Category: Symptoms and treatments

Should we deny non-whites access to DMTs?

A question about whether or not currently licensed DMTs are effective in African-Americans has arisen. Why?


Lack of evidence does not mean lack of efficacy. 



If you are a non-Caucasian pwMS you will become disabled quicker than your Caucasian counterparts. The evidence that so-called ‘non-whites’, which includes African-Americans, Africans and Asian do worse than ‘whites’ is pretty well accepted. However, most of this data was derived from the pre-DMT and 1st-generation, or injectable (IFNbeta and GA), DMT eras. The question of whether or not the same now holds true in the post-Natalizumab era is unclear. 


Jagannadha Avasarala suggests in an editorial below that we should question the assumption that licensed DMTs work in these populations because we don’t have the necessary data to support our assumptions. Why? Simply, because there are too few African-Americans, Africans and Asians in the pivotal phase 3 trials to do sub-group analyses and answer the question he has proposed (see OPERA I & II data below). 

These issues also apply to paediatric or childhood MS. In response to the latter, the FDA and EMA now mandate as part of the licensing process that Pharma have to do paediatric trials as part of their post-marketing commitments. Should the regulators be doing the same for the ethnic minority groups? Maybe, but this would come at a cost. Post-marketing commitments are expensive and their costs are built into the drug pricing. Do we want more expensive DMTs? A better solution would be to rely on real-world evidence collected in a systematic way via national and regional registers. I have little doubt that registry data will be able to tell us if ‘non-white’ pwMS respond or not to DMTs. 


This editorial will not change our practice. We treat people with active MS who are from ethnic minorities in the same way we treat Caucasian pwMS. Why wouldn’t we? Lack of evidence does not mean lack of efficacy. In my experience pwMS who are from an ethnic minority background respond as well to high efficacy DMTs in terms of treating-2-target of NEDA than Caucasian pwMS. What tends to happen is that they are more likely to end up at the top of the treatment pyramid on one of the monoclonals. The reason for this is that they probably need these higher efficacy DMTs because they have more active MS. Should we rely on anecdotes? Probably not, I suggest we and others audit our data and get back to you on this specific question. 

Avasarala. FDA-approved drugs for multiple sclerosis have no efficacy or disability data in non-Caucasian patients. CNS Spectr. 2019 Jan 3:1-2. doi: 10.1017/S1092852918001517.

Pharmacotherapy of multiple sclerosis (MS) is evolving rapidly. Despite impressive gains over the past 2 decades in the approval of multiple drugs for MS, lack of recruitment of minorities with MS in phase 3 clinical studies is a persistent concern and skews efficacy and disability data.


CoI: multiple

Do you suffer from alexithymia?

What has alexithymia got to do with having MS?



In fact quite a lot; it is something pwMS should take note of. 

Alexithymia. : inability to identify and express or describe one’s feelings. Note: People with alexithymia typically display a lack of imaginative thought, have difficulty distinguishing between emotions and bodily sensations, and engage in logical externally oriented thought.

Don’t worry if you had never heard of alexithymia before; nor had I until reading and reviewing the article below. MS causes alexithymia, which is not surprising, The ability to identify and express one’s feelings is a cognitive task and as MS causes cognitive impairment it must impair this function in a subset of pwMS. 

Alexithymia is a personality trait that can be found in more than half of pwMS. The study below and other data show that alexithymia is associated with MS-related fatigue. Alexithymia can be assessed using a questionnaire. You can complete an alexithymia screening tool online. You can also assess your levels of MS-related fatigue using the online Modified Fatigue Impact Scale (MFIS) calculator. I would be interested to see if we can confirm these results. 


The questions that need to be asked is alexithymia irreversible; or is it potentially reversible as has been shown with other cognitive impairments in MS? Is there a specific part of the brain where a single lesion can cause alexithymia; in other words can a single MS lesion in a strategic area cause alexithymia as part of a relapse? 

Alexithymia is associated with damage to the limbic system and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor areas. It appears that alexithymia is another cognitive symptom that is associated with MS-related damage. Therefore, to prevent developing alexithymia we need to treat MS early and effectively; i.e. to turn off the shredder before it causes irreversible damage. 

Chalah et al. Neurophysiological, radiological and neuropsychological evaluation of fatigue in multiple sclerosis. Mult Scler Relat Disord. 2018 Dec 21;28:145-152.

BACKGROUND: Fatigue is a multifactorial symptom frequently reported by multiple sclerosis (MS) patients. To date, the pathophysiology of MS fatigue remains poorly understood and little is known about the relationship between this symptom and various clinical, neuropsychological, neurophysiological and radiological data. The aim of this work is to understand the underlying mechanisms of MS fatigue by means of a multidimensional evaluation.

