Sunday, 31 August 2014

An alternative test for oligoclonal bands again

Hassan-Smith G, Durant L, Tsentemeidou A, Assi LK, Faint JM, Kalra S, Douglas MR, Curnow SJ.High sensitivity and specificity of elevated cerebrospinal fluid kappa free light chains in suspectedmultiple sclerosis. J Neuroimmunol. 2014. pii: S0165-5728(14)00236-7. doi: 10.1016/j.jneuroim.2014.08.003. [Epub ahead of print]
Cerebrospinal fluid (CSF) analysis is routinely used in the diagnostic work-up of multiple sclerosis (MS), by detecting CSF-specific oligoclonal bands (OCB). More recently, several studies have reported CSF free light chains (FLC) as an alternative. We show that absolute CSF κFLC concentrations were highly sensitive - more than OCB testing - and specific for clinically isolated syndrome, relapsing remitting and primary progressive MS. Measurement of κFLC alone was sufficient. Our results suggest that CSF κFLC levels measured by nephelometry, if validated in a larger series, are a preferred test to OCB analysis in the diagnostic work-up of patients suspected of having MS.
On of the diagnostic tests in MS the presence of oligoclonal bands
another test is the presence of free immunoglobulin light chains.  This study suggests they could be better however we have posted on this before and what specificity and sensitivity means as well as whether oligoclonal bands have had there day.

Multiple Sclerosis Research: Have oligoclonal bands had ...
20 Feb 2013

Multiple Sclerosis Research: Students are you reading this?
09 Apr 2014

Multiple Sclerosis Research: Research: predicting MS
27 Jul 2012

Peripheral and central B cells involved in MS

Why does targeting systemic B cells in MS work? #MSResearch #MSBlog

"The B cell remains top of the MS pop chart. It is the cell that is responsible for producing antibodies and providing memory for future antibody production in the case of infection. B cells can also act as so called professional antigen presenting cells that takes up antigens and display the antigens on their surface to stimulate the T cell arm the immune system. There is also a subset of B cells that are regulatory and dampen down and help control inflammation. This short list tells you that B cells have many potential roles in MS."

"We know that B cells are critical player in MS as they are found in the central nervous system and produce oligoclonal bands (OCBs) that are an invariable finding in MS. The B cells that produce OCBs are highly selected and have undergone controlled mutagenesis to improve their binding capability to antigens. At present we still have not identified a specific antigen that these OCBs recognise; if we did we would be closer to the cause of MS."

"The studies below using new DNA sequencing technologies tell us that there is a link between the B cells that are found in the brain and those found in the peripheral blood of MSers. In other words the populations of cells in these compartments are linked to each other. I am not surprised by these results as there must be an exchange of cells between the two compartments. Interestingly the second study showed that so called founding members of the B cell clonal population, those with earlier or founder mutations, were found in the lymph nodes of the neck suggesting that this is the site where they get activated. The authors suggest that this may be the site where the so called B cell depleting therapies work, rather than in the CNS."

"This information is important and helps frame the role of B cells in MS as been a systemic (whole body) rather than purely local with the CNS. These studies may explain why system anti-B cell therapies that deplete or stop B cell trafficking work in MS. What is not explored in these studies is the role of EBV in B cell biology. I think the latter is critical if we want to understand how EBV triggers and maintains abnormal B cell function in MS."

This figure tries to explain the complex biology of B cell maturation. With each step selection of different immunoglobulin genes and mutation in the antigen binding regions allows one to track the development of clonal selection of B cells. This can be done in cells from the spinal fluid, brain, cervical or neck lymph nodes, and peripheral blood of MSers. This then allows one to pinpoint where the original clonal members come from. Some the techniques used in  these studies are cutting edge and require quite complex data analysis to track the families of B cells. What is important is that there is an overlap between B cells in the CNS and peripheral blood of MSers, providing a peripheral treatment target for anti-B-cell therapies.

Background: In MS, lymphocyte-in particular B cell-transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MSers; however, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen specificity with intrathecal B cell repertoires and whether their antigen stimulation occurs on both sides of the blood-brain barrier. 

Methods: To address these questions, we combined flow cytometric sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MSers were compared with their CSF Ig-VH transcriptomes. 

Results: In six of eight patients, we identified peripheral CD27(+)IgD(-) memory B cells, CD27(hi)CD38(hi) plasma cells/plasmablasts, or CD27(-)IgD(-) B cells that had an immune connection to the CNS compartment. 

Conclusion: Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current B cell-targeting therapeutic strategies and may lead to more targeted approaches

Stern et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014 Aug 6;6(248):248ra107.

Background: MS is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of MSers harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. 

Methods: Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). 

Results: High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. 

Conclusion: These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.

Preliminary alemtuzumab survey results

When the results of a survey change the way you see the world; having progressive MS is like having a different disease. #MSBlog #MSResearch

"Last week I did a ClinicSpeak post on 'when to say no to alemtuzumab' and linked it to a survey. The preliminary results of the survey are quite surprising and a real eye-opener for me. Despite blogging on alemtuzumab for several years over 40% of respondents were not aware that alemtuzumab has yet to be shown to be effective in SPMS. I suspect many of the readers were shocked to find out that it may not alter the course of SPMS."

"It was reassuring though that the vast majority of you support a trial to test Alemtuzumab in SPMS and  that you don't think the risks of alemtuzumab outway the undefined benefits in this population, despite the Cambridge group suggesting the drug may not be effective in SPMS. I hope Genzyme staff take note of this."

