity (aSPMS) was defined on the basis of MRI lesions (59.1%), relapse status (12.6%), and both MRI and relapse (28.3%). In the past 12 months, aSPMS (vs naSPMS) patients had a lower mean Expanded Disability Status Scale score (4.6 vs 5.2), a higher proportion of patients undergoing MRI (87.7% vs 58.7%), and more MRIs per patient (1.24 vs 0.87). A greater proportion of naSPMS (vs aSPMS) patients were without treatment (45.1% vs 23.4%). In EXPAND, 52.6% of patients (n/N=866/1645) who had no relapse in the 2 years prior to screening and no Gd+ T1 lesions at baseline were categorised under naSPMS; of these naSPMS patients who were on placebo, 52.7% experienced on-study relapse and/or MRI activity: MRI (41.8%), relapses (4.6%), and both MRI and relapse (9.2%).

Conclusions: In both real-world and clinical studies, MRI activity appears to be a more sensitive measure of disease activity versus relapses. Even after 2 years of no relapse and no MRI activity at baseline, disease activity returned in >50% of previously ‘non-active’ patients on placebo in EXPAND. Further, reduced MRI monitoring in ‘naSPMS’ patients in the real world is a concern, which decreases the chance to detect and treat any new disease activity in these patients.

Some pointed out to me yesterday that they thought it was quite cool that I was P001; I think they were drawing an analogy to 007, but let’s not go there 😉

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Should we reclassify MS as a sleep disorder?

Barts-MS rose-tinted-odometer: ★★ (Dark blue sleepy Friday #00008B)

The study below is another demonstration of how MS affects sleep. Sleepiness, abnormal sleep timing, and poor sleep quality is just the tip of the iceberg. Two-thirds of subjects were in the extreme ranges in at least two sleep domains studied. Worryingly, markers of sleep disruption were associated with more depressive symptoms, fatigue and cognitive function.

The problem is that most routine MS consultations rarely address sleep and sleep quality. How do you diagnose and manage MS fatigue in pwMS without knowing about sleep hygiene and architecture? Isn’t this an example of why we need to transform the management of MS with routine remote home sleep assessments?

How many of you have had sleep assessments?

Whibley et al. A multidimensional approach to sleep health in multiple sclerosis. Mult Scler Relat Disord. 2021 Sep 20;56:103271.

Background: Although sleep disturbances are common among people with Multiple Sclerosis (PwMS), understanding of their impact has been stymied by limitations in approaches to sleep measurement within this population. The aim of this study was to comprehensively phenotype sleep patterns in PwMS through application of an emerging seven-domain framework that includes sleep duration, continuity, timing, quality, rhythmicity, regularity, and sleepiness.

Methods: Sleep domains were estimated from wrist-worn accelerometry, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index responses. Extreme sleep values within each domain were constructed using previously published guidelines. A composite score of extreme values was calculated for each participant. Associations between sleep domains and severity of MS symptoms were explored (pain, fatigue, depressive symptoms, and cognitive dysfunction).

Results: Among n = 49 participants, median total sleep time was 456.3 min. Median time spent awake after sleep onset was 37 min. Sleepiness, abnormal sleep timing, and poor sleep quality affected 33%, 35%, and 45% of participants, respectively. Seventy-six percent had ≥2 sleep domains in extreme ranges. PwMS had longer sleep duration and decreased sleep regularity compared to a non-MS historical cohort of older men. Greater daytime sleepiness, poorer sleep quality, and higher composite sleep health score were associated with more depressive symptoms, and lower sleep rhythmicity was associated with higher fatigue. Associations were observed between measures of cognitive function and sleep fragmentation, duration, quality, rhythmicity, and composite score.

Conclusion: Application of a seven-domain sleep health framework that captures the dynamic and multifaceted aspects of sleep is feasible in PwMS, and offers potential for an improved understanding of the scope and impact of sleep disturbances in PwMS.

Conflicts of Interest

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More evidence to support the smouldering MS hypothesis?

Barts-MS rose-tinted-odometer: ★★★★★ (neon tennis ball green #dfff4f)

Yet another study showing that there are abnormalities in the so-called normal-appearing white matter (NAWM) that precede the development of new MS lesions.

This supports the hypothesis that there is something in the brain tissue that triggers the development of lesions and relapses. Could this be a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when pwMS were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. 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 a fundamental observation 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 and 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 is what 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 simply IRIS in response to the virus that causes MS.

Other serial MRI studies have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears.

These studies all suggest that the primary pathology is smouldering MS and is due to something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The inflammation is secondary to what is causing the disease. The challenge for us all is to find out what the abnormality is that is causing these changes in the NAWM. I think 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. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post of mine from 2012 on this subject.