 METHODS: Fatigued (n = 21) and non-fatigued (n = 17) MS patients were enrolled based on the Modified Fatigue Impact Scale. They underwent clinical (disability score and disease duration), neuropsychological (scales of depression, anxiety, alexithymia, sleep, and Symbol Digit Modalities Test), neurophysiological (corticospinal excitability measures using transcranial magnetic stimulation), and radiological (volume-based morphometric magnetic resonance imaging) evaluations. The normality of data distribution was studied by the Kolmogorov-Smirnov test. Group comparison was performed using the Mann-Whitney or Student t test (quantitative data) and the exact Fisher’s test (qualitative data). Correlation analysis was done using Pearson and Spearman tests.

 RESULTS: Fatigued patients had higher depression (p = 0.02), anxiety (p = 0.02) and alexithymia (p = 0.04) scores compared to non-fatigued patients. On the neurophysiological and radiological evaluations, they also had higher short-interval intracortical inhibition (p = 0.04), larger caudate nuclei (p ≤ 0.01) and smaller left parietal cortex (p = 0.01). These findings were in line with the correlation analyses results.

 CONCLUSION: The neuropsychological findings suggest common underlying mechanisms as well as bi-directional relationships between fatigue and each of anxiety, depression, and alexithymia. The neurophysiological findings may reflect maladaptive neuroplasticity processes and an aberrant GABAergic transmission in the generation of fatigue. The radiological findings could be interpreted in the light of the ‘dysfunctional hypertrophy’ or ‘compensatory hypertrophy’ hypotheses.

Happy New Year: some reflections on 2018

Happy New Year! In response to a comment yesterday I produced the following overview of some of Barts-MS’ activities for 2018. It makes me very proud to be part of the team and I would like to thank them all for all their hard work and perseverance.


I would like to think of 2018 as the year of the #HashTag.

Some of our long-running social media campaigns have started to deliver returns on the time and effort that have gone into them. All of these have been linked to a particular #HashTag.


In short Barts-MS’ 2018 activities can be classified into five categories which are research, services, policy, education and PPI (patient-public involvement).


1. Research


#ThinkHand – We continued to make a strong case for our #ThinkHand campaign with numerous research outputs. These are all being used to support further work in this area. I am the principal investigator for ORATORIO-HAND a phase-3b study of ocrelizumab in PPMS that will include patients with an EDSS of up to 8.0. The primary outcome is the 9-HPT. In parallel, DrK has been working hard to get an NIHR funded trial off the ground called CHARIOT-MS. DrK has shepherded the grant through round 1 and is waiting to hear whether or not the study will get funded. CHARIOT-MS is a study of oral cladribine in advanced MS targeting both SPMS and PPMS with the primary outcome being the 9HPT.  If there is one person in our group who deserves an award for resilience and perseverance it is DrK; he has doggedly stuck to the task. There will be much celebration at Barts-MS if he gets his just rewards for all his hard work over the last few years. More importantly, CHARIOT-MS will become a beacon of hope for people with advanced MS.


#SelfMonitoring – Nicholas Dubuisson completed a herculean meta-analysis to analyse inclusion criteria used for progressive MS trials. In summary, it shows what a mess the field is in when it comes to identifying who is worsening or progressing prior to being recruited into progressive clinical trials. We have used this meta-analysis to make the case for using self-monitoring to document worsening in the 12-24 month prior to trial recruitment. In response to this, we have been gradually building our suite of online web apps to empower and activate the MS community to do just this.


#under&over – Alison our design researcher developed a hand and upper limb rehabilitation tool called under&over, which was launched at ECTRIMS2018 in Berlin. Alison has been successful in getting a grant to test whether or not under&over will work as a remote rehab tool.


#ThinkCognition – I have been pushing the concept of MS being a preventable dementia for several years and that by focusing on cognition early on in the course of the disease we would get the MS community to adopt the early-effective treatment paradigm. One hypothesis that I proposed several years ago came to fruition this year; i.e. that pwMS who are able to learn on a cognitive test do better than poor-learners. This analysis was done with Maria-Pia Sormani using the combined FREEDOMS fingolimod data set.


#ThinkSocial – You will notice some early activity from our group on social capital as a potential predictor of outcomes in pwMS. We have been very fortunate to have Saul Reyes a Colombian neurologist join us an ECTRIMS fellow for one year. Saul will be studying social capital in MS. The other excellent news is that the Horne Family Foundation has awarded us a grant to study whether or not our PPI programme increases social capital and if it does will this increase the quality of life of pwMS and reduced healthcare utilization. Ultimately, we want to be able to do long-term studies to assess whether or not increasing social capital improves outcomes for pwMS. An interesting point worth noting is that the UK government has just appointed a loneliness minister to address social isolation at a population level. I interpret this as a sign that our #ThinkSocial campaign is of the moment.


