Saturday, 31 January 2015

B cells: treatment effects on B cells may hold the clue to progressive MS

Natalizumab vs. Alemtuzumab: effects on B cells in the brain and spinal cord are different. #MSBlog #MSResearch

"Natalizumab vs. alemtuzumab: yesterday someone asked the question about why would anyone choose natalizumab over alemtuzumab? I have posted on this topic before and it essentially comes down to choice; a philosophical question about a treatment strategy."

"A large number of MSers have been pinning their hopes that these highly effective therapies may work in progressive MS. The answer is we don't know. Why? Alemtuzumab was tried in relapsing SPMS and although it stopped relapses the majority of MSers continued to progress. Whether they progressed at a slower rate, or whether or not their progression would have plateaued out after several years is not known (therapeutic lag). To answer these questions we need to a randomised controlled trial and compare alemtuzumab to placebo, or active comparator, to find out. I have hypothesised before that I think we need to do SPMS trials differently using neuronal subsystems not in the clinical progressive phase as the primary outcome; this latter is based on the asynchronous progressive MS hypothesis. Doing this may increase the chances of SP & PPMS trials being positive."

"What about natalizumab in SPMS? We don't know. But there is a clinical trial running at presenting assessing whether or not natalizumab is effective or in SPMS. This is called the ASCEND Trial. I have concerns that this trial may not be long enough, but as natalizumab is one of the most effective DMTs we have I may be proved wrong. What natalizumab has on its side is that it may impact on the B cells biology within the brain and spinal cord. Almost all MSers have oligoclonal IgG bands (OCBs) in their spinal fluid. These bands indicate that there are clones of B cells and plasma cells (immunoglobulin factories) in the brain and spinal cord. Several studies have shown that the presence of OCBs predicts a poorer outcome and the presence of the so called B cell follicles that make these antibodies on the surface of the brain are associated with progressive MS and a poorer outcome. A large number of people in the field think that B-cells are one of the main drivers of progressive MS. The small studies below suggests natalizumab impacts on B cell biology in MS; a proportion of MSers on natalizumab lose their OCBs and there is a drop in number of IgG and B cells in the spinal fluid when MSers are treated with natalizumab. The loss of OCBs does not happen with alemtuzumab. Why? I suspect because alemtuzumab does not stop T-cell trafficking into the brain and spinal cord. These B cell follicles need T cell help to survive; T cell produce a cocktail of growth factors or fertilizer that the B cell follicles need to maintain their structure. Stop providing the B cell follicles with fertilizer and they regress. The studies below are very small and need to be repeated, but they provide a tantalizing hint that there are major differences between how alemtuzumab and natalizumab work; this may be important for progressive MS."
"What next? I think we need to repeat the natalizumab spinal fluid studies and in parallel do similar studies on alemtuzumab-treated subjects. We need to lobby Genzyme to do a properly powered study to assess alemtuzumab in SPMS. I think if we are clever about the trial design the study could be positive. This is why I am trying to put a consortium together to study the asynchronous progressive MS hypothesis."



** Paper 1**

von Glehn et al. Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients. Mult Scler. 2012 Jul;18(7):1038-41.

Background: Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MSers. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. 


Case studies: This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. 

Conclusion: In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.

** Paper 2**

Mancuso et al. Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: A longitudinal study. Mult Scler. 2014 Dec;20(14):1900-3.

Background: Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of MSers. 

Objective and Methods: In this study, we prospectively analyzed both serum and CSF samples from 24 MSers, before and after 2 years of natalizumab-based therapy. 

Results: Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. 

Conclusion: Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.

** Paper 3**

Epub: Warnke et al. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler. 2014 Nov 12. pii: 1352458514556296.

BACKGROUND: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).

OBJECTIVE:  We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients withnatalizumab-associated PML (n=37).

METHODS: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.

RESULTS: In MSers treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MSers not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.

CONCLUSIONS: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.

B cell depletion in progressive MS appears to be marginal

Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 ;8(7):e66308

BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.
OBJECTIVES:To evaluate the efficacy and safety of rituximab for MS treatment.
DATA COLLECTION:Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.
MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MSwhile the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-labelrituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. A

UTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.


I am really happy that the blog is empowering you guys. 

However, with all this knowledge you  can ask some tough questions that we can't answer, because we don't know the answer. (Does this make us look stupid..or just human)  or we can't answer because the blog is not the correct forum for us to answer. 

However the musing of scientists can obviously get you guys thinking and you can put "2 and 2 together".

Whilst ProfG has built up the idea that MS DMT may be killing a causative infection that prevent relapsing MS, some other scientists have come up with the idea of B cells in the brain causing progressive MS, because they find progressive MSers having B cell clusters in their brains. 

Therefore pwMS may think about giving up their T cell therapies in favour of anti-B cell treatment is the way because of we have present the argument that way, but there are always differences in opinion.

However it has to be said that some pathologists think this is just the product of the BBB, not the blood brain barrier but the British Beer-drinking Body (pathologists & nothing to do with me:) seeing things that others can't see. 

This has given people the thought that depleting B cells is going to be good for PPMS. However the data at present does not support this idea.  It is clear that RRS responds to CD20-B cell depletion and whilst some PPMSers respond to anti-CD20 depletion, to date it is only relapsing PPMSers or PPMSers with gadolium-enhancing lesions who show clear benefit.

Some people think that this is because immunosuppression of the white cells in the blood can inhibit relapses but the drugs can't reach the immune response within the brain, because of the BBB (blood brain barrier) and so don't work. Therefore some people think if they inject anti-B cell therapy into the brain it will work.

Cyclophosphamide is an anti-B cell drug and is one of the few MS drugs that can get into the brain in high concentrations to have an effect.  This is used at very high concentrations in HSCT to kill immune cells and get the stemcellsto come into the blood.This ose is effective at inhibiting relapsing EAE. This is the exclusively-immunology world-view held by many senior people. I no longer buy into this idea and think that the immune response preconditions a neurodegenerative effect that no longer responds to immunotherapy that blocks relapses ( I could be wrong). So you need to think outside the immunological box if you want to really get to grips with progressive MS. 

This concept is supported by the HSCT as it appears that progressive MS responds poorly. Likewise so does progressive MS respond poorly to B cell depletion as shown in this analysis.

In reality I believe that the immune response is part of the problem and solution of PPMS/SPMS and optimal therapy will require combinations of treatment to protect and repair and stop immunity in the CNS

Does having MS affect your children?

