Tuesday, 31 July 2012

Stress management

Epub: van der Hiele et al. Daily hassles reported by Dutch multiple sclerosis patients. J Neurol Sci. 2012 Jul 14.

Background: There is growing evidence for the association between stress and relapse risk in MS. The current study focuses on daily hassles, which by their chronic and accumulating nature can cause considerable psychosocial stress. 

Aim: The main aim was to investigate the frequency, associated distress and type of daily hassles encountered by Dutch MSers from a large community-based sample. They further examined factors associated with high levels of psychosocial stress. 

Methods: Questionnaires concerning demographics, disease characteristics, physical functioning, daily hassles, fatigue, depression and anxiety were completed by 718 MSers. Three MSers younger than 18 were excluded, resulting in 715 MSers. 

Results: Compared with published norm data, more than 50% of the participants reported a high number of daily hassles (57.5%) and high levels of associated distress (55.7%). Frequently mentioned daily hassles concern personal functioning and social developments. A logistic regression model revealed that being female, being younger, having a higher educational level, using benzodiazepines*, exhibiting more symptoms of anxiety, and a higher physical impact of fatigue were all independently associated with high levels of psychosocial stress. 

*benzodiazepines are a group of drugs that can be prescribed as sedatives, anxiolytics, hypnotics, anti-convulsants or anti-spastic medications. The most well known in the class is diazepam. MSologists probably use clonazepam the most as an add-on drug to help with the control of spasticity. 

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. 

"This study is self-explanatory. Do the results strike a cord with you?"

"Please complete our 3 question poll on stress that is active on the blog at present. You may not see the poll if  you are using a mobile device and will need to access the blog via a web browser.Thanks."

Research Pain in MS

Truini A, Galeotti F, La Cesa S, Di Rezze S, Biasiotta A, Di Stefano G, Tinelli E, Millefiorini E, Gatti A, Cruccu G.Mechanisms of pain in multiple sclerosis: A combined clinical and neurophysiological study. Pain. 2012 Jul. [Epub ahead of print]

In this clinical and neurophysiological study, we examined the clinical characteristics and underlying mechanisms of neuropathic pain related to multiple sclerosis. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination. In patients selected for having ongoing extremity pain or Lhermitte's phenomenon, we recorded somatosensory evoked potentials (sensation triggered electrical signalling), mediated by non-nociceptive fibres (non pain nerve fibre often transmitting signals from the muscle), and laser-evoked potentials (Laser triggered nerve impulse), mediated by Aδ nociceptive (pain) fibres (These respond to cold and pressure of contact). Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas, in patients with ongoing neuropathic pain, laser evoked potentials were more frequently abnormal than somatosensory evoked potentials, we found the opposite in patients with Lhermitte's phenomenon. Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain that we found, which was lower than that reported in previous studies, may reflect the lesser disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte's phenomenon is related to damage of non-nociceptive pathways.
The spinothalamic tract is a sensory pathway originating in the spinal cord. It transmits information to the thalamus about pain, temperature, itch and crude touch. This study indicates that the more severe your MS is the more likely you are to have pain. If you have Lhermittes sign (tingling down neck and limbs when you bend your head forward) this may involve a different nerve signalling pathway compared to other pains that are sent via pain/sensation pathways. There are lots of other posts on pain in MS on the Blog.

Unrelated Blogger comments 2

Unrelated Blogger Comments July-2

Unrelated BLOGGER Comments

Sometimes you want to say something that is unrelated to the threads. This is a spot for you
"If you are a MSer at the Royal London Hospital please sign-up for our cognition study!"

Anonymous said...
I see you are recruiting for ppms. I turned 50 in June would I still be able to apply?
MouseDoctor said...
As long as you fit the criteria required for trial entry there should be no issues. I am sure G can tell you more.
Vasilis Vasilopoulos said...
Why did you tag the article "Veins in MS" as CCSVI? It is a histological study for people with MS. Should we only be intersted in what happens in our CNS only?
MouseDoctor said...
Why was the study on veins done, because of context of CCSVI simple as that.

At some stage we will streamline the tags because we have been told their are too many.

Should we be only interested in what happens in CNS.

Stupid comment off course not

You should be interested in other things like music literature and sport;-)
Vasilis Vasilopoulos said...
" Why was the study on veins done, because of context of CCSVI simple as that."

