Tuesday, 30 September 2014

Stem cell trials are here

Fred D. Lublin, James D. Bowen, John Huddlestone, Marcelo Kremenchutzky, Adam Carpenter, John R. Corboy, Mark S. Freedman, Lauren Krupp, Corri Paulo, Robert J. Hariri, Steven A. Fischkoff DOI: http://dx.doi.org/10.1016/j.msard.2014.08.002

Background:Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis.
Objective: This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis.
Methods:This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150 million cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×million cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter's rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse.
Results Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter's rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score >0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection.
Conclusion:PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.

So in this study stem cells were given to MSers and there as no disease worsening. However was their any improvement,  Maybe but too early to tell but effects were clearly not miraculous, or it would be plastered over the media. However what happens to the cells that are transplanted?

Another pro-myelinating factor

 Cruz-Martinez P, Martinez-Ferre A, Jaramillo-Merchán J, Estirado A, Martinez S, Jones J.FGF8 Activates Proliferation and Migration in Mouse Post-Natal Oligodendrocyte Progenitor Cells. PLoS One. 2014 Sep;9(9):e108241. doi: 10.1371/journal.pone.0108241. eCollection 2014

Fibroblast growth factor 8 (FGF8) is a key molecular signal that is necessary for early embryonic development of the central nervous system, quickly disappearing past this point. It is known to be one of the primary morphogenetic signals required for cell fate and survival processes in structures such as the cerebellum, telencephalic and isthmic organizers, while its absence causes severe abnormalities in the nervous system and the embryo usually dies in early stages of development. In this work, we have observed a new possible therapeutic role for this factor in demyelinating disorders, such as leukodystrophy or multiple sclerosis. In vitro, oligodendrocyte progenitor cells were cultured with differentiating medium and in the presence of FGF8. Differentiation and proliferation studies were performed by immunocytochemistry and PCR. Also, migration studies were performed in matrigel cultures, where oligodendrocyte progenitor cells were placed at a certain distance of a FGF8-soaked heparin bead. The results showed that both migration and proliferation was induced by FGF8. Furthermore, a similar effect was observed in an in vivo demyelinating mouse model, where oligodendrocyte progenitor cells were observed migrating towards the FGF8-soaked heparin beads where they were grafted. In conclusion, the results shown here demonstrate that FGF8 is a novel factor to induce oligodendrocyte progenitor cell activation, migration and proliferation in vitro, which can be extrapolated in vivo in demyelinated animal models.

Fibroblast growth factor 8 is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This promoted cell activation, migration and proliferation, so is yet one more signalling molecule that stimulates myelination

ClinicSpeak: switching from injectables to fingolimod

Satisfaction is high in those who switch from injectables to fingolimod: #ClinicSpeak #MSBlog #MSResearch

"This open-label study below shows that MSers switching from injectables therapies (IFNbeta and GA) do better on fingolimod a second-line DMT in most of Europe. This study mirrors our clinical experience with the drug. Are you surprised MSers do better when moving to an oral therapy that on average is more effective that the injectable therapies and is not associated with injection-site reactions or flu-like side effects? You also have to remember that the commonest reasons to switch therapies is breakthrough disease activity hence it is not surprising MSers do better on fingolimod. It is also reassuring that the side effect profile is no different to that seen in the pivotal phase 3 studies."
"There is data that has emerged from MSBase that if stay fail one so called 1st-line DMT and switch  to another 1st-line DMT you do worse on average than if you are escalated to more effective 2nd-line therapies, i.e. fingolimod or natalizumab. For this reason it is our practice to only let MSers have on trial of so called 1st-line or platform therapies. Please note these observations are average effects and individual MSers may do better than others on particular drugs. Unfortunately we still don't have any data to support stratification, so it remains a trial and error to select the most effective drug for the individual." 

Background: The Evaluate Patient OutComes (ClinicalTrials.gov Identifier: NCT01216072) study was conducted in North America to assess MSer- and physician-reported treatment satisfaction in MSers with relapsing multiple sclerosis (MS) who received oral fingolimod for 6 months after switching from an injectable disease-modifying therapy (iDMT), without an intervening washout.

Methods: In this open-label, multicenter study, MSers were randomized 3:1 to once-daily fingolimod 0.5 mg or iDMT. The primary study objective was to evaluate differences in satisfaction measured using the Treatment Satisfaction Questionnaire for Medication v1.4.

Results: Of 1053 MSers randomized, 790 MSers received fingolimod and 263 MSers received iDMT. Treatment satisfaction improved significantly in MSers who switched to fingolimod compared with those who continued iDMT. MSers also reported significant improvements in health-related quality of life, reduced depression, and reduced fatigue severity after a switch to fingolimod. No difference between the treatment groups was detected on the Patient Reported Indices for MS Activities scale. The safety profile of fingolimod was consistent with that reported in the pivotal phase 3 studies. The most commonly reported adverse events were more prevalent in MSers who switched to fingolimod than in those who continued iDMT (headache: 12% vs 3%; fatigue: 12% vs 6%). No significant relationship between lymphocyte counts and infection rates was observed and there was no evidence of additive immune-system effects, which might be expected when switching to a different class of immunomodulatory therapy with no intervening washout.

Conclusion: MSers who switched from iDMT to fingolimod had significant improvements in most self-reported outcomes compared with those who continued iDMT.

CoI: multiple

Monday, 29 September 2014

How much does a Relapse Cost?

K. O׳Connell K et al. Economic costs associated with an MS relapse Mult Scler Rel DisordDOI: 10.1016/j.msard.2014.09.002

Background:Multiple sclerosis (MS) commonly affects young adults and can be associated with significant disability resulting in considerable socioeconomic burden for both patient and society.
Aims:The aim was to determine the direct and indirect cost of an MS relapse.
Methods: This was a prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration,expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals and travel costs.
Results: Fifty-three patients had a clinically confirmed relapse. Thirteen were of low intensity; 23 moderate intensity and 17 high intensity with mean costs of €503, €1395 and €8862, respectively. Those with high intensity episodes tended to be older with higher baseline EDSS (p<0.003) and change in EDSS (p<0.002). Direct costs were consistent in both low and moderate intensity groups but varied with length of hospital stay in the high intensity group. Loss of earnings was the biggest contributor to indirect costs. A decision to change therapy as a result of the relapse was made in 23% of cases, further adding to annual MS related costs.
Conclusions: The cost of an MS relapse is dependent on severity of the episode but even low intensity episodes can have a significant financial impact for the patient in terms of loss of earnings and for society with higher annual MS related costs.
How much does a relapse cost is so difficult to calculate and in human terms this could be devastating. One catastrophic relapse where the lesions occur in a very important place, can leave you very disabled...So my advice is best not to have them.

