Thursday, 31 March 2016

ClinicSpeak: do vaccines cause MS?

Are live vaccines a no-no for people with MS? #ClinicSpeak #MSBlog #MSResearch

"Most people diagnosed with MS analyse their lives and look for 'potential causes' for their MS. It is not surprising that vaccinations get fingered as being the trigger, or cause, of MS in many people. The evidence suggests the contrary (see review below). MS is relatively common and vaccinations are even more common, therefore by chance MS is going to present in some people shortly after they have had a vaccination. Therefore we  have to rely on large population studies to see if there is any temporal (timing) relationship between vaccinations and MS. To the best of my knowledge the answer is no; we have no evidence that MS is caused by, or related, to any vaccine."

"With regard to relapses the evidence is less certain, simply because not all vaccines have been systematically studied. In relation to inactivated component vaccines, for example influenza and hepatitis B, there is no convincing evidence that would indicate that these vaccines trigger relapses. In relation to live vaccines I don't know. I say I don't know is that we know that infections are a well-defined, and studied, trigger of relapses. Approximately a third of relapses occur in the at-risk period (last 4-6 weeks) in relation to a recent infection. Live vaccines work because they are an infection, albeit an attenuated infection, with a virus or bacteria that is derived from a known human pathogen. This is why I always warn my patients with MS about live vaccines; live vaccines have the potential to trigger relapses. As always the decision to have a live vaccine is an individual one; a personalised risk:benefit decision about whether or not to have a vaccine to protect you against a potential infection and the undefined risk the vaccine may trigger an MS attack. For those of you on immunosuppressive DMTs live vaccines are generally a no-no, so the decision has already been made for you."

"What this post tells me is that there is a lot we still don't know about MS and how it relates to general immune function. May be when we know the cause of MS we will be able answer the questions about the safety of vaccines in people with MS based on evidence and not opinion."


Nguyen et al. Vaccine-associated inflammatory diseases of the central nervous system: from signals to causation. Curr Opin Neurol. 2016 Mar 26.

PURPOSE OF REVIEW: As the most cost-effective intervention in preventive medicine and as a crucial element of any public health program, vaccination is used extensively with over 90% coverage in many countries. As approximately 5-8% of the population in developed countries suffer from an autoimmune disorder, people with an autoimmune disease are most likely to be exposed to some vaccines before or after the disease onset. In fact, a number of inflammatory disorders of the central nervous system have been associated with the administration of various vaccines. These adverse events, be they spurious associations or genuine reactions to the vaccine, may lead to difficulties in obtaining public trust in mass vaccination programs. There is, thus, an urgent need to understand whether vaccination triggers or enhances autoimmune responses.


RECENT FINDINGS: By reviewing vaccine-associated inflammatory diseases of the central nervous system, this study describes the current knowledge on whether the safety signal was coincidental, as in the case of multiple sclerosis with several vaccines, or truly reflected a causal link, as in narcolepsy with cataplexy following pandemic H1N1 influenza virus vaccination.

SUMMARY: The lessons learnt emphasize a central role of thorough, ideally prospective, epidemiological studies followed, if the signal is deemed plausible or real, by immunological investigations.

Biomarkers show that highly active DMT block inflammation and save nerves

Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström C, Piehl F, Olsson T, Lycke J. Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis. Mult Scler. 2016. pii: 1352458516639384. [Epub ahead of print]

BACKGROUND: The disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) vary in their mode of action and when therapies are changed, the consequences on inflammatory and degenerative processes are largely unknown.
OBJECTIVE: We investigated the effect of switching from other DMTs to fingolimod on cerebrospinal fluid (CSF) biomarkers.
METHODS:43 RRMS patients were followed up after 4-12 months of fingolimod treatment. Concentrations of C-X-C motif chemokine 13 (CXCL13), chemokine (C-C motif) ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light protein (NFL), and neurogranin (NGRN) were analyzed by enzyme-linked immunosorbent assay (ELISA), while chitotriosidase (CHIT1) was analyzed by spectrofluorometry.
RESULTS: The levels of NFL, CXCL13, and CHI3L1 decreased (p < 0.05) after fingolimod treatment. Subgroup analysis revealed a reduction in NFL (p < 0.001), CXCL13 (p = 0.001), CHI3L1 (p < 0.001), and CHIT1 (p = 0.002) in patients previously treated with first-line therapies. In contrast, the levels of all analyzed biomarkers were essentially unchanged in patients switching from natalizumab.
CONCLUSION: We found reduced inflammatory activity (CXCL13, CHI3L1, and CHIT1) and reduced axonal damage (NFL) in patients switching from first-line DMTs to fingolimod. Biomarker levels in patients switching from natalizumab indicate similar effects on inflammatory and degenerative processes. The CSF biomarkers provide an additional measure of treatment efficacy.

You have heard of chitinase from NDG and this is another study suggesting it has some biomarker like activity and you all know about neurofilament as a surrogate maker of nerve damage and in this study it drops when you go from people failing first line DMT, i.e. CRAB drugs, and you are put on a highly active second line treatment. Another example where it is clear that that too much inflammation = BAD and drugs that put a halt to this can save brain. Are you willing to have a lumbar puncture to find this out?

I think the answer is no....However you can reduce those headaches if you use atraumatic needles and ultrasound guidance.

If you are on effective DMT your NFL level will drop can we drop this further....if you want to find out and are willing to try a neuroprotectant on top of your DMT you could please check out the PROXIMUS Study  (CLICK HERE)

Wednesday, 30 March 2016

ResearchSpeak: stenoses and asymmetry of jugular veins common in non-MSers - are these abnormal?

Are venous asymmetry's specific to MS? #MSBlog #MSResearch #ResearchSpeak

"The descriptive study below describes frequent asymmetries in the internal jugular veins (IJV) of non-MSers. It is a pity this was not compared to another control group, in particular a group of MSers. In my experience from looking at 1000's of scans is that asymmetry in blood vessels, including arteries, veins and venous sinuses, is the norm. This is not surprising if you consider the embryonic development of the vasculature. They author's also found a very high incidence of stenoses, which seems much higher than what one would expect. However, without comparative data it is hard to draw any conclusions from these observations. I wonder if anyone has looked at animals with chronic EAE, or other disease models, for similar findings or for that matter other inflammatory diseases of the CNS? Could this be linked to inflammation in the blood vessels? Or viral infection of the vasculature? Some herpes viruses have a predilection for blood vessels. These findings are non-specific to me and clearly change the way we should view similar findings in MSers."



