Category: Politics, campaigns and information

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.

Do we need to obey the NHS’s DMT stopping criteria?

I saw a patient yesterday who was forced to stop fingolimod as she had developed SPMS. She has been activity free on fingolimod for close to 5 years (relapse-free and no new T2 lesions) but had noticed a continued worsening of her gait. Her neurologist at St Elsewhere said that because her MS was now secondary progressive she had to stop taking fingolimod under the current NHS England guidelines. What happened next?



Four months after stopping fingolimod she had a major relapse with cerebellar ataxia (unsteady gait) and bladder problems. In addition, she has developed oscillopsia (jumpy vision) and intention tremor in her hands. As a result of these new disabilities, she is falling on an almost daily basis and has become housebound. I have little doubt that she has had rebound disease activity. My response is to put her back on fingolimod and hope she recovers some of the function she has lost. This is a tragedy. 

This patient is now the third patient we have seen in the last few months with rebound on stopping fingolimod. 

The danger of stopping drugs that target trafficking of lymphocytes into the CNS (natalizumab) and/or sequester lymphocytes in lymph nodes (fingolimod and other emerging S1P modulators) are well known. The study below describes this phenomenon of rebound that occurs on stopping fingolimod. 


I find it fascinating that when you remove the brakes on the immune system and allow the so-called ‘auto-reactive lymphocytes’ the opportunity to recirculate, they enter the CNS and cause disease activity that can be way and beyond what you would have expected, based on baseline levels of disease activity documented before patients started on these therapies. In the case of fingolimod, we have even seen rebound in patients with PPMS who had to stop fingolimod after the negative phase 3 INFORMS trial results. Isn’t it interesting that a DMT, such as fingolimod or for that matter natalizumab, can convert a non-relapsing phenotype into a relapsing phenotype? This is just further evidence that the MS disease classification based on the clinical course is flawed. MS is one and not two or three diseases.


Why we get rebound needs to be studied further. I have proposed the concept of the field hypothesis in the past. Whatever is causing MS is allowed to proliferate and spread in the brain and spinal cord when the immune system is stopped from doing what it is supposed to do; survey the CNS. When the brakes of the immune system are then removed and immune surveillance recommences the cells find the cause of MS and set-up multi-focal inflammatory lesions, i.e. rebound. If I was a betting man I suspect the best brains to study to find the virus that causes MS is the brains collected from people dying of MS on natalizumab or fingolimod who have not had immune reconstitution. The question that is often asked is why then do people on long-term fingolimod and natalizumab don’t develop any problems from the proliferation of whatever is causing MS? I don’t know, but maybe they do we just haven’t looked for it. Or we live unperturbed with the viral cause of MS in our brains provided we don’t mount an immune response to it. A similar thing happens in some people with hepatitis B who have a chronic persistent infection of the liver with no overt liver damage.


The bottom line is if you have MS that is well controlled on fingolimod you may want to consider any decision to simply stop taking it more carefully. I suspect it will be safer to transition onto another DMTs long before the action of fingolimod wears off (~3-4 weeks). The latter is really important for women on fingolimod who are planning to fall pregnant. This may be the place to use an IRT (immune reconstitution therapy). IRTs get the disease under control and are out of the system when the woman wants to fall pregnant. 

Another lesson here is that the NHS England stopping criteria are potentially dangerous for individual patients. We need to push back on their implementation or at least randomise these patients into a trial to generate the evidence that we need to convince NHSE to change the criteria. We have proposed the following salavage trials:

Hatcher et al. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016 May 2. doi: 10.1001/jamaneurol.2016.0826.


IMPORTANCE: The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.


OBJECTIVE: To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.


DESIGN, SETTING, AND PARTICIPANTS: Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.


EXPOSURES: Each patient received treatment with oral fingolimod for various durations.


MAIN OUTCOMES AND MEASURES: Occurrence of rebound after ceasing fingolimod treatment.


RESULTS: The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.


CONCLUSIONS AND RELEVANCE: These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.


Alvarez-Gonzalez, et al. Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis.

Ann Clin Transl Neurol. 2017 May 17;4(7):506-511. doi: 10.1002/acn3.410. eCollection 2017 Jul.

