Monday, 30 November 2015

Junior doctors’ industrial action suspended

From: BMA
Sent: 30 November 2015 19:27
To: g.giovannoni
Subject: Junior doctors' industrial action suspended

Dear Dr Giovannoni,

Following conciliatory talks with NHS Employers and the Department of Health, we have agreed to suspend industrial action in England, which was due to begin at 8am tomorrow. The Government has also agreed not to proceed unilaterally with the introduction of a new contract.

Full statement from Acas:

Agreement between BMA, DH and NHS Employers 30 November 2015

Following productive talks under the auspices of ACAS, the BMA, NHS Employers and the Department of Health are all agreed that a return to direct and meaningful negotiations in relation to a new contract for junior doctors is the right way forward. We intend to reach a collaborative agreement, working in partnership to produce a new contract for junior doctors, recognising their central role in patient care and the future of the NHS.

All parties are committed to reaching an agreement that improves safety for patients and doctors and therefore NHS Employers have agreed to extend the timeframe for the BMA to commence any industrial action by four weeks to 13 January 2016 at 17:00, to allow negotiations to progress. Within that timetable, the BMA agrees to temporarily suspend its proposed strike action and the Department of Health agrees similarly to temporarily suspend implementation of a contract without agreement.

All parties acknowledge that they share responsibility for the safety of patients and junior doctors, which must be paramount. In reaching this agreement to return to negotiations the BMA acknowledge the wish of NHS Employers and the Department of Health to agree and implement a new contract without undue delay. All sides wish to achieve a contractual framework that provides fair reward and a safe working environment for junior doctors throughout the week.

Note: for the purposes of this agreement, NHS Employers is acting on behalf of all employers of junior doctors.

Memorandum of understanding

This memorandum sets out the basis on which the parties will progress the agreement to return to negotiation reached on 30 November 2015.

We acknowledge the commitment of the BMA, NHS Employers and DH to the centrality of junior doctors in the current and future NHS, to recognise their dedication to patients and the NHS, and to provide a safe and supportive environment and fair reward.

The parties support the commitment to patients to ensure that the quality of care and patient outcomes (including appropriately adjusted mortality rates) are the same every day of the week. In that context we recognise the commitment of the government to work with the medical profession and other staff groups in partnership to improve access to seven day services. The parties recognise that junior doctors currently make a significant contribution across seven days, that urgent and emergency care is the priority for such services and that any new contract would support these aims

All parties acknowledge the crucial role of doctors in training across the NHS in providing safe patient care and the need to properly recognise that contribution not only through terms and conditions but also by reaffirming the commitment to a high-quality training experience, the very best working environment and appropriate work-life balance.

The current cost-neutral November 2015 offer is the basis for further negotiation, and the BMA, NHS Employers and DH have agreed to work collaboratively to develop and oversee new contractual terms and conditions of service for junior doctors.

Contractual safeguards for safety are paramount and we therefore commit to develop a jointly selected and supported guardian role to oversee the hours of work of doctors in training and ensuring appropriate payment for hours worked outside planned work schedules.

A commitment is also made to define propositions on work schedules, including the number of hours designated as plain time ensuring that doctors in training would not be expected to work consecutive weekends, and how time for administrative duties and training should be recognized.

Our discussions will also address access to flexible training (through joint work between HEE, BMA and NHS Employers), taking into account the changing demographic of the medical workforce, as well as developing further our shared commitment to ensuring that the training and working environment for junior doctors is improved (including addressing issues of fixed leave, study leave, notice of deployment and duty rosters, access to rest and refreshment facilities).

Collaborative work on pay will include an 'open-book' approach to the November 2015 pay calculator and supporting data and models, including cost-neutrality and equality impact, helping ensure clear systems for pay progression and managing transition. This agreement also recognises the need to work in partnership with HEE and where relevant the medical royal colleges to improve the training experience for junior doctors, including improving access to flexible working and enabling the transition to a fully competency-based approach to support junior doctors to progress through their training.

Today's decision is in the best interests of patients, doctors and the NHS. It is unfortunate that we have not been able to reach agreement sooner but patients, doctors and everyone else who works across the NHS will be pleased that in the end the right decision has been made.

A return to genuine negotiations is clearly preferable to the imposition of a new contract or industrial action and provides us with the best opportunity to deliver a contract for junior doctors which recognises the central role they play in delivering patient care across the NHS.

Industrial action will now be suspended throughout December. In January, the parties will decide whether meaningful progress is being made. At that point, we will need to consider whether industrial action should be reinstated.

The coming weeks will be challenging, but it is vital that we do all we can to come to a negotiated agreement. I know that you will continue to support us in this, as you have over the past few months.

We are one profession. We stand together.

Yours sincerely

Mark Porter
BMA council chair

Intravenous Tolerance study indicating autoimmunity in MS

van Noort JM, Bsibsi M, Nacken PJ, Verbeek R, Venneker EH.
Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial. PLoS One. 2015 Nov 23;10(11):e0143366.

As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN-γ, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5.

It has been shown that HspB5 is a potential target for autoimmunity and delivery of HspB5 via the tolerogenic route can reduce the number of MRI lesions by three quarters although the groups were too small to see an impact on relapsing disease. So is this the evidence that MS is due to autoimmunity to HspB5. I guess we should say yes.

There as many immunologists that think that the autoimmune target is myelin basic protein (MBP), which is easy to make and work with. 

This is not a good reason why this is a sensible target and there may be more holes in this hypothesis than a piece of emmental. MBP is present in the peripheral and central nervous system, and so it is perhaps not surprising that MBP-specific T cell receptor transgenic mice get peripheral neuritis (disease of the peripheral nervous system) as do some people with MS when immunised with myelin basic protein. Whilst there can be some peripheral nerve involvement in MS, this is not what MS is known as…a CNS related disease.

