Monday, 29 February 2016

PoliticalSpeak & NewsSpeak: industry shenanigans

Pharma making things worse; the issue of high-cost drugs! #PoliticalSpeak #NewsSpeak #MSBlog #OffLabel

"Do you think Pharma should be spending money on advertising to justify why they charge so much for their innovative drugs? Have your say and let's continue the debate."

"Obviously, high-cost drugs and the reasons why they cost so much remains a political hot potato. We at Barts-MS consider this issue to be one of the major hurdles to the adoption of effective treatments for pwMS across the planet; this is a particular problem in resource-poor healthcare environments. This is why we are trying to get an initiative off  the ground to focus on this issue and is what drives our Barts-MS Essential Off-label MS DMT list. Pharma don't like our list, but what would you do if you had no medical insurance or lived in a country where MS was not a major priority of the government? Would you let MS run its natural course, and shred your brain and spinal cord, or would you give a cheap off-label drug a try? For me the decision is a 'no-brainer'; excuse the pun, I am using it to highlight the issue." 

Anne Gulland. MSF accuses Pfizer of misleading advertising. BMJ 2016;352:i896.


...... The charity Médecins Sans Frontières has accused the drug company Pfizer of using misleading advertisements in an attempt to justify to MPs and the public the high prices it charges for drugs.....

..... The advertisements, displayed at Westminster underground station in London, the nearest stop to parliament, at the beginning of February, claimed that to bring a single drug to market cost more than £1bn and took more than 12 years in research and development and “immeasurable dedication.”....

...... MSF slapped posters over the advertisements disputing the claims and highlighting the role of university research and public money.....

How to report epidemiology studies

Fiest KM, Marrie RA, Jette N, Bennett DA. The Standards of Reporting of Neurological Disorders (STROND) checklist: Application to multiple sclerosis. Mult Scler. 2016 Feb 26. pii: 1352458516634873. [Epub ahead of print]

BACKGROUND:Descriptive epidemiological studies documenting the incidence and prevalence of multiple sclerosis (MS) and studies that report morbidity, mortality, and economic burden provide essential information for patients, healthcare providers, and policymakers. However, the quality of reporting of observational studies is often poor, limiting the ability to evaluate the validity of the findings. The Standards of Reporting of Neurological Disorders (STROND) reporting guideline comprises recommendations and a 15-item checklist of reporting items to aid high-quality reporting of incidence and prevalence studies of neurological disorders.
METHODS:We explain the basic reporting items of the STROND checklist for the methods, results, and discussion sections in the context of the MS literature and searched for examples of good reporting of those items.
RESULTS:We identified examples of good reporting of the basic reporting items from previous systematic reviews of the descriptive epidemiologic literature in MS.
CONCLUSION:The adoption of the STROND reporting guidelines should improve the quality of reporting of descriptive epidemiological studies in MS. Along with efforts to improve methodological aspects of epidemiological studies and harmonization of data collection efforts, improved reporting could contribute to furthering our understanding of the epidemiology of MS.

For clinical trials we have the CONSORT guidleines, for animal experiments we have ARRIVE guidelines and we have STROND guidelines for epidemeological studies. 

Why follow guidelines. Maybe to limit the poor quality stuff that litters pubmed.  Many of the papers not following this approach reach "cure of the week" that often go nowhere because there is no translatable value and no-one can ever repreat the work. because its methodologies are unintelligable

It started with CONSORT and most clinical trials now follow this appraoch. However, I can't tell you  the number of papers on animal work, I have reviewed stating "we did the experiments according to the ARRIVE guidelines". 

This indicates that the authors view the ARRIVE guidelines as meaningless and are trying to pay lip service to the journals that support use of the ARRIVE guidelines. 

This is because they are reporting guidelines and not experimental design guidelines, although they can help focus the mind in experimental design. Therefore, if you do not report the information required by the guidelines you are not adhering to them. So a statement saying "we did experiments according to the ARRIVE guidelines" without reporting the elements of the ARRIVE guidelines says the authors have difficulty reading and assimilating knowledge and so be warned about the rest of the content.

Journals sign up to these concepts but often very few enforce their own policies. Abit like enforcing EU policies in some EU countries:-). What is the point of it or don't request it. We caught out a few, however if journals don't enforce their own policies then change never happens.

The Wellcome Trust, the Medical Research Council and the MS Society all have the ARRIVE guidelines as a condition of grant. How many people they support actually do this? A summer project for a student I think:-). The authors own publications acknowledging the charities for support is the noose:- What do you think we will find:-)

Any way back to this one and the STROND guidelines. 

This paper puts the STROND guidleines in the context of MS,
we did one in the context of EAE.

Baker D, Amor S. Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis.J Neuroimmunol. 2012 Jan 18;242(1-2):78-83.

Although we got most people from the International Neuroimmunology Society board to agree to the content, it should have had big gun names on it to give it could be the case here because if they all endorse it sets the example. Unfortuanately the big guns are often the guilty ones.

Likewise, although we were guilty of this faux pas too, it is abit silly issuing guidelines that are not open access because most people can't read them. So if you want to know the 15 guidelines which are actually more than 15 because there are sub guidelines

Development of the Standards of Reporting of Neurological Disorders (STROND) checklist: A guideline f or the reporting of incidence and prevalence studies in neuroepidemiology.Bennett DA, Brayne C, Feigin VL, Barker-Collo S, Brainin M, Davis D, Gallo V, Jetté N, Karch A, Kurtzke JF, Lavados PM, Logroscino G, Nagel G, Preux PM, Rothwell PM, Svenson LW. Neurology. 2015 ;85(9):821-8. doi:

It should be open source so you can read them.

Education: Divisions of the Nervous System

Here is a video explaining the division of the nervous system. The central nervous system is made up of the brain the spinal cord AND the eyes.

Tolerability of Di Methyl Fumarate

Fox EJ, Vasquez A, Grainger W, Ma TS, von Hehn C, Walsh J, Li J, Zambrano J.Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE).Int J MS Care. 2016 Jan-Feb;18(1):9-18. doi: 10.7224/1537-2073.2014-101

BACKGROUND: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval.
PATIENTS AND METHODS: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales.
RESULTS: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, anti-diarrheals, and anti-emetics (nausea). Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco.
CONCLUSIONS:Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these event

If you are thinking of using tecfidera this may be of interest to you and how you deal with some of the side-effects. I would say talk to your neuro/MS nurse for treatment options and MS management.

ResearchSpeak: what have the leukodystrophies and MS in common?

