Wednesday, 31 December 2014

Interim trial results: Bone Marrow Stem Cell Replacement Therapy

Is  hematopoietic stem cell transplant a realistic treatment for MS? #MSBlog #MSResearch

"We are aware that a lot of readers of this blog are proponents of more aggressive therapy. The abstract below is the interim, or 3-year, results of the international autologous hematopoietic stem cell transplant (HCT) trial. The results are very encouraging. Please note that this is an open-label study and hence it is difficult to draw comparisons with other licensed DMTs. NEDA rates at 3-years were a remarkable 78%; higher than any of the licensed DMTs. HCT is not a licensed therapy for MS and hence cannot be offered as part of routine care; at least this is the situation in the UK. How do we get HCT licensed for treating MS? A difficult question; I suspect the community would need to do a head-2-head study against a licensed therapy. I would think the best comparator here would be alemtuzumab considering the potential risk of HCT. It is clear that when HCT is done in specialist units it is much safer than previous studies have suggested."

"These results mirror those of the Canadian BMT collaborative that have been presented at meetings, but have yet to be published in a peer-review journal. On my recent visit to Canada I was told that both Ottawa and Calgary are now providing HCT as a treatment option for MSers who have very active MS and have failed all DMTs. I would be interested to know if their guidelines will include alemtuzumab as it has recently been licensed in Canada."

"Will HCT work for progressive MS? I suspect it will have the same effect as other highly active drugs have in MSers with progressive MS; i.e. it will stop focal MRI activity, prevent any superimposed relapses, but it won't necessarily stop the gradual progression that defines this phase of disease. Unfortunately, we don't have enough long-term data on whether or not there is therapeutic lag with BMT/HSC. However, based on the published trials of BMT in progressive MS most MS centres doing BMT have stopped using BMT/HSC in progressive MS and reserve it for treating early relapsing disease. A situation that is not dissimilar to how we use alemtuzumab."


"What is the difference between autologous bone marrow (BMT) and autologous hematopoietic cell (HCT) transplant? In BMT the stem cells are harvested via a bone marrow aspirate and with HCT they are taken from the peripheral blood after they are mobilised from bone marrow using chemotherapy and in some instances growth factors."

A bone marrow aspirate

Epub: Nash et al. High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS): A 3-Year Interim Report. JAMA Neurol. 2014 Dec 29.

Background: Importance Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.

Objective: To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT.

Design, Setting, and Participants: Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.

Interventions: Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.

Main Outcomes and Measures: The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.

Results: Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.

Conclusions and Relevance: At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

HALT-MS is a prospective, open-label, single-arm, multicenter phase 2 clinical trial (clinicaltrials.gov Identifier: NCT00288626).

CoI: multiple; the Royal London Hospital referred patients to the Imperial College Hospital for potential inclusion in this study.

Blocking white blood cell trafficking into the brain

Wu D, Cerutti C, Lopez-Ramirez MA, Pryce G, King-Robson J, Simpson JE, van der Pol SM, Hirst MC, de Vries HE, Sharrack B, Baker D, Male DK, Michael GJ, Romero IA. Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation. J Cereb Blood Flow Metab. 2014 Dec 17. doi: 10.1038/jcbfm.2014.207. [Epub ahead of print]
Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.

MicroRNA are bits of genetic material that can influence the production of  protein from translation of the DNA in genes. We have previously reported that microRNA 155 (miR-155) can inhibit migration of white blood cells across blood vessels (Click here). In this study another Mir...Mir142 does a similar thing, but it blocks nuclear factor kappa B, which is involved in cytokine production and is also a target for some MS drugs.
CoI work of TeamG and chums

Connecting the cerebllum

Romascano D, Meskaldji DE, Bonnier G, Simioni S, Rotzinger D, Lin YC, Menegaz G, Roche A, Schluep M, Pasquier RD, Richiardi J, Van De Ville D, Daducci A, Sumpf T, Fraham J, Thiran JP, Krueger G, Granziera C. Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis. Hum Brain Mapp. 2014. doi: 10.1002/hbm.22698. [Epub ahead of print]

Background: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. Methods: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. 
Results: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, p= 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. 
Conclusion: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage.

Some odd assumptions in the abstract aside ("cerebellar pathology occurs in late multiple sclerosis..."), the findings of this study performed in MSers are line with work by our group using post mortem brain of people who had died with MS (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277890/). 

Using MRI changes are detectable in MS brain tissue outside of lesions, and the substrate of these changes may be early axonal "stress" (e.g. swelling due to changes in the phosphorylation status of neurofilaments).  These "non-lesional" pathological changes in MS remain poorly explained though there is some evidence they occur as a result of lesions elsewhere in the nervous system (retro- or anterograde axonal degeneration). 

Tuesday, 30 December 2014

Statistics

One comment today has asked if we look at the use of  soap and whether this correlates with MS.

I guess the list of possibilities are endless, and if you do enough analysis you will find associations (for some weird ones click here)

We have to be careful how we use statistics

"He uses statistics as a drunken man uses lamp-posts... for support rather than illumination." - Andrew Lang (1844-1912)




ClinicSpeak: the legacy of Debbie Purdy

Imagine being diagnosed with MS and your only reference to the disease is someone in a wheelchair seeking assisted suicide? #ClinicSpeak

"In the UK Debbie Purdy is a household name; she became a MS celebrity for her campaign to decriminalise assisted suicide. Her status in UK society is cemented by the fact that her premature death has been covered by the BBC, Sky News and ITV TV news channels and the Guardian, the Telegraph, the Daily Mail, the Independent and the Mirror newspapers. I am sure many more will have detailed obituaries on Debbie and continue her legacy."