But if you think MS is autoimmune and you ask what does the immune response react to in an MS brain? It 
was found that it was alpha B cyrstallin (HspB5) and not any of the myelin proteins was the target for autoreactive cells in MS brains. It was found that people without MS could also respond to this protein too, but in healthy brains HspB5 was not expressed. It seemed that HSP5 was not expressed in the human thymus unlike in monkeys and rats and some mouse strains were it was expressed such that it would cause deletion of HspB5 reactive cells and so be relatively unique to humans. So in humans HspB5 reactive cells could escape thymic killing and escape into the blood and off they would into lymph glands waiting to get stimulated. Then viruses, notably EBV, would infect B cells and they would express and present HspB5 to T cells causing their priming and then you have everything ready for an autoimmune disease. Then something infects or stresses the oligodendrocytes and they them upregulate HspB5, which they do, such that it becomes the most abundant protein expressed and a target for autoimmunity. 

So simple turn off the immune response to HspB5 and that is the end of MS! 

Furthermore as HspB5 is a heat shock protein and molecular chaperone it should be neuroprotective and delivery of the HspB5 protein in EAE has been suggested to be an “immunological brake” So deliver it to MS and there should be neuroprotection and it should cause immunological tolerance when injected intravenously. 

So this is a very nice concept and has few limitations except that MS should also cause a lot of lens problems as HspB5 is expressed in the eye and one wonders how much protein will actually get to the CNS to be a microglial inhibitory molecule via Toll2-like receptor?

Anyhow, now this study reports that gadolinium  responses were reduced as were the T cell responses, but they were not eliminated. So is this the start of something good? If this does not get developed will it be the end of a missed oppertunity as the best chance to control autoimmunity in MS using antigen-specific therapy, which should have limited side effects. The future now depends on whether there are larger Phase II or Phase III studies. 

We have been saying for some time that intravenous tolerance works best when it is applied following CD4 T cell depletion. Would this have got rid of more lesions, T cell responses and importantly relapses as 1/4 (low dose), 1/7 (medium dose) and 3/7 (high dose) people relapsed and could point to failure of the project. However it surely does suggest that there is an autoimmune process in MS. 

CoI. ProfG was on the advisory panel 

PoliticalSpeak: preventable adverse events with off-label prescribing

Off-label use of drugs are associated with higher rates of preventable adverse drug events. #PoliticalSpeak #MSBlof #MSResearch #OffLabel

"Various academics within our University are strongly against our position of promoting off-label prescribing of DMTs to pwMS in resource-poor settings; the most outspoken person being Professor Allyson Pollock. If any of you have met Allyson, and debated with her, you simply don't want to be in her firing line. The paper below highlights yet another issue with off-label prescribing, preventable serious adverse events (ADEs), which supports her, and her department's, position. The study below using electronic patient records shows that preventable adverse drug events (ADEs) are more common with off-label prescribing compared to on-label prescribing. What protects our position, apart from the unmet need, is that ADEs in relation to off-label use with strong scientific evidence had a lower ADE rates than off-label use lacking strong scientific evidence. The latter depends on if you agree with our position on the evidence supporting off-label use of DMTs. Please keep in mind that the majority of pwMS in resource poor settings, for whom we are recommending off-label DMTs, are not on any DMT; in other words they are left to ravages of MS. When prescribing DMTs you also need to consider what the impact of untreated MS is. What does the natural history of MS look like? My infographic below tries to capture the headlines in relation to the impact of MS. The data on which this infographic is based is from studies in resource-rich countries. I suspect the impact may be worse in resource poor settings where there are no social safety nets. I have stated many times in the past that if I worked in a resource-poor setting I would have no hesitation in using cheaper off-label drugs to treat MS. At  the end of the day I would have a commitment to look after pwMS with the best tools at hand and with the evidence at hand. I would still treat-2-target of NEDA, simply using different DMTs."

Epub: Eguale et al. Association of Off-Label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2015 Nov 2:1-9. doi: 10.1001/jamainternmed.2015.6058. 

IMPORTANCE: Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed. 

OBJECTIVE: To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.

DESIGN, SETTING, AND PARTICIPANTS: A cohort of 46 021 patients who received 151 305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Data were analyzed from January 5, 2012, to March 15, 2015.

EXPOSURES: Off-label prescription drug use with and without strong scientific evidence.

MAIN OUTCOMES AND MEASURES: Adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis.

RESULTS: A total of 3484 ADEs were found in the 46 021 study patients, with an incidence rate of 13.2 per 10 000 person-months. The rate of ADEs for off-label use (19.7 per 10 000 person-months) was higher than that for on-label use (12.5 per 10 000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10 000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10 000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10 000 person-months; AHR, 1.17; 95% CI, 1.06-1.28), patients receiving 5 to 7 drugs (12.1 per 10 000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10 000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10 000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12-1.26).

CONCLUSIONS AND RELEVANCE: Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.

Sunday, 29 November 2015

ClinicSpeak: MRI monitoring for PML is simply not good enough yet

Are you having regular MRI PML monitoring scans? #ClinicSpeak #MSBlog #MSResearch

"Earlier this week a colleague of mine was discussing the junior doctors' industrial action and how we must support them; which I do. The discussion got down to how at the core of the new junior contract is simply the downward income spiral facing doctors. My colleague mentioned that this is part of a global trend. I couldn't agree more, it is part of a global trend as more and more of our work becomes automated. Doctors are earning less because their general skills are simply not as good as we think they should be and technology is proving better at doing it than we are. This is part of the process of creative destruction, which is driven by technology. Yes, there are losers, the doctors, but there are also winners, and the winners tend to be society, in this case patients."