ABSTRACT: Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.

CoI: multiple

Is there a place for watchful waiting in the management of MS?

Yesterday in response to my blog post on ‘slaying the Gambler’s dilemma‘ somebody asked ‘Is there really a place for watchful waiting in the modern management of MS?’.


Yes, there is.

Not all patients have active MS, i.e. relapses within the last 2 years and/or new or enhancing lesions on MRI in the preceding 12 months, and therefore would not be eligible for DMTs under NHS England Guidelines. The same applies for people who have progressive or more advanced MS; we see these patients in the hope of being able to offer them a treatment in the future. Rather than discharge these patients they need to be followed and monitored. This is called watchful waiting.


The following systematic review in the Cochrane library defines and reviews this treatment approach, albeit for other diseases. 

Please note “Watchful waiting” is defined as an alternative approach in the medical management of certain diseases. Interestingly the authors’ equate “watchful waiting” with “active surveillance” and therein lies the rub. The problem with a lot of neurologists is that when it comes to MS “watchful waiting”  is a passive, rather than an active, process. Active surveillance means interrogating the patient at fixed time points for MS disease activity and for this to happen pwMS will need to have MRI scans and systematic visits. At Barts-MS this happens annually. The annual visit should be supplemented with unscheduled visits if the pwMS has new complaints or self-monitoring raises concerns.

The conclusions of this review are telling:


….. the process of making the decision to choose watchful waiting is complex. Through the process patients and their significant others experience an array of emotions that often lead to uncertainty and anxiety. Once the decision is made patients must cope with the knowledge that they have a troubling diagnosis and make the necessary adjustments. An empathic, reassuring relationship with a healthcare practitioner eases the burden of this process. Healthcare providers need to recognize that not all patients are “at peace” with the decision of choosing watchful waiting. Uncertainty and fear may intensify during this time as well as feelings of stress and anxiety. Patients and their significant others often attempt to adapt in the best way they know how but the effectiveness of their coping strategies needs to be assessed. In addition, healthcare providers need to also be aware that with the increased anxiety and stress associated with watchful waiting, patients’ understanding of healthcare information and the ability to ask questions may be diminished. Both providers and patients benefit from open discussions related to the many aspects of uncertainty and fear related to making and living with the decision. Employing a shared decision-making model with regard to the management of the array of issues that comes from both making the decision and living with it is recommended. It appears that patients are very sensitive to recognizing when the care they are receiving lacks empathy. Communication that is open, empathic, and non-judgmental is essential. A willingness to discuss sensitive issues such as sexual function needs to be conveyed. Lastly, providers and their staff need to remain attentive to the importance of articulating aspects of the situation that are hopeful and optimistic as many patients, during their visits, take their cues regarding their health status from non-verbal and verbal interactions …..

Rittenmeyer et al. The experience of adults who choose watchful waiting or active surveillance as an approach to medical treatment: a qualitative systematic review. JBI Database System Rev Implement Rep. 2016 Feb;14(2):174-255. doi: 10.11124/jbisrir-2016-2270.

BACKGROUND: “Watchful waiting” or “active surveillance” is an alternative approach in the medical management of certain diseases. Most often considered appropriate as an approach to treatment for low-risk prostate cancer, it is also found in the literature in breast cancer surveillance, urinary lithiasis, lymphocytic leukemia, depression and small renal tumors.


OBJECTIVES: This systematic review sought to: Identify and synthesize the best available international evidence on the experience of adults who choose watchful waiting or active surveillance as an approach to medical treatment. To this end the questions addressed in this review were: 
1. How do patients who have chosen watchful waiting or active surveillance describe the process of coming to the decision?
2. What were the factors that influenced their decision to choose?
3. How do patients who have chosen watchful waiting or active surveillance describe the experience?