Torres et al. Extracranial Venous abnormalities: A true pathological finding in patients with multiple sclerosis or an anatomical variant? Neuro European Radiology pp 1-8, First online: 24 March 2016.


Objective: To evaluate the extracranial venous anatomy with contrast-enhanced MR venogram (CE-MRV) in patients without multiple sclerosis (MS), and assess the prevalence of various venous anomalies such as asymmetry and stenosis in this population.

Materials and methods: We prospectively recruited 100 patients without MS, aged 18–60 years, referred for contrast-enhanced MRI. They underwent additional CE-MRV from skull base to mediastinum on a 3T scanner. Exclusion criteria included prior neck radiation, neck surgery, neck/mediastinal masses or significant cardiac or pulmonary disease. Two neuroradiologists independently evaluated the studies to document asymmetry and stenosis in the jugular veins and prominence of collateral veins.

Results: Asymmetry of internal jugular veins (IJVs) was found in 75 % of subjects. Both observers found stenosis in the IJVs with fair agreement. Most stenoses were located in the upper IJV segments. Asymmetrical vertebral veins and prominence of extracranial collateral veins, in particular the external jugular veins, was not uncommon.

Conclusion: It is common to have stenoses and asymmetry of the IJVs as well as prominence of the collateral veins of the neck in patients without MS. These findings are in contrast to prior reports suggesting collateral venous drainage is rare except in MS patients.

Meta analysis of the Week.

Zhang P, Wang R, Li Z, Wang Y, Gao C, Lv X, Song Y, Li B. The risk of smoking on multiple sclerosis: a meta-analysis based on 20,626 cases from case-control and cohort studies. PeerJ. 2016;4:e1797. 

Background. Multiple sclerosis (MS) has become a disease that represents a tremendous burden on patients, families, and societies. The exact etiology of MS is still unclear, but it is believed that a combination of genetic and environmental factors contribute to this disease. Although some meta-analyses on the association between smoking and MS have been previously published, a number of new studies with larger population data have published since then. Consequently, these additional critical articles need to be taken into consideration. Method. We reviewed articles by searching in PubMed and EMBASE. Both conservative and non-conservative models were used to investigate the association between smoking and the susceptibility to MS. We also explored the effect of smoking on the susceptibility to MS in strata of different genders and smoking habits. The association between passive smoking and MS was also explored. Results.The results of this study suggest that smoking is a risk factor for MS (conservative model: odds ratio (OR) 1.55, 95% CI [1.48-1.62], p < 0.001; non-conservative model: 1.57, 95% CI [1.50-1.64], p < 0.001). Smoking appears to increase the risk of MS more in men than in women and in current smokers more than in past smokers. People who exposed to passive smoking have higher risk of MS than those unexposed. Conclusion.This study demonstrated that exposure to smoking is an important risk factor for MS. People will benefit from smoking cessation, and policymakers should pay attention to the association between smoking and MS.


ProfG described loosing his mojo and one of the issues is maintaining enthusiasm about posting. This is certainly a time drain, and is not helped by not having good quality information to post on.

Many of you are not interested in animal work. That is fine by me because to explain things properly takes a lot of time. However, how many times do you want to hear the same thing?

That is what science is...an Idea and then repetition.

Here is a good example

This is the risk of smoking and risk of MS. 

This is yet another meta analysis and it says smoking is a risk factor for MS. How many times do we need to say this?

Well it helps if you don't smoke and make sure your kids don't start smoke, it will be alot better for their pockets and their health.

However, who doesn't say smoking is bad for you. If you look at the figure above and if you are to the left of 1 then smoking decreases your risk and to the right of one, it shows increases your risk increase slightly.

Here we have 25 studies and they all point to the same thing...how many more papers will we have on this subject...A few more I suspect, but let's face it this is no longer an experiment you know what you are going to get.

If you do an experiment for Pharma they want a positive control...i.e. a drug that works in the system being tested. This is not very 3Rs of animal use because it is not an experiment. You know what is going to happen, if the test drug doesn't work it doesn't work and if you are that concerned you can repeat the negative result, so who cares about the positive control as long as the experiment performs properly i.e., it has some quality control in it. We see many experiments EAE where there is such QC. One time the control group scores say = one the next experiment the control group = four. If we don't get the same score in our control groups thent there is a QC issue, which makes you cautious about any result. If the drug works who cares about a positive control.

Likewise the number of papers I see, where they have a negative control so the animals don't get disease...is frankly in most cases an unethical waste of animals.

Tuesday, 29 March 2016

ClinicSpeak: time to focus on hand function to measure worsening MS

How important is arm function, speech and swallowing to you? #MSBlog #MSResearch #ClinicSpeak

"It is clearly  time to rethink how we do progressive, or worsening, MS trials (I am trying to move away from using the term progressive). The days of relying on the EDSS to measure the impact of worsening/progressive MS are going fast. The study below shows that when using the EDSS-Plus to measure worsening in SPMS it is more sensitive than the EDSS alone. The EDSS-plus is a composite of the EDSS, timed 25-ft walk and the 9-hole peg test. What this study doesn't address is the possibility of different biological processes driving worsening in different neuronal subsystems. The systems with no reserve capacity that are worsening clinically (in old terminology clinically-apparent SPMS) may not be modifiable in the short-term with anti-inflammatory DMTs; these systems may require neuroprotectants. In comparison, the subsystems with reserve, e.g. upper limb and bulbar function, may still be modifiable with anti-inflammatories. Therefore we may need to design our outcomes based on what the proposed DMTs can do and on how advance the disabilities are in the populations being studied. The latter is all part of our length-dependent axonopathy and therapeutic lag hypotheses."


"When you have MS and you lose the function of your legs, your arms and hands become your legs. When you lose the function of your arms your lips, tongue and throat muscles become your arms, hands and legs. At the moment we seem to focus too much attention on leg function and forget the upper body. In the NHS we are meant to stop DMTs when a person becomes wheelchair bound; what we actually saying to them is we don't really care about your upper limb or bulbar function. Clearly this position is wrong and we need to do something about it. Data will emerge later this year that DMTs continue to work on the upper limbs despite lower limb function working. What this observation is telling is that MS is that the pathogenesis of MS may be modifiable regardless of how disabled you are."

