Wednesday, 31 October 2012

Lethal MS post-natalizumab


Natalizumab dramatically reduces relapses in MSers with active MS, but it may induce progressive multifocal leukoencephalopathy (PML).(1) A rebound of MS or an immune reconstitution inflammatory syndrome (IRIS) were described after natalizumab withdrawal, even in the absence of PML. Very few data concerning the potential severity and the neuropathology of this event are available. These investigators' report a case of a 50-year-old MSer who developed a fulminating relapse 3 months after stopping natalizumab, leading to death despite intensive care and immunosuppressive therapy. Radiologic and neuropathologic findings provide interesting data regarding the nature of the rebound.

"Rumour has it that there are quite a few cases with fulminant / pseudotumoural cases of MS that have occurred after switching from natalizumab to fingolimod. What is this telling us about MS? Could there be a virus hidden behind a sealed blood brain barrier that is exposed to the immune system after withdrawal of Natalizumab? These observation support the viral hypothesis of MS. This also has major implications of how we manage natalizumab-fingolimod switchers."

CoI: multiple

Recent post of interest:

30 Oct 2012
Disease reactivation was observed in 11/22 (50%) MSers: clinical relapses in six MSers (four MSers within the first month of therapy) and MRI activity in a further five MSers (three MSers within the first month of therapy).

Rivastigmine fails to show effects on cognition

EpubMäurer et al. Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients. Mult Scler. 2012 Oct.

BACKGROUND: Cognitive decline has been recognised as a frequent symptom in multiple sclerosis (MS). Cholinesterase inhibitors (ChEIs) are employed for the treatment of Alzheimer's disease, but there is some evidence that ChEIs might also be effective in MS patients with cognitive deficits, particularly deficits of memory function.

OBJECTIVE: The aim of this study was to evaluate efficacy on memory function and safety of the ChEI rivastigmine in MS patients with cognitive deficits as measured by the change from baseline of the total recall score of the selective reminding test (SRT) after 16 weeks of treatment.

METHODS: Efficacy and safety of rivastigmine were analysed in a 16-week, multicentre, double-blind, randomised, placebo-controlled study, followed by an optional one-year open-label treatment phase. Effects of rivastigmine and placebo were compared by an analysis of covariance.

RESULTS: In total, 86 patients were enrolled. Patients who received rivastigmine (n = 43) showed a non-significant increase in total recall score (sum of all words immediately recalled over all six trials) over placebo (n = 38) after 16 weeks of treatment (p = 0.2576). Other outcome measures provided no evidence supporting benefits of rivastigmine. Treatment with rivastigmine was well tolerated.

CONCLUSIONS: With the results of this study, the need for an effective therapy in cognitively impaired MS patients is still required. Thus, intensive and continued clinical research is required to explore therapeutic options for cognitive deficits in MS patients.

This study failed to show any evidence of benefit with Rivastigmine a non-significant increase is not good enough, it is not significant and this is no effect of drug. However, this was a small study, was it too small? Underpowered studies do us little favours because they usually mean nothing conclusive and trials need to be done again, wasting time and resource. Furthermore because of failure, interest in a repeat trial is not there. They should be done once properly and get definitive answers.

CoI: None

Blog in the Media

The Blog been recognised for excellence due to the contribution its top quality editorial offers the Multiple Sclerosis world by KwikMed. This year, their specialist panel of judges have reviewed hundreds of different sites from across the internet before hand-picking the very best for each category. The Blog is among the elite selection of awardees that our judges felt made a real contribution to the Multiple Sclerosis category.

This was one of 19 sites some familiar, some not so familiar!

What do we know about the genetics of MS?

Epub: Watson CT, Disanto G, Breden F, Giovannoni G, Ramagopalan SV. Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs. Sci Rep. 2012;2:770. Epub 2012 Oct 25.

Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.

"Genome-wide association studies have been performed in MS to try and find disease associated genes. These studies typically test hundreds of thousands of markers at a time, and only those that are statistically significant after correcting for testing for all of these markers are given further attention. There are about 60 of these markers that currently pass this statistical threshold, and together they explain about 1% of the genetic basis of MS. Using new statistical methodology, we looked at more than 475000 markers and asked how much of the genetics of MS is explained by all of them together. Surprisingly, this was only 30%. Much therefore remains to be understood about MS genetics. Rare variants (variants only seen in less than 1% of the population and not really tested in the current study) are likely to play a big role in future studies".