"What I did find very startling that considering its risks of alemtuzumab that the majority of SPMSers would consider taking the drug on the chance of it possibly working in SPMS. I am sure this driven by the fact that we have no licensed therapies for non-relapsing SPMS. Some of the comments below reflect this."

"As I suspected the hype surrounding alemtuzumab treatment for RRMS has unfortunately created unrealistic expectations for SPMSers; this has been my personal observation in clinic and one of the reasons for doing the 'when to say no to alemtuzumab' post." 

Comments from the survey
  1. My biggest suggestions are to (1) show them the scientific study that shows it has no impact on SPMS and (2) provide them some hope in an alternative. This is why I am not sure if the risks outweight the benefits. If there are no effective treatment or the patient has failed other potential fixes, I think the patient has the right to make the call on whether to roll the dice and try alemtuzumab. In my view, the doctors job is to make clear to the patient the risks/benefits and prevent blatantly wrong treatment choices, but it is not to prevent a patient from taking a reasonable long shot treatment.
  2. Need to explain this post to MSers. 
  3. They need an alternative- maybe fingolimod?
  4. I attended a presentation by Professor Alastair Compston a few years ago and he was quite clear that Campath was only effective for the newly diagnosed. Apart from explaining the research, I don't see what else can be done.
  5. Sadly, dealing with desperate people is always going to be tricky.
  6. This sounds a bit vague, but I think that we all need a really good 'package of information' regarding expectations, treatment and goals for the progressive phase of MS. I have had RRMS for 11 years and know the day will come when I'm told it''s becoming progressive. The anxiety is already building. I've heard it's not necessarily going to be absolutely dreadful (I'm pretty good at the moment) but the whole subject seems to be studiously avoided, on the need-to-know basis - understandably. Isn't it time to blow it open? Break it down into manageable chunks, set out the meds for each bit of the picture? I reckon the hype around alemtuzemab is partly because of the vacuum of information. It needs to be put in the context of ongoing management. Something like 'What to expect/what we can do'. 
  7. Only to reiterate that no, or uncertain, benefits accrue to SPMSers from taking Alemtuzumab. It might help if symptomatic treatments like Sativex and Fampyra were more readily accessible. People get desperate because there is nothing available/accessible that helps them. At the same time they are being knocked by having to reapply for PIP, with the 20metre rule, and I have heard anecdotally that it is getting much more difficult to obtain a Blue Badge. For many people these two things make life a little easier and helps them stay in work [and pay tax] (ie able to afford the journey, park reasonably close by etc) and bearing in mind that you don't recover from MS it shouldn't be made MORE difficult to obtain these things as time goes on. I think MSers should be more militant, which I realise is a bit of a tall order!
  8. LDN, Sativex? A nicer NICE? The red pill or the blue pill?
  9. Neurologists need to be on the same page when using alemtuzumab. Patients are confused when there is no consensus.
  10. Show them the inclusion criteria and that the mean age in the alemtuzumab studies was less than 4 years - there risks are relatively high with unproven benefit. 
  11. Sorry, I really don't know. Better diagnosis of SPMS might help because lots of people feel in limbo, are they RRMS or SPMS. Some say it does not matter but if it defines what treatment you can have maybe the transition needs to be diagnosed and discussed (and patients actively monitored). You need to know what camp you are in and can then inform yourself about the situation.
  12. Otherwise it is just going to have to be continued discussions on these sites and MS Trust/society websites. Where do patients get their info from?
  13. Then we get to treating early before we get SPMS and are no longer eligible. I am up for a phase 3 trial for SPMS though!
  14. No. The research doesn't back up that it would be useful if have SPMS. I have relapsing remitting with no significant disability YET. But cannot get my neurologist to agree that it should be used first line - I would be extremely keen to consider it (aware there are significant risks) if it was shown to reduce disability progression. My impression of the research is it does reduce progression, but neurologist disagrees. 
  15. I was on the cusp, diagnosed 11 years with significant disease accumulation. I live in the US & traveled to Germany for Alemtuzumab April 2014. I have experienced a renaissance of remission. 
  16. I am alarmed by this article and conclusions of the neurologist. By his criteria I would not have qualified (11 years, disabling fatigue, unable to more more than a few hours a day, resigned primary career in medicine due to mental fog & large amounts of pain & spasticity). 
  17. I now have almost NONE of these symptoms & feel as if I don't 'have MS' excepts for the use of 3 tablets of muscle relaxers a day. I don't even use pain meds or anything for fatigue. These are all chronicled on the blog
  18. MSers should have the option of going onto this therapy regardless of their type of disease. As there is no treatment for progressive MS taking a chance on the possibility of benefit it better than waiting to deteriorate. 
  19. No not really but can understand why people are so desperate for anything that will stop MS in its tracks Perhaps people underestimate the risks because there is not the associated PML with alemtuzumab so think anything else is worth the risk
  20. Show them the results of the trials and discuss the risks. Be clear that the evidence suggests that they are pointless risks. Forget the costs, that's for you to worry about. We do not want to hear that we can't have something because it's too expensive, we want to hear that it won't be good for us if we have to hear a no. 
  21. Tell the patient the bare truth of knowledge as it should be for them. Cut the nonsense. Do not allow neurologists who know very little re MS from being allowed to see MSers
  22. MSers and prescribe inappropriate treatment in a wholly wrong fashion.
  23. There are very many MSers putting up with very very second rate care if any!
CoI: multiple