Razaz N, Tremlett H, Boyce WT, Guhn M, Joseph K, Marrie RA. Impact of parental multiple sclerosis on early childhood development: A retrospective cohort study. Mult Scler. 2015. pii: 1352458514559298. [Epub ahead of print]

BACKGROUND:Exposure to parental chronic illness is associated with several adverse developmental outcomes.
OBJECTIVES: We examined the association between parental multiple sclerosis (MS) and childhood developmental outcomes.
METHODS: We conducted a population-based retrospective cohort study in Manitoba, Canada, using linked databases. The outcome was childhood development at 5 years of age, expressed as vulnerability (absent vs. present) on the Early Development Instrument (EDI).
RESULTS: Children with an MS parent (n=153) were similar to children of unaffected parents (n=876) on all EDI domains. 

However, mental health problems was more common among MS parents compared with non-MS parents 49.5% vs. 35.3%. Among MS parents, mental health problems was associated with children's vulnerability on the social competence (OR, 5.73 [95% CI:1.11-29.58]) and emotional maturity (OR, 3.03 [95% CI:1.03-8.94]) domains. The duration of child's exposure to parental MS was associated with vulnerability on the physical health domain (OR, 1.49 [95%CI:1.03-2.15]).
CONCLUSION: Parental MS was not associated with adverse early childhood developmental outcomes. However, children of parents with mental health problems, and those with longer duration of exposure to parental MS, were at higher risk for early childhood developmental vulnerability.

The Early Development Instrument (EDI) is a questionnaire developed by Dr. Dan Offord and Dr. Magdalena Janus at McMaster University. The questionnaire has 104 questions and measures five core areas of early child development that are known to be good predictors of adult health, education and social outcomes:


Physical Health & Well-Being. Sample EDI questions: Can the child hold a pencil? Is the child on time for school each day?

Language & Cognitive Development.Sample EDI questions: Is the child interested in reading and writing? Can the child count and recognize numbers?

Social Competence.Sample EDI questions: Does the child share with others? Is the child self-confident? Will he/she invite bystanders to join in a game?

Emotional Maturity.Sample EDI questions: Is the child able to concentrate? Is the child aggressive or angry? Is the child impulsive (does he/she act without thinking)?

Communication Skills & General Knowledge.Sample EDI questions: Can the child tell a short story? Can the child communicate with adults and children?

Definition of child vulnerability is statistical and population
based.It refers to the portion of the population which, without additional support and care, may experience future challenges in school and society.

The positive is that having MS does not mean an adverse effect on your kids.

Answering to the Man..

             Whilst ProfG is starting with Greek Mythology
What does the oracle predict?

Friday, 30 January 2015

ClinicSpeak: natalizumab PML update - Q4 2014

December 2014 natalizumab PML update: underestimating the PML risk? #ClinicSpeak #MSBlog #MSResearch

"The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; if you are not a health professional Biogen-Idec don't want you to see this presentation. If you are a MSer you should be reading my previous post that has been designed for MSers. There is a change in that Biogen-Idec will only be providing these figures from now on every quarter. 


Headline information


"As of the 3rd December 2014 there have been 517 cases of natalizumab-associated PML; an increase of 22 cases over the previous 3 months. Over 132,600 MSers have been exposed to natalizumab. The following graph demonstrates the number of new PML cases per month seems to be relatively stable, despite a gradual and linear increase in number of exposed MSers. Clearly the ratio is decreasing which indicates that the PML de-risking programme is working; in other words less MSers at risk of PML are staying on the natalizumab. Herein lies the problem; this means that the proportion of JCV-ve MSers on natalizumab is increasing. However the total number of MSers on treatment is used in the denominator to calculate the risk of getting PML. If this denominator is changing by including an increasing proportion of MSers who are not at risk of getting PML it will give a falsely low risk of PML. What we need are monthly updates of the PML risk, by excluding all JCV-ve MSers from the analysis. Unfortunately, Biogen-Idec are unable to access this information, despite them providing the JCV antibody assay free. Why? They don't have consent from the MSers who are being tested for JCV to use their data in this way."




"The following ratios are my attempt to explain why I think we are under-estimating the PML risk. At present Biogen-Idec is calculating the PML risk using the top equation. What I would like to see are PML risks calculated using the lower equation."


"The overall mortality associated with PML was 23% in December; in other words 119 MSers have died as result of PML. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of over 132,600 MSers been treated with natalizumab worldwide with over 381,000 years of natalizumab exposure."


"Since NHS England gave us permission to switch high-risk natalizumab patients to fingolimod, we are continuing to de-risk our natalizumab-treated population. We are hoping by doing this to prevent anyone at our centre from getting PML. Despite this some MSers are not prepared to stop natalizumab, simply because they are doing so well on the drug."


"The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosuppression


In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models."


"We have developed a simple infographic to help you integrate all this information. You can download and print this infographic for your own information."




Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.








"The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above."

CoI: multiple

HSCT vs. Alemtuzumab: is it time for a head-2-head study?

Have your say and help design a clinical trial? #MSBlog #MSResearch

"In view of the current interest in HSCT I have made a first attempt at designing a trial to ascertain whether or not HSCT (hematopoietic stem cell transplantation) is non-inferior to alemtuzumab. The latter is the only realistic way of powering the study. For this to be developed into a protocol each section needs work. Any volunteers? It also needs a name; I have come up with ZEUS, but as with all community-designed trials I think we should have a competition with a vote to name the trial. Therefore suggestions are welcome."

"I assume a lot of of you will still disagree with the need for a comparator trial; I think it is essential. Without data from at least one, and preferably two,  well-designed phase 3 studies the MS community, the regulators and the payers won't accept HSCT as a treatment for MS."

"Some of you will say that HSCT is too risky and that this proposal is crazy? I would have said so myself, until a week  ago; the recent poll on this site about risk and HSCT has made me reassess my position. It is clear that MSers are much more willing to take risks than I realised. There is one caveat; MSers who follow this blog are unlikely to be representative of the wider MS community."

"Finally, at some point in time we will need to assess the wider communities appetite for a trial of this nature; without buy in from a larger group of people this study even as a fledgling concept is going nowhere. We can do some quantitative and qualitative work once we have a workable trial protocol in place."