However, there are monitory costs also...this paper does not concern itself with the costs to the affected person which could equally be devastating, such as loss of employment....So my advice is best not to have relapses

However their are costs to the hospital service too. How much are the costs...This depends on where you are located if it was Dr. House in the USA doing the work up you would have brain biopsy lumbar puncture, brain scane etc etc etc. However this study was based out of the Republic of Ireland (Eire).

The average cost in Ireland is €15,000 per year for first-line therapy rising to €22,000 per year for second-line agents and are a significant contributor to the direct costs early in the disease.
The cost of an MS relapse was determined by the severity of the episode and the baseline disability level of the person with MS.  Higher costs were driven primarily by hospital admission and length of stay.

Greater variability was seen in indirect costs across all three groups as might be expected from the diverse demographics of a relatively small patient sample. Unsurprisingly, the main component of this figure was loss of earnings. MS typically affects young adults when they are most economically productive. High rates of early retirement on medical grounds are seen in patients with MS with significant socioeconomic consequences for the individual, their family and society as a whole. 

This study showed that even low intensity episodes can have significant financial implications both for the patient, in terms of loss of income and for society, with increasing annual MS related costs due to initiation or change of treatment

Fampridine making facial pain worse?

Birnbaum G, Iverson J. Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis. Neurology. 2014 Sep. pii: 10.1212/WNL.0000000000000931. [Epub ahead of print]

OBJECTIVE: To determine the effect of dalfampridine (4-aminopyridine), a broad-spectrum, voltage-dependent potassium channel blocker, on patients with trigeminal nerve dysfunction due to multiple sclerosis (MS).
METHODS: We reviewed histories of 71 patients in our clinic with clinically definite MS who were treated with dalfampridine for at least 2 to 3 months. Of the 71 patients, 5 had a history of either trigeminal neuralgia or altered facial sensation.
RESULTS: Of these 5 patients, 3 with preexisting trigeminal neuralgia had a marked worsening of facial pain in close proximity to starting dalfampridine. One patient with altered facial sensation developed trigeminal pain after being on dalfampridine for 18 months. Pain in this individual rapidly subsided when dalfampridine was discontinued. Pain in the worsened 3 patients persisted, became more refractory to previously effective medications, and in one instance required trigeminal surgery for pain control.
CONCLUSIONS: Dalfampridine should be used with caution in persons with trigeminal neuralgia due to MS

We are all just a bag of nerves and MS interfers with nerve signalling. Dalfamprydine can help nerves to signal and can improve walking speed. However, to get a positive signal may mean that some negative signal may be absent. Positive signalling can be excitatory, inhibitory or disinhibitory (inhibitor of an inhibitory circuit leads to more excitation). So in this study it was found that facial pain may be worse on drug. This shows the complexities of the nervous system and that drug treatment may not always result in a "black and white" answer. This is a small study but pain has been a noted side effect.

coI None 

Sunday, 28 September 2014

IL-17 increases in secondary progressive MS

Huber AK, Wang L, Han P, Zhang X, Ekholm S, Srinivasan A, Irani DN, Segal BM. Dysregulation of the IL-23/IL-17 axis and myeloid factors in secondary progressive MS. Neurology. 2014 . pii: 10.1212/WNL.0000000000000908. [Epub ahead of print]

OBJECTIVE:In the current exploratory study, we longitudinally measured immune parameters in the blood of individuals with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), and investigated their relationship to disease duration and clinical and radiologic measures of CNS injury.
METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma were obtained from subjects with RRMS, SPMS, and from healthy controls on a monthly basis over the course of 1 year. MRI and Expanded Disability Status Scale evaluations were performed serially. PBMCs were analyzed by enzyme-linked immunosorbent spot assay to enumerate myelin basic protein-specific interleukin (IL)-17- and interferon (IFN)-γ-producing cells. Plasma concentrations of proinflammatory factors were measured using customized Luminex panels.
RESULTS: Frequencies of myelin basic protein-specific IL-17- and IFN-γ-producing PBMCs were higher in individuals with RRMS and SPMS compared to healthy controls. Patients with SPMS expressed elevated levels of IL-17-inducible chemokines that activate and recruit myeloid cells. In the cohort of patients with SPMS without inflammatory activity, upregulation of myeloid-related factors correlated directly with MRI T2 lesion burden and inversely with brain parenchymal tissue volume.
CONCLUSIONS: The results of this exploratory study raise the possibility that Th17 responses and IL-17-inducible myeloid factors are elevated during SPMS compared with RRMS, and correlate with lesion burden. Our data endorse further investigation of Th17- and myeloid-related factors as candidate therapeutic targets in SPMS.

Th17 what do they do? At one point autoimmunity was caused by Th1 cells andthese were generated by interleukin 12 because the disease in animals could be blocked by antibodies that blocked the Interleukin 12 receptor (p40 molecule). But Oops it was found that it was not interleukin 12 (the receptor is two chains a p40 and p35 molecule) but interleukin 23 (the receptor is a p40 and a p19 molecule). The cells generated by interleukin 23 produce interleukin 17 and (Th17) cells were born. These were then the cells that cause autoimmunity, or are they. Now there is a school showing that you can get Th1 disease in mice and also a Th17-induced disease in mice. This is different from typical EAE and is associated with lots of neutrophils (white blood cell type) rather than  monnuclear (lymphocytes and macrophages). What do they do.

So as soon a interleukin 12 was found clinical trials were initiated anti-IL12/23 stopped animals from getting EAE, however it did nothing to stop spontaneously relapsing EAE (forgotten paper), and it did not stop relapsing MS. So lets inhibit interleukin 17 and see what happens and in most cases not very much in early EAE, but better in late EAE. Studies are ongoing in MS, but where do you target the Th17? 