"The study below shows how much we need a technological solution for MRI monitoring, be it for MS disease activity or the detection of early PML. The study compared how good neuroradiologists were at agreeing with each other about new the occurrence of new lesions on MRI and whether or not these lesions were due to MS or early PML. Although the investigators' conclude on a positive note the inter- and intra-rater agreement rates are simply not good enough. Why am I being so critical? Because PML is a life threatening disease and any delay in making the diagnosis at an individual patient level could be the difference between life and death."

"When we started PML surveillance, with 3-monthly MRI scanning, in MSers who were JCV-seropositive and at high-risk of PML, I had to scare our neuroradiologists about the task in hand. Essentially if they missed early PML it could mean the difference between life and death, or minimal or severe disability, for the patient concerned. Missing PML could potentially have legal implications for the neuroradiologist concerned. Most neuroradiologists are used to diagnostic scans that can take literally minutes to read and report. In comparison, monitoring scans, particularly those for PML monitoring, need a lot of time. You first have to call up the old scans and compare each slice fom the new scan with the older scan and you have to repeat the process across multiple sequences (different imaging parameters). As the first signs of PML can be very subtle you have to look at each section of brain very carefully. This is a laborious process and takes a long-time, which is why neuroradiologists don't like reading MS activity and PML monitoring scans. Enter technology. We acquired new software from Siemens that automatically compares images with each other and colour codes any changes. This allows the neuroradiologist to zoom in immediately and focus on what has changed between the old and new scans and focus their attention on the changes. All of a sudden the reading of these monitoring scans has sped up by an order of magnitude. What would we do without technology?"

"I see a future, an era, when the software will be clever enough to read the scans without human input. The software will almost certainly be quicker and more accurate than the human eye. Will this put neuroradiologists out of a job? Unlikely, this will free up the neuroradiologist time to do new and more interesting things; to innovate and improve. The only way we can protect our jobs and earning capacity to is to add-value, to make things better. Believe me the way we practice medicine, and neurology, is ripe for creative destruction; the status quo is simply not an option."

"If you are JCV-positive and are at high-risk of getting PML you should be undergoing frequent MRI scans to pick-up PML early or you should consider coming off natalizumab and switching to a safer DMT. In short you don't want to get PML if you can avoid it." 

Epub: Wattjes et al. Diagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients. Mult Scler. 2015 Nov 12. pii: 1352458515615225. 

BACKGROUND: In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML).

OBJECTIVE: To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability.

METHODS: In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions (n = 21) or new MS lesions (n = 20) or no new lesions (n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated.

RESULTS: Overall sensitivity and specificity for the detection of new lesions regardless of whether MS or PML lesions were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate.

CONCLUSION: The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate.

CoI: multiple

Cannabis for spasticity

Paolicelli D, Direnzo V, Manni A, D'Onghia M, Tortorella C, Zoccolella S, Lecce VD, Iaffaldano A, Trojano M. Long-Term Data of Efficacy, Safety and Tolerability in a Real Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients.
J Clin Pharmacol. 2015 Nov 26. doi: 10.1002/jcph.670.

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with Multiple Sclerosis (MS). We showed our forty-weeks post-marketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After four weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort patients received an average of 6.5±1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5±1.2 points (p<0.0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of Adverse Events (AEs) was of 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunctions were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (p = 0.011 and p = 0.001 respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms.

This is another study that shows that cannabis can have some benefit for people with MS, however it also shows that there is room for improvement, because of side-effect, this is one of the reasons for developing new treatments. Our new treatment works by a new mechanism unrelated to cannabis system. This will be revealed soon.

CoI: We are developing an alternative to cannabis. If you fit the criteria recruitment is ongoing in London (CLICK)

A way to silence Neuropathic Pain

Laumet G, Garriga J, Chen SR, Zhang Y, Li DP, Smith TM, Dong Y, Jelinek J, Cesaroni M, Issa JP, Pan HL.G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.Nat Neurosci. 2015;18(12):1746-55.

Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K+ channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation (addition of two methyl groups- which is a carbon and three hydrogens) of Lys9 (The nineth amino acid in the protein which is a lysine amino acid) at postion on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 (potassium channels) promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K+ channel expression. Selective knockout of the gene encoding G9a in DRG neurons completely blocked K+ channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced genes associated with K+ channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K+ channels and in acute-to-chronic pain transition after nerve injury.

Neuropathic pain is caused by aberrant nerve signals generated within the nervous system, typically unrelated to any real pain causing sensation. Pain is often treated by using opiates but in neuropathic pain the opioid receptors are down regulated and this is why opioids , like morphine don't do the business when it comes to treating neuropathic pain.

In biochemistry, transferase is the general name for the class of enzymes that enact the transfer of specific functional groups(e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of different biochemical pathways throughout biology, and are integral to some of life’s most important processes. It is interesting that loss of activity of a methyl transferase (removes methyl group from the begining of the protein). The central point is that this effects way some genes are expressed in the dorsal root ganglia, which contain the nerve cell bodies of sensory nerves. In these nerves there is a excessive activity of methyl transferase function that result down regulation of some potassium channels such as the calcium activated potassium channel (Kcnma1) or voltage sensitive channels. These channels serve to limit rate the firing of nerves, so if the nerves are damaged and these channels are down regulated you get more firing of nerves and so things like pain and possibly spasticity can be aberrantly triggered. So this study indicates that therapy of pain may be achieved by upregulating the potassium channel activity and this may be achieved by blockade of of this transferase. So a new target for neuropathic pain 

PoliticalSpeak: are you an early adopter?

