Tuesday, 13 October 2015

Diaries to be published

White knight second class

       Not long to wait now

ClinicSpeak: MS masquerading as a dementia

Dementia another MS mimic. #ClinicSpeak #MSResearch #MSBlog #ECTRIMS2015

"About 3 years ago we started a campaign to rebrand MS a dementia. The reason for this was to get people to think about MS as a cognitive disease that can be disabling long before it causes physical disability. The 50% European unemployment rate in MSers before they become physically disabled is driven by cognitive fatigue, depression and anxiety; symptoms which are all a manifestation of gray matter or cortical disease. When I presented the concept of MS being a 'preventable dementia' at the EMA MS taskforce meeting I was chastised by several colleagues. One said to me that it would be unhelpful to focus on the cognitive impact of MS; people with MS don't need to know this. Another said the term dementia was too stigmatizing. I had to remind this individual that I deliberately used the term 'preventable dementia' rather than 'irreversible dementia' and that if we treated MS early and effectively we would almost certainly change things. This issue is very timely in view of the emerging data showing that early cognitive impairment is the best predictor of poor outcome in MS and the focus on end-organ damage or brain atrophy."

"The case study below illustrates the extreme example of MS being a dementia. The authors' describe a patient who was diagnosed as having Alzheimer's disease in life who turned out to have a multiple sclerosis at post-mortem. I have a handful of cases not too dissimilar to this case report, who have been referred to me from memory clinics with a diagnosis of possible MS. These patients typically present with cognitive symptoms and when they have an MRI scan they have lesions consistent with demyelination."

"The upside of the MS dementia campaign is that it may have helped with alemtuzumab getting a first-line license in Europe. I think the EMA rapporteur for alemtuzumab grasped the importance of treating MS effectively and early. If you have active MS why would you not at least want to have the option of the most effective therapy first-line? You can either say yes, no or maybe! It is all about choice. With major caveats that I have mentioned before the 5-year alemtuzumab brain atrophy data presented at ECTRIMS vindicates the EMA's decision. Let's hope my cynical hypothesis about reversal of pseudo-atrophy is wrong about the alemtuzumab brain atrophy data and that the data truly reflects optimised brain health from a DMT perspective. I remain concerned that some of the alemtuzumab brain atrophy data is confounded by a proportion of brains swelling as MS-related inflammation returns. This is why I question whether or not the data are too good to be true. As this is a hypothesis we can test it with further data analysis or a new deep phenotyping study."

"After the EMA MS taskforce meeting one very prominent neurologist told me a personal anecdote. In his very eminent career he had looked after numerous patients with MS who became demented and eventually ended up living in nursing homes, but had ended up being very happy and content with their lives due to their dementia. In his opinion they had ended-up with a very good quality of life. He felt the graph I had shown correlating poor quality of life with disability did not tell the whole story. He made the point that if  he had treated these patients 'aggressively early on', they way I had proposed in my talk, that several of them may have died of adverse events from the treatment and that these patients would have been denied the right to live out their lives albeit in a nursing home with dementia. The latter is an interesting take, albeit an old one, on the doctor-patient relationship. I wonder if MSers today would relate to this attitude?"

"The following are the results of the survey we ran on this blog to support our campaign. Although the survey is not 'scientific' they tell a compelling story."

Tobin et al. Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings. Mult Scler. 2015. pii: 1352458515604382.

BACKGROUND AND OBJECTIVES: We report a comprehensive clinical, radiological, neuropsychometric and pathological evaluation of a woman with a clinical diagnosis of AD dementia (ADem), but whose autopsy demonstrated widespread demyelination, without Alzheimer disease (AD) pathology.

METHODS AND RESULTS: Initial neuropsychometric evaluation suggested amnestic mild cognitive impairment (aMCI). Serial magnetic resonance images (MRI) images demonstrated the rate of increase in her ventricular volume was comparable to that of 46 subjects with aMCI who progressed to ADem, without accumulating white matter disease. Myelin immunohistochemistry at autopsy demonstrated extensive cortical subpial demyelination. Subpial lesions involved the upper cortical layers, and often extended through the entire width of the cortex.

CONCLUSIONS: Multiple sclerosis (MS) can cause severe cortical dysfunction and mimic ADem. Cortical demyelination is not well detected by standard imaging modalities and may not be detected on autopsy without myelin immunohistochemistry.

CoI: multiple

Digesting Science course for kids aged 6-12 years Oct 24th

Digesting Science is our educational event for children aged 6-12 years old with a parent with MS. Our next event date is Saturday the 24th October and registration is now open!