CoI: This is the work of Team G.

Natalizumab PML Update - September 2012

"Apologies about not getting these latest figures to you. I have also included the presentation from Biogen-Idec for your information."

Natalizumab Safety Update September 2012 from gavingiovannoni

"As at the 5th September, 2012, there have been 285 reported cases of MSers with PML as a complication of natalizumab treatment. This is with a denominator of over 104,000 treated MSers worldwide or greater than 224,000 years of natalizumab exposure."

"The risk is presented for your to see and depends on whether or not you are JCV+ve, have had previous exposure to immunosuppressants and how many infusions you have had."

"In response to a question about how do you count the number of infusions you have had if you convert from being JCV-ve to JCV+ve. This is a difficult question as the switch could be due to the variability of assay or a real biological conversion due to infection with the virus. This is when a titre may help; i.e. if it is a low titre or low antibody levels to the virus it is likely to be due to the variability of the assay a so called false negative or positive result. In comparison, if the titre is high it is likely to represent a true seroconversion due to a new infection. I also would ask for IgM antibodies to the virus. These antibodies are made with an initial infection. If positive for IgM antibodies this would indicate a recent infection."

"If your JCV+ve is due to a recent infection I would start the clock from the previous negative sample; this is being conservative and assumes you became infected shortly after that negative test. If it is due to assay variability  i.e. low titre with no IgM antibodies I would not reset the clock and start counting from your first infusion; in other words you have been infected from the beginning. I would also assume the first test was a false negative result and the new test was correct. Why am I being so conservative? You don't want to down play the risks when the potential complications are so bad!. One in 5 people who get PML die from the infection and 90% of the survivors of PML have moderate or severe disability."

CoI: multiple

Unrelated Blogger Comments 2 - October

Sometimes you what to say something that is unrelated to the threads. This is a spot for You. Previous comments can be got at on the posts on the right of the main page.
Prof G has changed the comments posts so they do not pop-up but allows replies. Let us know what you prefer

P.S. Check out MouseDoc & The Not so Great North Run

Tuesday, 30 October 2012

Research: Repair of grey matter lesions

Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, Yong VW, Fox RJ, Kidd GJ, Trapp BD.  Cortical remyelination: A new target for repair therapies in multiple sclerosis. Ann Neurol. 2012  doi: 10.1002/ana.23693. [Epub ahead of print]

OBJECTIVE: Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis (MS). Because demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter.

METHODS: Post-mortem brain tissue from 22 patients with MS (age 27-77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination.

RESULTS: New oligodendrocytes that were actively forming myelin sheaths were identified in 30 of 42 remyelinated subpial cortical lesions, including lesions from 3 patients in their 70s. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes, and fewer reactive astrocytes. Astrocytes in the white matter, but not in cortical portions of these lesions, significantly upregulate CD44hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination.

INTERPRETATION: Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.

MS is a chronic inflammatory-demyelinating disease of the white matter (WM) of central nervous system. In addition studies have shown that a large number of lesions are located in the cortical and deep gray matter.  The available MRI data obtained on large cohorts of MSers, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment. Remyelination in the white matter occurs but this is hampered by loss of immature oligodendrocyte (myelin-forming cell) surrounding the lesions and the production of an astrocytic scar. This study shows that in lesions in the grey matter there is evidence of robust remyelination and no loss of the immature oligodendrocyte cells. This indicates that there is nothing inherently wrong with the repair mechanism. This suggests that if we could change the environment in the white matter such that it is not hostile to repair, then it may be feasible to promote repair. Also DoctorKlaus pointed out to me that the repairing cells are lining the lesions and this will help repair the lesions.This is going to be a more difficult task than in the grey matter. If we are looking for drugs to promote repair, then it may be best to look at grey matter lesions for evidence of efficacy.

Disease reactivation after cessation of natalizumab and switching to fingolimod

Rinaldi et al. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler. 2012;18:1640-3.

Background: Clinical and/or neuroimaging evidence of disease reactivation has been described in MSers  after a break from natalizumab. 

Objective: To evaluate fingolimod as therapeutic option following natalizumab. 