Well done to Emma Raducanu, whose US Open victory was a joy to watch. But best of all is her Twitter bio which contains just four words “london|toronto|shenyang|bucharest”. Another example of the pros of diversity, similar to the author list of the paper below “Colm Elliott, Parya Momayyezsiahkal, Douglas L Arnold, Dawei Liu, Jun Ke, Li Zhu, Bing Zhu, Ilena C George, Daniel P Bradley, Elizabeth Fisher, Ellen Cahir-McFarland, Peter K Stys, Jeroen J G Geurts, Nathalie Franchimont, Arie Gafson, Shibeshih Belachew”.

Elliott et al. Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise.

Brain Communications, Volume 3, Issue 3, 2021, fcab176.

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.

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C-sections: how common are they in women with MS?

Barts-MS rose-tinted-odometer: ★★ (Indian summer orange #FF7722)

I have always said that women with early MS who start and extend families should have no reason to worry about additional problems with their pregnancy and childbirth because. It may be different for women with more advanced MS who are disabled. Maybe I should revise this general advice based on the study below.

In this study, 15 women with MS had 16 children. The cesarean section rate was 14 out of 16 deliveries or a staggering 87.5% of pregnancies. The main reason for C-sections was given as chronic fatigue and neurological deficits. The latter is interesting in that the mean disease duration of this cohort was less than 10 years with an average EDSS of 2.0. I suspect this cohort is biased and recruited women with MS via a high-risk clinic or an obstetric unit.

These results are incongruent with my experience as an MSologist. What about you? If there are any women with MS reading this post who have had children after being diagnosed with MS did you have a natural vaginal delivery, assisted delivery or a C-section?

Biringer et al. Fatigue as the limiting factor for vaginal birth in patients with multiple sclerosis. Neuro Endocrinol Lett. 2021 Aug 28;42(4):222-228.

Objectives: Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease. This study evaluated pregnancy-related issues in patients with MS in one perinatological centre.

Material and methods: A single-centre, retrospective study of the perinatal period in patients with MS admitted at the Dpt. of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University and the University Hospital in Martin, Slovak Republic, European Union from January 1, 2015 to December 1, 2020 was performed. Selected parameters from personal, obstetric, and neurological histories were analysed.

Results: A cohort of 15 patients (32.5±5.3 years) with a relapsing-remitting form of MS gave birth to 16 children. The mean length of MS at the time of delivery was 9±3.6 years. The severity of the Expanded Disability Status Scale score was 2.0±1.5. Caesarean section (CS) was indicated in 14 deliveries (87.5%). It was elective CS in 10 patients. The most common indication for elective CS was a combination of significant chronic fatigue syndrome and neurological deficit (paresis).

Conclusions: The basis for the management of pregnancy, childbirth, and the postpartum period in women with MS is a planned pregnancy based on close cooperation among patients, gynaecologists, and neurologists. Vaginal delivery is not primarily contraindicated. Indications for CS should be considered individually. One way to minimise the indications for CS is a more accurate diagnosis and personalised treatment of fatigue in pregnant women with MS. Presumably, both obstetricians and neurologists prefer vaginal delivery as the first choice in patients with fatigue syndrome.

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How demyelinated are my MS lesions?

Barts-MS rose-tinted-odometer: ★★★★★ (Vermillion Monday code #E34234)

There are very few what I call really deep-thinkers in MS research and Danny Reich is one of them. This paper from his group is so simple in its inception and execution; it is a fine example of seeing the woods for the trees. They use a relatively simple MRI technique to interrogate MS lesions to classify them as being remyelinated, demyelinated or mixed.

Using an MRI sequence they classify MS brains lesions as being “long-T1,” “short-T1,” and “mixed-T1”, which correspond to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively. Neat? You bet it is neat. Demyelination, rather than axon loss, dominantly contributed to initial T1 prolongation, which is a metric from the TI relaxation time* on imaging.

*T1 is the so-called longitudinal relaxation time and is the time constant that determines the rate at which excited protons return to equilibrium. It is a measure of the time taken for spinning protons to realign with the external magnetic field.

Short-T1 or remyelinated lesions were most common in the deep white matter, whereas long-T1/demyelinated and mixed-T1/demyelinated-remyelinated lesions were more common in lesions next to the cortex (juxtacortical) and ventricles (periventricular) and were much more likely to have paramagnetic or iron rims suggesting chronic inflammation. The latter are the so-called slowly expanding lesions that are one of the drivers of smouldering MS.

Please note older age at the time of lesion formation meant less remyelination, which is another reminder that as you get older your recovery mechanisms fail.

The question is whether or not this simple technique can be used as an outcome measure in trials and/or to profile pwMS for remyelination studies. There is little reason to load remyelination trials with patients who are not going to be able to respond to remyelination treatments. What about using this technique as a prognostic tool? Is there a biological reason, apart from age, why some pwMS remyelinate and others don’t?

Could this technique be used to supplement evoked potentials to assess whether or not a condition is demyelinating, i.e. as an aid to help make a diagnosis of MS?

You know a paper is good when it leaves you asking more questions than it answers.

Kolb et al. 7T MRI Differetiates Remyelinated from Demyelinated Multiple Sclerosis Lesions. Ann Neurol. 2021 Aug 14.