RESULTS: A total of 16 studies, critically appraised by two independent reviewers and deemed to be of high quality, were included in the final review. One study was excluded after appraisal. One hundred and fifty-five findings from the 16 studies were extracted into 10 categories and then into three synthesized findings. The synthesized findings explicated:

CONCLUSIONS: The synthesized findings of the review conclude that the process of making the decision to choose watchful waiting is complex. Through the process patients and their significant others experience an array of emotions that often lead to uncertainty and anxiety. Once the decision is made patients must cope with the knowledge that they have a troubling diagnosis and make the necessary adjustments. An empathic, reassuring relationship with a healthcare practitioner eases the burden of this process. Healthcare providers need to recognize that not all patients are “at peace” with the decision of choosing watchful waiting. Uncertainty and fear may intensify during this time as well as feelings of stress and anxiety. Patients and their significant others often attempt to adapt in the best way they know how but the effectiveness of their coping strategies needs to be assessed. In addition, healthcare providers need to also be aware that with the increased anxiety and stress associated with watchful waiting, patients’ understanding of healthcare information and the ability to ask questions may be diminished. Both providers and patients benefit from open discussions related to the many aspects of uncertainty and fear related to making and living with the decision. Employing a shared decision-making model with regard to the management of the array of issues that comes from both making the decision and living with it is recommended. It appears that patients are very sensitive to recognizing when the care they are receiving lacks empathy. Communication that is open, empathic, and non-judgmental is essential. A willingness to discuss sensitive issues such as sexual function needs to be conveyed. Lastly, providers and their staff need to remain attentive to the importance of articulating aspects of the situation that are hopeful and optimistic as many patients, during their visits, take their cues regarding their health status from non-verbal and verbal interactions. Future studies should investigate.


CoI: I am a neurologist who looks after pwMS

Is it time to slay the Gambler’s dilemma?

At a teaching session last week I presented several slides showing that at a population level rapid escalation (vertical switching) or flipping the pyramid (high-efficacy first-line) are really the only two treatment options we should be using to maximise life-long brain health of people with MS (pwMS). I also have little doubt that flipping the pyramid will also prove to be better than rapid escalation; there is some early data to support this and at least two clinical trials ongoing to address this.


The study below shows vertical switching  (low/moderate to high efficacy switching) is superior to horizontal switching (between low/moderate efficacy DMTs). 

 The issue we debated on the teaching course is that as neurologists we don’t treat populations, but individuals with MS and hence patient choice should always trump data like this. I explained to the audience that they must be careful not to share their patient’s biases, i.e. the gambler’s dilemma.  A gambler never goes into a casino to lose money. However, the gambler knows that on average he/she will lose money. The cognitive bias here is that they will be the lucky one that will win. Someone with MS is never going to have bad MS, they are always going to be the one that ends up with no problems in the future, therefore, they don’t need more effective treatments. This is wrong. Given sufficient time MS causes disability in the majority of people with MS. Time is brain and brain lost is never regained. Therefore the practices of watchful waiting (a British medical tradition) and slow stepwise escalation comes at a cost to individuals and populations of individuals with MS. 


Can I suggest to counteract these cognitive biases you play a little game and imagine how you would treat yourself if you had MS? 

The treatment targets in MS have evolved from simply reducing the frequency of relapses (NEDA-0), to becoming relapse-free (NEDA-1) to having no measurable disease activity (NEDA-3), to preventing end-organ damage (NEDA4 and NEDA-5) to finally maximising brain health to allow our patients with MS so that they can age normally. In the future, we will want to cure our patients with MS before any meaningful damage is done to their brains and spinal cords, and we will want to prevent MS in people at risk of getting MS. To achieve these latter targets we need a much more proactive treatment approach and we also need to manage MS holistically, which includes actively managing comorbidities and focusing on wellness and lifestyle factors.

 Is it time to slay the Gambler’s dilemma? 



You can download these slides via the new ProfG’s SlideShare site that I now control myself. Please feel free to use the slides. 

 Chalmer et al. Treatment escalation leads to fewer relapses compared with switching to another moderately effective therapy. J Neurol. 2018 Dec 4. doi: 10.1007/s00415-018-9126-y.

 BACKGROUND: Patients with multiple sclerosis who experience disease breakthrough often switch disease-modifying therapy (DMT).