Methods: Twenty-two relapsing remitting MSers having JC virus antibodies (JCVAb+) in serum were switched from natalizumab to fingolimod after a three-month washout period. Neurological evaluation with the Expanded Disability Status Scale (EDSS) was performed monthly for a mean follow-up period of nine months. 

Results: In 20/22 MSers, MRI was obtained within one month after therapy initiation. Disease reactivation was observed in 11/22 (50%) MSers: clinical relapses in six MSers (four MSers within the first month of therapy) and MRI activity in a further five MSers (three MSers within the first month of therapy). Clinical and/or MRI signs suggestive of disease rebound were observed in three MSers. 

Conclusions: Our data indicate that fingolimod does not exert clinical activity quickly enough to stop MS reactivation after a break from natalizumab.

Rigau et al. Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology. 2012 Oct 24. [Epub ahead of print]

Jander et al. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012;18:1650-2. doi: 10.1177/1352458512463768.
"These studies and case reports confirm mine and many other neurologists' observations of rebound on natalizumab withdrawal. Most of us feel that this rebound is in excess of what activity MSers had before they started natalizumab. How to prevent it? It is difficult, because you want to make sure that JCV+ MSers who are switching from natalizumab (Tysabri) to fingolimod (Gilenya) are not in the pre-symptomatic phase of PML, which is why we advocate a 3 month washout period. The washout allows your own immune system to reconstitute the CNS and find any rogue virus. The problem with this strategy is that it allows your MS to comeback with a vengeance. Some of us have started prescribing pulsed monthly steroids to cover this period, but this does not appear to prevent the rebound entirely. There are several trials testing different washout periods and switching options that will hopefully allow us to make more evidence-based recommendations shortly. At present I am too concerned about carry-over PML on fingolimod to recommend anything less than a 3 month washout. If we can increase the diagnostic confidence of excluding early asymptomatic PML I will obviously change my recommendation. Please stay tuned to this blog; we will come back to you with more posts as data becomes available."

Monday, 29 October 2012

Not So Great North Run

If you are like me, I can't run and  so I'm doing the Not So Great North Run on 9th December 2012. This is a half marathon with a twist

My travel is not going to be in the North of England but North London in a Gym. There I aim to travel the equivalent of 13.1 miles on a Low-Impact Cross Trainer.

Why don't you join me and pop down to your local gym, if you are a member, or do something else. Set yourself a goal: 1km, 5km 10km, 13.1miles etc, swim, cycle or something else. Get yourself sponsored and donate to my charity or another of your choosing. We can't all run but we can do our bit.


Text: MDOC50 plus amount (£x) to 70070 (I tried it on the Mouse Phone and you can even do gift aid so they can get you tax back off the UK Government)

Restless leg Syndrome

Epub: Schürks & Bussfeld. Multiple sclerosis and restless legs syndrome: a systematic review and meta-analysis. Eur J Neurol. 2012 Oct 18. doi: 10.1111/j.1468-1331.2012.03873.x. 

BACKGROUND: Restless legs syndrome (RLS) has been reported to occur more frequently in patients with multiple sclerosis (MS) than in people without MS.
METHODS: Systematic review and meta-analysis of studies investigating RLS in patients with MS published through April 2012. We calculated the prevalences and 95% confidence intervals (CIs) of RLS in patients with MS and people without MS as well as odds ratios (ORs) and 95% CIs of the association between MS and RLS based on data from the publications. We then calculated pooled effect estimates for the association between MS and RLS.
RESULTS: We identified 24 studies. RLS prevalence amongst patients with MS ranged from 12.12% to 57.50% and from 2.56% to 18.33% amongst people without MS. Heterogeneity amongst studies was high (RLS prevalence in patients with MS I(2) = 94.4%; RLS prevalence amongst people without MS I(2) = 82.2%). Hence, we did not pool the prevalence data for meta-analysis. Heterogeneity amongst studies investigating the association between MS and RLS was moderate (I(2) = 53.6%). Pooled analysis indicates that MS is associated with a fourfold increased odds for RLS (pooled OR = 4.19, 95% CI 3.11-5.66). This association was smaller amongst studies published as full papers (pooled OR = 3.94, 95% CI 2.81-5.54) than amongst studies published as abstracts only (pooled OR = 6.23, 95% CI 3.25-11.95). 