I wonder how many PPMSers have been misdiagnosed? #ResearchSpeak #MSBlog #MSResearch

"When I was still a 'junior neurology consultant' I made a spot diagnosis over the telephone that may have been life saving. One the lab technicians phoned me for advice. Her aunt who was in early 50's with a diagnosis of PPMS and been admitted to her local hospital in 'shock' with a very low blood pressure and low glucose level and was in intensive care and not doing well. She was asking me for advice. This lady had presented in her 40's with a progressive spastic paraparesis and was investigated and diagnosed as having PPMS. When I heard the story I suggested the medical team make sure she did not have Addison's disease (adrenal failure) and if she did the diagnosis of PPMS may be wrong; I suggested she could have adrenomyeloneuropathy (AMN) and adrenal failure. It turns out I was right and the diagnosis of PPMS was wrong. Don't be surprised this is not an uncommon mistake. AMN is a relatively rare inborn error of metabolism due to faulty, or mutated, gene located on the X-chromosome. The gene is called ABCD1 and encodes for the so called peroxisomal membrane transporter which is responsible for transporting very long chain fatty acids into the an organelle called the peroxisomes for degradation. Mutations in this gene that interfere with this process, damage the myelin, and cause AMN. We usually make the diagnosis by screening the blood for long-chain fatty acid levels (raised) and checking peripheral nerve conduction studies (slow conduction due to faulty myelin). In general I don't make a diagnosis of PPMS without a battery of tests that includes these two tests."

"As the ABCD1 gene is on the X-chromosome it has a different manifestation in males and typically causes adrenoleukodystrophy (ADL), a devastating white matter disease of males. ADL is interesting in that it has an inflammatory variant that has many imaging and pathological features similar to MS, including the presence of locally synthesised oligoclonal IgG bands (OCBs) in the spinal fluid. How the hell does a genetic disorder trigger focal inflammation in little boys that looks very similar to MS, but cause a more indolent delayed neurodegenerative disease in adult female carrier? Answer this question and we may be able to find the cause of MS. In addition to ADL/AMN, many of the other leukodystrophies (white matter dystrophies) have similarities to MS. Can those of us who work in the field of MS learn from those researchers and clinicians working in the leukodystrophy field, and vice versa? Yes, I am sure we can. To address this cross-fertilization of ideas we are hosting an open UCLP MS & Leukodystrophy meeting at Queen Square. I am giving an overview of the diagnosis of MS and how we define a disease when we don't know its cause. For the leukodystrophies the definition and diagnosis are usually based on a genetic test. Whatever happens at this meeting it should be good fun and hopefully it will generate some new ideas that may benefit you in the future."

Sunday, 28 February 2016

Extending the Dose interval of natalizumab

Extended interval dosing of natalizumab in multiple sclerosis.
Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, Pandey K, Donnelly S, Pawate S, Bomprezzi R, Smith D, Kolb C, Qureshi S, Okuda D, Kalina J, Rimler Z, Green R, Monson N, Hoyt T, Bradshaw M, Fallon J, Chamot E, Bucello M, Beh S, Cutter G, Major E, Herbert J, Frohman EM.J Neurol Neurosurg Psychiatry. 2016 Feb 25. pii: jnnp-2015-312940.

BACKGROUND:Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.

METHODS:A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.

RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.

CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.
In this study they look at the effect of extending the dose interval from 4 weeks and report that by extending the dose interval to 8 weeks dose not dimish effectiveness to natalizumab to MS. They are doing this on the grounds of diminishing the risk to PML, ProfG commented on this view before but is this a case of treatment by numbers?

If delayed treatment was used there were less PML, less new lesions and less enhancing lesions. However the changes were small. If you have less lesions you would think you have less immune survelliance of CNS and greater chance of PML. However, if you delay giving drug and people get break though disease it is a worry. ProfG has reported on this.
Maybe the intelligent way is to work out if you need redosing is to work ot what is happening to the CD49d on the lymphocyte/monocyte surface. If it is completely blocked then the CD49d is blocked, them it cant interact with VCAM on the cell surface of the endothelia in the blood vessel and white blood cells can't get into the CNS to cause lesions This could be tested with a blood test and the cells ability to cross endotheial barriers in a test tube. However is this type of personalisd medicine we should be aiming towards. Could it mean more frequent dosing

One person with MS called natalizumab their cocaine as they could tell when the drug was wearing-off and when it was time for their next fix.

Maybe the best way to avoid PMLif you are JC virus positive is to switch.  Maybe Prof G can give you his opinion

Saturday, 27 February 2016

BrainHealth & ClinicSpeak: can the Brits really beat the Aussies?

How competitive are you when it comes to the health of your brain? #BrainHealth #ClinicSpeak #MSBlog #MSResearch

"I have been banging 'the holistic management of MS - brain health' drum for sometime now, hoping that the community will take the message seriously. If you repeat things enough people may start to say, yes I think this Giovannoni character is making a serious point. This is why the paper below is so important; it shows that MSers who exercise more and have higher self-rated health had lower levels of functional limitations 11 years later, i.e. less disability. Is this chicken or egg? Did the exercise result in better outcomes or did those MSers who were doing well simply able to exercise more? Is this observation an association or is it causal? For this we need to do randomised trials or look to animal models and other data to make the case that exercise is actually good for you. It is clear that exercise is more than just a manifestation of being physically able; exercise has biological effects that change the way the brain functions. Therefore I am going to stick my head out and state that exercise should be classified as a disease-modifying treatment for MS and that everyone with MS should be enrolled in an exercise programme of some description. It doesn't matter how disabled you are there is always a form of exercise that you will be able to perform. If you don't have MS and are reading this post you should also be doing regular exercise. The data linking regular exercise to a reduced risk of developing dementia, or age-related cognitive impairment, is overwhelming. The problem we face is that as our society gets more sedentary how do we get people to do more exercise? This is a big public health challenge. Any ideas? May be we need to formalise our Barts-MS Brain Health Challenge into something more concrete? A MS clinical nurse specialist from Australia contacted me about setting up a platform so that Australian MS Healthcare professionals and MSers can compete against UK MS HCPs & MSers. I think this is great idea, but have no idea how to do it and how we would judge the outcome. I would also expect the Aussies to whip the Brits they seem to be much more competitive by nature. This may have something to do with the 'Empire always fights back' and wins. However, going on the last haul of medals in the summer Olympics I may be incorrect. Mouse Doctor tells me even his beloved county of Yorkshire won more medals than Australia; 'the times they are a-changin'. 