#PreventMS – The MouseDoctor and I left Queen Square to move to Barts and The London School of Medicine and Dentistry (Queen Mary University of London) in 2006. One of the main drivers for me personally was to shift my long-term research focus on MS prevention. This year saw the activation of a priming grant to set-up a Preventive Neurology Unit that includes a group working on MS. We were able to get Dr Ruth Dobson back to QMUL to lead the MS Prevention programme. We have a lot of activities planned under this banner for 2019 and beyond. We will keep you posted on developments in this space, but you can get the gist of things to come from our recent blog posts on ‘proving EBV is the cause of MS’ and ‘Why do I have MS?.. Because you have a common virus?’.


#CharcotProject – We finally got publish the results of INSPIRE trial and our #CrowdaCure EBV saliva shedding project. The saliva data has been instrumental for powering our FamV study, which we hope to start in the next few months. Please note the contrary to some commentators the #CharcotProject is alive and kicking.


2. Services


#OffLabel – We published our own experience with using off-label subcutaneous cladribine in MS and provided anecdotal evidence, using case studies, that it will work in people with more advanced MS. The latter has been vital in supporting our CHARIOT-MS grant application. Whether or not these publications will get other centres in the UK and other countries to follow our lead is a moot point. Interestingly, we have had a few centres requesting our off-label protocol so there may be the gradual rumblings of an off-label movement starting.


#AtraumaticLP – We continue to promote using lumbar punctures and CSF analysis to monitor MS. Central to this is our LP service that now only uses atraumatic or non-cutting needles to reduce the complications of LPs in particular post-LP headaches.


#EndOrganDamage – Our lab service measuring CSF neurofilament levels more than trebled last year. Sharmilee and Lucia have done a remarkable job. At least four other UK centres are regularly requesting CSF NFL levels via our laboratory. We also have the peripheral blood assay working and are part of an International consortium to validate the assay. I suspect we may move from CSF to peripheral blood monitoring very soon.


#NAbs – We are in the process of validating our anti-alemtuzumab and other anti-drug antibody assays. We know NAbs are an important issue and explain why some pwMS fail to respond to biological therapies. NAbs, in particular, those targeting alemtuzumab, are also a window into the immunology of the drug and may be telling us why pwMS treated with alemtuzumab get so many secondary autoimmune diseases. Watch this space!


3. Policy


#OffLabel & #EssentialMedicine – In 2014 whilst I was on my 6-month sabbatical we formulated the Barts-MS Essential Off-label DMT list. This was to address limited access to DMTs in resource-poor countries. Off-label subcutaneous cladribine is one of the drugs on this list. We soon realised that trying to sort out access to essential medication was a problem and task too big for Barts-MS. I was fortunate to be invited to present some of our ideas to the board of the MSIF in 2015 and as some of our ideas dovetailed with their 5-year strategy they were able to take up the challenge. I was honoured and privileged to be asked to co-chair the MSIF’s WHO Essential Medicines panel with Brenda Banwell and to help prepare and submit a proposal to the WHO to get a limited number of DMTs on the WHO Essential Medicines List. We successfully submitted an application in early December. This was a mammoth task as it involved many different stakeholders and I want to thank the MSIF for making this a reality. Fingers-crossed!  


#BrainHealth – Our Brain Health initiative turned three last year. We have continued to promote #BrainHeallth awareness in the 3-years since we launched the original policy document at ECTRIMS-2015 in Barcelona. However, as information is not sufficient to change behaviour we made progress in developing our international quality standards and have piloted them in three countries. In 2019 we will be focusing on disseminating the quality improvement tool and developing a #PatientActivation programme.


#Women4MS – In collaboration with Alasdair Coles, we highlighted the inequities in relation to women at the top table in the field of MS. Our blog posts and subsequent publication has set off a chain reaction and a response letter by female academics, who make the point that gender inequality occurs despite the availability of a substantial number of successful senior female academic neurologists and neuroscientists worldwide. DrRuth and her team have done some data trawling to highlight the problem further and these data will be published later this year.


#Run4MS – This is an initiative using parkrun programme to get pwMS and HCPs more active. #Run4MS is an ambitious, but important, initiative and is being run by the MS Trust.


#MS_is_1_and_not_2_or_3_diseases – We have continued to challenge the current dogma and promote MS as being one disease.


4. Education


#MSPreceptorship – We continue to run our MS Preceptorships that are designed to teach people about MS and the modern management of the disease.


#MSAcademy – I am the director of the MS Academy. This programme has expanded and included a meeting to tackle variance in the provision of MS Services in the UK. If you want to participate in the MS Academy please register for one of the upcoming courses.