CoI: multiple

Japanese MSers accumulate less disability

Piccolo L, Kumar G, Nakashima I, Misu T, Kong Y, Wakerley B, Ryan S, Cavey A, Fujihara K, Palace J. Multiple sclerosis in Japan appears to be a milder disease compared to the UK. J Neurol. 2015 Jan 22. [Epub ahead of print]

Multiple sclerosis (MS) is relatively common in the West, but rare in Japan. In the literature, there are few comparative data regarding disease severity throughout the world. The objective of this study was to compare disability in patients from a UK and a Japanese MS cohort. We retrospectively analysed the clinical features of patients with MS from a UK and Japanese MS centre. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Expanded Disability Status Scale score according to disease duration, was used as a marker of disease severity. One thousand one hundred forty-eight UK patients and 104 Japanese patients were identified representing the relative national prevalence. Demographics and disease duration did not differ between the groups. Median MSSS was significantly different between the two groups (Japan 3.34 vs. UK 5.87, p < 0.001). Primary progressive MS was more common in the UK (12.9 %) than in the Japanese cohort (3 %, p = 0.044). The majority of Japanese patients (83.7 % vs. UK 17 %) had been exposed to disease modifying treatments (DMTs). Exposure to DMTs did not show a significant effect on disability. In conclusion, this study suggests that MS in Japan may be associated with less disability than in UK. More Japanese patients were treated with DMTs. Differences in treatments do not seem to explain the disparity in disability severity. This suggests either genetic or environmental influences on disease severity.

Is it genes,environment of therapeutic lag

Placebo and Nocbo effects

Bittar C, Nascimento OJ. Placebo and nocebo effects in the neurological practice.Arq Neuropsiquiatr. 2015 Jan;73(1):58-63. doi: 10.1590/0004-282X20140180. Epub 2015 Jan 1

Knowledge of placebo and nocebo effects is essential to identify their influence on the results in clinical practice and clinical trials, and thereby properly interpret their results. It is known that the gold standard of clinical trials research is the double-blind, placebo-controlled, randomized clinical study. The objective is to distinguish specific from non-specific effects, so that the presence of positive effects in the group that received placebo (placebo effect) and the presence of adverse effects in the group receiving placebo (nocebo effect) lead to confounding in interpreting the results. Placebo and nocebo effects have been considered in neurological diseases such as depression, pain, headache, multiple sclerosis, epilepsy. As placebo and nocebo effects are also present in clinical practice, the purpose is to draw attention to their influence on neurological practice, calling attention to the development of measures that can minimize them.


This open source article from Brazil. ProfG has posted on these before.

Thursday, 29 January 2015

IS timing of Optic Neuritis eye damage and slow treatment why drugs are showing no effect

Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E, Ortiz-Perez S, Torres-Torres R, Andorra M, Llufriu S, Zubuizarreta I, Saiz A, Sanchez-Dalmau B, Villoslada P.Dynamics of retinal injury after acute optic neuritis. Ann Neurol. 2015 Jan. doi: 10.1002/ana.24351. [Epub ahead of print]

Background: We set out to assess the dynamics of retinal injury after acute optic neuritis (ON), and their association with clinical visual outcomes. 
Methods: 31 consecutive patients with acute ON were prospectively analyzed over a 6 month follow-up period. Each month, we used Optical Coherence Tomography (OCT) to assess the thickness of peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers, as well as high contrast, low contrast (LCVA) and colour visual acuity (CVA), and visual fields (VF). Results: In this prospective study, we found that 6 months after clinical onset, ON-eyes suffered a reduction in pRNFL (-45.3 µm) and macular thickness (-17.3 µm). Macular atrophy was due to the decrease of macular RNFL thickness (-7.8 µm) and that of the ganglion cell layer and inner plexiform layer (GCIP, -11.3 µm), while the thickness of the outer retinal layers increased slightly. The macular RNFL and GCIP thickness decreased in parallel, yet it always occurred more rapidly and more severely for the GCIP. The change in the GCIP thickness in the first month predicted the visual impairment by month 6: a decrease ≥ 4.5 μm predicted poor LCVA (sensitivity of 93 % and specificity of 88%); and ≥ 7 μm predicted poor VF and CVA (sensitivity of 78% and 100% and specificity of 63% and 66%, respectively). 
Interpretation: Retinal axonal and neuronal damage develops quickly after ON onset. Assessment of ganglion cell layer thickness by OCT after ON onset can be used as an imaging marker of persistent visual disability. 
After optic neuritis which is an immune attack on the optic nerve and this is associated with retinal cell loss. There is thinning of the retinal ganglion cell layer and the inner nuclear Layer. This study shows that most of the damage is done within two months in fact in severe optic neuritis within one month.

Is this the reason why we have seen some recent failures in trials with riluzole, anti-LINGO-1 and Erythropoetin. Erythropoetin has been shown to work in optic neuritis but the recent trial failed
Waubant E, Maghzi AH, Revirajan N, Spain R, Julian L, Mowry EM, Marcus J, Liu S, Jin C, Green A, McCulloch CE, Pelletier D. A randomized controlled phase II trial of riluzole in early multiple sclerosis. Ann Clin Transl Neurol. 2014;1(5):340-7

Shayegannejad V, Shahzamani S, Dehghani A, Dast Borhan Z, Rahimi M, Mirmohammadsadeghi A.Graefes A double-blind, placebo-controlled trial of adding erythropoietin to intravenous methylprednisolone for the treatment of unilateral acute optic neuritis of unknown or demyelinative origin.Arch Clin Exp Ophthalmol. 2015 Jan. [Epub ahead of print]

There media hints that there was a hint that anti-LINGO-1 given up to one month after the attack promoted remyelination when this was asses
sed by electrical conduction from the eye to the brain. But nerves were not saved in the eye. 

Was this a failure?...yes in the eyes of people saying that remyelination should save nerves, but lack of protect of the nerve cells is surely what should have been expected. 

I think there is no real logic why anti-LINGO should block the inflammatory response from developing and no reason why the nerves should have been saved because anti-LINGO-1 has no logical proven neuroprotective effect. So is it going to stop nerve loss....probably not. It needs anti-inlammatories/neuroprotectors

In mice we and others have shown that nerve loss in the eyes starts within a few days of the onset of the inflammatory attack of the nerves and is complete within a week or so. So this current study shows that by the time treatment with anti-LINGO-1 was started a significant proportion of nerves would already be dead and so the drug would stand little to no chance of saving the nerve loss. 

So anti-LINGO-1 would have trouble remyelinating nerves that weren't there.

Lets avoid MS Drug Made by Science....Killed in the clinic.