Saturday, 30 August 2014

ClinicSpeak: life-threatening exacerbation on stopping natalizumab

Do we have enough evidence to stop MSers walking the natalizumab-rebound gauntlet? #ClinicSpeak #MSBlog #MSResearch

"The tragic case report below highlights what we know already that when you stop natalizumab MS comes back with a vengeance. This poor lady had massive rebound and when they decided to restart natalizumab her conditioned go much worse. I assume they were worried about her having PML, or a tumour, so that did a brain biopsy that showed acute demyelination with a large number of B cells present. This case highlights that whatever is driving MS must reside within the central nervous system, and that if keep the immune system out nothing happens. If you remove the sticky plaster, or natalizumab, the immune cells pour back in find what they are meant to find and cause severe inflammation and in this case a life-threatening and devastating relapse."
"I have been proposing for a few years now that we need to use natalizumab rebound as a model of MS relapse to study the disease. If MS is due to a virus the best tissue to use to search for this virus must be tissue from natalizumab treated patients."

"I am so sensitised to natalizumab-rebound after seeing it several of my own patients that I don't allow people to stop natalizumab treatment without starting some other form of alternative treatment. I am using fingolimod at the moment, but we really need evidence for teriflunomide and DMF in this situation. The data on using interferon-beta, glatiramer acetate and steroids in this situation is not good; rebound occurs with all of these agents. I have highlighted my concerns about using alemtuzumab in this situation; in this post and have proposed that the safest option is the bridging option (see figure below). The biggest problem we have are woman wanting to come off natalizumab to fall pregnant. I have one patient who had been stable on natalizumab for over 8 years, having previously had only 2 relapses, who stopped natalizumab to start a family. Four months later she came in with a devastating spinal cord relapse and an MRI that lit up like a Christmas tree with 60-80 gadolinium-enhancing lesions. Needless to say she went back onto natalizumab and has decided against starting a family. I am aware that some neurologists are instructing their patients to fall pregnant on natalizumab before stopping it and then restarting it just before, or shortly after, delivery. Other neurologists are telling patients to stay on natalizumab throughout pregnancy. All this advice is not evidence-based; we simply don't have enough data to say whether or not natalizumab is safe during pregnancy. Natalizumab is a so called IgG4 antibody and will cross the placenta. In a small series of babies born to mothers on natalizumab there were transient minor changes to their blood counts. Although small this series is reassuring in that these babies had not long lasting effects of natalizumab on their bone marrow function. This is where alemtuzumab, an induction therapy, has the advantage over natalizumab and other maintenance therapies." 

"The authors below hypothesise that restarting natalizumab during rebound made things worse as it affected the population of cells in the brain of this patient. I am not sure I buy this at present as all the cases that I have been involved in have not had worsening of lesions when restarting natalizumab. I think we need to be vigilant and watch out for this in this situation in the future."

"I can't help but feel very sorry for this lady; it shows you had bad MS can be despite having been treated with a transformational drug."

Beume et al. Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab. J Clin Neurosci. 2014 Aug 20.

We present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy revealed acute demyelination and B-cell dominated inflammation. The patient improved during therapeutic plasma exchange. We speculate that early restart of natalizumab in the case of a relapse may worsen disease evolution possibly by modifying regulatory immune effector processes during an inflammatory rebound phase. A restart of natalizumab in MS patients suffering from a recent relapse or with signs of active inflammation should be considered with caution.

CoI: multiple

Insoles don't work?

Kalron A, Pasitselsky D, Greenberg-Abrahami M, Achiron A. Do textured insoles effect postural control and spatiotemporal parameters of gait and plantar sensation in people with multiple sclerosis? PM R. 2014 Aug 18. pii: S1934-1482(14)01327-6

BACKGROUND:Balance and gait deficits are common in people with multiple sclerosis (MS). Physical interventions directed at improving balance and walking abilities have implemented using various approaches.
OBJECTIVES:  To determine if textured insoles have immediate effects on postural control and spatiotemporal parameters of gait and plantar sensation in people with people with MS and to explore effects 4 weeks after insole wear as to whether any immediate effects are maintained over time.
RESULTS: Textured insoles did not alter static postural control parameters when examined with eyes open. Examination during the eyes closed task demonstrated an immediate reduction in the CoP path length (298.4 (S.E.=49.7) vs. 369.9 (S.E.=56.3); mm; P=.04) and sway rate (12.0 (S.E.=1.4) vs. 15.1 (S.E.=1.6); mm/s; P=.03) following insertion of the textured insoles compared to casual shoes. These findings were maintained at termination of the insole 4-week intervention period. In terms of spatiotemporal parameters of gait, differences were not observed between casual shoes and shoes with textured insoles at baseline. Likewise, no differences were observed between initial and concluding gait trials. Significant differences in plantar sensitivity measures were not observed following the insole 4-week intervention phase.
CONCLUSIONS: Although there were improvements in some aspects of balance, the efficacy of textured insoles in the MS population remains unclear.

So this study questions the value of textured insoles and puts other studies in doubt. 