Cadavid et al. The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis. Mult Scler. 2016 Mar 22. pii: 1352458516638941.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function.

OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment.

METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT.

RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone.

CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

The eye as a predictor of brain activity

Martinez-Lapiscina EH, Arnow S, Wilson JA, Saidha S, Preiningerova JL, Oberwahrenbrock T, Brandt AU, Pablo LE, Guerrieri S, Gonzalez I, Outteryck O, Mueller AK, Albrecht P, Chan W, Lukas S, Balk LJ, Fraser C, Frederiksen JL, Resto J, Frohman T, Cordano C, Zubizarreta I, Andorra M, Sanchez-Dalmau B, Saiz A, Bermel R, Klistorner A, Petzold A, Schippling S, Costello F, Aktas O, Vermersch P, Oreja-Guevara C, Comi G, Leocani L, Garcia-Martin E, Paul F, Havrdova E, Frohman E, Balcer LJ, Green AJ, Calabresi PA, Villoslada P; IMSVISUAL consortium. Retinal thickness measured with optical coherence tomography and risk of disability worsening inmultiple sclerosis: a cohort study. Lancet Neurol. 2016. pii: S1474-4422(16)00068-5. doi: 10.1016/S1474-4422(16)00068-5. [Epub ahead of print]

BACKGROUND:Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available.
METHODS: In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates.
FINDINGS: 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis(n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume.
INTERPRETATION: Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis.


When I was at the Anne RowlingCentre in Edinburgh, there was an OCT suite within the centre and this was part of set-up. In this study if they find that if there is evidence of nerve damage in the eyes at the onset was a poorer prognostic marker

To boldly go where no man/woman has gone before

Proc Natl Acad Sci U S A. 2016 Mar 14. pii: 201519286. [Epub ahead of print]

Identification of tissue-specific cell death using methylation patterns of circulating DNA.

Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A, Rubertsson S, Nellgård B, Blennow K, Zetterberg H, Spalding K, Haller MJ, Wasserfall CH, Schatz DA, Greenbaum CJ, Dorrell C, Grompe M, Zick A, Hubert A, Maoz M, Fendrich V, Bartsch DK, Golan T, Ben Sasson SA, Zamir G, Razin A, Cedar H, Shapiro AM, Glaser B, Shemer R, Dor Y.

Abstract

Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

Figure: The tricorder, a handheld device combining sensors, recorders and built-in computing capability. As of 2366, the standard model could not detect subspace phenomena or neutrino particles (info from www.startrek.com)

Admittedly, this work is a long way from the medical tricorder, and involves machines much larger by comparison; but I wonder if the authors themselves realize the potential for their work?

Cell-free circulating DNA (cfDNA) are small fragments released by dead cells in the body, on average there are 5,000 genome equivalents/ml. As cell death occurs in many disorders affecting the human body, the ability to pick up this damage early on before there is functional consequence (for example, weakness) would be invaluable diagnostically, and also allows potential therapeutic windows to be accessed early on.

The DNA of each cell type can be identified by the methylation markers it carries, which are unique to that cell type and conserved in other cells of the same tissue in an individual and between individuals. The DNA methylation pattern of the cfDNA can therefore be used to identify the tissue of origin, as well as cell death in the source tissue/organ.

Here, they describe evidence of oligodendrocyte (myelin) cfDNA circulating in the blood of MS subjects and those with neuromyelitis optica. It is likely that the breakdown in the blood-brain barrier facilitates the transfer of these fragments into the blood.

I live in hope that this comes in hand held device, what I wouldn't do to have the capability on my rounds!

Monday, 28 March 2016

ResearchSpeak & GrandChallenges (7): how do anti-B cell therapies work?

Why are plasma cells potentially so important in MS? #ResearchSpeak #GrandChallenges #MSBlog #MSResearch

It is clear that B cells play a central role in pathogenesis of MS, could the role for plasma cells be even bigger?

1. MS has not be seen in people who don't make immunoglobulins due to rare genetic disorders (agammaglobulinaemia).

2. Oligoclonal IgG bands are invariably found in the cerebrospinal fluid (CSF) and brain/spinal tissues of MSers. These immunoglobulin bands have been highly selected; in other words whatever is driving their production is getting help from other cells (antigen presenting cells and T cells). This selection process is typically seen with infections or foreign antigens (proteins).

"If we can uncover what these OCBS are reacting with we will uncover the cause of MS."

MSers who don't have these oligoclonal bands have a more benign course; this applies to MSers with relapse-onset MS and PPMS.

"OCB-negative MSers don't have 'classic MS' and if I had my way they would be given a separate diagnosis or at a minimum a definitive MS should be delayed; this is particularly important when diagnosing PPMS! This is another reason why lumbar punctures and spinal fluid analysis should be done in all MSers. You only get one chance not to make the diagnosis of MS and that is in the beginning, or the diagnostic phase, of the disease. Spinal fluid analysis helps you exclude other conditions and tells you if you have OCBs or not."

3. B-cell follicles, were the B-cells mature and become antibody factories or plasma cells, are found in CNS of MSers. These are ectopic follicles as they are normally found in lymph nodes and the spleen. These follicles appear to be more common in progressive MSers and appear to be driving the cortical, or gray matter, pathology. The current thinking is the gray matter pathology is what drives the clinically-apparent progressive phase of the disease.

4. Pathological studies show immunoglobulin deposits in the brains of MSers and associated complement activation. Complement is one of the molecules that certain classes of immunoglobulins use to damage or kill target cells and organisms. Interestingly in the, now famous, Barnett and Prineus lesion immunoglubluin deposition was seen without the classic T cell infiltrates. Many of us now consider this to be the earliest relapse-causing lesion and based on the observations in these lesions immunoglobulins seem to be is very important inflammatory mediators.

5. B cells are the cells were EBV, the virus that is causally linked to MS, resides.

"Could the B cell be the Trojan horse that takes EBV into the brain and spinal cord? Unfortunately, the evidence on this topic is rather mixed at present, but I suspect the B-cell is the cell that EBV hitches a ride in."

6. Most if not all highly effective MS DMTs target B cells.

"This is an observation that I made several years ago! The one exception is daclizumab and working out how this drug works in MS will be very important."