Wednesday, 28 January 2015

Nerve loss in childhood MS

Why is paediatric MS so much worse than adult MS? #MSBlog #MSResearch

"The pathology study below suggests that acute MS lesions in children with MS are more damaging that those that are found in adults. The number of transected, cut or shredded, axons (nerve processes) was 50% greater in inflammed MS lesions from children compared to lesions from adults. This may explain why children with MS are more likely to manifest with cognitive problems than adults. We have always put down the cognitive problems in paediatric MS to the fact that paediatric brain is not fully developed, or mature, therefore it can't deal with the damage. This study suggests that there may be something different about the inflammatory response in children that is more damaging than that which occurs in adults. The latter is something that needs to be looked into; may be a young immune system has more robust and primed inflammatory mechanisms than an older immune system. The other explanation is that this study is biased by MSer selection. The children who had died of MS or needed biopsies were sicker, or had more active disease, compared to the adults MSers studied."


"Whatever the explanation is this is another study that confirms that focal MS lesions are not good for the brain and spinal cord. This is why we try and suppress their development and is what underpins our zero tolerance (ZeTo) strategy with regard to NEDA. Not all neurologists buy into ZeTo; they state that if we target complete suppression of new lesion formation on MRI then most MSers will end-up on the most effective therapies. They don't think is right, because what do you have to offer them if their disease gets really active. They prefer to keep the big guns for a rainy day. My counterargument is that if most MSer end-up on highly effective therapies it indicates that most MSers need to be on the most effective therapies. ZeTo is based on a scientific principle that focal lesions are bad for you, therefore any evidence of ongoing inflammation needs to be suppressed."


"Just to make you aware that there are large number of neurologists who don't support the concept of NEDA (no evident disease activity), but prefer to target MEDA (minimal evident disease activity) and still others who don't think we should be monitoring a response, or lack of a response, to therapy with MRI at all. I cover these issues in my a recent commentary I have just written." 

Giovannoni G. Any evident MRI T2-lesion activity should guide change of therapy in multiple sclerosis - Yes. Mult Scler. 2015 Jan 26. pii: 1352458514566261.

Excerpt (concluding paragraph):

Critics claim that a zero-tolerance strategy would result in the majority of MS patients ending up on so-called highly effective, and potentially more risky, therapies. My response to this criticism is that if they have ongoing inflammation they probably need to be on highly effective therapies. A good analogy is the treat-to-target strategy adopted by rheumatologists to manage rheumatoid arthritis; their treatment algorithms are designed to suppress joint inflammation as much as possible and induce long-term remission with the aim of preventing end-organ, or permanent joint, damage. I don’t understand why MS neurologists would want to manage MS any differently. At least rheumatologists have the option of replacing joints when their treatment strategies fail. Unfortunately, MSologists do not have the luxury of being able to replace the brain and spinal cord; sadly, walking sticks, wheelchairs, beds and coffins await the victims of therapeutic nihilism. Will the non-adoption of a zero-tolerance strategy to focal inflammatory events in MS be viewed as a form of subliminal therapeutic nihilism by the next generation of MS neurologists and patients?

Epub: Pfeifenbring et al. Extensive acute axonal damage in paediatric multiple sclerosis lesions. Ann Neurol. 2015 Jan . doi: 10.1002/ana.24364.

Objective: Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between paediatric and adult MSers. 


Methods: We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky's silver impregnation (axon stain) and immunohistochemistry for amyloid precursor protein (APP) respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MSers.

Results: Acute axonal damage was most extensive in early active demyelinating (EA) lesions of paediatric MSers and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult MSers showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in paediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults. 

Interpretation: Our results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults.

CoI: multiple

B cells and their role in relapse

Hohmann C, Milles B, Schinke M, Schroeter M, Ulzheimer J, Kraft P, Kleinschnitz C, Lehmann PV, Kuerten S. Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.
Acta Neuropathol Commun. 2014 ;2(1):138.


INTRODUCTION:B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) taken directly from the blood  and after 96 h of stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).
RESULTS:Nine patients displayed B cells in the blood producing brain-specific antibodies. Six patients were classified as B cell positive donors only after B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly from the blood and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).
CONCLUSIONS:Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

This data indicate actively ongoing B cell-mediated immunity against brain antigens in a small subset of people with MS and they appear around the time of relapse whether this causative, is up for debate but will particularly interesting in those sceientists looking at B cell autoimmunity




Education: Multiple Sclerosis the facts you need to know

Light Reading from Canada 



Some of you many find this Interesting (CLICK HERE)

Pg97 Alternative Therapies
"If you wanted to design a disease that is a charlatan’s dream, you could not do better than MS. It is a chronic illness with long periods of remission and occasional relapses. The cause is un- known and the treatment is far from satisfactory. Therefore, if you happen to give somebody an alternative therapy just as the disease goes into remission, he or she will attribute the recovery to that treatment. If the treatment goes badly, you can blame the person for not using enough or the right type of your potion or diet, and proceed to the next level of “treatment.” Since the cause of the disease is unknown, even the most ludicrous theory can be given a surface plausibility by the glib."

Knowledge empowers you in your choices

Tuesday, 27 January 2015

ClinicSpeak: Helicobacter pylori infection might prove the hygiene hypothesis in MS

How convinced are you by the hygiene hypothesis? #MSBlog #MSResearch #ClinicSpeak

"There is a theory that MS, and other putative autoimmune diseases, are due to excessive hygiene. The cleaner the environment you grow up in, the less infections you get as a child, the less your immune system gets educated by infections, the more likely it is your immune system will go awry when you are older, the more likely you are to get MS. The hygiene hypothesis has its many proponents; I am yet to be convinced as the data is inconsistent. The study below shows that MSers are less likely to be infected with the bacteria Helicobacter, which causes peptic (high acid) ulcers in the stomach and duodenum (upper small intestine). This study supports the hygiene hypothesis."

"A large component of the hygiene hypothesis relates to parasitic infections; there is data showing that the prevalence of MS is inversely proportional to prevalence of parasite infections in the population. This and other data have led to several clinical trials of worm therapy in MS; if you are infected with worms it changes your immune function that suppresses MS disease activity."