CONCLUSION: This systematic review indicates that RLS prevalence amongst patients with MS ranges from 12.12% to 57.50% in different populations. Pooled analysis further indicates that the odds of RLS amongst patients with MS are fourfold higher compared to people without MS.

Post traumatic Stress

Epub: Ostacoli et al. Prevalence and Significant Determinants of Post-traumatic Stress Disorder in a Large Sample of Patients with Multiple Sclerosis. J Clin Psychol Med Settings. 2012 Oct.

Background: Chronic and life-threatening neurodegenerative diseases may be associated with post-traumatic stress disorder (PTSD). 

Aims: Therefore, the current study was an investigation of the prevalence of PTSD in MSers, and identification of significant determinants of PTSD. 

Methods: Two hundred thirty-two MSers were consecutively recruited and screened for the presence of PTSD with the Impact of Event Scale-Revised, corroborated by the Structured Clinical Interview for DSM-IV. Furthermore, participants were administered the Hospital Anxiety and Depression Scale and the Fatigue Severity Scale. Twelve MSers (12/232, i.e. 5.17 %) were diagnosed as suffering from PTSD. 

Conclusions: Levels of education, anxiety and depression were significant determinants of the presence of PTSD.

"1 in 20 MSers have PTSD. Are you surprised? Being diagnosed with a chronic lifelong disabling condition is very stressful. The anxiety of uncertainty does not help. Do any of you have PTSD? An important message is that PTSD is a treatable disorder, please don't suffer in silence."

Additional reading: PTSD

Other posts of interest on this blog in relation to anxiety and stress:

24 Oct 2012
Participants were sent questionnaires to measure factors potentially related to anxiety. The factors included disability, depression, self-efficacy, locus of control, general stress, psychological distress and factors specific to MS.
12 Aug 2012
INTRODUCTION: Studies have found that people with Multiple Sclerosis experience relatively high rates of anxiety and depression. Although methodologically robust, many of these studies had access to only modest sample ...
27 Jun 2012
The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (≥5). Results: At cohort entry, prevalence of ...
03 Oct 2012
Clinical data including disability (Expanded Disability Status Scale: EDSS) and depression symptoms (Hospital Anxiety and Depression Scale depression subscale: HADS-D) were recorded at 0, 2 and 6 months post-relapse.

11 Sep 2011
Background: Self-report measures of cognition have consistently been shown to correlate better with depressed mood than neuropsychological test performance in MS'ers, with few studies focusing on the role of anxiety and ...
31 Jul 2012
Conclusion: These findings may alert clinicians of the high prevalence and impact of daily hassles in MS and underline the need to incorporate stress and anxiety management strategies in (psycho)therapeutic interventions.
17 Oct 2012
has NOT been concerned with MS, so the map would show family, studying, exercise, employment etc as overwhelmingly the largest elements, with a tiny percentage devoted to anxiety (around the time of diagnosis) and ...

Sunday, 28 October 2012

Research: Genetics of MS

Epub: O'Gorman C, Lin R, Stankovich J, Broadley SA. Modelling Genetic Susceptibility to Multiple Sclerosis with Family Data. Neuroepidemiology. 2012; 40:1-12.

A genetic contribution to susceptibility is well established in multiple sclerosis (MS) and 57 associated genetic loci have been identified. We have undertaken a meta-analysis of familial risk studies with the aims of providing definitive figures for risks to relatives, performing a segregation analysis and estimating the proportion of the overall genetic risk that currently identified genes represent. We have used standard methods of meta-analysis combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. The overall recurrence risk for monozygotic twins (identical twins) was 18.2% and for siblings (brothers and sisters) 2.7%. The recurrence risk for dizygotic twins (non-identical twins) was significantly higher than for siblings. The overall estimate of sibling relative risk (λ(S)) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for λ(S) was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect (probably the major histocompatibility complex) with many loci of small effect. The estimated contribution of the 57 known MS loci is 18-24% of λ(S). This meta-analysis supports the notion of MS being in part the result of multiple genetic susceptibility factors and environmental factors.

This tells us what we already know that there the major genetic susceptibility factor is the major histocompatibility complex and there are many other genes that are a minor part of the risk process, which also has an environmental influence.

Research: information about having a baby with MS

Epub: Kosmala-Anderson & Wallace. A qualitative study of the childbearing experience of women living with multiple sclerosis. Disabil Rehabil. 2012 Oct 17.