Despite that, it says something about MS that you didn't know before, doesn't it? Are you willing to B-rate it just because it's not about the immune system?
MouseDoctor said...
I did not know we were A-rating or B-rating articles, so do not know what you are talking about....As is often the case.

Maybe I should have tagged it- yellow-green birefringence or collagen, vein but these were not in the list
Gavin Giovannoni said...
Re: "I see you are recruiting for ppms. I turned 50 in June would I still be able to apply?"

Potentially; the ocrelizumab study has extended the age cut-off to 55 years. I must warn you that the inclusion and exclusion criteria are very strict and most PPMSers fail pre-screening or screening.
Anonymous said...
What is the use of having such strict exclusion criteria? If most PPMSers fail to qualify for the trial, it means the trial population isn't representative. Finally the same PPMSers will need treatment.

Monday, 30 July 2012

Research: Interleukin 1 activity depends on lesion activityifferents

EpubMurta et al. CNS response to a second pro-inflammatory event depends on whether the primary demyelinating lesion is active or resolved.Brain Behav Immun. 2012 Jul. 

Interleukin-1 β (IL-1β) is considered to be one of the most important mediators in the pathogenesis of inflammatory diseases, particularly in neurodegenerative diseases such as multiple sclerosis (MS). MS is a chronic inflammatory disease characterized by demyelination and remyelination events, with unpredictable relapsing and remitting episodes that seldom worsen MS lesions. We proposed to study the effect of a unique component of the inflammatory process, IL-1β, and evaluate its effect in repeated episodes, similar to the relapsing-remitting MS pathology. Using adenoviral vectors, we developed a model of focal demyelination/remyelination triggered by the chronic expression of IL-1β. The long-term expression of IL-1β in the striatum produced blood-brain barrier (BBB) breakdown, demyelination, microglial/macrophage activation, and neutrophil infiltration but no overt neuronal degeneration. This demyelinating process was followed by complete remyelination of the area. This simple model allows us to study demyelination and remyelination independently of the autoimmune and adaptive immune components. Re-exposure to this cytokine when the first inflammatory response was still unresolved generated a lesion with decreased neuroinflammation, demyelination, axonal injury and glial response. However, a second long-term expression of IL-1β when the first lesion was resolved could not be differentiated from the first event. In this study, we demonstrated that the response to a second inflammatory stimulus varies depending on whether the initial lesion is still active or has been resolved.


Interleukin-1 can do many things . This study used gene therapy to deliver the cytokine, adenoviral vectors produced transient but high levels of the cytokine. This triggered inflammationn and some demeylination which repairs. If it had repaired then another hit causes the same type of lesions but if the lesion had not remyelinated it decreased the inflammatory response so the response was not the same, therefore maybe treatments could have different effects depending on the lesion activity. This would be a cause for concern as lesions come and go at different times

Interferon response genes and the therapeutic response to interferons

"The following study may be hard to understand if you don't have a biology background. What these investigators are doing is simply studying variants in a gene that are affected by intereferon beta. Interferon beta is injected into your body and binds to a receptor on white blood cells causing it to change the way it functions. To do this interferon beta affects the way certain genes function, by switching some genes on and other off. The level of ON and OFF varies like a dimmer switch and depending on what variation you have in your genes the affects differ from one person to the next. This study found that if you have a particular variant of the gene IRF5 you were less likely to respond compared to someone with another variant."

Vosslamber et al. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis. Genes Immun. 2011 Sep;12(6):466-72. doi: 10.1038/gene.2011.18.

Background: Interferon-β (IFNβ) therapy is effective in approximately half of the MSers with RRMS. Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, the investigators carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNβ treatment. 

ResultsThey found that MSers with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNβ compared with MSers carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, MSers with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNβ treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNβ treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). 

Conclusions: These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNβ therapy that might have relevance as biomarker to predict the response to IFNβ in multiple sclerosis.
"This is now the third group that have found that genes linked to an interferon signature in the peripheral blood is a poor response marker for interferon beta in MS. This suggest that a test may be developed to use in clinical practice to predict interferon responses. Before this happens this data will need to be reproduced in a larger number of MSers on treatment. Fortunately, a lot of data has already been collected in other clinical trials making this a relatively easy task to do; assuming the Pharma companies who have this data agree to do the analysis."