"The corollary to exercise and health was that stress and barriers in relation to health responsibilities were related to higher levels of functional limitations in year 11. Again this makes sense and suggests that we really need to proactively manage stress and do something to activate MSers to remove barriers that prevent them taking responsibility for their health. I see the latter play out in my clinic week after week; my patients who take responsibility for their disease and are proactive about their disease do better when compared to my patients who are passive recipients of our advice, remaining in denial about their disease or are perpetually worried about the future."

"Carpe Diem, seize the day, today will be yesterday tomorrow! You have don't have time to waste, remember 'time is brain'."

BACKGROUND: Multiple sclerosis (MS), a chronic neurological disease typically diagnosed in young adulthood, presents with a wide variety of symptoms, impairments and functional limitations. Given the chronic, unpredictable and long-term nature of this disease, preserving function is essential.

OBJECTIVE: The purpose of this study was to identify psychosocial and behavioral factors that might influence the trajectory of functional limitation through eleven years of longitudinal follow-up of a sample of persons with MS.

METHODS: Participants (N = 606) completed measures of health behaviors, related constructs and functional limitations annually over eleven years. Longitudinal measures of functional limitations were analyzed using random-effects regression that allows for study of individual differences in the trajectories of a measure. Using the best fitting quadratic growth model, we tested the within and between-person effects of Nutrition, Interpersonal Relationships, Exercise, Stress Management, Health Responsibilities, Spiritual Growth, Self-rated Health and Barriers, controlling for Age, Year since Diagnosis and Year of Dropout, on Functional Limitations in the 11th year.

RESULTS: After adjusting for covariates, higher mean scores for Exercise and Self-rated Health were related to lower levels of Functional Limitations in Year 11. Higher mean scores for Stress Management, Health Responsibilities and Barriers were related to higher levels of Functional Limitations in Year 11. Higher mean Exercise scores and lower mean Health Responsibilities scores were related to slower rates of progression of functional limitations in Year 11.

CONCLUSION: Findings suggest that the highly variable trajectory of functional limitations in MS may be extended and shaped through health behavior strategies.

MS is Asia

Eskandarieh S, Heydarpour P, Minagar A, Pourmand S, Sahraian MA.Multiple Sclerosis Epidemiology in East Asia, South East Asia and South Asia: A Systematic Review. Neuroepidemiology. 2016 ;46(3):209-221. 

BACKGROUND: Multiple sclerosis (MS) is one of the most common chronic immune-mediated diseases of the human central nervous system and an important cause of non-traumatic neurologic disability among young population in several countries. Recent reports from East Asia, South East Asia and South Asia have proposed a low to moderate prevalence of MS in these countries.
METHODS:A literature review search was carried out in December 2014 in Medline, Embase, Scopus and Cochrane library to recover original population-based studies on MS epidemiology in East Asia, South East Asia and South Asia countries published between January 1, 1950 and December 30, 2014. We intended search strategies using the key words: multiple sclerosis, prevalence, incidence and epidemiology. Based on our inclusion criteria, 68 epidemiologic studies were included in this systematic review.
RESULTS: The most extensively used diagnostic criteria in the studies were McDonald's criteria. Most studies were performed in a multi-center hospital setting. The female to male ratio varied and ranged from 0.7 in India to 9.0 in China. The mean age at disease onset ranged from the lowest age of 25.3 in Iran to the highest age of 46.4 in China. MS prevalence ranged from 0.77 in 100,000 populations in Hong Kong (1999) to 85.80 in 100,000 in Iran (2013).
CONCLUSIONS: Advances in MS registries around the globe allow nationwide population-based studies and will allow worldly comparisons between the prevalence and incidence in different regions that are provided to monitor estimation

Friday, 26 February 2016

ResearchSpeak: reply to an email from an expert PPMSer

Why shouldn't MSers engage with drug development for progressive MS? #ResearchSpeak #MSBlog

"The following is a personal email I received from a reader on the blog that I thought I should respond to via the blog as it has relevance to many people with PPMS."

Problem with sleeping, due to anxiety, so I thought I just drop you a line, that hopefully you can air about in your blog.

I wonder if you can bring up in your blog, the statement you made earlier on in your blog about an experimental agent called laquinimod (LAQ). It was written some time ago, namely 10 sept 2013 and also I managed to google an abstract where you were one of the authors connected to Ectrims 2014.

The title of the blog that you wrote is: "Is laquinimod the new wonder drug that progressive MSers need?". The statement you made in this blog , was that laquinimod is the first drug that has shown in phase III Clinical trials to have an impact on disability INDEPENDENT of RELAPSES and MRI activity. And to my understanding the HR was 0.61, in essence a 39% risk reduction in relapse free patients to have CDP (confirmed disability progression) in favour for laquinimod.

QUESTION 1: so since I have progressive MS myself, I of course wonder if that statement sticks, to your best knowledge; I mean that laquinimod is the first drug able to halt disability in non-relapsing MS patients in the Phase III studies, even if it was in RRMS patients? If your statements sticks, it sounds inspiring and that I as a patient could be cautiously optimistic about the ongoing PPMS trial with this laquinimod. Who knows, maybe this agent will have a fair chance for success in PPMS. We have now Ocrelizumab, but I was a little disappointed by the results. But the hype was too big, so there were bound to be some disappointments.

REPLY: "Yes, I stick by my statement that laquinimod has a striking impact on disability, and for that matter progressive brain volume loss, or brain atrophy, independently of relapses. It is not necessarily the only drug, when we do so called post-hoc analyses of subjects in other studies of high efficacy drugs we also see an effect when we compare these to placebo-treated subjects who were relapse-free in the studies. However, are these patients really relapse-free? In other words they may have had subclinical relapses (MRI activity) that was driving disease progression. But laquinimod is a DMT that only has a modest effect on relapses and focal MRI activity and yet has a much larger impact on disability progression and brain atrophy. This observation is not unique to laquinimod and has been observed with another drug called ibudilast, which is also in phase 2 clinical trials in progressive MS. It is clear that these drugs are working downstream of focal inflammatory MS lesions and may be targeting the so called hot-microglia that we think are responsible for driving some of the nerve and axonal loss in progressive MS."

REPLY"I don't think you should be disappointed by the results of the ocrelizumab results. They were clearly positive in an early population of people with PPMS. Ocrelizumab may become the platform treatment onto which we add neuroprotective drugs like laquinimod. Who knows the combination of ocrelizumab and laquinimod may be so much more effective than either agent alone."