Background: Although at any time in the UK, there are about 20,000 women with MS who may be considering having children, healthcare systems often fail to provide them with information and support they need to make informed decisions about their health and pregnancy management. 

Aim: The aim of this paper is to explore the childbearing experience of women MSers to determine what support and information may be useful to this target group.

Method: Interviews were conducted with women with MS (n = 9). Transcripts were analysed using thematic analysis.

Results: Three major themes emerged from the interviews with women living with MS. We found women were concerned about both medical and practical issues associated with having children. Limited access to information about relationships between MS and childbearing and receiving conflicting or wrong information was recounted. Opinions of family members and clinicians regarding having children in the context of MS impacted on women's experience of making decision about having children and childbearing.

Conclusions: Women with MS can benefit from having access to comprehensive, structured sources of information about MS and childbearing. Healthcare professionals and family members' support could be channelled more appropriately to enhance their experience of making choices about childbearing.

"If you are woman with MS do you have an opinion? This is a small qualitative study that many will call 'soft science'. However, the topic is important and if we want to provide holistic care for woman with MS we need to address how we handle the issue of pregnancy and the advice we give. Misinformation or inconsistent information is one way that we let MSers down."

Other posts on pregnancy and MS on this blog:

25 Oct 2012
Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in MS, these investigators aimed to assess pregnancy and foetal outcomes after in utero exposure to GA, using the same dataset, ...
14 Aug 2012
The mean annual relapsing rate 4 years prior to pregnancy was significantly higher than at the subsequent 6 years after delivery (1.06 vs. 0.45, p < 0.001). In addition, the annual relapsing rate in years prior to pregnancy was ...
05 Jun 2012
BACKGROUND AND OBJECTIVE: Women with multiple sclerosis (MS) who intend to get pregnant are often advised to discontinue disease modifying therapy (DMT) prior to conception. This recommendation is not based on ...
14 Apr 2012
The investigators reviewed medical records and used a structured questionnaire to investigate gravidity (number of pregnancies), parity (number of births), and the number of relapses during the 2 years before pregnancy, ...

11 Oct 2012
To investigate if women with multiple sclerosis (MS) experience changes in MS symptoms related to pregnancy, the postpartum period, menopause or use of oral contraception (OC) or postmenopausal hormone therapy (HT).
28 Jul 2011
This allowed these investigators to study the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum vitamin D during pregnancy and their daughters' risk of developing MS.
16 Jul 2011
"Because of this study, and the fact that pregnancy itself reduces the attack rate, researcher's have been trying to find out what it is about pregnancy that is so beneficial for MS'ers." "We assume that the profound changes that ...
16 Sep 2011
21/101 (21%) of births to MS women treated with DMD prior to pregnancy were exposed to a DMD. In all cases, exposure was documented as unintentional and DMD treatment was stopped within 2 months of gestation.

31 May 2011
Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly (an extra finger), 5 pregnancies ended in an early miscarriage and one woman ...
15 Jul 2011
The average or mean rate of relapse was 0.7 per year in the year before pregnancy, 0.5 during the first trimester, 0.6 during the second trimester and 0.2 during the third. The rate increased to 1.2 during the first three months ...
27 May 2012
Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months post-partum (after delivery).
20 Dec 2010
A report on 88 pregnancies in Italian woman that were exposed to interferon-beta (average exposure 4 to 5 weeks) has demonstrated that exposure to interferon-beta was not associated with an increased risk of spontaneous ...

16 Jul 2012
Of the 20.9% of participants who decided to become pregnant (or father a pregnancy) following a diagnosis of MS, 49.5% had two or more pregnancies. Conclusion:This study indicates that an MS diagnosis does not ...
19 Sep 2011
Natalizumab did not affect the ability of treated males to produce pregnancies in untreated females. In female guinea pigs, no treatment-related changes were seen in uterine weights or ovary weights. Pregnancy rates were ...
05 Aug 2011
As is well known the relapse rate decreases during pregnancy, but as is known to occur there was a surge in relapses within 3 months after the birth. However when doctors looked at 9 months after birth compared to before ...
13 Jul 2011
The only significant predictor of having a relapse after childbirth was an increased number of relapses in the year before pregnancy and during the pregnancy itself. Therefore, the reported association between breastfeeding ...