7. Targeted anti-B cell therapies (anti-CD20 - rituximab, ocrelizumab, ofatumumab) are among the most promising emerging MS therapies. There superior efficacy was not expected given the current dogma that MS is T-cell driven disease.

"It is a pity that anti-CD20 therapies do not target plasma cells or plasmablasts; these are the immunoglobulin factory cells and are also part of immunoglobulin pathway. May be the newer anti-CD19 agents that target plasma blasts will be more effective than anti-CD20? Or we may have to add-on agents that target plasma cells. Plasma cells are long-lived and may therefore be the driver of progressive MS despite other upstream, adaptive, immune responses being switched off."

The Grand Challenge: "Are B cells the pivotal cell in the pathogenesis of MS? How do anti-B cell therapies work in MS? Do anti-B cell therapies work as anti-EBV agents? Are long-lived plasma cells drivers of the non-relapsing progressive phase of the disease? Will drugs targeting plasma cell biology be effective in MS?"


O Plasma-cell, Plasma-cell, wherefore art thou Plasma-cell? Deny thy father and refuse thy name; or if thou wilt not, be but sworn my love and I'll no longer be a T-cell. Shall I hear more, or shall I speak at this? 'Tis but thy name that is my enemy: thou art thyself, though not a B-cell.

CoI: multiple

Halting B cell Activation

Glatigny S, Wagner CA, Bettelli E. Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis. J Immunol. 2016. pii: 1502614. [Epub ahead of print]

The neutralization of integrin α4(Itga4) is currently used as treatment in multiple sclerosis. Although most studies have focused on its function on lymphocyte migration to the CNS, we have uncovered the importance of Itga4 for the generation of regulatory B cells in peripheral immune organs and their control of pathogenic T cell response and CNS pathology. Our study underscores the importance of looking at the dual role of B cells in CNS autoimmunity and provides important perspectives regarding the efficacy and side effects associated with Itga4 neutralization and other B cell-targeting therapies.


We have heard alot about Treg cells, but there are also B regulatory cells which influence immune responsiveness and presumably because of their inhibition with Atacicept that MS worsened. Now this study suggests that the target for natalizumab controls B regulatory cells and the authos argue that this may be important in the function of natalizumab.

So whilst my mojo is rising I ask if this is the case what does natalizumab treatment tell us about B reg control of MS, because it seems that Natalizumab can do a good job in quelling relapses. Do the B regs control anti-viral responses?

Maybe we will see the same for anti-CD20 antibodies because they can make EAE better, do nothing or make it worse and this tells us that timing is critical in terms of effect and outcome.This is true of a great number of agents and so treatment is often a balance of effects.


Sunday, 27 March 2016

ClinicSpeak: frontloading risk; not one but two autoimmune diseases

Are you prepared to trade-in MS for one, or maybe two, other autoimmune diseases? #ClinicSpeak #MSBlog #MSResearch

"Are you prepared to trade in your MS, on the promise of long-term remission, for a second autoimmune disease? If not alemtuzumab is not for you. The two case reports below are of two MSers who developed both autoimmune thrombocytopenia and autoimmune thyroid disease after their first course of alemtuzumab. Interestingly, both these MSers had previously been treated with fingolimod with marked lymphopaenia. Is it possible previous fingolimod treatment predisposes you to secondary autoimmunity? We will learn very quickly as many MSers in our centre are transitioning from natalizumab to alemtuzumab via a fingolimod bridge."

"Please note that one of the selling points for alemtuzumab is pregnancy, i.e. you can fall pregnant ~4 months after having a course of treatment with no drug on board. However, if you develop autoimmunity whilst pregnant the auto-antibodies can cross the placenta and affect the unborn foetus. For thyroid disease this may not be such a big problem (transient neonatal hyperthyroidism), but this may be much more serious for autoimmune thrombocytopenia and kidney disease. Please note that the secondary autoimmune complications of alemtuzumab treatment are frontloaded; if you get through 5 years (4 years post last course) you are likely not to get the secondary autoimmune complications. However, the 4 year rule does not answer the other major outstanding question of delayed secondary malignancies post-alemtuzumab. The latter  question will only be answered after thousands of treated MSer go beyond 10, or even 20, years of follow-up; the same timeframe we require to see if the long-term remission becomes a cure in a proportion of MSers."

Frontloading Risk!

Obermann et al. Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler. 2016 Mar 15. pii: 1352458516638558.

OBJECTIVE: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab.

METHODS: Case series and review of the literature.

RESULTS: Both patients showed severe thrombocytopenia with platelet counts of 2 × 109 and 11 × 109/L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation.

CONCLUSION: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia.

CoI: multiple

oligoclonal bands can be fouund if you look hard enough

Halbgebauer S, Huss A, Buttmann M, Steinacker P, Oeckl P, Brecht I, Weishaupt A, Tumani H, Otto M.Detection of intrathecal immunoglobulin G synthesis by capillary isoelectric focusing immunoassay in oligoclonal band negative multiple sclerosis.
J Neurol. 2016 Mar 19. [Epub ahead of print]


Oligoclonal immunoglobulin G bands (OCBs) restricted to the cerebrospinal fluid indicate intrathecal inflammation. Using isoelectric focusing and immunoblotting, they are detected in about 95 % of patients with clinically definite multiple sclerosis (MS). To elucidate whether in the remaining 5 % OCBs are truly absent or alternatively missed due to insufficient sensitivity of the routine measurement, we employed a new, highly sensitive nanoscale method for OCB detection. Capillary isoelectric focusing followed by immunological detection served to analyze OCBs in 33 well-characterized OCB-negative and 10 OCB-positive MS patients as well as in 100 OCB-negative control patients with non-inflammatory neurological diseases and 30 OCB-positive control patients with inflammatory neurological diseases. We detected intrathecal immunoglobulin G production in 10 out of 33 MS patients (30 %), initially diagnosed as being OCB-negative, and in all 10 OCB-positive MS patients, but in only 3 out of 100 non-inflammatory neurological controls (3 %) and in 29 of 30 inflammatory neurological controls (97 %). At least about one-third of MS patients without intrathecal immunoglobulin G synthesis according to standard methods are OCB-positive. Advanced methods for OCB detection may increase the analytical sensitivity for detecting OCB in patients with MS who are OCB-negative according to current routine methods.
 