Please adopt our policy and pledge your support. #PoliticalSpeak #BrainHealth #MSBlog

“I have just got back from the 23rd European Charcot Meeting, in Baveno, Italy. I was invited to present our ‘Brain Health – Time matters in MS’ policy document. My presentation was a bit rushed as I was expecting to have 30 minutes, but was told to cut it down to 15 minutes just before I presented. As promised, my slides are below for you to see and/or download. I received a lot of positive feedback about my presentation and the policy document. One neurologist from Canada will be using the policy document next week as part of a lobby in Canada to get more effective 2nd-line treatments available earlier for people with MS. A Dutch neurologist asked why the Netherlands were not more involved with this initiative; they can be all they need to do is sign-up and pledge their support. A Swiss neuroradiologist volunteered to help with the imaging, and MRI monitoring component, of the policy document. All these anecdotes are good news for me as it indicates that people are engaging with the initiative. I sincerely hope 'Brain Health in MS' as treatment concept evolves over the next 12-24 months into something much bigger. Our vision for the document is for it become a real change agent so that we actually ‘create a better future for people with MS and their families’.”

“If you haven’t pledged your support for the policies please do via our Brain Health website.”

CoI: multiple

Saturday, 28 November 2015

Your Genes can protect you from MS

Bettencourt A, Carvalho C, Leal B, Brás S, Lopes D, Martins da Silva A, Santos E, Torres T, Almeida I, Farinha F, Barbosa P, Marinho A, Selores M, Correia J, Vasconcelos C, Costa PP, da Silva BM. The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases.J Immunol Res. 2015;2015:948723.

Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(∗)15 (OR = 2.17) and HLA-DRB1(∗)03 (OR = 1.81) alleles with MS, HLA-DRB1(∗)03 with SLE (OR = 2.49), HLA-DRB1(∗)01 (OR = 1.79) and HLA-DRB1(∗)04 (OR = 2.81) with RA, HLA-DRB1(∗)07 with Ps + PsA (OR = 1.79), HLA-DRB1(∗)01 (OR = 2.28) and HLA-DRB1(∗)08 (OR = 3.01) with SSc, and HLA-DRB1(∗)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(∗)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1(∗)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(∗)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(∗)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

When I was is Boston I visited the Harvard MS group and saw one of the bags for screening that could be done and was very impressed by the range of assays. One of the assays was to test for the HLA-DR type. We know that HLA-DR2 (serotype) or HLA-DRB1*1501 (geneotype) is the major susceptibility allele for MS. I bet we at Barts don't do this as a regular check.

How is a T cell stimulated.

This study shows that HLA-DR13 is unrepresented in MS and it looks like people with DR13 delete self reactive cells.

So I say hurray, because I am HLA-DR7 and HLA-DR13. I know this because I donated my blood for experiments and I was found not to respond to myelin oligodendrocyte glycoprotein. Is this why I have ot got MS yet? 

However MD2 is HLA-DR3 and HLA-DR4 and this is the major, major risk factor for type 1 diabetes and rheumatoid arthritis. 

However as MD2 hasn't got either of these things yet, it shows you that having MS risk genes does not mean you will get MS. Likewise just because you have MS, does not mean that our children will get MS.

JCV virus infection at presentation of MS

Delbue S, Tadeo CS, Elia F, Ferrante P. Intervirology. JC Virus Replication at the First Symptoms of Multiple Sclerosis: A Case Report. 2015;58:278-282.

Multiple sclerosis (MS) is an autoimmune, demyelinating disorder of unknown aetiology, in which viruses have been suggested as aetiological/triggering agents. The attention to the association between viruses and MS has been rekindled by the development of progressive multifocal leukoencephalopathy in natalizumab-treated MS patients. Here we report the case of a woman with JC virus (JCV) replication in the cerebrospinal fluid, blood and urine collected at the first symptoms of MS and during several follow-up visits. This observation shows that JCV can be associated with MS without a relation with natalizumab treatment, although the triggering role of JCV in some cases of MS will require further studies.

This is interesting. Someone with MS with frank viral infection. Is this MS or is it PML masqurading as MS. Is MS due to the effective killing of JC virus infected oligodendrocytes so that it remains undetected? Could it remain undetected when so many people have looked for virus. People say that JC virus only infects 50% of people  with MS, but anti-viral ELISAs and PCR are not infallable. However if this were the case once you have Stem cell transplants would we not get PML raising its head. Maybe ProfG can take a break from enjoying Lake Maggoire to tell us why not. 

Friday, 27 November 2015

ClinicSpeak: who writes your blog posts for you?

Why are people suspicious of something that is free? #MSBlog #ClinicSpeak

"Yesterday on our Barts-MS Preceptorship one of the attendees asked me if (1) I write all my own blog posts and (2) if the blog really costs nothing. The answers to both these questions is yes.”

“The abstract triage system is run by the Mouse Doctor. He identifies most of the articles for the blog. The articles he allocates to me to cover are typically clinical ones; subjects he thinks are better covered by me, rather than him, or someone else in the group. He then leaves the abstracts of these articles in a draft post for me. I then open the draft read the abstract and if I find these abstracts of value I may then read the full article, before editing the abstract, writing a commentary, formatting it, inserting figures and hyperlinks, inserting other social media links, choosing suitable keywords and then posting it on the blog. Occasionally the topic may generate a question that you the readers could answer; when this occurs I set-up and embed a survey. As you are aware these surveys are not high science, but simply a quick and easy barometer; I also think they encourage reader participation. I estimate that I spend around 30-45 minutes on average per post. I typically do my posts early in the morning before work. I view the time I contribute to the blog as free time; my contribution to the common good. I don't expect to be paid for it. Regarding the software; we use Blogger, Google's free blogging platform. The only money we have spent on the blog was to pay a freelance designer a small honorarium for helping with the new skin (design). The designer we used is a friend of Alison Thomson who did his masters with Alison at the Royal College of Art. In addition, to this I pay a monthly personal subscription for a Google Pro account and to LinkedIn for my SlideShare site. I use both of these accounts to support the blog. My Google account hosts the surveys and pictures and I use SlideShare to host my presentations and some of the embedded documents. I am in the process of migrating my presentations from SlideShare to Google Docs as the latter is easier to use and much more powerful; edits on existing documents are updated in real-time.”