Research: hepatitis B vaccination is not a risk factor for MSers

Epub: Martínez-Sernández & Figueiras. Central nervous system demyelinating diseases and recombinant hepatitis B vaccination: a critical systematic review of scientific production. J Neurol. 2012 Oct.

Background: The aetiology of MS has not yet been fully described. A potential link between the recombinant hepatitis B vaccine and an increased risk of onset or exacerbation of MS emerged in the mid-1990s, leading to several spontaneous reports and studies investigating this association. 

Aims: These investigators' conducted a critical systematic review aimed at assessing whether hepatitis B vaccination increases the risk of onset or relapse of MS and other central nervous system demyelinating diseases. 

Methods: MEDLINE and EMBASE were used as data sources, and the search covered the period between 1981 and 2011. Twelve references met the inclusion criteria. 

Results: No significant increased risk of onset or relapse of the diseases considered was associated with hepatitis B vaccination, except in one study. Most studies included in this review displayed methodological limitations and heterogeneity among them, which rendered it impossible to draw robust conclusions about the safety of hepatitis B vaccination in healthy subjects and MSers 

Conclusions: On the basis of current data there is no need to modify the vaccination recommendations; however, there is a need to improve the quality of observational studies with emphasis on certain considerations that are discussed in this review.

"This meta-analysis is further evidence that the link between hepatitis B vaccination and MS is probably non-existent or if it is there is very weak. In other words having a hepatitis B vaccine is unlikely to trigger the onset of MS or MS attacks."

ECTRIMS 2012: alemtuzumab presentation

"Several people have now requested my slides on Alemtuzumab that I presented as part of the Genzyme satellite symposium at ECTRIMS. I have now loaded them onto slideshare for you to view and download." 

"The aim of this presentation was to present the phase 3 trial data on Alemtuzumab in early RRMS as a therapeutic strategy that probably works by depleting circulating lymphocytes. The slides may be a little complicated as they were designed for a professional meeting. However, if you have any questions I will be around this weekend to answer them."

CoI: multiple

Saturday, 27 October 2012

CCSVI Monthly October

As the nonsense arrives, whenever there is a contentious post on CCSVI, to keep some balance for those interested, we will go back to the last Saturday of the month with no comments taken. Make your own mind up and keep it to yourself.

Epub: Sati et al. FLAIR*: A Combined MR Contrast Technique for Visualizing White Matter Lesions and Parenchymal Veins. Radiology. 2012 Oct 16.

Purpose: To evaluate a magnetic resonance (MR) imaging contrast technique, called FLAIR*, that combines the advantages of T2-weighted fluid-attenuated inversion recovery (FLAIR) contrast and T2*-weighted contrast on a single image for assessment of white matter (WM) diseases such asmultiple sclerosis (MS).

Materials and Methods: This prospective pilot study was HIPAA compliant and institutional review board approved. Ten patients with clinically definite MS (eight men, two women; mean age, 41 years) provided informed consent and underwent 3.0-T MR imaging. Images from a T2-weighted FLAIR sequence were combined with images from a T2*-weighted segmented echo-planar imaging sequence performed during contrast material injection, yielding high-isotropic-resolution (0.55 × 0.55 × 0.55 mm(3)) FLAIR* images. Qualitative assessment was performed for image quality, lesion conspicuity, and vein conspicuity. Contrast-to-noise ratio (CNR) was calculated to compare normal-appearing WM (NAWM) with cerebrospinal fluid, lesions, and veins. To evaluate the differences in CNR among imaging modalities, a bootstrap procedure clustered on subjects was used, together with paired t tests.

Results: High-quality FLAIR* images of the brain were produced at 3.0 T, yielding conspicuous lesions and veins. Lesion-to-NAWM and NAWM-to-vein CNR values were significantly higher for FLAIR* images than for T2-weighted FLAIR images (P < .0001). Findings on FLAIR* images included intralesional veins for lesions located throughout the brain and a hypointense rim around some WM lesions.

Conclusion: High-isotropic-resolution FLAIR* images obtained at 3.0 T yield high contrast for WM lesions and parenchymal veins, making it well suited to investigate the relationship between WM abnormalities and veins in a clinical setting

This may have interest for people in the vasculature!