This study looks at oligoclonal bandsand negative people and says that if you look hard enough they can be found 

Saturday, 26 March 2016

FeedbackSpeak: Are we losing our mojo?

Comments and suggestions needed to improve the blog? #MSBlog #MSReasearch #FeedbackSpeak



"I started this blog in September 2009 in response to CCSVI, which seems to be less of an issue 6+ years later. The blog is now into its 7th year. In that time we have expanded and added many different things. We now have many more contributors to the blog and get the occasional guest bloggers involved. We have become political taking on government policy, pharma, NICE, the NHS, other researchers and even neurologists, to name a few. We have expanded from simply being a site to interpret research findings into providing clinical advice, albeit generic advice, education, news, personal stories and anecdotes, and even the occasional fundraising initiative. The blog is truly a 2-way vehicle and several of our current research initiatives have been driven by you. We have been approached by third parties to monetise the blog, i.e allow sponsored posts (advertorials). Google keeps harassing us to activate Adwords so that we offer you deals, etc. You have said no to advertising. I feel the current format is getting quite jaded and needs to be rejuvenated. To do this we need an administrator to help with editing and increasing the number of guest bloggers. Having a site administrator would also help with the NeuroSpeak case studies, which some of you found helpful. Before embarking on a major overhaul of the site any ideas and suggestions from you would be much appreciated. Thank you."

ClinicSpeak: fatigue and sleep disturbances impact on mood

What affects your mood? Are you fatigued, sleep-deprived and depressed? #ClinicSpeak #MSResearch #MSBlog Are #GroupClinics the solution?

"The study below demonstrates that fatigue and sleep disturbances predict the development of depression in MSers at follow-up a few years down the line. I am not surprised by this study's findings the brain responds to all complex percepts (integrated sensory perceptions) with an affective response, or a change in mood. What I mean is that if you are fatigued it is natural for you to feel low or depressed; fatigue is generally a negative symptom and you respond with a lowering of your mood. Fatigue and depression go hand-in-hand. Sleep disturbance is also related to the two problems. Not sleeping properly is very common in MSers and relates to many different, and varied, causes and is one of the main drivers of fatigue. Therefore it is not surprising that MSer who are sleep-deprived and don't get good quality deep sleep, feel fatigued and depressed. I am sure many of you relate to these problems."

"For many reasons, some of which are highlighted above, we are planning to start a trial of group clinics to target sleep disorders in MSers. We simply don't have enough time in the NHS-allocated 15 minute follow-up slots to manage your sleep problems properly. We are therefore asking 12 MSers to pool their 15 minutes slots to give us 3 hours during which we tackle sleep problems as a group. By doing this we can teach you about sleep disorders in MS get you to self-diagnose your problems and self-manage them with the help of the group. Group clinics are not new and  have been used in psychiatry for decades and have more recently been shown to improve outcomes in other chronic diseases. The question is are you prepared to share your time with others and speak about your problems with others? I suspect group clinics is not the answer for everyone. Are you prepared to try being part of the experiment?"


Edwards et al. The Relative Importance of Baseline Pain, Fatigue, Sleep and Physical Activity: Predicting Change in Depression in Adults with Multiple Sclerosis. Archives of Physical …, 2016. DOI: http://dx.doi.org/10.1016/j.apmr.2016.02.025

Objective: To determine if baseline levels of pain, fatigue, sleep disturbance and physical activity measured at the initial assessment predicted the development of or improvement of depression 3.5 years later, while controlling for sex, age, and disease severity. This research is important, as few studies have examined these modifiable factors using a longitudinal design.


Design: Observational longitudinal survey study.

Setting: A community-based population sample.

Participants: Adults with multiple sclerosis (MS; N = 489).

Interventions: Not applicable.

Main Outcome Measures: Primary outcome was classification of depression group measured using a PHQ-9 cut-off score of ≥ 10, indicating probable major depression.

Results: Fatigue severity (odds ratio, 1.19, 95% confidence interval, 1.12 - 1.26, P < .0001) and sleep disturbance (odds ratio, 1.06, 95% confidence interval, 1.02 – 1.10, P = .001) predicted probable major depression 3.5 years later among those not depressed at the initial assessment. An effect of age (odds ratio, 0.96, 95% confidence interval, 0.92 – 0.99, P = .008) was found among those who developed depression, indicating that younger adults were more likely to develop depression. Pain, fatigue, sleep, and physical activity at baseline were not significantly associated with recovery from depression among those depressed at the initial assessment.

Conclusions: Fatigue and sleep may contribute to the development of depression. Clinical trial research targeting these variables to determine their influence on depression is warranted.

Cannabis inhibits Spasticity

Marinelli L, Mori L, Canneva S, Colombano F, Currà A, Fattapposta F, Bandini F, Capello E, Abbruzzese G, Trompetto C. The effect of cannabinoids on the stretch reflex in multiple sclerosis spasticity. Int Clin Psychopharmacol. 2016 Mar 21. [Epub ahead of print]

The aim of this observational study was to assess the efficacy of a tetrahydrocannabinol-cannabidiol (THC : CBD) oromucosal spray on spasticity using the stretch reflex in patients with multiple sclerosis (MS). Numeric rating scale (NRS) for spasticity, modified Ashworth scale (MAS), and the stretch reflex were assessed before and during treatment in 57 MS patients with spasticity eligible for THC : CBD treatment.  A significant reduction in stretch reflex amplitude as well as significant reductions of NRS and MAS scores were observed. There was a low concordance between the three measures (stretch reflex, NRS, and MAS), likely related to the different aspects of muscle hypertonia assessed. Stretch reflex responders were taking a significantly higher number of puffs, whereas no differences were found in the responders by the other scales, suggesting that a higher dosage would add benefit if tolerated. The present study confirms the efficacy of cannabinoids in reducing spasticity in patients with MS, suggesting a higher sensitivity and specificity of the stretch reflex compared with other measures. As an objective and quantitative measure of spasticity, the stretch reflex is particularly useful to assess the effects of cannabinoids on spinal excitability and may play a role in future pharmacological studies

It is amazing that in the clinical trials of oral cannabis and of sativex spray they could not find an effect on the Ashworth scale involving trials of hundreds of people but now in the post licencing age when we realise that some people respond and others do not that you can get positive effects with 30-60 people. In this study of savitex spray there were positive effects but worryingly there was poor correlation between physician assess Ashworth scale (what do your muscle look like (normal, stiff, very stiff etc), patient assessed responses (how do you feel out of a scale 1-10) or a stretch response.