If you follow the dogma as TH17 being causal then it should be early in MS, but in this study looking at when Th17 responses appear in MS, there is an inference that maybe one should look later and notably in SPMS. Given that to date anti-immunologicals have failed in SPMS would you take the risk of $10,000,000 trial to find out. A case could be made on available data, (e.g. link to B cell follicles etc) will this happen? Will other cytokines be targeted?

Biomarker for transition to progression

Are the relapsing and progressive phases of MS truly different from each other? #MSResearch #MSBlog

"The following study uses a novel approach to differentiate MSers with different clinical forms of the disease, i.e. RRMS vs. SPMS vs. PPMS. The use a technique that profiles the metabolism of MSers and find that the metabolic profiles are different between the clinical sub-types. This is an exciting finding, but clearly needs to be reproduced in other cohorts of MSers."

"The other issue is cause or effect. Could having progressive MS change your metabolism as a result of factors associated with progressive disease? For example, as a result of progressive MS  you are more likely to be less mobile and not exercise. In addition, progressive MSers are more likely to be constipated and as a result change their diets to manage the constipation. Being constipated changes your bowel flora that is part of your metabolism. Progressive MSers are more likely to have bladder dysfunction and hence dehydrate themselves to manage urinary symptoms. What does dehydration do to metabolism? Progressive MSers are older and more likely to have co-morbidities and hence take other medications for these, for example hypertension and diabetes. Hence, their are a lot of potential confounders that can affect the metabolism in progressive MSers; age being the main one."

"What is interesting is that there a difference was found between SP and PP MSers? This may not be driven by factors I mentioned above and could relate to qualitative differences in the underlying mechanisms responsible for progression. This needs more work."

"I have said many time that there is no magical point in time when MS becomes progressive. The mechanisms that underlie progressive MS are their from the outset and it is only when reserve capacity is exhausted in a particular neuronal system that progressive MS manifests itself. The systems that read out first are the ones with the longest axons, i.e. bladder and bowel. The length of the axons increases the likelihood of the pathway being hot multiple times and increases the chance of it running out of reserve capacity sooner. This is my so called asynchronous progressive MS hypothesis. In reality most people with MS are already in the progressive phase from the outset as manifest by accelerated and progressive brain volume loss. What is more important is can we switch off the processes underlying this and delay or prevent them ever manifesting with clinically progressive MS. I think we can as we now have a handful of therapies that impact on brain atrophy slowing it down and in some cases bringing the rate of brain volume loss to within a 'normal range'. By preventing end-organ damage in MS we should maintain reserve capacity longer and at least delay, and possibly prevent, the clinical onset of SPMS."

Epub: Dickens et al. A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology. 2014 Sep 24. pii: 10.1212/WNL.0000000000000905. 

OBJECTIVE: We tested whether it is possible to differentiate relapsing-remitting (RR) from secondary progressive (SP) disease stages in MSers using a combination of nuclear magnetic resonance (NMR) metabolomics and partial least squares discriminant analysis (PLS-DA) of biofluids, which makes no assumptions on the underlying mechanisms of disease.

METHODS: Serum samples were obtained from MSers with primary progressive MS (PPMS), SPMS, and RRMS; patients with other neurodegenerative conditions; and age-matched controls. Samples were analyzed by NMR and PLS-DA models were derived to separate disease groups.

RESULTS: The PLS-DA models for serum samples from MSers enabled reliable differentiation between RRMS and SPMS. This approach also identified significant differences between the metabolite profiles of each of the MS groups (PP, SP, and RR) and the healthy controls, as well as predicting disease group membership with high specificity and sensitivity.

CONCLUSIONS: NMR metabolomics analysis of serum is a sensitive and robust method for differentiating between different stages of MS, yielding diagnostic markers without a priori knowledge of disease pathogenesis. Critically, this study identified and validated a type II biomarker for the RR to SP transition in MSers. This approach may be of considerable benefit in categorizing MSers for treatment and as an outcome measure in future clinical trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum metabolite profiles accurately distinguish MSers with different subtypes and stages of MS.


One poster asked what are the Rules of Engagement and how to post. What are the do's and importantly don'ts of posting a comment.

Many moons ago you will remember that you could post at will, you would post and it would appear. There could be some heated discussions. 

However, invariably posts particularly on CCSVI would attract destructive Trolls...leading to all comments being moderated. This means they are slow to arrive and depending on content may not arrive at all. 

Some we may remove even after posting, because we have not thought the issue through enough. If we have time we may redact them.

ProfG has developed a defense mechanism against rude posters, others have not. However, this does not mean it is a free for all. We are not here to be punchbags and we may bite back, because we are not wet blankets. However, we may get our wrists slapped for that too.

The views present on this Blog are those of the authors and have nothing to do with QMUL

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  •  This is a not a private consultation, keep your comments general. We can not do consultatations and without your notes and history it is difficult to give advice anyway.
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More to follow as ProfG may want to add a few

Saturday, 27 September 2014

ClinicSpeak: second opinions in the NHS

You don't have a legal right to a second opinion under the NHS. #ClinicSpeak #MSBlog #MSResearch

"Somebody asked my advice at the Imperial Research Day yesterday about how to get a second opinion when their GP refuses. I told you that all NHS patients had a right to second opinion as enshrined in the NHS patient Charter. Apologies, I gave you incorrect information. The NHS Patient Charter has now been replaced by the NHS Constitution (March 2013), which does not give you a legal right to second opinion. However, there are other ways to ask for a second opinion. I have copied the following section from NHS Choices about the process. I hope this information is helpful to you. If this fails you can always raise the issue you with your local Member of Parliament (MP); GPs tend react positively when MPs' intervene on behalf of their constituents."

How do I get a second opinion?

You can ask your GP or another healthcare professional for a second or further opinion (an opinion about your health condition from a different doctor).

Although you do not have a legal right to a second opinion, a healthcare professional will rarely refuse to refer you for one.

For more information, see your right to choice in the NHS.

Do you need a second opinion?

Before asking for a second opinion, it’s worth asking your GP or consultant to go over your diagnosis and explain anything you don’t understand.

If you’re unhappy with your diagnosis or would like to consider a different course of treatment, discuss this with them. Your GP or consultant will be happy to explain things and, in many cases, there may be no need for a second opinion.
Can anyone else ask for a second opinion?