"Although assisted suicide is illegal in the UK it does not stop people travelling to countries where it is legal for help achieving this aim. Prior to Debbie Purdy getting the law changed any family member, or friend, who travelled with someone to be with them when they committed suicide could potentially be charged under British law with murder. The latter is still likely if there are no extenuating circumstances, for example being the recipient of large inheritance would be a potential issue. Debbie Purdy got the law changed; she wanted the option of seeking an assisted suicide abroad and dying with her husband by her side in the knowledge that he would be free of any potential criminal charge on returning to the UK." 

"Debbie Purdy clearly raised the profile of assisted suicide by getting the law changed. There has been an endless debate in the medical community about this issue and the ethical issues it raises for society. At a personal level I have no problem with assisted suicide; I can give you a list of potential scenarios were I may want access to this option for myself. Please note that I only state that 'I may want' access to this option; you can never prejudge how you see things in a particular situation until you are there. As I write this I am acutely aware that in almost all religions assisted suicide is a no go area and I appreciate and respect that perspective. From a professional, or medical perspective, I don't agree with assisted suicide; it is a slippery slope. The dividing line between assisted suicide and euthanasia is a blurred one, particularly if the disease in question, such as multiple sclerosis, affects cognition."

"One of the hardest things I have have done as an MSologist is to prepare medical reports for patients of mine seeking an opinion from Dignitas, the Swiss clinic specialising in assisted suicide. I initially refused to write my first 'Dignitas report' then realised that as the clinician in charge of the particular patient's care it was my duty to write the required medical report. All that Dignitas require is an objective verification of the background medical details. All I do now is write factual reports and state that I am not in a position to make an assessment whether or not the particular patient is of a sound enough mind to make a rational decision about assisted suicide. The latter would need to be done by experts in the field and only after detailed neuropsychological and psychiatric assessments. I assume Dignitas provides this service."

"It is impossible to be a clinician who looks after patients with the primary aim of trying to improve clinical outcomes, and quality of life, to then have to shift into assisted suicide mode to end life. If assisted suicide does become legal in the UK, doctors who take this on would need to be specialists in the area and not part of the teams who look after patients with specific illnesses. In other words patients would need to be referred to a new, an independent, team of healthcare professionals for assisted suicide. Please note the issue of assisted suicide is different from palliative care. Most doctors who are well trained know when to they have lost the battle with an illness and their role becomes palliative; i.e. shifting the focus on making a patient's life comfortable and allowing them to die with dignity in the environment of their choosing."



"What Debbie Purdy did was create the impression in the UK that MS is a terminal illness; it is not. By definition a terminal illness is a disease that has no treatment and leads to death in a short period of time (months). MS has treatments and if MSers are looked after they can expect to have a near normal life expectancy; MS reduces life expectancy by approximately 8-10 years on average. As a result of her celebrity status Debbie Purdy inadvertently became 'the poster child of MS' in the UK. We are continually trying to change that. Imagine being diagnosed with MS and your only reference to the disease is someone in a wheelchair seeking assisted suicide?"

EBV and fatness increase the risk ofMS

Hedström AK, Lima Bomfim I, Hillert J, Olsson T, Alfredsson L.Obesity interacts with infectious mononucleosis in risk of multiple sclerosis. Eur J Neurol. 2014 Dec 20. doi: 10.1111/ene.12620. [Epub ahead of print]
BACKGROUND AND PURPOSE:The possible interaction between adolescent obesity and past infectious mononucleosis (IM) was investigated with regard to multiple sclerosis (MS) risk.
METHODS:This report is based on two population-based case-control studies, one with incident cases (1780 cases, 3885 controls) and one with prevalent cases (4502 cases, 4039 controls). Subjects were categorized based on adolescent body mass index (BMI) and past IM and compared with regard to occurrence of MS.
RESULTS: Regardless of human leukocyte antigen (HLA) status, a substantial interaction was observed between adolescent obesity and past IM with regard to MS risk. The interaction was most evident when IM after the age of 10 was considered (attributable proportion due to interaction 0.8, 95% CI 0.6-1.0 in the incident study, and attributable proportion due to interaction 0.7, 95% CI 0.5-1.0 in the prevalent study). In the incident study, the odds ratio of MS was 14.7 (95% CI 5.9-36.6) amongst subjects with adolescent obesity and past IM after the age of 10, compared with subjects with none of these exposures. The corresponding odds ratio in the prevalent study was 13.2 (95% CI 5.2-33.6).
CONCLUSIONS:An obese state both impacts the cellular immune response to infections and induces a state of chronic immune-mediated inflammation which may contribute to explain our finding of an interaction between adolescent BMI and past IM. Measures taken against adolescent obesity may thus be a preventive strategy against MS.

You were 15 times more likely to get MS if you had infectious mono-glandular fever-kissing disease and were overweight in your youth. Until there is a vaccine for EBV it may be difficult to control infectious mono but with regard to obesity this is modifiable.   

ClinicSpeak: suicidal ideation and suicide in MS

This is a reposting from the 23 March 2014.

How should I address the problem of suicide in MS? #ClinicSpeak #MSBlog #MSResearch

"We know that MSers are at increased risk of suicide; various studies put this risk at between 2 and 7 times the background risk. The study below studies suicidal ideation in MSers and found that at baseline 8% of MSers had suicidal ideation with an increase to 22% within 6 months.Wow 1 in 5 MSers think about suicide within a 6 month period. This much higher than I would have expected. Could the study have primed study subjects to consider suicide as an option? Interestingly being of 65 years of age and been disabled requiring help, predicted suicidal ideation. Not surprising depressive symptoms was also associated with suicidal ideation. I note in this study that gender did not emerge as a risk factor. In previous studies being male was a risk factor."