But this study further supports our prior animal work that cannabinoids can control spasticity. However our prior work also shows the achilles heel of the approach is the side effect issue and the capacity to cause sedation and psychoactive effects and there is a small window between therapy and a high which some people do not want....some do.

CoI we are attempting to develop alternative treatment to Cannabis

CLICK HERE  FOR DETAILS

In our clinical trial we are looking at the Ashworth scale, the Numeric rating scale and a thing called the Tardieu response with is a bit of a stretch test, where you lie down and you flex the muscle and you see when the stiffness occurs and how much the leg bends at different speeds of flexing the muscles.

Now if you fit the criteria and are interested and 
willing to try something different and live in London (you can be taxied to the centre doing the studies each day) or are willing to travel and stay in London for a few days (someone has come from hundreds of miles away) then you could come to Barts or Queens Square or the nearest test centre.

However, if you live near Liverpool you can now go to the Walton Centre, where they are now actively recruiting. Contact details have yet to be put on clinical trials.gov

If you live on the other(the best:-)side of the Pennines then you will I believe be able to go to Sheffield in the very near future too. I'll keep you posted.

Friday, 25 March 2016

ClinicSpeak & BrainHealth: what does the 'New Normal' look like

Do you feel normal? #ResearchSpeak #BrainHealth #MSBlog #MSResearch

"Yesterday, when I got home and picked-up our post, which included the Economist, the headline on its cover was 'Europe's New Normal' with reference to its war with terrorism. Simultaneously, sitting in my inbox was an email from a colleague asking me whether or not pwMS who are NEDA feel 'normal' and is  there a way of defining a 'new normal' for pwMS? I don't know the answer to this question, but said I would ask you the community.




The current dogma states that MS is an autoimmune disease of the central nervous system that is driven by focal inflammatory lesions or MS plaques. We think the MS lesion is responsible for both acute (now) and delayed (in the future) damage. Permanent loss of function (impairment or disability) is due to neuronal loss, which can be measured clinically, electrically, on MRI and biochemically in the spinal fluid. If we measure all these things and find no evident disease activity have we reset things back to normal, i.e. a 'new normal' state for pwMS?


Inflammation transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with age. This is why it is important to treat MS early so as to protect reserve capacity. The 'new normal' would need to take into account existing damage.

Neuronal processes (axons) that survive being transected are compromised and never recover back to full health. These axons may remain demyelinated, or if they are remyelinated the myelin sheath is never as thick as it was in health. In addition, the so called microenvironment within the chronic MS lesion is stressful to the axon. All this programmes the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal inflammatory lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. In other words progressive MS is like a ticking ‘time bomb’. If we define a 'new normal' state would this be compatible with delayed onset of clinical worsening?

We seem to forget that as we get older we lose brain this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail; this is normal. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to live as long as we are living today. What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. However, this drop-off in neuronal function will interpreted as MS-, and not age-, related decline. Is the loss of reserve compatible with defining a 'new normal' for pwMS?

The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and is tempting to suggest that if we treat pwMS early enough and effectively enough we may be give you an opportunity to be normal, or at least a chance of a 'new normal'.


Is it futile to think of the concept of a 'new normal'? May be it is simply because of the psychological burden that goes along with having a diagnosis of MS. However, I know many cancer survivors who are essentially cured of their disease who describe themselves as being normal. Why can't MSers do the same?"



CoI: multiple

NSS--Vitamin D could be an issue. TeamG in the News


Last week TeamG was in the news....well to be Precise DrK and the students. 

They had come to the conclusion that enviroment rather than genes were particularly important and within a generation, immigrants into the UK with black skin had acquired a high risk of MS such that MS was as common in black females as it was common in white males in East  London. 

I knew it was covered in "The Times"-Newspaper but I had not seen it. So when I saw the title it seems like the journalist who wrote the piece must have (been a 40watter:-) and) had a epiphany and wrote MS may have something to do with sunlight. Whilst this may have got the juices going in the average readership....I suspect you were all saying, as I was..... "NSS". Yawn is this a news worthy angle?

Hope they have more insight into Brexit and their view is contempary, otherwise they will be harping on about the British Empire:-)

Will it be a Sprint to PPMS

It has been announced that the FDA will fast track the assessment of Ibudilast for the treatment of Progressive MS.

At present a Phase II study in MS is ongoing "Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis" (NCT01982942) Estimated completion = May 2107 


It seems the trial is now recruited.

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the safety, tolerability and activity of ibudilast administered twice daily over a 96 week period in subjects with primary or secondary progressive multi
ple sclerosis who are currently untreated with long-term MS disease modifying therapy (DMT) or who are receiving either glatiramer acetate (GA) or interferon beta (IFNβ-1a [Avonex, Rebif] or IFNβ-1b [Betaseron Etavia]) treatment. Study drug will be administered as an adjunct to glatiramer or beta interferon treatment. A total of 250 male and female subjects from 21 to 65 years old, inclusive, are planned to be enrolled into two treatment groups. Randomization of subjects will be stratified by disease status (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) and immunomodulating therapy status: current use of immunomodulating therapy or no current use of immunomodulating therapy.

According to the FDA, in order to be granted Fast Track designation, a drug must (1) be intended for the treatment of a serious or life-threatening disease or condition; and (2) demonstrate the potential to address unmet medical needs for the disease or condition.
A drug that receives Fast Track designation may be eligible for:

  • More frequent meetings with the FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval;
  • Accelerated Approval, i.e., approval based on an effect on a surrogate, or substitute endpoint reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality;
  • Priority Review, with an FDA goal for completing review within six months of submission; and
  • Rolling Review, which means that a sponsor can submit completed sections of its New Drug Application (NDA) for review by the FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed.

Is this action occurring because the company making Ibudilast has been pushing for this to happen (I suspect so)....... or is it the trial because it is sponsored by the US Government (NIH) & the NMSS.