Your family or carer can also ask for a second opinion on your behalf, but only with your consent. If someone requests a second opinion on your behalf, they should have all the information about your illness or condition, and check they understand it thoroughly.

Sometimes a GP or consultant may ask a colleague to provide a second opinion. For example, doctors may ask their colleagues about a complicated case.
Second opinion from a different GP

If you would like a second opinion after receiving advice from your GP, you can ask them to refer you to another GP.

Alternatively, you may consider asking to see a different GP at your surgery, if you’re registered at a surgery with more than one GP, or changing to a different GP surgery. For more information, see choosing a GP.

Second opinion from a different consultant

If you would like a second opinion after seeing a consultant (a senior medical doctor who specialises in a particular field of medicine), you need to go back to your GP and ask them to refer you again. If your GP agrees to refer you to a new consultant, the consultant will be told that this is your second opinion. They will also be sent any relevant test results or X-rays previously carried out.

This does not mean that the new consultant will automatically take over your care. If you want to be treated by the new consultant, this will need to be arranged with the doctors and hospital.
How long will I have to wait for a second opinion?

People who ask for a second opinion have already seen a doctor, so they may have to wait. A second opinion with a different consultant will also usually be at a different hospital, which may involve some travelling.

Getting a second opinion may therefore delay any treatment that you need. If you have a serious medical condition, you should take this into account when deciding to ask for a second opinion. Ask your doctor whether a delay in starting treatment could be harmful.

Read the answers to more questions about NHS services and treatments.

Imperial College MS Study Day 2014

How to treat MS in 2014: treat-2-target and prevent end-organ damage. #MSBlog #MSResearch

"As promised the following is my presentation from yesterday at the Imperial College MS Study Day. My  talk generated a lot of questions about the new treatment paradigm of treating-2-target and preventing end-organ damage in MS. It will be interesting to see of the wider MS community adopt this approach."

Stem cells from an Mser myelinates a mouse.

Douvaras P, Wang J, Zimmer M, Hanchuk S, O'Bara MA, Sadiq S, Sim FJ, Goldman J, Fossati V. Efficient Generation of Myelinating Oligodendrocytes from Primary Progressive Multiple SclerosisPatients by Induced Pluripotent Stem Cells. Stem Cell Reports. 2014;3(2):250-259.

Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology that affects the CNS. While current therapies are primarily directed against the immune system, the new challenge is to address progressive MS with remyelinating and neuroprotective strategies. Here, we develop a highly reproducible protocol to efficiently derive oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes from induced pluripotent stem cells (iPSCs). Key elements of our protocol include adherent cultures, dual SMAD inhibition, and addition of retinoids from the beginning of differentiation, which lead to increased yields of OLIG2 progenitors and high numbers of OPCs within 75 days. Furthermore, we show the generation of viral and integration-free iPSCs from primary progressive MS (PPMS) patients and their efficient differentiation to oligodendrocytes. PPMS OPCs are functional, as demonstrated by in vivo myelination in the shiverer mouse. These results provide encouraging advances toward the development of autologous cell therapies using iPSCs.

Induced pluripotent stem cells are stem cells that start like as a normal cell such as a cell in the skin,you then deliver a cocktail of growth factor that reverts the cell to a stem cell,which can replicate itself and has the potential to turn into any cell type. This includes the production of myelin forming oligodendrocytes. In this study they do this from people with progressive MS. They then transplant the myelin forming cells into shiverer mice. These mice have a mutation in the myelin basic protein gene and don't make myelin so they start to shiver or tremor because of demyelination. In this study the  young mice transplanted with the myelin forming cells actually myelinate. We knew this could happen but this study shows (a) a way to generate lots of myelin-producing cells (b) there is nothing intrinsically wrong with the genetics etc that prevents myelination from occurring in people with MS and (c) you could can do this from an MSer and indeed from any MSer. Therefore you could personalise the repair. This is very interesting although we would ideally lie to see how these cells remyelinate and also how they remyelinate something that has been demyelinated for some time.

CCSVI saturday

Ploughman M, Harris C, Hogan SH, Murray C, Murdoch M, Austin MW, Stefanelli M. Navigating the "liberation procedure": a qualitative study of motivating and hesitating factors among people with multiple sclerosis. Patient Prefer Adherence. 2014;8:1205-13

BACKGROUND: The debate within the multiple sclerosis (MS) community initiated by the chronic cerebrospinal venous insufficiency (CCSVI) hypothesis and the subsequent liberation procedure placed some people with MS at odds with health care professionals and researchers.

OBJECTIVE: This study explored decision making regarding the controversial liberation procedure among people with MS.

SUBJECTS AND METHODS: Fifteen people with MS (procedure, n=7; no procedure, n=8) participated in audiotaped semistructured interviews exploring their thoughts and experiences related to the liberation procedure. Data were transcribed and analyzed using an iterative, consensus-based, thematic content-analysis approach.

RESULTS: Participants described an imbalance of motivating factors affirming the procedure compared to hesitating factors that provoked the participant to pause or reconsider when deciding to undergo the procedure. Collegial conversational relationships with trusted sources (eg, MS nurse, neurologist) and ability to critically analyze the CCSVI hypothesis were key hesitating factors. Fundraising, family enthusiasm, and the ease of navigation provided by medical tourism companies helped eliminate barriers to the procedure.

CONCLUSION: Knowledge of factors that helped to popularize the liberation procedure in Canada may inform shared decision making concerning this and future controversies in MS.

With a sample size so small it may be difficult to make any useful

Jandaghi AB, Amanian D, Roudbari SA, Kanafi AR, Pourghorban R.Evaluation of haemodynamic properties of cerebral venous drainage in patients with multiple sclerosis: a case-control study.
Pol J Radiol. 2014 Sep 19;79:323-7. doi: 10.12659/PJR.890690. eCollection 2014.

BACKGROUND: The purpose of this study was to compare patients with multiple sclerosis and healthy control subjects as regards haemodynamics of cerebral venous drainage.

MATERIAL/METHODS: Between December 2012 and May 2013, 44 consecutive patients with multiple sclerosis and 44 age- and sex-matched healthy subjects underwent the B-mode, color Doppler, and duplex Doppler evaluations of the internal jugular vein (IJV) and vertebral vein. The following four parameters were investigated: IJV stenosis, reversal of postural control of the cerebral venous outflow pathways, absence of detectable blood flow in the IJVs and/or vertebral veins, and reflux in the IJVs and/or vertebral veins in the sitting or supine position.