Objective: To noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7-tesla postmortem and in vivo MRI.

Methods: Using the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as “long-T1,” “short-T1,” and “mixed-T1” by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes.

Results: Postmortem, lesions classified qualitatively as long-T1, short-T1, and mixed-T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short-T1 lesions were most common in the deep white matter, whereas long-T1 and mixed-T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007).

Interpretation: 7-tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time.

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How important is your brain volume?

Barts-MS rose-tinted-odometer: ★★★★★ (A blue sky and sunflower yellow Tuesday; #87CEEB #ffda03)

I bang on about treating-2-target beyond NEIDA (no evident inflammatory disease activity) and targeting the end-organ, i.e. to try and normalise brain volume loss (BVL). The aim is to get pwMS to old age with a healthy brain so that they can age normally. Who wants to be at risk of premature ageing and being demented earlier than you have to be?

When it comes to BVL, not all DMTs are made equal. At the top of the ladder are HSCT and alemtuzumab, then natalizumab. Behind these come the anti-CD20 therapies, the S1P modulators, cladribine, teriflunomide and the also-rans.

In the smallish real-life study below pwMS who have been on natalizumab for at least 2 years appear to lose brain volume at a similar rate as normal controls. I wonder what would happen over a longer period of time? Natalizumab is very effective but it does not necessarily get on top of smouldering MS, so some patients will be doing better than others. Don’t be lulled into a sense of security by the average effect; 50% of people do worse than average (median) and 50% of people do better than average (median).

Please be aware that BVL is complicated with many physiological (day-2-day), biological (age), disease factors(duration, level of disability, lesion load, comorbidities) and other Influences (e.g. genomic factors) affecting the brain volume and rate of BVL. Despite BVL not being assessed in routine clinical practice, it is one of the metrics that need to be taken into account when choosing your DMT. Just maybe BVL should be the most important factor to consider in terms of efficacy? What do you think?

Yes, the volume of your brain predicts disability outcomes, cognition and how well you will do in old age.

Alvarez et al. Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls. Mult Scler Relat Disord. 2021 Jul 24;55:103170.

Background: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs).

Methods: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms.

Results: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups.

Conclusion: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

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Does MS exile you from the everyday of life?

Barts-MS rose-tinted-odometer: ★★★★★ (Sunday or Summer orange #f99f00)

Exercise has emerged as a safe, effective, low-cost, non-pharmacological intervention for managing disability experienced by pwMS. Despite the evidence, it is the most under-prescribed and under-utilised disease-modifying therapy we have at our disposal.

Exercise promotes improvements in aerobic capacity, muscular strength, balance, walking performance, and gait kinematics, whilst it also reduces fatigue, depression and anxiety.

The meta-analysis below asks whether exercise training increases participation in everyday life, such as carrying out daily tasks and self-care, walking and movement, interpersonal relationships, and recreation and leisure. Are you surprised that the answer is YES?

EXERCISE INCREASES PARTICIPATION!

So for those of you who are letting ‘MS exile you from the everyday of life’ I would advise trying exercise to help you re-engage with the everyday.

Do any of you have any personal anecdotes that you can share with us about how exercise has changed your life?

Edwards et al. Exercise training improves participation in persons with multiple sclerosis: A systematic review and meta-analysis. Review J Sport Health Sci. 2021 Jul 26;S2095-2546(21)00089-2. doi: 10.1016/j.jshs.2021.07.007.

Objectives: While previous studies have examined the effects of exercise training on other International Classification of Functioning, Disability and Health (ICF) component levels in persons with multiple sclerosis (MS), the effects of exercise training on participation remains unclear. The objectives of this review were to: (1) systematically characterize the use of outcome measures that capture participation in exercise training studies; (2) quantify the effect of exercise training on participation in persons with MS.

Methods: A search of 6 electronic databases (CINAHL, Sport Discuss, EMBASE, MEDLINE, Cochrane Central, Scopus) was conducted to identify controlled and non-controlled trials involving exercise training and participation in persons with MS. Search strings were built from Medical Subject Headings (MeSH) and “CINAHL headings”. ICF linking rules were used to identify participation chapters and categories captured. Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials (RCTs) comparing exercise effects to no intervention/usual care.

Results: Forty-nine articles involving controlled and non-controlled exercise trials were included in the systematic review of outcome measures. Sixteen different outcome measures that captured all 9 participation chapters and 89 unique participation categories were identified. Across these 16 outcome measures, “mobility” was the most represented participation chapter, with 108 items. A subsample of 23 RCTs were included in the meta-analysis. An overall effect of 0.60 (standard error = 0.12, 95% confidence interval: 0.37-0.84, z = 4.9, p < 0.001) was calculated, indicating a moderate, positive effect of exercise training on participation.

Conclusion: The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS. Exercise training has a positive effect on outcomes that capture participation, providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.

Keywords: ICF framework; exercise training; multiple sclerosis; participation.

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