"How should we use this information in clinical practice? Should we be telling MSers about the increased suicide rate in MSers compared to the general population and people with other chronic diseases? Should we be screening for it on a regular basis using structured questionnaires? It is noteworthy that the ethics committee of the PROXIMUS study have asked us to do regular suicide screening in our study population. I am not convinced this is necessary; MSers who are not depressed may not like being asked about suicide each time they see is in the trial unit. What about assisted suicide in very disabled MSers as part of terminal care? Should we be supporting MSers accessing services that assist with suicide? Assisted suicide is illegal in the UK so many travel to Switzerland for this purpose. I have only one MSer in my care who has registered with Dignitas for this purpose. I had to provide a neutral medical report on their behalf for the clinicians at Dignitas; the report that Dignitas requires is a factual report documenting the diagnosis, level of disability and whether of not the person concerned is mentally competent to make decisions concerning their care. There is no requirement to make a judgement call on whether or not you support assisted suicide or not. When I wrote the report I addressed the report to the patient themselves; I did not feel comfortable writing a report directly to Dignitas. I did not want to be complicit with their decision. I suppose you could argue that because I knew what the report was being used for simply writing it makes me complicit. May be I am a coward? I sincerely hope they never takes up the option of travelling to Switzerland. I suspect they won't they have a very supportive family and is much loved by their partner and children. It has changed the way I manage this patient; I spend much more time with them when they come to clinic and we tend to go walk the extra mile to address quality of health issues; for example respite care for their partner and making sure counselling is ongoing and that their depression is managed as best we can."

"Suicide is difficult topic and may be we should have more open discussions about it as in issue for people with MS. I would appreciate your thoughts on this issue?"



Epub: Viner et al. Prevalence and risk factors for suicidal ideation in a multiple sclerosis population.  J Psychosom Res. 2014 Apr;76(4):312-6. doi: 10.1016/j.jpsychores.2013.12.010. 

OBJECTIVE: To estimate the prevalence, incidence and determinants of suicidal ideation in the MS population.

METHODS: A sample of 188 subjects were randomly selected from a community-based MS clinic registry and participated in as many as 13 interviews over 6 months. Thoughts of "being better off dead" or of "harming oneself" were assessed using item 9 on the Patient Health Questionnaire, Brief (PHQ-9).


RESULTS: At baseline, the 2-week period prevalence of suicidal ideation was 8.3%. Over the course of 6 months, 22.1% of respondents reported having such thoughts at least once. Survival analysis incorporating baseline PHQ-8 scores as a covariate confirmed that being age 65 and over (HR=4.3, 95% CI 1.7-11.3) and having lower quartile self-efficacy ratings (HR=3.5, 95% CI 1.5-8.2) predicted suicidal ideation. Lower levels of task-oriented coping (treated as a continuous variable) also predicted suicidal ideation after adjustment for depressive symptoms (p=0.015), as did self-reported bladder or bowel symptoms (HR=2.6, 95% CI 1.1-6.0) and difficulties with speaking and swallowing (HR=2.9, 95% CI 1.3-6.8). Associations with MS symptoms were not confounded by depressive symptoms.


CONCLUSION: This study identified several potentially modifiable factors that may be useful for preventing suicide in people with MS.


Disclosure: Please note the specific details of the brief case scenario above have been change to make sure the individual patient is unidentifiable.

Monday, 29 December 2014

Debbie Purdy: Right-to-die campaigner dies



Debbie Purdy (c. 1963 – 23 December 2014) was a British political activist from Bradford, West Yorkshire, with primary progressive MS, notable for her challenge to the law in England and Wales as relates to assisted suicide

Debbie wanted choice and control over her death should she consider her suffering unbearable. She was seeking peace of mind that her wishes would be respected, but also crucially that her decisions would not result in the potential imprisonment of her husband. She rallied against the hypocrisy of the current law, which turns a blind eye to people travelling abroad to die, whilst threatening the imprisonment of their loved ones after their death.

On 20 September 2009, it was announced that guidelines on assisted suicide law would be published by the UK Government. The Director for Public Prosecutions reported 16 factors which would tend to lead to prosecution of those who helped with a suicide. However, it still remains an offence to encourage or assist a suicide or a suicide attempt in England and Wales.

Will this change?  I suspect it is a matter of time. 

Our thoughts go out to her friends and family

Cannabinoids as neuroprotectants

#MSreseach. Treatment of progressive MS. Lost opportunity

Gareth Pryce, Dieter R. Riddall, David L. Selwood, Gavin Giovannoni, David BakerNeuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. Journal of Neuroimmune PharmacologyDecember 2014

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.
The biology of the cannabinoid system indicates that it should exert a neuroprotective effect and this can be seen in many, many experimental models. We have been looking at symptom control and we could find evidence for THC within cannabis and the CB1 cannabinoid receptor mediated effects. We have also found that these two components can mediate a neuroprotective effect and they can do this by many different mechanisms.

However, until now we have not found any use for cannabidiol, which is major non-phycoactive compound within some strains of cannabis.  In this study we find that cannabidiol can protect nerves from inflammatory damage in experimental animal models of MS, possibly via blocking ion channel activity.

Likewise, so could tetrahydrocannabinol (THC). However, the mixture (as in sativex) of cannabidiol and tetrahydrocnnabinol  was not additive and appeared worse than the individual compounds. 

It has been argued that cannabidiol blocks the psychoactive effects of THC maybe it does and maybe it blocks the beneficial effects of THC...you can't have it both ways.

But what happened in MS, The trial of THC (CUPID) in progressive MS as a neuroprotectant was considered a failure. Thus binning years of basic science work.