“I am not against us obtaining financial support for the blog. We will almost certainly need professional help when we start using the blog as a portal for continuing medical education (CME) or continuing professional development (CPD). The objective is to teach healthcare professionals (HCPs) about the management of MS using real-life cases studies. To do this we need to identify patients who are willing to allow their case histories and investigations to be presented online. We will then need to get consent and document this. We are also planning to ask clinicians from all over the world to contribute to the teaching and do this we will need to collate their biographies, mugshots and conflicts of interests when we prepare the posts. I suspect we may have to pay them a small honorarium for their time. All of this will require administration time. Hence we are in the process of applying for funds to appoint a CME/CPD administrator to coordinate this aspect of the blog. We will also ask this person to help proof read and edit the posts to make sure they are of a consistent style and quality. We also want this person to be responsible for cleaning up the log of blog keywords. We use too many keywords, have a large number of duplicates and there are many keywords with typos. This task is important as the keywords are an important feature of the blog and label each post. Keywords are important when it comes to searching for specific topics and for generating alerts using IFTTT (If this then that).”

“So in the near future our NeuroSpeak case studies on the blog will be supported by an administrator and that will need resource. However, it is getting to point that if we want the blog to evolve we will need help running it. We think it is important to use the blog for our CPD/CME activities as it will help you, people affected by MS, to understand how HCPs think and approach MS. It will also help you understand that clinical neurology is not a science, but an art, and why clinical opinions differ. It is common for clinicians to differ in their approach to the diagnosis and management of MS. The case studies will allow you to see this in real-time; more importantly it will empower you to self-manage your MS and/or become more active in the decisions your HCPs make concerning the management of your MS.”

Automated lesion detection

Fartaria MJ, Bonnier G, Roche A, Kober T, Meuli R, Rotzinger D, Frackowiak R, Schluep M, Du Pasquier R, Thiran JP, Krueger G, Bach Cuadra M, Granziera C. Automated detection of white matter and cortical lesions in early stages of multiple sclerosis. J Magn Reson Imaging. 2015. doi: 10.1002/jmri.25095. [Epub ahead of print]
PURPOSE:To develop a method to automatically detect multiple sclerosis (MS) lesions, located both in white matter (WM) and in the cortex, in patients with low disability and early disease stage.
MATERIALS AND METHODS:We developed a lesion detection method, based on the k-nearest neighbour (k-NN) technique, to detect lesions as small as 0.0036 mL. This method uses the image intensity information from up to four different 3D magnetic resonance imaging (MRI) sequences (magnetization-prepared rapid gradient-echo, MPRAGE; magnetization-prepared two inversion-contrast rapid gradient-echo, MP2RAGE; 3D fluid-attenuated inversion recovery, FLAIR; and 3D double-inversion recovery, DIR), acquired on a 3T scanner. To these intensity features we added the information obtained by the spatial coordinates and tissue prior probabilities provided by the International Consortium for Brain Mapping (ICBM). Quantitative assessment was done in 39 early-stage MS patients with a "leave-one-out" cross-validation.
RESULTS: The best lesion detection rate (DR) performance in WM was obtained using MP2RAGE, FLAIR, and DIR intensities (77% for lesions ≥0.0036 mL; 85% for lesions ≥0.005 mL). Similar results were obtained excluding the DIR intensity as well as when using only MPRAGE and FLAIR (DR = 75%, P = 0.5720). However, the combination of FLAIR with DIR and MP2RAGE appeared to be the best for detecting cortical lesions (DR = 62%), compared to the other combination of sequences (P < 0.001).
CONCLUSION: For WM lesion detection, similar results were observed when only conventional clinical sequences (FLAIR, MPRAGE) were used compared to a combination of conventional and "advanced" sequences (MP2RAGE, DIR). Cortical lesion detection increased significantly when "advanced" sequences were used.

DrK was presenting today at the lab meeting about our database of people with MS at Barts. We are also linking up with the MS register. The issue of getting data from scans uploaded was mentioned  tobe a bottleneck because radiographers are snowed under with their day to day MRI duties, so having an automated way to read scans would  be a time saver but would put the imaging centres out of business as the central hubs are used to read scans for clinical trials. This paper reports on attempts to do this, maybe DrK can comment on how accurate it would need to be before we ditch the human touch. 

Sorry I don't have time to try and explain the different types of images used here I would need  to do some reading.

Maybe we can do it in an educational  post in future. If you click on the tab "education" above their are a few in "teaching posts"

Thursday, 26 November 2015

To correlate or not to correlate that is the question

Aboulenein-Djamshidian F, Krššák M, Serbecic N, Rauschka H, Beutelspacher S, Kukurová IJ, Valkovič L, Khan A, Prayer D, Kristoferitsch W. CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable? PLoS One. 2015 Nov 13;10(11):e0142272.

BACKGROUND:To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration.
METHODS:28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study.
RESULTS:There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability.
CONCLUSIONS:Based on the findings of this study, we recommend that the concept of 'clinico-radiologico paradox' in multiple sclerosis be extended to CROP-'clinico-radiologico-ophthalmological paradox'. Furthermore, OCT data of MS patients should be interpreted with caution.