QUESTION 2: Furthermore, I also found an abstract, where you contributed, with the title "Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression". It was published at Ectrims in October 2014 (see abstract below). Now my second and last last question would be, that apart from that this poster and abstract showed some positive result for the subgroup EDSS over 3, in that the laquinimod subgroup showed a 59% treatment effect on the MSFC measure T25FW, you also made a remark or conclusion, that "an interaction between LAQ treatment effect on T25FW and CDP (I quote abstract) was found: pts on PBO in the EDSS > 3, who also showed CDP declined with 8.6 seconds more than equivalent LAQ treated patients". This should also work in favour for having some hopes for laquinimod in PPMS. So this measure also works in favour, or points, in a direction that laquinimod could serve a treatment purpose in PPMS in the future, given that ongoing trials will hopefully show positive results. So my question is then: does this abstract, "Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression ", provide a reasonable rational to perform a PPMS study with laquinimod - especially combined with the positive results on CDP in non-relapsing patients - a penny for your thoughts on the matter Prof Gavin? 

REPLY"Yes, these observations and the effect of laquinimod on brain volume loss is precisely the reason why we are doing a study of laquinimod in PPMS. Teva the sponsor of this study would not be spending large amounts of money unless there was a compelling case for testing laquinimod in PPMS. I should add that there is also a large unmet need in this group as well."

To be noted: I am aware of that Teva have had to terminate the highest dose, 1.5 mg in PPMS. But the dose 0.6 mg continues, and the above results is, to my best understanding, based on the 0.6 mg dose, which were used in both previously performed phase III studies with laquinimod. To my best understanding, this dose 0.6 had no arising safety problems, as the case were with the dose 1.5 mg.

REPLY"Yes, you are correct the safety signal that has been noted with with the higher doses of laquinimod. There was a press release earlier this year that stated that non-fatal cardiovascular events occurred in 8 people on the higher doses (1.2mg or 1.5mg)."

Remark, for the record: According to abstract there were no significance different between PASAT and 9HPT z scores. But the MSFC measure T25FW results seem solid enough - yes encouraging; which, to my opinion was rather impressive, if it would stick in the PPMS study Arpeggio with laquinimod. 

REPLY"Yes, I agree with you and that is why we are continue to recruit and follow-up all the patients in the ARPEGGIO, or PPMS laquinimod, study. I am the principal investigator on this study and am very supportive of it continuing, for the reasons you highlight above."  

I have some problems with upper limbs, which negatively affect my ability to write, so please excuse me for all spelling errors and also it is very late into the night. Most obliged if you could give an comment on this agents prospects in PPMS, based on your "claims" or statement before, as aired above.

REPLY"I remain very optimistic about laquinimod as a potential treatment for PPMS. I still standby my previous posts that I think laquinimod, or a laquinimod-like drugs, will be best used as add-on neuroprotective therapies. According to our treatment pyramid below they will need to be added onto a platform anti-inflammatory therapy. However, to do combination therapy trials you have to have one of the drugs licensed. So the big debate in our heads is which agent should you add laquinimod on to? My preference would be to add on  top of an induction therapy."

Now time to go to bed. And in fact a little less anxiety about my MS disease after this writing. Sometimes it helps just to write on the matter, especially if you see some hope out there.

REPLY"Thank you for taking the time to read our blog and to make quite sophisticated arguments about how we need to treat PPMS. I actually thrilled to see someone with PPMS have such a clear understanding what we are trying to achieve and more importantly has hope. Hope is such a positive thing; a world without hope would be a very dark place."

"Don't worry about your writing, I took the liberty of make a few minor grammatical and typographical corrections to make it easier for the readers. Sleep well."

Background: In pooled data from the Phase III ALLEGRO and BRAVO studies of oral laquinimod (LAQ) 0.6mg once-daily (QD) vs. placebo (PBO) in RRMS, a 46% reduction in 6-month confirmed disability progression (CDP) was not accompanied by a significant treatment (Tx) effect on the Multiple Sclerosis Functional Composite (MSFC). However, for a subgroup of LAQ-treated patients (pts) with worsening MS (EDSS >3 at baseline [BL]), a 53% reduction in 6month CDP was accompanied by a significant MSFC effect vs. PBO.

Objectives: To investigate LAQ 0.6mg QD Tx effects on individual MSFC components in the pooled ALLEGRO and BRAVO pt subgroup with BL EDSS score >3, and to determine the association between MSFC component scores and improvements in CDP. 

Methods: Pooled data from ALLEGRO and BRAVO (N=1990) were used for this post hoc analysis of LAQ vs. PBO Tx effects on change in MSFC subscores at 24 months for the Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HPT), and Timed 25-Foot Walk (T25FW), in pts with EDSS >3 at BL. Adjusted mean z-score differences and 95%CIs were evaluated by ANCOVA. CDP was defined as an increase of 1 point if BL EDSS was ≤5.0, or of >0.5 point if BL EDSS was 5.5.

Results: Overall, 655 pts (33%) had a BL EDSS score >3 (LAQ n=328, PBO n=327), with a mean (SD) BL EDSS score of 4.1 (0.7). At BL, pts in the EDSS >3 subgroup were older than pts with BL EDSS ≤3 (mean age 41 vs. 37 years, respectively), had longer disease duration (5.2 vs. 3.7 years), and less brain volume (1547 vs. 1601 cm3). Mean (SD) T25FW time at BL was 8.29 (6.8) seconds (5.40 [5.3] seconds in the EDSS ≤3 subgroup). A 59% LAQ Tx effect on mean [SE] T25FW time (-2.79 [0.96] seconds, 95%CI -4.66, -0.92; p=.0035) appeared to drive the overall MSFC benefit in the EDSS >3 subgroup. There was no significant difference between LAQ and PBO for change in PASAT or 9HPT z-scores, though change directions favored LAQ. Further, an interaction between LAQ Tx effect on T25FW and CDP was found: pts on PBO in the EDSS >3 subgroup who also showed CDP declined by 8.6 seconds more than equivalent LAQ-treated pts.

Conclusions: In pts with worsening MS and EDSS >3 at BL, LAQ was associated with a substantial benefit on ambulatory function as measured by the T25FW, consistent with LAQ CDP benefit in these pts.