"Is it not amazing that we can go from bone marrow transplantation, or haemopoietic stem cell transplantation (HSCT), one day as means of rebooting your immune system to deliberate parasitic infections to subtly tweak your immune system as treatments for MS? How disparate can these two scenarios be. The difference with the parasite infection lobby is that they are doing randomised, double-blind, placebo-controlled trials to generate data to prove or disprove their hypothesis (Trichuris Suis Ova (TSO) in Recurrent Remittent Multiple Sclerosis and Clinically Isolated Syndrome (TRIOMS); NCT01413243). In comparison, the HSCT lobby simply want us to accept the evidence based on open-label observational studies that this treatment works and everyone should have access to the treatment because they know best and are prepared to take the risk. Either we accept the scientific process or we don't. If we don't set a very high-bar of scientific evidence for HSCT we are going to have all the same problems we have seen with other fringe therapies in MS and it will end-up condemning HSCT as a potentially very effective treatment for MS and open it up to abuse from unscrupulous clinics and clinicians wanting to make money out of desperate MSers and their families. It is important that the HSCT lobby take the MS community along with them; the only way this will be achieved is by a deliberate and well thought out public engagement campaign underpinned by due scientific process."

"Is anyone out there keen to help design a clinical trial to raise the level of evidence for HSCT above what it is at the moment? It is not just about whether HSCT works, but about its safety and durability and how it stacks up against existing licensed therapies."

"Back to this post. What is Helicobacter? It is a bacteria which infects up to 50% of the human population. Some strains of this bacterium cause disease in particular peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. Helicobacter species are able to thrive in the very acidic mammalian stomach by producing large quantities of the enzyme urease, which locally raises the pH from about 2 to a more compatible range of 6 to 7. Helicobacter are usually susceptible to antibiotics. There is an amazing story behind the discovery of Helicobacter as a cause of peptic ulcer disease that eventually led to a Nobel prize. I would recommend reading about how Marshall and Warren came to win the 2005 Nobel Prize in Medicine; science does not get more inspiring than this. The Helicobacter story is not too dissimilar to countless others, whenever there is a paradigm shift in a field the community rejects it. I touched on this a few weeks ago when I discussed Zur Hausen, HPV and cervical cancer. I would not be surprised if a similar story is waiting in the wings for MS. Please remember Arthur Schopenhauer’s Dictum; all truth passes through three stages: (1) It is ridiculed, (2) it is violently opposed and (3) it is finally accepted as self-evident. Are we anywhere near this with the autoimmune MS theory or is there a black swan circling?"


Epub: Fabis et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.J Neurol Neurosurg Psychiatry. 2015 Jan 19. pii: jnnp-2014-309495. doi: 10.1136/jnnp-2014-309495.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results.

OBJECTIVE: To determine the association between the H. pylori infection and MS.

METHODS: 550 MSers were included in the study and were matched by gender and year of birth to 299 controls. MSers were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups.

RESULTS: H. pylori seropositivity was found to be lower in MSers than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate.

CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life.

Getting rid of hot microglia

Airas L, Dickens A, Elo P, Marjamäki PM, Johansson J, Eskola O, Jones P, Trigg W, Solin O, Haaparanta-Solin M, Anthony D, Rinne J. In vivo Positron Emission Tomography Imaging Demonstrates Diminished Microglial Activation after Fingolimod Treatment in an Animal Model of Multiple Sclerosis. J Nucl Med. 2015 Jan 8. pii: jnumed.114.149955. [Epub ahead of print]

There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions as this is thought to be driving the widespread neuronal damage. Recently, 'second generation' positron emission tomography (PET) radioligands have been developed which can reveal the extent of microglial activation by quantifying the increased expression of the 18 kDa translocator (TSPO) protein. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion following treatment with fingolimod, an established MS therapy.
METHODS: Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotaxic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund's adjuvant. This results in a delayed type hypersensitivity (DTH)-like EAE-lesion. The extent of neuroinflammation surrounding the lesion was measured using 18F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/day po, 28 days) or vehicle as a control. In addition to this, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results.
RESULTS:The chronic DTH-EAE lesion led to increased ligand binding in the ipsilateral compared to contralateral hemisphere when PET imaging was performed with the TSPO-binding radioligand 18F-GE180. Treatment with fingolimod led to highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, p<0.0001). The area of increased 18F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry.
CONCLUSION:PET-imaging, unlike magnetic resonance imaging (MRI), can be used to visualise the microglial activation surrounding a chronic DTH-EAE lesion. Importantly, treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH-EAE lesion. This work gives promise for introduction of new outcome measures applicable in treatment studies of progressive MS.


This study suggests that we have a tool to measure hot microglia it is a short-activing radioactive tracer,in this can it is a 8 kDa translocator (TSPO) protein, another previously used is the benzodiazapine receptor. In this study the hot microglia were blocked by fingolimod. This will block the inflammatory penubra and blockinflammatory lesion formation,but what we need to block is the microglial inflammation in progressive disease. Can fingolimod do this in progressive MS, apparently not based on the recent failings in PPMS or are hot microglia a  smokescreen, I somehow suspect not. Could this be useful in humans



Image reveals higher levels of inflammation-associated translocator protein (orange/red) in the thalamus and other brain regions of chronic pain patients.

I guess so as images have now just been shown in humans in pain in the thalamus. Maybe this can be used to monitor progression in MS.

Monday, 26 January 2015

How Deep is Your Knowledge. Is this the MSer view of Neurologists

Had to laugh a recent comment posted

How deep is a Neuros knowledge....you say...as deep as a Carpark puddle? :-)

I suspect that is unfair on Neuro's reading this blog, but what about those non-specialists? 

I suspect that if you get good treatment and advice you are don't think like this.

Please keep comments constructive:-)

Survey results: why are MSers such risk takers?

I had no idea that MSers were such risk takers. #MSBlog #MSResearch

"Live and learn something everyday. I am bowled over by the preliminary results of haemopoietic stem cell transplant (HSCT) survey. I had no idea how willing MSers are to accept unlicensed treatments, with evidence that is essentially multiple case series, rather than the gold-standard randomised controlled clinical trials. Not to mention the risks they are prepared to take. We will need to follow this up with some high quality qualitative research in the UK; but if the message holds we will need to explore how we can start to offer this treatment in the context of a clinical trial. We will need to show that HSCT is effective and more importantly a cost-effective alternative to licensed treatments."


"If you want to contribute to the survey it is still open."