There have been a number of reports looking at optic nerve damage and then correlating this with the degree of damage in the brain using MRI and it is said by some that they are correlated but in this study they do not find such correlates. 

Whilst one can understand that if you have more active MS then the chance of having an optic nerve lesion may be higher and so likewise having a brain lession maybe higher, but they are distinct regions of the CNS and to look at they eye and them think you know what is going on in the brain, is in my view not going to be a sensible approach. Optic neuritis is on of the early features of MS and can cause damage to the eye that may not be reflected in the brain. So this is yet another clinical correlation that is best left in the bin if you want to look for brain lesions do an MRI and if you want to look at eye problems do an OCT, but it is my view rather daft to do an OCT an then to think it tells you enough information about what is going on in the brain.

ClinicSpeak: Is it your right to die with dignity?

Passive or active euthanasia; what is the difference? #ClinicSpeak #MSBlog #MSResearch

"We have debated end-of-life care and advanced directives on our blog posts many times before. The consensus has been that PwMS choice is what is important in driving key decisions around end-of-life issues. I believe strongly in the holistic management of MS and to do this properly we need some kind of metric in relation to end-of-life care; simply having it as part the quality debate will get healthcare professionals, and PwMS, to think about it and consider their role in the management of MS in its terminal phase. A lot of end-of-life care is futile, expensive and undignified. Don't we all deserve the right to choose a dignified death?"

"The legal case below has generated a lot of debate in the UK; it describes a ruling that allows healthcare professionals to withdraw supportive care to allow an elderly PwMS with minimal consciousness to die in a dignified way. Why did the judge rule on a passive process? Wouldn't it be more dignified for the PwMS if the the doctors looking after her gave her a lethal injection?"

"It is clear that PwMS need to prepare an advanced directive or living will to help their families make a decision on their behalf. There are many website that offer advance directives that you can use. The simple one below from McMillan Cancer Support covers all the relevant issues. When I get the time I will transfer this onto a Barts-MS letterhead."

"You may also be interested in reading the NICE quality standard on end-of-life cure. The principles are captured succinctly in the summary statements. Do you agree, or disagree, with NICE?"

List of statements (NICE quality standard [QS13]. End of life care for adults. November 2011)

Statement 1. PwMS (people with MS) approaching the end of life are identified in a timely way.

Statement 2. PwMS approaching the end of life and their families and carers are communicated with, and offered information, in an accessible and sensitive way in response to their needs and preferences.

Statement 3. PwMS approaching the end of life are offered comprehensive holistic assessments in response to their changing needs and preferences, with the opportunity to discuss, develop and review a personalised care plan for current and future support and treatment.

Statement 4. PwMS approaching the end of life have their physical and specific psychological needs safely, effectively and appropriately met at any time of day or night, including access to medicines and equipment.

Statement 5. PwMS approaching the end of life are offered timely personalised support for their social, practical and emotional needs, which is appropriate to their preferences, and maximises independence and social participation for as long as possible.

Statement 6. PwMS approaching the end of life are offered spiritual and religious support appropriate to their needs and preferences.

Statement 7. Families and carers of PwMS approaching the end of life are offered comprehensive holistic assessments in response to their changing needs and preferences, and holistic support appropriate to their current needs and preferences.

Statement 8. PwMS  approaching the end of life receive consistent care that is coordinated effectively across all relevant settings and services at any time of day or night, and delivered by practitioners who are aware of the person's current medical condition, care plan and preferences.

Statement 9. PwMS approaching the end of life who experience a crisis at any time of day or night receive prompt, safe and effective urgent care appropriate to their needs and preferences.

Statement 10. PwMS approaching the end of life who may benefit from specialist palliative care, are offered this care in a timely way appropriate to their needs and preferences, at any time of day or night.

Statement 11. PwMS in the last days of life are identified in a timely way and have their care coordinated and delivered in accordance with their personalised care plan, including rapid access to holistic support, equipment and administration of medication.

Statement 12. The body of a PwMS who has died is cared for in a culturally sensitive and dignified manner.

Statement 13. Families and carers of PwMS who have died receive timely verification and certification of the death.

Statement 14. PwMS closely affected by a death are communicated with in a sensitive way and are offered immediate and ongoing bereavement, emotional and spiritual support appropriate to their needs and preferences.

Statement 15. Health and social care workers have the knowledge, skills and attitudes necessary to be competent to provide high-quality care and support for PwMS approaching the end of life and their families and carers.

Statement 16. Generalist and specialist services providing care for PwMS approaching the end of life and their families and carers have a multidisciplinary workforce sufficient in number and skill mix to provide high-quality care and support.

Nicola Slawson. MS sufferer should be allowed to die, says judge in landmark ruling. Thursday 19 November 2015


..... Granting application to daughter of 68-year-old woman in end stage of multiple sclerosis, judge concludes it would be disrespectful to keep her alive.....

...... A woman in the end stage of multiple sclerosis has been granted the right to die, in a landmark legal ruling.......

...... The woman’s daughter had told how her mother was “completely incapacitated” and had asked Mr Justice Hayden to allow doctors to stop providing “clinically assisted nutrition and hydration”.......

...... Medical experts said the woman, who cannot be named for legal reasons, was in a “minimally conscious state”, however the judge concluded that it would be disrespectful to the woman to keep her alive in a manner she would “regard as grotesque”.......

...... Granting the application on Thursday, he said the focus of the case was her right to live the last of her days in the way that she would have wished.......

...... “[The woman] now 68 years old is profoundly impaired both physically and cognitively in consequence of the progressive degenerative impact of multiple sclerosis. It is now 23 years since [she] received her diagnosis.”......