 OBJECTIVE: To compare treatment effectiveness of switch to highly effective DMT (heDMT) with switch to moderately effective DMT (meDMT) for patients who switch due to disease breakthrough defined as at least one relapse within 12 months of their treatment switch.

 METHODS: We retrieved data from The Danish Multiple Sclerosis Registry on all relapsing-remitting MS patients with expanded disability status scale (EDSS) less than 6 who experienced disease breakthrough. We used propensity score matching to compare annualized relapse rates (ARRs), time to first confirmed relapse, time to first confirmed EDSS worsening and time to first confirmed EDSS improvement.

 RESULTS: Each matched group comprised 404 patients. Median follow-up time was 3.2 years [interquartile range (IQR) 1.7-5.8]. ARRs were 0.22 (0.19-0.27) with heDMT and 0.32 (IQR 0.28-0.37) with meDMT; relapse rate ratio was 0.70 (95% CI 0.56-0.86; p = 0.001). Escalation to heDMT reduced the hazard of reaching a first relapse (HR 0.65; 95% CI 0.53-0.80; p < 0.001). We found no evidence of delayed disability worsening (HR 0.83; 95% CI 0.62-1.10; p = 0.20) and weak evidence of disability improvement (HR 1.33; 95% CI 1.00-1.76; p = 0.05) with heDMT.

 CONCLUSION: Switching to heDMT is associated with reduced ARR and delay of first relapse compared with switching to meDMT. Patients on DMT who experience relapses should escalate therapy to heDMT.

CoI: multiple

Prof G what is therapeutic lag?

Worsening disability in someone with progressive MS over the next 2 years is primed by inflammation from years ago. Suppressing inflammation today, therefore, will have little, or potentially no, impact on worsening disability over the next one to two years as the damage priming progression over this time has already occurred. Therefore, all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.


The PPMS Barcelona study of interferon-beta-1b treatment was negative after 2-years of treatment; there was no difference between pwPPMS who had been treated with IFNbeta or placebo. The investigators’ concluded that interferon-beta was ineffective in PPMS. However, when these patients were reassessed 5-years after the end of the study there was a clear benefit (clinical and MRI) in favour of the interferon treatment. Based on this, and other observations, we have proposed that in progressive MS there is a lag between the onset of action of anti-inflammatory medication and its impact on the biology that underpins progression.

The impact of anti-inflammatory medications in progressive MS takes several years to play out in the system that is already in the ‘clinically apparent’ progressive phase. Please note the biology that results in progressive MS is there from the start. The only reason you don’t see progression clinically early on is that several compensatory mechanisms allow you to continue functioning relatively normally. Once these compensatory mechanisms have been shredded gradual worsening becomes apparent.

In progressive MS, worsening disability over the next 1-2 years is primed by focal inflammatory events that have occurred in the past. Therefore, suppressing inflammation today in progressive MS will have not have an impact over the next 1-2-years as the damage that has primed progression has already occurred. This is what I call therapeutic lag and it occurs with all anti-inflammatory therapies. Importantly the more disabled you are the longer the lag. Why? The more disabled you are the less reserve you have and therefore you are unable to compensate nor recover function.

This diagram below illustrates the concept of the therapeutic lag. The natalizumab SPMS trials (ASCEND) was only 2-years in duration, which explains why it was negative. However, at 3-years the trial became positive because of lag.

Neurological systems to be affected first by progressive MS are those that have the longest, or most, wiring and hence more likely to be hit by multiple lesions. This is why the motor system to the legs, bladder and the cerebellar, or balance, system are typically affected first when clinically-apparent progressive disease starts. The other systems (vision, motor system to the upper arms and face, sensory systems, cognition (poorly tested), etc.) tend to be affected later by ‘overt’ progressive disease. I say overt because there is now good MRI evidence (brain volume loss, black holes, slowly expanding lesions (SELs)) that the progressive component of MS is present from the start of the disease. The only reason you don’t see progression clinically is that your nervous system compensates for the damage. However, once the compensatory systems fail in a particular pathway progressive MS ensues. What this means is that we may have different windows of opportunity for treatments to impact on the different functional systems. In other words there are multiple windows of therapeutic opportunity to act in MS and we should, therefore, shift our focus in progressive MS away from the systems already in the clinically progressive phase to those systems that still have reserve capacity and not yet in the clinically progressive phase, for example, arm and hand function (#ThinkHand).