CoI: multiple, I am the principal investigator on the PPMS laquinimod trial

Collecting Stem Cells

Kyrcz-Krzemień S, Helbig G, Torba K, Koclęga A, Krawczyk-Kuliś M. Safety and efficacy of haematopoietic stem cells mobilization in patients with multiple sclerosis. Hematology. 2016 Feb. [Epub ahead of print]

Introduction Multiple sclerosis (MS) is a T-cell-mediated chronic inflammatory disorder of the central nervous system. Several agents have been approved for treatment of MS, however their efficacy is limited and short term. Autologous haematopoietic stem cell (HSC) transplantation may remain an encouraging option for some MS patients who failed prior conventional treatment. Objective To assess the safety and effectiveness of HSCs mobilization in patients with MS. 
Material and methods Thirty-nine patients (20 females, 19 males) with relapsing-remitting MS at median age of 40 years (range 25-63) were included in this study. As a stem cell mobilization they received either granulocyte colony-stimulating factor (G-CSF) alone (10 μg/kg s.c. daily; n = 1) or cyclophosphamide (CY; 2.0 g/m2 i.v. on days 1-2) followed by G-CSF (n = 38). 
Results The median number of mobilized HSCs per kilogram was 6.32 × 106 (range 2.64-26.3 × 106). One apheresis was sufficient for collection of HSCs in 30 out of 39 MS patients (77%). Two aphereses were required for seven patients, three for one patient, and four for one patient (17, 3, and 3%, respectively). 
Side effects of HSCs mobilization have been reported for eight patients (30%) and they were as follows: Staphylococcus epidermidis bacteremia (n = 1), fever of unknown origin (n = 3), diarrhea (n = 3), and headache (n = 1). 
Conclusions Mobilization using CY and/or G-CSF resulted in effective mobilization in all MS patients. This procedure was found to be safe. No fatal outcome has been reported.

This study takes about stem cell mobilization from the bone marrow into the blood. This is the first part of the immunosuppression. 

Apheresis (ἀφαίρεσις (aphairesis, “a taking away”)) is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation.

Other agents are then used  to deplete the immune system such as ant-T cell treatments.

Imaging myelination

Dynamic imaging of individual remyelination profiles in multiple sclerosis.Bodini B, Veronese M, García-Lorenzo D, Battaglini M, Poirion E, Chardain A, Freeman L, Louapre C, Tchikviladze M, Papeix C, Dollé F, Zalc B, Lubetzki C, Bottlaender M, Turkheimer F, Stankoff B. Anals Neurol. 2016. doi: 10.1002/ana.24620. [Epub ahead of print]

BACKGROUND: Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, [11C]PIB can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.
METHODS: Patients with active relapsing-remitting MS (n=20) and healthy controls (n=8) were included in a longitudinal trial combining PET with [11 C]PIB and magnetic resonance imaging. Voxel-wise maps of [11 C]PIB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.
RESULTS: At baseline, there was a progressive reduction in [11 C]PIB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p=0.006 and beta-coefficient=-0.67 with the Expanded Disability Status Scale; p=0.003 and beta-coefficient=-0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.
CONCLUSIONS:[11 C]PIB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs
If you want to promote remyelination. The key is to measure it.
This has relied on electrophysiology but this means that the optic system has been the focus for studies. If you want to look in brain or spinal cord you need to be able to image it. Using a radioactive tracer this was achieved. However PIB is not specific for myelin and detects beta amyloid 

Thursday, 25 February 2016

PoliticalSpeak & OffLabel: high-cost drugs in the US

Will the war on high-cost drug pricing stifle innovation? #PoliticalSpeak #MSBlog #OffLabel

"We have had much debate on the issue of high-cost drugs on this blog and have discussed the pros and cons endlessly. We have also taken a stand on the issue of the unaffordability of high-cost DMTs for pwMS living in resource-poor healthcare environments and have actively promoted off-label prescribing as a way of addressing this issue. If you have MS and couldn't afford a high-cost drug aren't you better off on a cheap off-label DMT that has some evidence supporting its efficacy in MS? This strategy is pragmatic and makes sense as we move from 'simply putting pwMS on a DMT and hope for the best' strategy to 'treat-2-target of NEDA'. With a treat-2-target strategy pwMS who don't respond to one DMT will be switched to another class of DMT with more efficacy."

"The following perspective article in the NEJM highlights some of the issues in the US with high-cost drugs and some of the options the US Federal government has to reduce the price of drugs. This is not a trivial issue; in relation to MS DMTs some products cost 5x more in the US than they do in the UK. NICE has been very effective at driving a hard bargain with Pharma to get down the costs of DMTs for pwMS in the UK. This is also happening in most other countries with socialised healthcare systems. It was only a matter of time before the US Federal Government would put a stop to the US subsidizing drug development costs for the world. The new fight on high-cost drugs in the US, is the beginning of this process of sharing the burden of drug development costs. These US initiatives will have knock-on effects and I suspect as we see drug prices fall in the US we will seem them start to rise in Europe and the rest of world."

"Some of the issues raised in this perspective piece are very interesting and hence I would suggest you read the whole article. A very interesting point highlighted in the perspective is that when central governments get involved in procuring access to new and innovative drugs they reduce pharma investment in innovation. Good examples of this is the virtual absence of a market for innovation in vaccines and antibiotics in the US. I recall a similar problem in the UK about 15 years ago when the Department of Health interfered with the market for IVIG (intravenous immunoglobulin); they allowed a subsidised product onto the market that was being made by a spin-off company from the Blood Transfusion Service. The subsidised UK product had an unfair advantage undercutting the private providers to such an extent they couldn't make any money; they voted with  their feet and pulled out of the UK market. As the blood transfusion service couldn't produce enough IVIG we had a shortage of IVIG in the UK that led to its rationing. A a result of this rationing many patients couldn't be treated with IVIG and we had to use resort to using more invasive alternative treatments, such as plasma exchange. This is an example of the law of unintended consequences; you think you are doing good by lowering prices, but in the long run you may be doing the exact opposite by reducing incentives for innovation. This is a difficult balancing act  for politicians and is probably why there is so much debate and disagreement about how to deal with the issue of high-cost drugs. Another question we need to ask ourselves is how did we allow ourselves to get into the situation where drug development costs have become so high (and risky)?"

Conti & Rosenthal. Perspective: Pharmaceutical Policy Reform — Balancing Affordability with Incentives for Innovation. N Engl J Med 2016; 374:703-706.


......The high prices of prescription drugs have become an issue of paramount concern to Americans. This concern has now found its way into policy proposals from presidential candidates and is preoccupying state and federal lawmakers.....

...... Congressional investigations are examining the way in which drug companies set prices, and proposals for making drug pricing more transparent are pending in seven state legislatures.....

..... Lawmakers and others have identified multiple possible reforms to address the affordability of prescription drugs......

...... Direct negotiation of prescription-drug prices by the federal government, however, is a solution for which there may be little congressional appetite.....