RESULTS: In the study group, IJV stenosis, postural control reversal of the cerebral venous outflow pathways, and absence of flow in the IJVs and/or vertebral veins were found in 3 (6.8%), 2 (4.5%), and 3 (6.8%) patients, respectively. In the control group, IJV stenosis (P=0.12), postural control reversal of the cerebral venous outflow pathways (P=0.50), and absence of flow (P=0.12) were not detected. Abnormal reflux was found neither inmultiple sclerosis patients nor in healthy subjects.

CONCLUSIONS: No significant difference in the cerebral venous drainage through the IJV or vertebral vein was found between patients with multiple sclerosis and healthy subjects within any of the investigated ultrasonographic parameters.

Nothing of interest. Maybe it is time to kick these posts into touch? 

The following is a Google Trends Update:

Friday, 26 September 2014

They're back and talking

Time to push the button

Brain F**k

I was close to the red light district in Amsterdam (at a Post PhD viva dinner-I may add), when I got this email from MD2 about "perhaps the most bizarre post I've ever seen". Whilst I do not usually report on the "cure of the week" about what can stop EAE from developing, this is certainly going to take the biscuit. 

We've had the inference of resveratol stopping EAE, which may make you have a glass of red wine or some blueberries (until you realise that the amount of resveratol in blueberries/wine is miniscule compared to the dose to stop EAE...but wrap the study up in a plausible mechanism and Bobs your uncle), but where is this current study going to have us all going?.....I shudder to think. No comments please. 

Is this the Next CCSVI craze you don't need a neuro to get it...and some unscruplious people could make money from it....So sounds familiar:-)

Pakravan N, Ghaffarinia A, Jalili C, Riazi-Rad F, Tajedini M, Mostafaie A. Seminal vesicle fluid ameliorates experimental autoimmune encephalomyelitis by increasing FoxP3+ regulatory T-cell numbers. Cell Mol Immunol. 2014 Sep. doi: 10.1038/cmi.2014.88. [Epub ahead of print]

Previous studies have shown that insemination elicits the expansion of the natural FoxP3+ regulatory T cell (Treg) pool in female reproductive tissue during mating. Further research demonstrated that this effect was due to seminal vesicle fluid. Indeed, seminal vesicle fluid causes differential recruitment of Tregs into different organs. The recruitment of Tregs into the brain occurs at the lowest rate of all studied organs. In addition, Tregs are present at a lower frequency and/or have a reduced function in multiple sclerosis. These observations prompted us to investigate how intra-CSF administration of seminal vesicle fluid affects experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Our results suggest that seminal vesicle fluid contains all of the ligands required to activate the Treg pool and exhibits an anti-inflammatory effect on organs outside the reproductive system.

If you are going to have a treatment of EAE these days any self-respecting paper usually has a "flavour of the time" as the mechanism of action. 

Historically it was suppressor T cells then came along Th" cells and more recently Fox3P T regulatory cells...So what drives T regulatory cells, well apparently artificial insemination according to  some reports. Seems pretty easy concept to test in humans,

You need enough T regulatory cells to conceive and T regs can block autoimmunity and are part of mum's immune machinery that blocks mum rejecting dads bits in the unborn. Maybe this approach has mileage. Wonder if we would get a grant to test this hypothesis:-)

The paper says......inject seminal fluid in the brain....?....This is what the authors did and EAE was inhibited. This is my most interesting "cure of the week" 

So why brain injection and what is the translational route to this approach? Answers on the back of a postcard...but please don't tell me :-)

Where did the seminal fluid come from?. 

It reminds me of a time in the Lab with MD2 when we were looking for a symptomatic treatment and as side effect of one drug we got covered, it was if we had given the beasties a Lad's Mag....maybe we should have published this too.

Thursday, 25 September 2014

Making Sense of Genetic Manipulation in humans results of Oligonucleotide trials

Limmroth V, Barkhof F, Desem N, Diamond MP, Tachas G; For the ATL1102 Study Group. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS.
Neurology. 2014 Sep. pii: 10.1212/WNL.0000000000000926. [Epub ahead of print]

OBJECTIVE: This study evaluated the efficacy and safety of ATL1102, an antisense oligonucleotide that selectively targets the RNA for human CD49d, the α subunit of very late antigen 4, in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: In a multicenter, double-blind, placebo-controlled randomized phase II trial, 77 patients with RRMS were treated with 200 mg of ATL1102 subcutaneously injected 3 times in the first week and twice weekly for 7 weeks or placebo and monitored for a further 8 weeks. MRI scans were taken at baseline and weeks 4, 8, 12, and 16. The primary endpoint was the cumulative number of new active lesions (either new gadolinium-enhancing T1 lesions or nonenhancing new or enlarging T2 lesions) at weeks 4, 8, and 12.
RESULTS: A total of 72 patients completed the study and 74 intention-to-treat patients were assessed. ATL1102 significantly reduced the cumulative number of new active lesions by 54.4% compared to placebo (mean 3.0 [SD 6.12] vs 6.2 [9.89], p = 0.01). The cumulative number of new gadolinium-enhancing T1 lesions was reduced by 67.9% compared to placebo (p = 0.002). Treatment-emergent adverse events included mild to moderate injection site erythema and decrease in platelet counts that returned to within the normal range after dosing.
CONCLUSIONS: In patients with RRMS, ATL1102 significantly reduced disease activity after 8 weeks of treatment and was generally well-tolerated. This trial provides evidence for the first time that antisense oligonucleotides may be used as a therapeutic approach in neuroimmunologic disorders.

We all know that tysabri which blocks CD49d can inhibit lesion formation and the development of relapse. This is given once a month and blocks MRI lesions by about 90% and relapse rate by about 70% compared to placebo. This study looks at another way to block CD49d and uses antisense DNA

DNA is made of the doublehelix of nucleotides. A a single strand of DNA sense (or positive (+) ) if an RNA version of the same sequence is translated or translatable into protein. Its complementary strand is called antisense (or negative (-) sense).