In the natalizumab SPMS or ASCEND study, this is exactly what happened. The trial was positive on upper limb function (9-hole peg test) at 2-years, but not on the EDSS and the 25-foot timed walk, which are driven by lower limb function. If the ASCEND trial has been event-driven or was done for 3-years it would have been positive and we would have almost certainly had natalizumab licensed for SPMS. This is why I am so keen for Biogen to the ASCEND-2 study and extend it into wheelchair users. So far I have been unsuccessful in covincing them to do the study. Can you help?



The implications of the therapeutic lag and asynchronous progressive MS hypotheses is that we have been designing, and doing, trials in progressive MS incorrectly. More importantly, these concepts challenge the so-called therapeutic window concept. It also means that instead of writing someone off with progressive MS because their so-called therapeutic window has closed is that we can now focus on the other therapeutic windows that are still open.

It has never made sense to me not being able to prescribe a DMT to pwMS simply because they needed a wheelchair as a result of a devastating spinal cord relapse. What about their upper limb, cognitive and cerebellar function? Do we simply write these systems off because one, or two, systems are severely damaged? I personally think the therapeutic lag and asynchronous progressive MS hypotheses gives pwMS hope; hope for treatments that can at least preserve the function of pathways with reserve capacity, whilst we work on remyelination and neurorestorative strategies. This will at least buy us time and spread hope!



Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 pwMS, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 pwMS, respectively.

EDSS = Expanded Disability Status Scale
MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)
9-Hole Peg Test = test of upper limb function
Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

CoI: multiple

#ThinkSocial: survey results

Thank you and Thank you! 


Firstly, for completing our #ThinkSocial survey, which was very useful and a  good guide of why this campaign is important. And secondly, for the very kind donor who has given us a very generous grant to study whether, or not, targeted public engagement and patient-public involvement activities increase social capital and improve outcomes for people living with MS. By formally studying this we hopefully generate the necessary evidence to help others adopt our approach and to help get their PeS and PPI initiatives funded by the NHS and other relevant payers. 


This survey and funding news coincides with the publication of our review on social capital. Well done to Saul and Alison for taking this forward. Saul is funded by an ECTRIMS fellowship and this paper will count towards his outputs. 




Saúl Reyes, Gavin Giovannoni and Alison Thomson. Social capital: Implications for neurology. Brain and Behaviour ePub 08 December 2018.

 
Social capital (SC) is a broad term that encompasses the many resources derived from social connections. The contemporary study of SC in public health has deep roots in the related fields of sociology, economics, and politics. Its multidisciplinary nature and the varying potential ways it could affect individuals have resulted in different but overlapping models to approach SC in the health field. There are currently no standardized measures of SC, and even more, challenging its impact on health outcomes seems to vary according to the level of analysis. Despite the accumulating evidence that supports a protective effect of SC on mental and physical health, and mortality, not enough attention has been paid to the potential drawbacks of SC. The role of SC in neurological disease is just beginning to be explored. Concerted efforts are needed to ensure that empirical evidence on SC could be properly translated into interventions for health‐promoting purposes. In this paper, we review the current state of scientific knowledge on the subject of SC, with a focus on its application in the field of neurology.

CoI: none for the post

An interview with myself: secondary progressive MS

I did a post-ECTRIMS interview with a Portuguese health magazine last week. The interview has helped me reflect and formalise some of my many ideas about secondary progressive MS that have been fermenting in my cortex for some months. I have therefore put pen to paper using a new format the self-interview.




Q: Prof G what was your main highlight at ECTRIMS 2018?


Without a doubt the acceptance by the wider MS community that progressive, or more advanced, MS is modifiable. Until quite recently most people thought that once someone with MS loses the ability to walk it is over for them from a treatment perspective. The two-stage MS hypothesis has been responsible for entrenching this worldview, i.e. an early modifiable inflammatory phase that is then followed by a secondary neurodegenerative phase.