The placebo group did not progress as expected..maybe the placebo effect of being on a trial. However many people in the trail were using walking aids but it is those people less affected that progress the quickest and when planned subgroup analysis was done there was indeed a significant neuroprotective effect of THC. We got the trial data and can confirm this

So here you have another potential treatment that works in progressive MS....Now what?.....Sadly nothing.

This trial involved over 600 MSers and took 6-7 years to do. There is no enthusiasm to do it again. Likewise who is going to pay for another study. I suspect no one 

The original CAMS trial in 2003 for symptom control of cannabis failed, but they adapted their trial protocol and in 2012 the MUSEC study succeeded.  Throughout out history of MS pioneering trails have failed, such that neuros learn and are more likely to finding something that works next time.

To repeat a symptom control trial lasting a few weeks is different for a trial taking years to do. Sadly the CUPID did not attempt to repeat the CAMS extension data that also showed a treatment effect of THC so we will never know if these results were real or a fluke. Likewise, sadly we will not know if the positive data in the CUPID study was real or a fluke.

In the USA, medical marijuana is becoming increasingly available...and this study will no doubt help justify the claims from the suppliers for some benefit. "Hey they don't need real proof of benefit because they know it does everything...too much sampling of their own wares I suspect :-)".  However, will a study be done I doubt it. With access to pot for a few dollars, no-one is going to want to pay hundred for sativex, even if it did become available in USA . Likewise who would want to take a placebo in a trial when they could get the real thing . 

So the history books will simply state that cannabinoids are no good for neuroprotection.....sadly this one that got away. 

CoI. TeamG did this work

Autoimmunity and MS

Marrie RA, Reider N, Cohen J, Stuve O, Sorensen PS, Cutter G, Reingold SC, Trojano M. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis.
Mult Scler. 2014 Dec . pii: 1352458514564490. [Epub ahead of print]

BACKGROUND:As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS).
OBJECTIVE: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS.
METHODS:The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies.
RESULTS: Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid.
CONCLUSION: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide.

One of the major side effects of Lemtrada isthe development of secondary B cell mediated autoimmunities and this occurs in about 20-50%  of people. This study looks to see if these occur independent of Lemtrada treatment and it can be seen in a low number of MSers. Psoriasis is not the main autoimmunity after Lemtrada but thyroid problems.

Neurospeak Posts

Sunday, 28 December 2014

ClinicSpeak: exercise the next big thing in neurodegenerative disease

Exercise therapy; will it work in MS? #MSBlog #MSResearch #ClinicSpeak

"Exercise is the next big thing in neurodegenerative diseases. It looks as if exercise delays the onset of age-related neurodegenerative diseases. It may have a similar effect in MS. Hence the interest in using exercise as a treatment for MS; to improve symptoms and possibly as a disease-modifying therapy to delay the onset of clinically-apparent progressive MS and to slow the rate of progression. The abstract below describes a randomised controlled trial that has started in Ireland to assess the impact of exercise on MS."

"How does exercise work? Firstly, it conditions you and as a result improves your overall health. As a result you feel better. Exercise also stimulates the production of endorphins in the brain that act as anti-depressants. In addition, it causes the production of growth factors, in particular IGF-1 (insulin-like growth factor-1) that may be neuroprotective. People who exercise regularly sleep better and generally not improved quality of life."

"We recommend to all our patients to try and engage in an active exercise programme. Even patients who are disabled can do exercise; physiotherapists are very good at designing exercise programmes if have a disability. Exercise is a core component of the brain health initiative that many public health doctors are beginning to promote at a National level to deal with the incipient dementia epidemic in developed countries."


If you live in Ireland you may be eligible for this study; please checkout the eligibility criteria here. You can also contact the PIs who are running the trial:

Contacts: Susan Coote, PhD, +35361234278, susan.coote@ul.ie   
Contact: Sara Hayes, PhD, +35361234861, sara.hayes@ul.ie   

Epub: Coote et al. A randomised controlled trial of an exercise plus behaviour change intervention in people with multiple sclerosis: the step it up study protocol. BMC Neurol. 2014 Dec 21;14(1):241.

Background: Exercise has consistently yielded short-term, positive effects on health outcomes in people with multiple sclerosis (MS). However, these effects have not been maintained in the long-term. Behaviour change interventions aim to promote long-term positive lifestyle change. 


Aims: This study, namely, "Step it Up" will compare the effect of an exercise plus Social Cognitive Theory (SCT)-based behaviour change intervention with an exercise plus control education intervention on walking mobility among people with MS.

Methods/design: People with a diagnosis of MS who walk independently, score of 0-3 on the Patient Determined Disease Steps, who have not experienced an MS relapse or change in their MS medication in the last 12 weeks and who are physically inactive will be randomised to one of two study conditions. The experimental group will undergo a 10-week exercise plus SCT-based behavioural change intervention. The control group will undergo a 10-week exercise plus education intervention to control for contact. Participants will be assessed at weeks 1, 12, 24 and 36. The primary outcome will be walking mobility. Secondary outcomes will include: aerobic capacity, lower extremity muscle strength, participant adherence to the exercise programme, self-report exercise intensity, self-report enjoyment of exercise, exercise self-efficacy, outcome expectations for exercise, goal-setting for exercise, perceived benefits and barriers to exercise, perceptions of social support, physical and psychological impact of MS and fatigue. A qualitative evaluation of Step it Up will be completed among participants post-intervention.

Discussion: This randomised controlled trial will examine the effectiveness of an exercise plus SCT-based behaviour change intervention on walking mobility among people with MS. To this end, Step it Up will serve to inform future directions of research and clinical practice with regard to sustainable exercise interventions for people with MS. 

Trial registration ClinicalTrials.gov: NCT02301442.