The two complementary strands of double-stranded DNA (dsDNA) are usually differentiated as the "sense" strand and the "antisense" strand. The DNA sense strand looks like the messenger RNA (mRNA) and can be used to read the expected protein code (e.g. ATG codon = Methionine amino acid). However, the DNA sense strand itself is not used to make protein by the cell. It is the DNA antisense strand which serves as the source for the protein code, because, with bases complementary to the DNA sense strand, it is used as a template for the mRNA. Since transcription results in an RNA product complementary to the DNA template strand, the mRNA is complementary to the DNA antisense strand. The mRNA is what is used for translation (protein synthesis).

The DNA sense strand is called a "sense" strand not because it will be used to make protein (it won't be), but because it has a sequence that looks like the protein codon sequence. In biology and research, short antisense molecules can interact with complementary strands of nucleic acids, modifying expression of genes.

In this case the anti-sense nucleotide interacts with CD49d and so the CD49d protein does not get made and this results in no CD49d protein and so the cells cannot migrate into the CNS.

Whilst this interesting we are taking a one a month drug and converting it to a twice a week drug, which is not quite as active as the monoclonal antibody it seeks to replace. Will it have the side effect of PML....Quite possible but as it is less active it may not cause as many problems.

Is this a drug to knock tysabri of its perch well on cost front.... an oligonucleotide could cost a few cents/pence compared to thousands o euros/dollars/pounds for antibodies. However the implication is that we could knock out/knockdown any of the 30,000 genes in the human or easily combinations of genes. This could be say an anti-sense LINGO-1 to promote repair. We could reinvestigate CD4 removal, we could knockdown CD20, CD19 of CD52, Sphingosine-1-phosphate etc, etc. The sky could be the limit. Neuroprotection or repair. This is the very exciting implication from this study. However we would have to work out how best to deliver to the brain.

However, We are still at it when it comes to MS trials, placebo control is name of the game, especially when pharma is involved.

The regulators and people on the ethics panels have yet to get the spine to say enough is enough. There are treament options for RRMSers, However, it seems OK that we can go to Eastern Europe and offer test or nothing.

Maybe I should shut my cakehole as maybe people are being offered something, when there maybe no treatment option, but if the regulators got a spine they could insist on head to head trials of active verses active. Would they get away with this in Western Europe or USA? But hey the EMA is largely funded by Pharma and would they bite the hand that feeds them

Roll on the time when a cheap generic arrives and this practise for DMT function will stop! Come on you Neuros make an effort and find a way to do it...For the sake of people in areas of "Have nots" when it comes to DMTs

In this day and age there should be no excuse not to offer some form of treatment for MSers in trials. However if they had done a none-inferitority trial (the drug is no worse than the comparator) compared to tysabri which is the obvious comparator they would have lost.  This is why pharma want to test their drugs against nothing so it stands a chance of looking better

CoI None

Charcot Project: EBV in mIce

Frankenstein mice provides insights into the immunology of EBV infection. #MSBlog #MSResearch

"This study using a tansgenic mice, or Frankenstein mice, may of interest to those of you following the evolving story of EBV in MS. EBV does not have a non-human host; it is a virus that is human specific. Therefore to create an animal model you have to make the animal humanoid. In this case a mouse was created in the lab to have a human-like immune system that allows it be infected with EBV. The investigators then looked at the cellular immune responses to EBV; the so called CD8+ T cell responses. You may recall that Professor Pender has data suggesting MSers have a deficient CD8+ cytotoxic CD8+ T cell response to EBV. In this study they show that CD8+ are responsible for controlling the EBV virus viraemia in this animal model. Whether or not this is relevant to MS is a moot point, but does provide a model system for testing vaccines. The latter is clearly what we need to do the ultimate experiment; to whether or not EBV causes MS. If vaccinating high-risk people against EBV prevents them from developing MS then we will have proved that EBV is the cause of MS. This is similar to HPV and cervical cancer; vaccinating girls against this virus has resulted in a fall in incidence of cervical cancer, thus proving that HPV is a cause of cervical cancer."

"The following is a link to Professor Pender's post; it is one of the most popular all-time posts on this blog."

Guest Post: Professor Michael Pender - Multiple Sclerosis ..., 11 Feb 2014
Professor Michael Pender graduated from The University of Queensland in 1974 with First Class Honours in Medicine and a University Medal. Over the next six years he trained as a physician and neurologist at the Royal ...

Wesnes et al. Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice. PLoS Pathog. 2014;10(8):e1004333. doi: 10.1371/journal.ppat.1004333

Background: Epstein Barr virus (EBV) infection expands CD8+ T cells specific for lytic antigens to high frequencies during symptomatic primary infection, and maintains these at significant numbers during persistence. Despite this, the protective function of these lytic EBV antigen-specific cytotoxic CD8+ T cells remains unclear. 

Methods & Results: Here we demonstrate that lytic EBV replication does not significantly contribute to virus-induced B cell proliferation in vitro and in vivo in a mouse model with reconstituted human immune system components (huNSG mice). However, we report a trend to reduction of EBV-induced lymphoproliferation outside of lymphoid organs upon diminished lytic replication. Moreover, we could demonstrate that CD8+ T cells against the lytic EBV antigen BMLF1 can eliminate lytically replicating EBV-transformed B cells from lymphoblastoid cell lines (LCLs) and in vivo, thereby transiently controlling high viremia after adoptive transfer into EBV infected huNSG mice. 

Conclusions: These findings suggest a protective function for lytic EBV antigen-specific CD8+ T cells against EBV infection and against virus-associated tumors in extra-lymphoid organs. These specificities should be explored for EBV-specific vaccine development.

Wednesday, 24 September 2014

MS Role Models Take 2

Despite the mixed reception on my previous post on MS Role Models I'm going to brave the storm and talk about another inspiring MSer - Ann Romney.

Ann Romney is the wife of Mitt Romney the Republican nominee in the 2012 US Presidential election. Wherever your political leanings lie, try to stay with me! 

Ann Romney was diagnosed with relapsitting-remitting MS in 1998 following an episode of numbness in her leg. She began to be treated with steroids but gave up on conventional medicine in favor of alternative therapies such as acupuncture and reflexology. Another one of these is 'equestrianism'!! She has had occasional relapses since her diagnosis but credits alternative therapies as the main source of her remission.