#MS@TheLimits – I co-chaired our second MS@TheLimits meeting in London in November. Feedback from the delegates was remarkably good and we will endeavour to make this an annual event. For those of you who are interested, all the talks are now online, including Prof G taking a battering in a debate. To be fair I had to prepare my arguments in a few hours on the day of the debate as one of our debaters had to pull out at short notice.


#triMS-Online – We finally managed to get our virtual online conference started. Our first event was very well received and addressed all our objectives. The idea for this meeting was germinated and developed on this blog; so thank you. Who said social media was a one-way street? We learn as much from you as you learn from us. Please note that more than half of the steering committee of triMS.online are women and it includes many young people from all over the world; this is no accident.


#ECTRIMS2018 – We hosted a #ClinicSpeak stand at ECTRIMS; this year with a focus on #SelfMonitoring. The MouseDoctor and Sharmilee did their annual MS Hangout that is a real hoot and worth watching. We also arranged and ran the annual ECTRIMS Burning Debate. The motion debated was “The new McDonald diagnostic criteria make them difficult to use in clinical practice”. This year it was an all female event, which was to compensate for the all-male affair in 2017.


#MSFellowships – We continue to encourage and accept young trainees to our centre. This year was no exception and included a very bright and energetic Erasmus exchange student.


5. Patient-public Involvement or PPI


#DigestingScience – Alison and her team have continued to disseminate her Digesting Science programme in the UK and globally. The Digesting Science packs have been translated into two other languages. As this programme targets children of pwMS, we will be embedding it our PPI programme for #PreventMS going forward.


#ResearchDay – This year we decided to take our research day to the Hebrides and had a very successful meeting in Stornoway. The Stornoway talks are all online. Unfortunately, the London MS Research Day didn’t happen for a second year in a row. We need to do something about it. Any suggestions?


#ResearchBlog & #SocialMedia – We continue to run our blog with almost daily postings. I took a break from the blog to focus on grant writing but will make an effort in 2019 to post more frequently. I increased my social media activity to try and compensate, but there is not much you can say in 280 characters, which is not ideal


#ThinkHand – We held a very successful #ThinkHand event in London in Feb last year to celebrate hand function in pwMS. Our #ThinkHand event was bigger than simply an awareness campaign and we managed to get wider media coverage and bring several important stakeholders on board to support #Chariot-MS


 What about 2019 and beyond?

The above summary is only a brief overview of some of #BartsMS’ activities in 2018. The list is not exhaustive but does give you an idea of what we are trying to achieve. 2019 will be more of the same, with an emphasis on the following #HashTags:


#ThinkHand
#ChariotMS
#OffLabel
#ThinkCognition
#ThinkSocial
#ThinkSequential
#AttackMS
#ThinkCombination
#PreventMS
#Women4MS
#Run4MS
#Walk4MS
#PlasmaCells
#Neuroprotection
#ThinkCure


#DietSpeak

CoI: multiple

#ThinkHand – taking telerehabilitation one step further

What does 2019 hold for the various Barts-MS campaigns? 



We are continuing to make the case for our #ThinkHand campaign with several outputs in 2018, which are being used to support our work in this area. I am very proud that ORATORIO-HAND, a phase-3b study of ocrelizumab in PPMS, which will include patients with an EDSS of up to 8.0 and will start recruiting in the first quarter of 2019. The primary outcome in ORATORIO-HAND is the 9-HPT; this in itself is a first and a major milestone for the field of MS. 


In parallel, DrK has been working very hard to get his NIHR funded trial off the ground called CHARIOT-MS. DrK’s perseverance has gotten the study through round 1 of peer-review and we are now waiting to hear whether or not the study will get funded. CHARIOT-MS is a study of oral cladribine in advanced MS will target both SPMS and PPMS up to an EDSS of 8.5 and again the primary outcome will be the 9HPT. 


These two studies are remarkable for several reasons. Firstly, these trials are challenging the dogma that MS is not modifiable beyond EDSS 7.0, secondly, it is shifting the focus away from the lower limbs and EDSS to a new primary outcome the 9-HPT and, finally, it is giving people with advanced MS hope in valuing their hand function and independence. 

As part of our #ThinkHand campaign Alison Thomson, our research designer, in collaboration with the Agency of Design, helped design an upper limb rehabilitation tool called under&over, which we launched at ECTRIMS-2018 in Berlin. We have now been successful in obtaining a grant to test whether or not under&over will work as a rehab tool and are planning a remote web-based study to test it. Again our primary outcome will be stabilisation, or improvement, in the performance of the 9HPT only this time we will be using our cardboard 9HPT. 