Some of the comments from the survey so far
  1. Anecdotal reports suggest HSCT can halt progression in PPMS and a trial would help discover the truth.
  2. There's a difference in having a life to being alive. For that reason, I'd take a 1-in-20 risk of dying at the outset of MS if that's a 19-in-20 chance at a normal life.
  3. I was dx'd at 30 years old. All my grandparents lived into their late 80s/90s. The prospect of 60 years of terminal decline, unemployment & financial destitution, relationship/family issues, chronic pain, progressive disability, dementia, and general despair is not for me.
  4. If there was a treatment with 50/50 chance of cure or death, i'd still take it over the propsect of 60 years of drawn out misery.
  5. Stop selling us such high risk, please.
  6. I think I would opt for meyoblative HSCT if I had highly active disease since there is enough data in my mind that it is the most effective therapy out there.
  7. Please enable self-funded international patients to be treated off-trial.
  8. I don't think you are too hung over on aggressive treatments or a laggard on HSCT. I think you are very sensible in your approach. My neurologist also thinks like you. He knows we will have little to no options once my disease becomes progressive and wants to stop it on it's track right NOW!
  9. Having a wife who "HAD" CIDP and saw the amazing results of HSCT for 80% + of people getting HSCT for all the autoimmune conditions treated by Dr Burt Chicago I as a patient would 100% want HSCT.
  10. I have PPMS and had HSCT with great results in Moscow with Dr Fedorenko. So pleased and grateful that this option was available to me.
  11. A bit academic for me as unfortunately I have SPMS. 
  12. I did HSCT with Dr. Richard Burt one year ago at Chicago Northwestern. HSCT stopped my MS after Tysabri had failed. 
  13. I fly in exactly 4 weeks to Moscow to be treated for SPMS with HSCT. I tried in this country with both Dr Silber at Kings and Prof Sharrack at Sheffield Hallamshire. I think we can safely say the UK Neurologists are too conservative! I did not want miracles; just to have the disease stopped in it's tracks. I have contributed 12% of my salary to the NHS for over 30 years and now I will be spending my life savings ($40,000) on being treated in Vladimir Putin's hospitals!
  14. If my MS progressed to be more of a burden on my life I would likely be prepared to take a higher risk of dying from a treatment.
  15. The level of risk (ie the risk of dying) acceptance is not constant: the older my children are growing, the higher the level of acceptance will be.
  16. As protocols evolve and increase the safety of the procedure HSCTs could provide a more cost effective treatment in the long term.
  17. The severity and progression of my MS would definitely dictate the risk I would be willing to take. Sometimes the risk of dying would be worth it if it meant that ridding this terrible disease and pain might end with treatment. Pain, whether physical or mental is tough to live with and I think patients should be given the choice. Its their body and their suffering they have to live with, not the doctors or lawmakers. 
  18. As protocols evolve and increase the safety of the procedure HSCTs could provide a more cost effective treatment in the long term.
  19. Well HSCT is a better option than euthanasia. 
  20. Why am I only now being made aware of Ocrelizumab ? My walking over the past month has deteriorated from 500 metres to 100 metres before needing a break.
  21. From the perspective of having grumbling but progressive MS rather than highly active MS i am not sure my opinion is valid. I find my slowly diminishing function frustrating and upsetting but I can adapt. If I had highly active MS I am sure I would want aggressive treatment, though 1:200 mortality risk seems quite a big risk still. 
  22. No chemo no cure?
  23. HSCT would be my treatment of choice and I will try to fund it myself should my MS start to kick off. Reason being I am young and have a life ahead of me. I want to live life as much as possible. Long term stats for MS are grim. HSCT is in my opinion the best change of curbing MS and all the destruction and lost dreams it brings. The low risk of death does not worry me but a prolonged period of severe and end stage MS does. 
  24. I am confused at how HSCT is safer (has less autoimmune problems) if it uses chemotherpay (such as alemtuzumab) to destroy bone marrow. 
  25. What about the genetic component of MS that was discussed at A/ECTRIMS in Boston? If a person's own stem cells are used aren't they at the same risk for MS before and after the therapy?
  26. The changes that happen otherwise healthy young adults who are diagnosed with MS is to me, worse than death- it is death by 1000 little 'losses' overtime that you 'get' to observe happen to your body without your input or consent. You know you will eventually loose most function and die an early unhealthy death to this disease- taking a chance on the front end to maintain your 'selfhood' seems a small risk compared to loosing everything slowly.
  27. I think the more options available to people, the better. I don't see HSCT as being different to any other type of treatment where the MSer and treating neurologist have to weigh up the risks and benefits. The trial results quoted on this blog do look very impressive. 
  28. The benefits far outweigh the risks! 
  29. MS is a terrible, debilitating, life-sentence of a disease. If HSCT slows it down or stops it, it should be offered. HSCT is a safe cancer treatment that has been around for many years.
  30. MS is known to be auto-immune. Therefore, HSCT, by ablating some or all of the immune system, will provide benefit for all types of MS. Even progressive.
  31. I think all effective therapies should be approved and allow doctors and patients to make the call on the risk-benefit trade-off. While HSCT appears to be pretty effective, I don't feel like I've seen good science on it, and so it seems more similar to CCSVI than the pharmaceuticals. However, I would be willing to take on fairly high risk to cure MS.
  32. What risk am I taking by not pursuing HSCT now that I am 54, healthy and don't have any current medical issues. What issues do I face by using Gilenya for 4+ years.
  33. In my opinion NIHR should fund a trial comparing HSCT to alemtuzumab, but not a randomized one. There are enough-patients who themselves would choose alemtuzumab because of the lower short term risk, and there certainly are many enough who wants HSCT. Therefore the trial hasn't at all have to be randomized (make a protocol with suitable inclusion and exclusion criteria). It is mandatory that besides using NEDA (number of relapses after treatment, EDSS after treatment and plaques and contrast enhancements on MRI) you also have to use quality of life (QoL) as an endpoint, for instance SF-36. For all ms-patients quality of life is greatly decreased and each day because of fatigue, pain, cog fog, bad sleep etc., and it is incredible that studied on DMDs - practiacally all of them - haven't applied QoL as an endpoint (but then, practically all the DMDs reduces QoL even more in addition). Therefore in a non-inferiority trial when you define a noninferiority margin and include a noninferiority hypothesis, you have to also include QoL as an endpoint!!!
  34. Besides, the NIHR should fund the same type of study for patients who have not had ms for a long time, and without highly-active ms (frequent relapses). The absolute majority of ms-patients are in this category, and their quality of life is low (it is mandatory for you to apply quality of life in all studies on DMDs and HSCT, and as Burt points out you haven't because DMDs don't improve QoL), and most of them have a dismal prognosis ending up out of work and in the long term with a high EDSS.