Again one wonders where studies need to be large enough to provide definitive answers

CCSVI August

Leone MA, Raymkulova O, Lochner P, Bolamperti L, Rivadossi G, Stecco A, Zaccala G, Maggio M, Liboni W, Guido M, Coppo L, Imperiale D.Chronic cerebrospinal venous insufficiency is not associated with chronic venous disorders: A case-control study.
Phlebology. 2014 Jul 31. pii: 0268355514544782. [Epub ahead of print]

OBJECTIVES:To evaluate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and the presence of a Chronic Venous Disorder (CVD).
METHOD:We included 55 subjects with CCSVI aged >18 years, and 186 controls without CCSVI. Each subject was evaluated with color Doppler sonography in accordance with Zamboni's five criteria, examined by two neurologists and interviewed with an ad-hoc designed form. The neurologists and the sonographers were mutually blinded. CVD were classified according to CEAP.
RESULTS:Mean age was 42 years (SD = 9) in cases and 43 years (10) in controls (p = ns). The odds ratios in subjects CCSVI were 0.6 (0.2-2.2) for CEAP 1, 0.9 (0.2-4.5) for CEAP 2, and 1.0 (0.6-1.9) for family history of varicose veins. The prevalence of CVD and, family history of varicose veins, was similar between cases and controls for each Zamboni criterion.
CONCLUSIONS:We found no association of CCSVI with the presence of CVD or family history of varicose veins

Müller K, Kuchling J, Dörr J, Harms L, Ruprecht K, Niendorf T, Wuerfel J, Paul F, Sinnecker T. Detailing intra-lesional venous lumen shrinking in multiple sclerosis investigated by sFLAIR MRI at 7-T.J Neurol. 2014 Aug 14. [Epub ahead of print]

Intra-lesional venous lumen shrinking detectable by MRI was suggested as an in vivo marker of inflammation in multiple sclerosis (MS). In our study mean diameters of pre-, post- and intra-lesional venous sections were determined in 49 patients with MS or clinically isolated syndrome (CIS) using a pixel-wise analysis on susceptibility-weighted fluid-attenuated inversion recovery (sFLAIR) images and T2*-weighted (T2*w) imaging at 7 Tesla (T). We observed post-to-intra-lesional venous lumen shrinking on T2*w images (p = 0.036) in an analysis of 338 venous sections. Pre-to-intra-lesional venous lumen reduction was only detectable in less than 50 % of lesions and failed statistical significance when analysing T2*w (p = 0.325) and sFLAIR images (p = 0.258). In conclusion, thinning of intra-lesional veins in MS is-if detectable at all-probably less severe than previously reported, and affects only a minority of MS lesions.

Marshall O, Lu H, Brisset JC, Xu F, Liu P, Herbert J, Grossman RI, Ge Y.Impaired Cerebrovascular Reactivity in Multiple Sclerosis.
JAMA Neurol. 2014 Aug doi: 10.1001/jamaneurol.2014.1668. [Epub ahead of print]

IMPORTANCE:Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS).
OBJECTIVE: To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS.
DESIGN, SETTING, AND PARTICIPANTS:A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF.
MAIN OUTCOMES AND MEASURES:Cerebrovascular reactivity was calculated as the percent increase of normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS.
RESULTS:A significant decrease of mean (SD) global gray matter CVR was found in patients with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a significant negative correlation between gray matter CVR and lesion volume (R = 0.6, P = .004) and a significant positive correlation between global gray matter CVR and gray matter atrophy index (R = 0.5, P = .03).
CONCLUSIONS AND RELEVANCE: Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.

Friday, 29 August 2014

ClinicSpeak: When to treat CIS?

When to start a DMT if you have CIS? #ClinicSpeak #MSBlog #MSResearch

"I received an email query from a young woman who has had a clinically-isolated syndrome (CIS) and had difficulty getting onto an injectable 1st-line therapy because of confusion around the guidance from NHS England regarding eligibility for treatment. The guidance simply states that 'Patients are eligible for treatment within 12 months of a clinically significant clinically isolated syndrome when MRI evidence predicts a high likelihood of recurrent episodes'. The question proposed is what is a high likelihood of recurrent episodes? This guidance refers back to the Association of British Neurology (ABN) 2009 guidelines and is deliberately loosely-defined to leave it up to the neurologist to make a judgement call. In the past we had to make sure all patients with CIS fulfilled MacDonald criteria for having multiple sclerosis, i.e. dissemination in time and space, and had a high lesion load (>9 T2 lesions) and/or an active lesion(s) (Gd-enhancing lesion) on their baseline scan. This guidance is based on the Queen Square and other data sets demonstrating that baseline lesion load, and baseline activity (Gd-enhancement), predicts a poorer prognosis and more rapid conversion time to clinically definite MS or the next clinical attack."

"The figure above shows that CISers with 1-3 lesions take longer to become disabled than those with 4-10 baseline lesion and both these groups have a better short-term prognosis than CISers presenting with 10 or more lesions. Are you surprised? CISers with 10 or more lesions have had MS longer and therefore they tend to hit disability milestones earlier. I agree that there will always be a small number of patients who will end up with benign MS, but the proportion of people with benign MS shrinks with time, so that by the time you have MS for 40 or more years the proportion of patients with benign MS, in hospital-based practice, is less than 5%. Please note that this figure refers to natural history data and in the era of DMTs this figure will be much higher. DMTs should increase the proportion of MSers with benign MS."

"I personally think the prescribing guidance, based on baseline lesion load and/or presence of Gd-enhancing lesions, is outdated and is not in keeping with our current understanding of multiple sclerosis. It is clear that MS has a relatively long asymptomatic period and what determines when you present with your first clinical attack is whether, or not, a new lesion happens to occur in a clinically eloquent site. Therefore baseline MRI is an indicator of how long you have had the disease; the higher the lesion load the longer you have had the disease the and the more likely you have underlying end-organ damage. If our aim is to prevent damage with DMTs the lower you lesion load the earlier you are in the course of the disease the more there is to protect. According this logic you are lucky if you present with a low lesion load as you are earlier on in the course of the disease and hence more likely to benefit from DMTs. Please remember that the aim of DMTs is to prevent damage not repair damage; to maximise this prevention strategy you have to start treatment early."