Interestingly the telerehabilitation study below showed that remote rehab can work. I see no reason why a web-based rehab programme won’t work either. We will obviously keep you posted on this study, we may even be given permission from the ethics committee to recruit via our blog. 


Would you be interested in helping us design the study and/or participating?



Fjeldstad-Pardo et al. Telerehabilitation in Multiple Sclerosis: Results of a Randomized Feasibility and Efficacy Pilot Study. Int J Telerehabil. 2018 Dec 11;10(2):55-64.


A prospective, randomized, three-arm, evaluator blinded study to demonstrate the feasibility of a telerehabilitation (TR) program in individuals with ambulatory deficits secondary to Multiple Sclerosis (MS) and evaluate its efficacy when compared to conventional on-site physical therapy (PT) was completed. Thirty participants were evaluated at baseline and randomized to one of three groups with intervention lasting 8 weeks: Group 1 (control)- customized unsupervised home-based exercise program (HEP) 5 days a week; Group 2 (TR)- remote PT supervised via audio/visual real-time telecommunication twice weekly; Group 3 (PT)- in-person PT at the medical facility twice weekly. Outcomes included patient reported outcomes (PROs) obtained through questionnaires, and measurements of gait and balance performed with bedside tests and a computerized system. Functional gait assessment improved from baseline in all three groups. There were no significant differences between the TR and the conventional PT groups for a variety of outcome measures. TR is a feasible method to perform PT in persons with MS and has comparable efficacy to conventional in-person PT as measured by patient reported outcomes and objective outcomes of gait and balance.


CoI: The design, development and manufacture of the under&over rehab tool and the follow-on web-based rehab study has been kindly funded by unrestricted grants from F. Hoffmann-La Roche AG.

All I want for Christmas is a cure

How do we know if someone is cured of having MS?



This is a very difficult question that I keep getting asked.


How will we know if we have cured MS?

 Based on what I have said in my recent post ‘Explaining why you get worse despite being NEDA‘ you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time, your worsening disability should eventually stop or flat-line. In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be a much easier task. 


 I hope you understand that this definition of a cure is incompatible with the terms ‘repair’ and ‘regeneration’. The latter are separate processes that are independent of a so-called biological cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems.

 Based on our current understanding a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before.

 Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion.

 In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don’t work then I would estimate at least a third should have SPMS at 15 years if our hypothesis is wrong. The problem with 15 years is that it is a long to wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.

 Deep phenotyping: In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.

 The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all have highly active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all be done quite early on hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know? 

So yes, ‘if all you want for Christmas is an MS cure’ it may be staring you in the face.  


Banwell et al. Editors’ welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.

 …. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..

 References:

Giovannoni, G., S. Cook, et al. (2011). “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.” Lancet Neurol 10(4): 329-337.

Havrdova, E., S. Galetta, et al. (2009). “Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.” Lancet Neurol 8(3): 254-260

Kremenchutzky, M., G. P. Rice, et al. (2006). “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.” Brain 129(Pt 3): 584-594.




 BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.


 METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

 FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no GdGd-enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

 INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.

CoI: multiple

Will 2019 be the year of sequential therapies?

We need to rethink how we want to tackle MS in 2019. Do we need a true induction approach; i.e. sequential therapies? Or will a simple combination therapy approach suffice?



In 2018 I continued to ask the MS community to ditch the term induction therapy (see ECTRIMS2018 slideshow, and Current Opinion review, below). The term ‘induction’ is not a very useful term when describing the mode of action of alemtuzumab, cladribine and HSCT, because it comes with baggage from other disease areas and is often misrepresented.

A lot of people in the field equate the term ‘induction’ with the use of high-efficacy treatment early on in the course of the disease. For example, many Italian neurologists refer to the use of natalizumab as first-line therapy as an induction strategy. Similarly, the use of mitoxantrone before interferon-beta or glatiramer acetate is referred to as an induction strategy in France (see below). The latter is correct, because induction usually means sequential therapies, with two or three phases of treatment. Induction, followed by a consolidation treatment and finally a maintenance therapy.

I have stopped using the term ‘induction’ outside of the context of mitoxantrone followed by maintenance treatment. I now use the term ‘immune-reconstitution therapy’ or ‘IRT’ to describe short intermittent courses of treatment. This is relevant to alemtuzumab, cladribine, monotherapy mitoxantrone and HSCT.

IRTs have many advantages over maintenance therapies, which I have highlighted in the past and cover in detail in my Current Opinion review. The main advantage is that IRTs (1) tend to be on average highly-effective treatments, (2) they only remain in the body for a short period of time, which is a very useful attribute if you are a woman who is thinking about falling pregnant, (3) they induce long-term remission in some patients, which may turn out to be a cure in the future and (4) they frontload risk. Most of the adverse events associated with IRTs occur early in the treatment hence the term frontloading. In comparison with maintenance therapies, the risks accumulate over time. The latter point is not a trivial point; with immunosuppressive drugs, the risks of opportunistic infections and treatment-related malignancies increases with time.