"The implications of this work are large and may result in a segmentation of the DMT market based on biomarkers. At last some data to truly personalise treatments! I wonder if NICE and the payers will accept this data?"

Olympics in London

                                    The River Thames in London in the Olympic stadium
If you saw the Olympic opening ceremony on Friday (I know that elements of it were cut from the USA presentation...why?). Then being in East London things are going to be hectic for the next few weeks.

Danny Boyle's (film director) main task was to portray Britain to the World and gave us the Isles of Wonders. Whilst you may have understood the green and pleasant "Merchant-Ivory" land, the Industrial Revolution, the Pride of Diversity and the Queen doing a joke, it is inconceivable non-Brits would have got all the subtleness of some of the content, Gregory's Girl and Kes..most people under 40 would have no clue either
It was splendidly British and magnificently Dizzee

There was a feature that also paid tribute to the National Health Service during the opening ceremony because universal healthcare is one of the core values of British society.........was it being attacked? We moan about it but we love it also..I suspect some of you will disagree

If we had the resource for MS that goes to Great Ormond Street Hospital (GOSH) for Sick Children then we would be further along today than we are. 

More than 300 hospital beds which featured in the Olympics opening ceremony to celebrate the NHS are to be donated to hospitals in Tunisia

Prof G said "The Olympics stir us to sit and watch but the Paraolympians inspire us to get off our arses (Asses in American) and do something, because it they can do something, why can't we". Sure I could never run as fast as Oscar Pistorius 

However, the point of this is that the lack of tickets and the mayhem to the East End are causing some of us to "Run to the Hills" so do not be too surprised if you do not get a fast response during August.

Sunday, 29 July 2012

Survey results: cognition

"Unfortunately, our blogger polls can only give us headline results. We would need to study this in more detail to get an idea of the particular cognitive problems MSers who read this blog are having. I would be interested to find out!"

"These results have important implications and are telling us that heathcare professionals are either not aware of the problem or they are avoiding discussing one of the major hidden disabilities of MS with you. I suspect we do this as we don't have effective treatments for MS-related cognitive impairment. Should this be a reason for not telling MSers about this problem?"

"I personally believe there is a time when all MSers need to know about the potential impact MS has can have on their lives and this includes the effect on cognition. Why? This information may help you when making a treatment about treatment; early aggressive treatments may be more desirable to someone with MS if they can prevent or substantially slow the development of cognitive impairment."

"I also believe that cognitive impairment is the main driver of early social disability in MS; loss of employment, breakdowns in relationships, depression and fatigue. Unfortunately, we don't have the tools to investigate and manage these problems in our routine clinics, but things are changing."

"I have been lobbying Pharma that the biggest unmet symptomatic needs in MS are cognitive impairment and fatigue, and that they should be developing drugs for these indications. Would you agree?"

"If you are a MSer at the Royal London Hospital please sign-up for our cognition study!"

Research: Early pathological changes in MS

There is little agreement among neuropathologists regarding the timing and nature of oligodendrocyte loss in multiple sclerosis (MS). This report describes changes that accompany acute oligodendrocyte loss in new lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic lesions exhibit cytopathic changes that include apoptosis of oligodendrocytes immunoreactive for caspase 3, phagocytosis of apoptotic oligodendrocytes, swelling of cells with abnormal nuclei, complement deposition, and lysis. These are nonspecific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged immunoglobulin (IgG)(+) microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood-brain barrier, and the presence of rare CD8 T cells. Myelin contacted by IgG(+) macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and gray matter plaques is scavenging activity directed at nonvital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica (NMO), including that demyelination in both is secondary to a loss of caspase 3-positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component.

In this report they look at lesions suspected to be early MS lesions. There is evidence of cell death of oligodendrocytes which will result in demyelination. It is reported that caspase 3 is present which is a cell death inducing molecule. There is complement activation and this would suggest some immune involvement this is triggered when cells contain infection or are targetted by antibodies. This can cause killing of the cell or can make them liable to attack by microglia and macrophages. It suggest that macropgaes are there to clear up the damage, but provide no more clues what is occuring and what is causing the the oligodendrocyte damage, although it continues to point to immune involvement. We have reported about pre-active lesions before.

Primidone for MS tremor

Epub: Naderi et al. The Efficacy of Primidone in Reducing Severe Cerebellar Tremors in Patients With Multiple Sclerosis. Clin Neuropharmacol. 2012 Jul 19.