Tai Chi for Balance

Azimzadeh E, Hosseini MA, Nourozi K, Davidson PM. Effect of Tai Chi Chuan on balance in women with multiple sclerosis. Complement Ther Clin Pract. 2014 . pii: S1744-3881(14)00063-2. doi: 10.1016/j.ctcp.2014.09.002. [Epub ahead of print]

OBJECTIVE:To examine the effect of Tai Chi Chuan on balance in women with multiple sclerosis in Iran.
DESIGN: 36 women with multiple sclerosis who were members of the Iranian Multiple Sclerosis Society participated in this study. 18 participants were allocated to the intervention group and 18 allocated to the control group. The intervention consisted of Yang style Tai Chi Chuan exercise sessions twice a week for 12 weeks.
MAIN OUTCOME MEASURES: This study used a demographic questionnaire and the Berg Balance Scale (BBS) to collect data.
RESULTS: After 12 weeks, the mean score of the BBS in the intervention group demonstrated a statistically significant improvement in comparison with baseline status.
CONCLUSIONS: The results suggest that Tai Chi Chuan could be used as a safe complementary intervention to increase balance in patients withmultiple sclerosis.


This small study examined Tai Chi on balance using the Berg Balance Scale

The Berg Balance Scale (BBS) was developed to measure balance among older people with impairment in balance function by assessing the performance of functional tasks. It is a valid
instrument used for evaluation of the effectiveness of interventions and for quantitative descriptions of function in clinical practice and research. 

Description:
14-item scale designed to measure balance of the older adult in a clinical setting.
Equipment needed: Ruler, two standard chairs (one with arm rests, one without),
footstool or step, stopwatch or wristwatch, 15 ft walkway

Completion Time: 15-20 minutes

Sitting to standing 
Standing unsupported 
Sitting unsupported 
Standing to sitting 
Transfers 
Standing with eyes closed 
Standing with feet together
Reaching forward with outstretched arm 
Retrieving object from floor
Turning to look behind
Turning 360 degrees 
Placing alternate foot on stool
Standing with one foot in front
Standing on one foot

Scoring: A five-point scale, ranging from 0-4. “0” indicates the lowest level of function and “4” the highest level of function. Total Score = 56

Interpretation: 41-56 = low fall risk
                        21-40 = medium fall risk
                         0 –20 = high fall risk

A change of 8 points is required to reveal a genuine change in function between 2 assessments


Saturday, 27 December 2014

Botox for bladder is cost effective

Hamid R, Loveman C, Millen J, Globe D, Corbell C, Colayco D, Stanisic S, Gultyaev D.Cost-Effectiveness Analysis of OnabotulinumtoxinA (BOTOX) for the Management of Urinary Incontinence in Adults with Neurogenic Detrusor Overactivity: A UK Perspective. Pharmacoeconomics. 2014. [Epub ahead of print]

OBJECTIVES:To evaluate the cost effectiveness of BOTOX, 200 units [200 U]) for the management of urinary incontinence (UI) in adults with neurogenic detrusor overactivity (NDO) due to subcervical spinal cord injury or multiple sclerosis that is not adequately managed with anti-cholinergic drugs (ACHDs).
METHODS: A Markov model was developed, which compared onabotulinumtoxinA + best supportive care (BSC) with BSC alone (comprising behavioural therapy and pads, alone or in combination with clean intermittent catheterization and possibly with ACHDs). Non-responders were eligible for invasive procedures. Health states were defined according to the reduction in UI episodes. Efficacy data and estimates of resource utilization were pooled from 468 patients on onabotulinumtoxinA in two phase III clinical trials. Drug costs (2013) and administration costs (NHS Reference Costs 2011-2012) were obtained from published sources. The time horizon of the model was 5 years.
RESULTS: In the base case, treatment with onabotulinumtoxinA + BSC over 5 years was associated with an increase in costs of £1,689 and an increase in quality-adjusted life-years (QALYs) of 0.4, compared with BSC alone, resulting in an incremental cost-effectiveness ratio of £3,850 per QALY gained. Sensitivity analyses showed that utility values had the greatest influence on model results. PSA suggests that onabotulinumtoxinA + BSC had a 100 % probability of being cost effective at a willingness to pay of <£20,000.
CONCLUSION: For adult patients with NDO who are not adequately managed with ACHDs, onabotulinumtoxinA + BSC appears to be a cost-effective use of resources in the UK NHS.
BoTox is cost-effective for treating bladder problems

CoI: BoToxmay compete against our compound in development

ClinicSpeak: NEDA at 7-years

Has NEDA come of age? #ClinicSpeak #MSBlog #MSResearch

"Good and bad news? The good news is if you go onto a DMT and have NEDA (no evident disease activity) at 2-years it is predictive of a good disability outcome at 7 years (no disease progression). The bad news is that only a minority (8%) of MSers are rendered NEDA at 7-years. The problem with the analysis in this paper is that they did not rebaseline subjects and used the baseline MRI scan as the reference scan. We have now shown across many data sets that DMTs take many months to start working and NEDA rates improve dramatically if you rebaseline using a 6 or 12 month MRI assessment. Disease activity that occurs within the first few months of starting a DMT should not be interpreted as a non-response to the specific DMT. When you look at the survival curves of NEDA in this paper about 50% fail in the first 12 months; therefore, I suspect that the 8% NEDA rate at 7-years will be a lot better if NEDA is redefined using the 12 month scan as the baseline. Some critics would argue that NEDA is too stringent treatment target and we should not aim for it but instead settle for a MEDA (minimal evidence of disease activity). I am against the latter, particularly since we know that a lot of disease activity occurs below the threshold of or current measurement tools and once damage accumulates in MS it tends to be irreversible, i.e. time is brain. In addition, if we have more effective treatments and if the disease is not be controlled on less effective DMTs why wait to offer the patient the option of escalating  to more effective treatments? I envisage some patients saying no as the risks associated with the more effective treatments may be unacceptable, some may want to be extending or starting a family and prefer the DMTs with a good safety profile in pregnancy and others may not accept NEDA as a treatment target. Yes, believe it or not, not all MSers are accepting of NEDA as a treatment target."