ECTRIMS-2018



However, I predict that based on recent insights we will need to use more sequential and combination therapy strategies to treat MS. We are already doing this without our realising it. I reviewed this in two sequential presentations at this year’s ABN in Birmingham.

ABN 2018



However, we are going to need a more systematic approach if we are going to get sequential and combination therapies right. For example, we need more anti-inflammatory in combination with neuroprotection trials. The latter is happening, but too many neuroprotection trials are still going ahead as monotherapy trials.

Another strategy is antivirals in combination with anti-inflammatories. The latter sound left-field, but we need to do these studies to address the EBV-HERV hypothesis. Something we have been pushing is anti-plasma cell agents on top of anti-inflammatories to scrub the CNS clean of OCBs that may be driving progressive MS. We will hopefully start our first trial in this space this year.

The question we have to ask is how ready is the MS community for adopting induction/sequential and combination therapy strategies to manage MS? Based on recent discussions they are not ready enough.

#ThinkCombination #ThinkSequential

CURRENT OPINION REVIEW


Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol. 2018 Jun;31(3):233-243.

PURPOSE OF REVIEW: The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment paradigm for using these DMTs effectively and safely.

RECENT FINDINGS: A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function.

SUMMARY: The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.

A TRUE INDUCTION THERAPY APPROACH

Edan et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1344-50.

OBJECTIVES: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.

METHODS: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.

RESULTS: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.

CONCLUSIONS: Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.


Ramtahal et al. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. J Neurol. 2006 Sep;253(9):1160-4. Epub 2006 Sep 21.

Background: Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity.

Objectives and methods: We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment.

Results: Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans.

Conclusions: Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.



CoI: multiple

Natalizumab is unable to stop the shredder

Is the treatment aim of ‘maximising the lifelong brain health of every person with MS’ realistic?


In this study below pwMS stable on natalizumab (one of our most effective DMTs) are still losing brain volume way and above what you would expect for age. Is this premature ageing or is this the slowly expanding chronically active lesion shredding the brain? 


We know that over many years brain volume loss, or brain atrophy, correlates with poor outcome; i.e. cognitive impairment and physical disability. What this study indicates that we clearly need something additional to an anti-inflammatory to treat MS and prevent end-organ damage. What it is telling me is that we are going to need additional add-on treatments to really make a difference for pwMS. What these add-on treatments turn out to be is speculative. At the moment we talk about add-on neuroprotective, remyelinating and neurorestorative therapies when what we may need are antivirals to suppress EBV and HERVs that are driving the slow burn and gradual loss of brain and spinal cord. 

It is clear that unless we normalise brain volume loss in pwMS they will not be able to age normally and nor will be able to ‘maximise‘ their brain health. 

One interpretation of this data is that the focal inflammatory lesion, and relapses, are not MS, but are simply the body’s response to what is really causing the disease. We need to ask the question what is MS and what is driving this accelerated brain volume loss in the absence of focal inflammation? 

Natalizumab continues to make me think about MS and continues to challenge the scientific dogma that MS is simply an organ-specific autoimmune disease. MS is clearly not an organ-specific autoimmune disease; it is a whole lot more complex than that. 


For more information please read my recent blog post ‘explaining why you get worse despite being NEDA‘. 


Koskimäki et al. Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment. PLoS One. 2018 Dec 21;13(12):e0209326.

BACKGROUND: Brain volume loss is an important surrogate marker for assessing disability in MS; however, the contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.


OBJECTIVES:  To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2-5 years.

METHODS: This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24-68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.

RESULTS: Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99-2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman’s r = 0.64, p = 0.003) but not white matter (Spearman’s r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.

CONCLUSIONS: These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

CoI: multiple

Have we thrown the baby out with the bath water?

Who are two of the most original and deep thinkers in the field of MS?



Do you want to know about some of the ideas of Thing1 (MD1) and Thing2 (MD2)?


Two of the most original and deep thinkers in the field of MS are my scientific partner David Baker (aka as the MouseDoctor) and Gareth Pryce (aka MouseDoctor2), David’s research assistant. Together they pioneered the field of cannabinoid research in MS. They showed that the CB1 agonist THC, which happens to be the main psychoactive ingredient in cannabis, has both anti-spastic and neuroprotective effects in their animal model of progressive MS. Their work led to the CUPID study below, which unfortunately was negative. Does this mean THC is not neuroprotective in MS? 


No!! Definitely not!