...... She told the judge: “I cannot emphasise enough how much the indignity of her current existence is the greatest contradiction to how she thrived on life and, had she been able to express this, then without a doubt she would.”......

...... No one involved opposed the daughter’s application.......

...... Four years ago, a brain-damaged, minimally conscious 52-year-old woman was denied the right to die by another judge.......

...... Mr Justice Baker’s ruling at the time was hailed as a decision which clarified the law relating to the care of the severely disabled.......

...... He had said there was dignity in the life of a disabled person who was well-cared for and kept comfortable and so concluded that life-supporting treatment should not be withdrawn.......

...... Responding to the decision made today, Davina Hehir, director of policy at campaign group Compassion in Dying, said: “This case represents a landmark for the courts taking into account a person’s previously expressed wishes when deciding what treatment they would or would not want.......

...... “The experience of the family in this case must have been harrowing and our hearts go out to them. People can help to avoid these distressing cases by planning ahead for their own treatment.”......

...... “This is the first time that the court of protection has agreed to withdraw treatment from someone receiving life sustaining treatment while considered by medical experts to be in a ‘minimally conscious state’,’ he said.......
...... “The judge has decided that withdrawing the life sustaining treatment is in the woman’s best interests given her current quality of life,” he said.......

...... Campaigners who oppose assisted dying warned the ruling could put vulnerable sick or disabled people at risk. Peter Saunders, director of Care Not Killing said: “This case demonstrates judicial mission creep whereby judges, through subjective application of vague and ambiguous legal precedent, are able to shape and remake the law.......

...... Arrangements will now be made for treatment to be withdrawn in line with national clinical guidelines....... 

Wednesday, 25 November 2015

ResearchSpeak: brain volume loss and disability progression

Do you want to know if you are losing brain volume? #BrainHealth #ResearchSpeak #MSBlog #MSResearch

"I am a big proponent of brain atrophy, or brain volume loss, as an integrator of end-organ damage in MS. Brain volume loss occurs in MS at a rate of between 2-7x the normal rate. Brain volume loss is linked to previous inflammatory activity and is a poor prognostic variable. In other words MSers with progressive brain volume loss do badly; brain volume loss is associated with cognitive impairment and physical disability progression. The analysis below from the fingolimod clinical studies shows that brain volume at baseline was predictive of brain volume loss over 2 years and was highly predictive of disability progression and reaching hard disability outcomes, for example needing to use a walking stick."

"I am not surprised by this data. Why? Disability progression must be linked to loss of axons and nerve cells and this is manifested in brain volume loss. The implications of this is that we need to use treatments to slow, or preferably normalise, brain atrophy rates. The good news is that emerging data suggests we can achieve this with current licensed DMTs. Unfortunately, we are not yet able to reliably implement brain atrophy measures into clinical practice at the individual patient level. This will change with emerging algorithms, or setting thresholds above what occurs as part of day to day variability that occurs as part of the measurement. These latter thresholds will get lower with multiple measurements that will be able to exclude day-to-day variability, particularly if they show a consistent trend over time. Our centre is in the process of testing brain atrophy measurements to see if we can start using them in clinical practice. Would you want your brain volume measured as part of your annual assessment?"

Epub: Jeffery et al. The relationship between the rate of brain volume loss during first 24 months and disability progression over 24 and 48 months in relapsing MS. J Neurol. 2015 Nov 14.

Background: Clinical evidence in patients with relapsing-remitting multiple sclerosis suggests an association between MRI outcome measures and disability progression (DP). 

Objective: Post hoc analysis to investigate the association and potential predictive value of brain volume loss (BVL) with long-term DP in FREEDOMS (Gilenya study). 

Methods: Patients were categorized into quartiles by SIENA-calculated percent brain volume change from baseline to month (M) 24. Patient characteristics at baseline were determined for each quartile, as were the proportions of patients at M24 and M48 reaching Expanded Disability Status Scale (EDSS) scores of ≥4.0 or ≥6.0 or DP confirmed at 3 months (CDP3) or 6 months (CDP6), and change in EDSS and Multiple Sclerosis Functional Composite. 

Results: MS disease activity and severity as well as brain volume at baseline were predictive of subsequent BVL over 24 months. The quartiles of patients with greater BVL at 24 months were at highest risk (odds ratio, p value) for reaching EDSS ≥4 (2.8, p = 0.001) or ≥6 (5.73, p = 0.0005) and experienced more DP at M24 (CDP3 2.13, p = 0.002; CDP6 2.17, p = 0.003) and M48 (CDP3 1.98, p = 0.006; CDP6 1.87, p = 0.018) compared to the quartile of patients with the least amount of BVL. 

Conclusions: These findings confirm the clinical relevance of early brain volume changes for long-term DP.

CoI: multiple

Spasticity treatment that doesn't cut the mustard

Rommer PS, Kamin F, Abu-Mugheisib M, Koehler W, Hoffmann F, Winkelmann A, Benecke R, Zettl UK. Long-Term Effects of Repeated Cycles of Intrathecal Triamcinolone Acetonide on Spasticity in MS Patients. CNS Neurosci Ther. 2015 doi: 10.1111/cns.12474. [Epub ahead of print]

MAIN PROBLEM:Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters.
METHODS:A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25-foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle.
RESULTS:Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long-lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months.
CONCLUSION: Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re-administration of TCA and that an interval of 3 months between the treatments might be too long.

So not every thing works in spasticity here is one example, will we be next?.... hope not.

CoI we are developing a novel anti-spastic agent

Translating Basic Science

Here are slides from the Meeting in Harwell

Tuesday, 24 November 2015

Season of Birth effects in Tunisia

Sidhom Y, Kacem I, Bayoudh L, Ben Djebara M, Hizem Y, Ben Abdelfettah S, Gargouri A, Gouider R.Season of birth and multiple sclerosis in Tunisia.Mult Scler Relat Disord. 2015 Nov;4(6):491-494.