Q: You say MS is #1_not_2_or_3_diseases; how does this position sit with the positive siponimod in secondary progressive (EXPAND) trial results and negative fingolimod in primary progressive (INFORMS) trial results?


Firstly, these were very different studies. The PPMS, or INFORMS, study was much smaller study and hence potentially underpowered for the question it was asking. The INFORMS population had less ‘inflammatory’ activity and was more advanced in terms of the biology of MS than the EXPAND population. More importantly, the SPMS or EXPAND study was event-driven and continued until there were enough events to get a result. I don’t think the discordance of these results supports MS being more than one disease. Another aspect that has been ignored is the obvious fact that fingolimod and siponimod are different drugs and may differ in their mode of actions, i.e. siponimod may have subtle effects within the CNS or potentially off-target effects that explain some of its efficacy.


Q: Do you think the EXPAND trial results are clinically meaningful?


Yes, I do think they are clinically meaningful because if you have SPMS having a drug that will slow down your disease progression is better than having no drug. The unmet need in SPMS is enormous. I agree that the effect on disease progression may seem small in terms of numbers, but this treatment effect will get bigger with time, because of therapeutic lag. It takes time for anti-inflammatory therapies to have an effect in more advanced MS because disease worsening in the next year or two is driven by damage sustained in the past. It takes time for this damage to work through the system, hence switching off inflammation now will take years to manifest as a treatment response.


It is also important to understand that siponimod will become a platform therapy on which we can build more effective combinations. It is clear that an anti-inflammatory therapy on it own is unlikely to make a big difference in more advanced MS. We need to build a therapeutic pyramid and add-on neuroprotectives, remyelination therapies and in the future neurorestoratives therapies. Regulators don’t like combination therapies unless one of them is a licensed product; siponimod could be that licensed product.


Q: What are you going to tell your patients about siponimod?


I am going to spread the hope. The ocrelizumab in PPMS (ORATORIO) and siponimod in SPMS (EXPAND) results are just the beginning of a new treatment era in MS. We need to celebrate the results of these trials and build on them. These trial results have challenged and killed the dogma of MS is a two-stage disease and that once you become disabled you are beyond hope.

It is also important to manage expectations in that these treatments are going to slow down and not reverse disability, hence many people with MS may not notice a treatment effect. However, we need these treatments as a platform to add on other therapies I refer to above.


I am definitely going to tell them about the effect siponimod has on cognition. Trial subjects treated with siponimod were more likely to have their cognition stabilise or improve compared to subjects on placebo. I am sure people with secondary progressive MS value their cognition and this bit of information may help them in making a decision about going onto this treatment or not. Please don’t forget MS is a cause of dementia and siponimod is one way of slowing down the development of MS dementia.


Q: In addition to being treated with siponimod is there anything else people with SPMS can do t help?


Yes, there is a lot they can do. This is about the holistic management of MS. If they smoke and they want to stop smoking they should seek professional advice about stopping smoking. The need to optimise their diets, exercise and sleep. The should review their medications and see if any medications that could be making their MS worse can be stopped. They should be screened for comorbidities or other diseases and have these treated. If they are having recurrent infections, particularly urinary tract infections, this should be addressed and treated. There is a lot that can now be done to reduce the risk of bladder infections.


People with MS should use it or lose it. If MS is affecting some function you should seek advice on what you can do to improve or stabilise function in that particular part of the nervous system. Don’t underestimate the value of rehabilitation and focused exercise programmes to help maintain function.


Q: Any final comments?


Don’t shoot the messenger. Although progressive, or more advanced, MS seems to have been neglected for many years these positive studies are catalysing many more studies in progressive MS. We need to reflect and celebrate these successes. Stopping to contemplate where we have come from and were are going to does not mean we have reached the end. One of my favourite poems makes this point very well.

Stopping by Woods on a Snowy Evening

BY ROBERT FROST

Whose woods these are I think I know.
His house is in the village though;
He will not see me stopping here
To watch his woods fill up with snow.

My little horse must think it queer
To stop without a farmhouse near
Between the woods and frozen lake
The darkest evening of the year. 