Has there been any hint that Amilioride, Prozac or Riluzole will be fast tracked, if there is evidence it works in MS-SMART,...Not that I've heard. Is this the difference between academic studies and pharma led studies or pro-active Americans verses lazy bummed Brits.

However, based on what happened with Simvastatin. I think we can be sure of slow track for academic-led stuff:-(The phase II happened in 2010 phase III yet to be funded and by the time it will complete pharma will have found something so that it will never be licensed:-(

As for MS-SPRINT I suspect they will still need to do a phase III if this trial is positive. So access may not happen soon.




MS -SMART is a UK based trial originally intended to test Ibudilast, Amiloride and Riluzole in Secondary Progressive MS.

However, the UK missed out because they could not get a drug supply as I guess it was being funnelled into MS-SPRINT in the USA

I first heard about Ibudilast when someone who had been trawling the patent data base brought this to my attention and wanted us to do some EAE work.

I can now fess up as the trial it has now recruited that I was a little concerned with this choice. 

WHY?

Because of the mechanism of action of Ibudilast and past experience.

Ibudilast is a phosphodiesterase 4 inhibitior....not viagra which is a phosphodiesterase 5 inhibitior.

So phosphodiesterase 4 inhibitors  inhibit enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s).

I first came across these, because phosphodiesterase 4 inhibitors were reported to block tumor necrosis factor (TNF) and not surprisingly it was reported that they block EAE, because at the time tumour necrosis factor was considered to be bad for MS. However...

Does this ring any alarm bells?

You may know that in contrast to EAE when you block TNF then two MS trials in relapsing MS were stopped because of apparent worsening and it seems that anti-TNF can exacerbate MS. Therefore blocking TNF=bad

Now there a loads of different PDE4 inhibitors, another one was called rolipram.

This too could block EAE if used at high doses and was also reported to block TNF. 

However, this could make some symptoms of disease worse in mice, which we reported in 2002 and importantly 

Clinical trial in MS was stopped because it was apparently making MS worse.

Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, Stürzebecher CS, Martin R. Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis. Mult Scler. 2009; 15:1206-14

Now you can say that this is yet another example of EAE failing, but rather than it making EAE worse, or better as was originally shown when TNF=Bad,  at doses equivalent to those used in humans, rolipram and ibudilast etc actually did nothing and had no effect on relapsing disease. Showing us that unless we read the animal data properly, we may get the wrong idea.


Thus animals in contrast, what many think actually,  predicted what was found with Ibudilast in humans ...in the first clinical trial there no effect on relapsing disease....No worsening Phew.

So maybe not all PDE 4 inhibitors are created equal. 
(Were the anti-TNF and rolipram trials flukes?.....the occurence in people with arthritis treated with anti-TNF says there is something in it and also that not everyone treated with anti-TNF gets MS so there is something selective in this.

I suspect TNF= good and TNF=bad also but it is context dependent and timing may be critical is what happens when. 

However the ibudilast trial was large and had nearly 300 hundred people in the trial and so if there was a problem you would hope it would have been seen.

Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R; MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010; 74:1033-40. 

However the ibudilast showed that it had no effect on relapses or lesion formation however unexpectedly there was a slowing of disability progression and less brain volume loss, indicating to me that it is neuroprotective. This is the basis for MS sprint. Hopefully there will not be any exacerbations but it there are, you heard it here first, and as people on the trials are on DMT this should be less likely.

It has also been reported that PDE4 inhibitors can promote remyelination

Now you may have missed out on MS-SPRINT, but if you live in the UK there is still time to get on MS-SMART where the trial is now looking at the effect of riluzole, amiloride or prozac. 

If you fit the criteria please consider volunteering click here to find out more

Thursday, 24 March 2016

ClinicSpeak: what type of pain are you suffering from?

Are you in pain? #ClinicSpeak #MSBlog #MSResearch

"As most of you with more advanced MS know pain is a big problem and is very poorly managed outside of specialist clinics. Why? Because most neurologists and pain experts don't understand the mechanisms that underpin MS pain syndromes. In addition to this pain affects mood; pain reduces your affect and is strongly correlated with depression. People who are depressed handle pain poorly and this leads to a downward spiral. This is why the management of pain in MS is so important and needs an holistic approach."
"The study below tries to differentiate two major types of pain using neurophysiological testing. Nociceptive pain means there is a peripheral painful stimulus that is causing pain. For example, urinary tract infection stimulates pain receptors in the bladder and you feel pain. Neuropathic pain is due to central mechanisms and usually occurs in MS due to lesions affecting the pain pathways with aberrant transmission of signals to the brain that is perceived as pain. The investigator's found that using laser evoked potentials (LEPs) they are able to work out the cause of the pain. When a laser light is targeted to the skin it causes a painful/hot stimulus that is activates pain or nociceptive receptors. The signal from this travels to the brain and is persceived as pain. We can measure the transmission of these electrical signals to brain; we call these evoked potentials or LEPs. Abnormal LEPs were associated with neuropathic, or central pain. This is important as this type of pain responds to different centrally acting drugs for example, sodium channel (carbamazepine or oxcarbazepine) or calcium channel (gabapentin, pregabalin) blockers and drugs that modulate pain perception (tricyclic or atypical anti-depressants; amitriptyline, duloxetine, etc.)."


"Do we need to do these tests to decide on what pain you have? No not really. We tend to make a call on the type of pain based on the history and examination and  then decide on a management plan. If you are in a lot of pain you need to see your neurologist. We are pretty good at managing pain in pwMS. You don't need to suffer in silence, which a lot of pwMS tend to do; they accept pain as another MS burden to live with. Why?"

Turri et al. Laser evoked potentials and quantitative sensory testing in patients affected by multiple sclerosis: Clinical, neurophysiological and psychophysiological correlates. Clinical Neurophysiology 2016;127:4(e137).

Background: Pain is a common finding in patients affected by Multiple Sclerosis (MS). Many different types of pain can afflict MS patients, including neuropathic, nociceptive, or mixed pain. TSA-II-Thermotest (QST) and Laser evoked potentials (LEPs) are psychophysical and neurophysiological tests commonly used to explore pain. 

Aims: The study aims to determine psychophysical and neurophysiological correlates in MS patients. 