We've been running the event for over 2 years and the feedback has been incredibly positive from both parents and children. At the course families have the opportunity to meet our team and learn about what happens in the body with MS. The event is held in Whitechapel and is facilitated by a drama teacher with the practical learning activities led by scientists from Queen Mary University of London. 

The event starts at 10am and ends by 12.30pm and we have a short break half way through where we will provide refreshments.

If you, and your family are interested in attending, please sign up through eventbrite: https://www.eventbrite.com/e/digesting-science-tickets-14572210875

We also have funding to cover travel expenses if this is an issue. We space for 5 families to attend so please get in touch soon!

You can see what topics are discussed on the day from the event website:www.digestingscience.co.uk

No association of EBV and tobacco use

Munger KL, Fitzgerald KC, Freedman MS, Hartung HP, Miller DH, Montalbán X, Edan G, Barkhof F, Suarez G, Radue EW, Sandbrink R, Kappos L, Pohl C, Ascherio A. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT.Neurology. 2015 Oct 9. pii: 10.1212/WNL.0000000000002099. [Epub ahead of print]
OBJECTIVE:To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS).
METHODS: In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type.
RESULTS: We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76-1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71-1.31) for cotinine levels >25 ng/mL vs <10.
CONCLUSIONS: Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up.
So we always here of this activity or that activity correlating with MS susceptibility, but here is a nagative study on smoking and EBV to counter the many other studies going the other way, These risks what ever only hae a small infleunce on risk.

Giovannoni Mobile

When you are are a head honcho at ECTRIMS you get the VIP
Was it going to a company business meeting or Uma?

My spies say the former...no wonder their drugs are so expensive:-)

We had to walk everywhere:-(

Spotting a relapse on copaxone - the era of personalised medicine

Kruszewski AM, Rao G, Tatomir A, Hewes D, Tegla CA, Cudrici CD, Nguyen V, Royal W 3rd, Bever CT Jr, Rus V, Rus H.

RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate inmultiple sclerosis.

Exp Mol Pathol. 2015. pii: S0014-4800(15)00199-9.


Currently there is critical need for the identification of reliable biomarkers to help guide clinical management of multiple sclerosis (MS) patients. We investigated the combined roles of Response Gene to Complement 32 (RGC-32), FasL, CDC2, AKT, and IL-21 as possible biomarkers of relapse and response to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients was clinically monitored and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12months. Target gene mRNA expression was measured in patients' isolated PBMCs by real-time qRT-PCR. Compared to stable MS patients, those with acute relapses exhibited decreased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), increased expression of IL-21 (p=0.04), but no change in CDC2 or AKT. Compared to non-responders, responders to GA treatment showed increased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), and decreased expression of IL-21 (p=0.02). Receiver operating characteristic (ROC) analysis was used to assess the predictive accuracy of each putative biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to GA was 85% for RGC-32, 90% for FasL, and 85% for IL-21. Our data suggest that RGC-32, FasL, and IL-21 could serve as potential biomarkers for the detection of MS relapse and response to GA therapy.

All drugs lead to changes in the physiology of your body through their action, but in some individuals the inaction itself can be telling. By categorizing responders and non-responders to a treatment, you can look for unique patterns in the two groups in order to determine those who are most likely to respond to your treatment.

RGC-32 is a cell cycle regulator and is expressed on T cells and in the brain. It regulates FasL and IL-21 levels. FasL is a member of the tumour necrosis family and induces cell destruction, whilst IL-21 is a cytokine that regulates the action of immune cells.

During acute MS relapse compared to the remission phase leads to a reduction in RGC-32 and FasL but increased IL-21 in PBMCs. After commencing treatment with glatiramer acetate RGC-32 and FasL levels are increased, whilst IL-21 levels are decreased in MSers who are responders to glatiramer acetate treatment. Therefore, the three markers in combination can be used as a marker to evaluate treatment response. A larger study needs to be carried out to see whether initial levels at the start of treatment can be predictive of future treatment response and whether relapses on treatment can be predicted - the era of personalised medicine.

Figure: Time course of RGC-32, FasL, and IL-21expression in Glatiramer Acetate (GA)-treated MS patients. A. Responders to GA showed persistently higher levels of RGC-32 compared to non-responders over time. B. A similar pattern was observed for FasL mRNA expression, with higher levels of mRNA expression seen in responders and lower levels in non-responders over time. C. Responders to GA showed persistently lower levels of IL-21 compared to non-responders over time.