....... Patient-advocacy groups and pharmaceutical companies are united in their concern that with substantially increased government involvement come the risks of reduced access of patients to new drugs and reduced company investment in innovation. They point to the virtual absence of a market for innovation in vaccines and antibiotics, therapeutic classes for which the federal government is the monopsony purchaser......

....... The prospect of losing ground on innovation and diminishing their own credibility with industry partners has chilled lawmakers’ previous resolve to enact direct regulation of pharmaceutical prices......

....... Public outrage over recent high-profile cases of extreme pricing in the U.S. pharmaceutical market suggest that our laissez-faire system may not be achieving the balance of affordability and incentives for innovation that Americans want.....

....... Realistically, the best options for meaningful reform of prescription-drug policy to improve this balance focus on increasing value-based competition......

........ However, market-driven policies are not a panacea. They do not resolve the dilemma of extremely high launch prices for arguably high-value new products without close competitors.....

....... To preserve incentives for welfare-increasing innovation, the rewards for developing such products must be substantial, but if prices are the only mechanism through which returns on research flow, affordability will be compromised.....

........ Evidently, there is no single, easy answer to high and escalating drug prices in the United States.......

CoI: multiple

Cannabis Discontinuation

Fernández Ó.THC:CBD in Daily Practice: Available Data from UK, Germany and Spain Eur Neurol. 2016;75 Suppl 1:1-3.

BACKGROUND:From the time Sativex (THC:CBD) oromucosal spray first became available in European Union countries in 2010 for the management of treatment-resistant multiple sclerosis (MS) spasticity, data from daily practice have been collected through various projects.
METHODS:A retrospective registry study and a prospective safety study of THC:CBD oromucosal spray are reported.
RESULTS:The most recent analysis of a retrospective registry established in the United Kingdom (UK), Germany and Switzerland, which collected safety data on more than 900 patients, has indicated a positive risk-benefit profile for THC:CBD oromucosal spray during long-term use. Long-term continuation rates were 68% (mean follow-up time 1 year) and the mean dose was 5.4 sprays/day. No new safety concerns were identified, and adverse events of special interest for a cannabis-based medicine were limited. The UK registry has since been closed but remains open in Germany and Switzerland. A prospective safety study undertaken in Spain involved 207 patients from 13 specialized MS centres who had been prescribed THC:CBD oromucosal spray. The findings aligned closely with the UK/German/Swiss registry data in terms of 1-year continuation rates (64.7%), mean daily dose (6.6 sprays/day) and safety profile, including no evidence of addiction, abuse or misuse.
CONCLUSIONS:The homogeneity between these observational studies supports the interest in THC:CBD oromucosal spray for management of MS spasticity in daily practice.
This study looks at the rate of continuing to take cannabis and there is about 30% discountinuation rate. This may be because of lack of efficacy or something unwantef such as side effects or perhaps the method of deliver is unpleasant. Sativex is essentiially cannbis in creme de menthe (mint tasting alcohol).

CoI We are developing alternatives and if you live in the London area and now Liverpool (Walton Centre) you could volunteer.

Ages Eligible for Study:  18 Years to 70 Years
Genders Eligible for Study:  Both
Accepts Healthy Volunteers:  No
Inclusion Criteria:
  • Have a confirmed diagnosis of MS
  • Have an Expanded Disability Status Scale (EDSS) ≤ than 6.5 at screening.
  • Spasticity due to MS of at least 3 months duration with minimum mean score of >/=2 m ASHWORTH SCORE
Exclusion Criteria:
  • Acute MS relapse requiring treatment with steroids within 30 days of screening.
  • Initiation or discontinuation of MS disease modifying treatment (DMT) within 30 days of screening.
  • Receiving medications that would potentially interfere with the actions of the study medication or outcome variables
  • Significant renal and hepatic abnormalities
  • Previous history of other significant medical disorders

Wednesday, 24 February 2016

A junior doctor contract example - know your facts

Below is one of the proposed templates for the 2016 junior doctors contract - in this case for ITU trainees.

This is what Jeremy Hunt said the BMA was being unreasonable about...

ClinicSpeak: migraine headaches and MS

Did you know if you have MS you have more than a 1 in 3 chance of being a migraineur? #ClinicSpeak #MSResearch #MSBlog

"How many of you suffer from headache? Did you know that migraine headache is much commoner in pwMS than in the general population? Why? It now become evident that in migraine is much more common in people who have brain disease in general. It seems as if focal pathology, particularly in the hypothalamus and brainstem areas of  the brain, may trigger migraine. In the study below 36% of pwMS had migraine; this is consistent with other studies and is about double the background risk in the general population. The fact that it is so common means that we should probably include headache on our scorecards when we review pwMS to make sure we are not missing headache. Clearly headache is a very common comorbidity in MS and may be contributing to poor quality of life."

"If you don't manage migraine properly you can convert it into a chronic daily headache,  usually as a result of analgesic misuse, that is very difficult to treat. If you have migraine, or frequent headaches, please discuss this with your neurologist so that you can get proper advice and treatment for your headaches. To make things easier for your neurology team I suggest starting a headache diary to document the frequency and severity of your headaches and how they respond to treatments. The management of migraine is broken-up into three classes of treatment; (1) prophylactic therapies, or strategies, to reduce the frequency of headaches, (2) abortive treatments to try a get rid of the migraine before it builds to a crescendo, these treatments are typically given after the onset of the headache and (3) symptomatic treatments, these treatments are given once the migraine is established, i.e. analgesics and antiemetics for the nausea."

"Would you like a more detailed post on the management of migraine headache in MS, including self-management strategies?"

Epub: Sahai-Srivastava et al. Headaches in multiple sclerosis: Cross-sectional study of a multiethnic population. Clin Neurol Neurosurg. 2016 Feb 1;143:71-75. doi: 10.1016/j.clineuro.2016.01.017. 

OBJECTIVES: Headaches in MS are common, but there is little data on the influence of race, comorbidities, MS disability and socioeconomic issues on headaches, especially migraine. We aimed at looking at prevalence and type of headache across a multiethnic MS population, and relationship between MS related clinical factors and migraine.

PATIENTS AND METHODS: This is a cross-sectional study of 233 MS patients at two clinical sites, one at a county hospital, and the other a private academic center clinic. We collected demographic data, MS characteristics, and headache histories using validated survey instruments including Headache Impact Test (HIT-6) and Patient Health Questionnaire-9 (PHQ-9). The relationship between MS and migraine was examined using logistic regression.