Epub: Beggs et al. Cerebral venous outflow resistance and interpretation of cervical plethysmography data with respect to the diagnosis of chronic cerebrospinal venous insufficiency. Phlebology. 2012 Oct 11.

OBJECTIVE: While chronic cerebrospinal venous insufficiency (CCSVI) can be characterized using cervical plethysmography, much remains unknown about the haemodynamics associated with this procedure. The aim of the study was therefore to gain a deeper understanding of the observed haemodynamics.

METHOD: Forty healthy controls and 44 CCSVI patients underwent cervical plethysmography, which involved placing a strain-gauge collar around their necks and tipping them from the upright (90(o)) to supine position (0(o)) in a chair. Once stabilized, they were returned to the upright position, allowing blood to drain from the neck. A mathematical model was used to calculate the hydraulic resistance of the extracranial venous system for each subject in the study.

RESULTS: The mean hydraulic resistance of the extracranial venous system was 10.28 (standard deviation [SD] 5.14) mm Hg.s/mL in the healthy controls and 16.81 (SD 9.22) in the CCSVI patients (P < 0.001).

CONCLUSIONS: The haemodynamics of the extracranial venous system are greatly altered in CCSVI patients.

This suggests there are differences in the resistance of blood flow between healthy control verses CCSVIers. However, with the large deviations, there are CCSVIers that have levels that are found in healthy controls (10.28 + 5.14 = 15.42. 16.81-9.22 = 7.59 so you can see there is overlap).

CCSVI survey results. BLOG readers are sceptical

The survey results on CCSVI have been interesting. When asking Prof G to the post survey, I would have predicted that if all trials were positive the majority of people would believe them and we would then move forward and push to get the treatment made available.

If negative the majority should believe that and move on. However I expected a few people to not believe anything, maybe people who have had good experiences. 
If one trial was positive and the other negative. I would have predicted that the majority should say that there was insufficient evidence to make a call and further studies would be required. If there was a difference between the two studies there would be bias. I was thinking that there could be people having faith in Zamboni against the establishment if sufficient CCSVIers voted. By posting on CCSVI at the same time as requesting the survey. I thought that it would attract traffic, which it did. But maybe, the trollers did not vote, too busy writing pants I guess. Maybe they did and they do not trust him.

So if both trials were negative the majority ( about 70%) of people would believe them and I guess is an indicator to stop investigating this. This indicated that 30% would not have any faith in the medical establishment to get it right and carry-on regardless. 

If there was disagreement in the studies the majority (about of 80%) of people thought that we would need more information. I think there are about 6 trials planned or ongoing. However, there was a suggestion that people would put more faith in a Zamboni-independent results and if we look below we can see that the vast majority would prefer that studies were not led by the Bard of CCSVI. 

Most surprising was that if both trials had a positive clinical result then the majority (55%) of people voting would not accept it that there was sufficient evidence to suggest that the CCSVI concept was a goer and that the venoplasty treatment would not be worth pursuing. This is a surprise. Whilst one may have opinions before studies start when the results are in you have to think if it modifies your thoughts.

Maybe our readers of the BLOG are more open-minded and sceptical than some other groups, as you have been following the developments. But that is reassuring and good to see that you would prefer independence in the People undertaking the studies, whether it was an interventional radiologist or Neurologists, so we get a right answer and move on, whatever that is.

Sorry no comments as we are not near computer today to deal with any unpleasantries.

Research: Men more likely to have More Nerve damage than Women

Epub: Costello et al. Sex-specific differences in retinal nerve fiber layer thinning after acute optic neuritis. Neurology. 2012 Oct 17.

OBJECTIVE: The primary objective of this study was to explore the potential influence of gender on recovery from optic neuritis (ON) by determining whether differences in retinal nerve fiber layer (RNFL) thickness can be detected between men and women 6 months after an ON event.

METHODS: In this prospective cohort study, 39 men and 105 women with acute ON underwent repeat visual and optical coherence tomography (OCT) testing. The main outcome measures were change in RNFL measurements for male and female patients 6 months after ON.