When you look at the design of the CUPID study wearing rose-coloured spectacles and a new worldview shaped by recent insights, which have surfaced in the last 4-5 years, we think the CUPID study was designed to be negative. Why? 
  1. CUPID enrolled too many pwMS who were EDSS 6.0 or 6.5 (78%), i.e. 78% of the trial population had lost too much lower limb function for the EDSS to report out in a reasonable point of time. When you have lost so much lower limb function it is difficult to show a treatment effect, in other words, the therapeutic window had shut. One way around this would have been to look at upper limb function, but this was not included in the CUPID study.
  2. Using the EDSS as the primary outcome; pwMS spend too much time at EDSS 6.0 and 6.5 and hence were less likely to worsen enough during the trial to be informative. This is called the ceiling effect and is a well-described problem with the EDSS.
  3. The study was a fixed-duration study and not an event-driven trial. The two positive trials in progressive MS (ocrelizumab in PPMS (ORATORIO) and siponimod in SPMS (EXPAND)) were both event-driven. In other words, these trials continued until enough progression events happened to give us an answer (please note I am on the steering committee of both these studies and hence I am conflicted).
  4. The CUPID study was a monotherapy trial. We know that THC is not an anti-inflammatory DMT. It should have been combined with an anti-inflammatory. This seems so obvious to us. We have been discussing combination-therapy trials for so long within Barts-MS that we assume the whole field agrees with us. This is not the case. MS-SMART and STAT2 trials were monotherapy neuroprotection trials. At least the ongoing high-dose biotin and opicinumab trials are being done as combination therapy trials. At least Pharma is listening. 
I am not sure if you are aware that in a post-hoc (after the event) analysis of the CUPID trial limiting the analysis to the population with a baseline EDSS < 6.0, THC was shown to significantly delay disease progression on the EDSS. In other words, THC was neuroprotective in this population. We now know that the reason for THC working in this population is based on the length-dependent axonopathy hypothesis. These study subjects had some reserve in their neuronal pathway subserving the legs and hence would report out earlier on the EDDS than the more advanced patients. CUPID would have been positive it had studied a less disabled population.

The great tragedy is that we have thrown out the baby with the bathwater. We think THC is neuroprotective in MS, but because of the trial design, the MS community now thinks it is not. What can we do about it? I propose we do a CUPID-2 study. Only this time it needs to be (1) event-driven, (2) focus on patients with reserve capacity, either EDSS < 6.0 or to use the 9-HPT as the primary outcome and (3) make it a combination therapy trial. 


Do you think the MS community has the appetite to do this? We owe it to people with more advanced MS and we owe it MD1 & MD2; they did all this ground-breaking research on THC and CB1-agonists as potential neuroprotective therapies in MS only to have their lives work destroyed by poor trial design. 




Zajicek et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 2013 Sep;12(9):857-865.


BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.



METHODS: In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668).


FINDINGS: Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group).


INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change.


FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.


CoI: multiple

Premature ovarian failure and the menopause

Are premature ovarian failure and the menopause important to people with MS?



If you have your menopause before the age of 40 it is considered premature and hence abnormal. If you are older than 40 it is considered normal.


Premature menopause is one of the main reasons women with MS are turning down the option of being treated with HSCT. The chemotherapy they use for myeloablation is toxic to ovaries. Our London based haematologists are quoting a figure of ~45% risk of premature ovarian failure (POF) from HSCT. The latter is age dependent; the older you are the higher the risk. 

If future pregnancy is an issue post-HSCT you can have your eggs harvested and frozen down. However, this takes time. From experience, this delays HSCT by 3-4 months and the cost of storage of the eggs and fertility treatment is not necessarily covered by the NHS. In England, this comes down to your Clinical Commissioning Group (CCG) and what its fertility policy is. Unfortunately, the level of fertility treatment offered is very much a ‘postcode lottery’ and is determined by each individual CCG. Some CCGs may not fund treatment if, for example, you have existing children – even if they are not from the current relationship, don’t live with you and/or are grown up. Some may fund if one partner has no children. You can find out the situation in your area at the Fertility Fairness website. 


Menopausal symptoms, post HSCT and chemotherapy, can be treated with by hormone replacement therapy (HRT).

Menopause is important for pwMS. Several studies show that in women with MS, menopause is associated with worsening disability. The average change in disability is very small but significant. The results, however, suggest this observation has a biological basis and can, therefore, potentially be manipulated to treat MS; i.e. by giving HRT. Whether these observations are due to a loss of the neurotrophic effects of oestrogen on the brain and nervous system or ageing is a moot point. The first study below did not find any impact of HRT on disability, but too few women were on HRT to be able to see a reliable effect on the outcome. We know from the dementia field that HRT is likely to delay the onset of dementia, therefore I would not be surprised if HRT had an impact on brain health in MS. 