"The good news is that neurologists are beginning to move towards NEDA as a treatment target. We are therefore beginning to adopt the approach rheumatologists pioneered for treating rheumatoid arthritis (RA) to MS. I am certain that with this approach we may prevent, or at least delay, the need for canes (EDSS 6.0), chairs (EDSS 7.0) and beds (EDSS 8.0) and at the same time improve quality of life of MSers substantially. A long time before MSers needs a cane they have problems with bladder, bowel and sexual function, fatigue, depression, anxiety and cognitive problems. The real burden of MS at least early on are the hidden symptoms of the disease. May be our focus should be on these instead of our fixation in mobility problems that typically comes on later?"


Epub: Rotstein et al. Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort. JAMA Neurol. 2014 Dec 22.

IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.

OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).

DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).

MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.

RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.

CONCLUSIONS AND RELEVANCE: NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

CoI: multiple

Friday, 26 December 2014

Saving Nerves if People take their drugs

Gnanapavan S, Grant D, Morant S, Furby J, Hayton T, Teunissen CE, Leoni V, Marta M, Brenner R, Palace J, Miller DH, Kapoor R, Giovannoni G. Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression.PLoS One. 2013 Aug 1;8(8):e70019. doi: 10.1371/journal.pone.0070019.

OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.
METHODS:SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.
RESULTS:Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.
CONCLUSIONS:The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.


In response to a comment posted yesterday, I was hunting for this post on the blog but could not seem to find it, so I post it again. 

As it will help with the Altimetrics ...Ho Ho.

What does this study say well if you talk to any neuro they will tell you that Lamotrigine was tried in progressive MS and it failed.


What this study does is test to see whether people on the trial were taking their drugs. So they looked at the packets of pills and they could see that 40% of people weren't taking their pills and then they measured the blood and found that 50% of people were not taking their meds.  The original animal work reporting a beneficial effects was poo-pooed by the neuros because the trial failed...so how would a trial ever work when only 50% of people were not taking their drugs? So the solid basic science gets binned because of dodgy clinical work.

The reason why people were not taking their meds is probably because of side effects.

However if you look at nerve proteins in the blood in the people who took their drugs verses those that didn't and you got a significant difference. There was less nerve proteins in people taking their drugs....suggesting less nerve damage (which would release the nerve proteins so they could be picked up in the blood).
This suggests that maybe Lamotrigine was slowing nerve loss

This suggests that the basic science was not such a load of bollony. However the failed trial, will doom development. However, we have taken other drugs in this class to see if they can protect nerves from damage. This is the basis of the PROXIMUS trial that we are doing.

What does the future hold for PPMS?

Do we need to rethink PPMS?  #MSBlog #MSResearch

“Now that the INFORMS (fingolimod) PPMS trial was negative we will have to rethink PPMS. It is clear that fingolimod, which is an anti-inflammatory with a potential neuroprotective effect, was not good enough. Is this because PPMS is not inflammatory? No, PPMS is very inflammatory; I have previously discussed the post-mortem findings of PPMS in comparison to SPMS. However, the type of inflammation in PPMS may be qualitatively different; i.e. the contribution of focal inflammatory lesions that cause relapses and new MRI lesions is less important in PPMS. What may be more relevant is the downstream activation of innate immunity, in particular microglia and macrophages; the hot microglial hypothesis."

"I hypothesise that we will need to tackle PPMS with combination therapies; i.e. a combination of drugs that tackle focal inflammation (e.g. fingolimod), innate immune activation (e.g. laquinimod), a neuroprotective (e.g. oxcarbazepine) and possibly a drug that targets anti-ageing mechanisms (e.g. simvastatin). Why anti-ageing? Age is the most powerful predictor of the onset of non-relapsing progression in MS. There is evidence that inflammation in the brain and spinal cord cause premature ageing and that what we are seeing clinically is age-related neurodegeneration. If this is the case we will need a whole new approach to progressive MS. The MS-STAT trial was very informative; it showed a positive impact of simvastatin in non-relapsing SPMS with a signal that was present in year 1 and year 2 of similar magnitude. If Simvastatin was working on MS-related mechanisms I would have anticipated a therapeutic lag, i.e. no or little impact in year 1 and a larger impact in year 2. The fact that no therapeutic lag was observed suggests the statin is working on non-MS mechanisms; i.e. on other disease-related mechanisms for example secondary vascular pathology. If I was running a drug development programme for a Pharma company I would seriously looking at these results and thinking how can we develop a combination pill to tackle non-relapsing progressive MS? I am also seriously considering starting taking the polypill, a cocktail of drugs that includes simvastatin, to prevent vascular disease and implementing all the other lifestyle changes to promote brain health."

"If you have PPMS please try and not get despondent; the INFORMS trial may have been negative but we will learn from it and move forward. The next results to report will be the ocrelizumab PPMS trial and following that the laquinimod PPMS trial. Ocrelizumab is likely to be a more potent anti-inflammatory than fingolimod and it is more likely to target the B cell response within the brain and spinal cord. Some in the field feel that the latter is one of the biggest drivers of progressive MS. Laquinimod is a very interesting drug and targets the hot microglia. The question is will ocrelizumab and laquinimod be good enough as monotherapies? I sincerely hope they are; PPMSers need a break.”