OBJECTIVES: Cerebellar tremor is a very disabling sign of MS, and various kinds of treatments have been proposed with different results. Primidone is one of the medications, mostly advised for essential tremor. The aim of our study was to determine the tolerability and efficacy of primidone in reducing severe cerebellar tremor in MSers.

METHODS: Ten MSers with severe cerebellar tremor were enrolled in this study. Primidone started with dose of 31.5 mg and gradually increased up to maximum of 750 mg/d. The severity of tremor was assessed with Activity of Daily Living (ADL), Nine-Hole Peg Test (NHPT), and Fahn Tremor Rating Scale (FTRS) at baseline and 2 follow-up studies after 6 and 12 weeks.

RESULTS: All outcome measures including ADL, FTRS, and NHPT of dominant and nondominant hands improved. The mean ADL changed from 51.8 at baseline to 36.8 after 12 weeks. FTRS was 14.8 at baseline, which reduced to 9.5 during this period. These changes were statistically significant. Although the time of the NHPT showed some improvement, it did not reach a statistically significant point after 6 weeks.The drug was well tolerated in all patients, and mild drowsiness reported by the patients disappeared at the end of the study.

CONCLUSIONS: Our study showed that primidone is tolerable in MS patients and effectively reduces severe cerebellar tremor in such MSers.

 "What is the problem with this study?"

"If you are are regular reader of this blog you will know that to assess whether or a treatment works or not you,to remover bias and to overcome the placebo effect you need to randomised, double-blind controlled trials. So these results are promising but not very convincing. As with most symptomatic therapies it would be interesting to know the proportion of responders vs. non-responders and whether or not a controlled withdrawwal resulted in a worsening of symptoms."

"I use primidone, which comes from the classs of drugs called the barbiturates. It is mainly used as an anti-convulsant to treat epilepsy. It is not used much because of  it causes excessive sedation and cognitive slowing. Most MSers find these symptoms a problem. Wouldn't you?"

"The following educational video from the NMSS covers tremor." 

Additional reading: primidone

Saturday, 28 July 2012

Research: a case for combined neuroprotection and immunomodulation

Braley et al. Differences in Diffusion Tensor Imaging-Derived Metrics in the Corpus Callosum of Patients WithMultiple Sclerosis Without and With Gadolinium-Enhancing Cerebral Lesions. J Comput Assist Tomogr. 2012;36:410-415.

OBJECTIVE: To analyze differences in corpus callosum diffusion tensor imaging metrics among MSers with RRMS and SPMS with enhancing and nonenhancing cerebral lesions.

The corpus callosum is the white matter tract that connects the two cerebral hemispheres together.

Diffusion tensor imaging is MRI technique that assesses the integrity of white matter tracts, in other words how intact they are.
DTI image of the corpus callosum
RESULTS: The subjects with SPMS with enhancing lesions had significantly lower genu and body of the corpus callosum fractional anisotropy (FA) values than those with nonenhancing SPMS and significantly lower genu, body, and splenium FA values than those with RRMS. Regression models: Enhancement was associated with decreased genu FA (P = 0.014). Secondary progressive MS was associated with decreased genu (P = 0.002) and splenium FA (P < 0.001) and significantly increased mean diffusivity.

CONCLUSION: Patients with SPMS with enhancing lesions may be at increased risk for neuronal damage compared to nonenhancing SPMS and RRMS subtypes.

"Nothing really new here. MSers with more advanced disease and active lesions are more likely to have damage to the corpus callosum and the nerve fibres that connect the two halves of the brain. Best to try and stop this happening! How? Early aggressive treatment before your MS becomes secondary progressive. There is no point waiting for damage to occur before treating; this is why we have to lobby NICE to give you access to the emerging more effective treatments as early as possible."

Stress management on trial as a DMT

Epub: Mohr et al. A randomized trial of stress management for the prevention of new brain lesions in MS. Neurology. 2012 Jul.

OBJECTIVES: This trial examined the efficacy of a stress management program in reducing neuroimaging markers of MS disease activity.

METHODS: A total of 121 MSers with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress.

RESULTS: SMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period.

CONCLUSIONS: This trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits .Trial registration:ClinicalTrials.gov, number NCT00147446.