Methods: 16 MS patients (5 men, 11 women, mean age 59years, mean EDSS 7) where clinically and neurophysiologically tested. 5 patients presented neuropathic central pain (according to NeuPSIG 2011 guidelines), 8 patients presented nociceptive or mixed pain, and 3 patients were pain-free. For QST, the dorsum of both hands and feet were examined; for LEPs, the dominant hand and both feet were tested. 

Results: Results were collected and compared to age and sex matched controls. Pin-prick was altered in 37.5%, LEPs were abnormal in 57.8% and QST was pathological in 85.9% of examined sites. We detected a significant correlation between pain and clinical examination (0.022), pain and altered QST (0.042), while LEP abnormalities correlated well with the presence of neuropathic pain (0.012). 

Conclusions: Our results suggest that LEPs are more specific than QST to differentiate neuropathic from nociceptive pain.

Pathologist view of progression...what do they think...let's sit on the fence.

Larochelle C, Uphaus T, Prat A, Zipp F. Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology? Trends Neurosci. 2016. pii: S0166-2236(16)00025-4


Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important field and directions towards development of treatment strategies to slow or prevent progression of disability.


It is clear that the development of progressive MS, on balance is a product of age/ disease duration.

What are the mechanisms of progression suggested?

1. The Same Processes Driving RRMS Eventually Lead to SPMS
As we get older there is a switch from active plaques to slowly expanding inactive and smoldering plaques. Aging and accumulation of damage in the peripheral immune system and the CNS over time can lead to chronic immune activation, increased oxidative stress-related damage, exhaustion of repair mechanisms, and loss of trophic support, all of which could significantly contribute to SPMS onset. Here are some suggestions
  • Alteration of the Peripheral Immune System with Aging
  • Aging is Associated with ‘Low-Grade Immune Activation’ in the CNS and Mitochondrial Dysfunction
  • Aging and Accumulation of Insults Result in Exhaustion of CNS Compensatory Mechanisms
  • Aging of Immune and CNS Cells and Reduced T Cell Infiltration in SPMS Can Result in Loss of Trophic Factors
2. Distinct Neuroinflammatory Processes Drive SPMS
  • High-Grade Chronic Inflammation’ Triggers New Independent Autoimmune Processes Within the CNS
  • Chronic Demyelination and Neuronal Dysfunction Can Exert Reciprocally Deleterious Influences
  • Reduced Social, Physical, and Cognitive Activity Impairs Remyelination and Neurogenesis
  • Microglial Profile in SPMS Can Hamper Neuroglial Repair Mechanisms
  • Intrinsic Neurotransmitter Imbalance in the CNS and loss of inhibitory molecules
Here are the views summarised



Mechanisms Underlying Secondary Progressive Multiple Sclerosis (SPMS) Pathophysiology. 

(A) Proposed schematic representation of events underlying relapsing-remitting multiple sclerosis (RRMS). Because the first trigger of MS relapse and the exact sequence of events leading to lesion formation or to remission are not known, a wheel (black circle and arrows) is used to represent the cycle of peripheral immune activation, central immune activation, and neuroglial damage observed in RRMS. Regulatory mechanisms (in blue) in the peripheral immune system and CNS are intervening to induce remission, and lead to partial or complete clinical recovery. 

(B) Proposed schematic representation of events underlying SPMS. Hypothesis 1 (upper panel): exhaustion of resources through aging and lesion accumulation as the mechanism underlying the clinical shift from RRMS to SPMS. Aging as well as lesion accumulation exacerbate and chronicize the RRMS pathophysiological mechanisms (bold black circle and arrows). Neurosenescence (green), characterized by microglial activation, iron deposition, mitochondrial dysfunction, and decreased network efficiency, is associated with reduced capacity of neuroglial cells to tame inflammation and to repair and regenerate (broken green line). Immunosenescence (orange) is characterized by (in specific immune cell populations) increased cytotoxic capacity, enhanced expression of adhesion molecules, and decreased trophic factor production, and is associated with impaired immunoregulatory capacity (broken orange line). The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS. 

Hypothesis 2 (lower panel): distinct CNS-restricted processes triggered by high-grade inflammation and neuroglial injury as the mechanism underlying the clinical shift from RRMS to SPMS. Upon reaching a given inflammatory threshold (shown by red arrow), aggressive immune cells can create an environment that supports the organization and persistence of a chronic inflammatory immune response within the CNS compartment. The CNS inflammatory environment, together with ensuing demyelination and neurotransmitter imbalance, impairs neuronal function while increasing energy demand. This initiates a vicious cycle of chronic demyelination, energy failure, neuronal degeneration, loss of function, disuse, and decreased remyelination and neurogenesis, exposing remaining neuroglial cells to further stress and energy demand, and sustaining independent degenerative and inflammatory processes in the CNS. The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS. The broken blue lines underline the impairment of regulatory mechanisms because peripheral regulatory immune cells cannot influence intra-CNS immune processes, and chronic neuroglial injury and neurological disability impair CNS repair mechanisms. 
Abbreviations: BBB, blood–brain barrier; CIS, clinically isolated syndrome; GM, grey matter; WM, white matter.

Every thing is caused by autoimmunity, this is the average EAEologists world view that every thing to do with MS is caused by autoimmunity, crack autoimmnity you crack the lot...only problem is....therapy in MS does not support this...hey if you look hard enough EAE does not support this view either. 

Maybe we have been flogging a dead horse too long and this is why treatments for progressive MS are lacking.

But what do the reviewers do...yep do what I would do and sit on the fence! Abit of this here and a bit of that there

"When weighing up the above-mentioned data for and against a specific pathology in SPMS, there is a degree of balance, and it is conceivable that both (i) the sum of aging and cumulative inflammatory injury exhausts resources and drives the system towards failure, and (ii) distinct intrinsic mechanisms in the CNS, emergent or present from onset, are triggered at some point and lead to chronic sustained neuroglial injury. In fact, aging and lesion accumulation could contribute to a threshold of inflammation and neuroglial dysfunction being reached upon which distinct intra-CNS mechanisms are triggered and in turn contribute to accumulation of damage. 

It remains to be determined if both (i) and (ii) are necessary to eventually lead to the typical disability progression seen in later stages of the disease".

So the only way to get a handle on this is get MS sorted early and then see what happens, quell autoimmunity and see if progression occurs. I think I know what happens in EAE, what will happen in MS, we need to use highly effective agents ASAP as we know that progressive nerve damage starts from the earliest time point.