"I decided I was very comfortable with my MS. Everybody has problems. Everyone has issues. And this happens to be a surprise thing that came in my life, and I didn't count on. Everywhere I go people come up to me, they mob me — anyone who has MS or has a relative with MS — they come up and hug and cry. I don't care what somebody else thinks about it. I know for certain people I'm championing a struggle that they're going through."

"There are certain things that don't mix well with MS. One is staying up late at night. Another is big, noisy crowds."

Have a look at this video of Ann Romney talking about her experiences with MS.

I will post in the next few days about the potential role of acupuncture in MS as it seems to be a recurring theme. ..

ClinicSpeak: Predicting brain stem involvement

Did you know posterior fossa lesions in MS portend a poor prognosis? #MSBlog #MSResearch #ClinicSpeak

"The brainstem is the part of the central nervous system (CNS) between the spinal cord and so called cerebral hemispheres. The brainstem is like a very busy railway junction with many fibre tracts (axons) passing through it on the way to the spinal cord and back from the spinal cord to the brain. In addition, it houses many of the so called autonomic centres that control breathing, blood pressure, pulse rates and swallowing. The brain stem also houses the centres for eye movements, hearing, balance, coordination, walking and the nerve cell bodies of most of the cranial nerves. The brainstem is also closely linked to the cerebellum or mini-brain that controls many motor functions. The brainstem and cerebellum are housed in the so called posterior fossa of the skull. When MS lesions occur in the posterior fossa, i.e. brainstem and cerebellum, they are frequently symptomatic and can be very devastating. MSers with posterior fossa disease have a far worse outcome than those without lesions in this area. I personally include posterior fossa signs in my crude prognostic index when advising patients about DMTs. Do you have posterior fossa disease? If you have had an MRI you should ask your neurologist if you have any lesions in the posterior fossa."

"The following is a list of symptoms that can be associated with  posterior fossa involvement in MS; double vision, oscillopsia (jumping images), jerky eye movements, unsteady gait, incoordination, vertigo, tinnitus, deafness, hyperacusis, nausea, vomiting, hiccoughs, slurred speech, swallowing problems, choking, loss of taste, loss of sensation on the face or in the mouth, emotional incontinence or inappropriate crying or laughing and rarely hallucinations (pontine hallucinosis). More recently we have begun to identify cognitive impairment been linked to disease of the cerebellar hemispheres; typically MSers with severe cerebellar dysfunction have poor memory and the temporal sequencing of memories. When you talk to them they are  come across as being very vague. As many fibre tracts pass  through the brainstem weakness of the limbs, loss of sensation on the body, bowel, bladder and sexual problems can also occur from brainstem disease. It is clear that the brain stem is a very important structure and needs to be protected from the ravages of MS wherever possible."

"The study below uses a new neurophysiological technique to assess brainstem function. Unsurprisingly, they show that MSers with brainstem involvement have more disability. It would be interesting to see in future studies if this technique could be used as part of a surrogate outcome to monitor MS progression, specifically of the brainstem."

"Please note that brainstem disease may be linked to sudden unexplained death in MS (SUDMUS), which I have posted on before."

Epub: Gabelić et al. The vestibular evoked myogenic potentials (VEMP) score: a promising tool for evaluation of brainstem involvement in multiple sclerosis. Eur J Neurol. 2014 Sep 8. doi: 10.1111/ene.12557.

BACKGROUND AND PURPOSE: Concerning the great importance of brainstem involvement in MS, the aim of this study was to explore the role of the newly developed vestibular evoked myogenic potentials (VEMP) score as a possible marker of brainstem involvement in MSers.

PATIENTS AND METHODS: This was a prospective case-control study which included 100 MSers  divided into two groups (without and with clinical signs of brainstem involvement) and 50 healthy controls. Ocular VEMP (oVEMP) and cervical VEMP (cVEMP) measurements were performed in all participants and analyzed for latencies, conduction block and amplitude asymmetry ratio. Based on this the VEMP score was calculated and compared with Expanded Disability Status Scale (EDSS), disease duration and magnetic resonance imaging data.

RESULTS: MSers with clinical signs of brainstem involvement (group 2) had a statistically significant higher percentage of VEMP conduction blocks compared with MSers without clinical signs of brainstem involvement (group 1) and healthy controls (P = 0.027 and P < 0.0001, respectively). Similarly, the VEMP score was significantly higher in group 2 compared with group 1 (P = 0.018) and correlated with EDSS and disease duration (P = 0.011 and P = 0.032, respectively). Multivariate linear regression analysis showed that the VEMP score has a statistically significant influence on the EDSS score (P < 0.001, R2 = 0.239).

CONCLUSIONS: Interpretation of the oVEMP and cVEMP results in the form of the VEMP score enables better evaluation of brainstem involvement than either of these evoked potentials alone and correlates well with disability.

Sleep Problems may have different roots

Vitkova M, Gdovinova Z, Rosenberger J, Szilasiova J, Nagyová I, Mikula P, Krokavcova M, Groothoff JW, van Dijk JP. Factors associated with poor sleep quality in patients with multiple sclerosis differ by disease duration. Disabil Health J. 2014;7(4):466-71

BACKGROUND:Sleep disturbance is a common symptom of multiple sclerosis (MS) and knowledge about factors that contribute to poor sleep quality is scarce.
OBJECTIVE:The aim was to explore the differences in the prevalence and determinants of poor sleep quality in a sample of patients with MS with disease duration ≤5 years and >5 years.
METHODS:We collected data from 152 consecutive patients with MS; 66 patients (78% women, averaged 37.35 ± 10.1 years) were in the group with disease duration ≤5 years and 86 patients (73.3% women, averaged 42.10 ± 9.4 years) in the group with disease duration >5 years. Patients filled out the Sleep Quality Index, the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Inventory, one item of the Incapacity Status Scale regarding bladder problems and one item of the Short Form-36 regarding pain.
RESULTS:The prevalence of poor sleep is significantly higher in patients with longer disease duration (34.8 vs. 51.2%). Anxiety, reduced motivation and mental fatigue (all p < 0.05) were associated with poor sleep quality in patients with disease duration ≤5 years, whereas pain (p < 0.01), depression and mental fatigue (both p < 0.05) were in patients with disease duration >5 years.
CONCLUSION: Sleep problems are present in patients with MS with both short and long disease duration, but these problems are associated with different factors. These should be recognized and managed in addition to the treatment of sleep disorders.