"Please remember that what we see on MRI in terms of lesions is only the tip of the MS iceberg; the majority of disease is not visible on MRI. All the CIS trials included patients with abnormal MRI scans and they have all shown that patients started early do better. So why wait? When you interrogate CISers at baseline you find a significant proportion (30-50%) have cognitive impairment, fatigue and depression. These hidden symptoms are probably due to gray matter involvement that is not visible on routine diagnostic MRI scans. If you apply specialised data analysis tools to the MRI scans in CISers you find a large proportion of them have baseline gray matter atrophy indicating that their disease has been active (shredding the cortex) prior to their CIS presentation."

"The exception to the above or those CISers presenting with no lesions; these CISers do very well with only 1 in 5 going on to develop a second attack, or MS, over the next 20 years. This would indicate that a large proportion of CISers with normal baseline MRI scans do not have MS. Therefore it is entirely appropriate to wait, watch and see what happens with these patients."

"In addition, to the lesion load which is an integrator of activity over the course of the disease the presence of active gadolinium-enhancing lesions provides a temporal metric and tells us that those enhancing-lesions are actively inflamed. As the duration of enhancement is about 3-4 weeks you can infer that these lesions probably appeared within the last month. This is why we have a greater tendency to treat CISers with active scans.”

"What is not frequently communicated to patients is that those CISers who access injectable therapies early, compared to those who have to wait until their second attack or were only started treatment as part of the open-label extension studies (typically 18-24 months later), do better. This has been elegantly shown with regard to cognitive outcomes in the BENEFIT study. The EDSS data is relatively weak in relation to disability, but that is not unexpected as the EDSS a very poor outcome measure for tracking disability early in the course of MS; in statistical jargon the EDSS has a floor effect and this was seen in the BENEFIT study."

"What I can say is that in general UK neurologists are the outliers when it comes to prescribing DMTs for CISers. In almost every country in the world CISers with an abnormal scan will be offered the option of going onto a treatment. Most UK neurologists would rather wait for the second attack, during which time irreversible damage could potentially accumulate. What you have to remember is that when you present with CIS some CISers are not ready for DMTs. They go often in denial and are not interested in knowing about the link between CIS and MS, and their future prognosis. It is not wise to push the issue with these patients, but to support them and be there if and when they are ready to make a decision. Poor adherence to DMTs are a problem and if you are not ready for treatment you are unlikely to adhere to your treatment. Therefore we really need to adapt and personalise decision making; doing things relatively slowly may result in the best long-term outcomes."

"What I haven’t discussed in this post in detail are the other prognostic factors that we tend to take into account when profiling CISers at baseline; these include whether or not there are lesions at the back of the brain in the so called posterior fossa, is there obvious baseline brain atrophy, which is a very poor prognostic sign, the type of clinical attack (motor/cerebellar vs. sensory), was the first attack mono or polysymptomatic (polysymptomatic attacks have been linked to worse outcomes in some studies), the degree of recovery from the attack (poor recovery poor prognosis), sex (males do worse), ethnicity (Asians and Africans do worse) and whether or not the spinal fluid analysis was abnormal (CISers with CSF OCBs do worse). In addition, to the disease profile personal factors come into the decision including psychological state, level of background knowledge and if you are a female whether or not you are planning to have children. Outside the UK and other countries with socialist healthcare systems, medical insurance coverage and being able to afford DMTs, are sadly a crucial factor deciding access to DMTs.”

“What do you do if your neurologist refuses to offer you DMTs for CIS? I suggest you have a frank discussion about why and ask him/her to justify their reasons. If the latter are unacceptable to you, you can always ask for a second independent opinion; the NHS Charter allows this. A reasonable compromise is to ask for a monitoring follow-up scan at say 3, 6 or 12 months on the condition that if your disease has been active (increased lesion load or active lesions) you can be started on treatment. This would indicate you have developed definite MS.”

"To the person who asked the question, please let me know if this post has answered your question?"

CoI: multiple

Thursday, 28 August 2014

MS register spots depression and anxiety

Jones KH, Jones PA, Middleton RM, Ford DV, Tuite-Dalton K, Lockhart-Jones H, Peng J, Lyons RA, John A, Noble JG. Physical Disability, Anxiety and Depression in People with MS: An Internet-Based Survey via the UK MS Register.PLoS One. 2014 Aug 25;9(8):e104604.

INTRODUCTION: People with Multiple Sclerosis are known to have a relatively high prevalence of both anxiety and depression. Studies of the relationship between physical disability and mental health in people with MS have reported mixed results, showing the need for further work.
METHODS: Between May 2011 and April 2012, 4516 people completed the MSIS-29 (v.1) and HADS scales via the dedicated internet site of the UK MS Register within a 7 day time window. These responses were linked with basic demographic and descriptive data.
RESULTS: The proportions of people experiencing anxiety or depression increased with physical disability such that 38.0% of respondents with low, and 66.7% with high disability reported at least mild anxiety, and 17.1% of people with low, and 71.7% with high disability experienced at least mild depression.
CONCLUSIONS: This study indicates that there is a positive relationship between physical disability and anxiety and depression, that physical disability impacts on anxiety and depression to differing extents, and that the effects vary with gender, age, disease course and disease duration. We have shown that physical disability is a predictor of anxiety and depression, and that other factors may mask the extent of this effect. It is essential that mental well being is given due attention in caring for people with MS so that all their health needs can be met.