He gives his harness bells a shake
To ask if there is some mistake.
The only other sound’s the sweep
Of easy wind and downy flake.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep..



CoI: multiple. I am an active steering committee member on both the EXPAND and ORATORIO studies.

Social prescribing survey

I have been taken to task and chastised for neglecting the blog and my patients. I realise that the blog is part of our #ThinkSocial campaign. To help understand the need for social prescribing I would appreciate it if you could please complete the following survey. 



Thank you. 




Social Medicine and Social Prescribing

We are launching a new campaign called #ThinkSocial. Why?



About a year ago Barts-MS was criticised for pandering to the informed rich. More than half the patients we treat are out-of-area and when it comes to our alemtuzumab-treated patients more than two-thirds are out-of-area; i.e. in an ideal world they should be treated and managed by their local team. The problem we have is that informed patients seek out and find centres who offer them highly-effective treatments.

The implications of this stinging criticism are that we are neglecting the patients on our own patch to look after these other patients. In response to this, we did an audit and showed that our patients (Tower Hamlets, Hackney and Newham) are as likely to be on high-efficacy second-line therapies as patients from other boroughs. Our patients are not being disadvantaged. At about the same time as this criticism, I became aware of the massive variance in the NHS when it comes to DMT prescribing and access to MS services, which prompted us to hold our Variance meeting last month.

In addition to this Barts-MS has been very proactive in promoting their off-label essential DMT list to address under treated MS in resource-poor environments. This has subsequently led to the MS International Federation (MSIF) taking up the challenge and leading on an application to the WHO to get a few highly selected DMTs on the Essential Medicines List (EML).

Independent of this I noticed that patients engaging with our PPI (patient-public involvement) programme seemed to do better than patients who didn’t engage. I suspect this is because PPI increases social capital, i.e. support networks, that helps people with MS. Social capital is well studied in other disease areas, but not MS. As a result of this, we have started to explore social capital as a treatment for MS and are actively studying it. The concept of social prescribing to address the social determinants of health is not new. However, it seems to be gaining traction as a mainstream topic.

On my flight back from MENACTRIMS in Dubai, I was catching up on some of my reading and read the following two articles that are of the moment. You know that when both the NEJM and the BMJ simultaneously review and discuss social medicine something is afoot.

Scott D. Stonington et al. Case Studies in Social Medicine — Attending to Structural Forces in Clinical Practice. N Engl J Med 2018; 379:1958-1961.

Excerpt: …. In this issue, the Journal launches Case Studies in Social Medicine, a series of Perspective articles, to highlight the importance of social concepts and social context in clinical medicine. The series will use discussions of real clinical cases to translate these tools into terms that can readily be used in medical education, clinical practice, and health system planning….

Ann Robison. Social prescribing: coffee mornings, singing groups, and dance lessons on the NHS. BMJ 2018;363:k4857


Excerpt: ….. “Dance lessons for the lonely on NHS,” led the Daily Mail in October. “GPs should prescribe hobbies like ballroom dancing, gardening and art classes to millions of people because it is often better than drugs,” said the Telegraph. This “social prescribing” is being touted widely as a panacea, including for loneliness, obesity, depression, and osteoarthritis. The health and social care secretary, Matt Hancock, is a fan: he wants social prescribing to relieve pressure on the NHS and improve patients’ outcomes…..

I have little doubt that social prescribing will make a massive difference to the way we manage MS. MS not only shreds the brain it shreds social networks. PwMS are frequently depressed, combine this with unemployment, divorce, poverty and reduced benefits and social isolation is not far away for a lot of pwMS. This is why we need to think differently about the holistic management of MS. The difficulty we have as healthcare professionals is to tackle this problem sensitively and with compassion. It is vital that we are not patronising when taking a social history and addressing social problems. A lot of pwMS think this not part of the neurology teams remit.

If you have any ideas on how about social prescribing in the MS space we would be interested to hear about them. Maybe you have examples of things that are working already.

Some of you may recall our readers’ response to the post on the BBC Radio 4 dramatisation of ‘An Instinct for Kindness’. Allyson the main character of the play is an example of someone who may have benefited from social prescribing. Do you agree?