Do you think we should do a study of HRT in women with progressive MS? Or should we simply offer women with MS the option of starting HRT? The latter has been difficult in view of some of the negative effects of HRT, i.e. an increased incidence of cardiovascular events, breast cancer and deep vein thrombosis. However, it is reassuring that a recent large meta-analysis published in JAMA did not show an increase in all-cause mortality (death) as a result of HRT. Therefore, you can now go onto HRT without having to worry about reducing your lifespan. However, you still need to be aware of a slightly higher risk of breast and endometrial cancer and thrombotic events on HRT compared to not being on HRT.

Another issue is that a lot of the symptoms due to the menopause can be confused with MS-related symptoms, for example, fatigue, low mood and brain fog. Menopause is known to worsen MS-related symptoms (study 2 below). This is another reason to potentially go onto HRT. Menopausal brain fog is covered in a recent New York Times article (The Brain Fog of Menopause). 


Finally, it is important to know that menopausal age is not affected by MS (study 3 below). However, long-term methylprednisolone and IFNβ-1b treatments may change menopausal age in a dose-dependent manner. I am not sure if these observations are clinically significant.

I am often asked what would I do if I had MS and I was a woman. If I didn’t have any contra-indications to HRT I wouldn’t hesitate in starting HRT. HRT is anti-ageing, it may modify the course of MS and it will counteract the worsening MS symptoms associated with the menopause mentioned in study 2 below. 


As I am not a woman, what would you do?

Common contraindications to HRT:
  1. Pregnancy
  2. Undiagnosed abnormal vaginal bleeding
  3. Active thromboembolic disorder or acute-phase myocardial infarction
  4. Suspected or active breast or endometrial cancer
  5. Active liver disease with abnormal liver function tests
  6. Porphyria cutanea tarda


Study 1: CLIMB Study

Bove et al. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort.Mult Scler. 2015. pii: 1352458515606211.

 BACKGROUND: Onset of multiple sclerosis (MS) is typically in early adulthood. The impact, if any, of menopause on the MS course is unknown.


OBJECTIVE: Our objective was to determine whether menopause is associated with changes in MS severity in a longitudinal clinical cohort.

 METHODS: Responses from an ongoing reproductive questionnaire deployed in all active female. CLIMB observational study participants with a diagnosis of clinically isolated syndrome (CIS) or MS were analyzed when the response rate was 60%. Reproductive data were linked with clinical severity measures that were prospectively collected every six months, including our primary measure, the Expanded Disability Status Scale (EDSS).

RESULTS: Over one-half of the respondents (368 of 724 women) were post-menopausal. Median age at natural menopause was 51.5 years. In our primary analysis of 124 women who were followed longitudinally (mean duration 10.4 years) through their menopausal transition (natural or surgical), menopause represented an inflection point in their EDSS changes (difference of 0.076 units; 95% CI 0.010-0.14; p = 0.024). These findings were not explained by vitamin D levels, nor changes in treatment or smoking status over this period. There was no effect of hormone replacement therapy (HRT) exposure, but HRT use was low.

 CONCLUSIONS: We observed a possible worsening of MS disability after menopause. Larger cohorts are required to assess any HRT effects.




 Study 2: PatientsLikeMe

 Bove et al. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord. 2015 Jan;4(1):18-24.


 BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown.

 OBJECTIVE: To investigate the patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM).

 METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores.

 RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration.

 CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.



 Study 3: MS and menopause

 Türk Börü et al. Effects of multiple sclerosis and medications on menopausal age. J Int Med Res. 2018 Mar;46(3):1249-1253.

Objectives: We aimed to determine whether multiple sclerosis (MS) and methylprednisolone and disease-modifying drugs have an effect on menopausal age. 


Methods: A total of 86 patients and 98 healthy subjects were included in this study. The natural menopausal age of the patients and healthy subjects were compared. The cumulative dosages of methylprednisolone, beta interferons (IFNβs), and glatiramer acetate were calculated. The effects of the Expanded Disability Status Scale (EDSS), duration of the disease, and cumulative dosage of medications on menopausal age were evaluated. 

Results: The patients’ mean menopausal age was 45.3 ± 4.8 years and healthy subjects’ menopausal age was 46.8 ± 4.3 years, with no significant difference between the two groups. The cumulative dosage of methylprednisolone showed an effect on menopausal age. There was a significant inverse correlation between menopausal age and dosage of IFNβ-1b, while the disease duration and EDSS score showed no correlation with menopausal age. 

Conclusions: We conclude that menopausal age is not affected by MS. However, long-term methylprednisolone and IFNβ-1b treatments may change menopausal age in a dose-dependent manner.