The results are self explanatory however the question is: Have you considered signing up to the MS register (CLICK HERE).

By joining the community of people in the UK affected by MS and contributing to the MS Register, you will be directly involved in generating new research. The knowledge we gain from this study will fuel campaigns for fair, relevant policy and improved healthcare for people living with MS.

Can we speed up the drug development process?

This is an Ebola virus and it is interesting that governments have approved the testing of an relatively-untested drug (it has not had the proper human trials) in people infected with this deadly virus.....However, when it comes to progressive MS, you have to wait until it goes through years of testing before you get a choice of whether you take the risk of a test drug in a trial. Is it time that governments are more inventive to speed the drug development process up? It should suit pharma and could suit you. 

However, should your protection be the primary driver? This is what the current process aims to do?

ClinicSpeak: When to say no to alemtuzumab treatment?

When good intentions turn sour; tipping the risk:benefit scales the wrong way #ClinicSpeak #MSBlog #MSResearch

“When I was a much younger MSologist I recall having to formulate mitoxantrone treatment guidelines for MSers with highly-active MS. At the time we had two competing protocols the monthly Edan protocol, for 6 months, for highly-active MSers who had failed the injectables therapies and the 3 monthly Hartung protocol, for 2 years, for MSers who have active disease with more advanced MS. MSers who were being considered for the 2-year protocol tended to have more advanced MS and tended to be on the cusp of developing secondary progressive MS. One patient taught me how delicately balanced therapeutic decisions can be when using risky therapies such as mitoxantrone in patients with more advanced MS. This particular patient had had a severe spinal relapse and needed a urinary catheter; the intention was this catheter was short-term and would be removed once he had recovered from his relapse. Because his MS was so active I went ahead and prescribed mitoxantrone, which was a mistake. A week later he was admitted urgently to his local hospital with neutropenic (low white blood cell counts) sepsis from a urinary tract infection. He ended up in intensive care unit with septicaemia and septic shock and almost died.”

“The lesson I learned from this unfortunate patient was the urinary catheter had tipped the risk:benefit scale the wrong way. A similar thing may be happening with alemtuzumab. A large number of neurologists that I am meeting across Europe are telling me that they are using Alemtuzumab third-line in patients with advanced MS who sound to me as being on the cusp of  having SPMS. We need to be careful using alemtuzumab in this population. Firstly, the Cambridge group showed almost a decade ago that alemtuzumab is unlikely to make much difference in SPMS, which is why the drug was developed in early RRMS. The baseline criteria for both phase 3 studies targeted early MS (see slide 14 below); disease duration for both studies was low. This is why the European Medicine Agency has given alemtuzumab a liberal 1st-line license; in their opinion the risk:benefit ratio in this population is favourable. At present we don’t know what the risk:benefit ratio is in patients who have had symptomatic MS for more than 10 years and are in the early secondary progressive phase. What we need is controlled phase 3 clinical trials in this phase of the disease to define the benefit:risk ratio. The aim of this study would be to see if alemtuzumab slowed the rate of progression or if there was at therapeutic lag and that MSers did well later on.”

“Why is this issue important? Because a large number of MSers with advanced disease, and/or SPMS, are seeking my opinion regarding alemtuzumab treatment and are going way disappointed, and frustrated, because I won’t agree to treat them with alemtuzumab. In the same way as urinary catheters became a contra-indication to mitoxantrone treatment, clinically progressive MS is a relative contra-indication to alemtuzumab treatment. We simply don’t have data to define whether or not the risks associated with alemtuzumab treatment, the burden of monthly blood & urinary monitoring and the cost of treatment justify the undefined benefits. This is why MSers with advanced MS or SPMS seeking my opinion regarding alemtuzumab treatment need to realise that until I have data to the contrary I will say no to alemtuzumab treatment in this phase of the disease.”

“The following is the paper from Cambridge showing a differential response to alemtuzumab based on disease duration and MS stage.”

Coles et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108.

Background: From 1991-2002, we treated 58 MSers using the humanised monoclonal antibody, Alemtuzumab, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed.

Results: In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Alemtuzumab reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of SPMSers, treated with Alemtuzumab 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differentially affected depending on the phase of the disease. SPMSers showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in MSers with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, RRMSers showed an impressive reduction in disability at 6 months after Alemtuzumab (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these MSers with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. 

Conclusion: We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Alemtuzumab and IFN-beta in the treatment of drug-naïve MSers with early, active RRMS.

CoI: multiple

Wednesday, 27 August 2014

Regulatory CD8 positive T cells controlling autoimmunity

Ping Y, Bamford R, Waldmann TA. IL-15-dependent CD8+ CD122+ T cells ameliorate experimental autoimmune encephalomyelitis by modulating IL-17 production by CD4+ T cells. Eur J Immunol. 2014 doi: 10.1002/eji.201444675. [Epub ahead of print]