RESULTS: Majority of our patients were female (N=156, 67%), average age 44 years, with relapsing remitting MS (N=214, 92%). Our cohort was multi-ethnic predominantly Whites (N=106, 46%) and Hispanics (N=87, 37%). Public sector patients were significantly disadvantaged in socioeconomic measures (p<0.0001) and younger (40 vs 47 yrs, p<0.0001), compared to the private sector patients who had a higher MS burden. Headaches were common, regardless of sector (N=115, 49.4%), the most common type being migraine (N=83, 36%). Chronic migraine was more common among Hispanics (82%) than Whites (18.2%) (p=0.012). Headache impact on daily life, measured by HIT-6 score (p=0.006) and PHQ-9 score (p=0.004) were significantly higher in the public sector. After controlling for income and education, female gender (OR 2.59, 95% CIs 1.312-5.127) and ambulatory disability were found to be more likely to suffer from migraines.

CONCLUSION: Headache, especially migraine is common among MS patients regardless of socio-economic status and treatment setting. Female MS patients with walking disability and longer disease duration tend to get migraines. Hispanic MS patients have a higher likelihood of suffering from chronic migraines. Thorough headache evaluation and headache treatment are essential to comprehensive MS care.

Waning Interest in CCSVI

Medical Tourism for CCSVI Procedures in People with Multiple Sclerosis: An Observational Study.Metz LM, Greenfield J, Marrie RA, Jette N, Blevins G, Svenson LW, Alikhani K, Wall W, Dhaliwal R, Suchowersky O. Can J Neurol Sci. 2016 Feb 4:1-8. [Epub ahead of print]

BACKGROUND:Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non-evidence-based medical tourism for CCSVI procedures.
METHODS: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013.
RESULTS:In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status.
CONCLUSIONS: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.

I will not comment on this, in case it sets off  the crazies, but it is evident that academic interest in this subject matter has waned and publications have become few. 

Tuesday, 23 February 2016

PoliticalSpeak: Judicial review & further junior doctor industrial action

Dear Dr Giovannoni,

Last Saturday, the BMA junior doctors committee met to discuss the decision by the secretary of state to impose a contract on junior doctors in England from August 2016. The resounding message from that meeting is that junior doctors cannot and will not accept this new contract.

As the government's own former patient safety adviser, Prof Don Berwick, pointed out: "You cannot achieve excellence in combat with your future workforce, it makes no sense at all."

It also appears that, in trying to push through these changes, the government failed to give proper consideration to the impact this contract could have on junior doctors. The BMA is now set to launch a judicial review following the embarrassing revelation that the government appears to have failed to undertake an Equality Impact Assessment (EIA) prior to its decision to impose a new contract on junior doctors in England.

The judicial review will seek to overturn the decision to impose the new contract and provide a declaration that the secretary of state had acted unlawfully.

Imposing this contract will seriously undermine the ability of the NHS to recruit and retain junior doctors in areas of medicine with the most unsocial hours, where there are already staffing shortages. As a result, there will be three further dates of industrial action:

− 8am on Wednesday 9 March to 8am on Friday 11 March

− 8am on Wednesday 6 April to 8am on Friday 8 April

− 8am on Tuesday 26 April to 8am on Thursday 28 April

Over each of these 48-hour periods, junior doctors will offer emergency care only.

The government can avert this action by re-entering talks with the BMA. If it pushes ahead with plans to impose a contract that junior doctors have resoundingly rejected we will be left with no option but to take this action. The government must put patients before politics, get back around the table and find a negotiated solution to this dispute which addresses rather than simply ignores the outstanding issues and concerns junior doctors have.

Our goal has always been to secure a properly negotiated contract which respects and values the 24-hour, seven day a week service that junior doctors provide. That goal remains.

Yours sincerely

Mark Porter
BMA council chair

NewsSpeak & PoliticalSpeak: junior doctors in the NHS

Support our junior doctors! The NHS needs them to be happy and satisfied. #NewsSpeak #PoliticalSpeak #MSBlog

ResearchSpeak & NeuroSpeak: JC viral escape post-natalizumab

How cunning is JCV or how foolish is our immune system? #ResearchSpeak #NeuroSpeak #MSBlog #MSResearch

"Nothing in immunology is simple. The dogma in the immunology world is that CD8+ cytotoxic T-lymphocytes (CTLs) are all that is needed to clear the brains of pwMS of JC virus when they have PML. The study below suggests that the CTL response is not enough and that you also need CD4+ T-lymphocytes to help their CTL partners in clearing mutant JCV. This would support the observation that T-cells in  general are important in keeping viral infections at bay in people who are immunocompromised. The 4 cases below of PML on natalizumab indicate that clearance of the virus from the central nervous system is a slow and delayed process. This is why it is not possible to start a pwMS who has recovered, or is recovering, from PML on any DMT that suppresses the immune system. If you do the PML may simply flare-up again. This is why the options of treating MS in this situation are so difficult. The problem we face is that some of these pwMS may have very active disease and are in need of a highly-effective DMT. Could daclizumab be the best DMT in this situation? It is not overtly immunosuppressive and appears to expand the NK-cell population that have antiviral effects. Daclizumab's impact on effector T-cell function, both CD4+ and CD8+, are more subtle, but not negligible. The other option is to use an anti-CD20 monoclonal antibody; there are two on the market at present (rituximab and ofatumumab). The problem with this strategy is that once you give an anti-CD20 monoclonal the effects on the B cell population take many months to wear off. At present we don't think you need B cells to fight JCV. A safer option would be to simply go back to interferon-beta or glatiramer acetate as a treatment option; these may not be high efficacy drugs on average, but if the person concerned has not been exposed to these agents in the past it may be worth seeing if they are interferon-beta or GA responders. Finally, there is the option of not doing anything regarding MS, but as most pwMS on natalizumab have rapidly evolving severe, or highly-active, MS they may need to be on a DMT. There are no easy decisions to make in this situation and all of the above advice is not evidence-based; it is simply supported by scientific, or immunological, principles. This is why the practice of medicine in part remains an art and not a science. Put another way all the advice in this post may be wrong."

Epub: Jelcic et al. Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant. Ann Neurol. 2016 Feb 13. doi: 10.1002/ana.24574.

OBJECTIVE: Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation.

METHODS: We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by delayed clinical improvement.

RESULTS: Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8+ T cells and clonal expansion of activated CD8+ effector T cells with a CD4dim CD8+ phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4+ T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD8+ T-cell responses after IRIS.

INTERPRETATION: Our findings suggest that efficient CD4+ T-cell recognition of neurotropic JCV variants is crucial to support CD8+ T cells in combating JCV infection of the CNS.