RESULTS: Men were older (mean age = 39 years) than women (35 years) (p = 0.05) in this study, and more men (62%) than women (41%) had a diagnosis of relapsing-remitting multiple sclerosis (MS) (p = 0.02). Because age and MS subtype were 2 significant covariates, both variables were controlled for in multiple regression analyses. Other covariates controlled for in the multivariate regression included disease duration (years), use of disease-modifying therapy (yes/no), and use of high-dose corticosteroids for acute ON (yes/no). After 6 months, mean RNFL values were lower in men (74 μm) than women (91 μm) (p < 0.001). Men showed more apparent change in RNFL thickness in their ON eyes from baseline to 6 months after ON than women (p = 0.003).

CONCLUSIONS: There may be differences in recovery between men and women after ON, which can be difficult to detect with conventional visual testing. Our findings raise interesting questions about the potential influence of gender in MS, which may be explored in future studies.

This study looks at nerve damage and loss between the sexes. In this case they look after optic neuritis and find that men have more retinal nerve fibre layer thinning, indicative of nerve loss. This study suggests that males are more likely to suffer nerve loss than females and so points at a protective effect from sex hormones. I am sure MD2 will agree with this thought that males may be more  susceptible to damage than females. Males tend to develop MS later than females but often develop progressive MS.

Friday, 26 October 2012

Protein-protein interactions

Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.

"In this study, we sought to see if genes associated to MS interact (work together) at the protein level (if you remember school biology lessons, genes code for proteins which are the molecules of life). We show that this is indeed the case, genes associated to MS are not random, they do interact at the protein level. Further, given what we know about the interactome (fancy word for interacting proteins) we are able to predict other genes that are likely to be involved in MS. The bottom line is that many genes involved in the immune system are perturbed in MS and targeting these are likely to be useful therapeutically". 

COI: This is the work of Team G.

Research: Statins and Immune function

Zhang X, Tao Y, Wang J, Garcia-Mata R, Markovic-Plese S. Simvastatin inhibits secretion of Th17-polarizing cytokines and antigen presentation by DCs in patients with relapsing remitting MS.Eur J Immunol. 2012 Oct 17. doi: 10.1002/eji.201242566. [Epub ahead of print]

Statins, widely used cholesterol-lowering agents, have also been demonstrated to have anti-inflammatory effects. Here we characterize the capacity of simvastatin to target DCs and modulate T-cell priming and Th17-cell differentiation, in a cohort of patients with relapsing remitting multiple sclerosis(RRMS). We report that simvastatin inhibits IL-1β, IL-23, TGF-β, IL-21, IL-12p70 and induces IL-27 secretion from DCs in RRMS patients, providing an inhibitory cytokine milieu for Th17 and Th1-cell differentiation. The effect on DCs is mediated via induction of SOCS1, SOCS3 and SOCS7 gene expression, which are associated with the inhibition of STAT1, STAT3 and ERK1/2 phosphorylation. A geranylgeranyl transferase inhibitor (GGTI) replicated simvastatin's effects on DC cytokine secretion, implicating that simvastatin-induced depletion of isoprenoids mediates this effect. Simvastatin inhibited antigen presentation by DCs via suppression of the MHC class I expression, costimulatory molecules CD80 and CD40, and by inducing a dramatic loss of dendritic processes. The changes in DC morphology were also mediated via inhibition of geranylgeranylation. The therapeutic use of geranylgeranylation inhibitors may provide selective inhibition of key pathogenic cytokines that drive the autoimmune response in MS; their use represents a promising therapeutic approach that requires further clinical testing.

Last week we had evidence of Simvastatin doing something in progressive MSers and here we have evidence that it does something on the immune system. Statins inhibit the production of cholesterol but can do other things.

This work indicates that the effect is mediated by isoprenoids in the pathway involved in chloresterol inhibition. Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. Geranylgeranylation is a form of prenylation, which is a post-translational modification of proteins that involves the attachment of one or two 20-carbon lipophilic geranylgeranyl isoprene units from geranylgeranyl diphosphate to one or two cysteine residue(s) at the C-terminus of specific proteins. Prenylation (including geranylgeranylation) is thought to function, at least in part, as a membrane anchor for proteins. In the pathway one route is to may cholesterol another thing the isoprenoids do is activate Rho. This is involved the arrangement of the cell skeleton and so can effect cell processes.
Team G and friends showed that geranylgeranylation inhibitors (and statins) may inhibit EAE years ago. However the evidence that statins inhibit the immune response to any major effect is slim in MS, so why will these fair better? I guess we shall see if they are developed.