Interleukin-15 (IL-15) is an inflammatory cytokine whose role in autoimmune diseases has not been fully elucidated. Th17 cells have been shown to play critical roles in experimental autoimmune encephalomyelitis (EAE) models. In this study, we demonstrate that blockade of IL-15 signaling by TMβ-1 mAb treatment aggravated EAE severity. The key mechanism was not NK-cell depletion but depletion of CD8+ CD122+ T cells. Adoptive transfer of exogenous CD8+ CD122+ T cells to TMβ-1-treated mice rescued animals from severe disease. Moreover, transfer of pre-activated CD8+CD122+ T cells prevented EAE development and significantly reduced IL-17 secretion. Naïve effector CD4+ CD25- T cells cultured with either CD8+CD122+ T cells from wild-type mice or IL-15 transgenic mice displayed lower frequencies of IL-17A production with lower amounts of IL-17 in the supernatants when compared with production by effector CD4+ CD25- T cells cultured alone. Addition of a neutralizing antibody to IL-10 led to recovery of IL-17A production in Th17 cultures. Furthermore, co-culture of CD8+ CD122+ T cells with effector CD4+ T cells inhibited their proliferation significantly, suggesting a regulatory function for IL-15 dependent CD8+ CD122+ T cells. Taken together, these observations suggest that IL-15, acting through CD8+ CD122+ T cells, has a negative regulatory role in reducing IL-17 production and Th17-mediated EAE inflammation.

Interleukin 15 (IL-15) is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain (gamma-C, CD132). IL-15 is secreted by mononuclear phagocytes (and some other cells) following infection by virus(es). This cytokine induces cell proliferation of natural killer cells; cells of the innate immune system whose principal role is to kill virally infected cells. interleukin-2 (IL-2) is necessary for the growth, proliferation, and differentiation of thymic-derived lymphocytes (T cells) to become 'effector' T cells. it acts via signalling through CD25. In this study they blocked IL-15 in EAE and things got worse. Not because of effects on natural killer cells but due to depletion of CD8 T cells

Immunology is coming full circle with the return of the CD8 suppressor cell, that express CD122 as previously reported. Thirty-forty years ago CD8 suppressor cells were the mechanism of choice for regulation. Then came along Th2 and T suppressor cells became a dirty word. The findings of yester year may be rediscovered. 

However what could it mean for Msers. Well if this subset is useful in humans, then Lemtrada is going to destroy them.It is a sledgehammer to crack a nut and it will destroy useful cells as well as the disease-causing cells. Therefore something that takes out less cells may be better.

Is this yet another part of the zigsaw about why people get secondary autoimmunity after Lemtrada?

In another recent studies these CD8 T cells work by targeting dendritic cells, a type of antigen presenting cell that stimulates T cells.

Kashi VP, Ortega SB, Karandikar NJ. Neuroantigen-Specific Autoregulatory CD8+ T Cells Inhibit Autoimmune Demyelination through Modulation of Dendritic Cell Function. PLoS One. 2014 Aug;9(8):e105763.

Lemtrada depletes dendritic cells too...oops

Future outcome measures in MS

How will the definition of NEDA evolve? #MSBlog #MSResearch

"As promised the following is my presentation from a meeting I spoke at in Copenhagen yesterday. I covered NEDA and how I see its definition evolving in the future. This presentation explains why we replaced DAF (disease activity free) with NEDA (no evident disease activity); DAF implies we know everything about MS disease activity, whereas NEDA is a more humble term and allows us to adapt the definition as new technologies come online."

"My talk was very upbeat, particularly for people with progressive MS. The audience were very responsive to my proposed asynchronous model of progressive MS and the therapeutic lag hypothesis. As a result of these hypotheses I have given the odds of the fingolimod PPMS, siponimod SPMS, natalizumab SPMS and ocrelizumab PPMS trials being positive as being greater than 50% for each study; please note that according the the therapeutic lag hypothesis the odds of the studies being positive go up the longer the blinded phase of the trials run."

CoI: multiple; please note this meeting was hosted by Professor Per Soelberg Sorensen and his centre and sponsored by Biogen-Idec.

Another guideline - but this time we're involved!

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders. Gnanapavan S, Hegen H, Khalil M, Hemmer B, Franciotta D, Hughes S, Hintzen R, Jeromin A, Havrdova E, Tumani H, Bertolotto A, Comabella M, Frederiksen J, Alvarez-Cermeño JC, Villar L, Galimberti D, Myhr KM, Dujmovic I, Fazekas F, Ionete C, Menge T, Kuhle J, Keir G, Deisenhammer F, Teunissen C, Giovannoni G.

Neurology. 2014 Aug 22. pii: 10.1212/WNL.0000000000000809. [Epub ahead of print] Review.

OBJECTIVE: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.
METHODS: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features.
RESULTS: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report.
CONCLUSIONS: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Why am I blogging about this on a multiple sclerosis research blog site? Am I right, or am I right?? Lets just say that this paper was a couple of years in the making, as with anything which involves regulation.

Firstly though what is a biomarker? A biomarker is...
"a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention". 

For example, blood pressure is a biomarker, oligoclonal bands is another example; simply anything that can be measured or you can put a value to.

And why?
It is important to standardise biomarker reporting in MS research to make the research that is published a) reliable and b) to allow others to reproduce it. 

What is very annoying is that some prominent names in the MS community still think that there is no reliable marker of disease activity in MS out there (diagnostic or otherwise). And there has never been convincing counter arguments. [What I like to think of as secular stagnation]. Hopefully with standardisation we may get some robust measures which will change the way we think and talk about MS!

CoI: We are authors on this paper

ClinicSpeak: natalizumab PML update - July 2014

July 2014 natalizumab PML update: we are 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 especially designed for you."

Headline information

"As of the 8th July 2014 there have been 475 cases of natalizumab-associated PML. This represents an increase of 3 cases from last month; the number of cases each month continues to go down despite the number of MSers being exposed to natalizumab increasing. Over 125,800 MSers have been exposed to natalizumab. The following graph that I have put together from the monthly updates demonstrates the number of new PML cases per month seems to be going down, 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. Let me explain. 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 I would like to see are monthly updates of the PML, 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."