CoI: multiple

MS in the USA

Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD.Multiple sclerosis prevalence in the United States commercially insured population.Neurology. 2016 . pii: 10.1212/WNL.0000000000002469. [Epub ahead of print]

OBJECTIVE:To estimate the US commercially insured multiple sclerosis (MS) annual prevalence from 2008 to 2012.
METHODS:The study was a retrospective analysis using PharMetrics Plus, a nationwide claims database for over 42 million covered US representative lives. Annual point prevalence required insurance eligibility during an entire year. Our primary annual MS identification algorithm required 2 inpatient claims coded ICD-9 340 or 3 outpatient claims coded ICD-9 340 or 1 MS-indicated disease-modifying therapy claim. Age-adjusted annual prevalence estimates were extrapolated to the US population using US Census data.
RESULTS:The 2012 MS prevalence was 149.2 per 100,000 individuals (95% confidence interval 147.6-150.9). Prevalence was consistent over 2008-2012. Female participants were 3.13 times more likely to have MS. The highest prevalence was in participants aged 45-49 years (303.5 per 100,000 individuals [295.6-311.5]). The East Census region recorded the highest prevalence (192.1 [188.2-196.0]); the West Census region recorded the lowest prevalence (110.7 [105.5-116.0]). The US annual 2012 MS extrapolated population was 403,630 (387,445-419,833).
CONCLUSIONS: MS prevalence rates from a representative commercially insured database were higher than or consistent with prior US estimates. For further accuracy improvement of US prevalence estimates, results should be confirmed after validation of MS identification algorithms, and should be expanded to other US populations, including the government-insured and the uninsured.

You may be interested in this figure with estimated 400,000 people in USA with MS.

Oral contraception in MS

Eur J Obstet Gynecol Reprod Biol. 2015 Oct;193:1-4. doi: 10.1016/j.ejogrb.2015.06.030. Epub 2015 Jul 9.

Symptoms of multiple sclerosis during use of combined hormonal contraception.

Kempe P, Hammar M, Brynhildsen J.

OBJECTIVE: The incidence and disease course of multiple sclerosis (MS) is influenced by sex steroids, and several studies have shown less disease activity during high estrogen states. We have previously shown variation in symptom experience related to the estrogen/progestogen phase in women using combined hormonal contraceptives (CHC) in a small sample. The aim of this study was to confirm these results in a larger sample.

STUDY DESIGN: Self-assessment of symptoms of MS in relation to CHC cycle by 22 female MS patients. A symptom diary based on a validated instrument for cyclical symptoms was used. Mean symptom scores for high and low estrogen/progestogen phases were compared.

RESULTS: The women scored four out of ten symptoms significantly higher during the pill-free week than during the CHC phase (p<.05).

CONCLUSION: Women with MS report more pronounced symptoms during the pill-free, low-estrogen/progestogen phase of CHC use. Future studies should investigate, with a prospective, controlled design, the effects that continuous-use regimens of CHC have in women with MS.

Hormonal Contraceptives and Multiple Sclerosis Susceptibility (S34.003)

Kerstin Hellwig, Lie Chen and Annette Langer-Gould
Published online before print April 8, 2015 Neurology April 8, 2014 vol. 82 no. 10 Supplement S34.003 

OBJECTIVE: To determine whether contemporary hormonal contraceptives (HC) use increases the risk of MS

BACKGROUND: Whether use of contemporary HCs contributes to the rising incidence of multiple sclerosis (MS) in women is unclear.

DESIGN/METHODS: We conducted a population-based nested case-control study from the membership of Kaiser Permanente Southern California (KPSC). We identified females ages 14-48 years with incident MS or it’s precursor-clinically isolated syndrome (CIS) between 2008 and 2011, who had at least 3 years of continuous membership prior to symptom onset. Ten controls per case were matched on age, race/ethnicity and membership characteristics. Data were obtained from the complete electronic health record and analyzed using conditional logistic regression, adjusted for smoking and live births 3 yrs prior to symptom onset.

RESULTS: We identified 305 incident female cases with MS/CIS and 3050 matched-controls. 29.2% of cases and 23.5% of controls had used a HC for at least 3 months within the 3 years prior to symptom onset. The majority used estrogen/progestin combination preparations. Women that used any hormonal contraceptive in the 3 years prior to symptoms onset, and particularly those that had stopped at least 1 month prior to symptom onset, had a slightly increased risk of MS/CIS (ever-users adjusted OR=1.35, 95%CI=1.01-1.80, p=0.04; not current users adjusted OR=1.50, 95%CI=1.05-2.14, p=0.026).

CONCLUSIONS: Our findings suggest that use of modern hormonal contraceptives may be contributing at least in part to the rise in incidence of MS in women.

Following on from my last weeks post on improving your MS outcomes by tackling obesity, one topic which as a woman I feel requires further exploration is the non-contraceptive effect of the pill on MS. To say the least, the evidence is conflicting. 

The oestrogen used in contraceptive pills is 100-500x more potent than what is naturally produced by our ovaries. Therefore, the effects of oestrogen will be more evident in the combined pill.

Studies have reported lower incidence of MS in those on the combined pill than non-users, whilst women using the pill after diagnosis had a more benign disease course than those who did not. Along the same lines, age of onset of MS symptoms is pushed back following use (onset of 31 years versus 33 years who used contraception), and the years increased based on the duration of intake (24 years old with less than an year of use versus 31 years with more than 10 years use). Above, the first abstract, is a more prospective assessment of MS symptoms on the pill and they found that women on the pill had greater symptoms during the low-oestrogen phase (i.e. over the pill free days 22-28); including vertigo, weakness, urinary symptoms, stiffness and numbness.

Then there is the opposite, the second abstract hints at increased risk of MS/CIS in women who have been on the pill; amounting to roughly 35% even after adjusting for smoking and pregnancy. This increases to 50% in those who stopped 1 month prior to first symptoms. In a follow up study Annette Langer-Gould found that products containing levonogesterol increased the risk by an odds ratio of 1.75 (95% CI 1.29-2.37), while those containing norethindrone increased the risk by an odds of 1.57 (95% CI 1.16-2.12). But it can be argued that in absolute numbers the risk doesn't amount to much owing to the rarity of the disease. In another study from Belgium, involving 973 women with MS, in a subgroup who were progressive onset, oral contraceptive use was associated with a higher risk of reaching EDSS 6 (i.e. the requirement for a walking stick).

This ambiguity over the unknown effects of oral contraceptives will therefore mean that there will be hesitation from prescribers in women with MS than without.