CoI: multiple, I sit on the steering committees of both the ocrelizumab and laquinimod PPMS trials.

Prognosis of MS

Kerbrat A, Hamonic S, Leray E, Tron I, Edan G, Yaouanq J; within the West Neuroscience Network of Excellence (WENNE).Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients.
Eur J Neurol. 2014. doi: 10.1111/ene.12600. [Epub ahead of print]BACKGROUND AND PURPOSE:

Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort.
METHODS: A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected.
RESULTS: In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6.
CONCLUSION(S): Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive-onset MS group. This finding impacts the prognosis given to patients in clinical practice.
This study indicates that PPMSers do worse than RRMSers in terms of accumulating disabilty 10 years after first symptoms. This is perhaps not surprising such that PPMSers often start their MS journey later than RRMSers and there are some studies suggesting that progression in RRMSers and PPMSers start at about the same age but RRMSers get diagnosed about 10 years earlier. If you have used DMT you do better, so betweeen to do something rather than nothing.

Thursday, 25 December 2014

6th Research Day

     The Advent Calender served to announce the 6th Research Day
          Alison has been working behind the Scenes and She will                                  update this very soon.

Advent Calendar-25

Advent calendars normally end on the 24th ready for Christmas Eve.

Our Advent Calendar was to advertise our research day on March 21st 2015 in Central London and showed how we are trying to develop drugs for symptom control in the process.


It just leaves us to say have a Happy Christmas day....

What are you doing looking at the Computer? You should be tucking into some Christmas Pub and Turkey
If you don't celebrate Christmas happy holidays.

Wednesday, 24 December 2014

The need for better treatments for spasticity

Vermersch P. MObility ImproVEment with spasticity in multiple sclerosis in Europe: the MOVE 1 EU study.Neurodegener Dis Manag. 2014 Dec;4(6):407-415.
SUMMARY  Aim: using a protocol similar to that of the MOVE 1 study in Germany, the multicenter, observational MOVE 1 EU study examined the burden of multiple sclerosis (MS)-related spasticity in other EU countries (Belgium, Finland, France, Ireland, Norway, Poland and Portugal). Materials & Methods: A 12-month retrospective chart documentation was combined with questionnaires for physicians and patients at the time of enrollment. A total of 281 patients from neurology departments and MS units formed the per protocol population. 
Results: in most patients, MS spasticity frequently restricted daily activities and caused some/moderate problems in EQ-5D subdomains of mobility, usual activities and pain/discomfort. Overall, 48% of physicians and 34% of patients were at least partly dissatisfied with the effectiveness of available pharmacotherapy options for MS spasticity. 
Conclusion: Results of the MOVE 1 Germany and MOVE 1 EU studies are aligned and highlight the need to optimize the therapeutic management of patients with MS spasticity across Europe so as to improve their overall well-being and quality of life.

This survey shows that you need better treatment or treatment strategies for the treatment of spasticity.

CoI Please look at the 2014 Advent Calendar

Remyelination with Citicoline

Skripuletz T, Manzel A, Gropengießer K, Schäfer N, Gudi V, Singh V, Salinas Tejedor L, Jörg S, Hammer A, Voss E, Vulinovic F, Degen D, Wolf R, Lee D, Pul R, Moharregh-Khiabani D, Baumgärtner W, Gold R, Linker RA, Stangel M. Pivotal role of choline metabolites in remyelination. Brain. 2014 Dec. pii: awu358. [Epub ahead of print]

Neuroprotective approaches for central nervous system regeneration have not been successful in clinical practice so far and compounds that enhance remyelination are still not available for patients with multiple sclerosis. The objective of this study was to determine potential regenerative effects of the substance cytidine-5'-diphospho (CDP)-choline in two different mouse animal models of multiple sclerosis. The effects of exogenously applied CDP-choline were tested in mouse myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. In addition, the cuprizone-induced mouse model of de- and remyelination was used to specifically test the hypothesis that CDP-choline directly increases remyelination. We found that CDP-choline ameliorated the disease course of experimental autoimmune encephalomyelitis and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, CDP-choline effectively enhanced myelin regeneration and reversed motor coordination deficits. The increased remyelination arose from an increase in the numbers of proliferating oligodendrocyte precursor cells and oligodendrocytes. Further in vitro studies suggest that this process is regulated by protein kinase C. We thus identified a new mechanism to enhance central nervous system remyelination via the choline pathway. Due to its regenerative action combined with an excellent safety profile, CDP-choline could become a promising substance for patients with multiple sclerosis as an add-on therapy.


Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids. Citicoline serves as a choline donor in the biosynthetic pathways of acetylcholine and neuronal membrane phospholipids, mainly phosphatidylcholine. This study suggests that it can promote remyelination. In EAE  there was an anti-inflammatory effect and less disease was accumulated and faster remyelination occurred in a chemical demyelination model. This molecule has been implicated as a neuroprotectant in other studies so could be a new tool to promote repair. But can this be translated.

Advent Calendar-24

So this is it for our drug development programme, we started with an idea and a number of years later we are ready to try treat  multiple sclerosis.

So you have your trial design and you eligibility criteria and you are ready for doing a phase II study in people with MS. This is to test the efficacy of the drug and also to check safety.
If (let's be hopeful and say when) this works then we are ready for the next step, so we will have to raise funds to do the pivotal Phase III trials.

This is the basis process that pharma will do to develop drugs to you. This is the end of our story so far.

When will ours be ready to go...Sometime in early 2015

CoI We are developing a drug for symptom control

Tuesday, 23 December 2014

Advent calendar-23

So we are on our journey of drug development and if you are pharma doing studies you have the resource to seamlessly go from trial to trial, but when academics do it they have to raise funds at each stage of the game so you have to go back to funders or investors or hope that pharma take up the gauntlet.