"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 mortality associated with PML in this setting is currently 23%, i.e. 109 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 well over 125,800 MSers been treated with natalizumab worldwide with over 347,000 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

Tuesday, 26 August 2014

Good News Tuesday- Too Good to Last

ProfG breaks the mold, so much for good news tuesday I guess you get the news as it comes

Knights Crushed

Sleep problems are common

Brass SD, Li CS, Auerbach S.The underdiagnosis of sleep disorders in patients with multiple sclerosis. J Clin Sleep Med. 2014 Sep 15;10(9). pii: jc-00207-12.

STUDY OBJECTIVES:To report at a population level the prevalence of restless legs syndrome, insomnia, and the risk of obstructive sleep apnea in multiple sclerosis patients. Sleep patterns and associations with fatigue and daytime sleepiness were identified.
METHODS:A cross-sectional study was performed using a written survey that was mailed to 11,400 individuals from the Northern California Chapter of the National Multiple Sclerosis (MS) Society Database who self-identified as having MS. The survey included individual questions relating to demographics as well as several standard validated questionnaires related to primary sleep disorders, sleepiness, fatigue severity, and sleep patterns.
RESULTS:Among the 11,400 surveys mailed out, 2,810 (24.6%) were returned. Of these, 2,375 (84.5%) met the inclusion criteria. Among the completed surveys, 898 (37.8%) screened positive for obstructive sleep apnea, 746 (31.6%) for moderate to severe insomnia, and 866 (36.8%) for restless legs syndrome. In contrast, only 4%, 11%, and 12% of the cohort reported being diagnosed by a health care provider with obstructive sleep apnea, insomnia, and restless legs syndrome, respectively. Excessive daytime sleepiness was noted in 30% of respondents based on the Epworth Sleepiness Scale. More than 60% of the respondents reported an abnormal level of fatigue based on the Fatigue Severity Scale. Both abnormal fatigue and sleepiness scores were associated with screening positive for obstructive sleep apnea, insomnia, and restless legs syndrome.
CONCLUSION:A significant percentage of MS subjects in our sample screened positive for one or more sleep disorders. The vast majority of these sleep disorders were undiagnosed. Greater attention to sleep problems in this population is warranted, especially in view of fatigue being the most common and disabling symptom of MS

I suspect you are thinking enough many more papers telling us that MSers have sleep disturbances. have you tried the Epworth Sleepiness scale? This measures your dozing potential.

  • If your score is below 10 you have a healthy level of daytime sleepiness in comparison to the general population
  • If your score is between 10 and 18 you have an excessive level of daytime sleepiness compared to the general population which may require further attention. You should consider whether you are obtaining adequate sleep, need to improve your sleep hygiene and consult your doctor for further medical help
  • If your score is 18 or above you have a very high level of excessive daytime sleepiness and it is vital that you consult your doctor for further medical help
  • (NB: The Epworth sleep test does not prove or disprove that you have a sleep related problem as many factors contribute to excessive sleepiness, and this is just an indication of whether further investigation is required. Please take notice of the results and consult your doctor if your score is high)

If you don't sleep you feel fatigued measured on the fatigue severity score.

There are a number or routes to promote sleep speak to your neuro

01 Mar 2014
"Sleep is a common topic of discussion on this blog. Why? Because it such a big problem in MSers. Sleep disorders, and poor sleep hygiene, are a major contributor to fatigue in MS.

Causes of Death in MSers

What is the commonest cause of death in MS? #MSBlog #MSResearch

"This US database study confirms that MS is responsible for excessive number of deaths and these are dominated by infections, particularly pulmonary infections as a result of aspiration. MS tends to affect swallowing, coughing and breathing late in the course of the disease. So these data indicate that MSers are living a long time with an accumulation of disability. There have been several recent posts on aspiration pneumonia, choking and breathing problems on the blog that you may want to go back to."
  1. Guest post: MSers with dysphagia - Multiple Sclerosis ..., 18 Jun 2014
  2. Multiple Sclerosis Research: Clinic speak: dysphagia survey ..., 01 Jul 2014
  3. Multiple Sclerosis Research: Clinic Speak: swallowing ..., 22 Jun 2014
"I am aware that everyone wants their MS to be cured, i.e flat-lined or even improved. However, the more realistic option with most of the DMTs is a slowing of disability accumulation and a delay in all the complications associated with late stage MS. Delaying the onset of swallowing and breathing problems by 3 to 5 years will have a big impact on survival. I suspect this is what happened with the 21-year follow-up study of the pivotal interferon-beta-1b trial cohort. Earlier access to interferon-beta, by approximately 3 years, led to a 50% greater chance being alive at 21 years after the beginning of the trial. This improved survival from earlier access to treatment must be disability related as the majority of deaths in this study were MS-related."

BACKGROUND: Information on causes of death (CODs) for MSers in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MSers was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes.

OBJECTIVE: To analyze disease categories in order to gain insight to pathways, which lead directly to death in MSers.

METHODS: Commercially insured MSers enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the "principal" COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized.

RESULTS: 30,402 MSers were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person-years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration (difficulty in breathing). No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs.

CONCLUSIONS: The principal COD algorithm improved on other methods of determining COD in MSers from death certificates. A greater awareness of the common CODs in MSers will allow physicians to anticipate potential problems and, thereby, improve the care that they provide.