  35. I think HSCT is not only the best avalaible option to MSers with highly-active MS but also for
  36. PPMSers . You said that Ocrelizumab could be effective for PPMSers so I guess a more radical approach will be more effective.
  37. Anyway as today PPMSers have no a single one aproved DMT ,HSCT remain the best and only option.
  38. Have had non myelo in Russia Feb 14. EDSS of 4 now EDSS of 2.
  39. Alemtuzumab is not as effective as HSCT. I dont want to go through a procedure that does that comes with secondary concern for thyroid disease. I'd rather go through a process that halts the progression of MS and get on with the rest of my life. As the HSCT process is continued and refined. I believe the mortality rate will continue to decline.
  40. For those of us with RRMS that is transitioning and for those with PPMS or SPMS who are deteriorating noticeably HSCT is an excellent option as it arrests the disease progression in approx 80% (perhaps more now) of patients. It seems the protocol used in Russia is particularly effective on the more progressive types of MS. Cyclophosphamide with Rituximab,I am actively looking to get BMT..or HSCT presently, before my disability prevents me from being able to work, where the govt will have to support me entirely. HSCT has got to be a better option than this as it works out MUCH cheaper if it stops the disease and prevents further drugs and allows me to support myself!! A clinical study such as the one that is already in place in Sheffield would take too long to implement. Equally it is outdated since Russia has proven that HSCT works for progressive patients in stopping the progression of the disease! I think that peer published papers and practices such as what is in place in Canada and other parts of the world should be reviewed and adopted. No time for more trials!
  41. There is not really anything to comment! Anybody really knows that the only reason you are not offering this treatment is the market system...
  42. Same story as with vitamin-D, no difference!
  43. HSCT is worth it at every step - from Quality of Life Improvements to Financial Cost to the State to undergoing a Short Sharp Shock for a massive gain at the end of it.
  44. St Bart's should be performing HSCT!
  45. My son had highly aggressive ms had HSCT is a life saver. He is doing great no medication
  46. I am booked to have HSCT is Moscow in April 2015. It is ridiculous I have to fly half way round the world for treatment. HSCT HAS been done before in Glasgow,Scotland but it is not a routine treatment. It is also done in London and Sheffield UK buy with such narrow entrance criteria it is impossible for people to get on trial.
  47. Try living with MS? Then the medical profession would know about risk aversion for treatment compared to living with a degenerative condition. There is strong research and trial results supporting HSCT for MS. When will neurologists pay attention and look seriously at the evidence that is there? Oh, that's right. . .no ongoing revenue from people not taking drugs for the rest of their lives. Big pharma companies have way to much control of the medical profession. 
  48. I'd have this done asap if I could!! But I don't qualify for the trial & I don't want to leave the country!!! It's really very sad that this isn't available to everyone.
  49. I had HSCT for PPMS in June, 2014. My progression has stopped and I'm stronger, have better balance and I'm walking better then before the treatment. I have no regrets.
  50. I have been fighting for hsct for 2 yrs, I think a lot of the problem with approval is no nuro's will ok because it hasn't been okay ed by the FDA. It's been a treatment for 15 yrs in the United States and studied had by dr. Richard burt at northwestern university for autoimmune diseases and even longer over seas. And this same sort of procedure has been out for about 6 yrs in the US for cancer. Every body has there own way 2 heal and we finally found it! People who receive HSCT get there lives back and people with an autoimmune disease. Now have hope. But the chances for some people like myself of getting HSCT in time so it's more effective is so hard because you need to have your health insurance approve it. It's not like other trials where it free for patients to get the trial approved by the FDA. And a lot of us think it's because it's not a drug trial. Drug companies run the world it seems like. There is something out there that can really Help i have seen it first hand. why are we not even talking about this there are so many people I talk to at my MS infusions that have never heard of HSCT, but they have heard about all these new drugs that they will be taking for the rest of there lives. WHY IS THAT? HSCT is one treatment no more drugs. 
  51. HCST is the most current advanced procedure. The sheapest in long run and the safest in comparison to other treatments
  52. HCST is the most current advanced procedure. The sheapest in long run and the safest in comparison to other treatments
  53. Time is something few MSers who have had the illness for a long time can ill afford. HSCT is proven to work in sufficient numbers to war rent it being offered to those willing to take it.
  54. Am on waitlist for Russia- 2017-2018
  55. had hsct moscow 2013. 
  56. I received HSCT at Heildelber
  57. The 1-2% recent TRM is precisely what is seen in new HSCT protocols. I, for one, would advocate for the choice to treat very early on without the onerous requirements of DMD failures, none of which have shown any durability in preventing or halting progression. I had myeloablative HSCT just completed after 12 years of diagnosis and realize I still may never be able to walk right again. Not a single of my neurologists even mentioned HSCT. My quality of life is now destroyed as a result of having wasted many years on ineffective DMDs. Now I have to wait for the "hope" of remyelination, which we all know is an illusion as it will do nothing in progressive MS with axonal loss. 
  58. There are very few treatments that can help patients with PPMS like HSCT but unless their usage is put into normal practise and easily accessible people are dying while waiting.
  59. My daughter who had MS now for 16 yrs in that time she has been on numerous medicine that has not help at all she steady declining we have made up our minds to go to Russia next year but it be a lot easier for her and us if it was available in Australia and WITHOUT A REFERRAL from a neurologist 
  60. I think the more your quality of life decreases the more willing you are to take the risk.
  61. The chance for some years of a more normal life is worth it!
  62. I had HSCT in Moscow 2013. I was diagnosed PPMS. No enhancing lesions on all MRI tests. Progressing from running half marathons to needing a cane after walking a quarter mile. All within 2 years. Post HSCT I do not need a cane at all and can walk 3 miles with a rest in the middle for about 10 minutes.
  63. Should be offered to people with PPMS as well; there is currently no therapies that are offered for this type of ms. I believe HSCT would stop the progression of PPMS as it does with RRMS. I just wish someone would throw us a bone who are dealing with PPMS.