Sleep problems are well recognised in MS and this looks at the causes and indicates that they may have different routes in early MS anxiety is a problem whereas as depression and pain  and morerelevant in late disease. 

Tuesday, 23 September 2014

Intrathecal Steroid may help Spasticity

Kamin F, Rommer PS, Abu-Mugheisib M, Koehler W, Hoffmann F, Winkelmann A, Benecke R, Zettl UK.Effects of intrathecal triamincinolone-acetonide treatment in MS patients with therapy-resistant spasticity. Spinal Cord. 2014 . doi: 10.1038/sc.2014.155

Objectives:Multiple sclerosis (MS) is an autoimmune disease affecting young people and is a major cause of disability. In the course of time, disability progresses and symptoms like spasticity may occur. Spasticity is a major cost factor in MS patients. Various agents are approved for the treatment of spasticity, but each of those agents may have several side effects. Intrathecally administered steroids (triamcinolone-acetonide (TCA)) may be efficient in treating spasticity in patients with lesions in the spinal cord and no response to first-line therapeutics. The aim of this study is to show effects of TCA treatment on clinical parameters in patients with MS.

Methods:This multicentre open label study included 54 patients with MS. The clinical outcome parameters were spasticity, disability, maximum walking distance, bladder function and quality of life. All patients received physiotherapy in addition to TCA treatment to obtain optimal effects on clinical parameters.
Results:Spasticity, maximum walking distance as well as disability improved significantly (P⩽0.001) during TCA applications. Bladder function improved in every seventh patient.
Conclusion:We observed the effects of intrathecally administered TCA on different clinical parameters including bladder function. TCA administration is a safe method to treat different symptoms in MS patients. Besides TCA treatment, physiotherapy contributes to the improvement of clinical parameters

Triamcinolone-acetonide is a corticosteroid tht is morepotent than prednisone. This was delivered into the spine and in this study there may have been some beneficial effect. But if you had physiotherapy it improved things also. This may be promising but will need controlled studies to formally show this.

CoI. TeamG are developing competing technologies

ClinicSpeak: Interferon-beta and thrombotic microangiopathy and nephrotic syndrome

How safe is safe? Rare renal complications of interferon-beta therapy. #MSBlog #MSResearch #ClinicSpeak

"At the latest ACTRIMS-ECTRIMS I became aware that it is not only MSers who read and use this blog. A large number of neurologists come to the site for up-to-date information; for example a Boston Neurologist approached me and thanked me for the resource; she said that she uses uses a print-out of our PML risk guide in her clinic. Therefore the following 'Dear Healthcare Professional' letter from the manufacturers of interferon-beta will be of interest to our professional readers. It is simply warning neurologists, and MS clinical nurse specialists, of the possibility of a rare, but serious, side effect of interferon beta therapy, namely thrombotic microangiopathy and nephrotic syndrome. We have previously posted on this issue before back in March 2014 and a new cluster of cases in Scotland has raised this as a potential problem with interferon beta treatment."

"Please note that thrombotic microangiopathy and nephrotic syndrome are serious diseases of the kidney and hence you need to be vigilant of any symptoms or signs of renal problems, in particular blood in the urine (coca-cola urine), frothy or foamy urine due to high protein, swelling of the feet and puffiness around the eyes (low blood protein levels) and hypertension. If  you have any of these symptoms and you are on interferon therapy I suggest you contact your MS team for advice."

Hunt et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med. 2014 Mar 27;370(13):1270-1. doi: 10.1056/NEJMc1316118.

ClinicSpeak: Vitamin D in pregnacy

Should we be supplementing vD during pregnancy? #MSBlog #MSResearch #ClinicSpeak

"The following study shows that vitamin D deficiency is common in woman with MS in pregnancy and post-partum. It is interesting that MSers had lower levels than normal control subjects, which raises the issue of whether or not MSers are consuming more vD as part of their disease. The so called consumptive hypovitaminosis D3 hypothesis."

"I currently recommend to woman with MS who are planning to fall pregnant, or who are pregnant, to take 10,000IU of vD3 per day and test blood levels after 4-6 weeks to adjust the dose; I target blood levels above 100 nmol/L and less than 250 nmol/L. My recommendation is simply based on an evolutionary medicine perspective as proposed by Reinhold Vieth. There is epidemiological evidence that low vD levels in utero and childhood may increase your risks of developing MS. This is particularly relevant to children of MSers who are already at increase risk due to genetic loading. I say vD supplementation may reduce your risk of getting MS, but I cannot be sure. Until we do a well powered definitive MS prevention studies we can't be sure of this."

"For  those of you interested in vD and pregnancy the following YouTube talk by Professor Reinhold Vieth may be of interest to you."

Epub: Jalkanen et al. Multiple sclerosis and vitamin D during pregnancy and lactation. Acta Neurol Scand. 2014. doi: 10.1111/ane.12306.

BACKGROUND: Both pregnancy and high vitamin D concentration seem to generate a protective environment against MS relapses. Longitudinal case-control analysis of vitamin D concentrations during pregnancy and lactation of MS mothers is lacking.

AIMS OF THE STUDY: To examine serum 25-hydroxyvitamin-D3 levels of MSers during and after pregnancy and compare these to the levels measured in healthy controls.

METHODS: Fifteen relapsing-remitting MS mothers underwent repeated testing for 25-hydroxyvitamin-D3 at 10-12, 26-28 and 35-37 gestational weeks and 1, 3 and 6 months post-partum. An identical series of samples was collected from six control mothers.

RESULTS: The prevalence of vitamin D deficiency (<50 nmol/l) during pregnancy was high (73%) among MSers. Vitamin D levels were significantly higher during pregnancy when compared to early post-partum values among MS patients. At the end of the follow-up period, the vitamin D levels returned to levels observed in early pregnancy. In healthy controls, the alterations during and after pregnancy were similar in nature, but the vitamin D concentrations were higher at all time points when compared to MSers (P = 0.037).

CONCLUSIONS: Vitamin D deficiency during the pregnancy and lactation seems to be common in mothers with MS and needs to be treated adequately.