 These usually investors drive a hard bargain
Pass this and you are on the home straight.

CoI We are attempting to develop a drug for people with MS

Frankincense and cognition

Sedighi B, Pardakhty A, Kamali H, Shafiee K, Hasani BN Effect of Boswellia papyrifera on cognitive impairment in multiple sclerosis. Iran J Neurol. 2014 Jul 4;13(3):149-153.PMID: 25422734 [PubMed - as supplied by publisher]

Background: Cognitive impairment is one of the most crucial disorders among multiple sclerosis (MS) patients. Since MS is an inflammatory disease and Boswellia papyrifera has anti-inflammatory effects, the influence of B. papyrifera on cognitive impairment in MS patients has been investigated in the present study. 

Methods: In this clinical trial, 80 MS patients who referred to the clinic of Shafa Hospital, Kerman, Iran were selected. Having completed a written consent form, patients with relapsing remitting MS, with no occurrence of a new attack throughout 1 month before the study, with no pregnancy or breastfeeding entered the study. The patients were randomly divided into two groups; then Brief International Cognitive Assessment for MS (BICAMS) test was carried out. One group received B. papyrifera (capsule 300 mg, twice a day) while the other group received placebo with the same dose for 2 months. After 2 months of treatment, BICAMS was redone and changes were analyzed. The significant change value on the before-after BICAMS points were considered to be 8, 13, and 7 points for the symbol digit modality test (SDMT), the California verbal learning test (CVLT), and the brief visual-spatial memory test revised (BVMT-R), respectively. 
Results:  In the BVMT-R, 13 patients (34.2%), who had already taken B. papyrifera, were shown to have significant improvement compared to the placebo group with no improvement (P < 0. 001). 
About 12 and 8 patients in the treatment and placebo groups in the SDMT, respectively (P = 0.200) and 17 and 12 patients in the treatment and placebo groups in the CVLT, respectively (P = 0.170) had significant change values. Conclusion: B. papyrifera showed significant improvement in visuospatial memory, but had no effect on verbal memory and information processing speed.

The Boswellia plant is the source of Frankincense, which the Three Kings brought to JC. This study asks if it can improve cognitive performance. So this study suggests that 13 people on active compound and none of the people had some improvement, I guess it means about three quarters showed no change, sowe best wait and see if this is repeated.

CoI: None

Monday, 22 December 2014

ClinicSpeak: What is the definition of high versus low lesion load on MRI?

Time is brain: what is a high-lesion load on MRI? #ClinicSpeak #MSBlog #MSResearch

"In response to a question from yesterday; what is the definition of a high lesion load on MRI? This is based mainly on data from the so called Queen Square CIS (clinically-isolated syndrome) cohort. These CISers had MRI at baseline and have been followed for over 20 years. The picture below show  a survival analysis of time to EDSS 3.0 or higher (non-benign MS); it is clear the CISers with more than 10 lesions do worse. CISers with no lesions at baseline do the best with very few becoming disabled; in fact 80% of this group never go onto develop MS and hence are unlikely to have MS."


"What is the difference between a CISer sith say 2 lesions at baseline and somebody with 20 lesions? Almost certainly the person with 20 lesions has had the disease longer, with a longer asymptomatic period during which time subclinical inflammation has been shredding their reserve capacity, hence the poorer prognosis on average. Another way of looking at this data is that someone with CIS who presents with a low lesion load is luck in that one of their initial or early lesions has caused symptoms before too much damage has occurred allowing them the possibility of starting DMTs early and giving them a greater chance of becoming NEDA. This strategy of using DMTs as a preventative treatment to preserve reserve capacity and delay all subsequent disability outcomes is not practiced by all; many MSologists, particularly in  the UK, would prefer to allow CISers or MSers to acquire more lesions before starting DMTs. These MSologists often quote that many MSers turn-out to have benign disease hence we need to wait for their disease to progress before treating them. The problem with this argument is that the damage that is acquired whilst waiting is irreversible, reduces reserve capacity and hence shortens their time to future disability end-points. In addition, benign MS is a moving target; the longer you follow benign MSers the smaller the proportion who remain benign."

"So if  you have more than 10 lesions at baseline this is generally considered a high lesion load. The lesion load does not tell the whole story. Some lesions are more destructive than others; the destructive lesions leave behind black holes on the so called T1-weighted scans. Similarly, lesions occurring in the posterior fossa or back of the brain cause more disability than those in the so called superior tentorial compartment of the brain. Active lesions, i.e. those with gadolinium enhancement are also associated  with a poorer outcome compared to inactive lesions. Finally, if there is already end-organ damage with overt brain atrophy this is associated with a poorer prognosis. Therefore, assessing prognosis on MRI is more complicated  than simply counting the lesions."

Table of poor baseline prognostic factors on MRI

  1. High-lesion load (>10 lesions on T2-weighted images)
  2. Presence of gadolinium-enhancing lesions
  3. Posterior fossa lesions
  4. Hypointense lesions on T1-weighted images (black holes)
  5. Overt brain atrophy (end-organ damage) 
"If you have any questions about your MRI scans you should ask your neurologist to go through them with you. Please note if you have a bland looking baseline MRI, with a good prognostic profile, you should consider yourself lucky in that your MS has presented at an early stage before you have acquired any damage. This means that with appropriate monitoring and/or treatment you can potentially preserve your brain's reserve capacity. On the other hand if you have a poor baseline MRI prognostic profile you will need to take your treatment decisions more seriously and have less time to play with. Please remember the dictum 'Time is Brain'."

CoI: multiple