BACKGROUND:Recent studies on date of birth of multiple sclerosis (MS) patients showed an association between month of birth and the risk of developing MS. This association has not been investigated in an African country.
OBJECTIVE:We aimed to determine if the risk of MS is associated with month of birth in Tunisia.
METHODS:Data concerning date of birth for MS patients in Tunisia (n=1912) was obtained. Birth rates of MS patients were compared with all births in Tunisia matched by year of birth (n=11,615,912). We used a chi-squared analysis and the Hewitt's non-parametric test for seasonality.
RESULTS:The distribution of births among MS patients compared with the control population was not different when tested by the chi-squared test. The Hewitt's test for seasonality showed an excess of births between May and October among MS patients (p=0.03). The peak of Births of MS patients in Tunisia was in July and the nadir in December.
CONCLUSION:Our data does support the seasonality hypothesis of month of birth as risk factor for MS in Tunisia. Low vitamin D levels during pregnancy could be a possible explanation that needs further investigation.

A pinch more salt in macrophages

Hucke S, Eschborn M, Liebmann M, Herold M, Freise N, Engbers A, Ehling P, Meuth SG, Roth J, Kuhlmann T, Wiendl H, Klotz L. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. J Autoimmun. 2015. pii: S0896-8411(15)30052-4.

The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro-inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity.

It has been reported that a high salt diet can induce higher levels of autoimmunity and it has been reported that a high sodium diet can make autoimmunity worse in some mouse strains. This is on of the hottest recent papers in MS research according to Altmetrics

What does an increase of abit of a non-linear scale of EAE or onset abit earlier in sub optimal EAE (controls are a 1 compared to the usual 3 in most other experiments) mean to someone with MS. 

Does it equate to worse disease? I guess we will see. 

In this new paper the salt story continues and this new study 
indicates  that macrophages are also more juiced up in high salt diets.

If you have more disease this is because you have more infiltration into the CNS and so you have more T cells in there and more macrophages in there, so chicken and egg. In this study the authors also find that macrophages from high salt diet are more stimulated as has been found for T cells, where it drives pathogenic Th17 (click) (click) apparently because  it blocks the suppressive effect of T regulatory cells (click) and also blocks the formation of M2 type macrophages that are the type of cells that are reported to promote re myelination (click)

Some authors argue (click) on "data generated by the world health organization (WHO), a direct correlation between salt intake and prevalence of MS is not apparent in the broad sense. Countries such as China and Japan, which traditionally have the highest salt intake (confirmed in a large number of studies) due to generous addition of salt during cooking and dietary regulars such as soy and miso, also show some of the lowest rates of MS prevalence in the population (< 0.5 per 100 000 of the population). Conversely, the United States of America and the United Kingdom, which both recorded an MS prevalence of > 100 per 100 000 of the population, have relatively low salt intakes compared to these Asian countries. A simple 'one-to-one' overlap was of course unlikely, but one cannot exclude the possibility that for individuals predisposed to autoimmunity through various susceptibility loci, increased salt intake may in fact aggravate their clinical symptoms. This is of course a very attractive concept, as some benefit to patients may be realized at minimal expense and with the greatest of ease simply by avoiding foods rich in salt content".
We already know that too much salt carriers health risks and one can modify diets. Is this why the North South (Sun-light) MS gradient (higher in North than the South) that used to exist in the USA is disappearing? Is it that the Southerners are eating more salt and it has nothing to do with cars and movement of people.

"One major question now is the physiological underpinning of their findings. Apparently increased dietary salt intake does not render higher concentrations of sodium in the blood or lymph nodes, where T cells usually dwell (click). But does this act via the gut
environment where elevated levels of salt might be sensed?  

Is it that the salt content influences the gut microbiome, so just like you get some fish living in freshwater and others that live in salt water and some can live in both. Is this where an effect occurs.

Given that a low-salt diet poses no safety concerns, such studies can be initiated without delay" and indeed they have been

The Effect of Dietary Salt Intake on Immune Function in Patients With Multiple Sclerosis (NCT02282878). Newly Diagnosed MS patients randomized to high sodium first diet will receive 2 weeks of controlled high sodium diet followed by a 1 week washout and 2 weeks of low sodium diet. Newly Diagnosed MS patients randomized to low sodium first diet will receive 2 weeks of controlled low sodium diet followed by a 1 week washout and 2 weeks of high sodium diet. The aim is to look at the influence of dietry salt on Th17 responses.

One question that keeps slipping the ediors/referees minds from the animal experiments is what is the relevance of this amount of salt given to mice when compared to humans. No dose response has been done in the mice experiments, so what does to you use in humans. The human equivalent dose to that used in mice calculated at 660g of salt a day, which is abit higher than 8-15g/day taken by humans. Given that 18g in water of salt makes humans vomit,  but mice and rats can't vomit, its alot.  

So should such data be taken with a pinch of salt? Dr. Pryce was brave to ask the question in public.....that's the end to his chances of career in Yale. Would you get the same result with less salt?, would you see an effect if you had typical full blown EAE?

But does it matter you say? 

As salt is the real deal as a study has already been done (NCT01846234).
Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015; 86:26-31.

Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS.

METHODS:We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated using regression analysis. We then replicated our findings in a separate group of 52 patients with MS.
RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group.
CONCLUSIONS: Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

So avoid too much salt as we know it is bad for your health but likewise you need it too. What will be the effect of salt on the action of a DMT because it a placebo-controlled trial should be difficult to do in RRMS?