  64. I have PPMS and had HSCT in Moscow, Russia Aug/Sept 2013. It has stopped my progression and saved my life. You can see my story at www.kickinms.com. I stopped using my trekking pole after 6 months, and can now ride my bike 10 miles, and pushing for longer rides. My gait has improved, as well as toe drop. Before HSCT I could barely walk 1/4 mile, I can now walk 2 miles. So, my quality of life has greatly improved with HSCT. I think it should be an option for anyone with MS, including PPMS/SPMS. I knew the chances of stopping the progression were less for me, than someone with RRMS, but I took the chance. So glad I did!!!
  65. As noted, I'm the spouse, but my husband's neuro has been too conservative all along - "not approved!" "not enough data!" and now my husband is 41 with an EDSS of 7.5-8. Neuro's need to DO MORE and UNDERSTAND that there is a COST to not doing anything or being conservative. 
  66. I'm PPMS,with out hsct there is no other options. Regardless hsct is the only proven treatment to benefit any type of ms,and some forms have great odds. Either way I had no option prior. Now I have hope and a chance. 
  67. Coincidentally, I'm making the choice between HSCT and Lemtrada right now. The more I read about Lemtrada, the more concerned I get about safety and efficacy (particularly among patients who have been on Tysabri before and/or have been diagnosed for 6+ years).
  68. I have CIDP, not MS, but have become friends with many people with MS through various programs. I have seen so many of them deteriorate in the past 5 years. Like me, they started out with canes or walkers when we started the program together 5 years and now most of them are in powerchairs and some are housebound. If they had had a treatment that could stop MS progression they would have some quality of life. 
  69. No drug has yet proven to be as successful as hsct at stopping the progression of ms. I have rrms, i had hsct; the disease was stopped, i got my life back. No chemo = no cure. Hsct is not a new treatment; there is plenty of evidence pointing to its efficacy.
  70. I'm PPMS and have got my name down for Moscow in 2016.
  71. As far as I'm concerned it's a absolute no brainer.
  72. I'm already taking risks by taking Tysabri.
  73. The health departments all around the world should a public (only suffers of diseases that would benifit) referendum and THEN whatever is our wish respect it!!!! WE ARE SUFFERING NOT THEM! I need hsct and I can't afford it. I will be a guinea pig if needed. 
  74. I am RRMS since 4.5 years, 44 years old and mother of 3 girls 5, 9 and 12 years old. I hate taking DMD's because of side effects and hate the uncertainty of thr decease itself and are therefore going to have HSCT to stop this beast. My currently EDSS is 2 and I want to keep it that way or better.
  75. I have been treated 1 year ago I had Fulminant MS which does not respond to any 1st or 2nd line treatments. I did not have time to fail one so I went overseas to be treated. It has been a long road to recovery as I have had to learn to feed myself again, talk again (still a bit slurred) walk again etc etc. I was told I was going palliative weeks before I received treatment. I was having multi-system failure.
  76. No one has actually done a comparison (that I can find) between the deaths occurring for BMT for autoimmune only it seems to be all linked in with the cancer treatments. 
  77. For some reason the use of Tysabri and its links to some 560 deaths from December last year seem to be passed over as a slight inconvenience by most neurologists. 
  78. I met a person about 12 weeks ago that had been on Tysabri for 4 years and other than the initial tests for JCV for which he was positive no further titre level tests had been taken he has since demanded this and has been found to be at a very high level he now has no where to go. 
  79. I know that the trial arm for Dr Burts Satellite trials (Sheffield being one of them in the UK) have a trial arm of Tysabri it is my understanding that if you go JCV+ you are then treated with HSCT. There is no risk of GVHD with Autoglous SCT but a higher risk between myelo and non-myelo the risk is a no brainer when you have aggressive disease.
  80. We should have the evidence for HSCT before it gets offered as a standard of care treatment for MS. 
  81. I chose to have hsct 3 months after diagnosis
  82. I have had HSCT for SPMS & have seen many improvements. Now able to do things that I have not been able to do for many years. If I had done this treatment years ago things would be better, regardless I am glad I did this treatment in Moscow and would have no hesitation recommending this treatment. 
  83. If it can be done daily for other conditions I don't understand why it MS can't be included. Also, I don't unde why all focus is on RRMS & not other types. 
  84. I am not sure about HSCT. I want it to be approved in Australia before i do it.
  85. I'm a 38yr old single father of a 16 yr old daughter when I was first diagnosed I had rapidly progressive MS and I would love too slow some of the progression down or try reverse some of the progression. So I'm willing to try just about anything and I would love to try this not only for myself but my daughter and everybody else that has MS to see if it will help. I'm not sure if you actually reads what is commented on these things but I hope you do. I would love to get a response from you to know that you actually read this. My name is Alan Carpenter my email address is APC 2612 @ live.com. 
  86. I was one of the highly active ms'rs in Canada.. I had Malignant MS I was willing to take any risk as I was dying anyway. I am a true believer in HSCT I was a 9.0 at my worst. I now walk, talk, feed myself, type this to you with fingers that once didn't work.
  87. I am a 42 year old woman with SPMS and I had HSCT in Moscow in October 2014. I had no active lesions but was continually declining, I have already had improvement. I was on Tysabri for 2 years prior and declined whilst on the treatment.
  88. I was diagnosed in 1991 and had 19 years of remission. In 2010, I came out of remission, and M.S. Became progressive. Over the next four years I went from teaching couples dance classes with my husband to a cane and a rollator in March 2014. By that time I had learned of HSCT and been accepted by Dr. Fedorenko's in Russia. I was declined by the trials in Seattle and Chicago. I see some minor improvements since returning in August 2014 and am grateful to have been accepted and treated by Dr. F. Even if I don't experience further improvements, I still know I've taken the only treatment that might halt MS.
  89. HSCT beats Lemtrada hands down why not just push HSCT?
  90. Im not sold of the HSCT I am very interested in getting Lemtrada as it is available (almost). I do not want to travel to another country to have HSCT when I can easily get Lemtrada. I put my faith in the neuro to suggest my options, he believes the risks of Lemtrada outweigh the risks of HSCT.
  91. I am RR/SP MS, 2Neurologists are unsure as my relapses and progression are not typical, progression has been relatively fast since diagnosis in 2010. I am on my 3rd DMD and still declining. I want a chance to halt and if I am lucky improve some of my sympoms before I end up in a wheelchair, which I think is likely to happen in the very near future. 
  92. I had hsct and am 100% better than I was.
  93. HSCT should be available in UK, even if MSers have to pay for it. 
  94. 15 Years RRMS, 8 Years SPMS. I'm desperate just to stop the slide!
  95. Ms is a death sentence in itself.
  96. I would without a doubt choose hsct
  97. There are tx in other countries we should be able to evaluate and have access.
  98. It appears thet have success but then we have no real data.
  99. I have MS and if I'm willing to pay for HSCT. I can't understand why I cannot have it in my own country.
CoI: multiple