"Interesting? Who would have thought that reducing stress would have had an impact on MS disease activity? These results would need to be reproduced; the trial is relatively small (121 MSers) and could be a false positive. Nevertheless this is something that needs to be looked into in more detail. Who is up for stress management therapy?"

Research: surgery for facial pain

Mohammadi et al. Surgical outcomes of trigeminal neuralgia in patients with multiple sclerosis. Neurosurgery. 2012;71(2):E563-4.

INTRODUCTION: Trigeminal neuralgia (TN) is relatively frequent in Multiple Sclerosis (MS) patients and procedural treatments are less effective than when used for classical TN. Outcomes from direct comparisons between different procedures for MS-related TN is lacking. In this study, initial pain-free rates (IPFR), duration of pain-free intervals (PFI) and associated prognostic factors were evaluated.

METHODS: This was a retrospective IRB-approved analysis performed on 96 MS-related TN patients who underwent 277 procedures (1-11/patient) in our institution (1996-2011). Patient, disease and treatments characteristics, as well as outcomes were statistically evaluated.

RESULTS: Most patients were female (60%). Median age at diagnosis of MS and TN were 39 and 50 years, respectively. 44 patients (47%) had brainstem plaques on MRI. At treatment, most of the patients had secondary-progressive (33%) or relapsing-remitting (31%) MS and 50% were receiving MS treatment. Overall, 89 patients (32%) underwent Glycerol Injection (GI), 82 (30%) Balloon Compression (BC), 54 (19%) Stereotactic Radiosurgery (SRS) and 52 (19%) other procedures. As upfront treatments GI (41%) and SRS (24%) were most common. IPFR was 72%, BC had the best (77%) and SRS the worst (56%) results. Overall failure-rate after 277 procedures was 77% with no significant difference between treatment modalities. Median PFI as 9 months. BC had the best (12 months) and SRS the worst (5 month) median PFI. Complications occurred after 94 procedures (34%), 77 of them (28%) were temporary or minor. SRS had the lowest complication rate (10%). In multivariable analysis, treatment type had significant effect on IPFR with better results for BC and GI.

CONCLUSION: The results of treatment in MS-related TN are suboptimal. In our large series, treatment failure occurred frequently (77%) independent of procedure type. The best IPFRs were achieved after BC and GI. SRS had the lowest complication rate (10%) but also the lowest IPFR (56%) and the shortest PFI (5 months).

Facial Pain is common in MS and is difficult to treat often because the pain is in part generated in the spinal cord and brain rather than in nerves in the face. This study looks at different treatment options and found that Balloon Compression (BC) of facial nerves was the most effective. However, there was failure of most treatments. Balloon compression gave approximately one year of pain-free time.

CCSVI Monthly July

Yet again nothing! Do you think it is time to wind-up this monthly post?

Friday, 27 July 2012

FDA warns about seizures with MS drug Ampyra or Fampridine

The U.S. Food and Drug Administration (FDA) on Monday said MSers who take the drug Ampyra (known as Fampridine in Europe), have a higher risk of seizures when starting the treatment. The FDA also updated the label for Ampyra / Fampridine , which is approved to help MSers walk, to warn about the need to check kidney function before people start taking it, and every year after that.

Abnormal electrical activity on an EEG recording of someone having a seizure. Fampridine makes this more likely to occur. Please remember that MSers are at increased risk of seizures from their disease. Seizure occur in 10-15% of MSers during the course of their MS. Seizures are more common in advanced MS. 

"Seizures are a well know side effect of the aminopyrdines (the active ingredient in fampridine). Fampridine works by making nerve cells more likely to discharge an electrical impulse. This is how they increase the walking speed of MSers."

"The great Professor W. Ian MacDonald, who was my mentor, was one of the first neurologists to use 4-aminopyridine in MS. The first MSer he treated with the drug as part of a clinical trial had a seizure. Needless to say he stopped the trial. Fampridine, is a slow release form of 4-aminopyridine, that has been designed to prevent high peak levels of the drug, which are associated with seizures. Nevertheless some MSers will still have seizures on the drug."

Research: predicting MS

Epub: Villar et al. High Levels Of Cerebrospinal Fluid Free Kappa Chains Predict Conversion To Multiple Sclerosis.Clin Chim Acta. 2012 Jul

BACKGROUND: A clinically isolated syndrome (CIS) may be the initial presentation of multiple sclerosis (MS). However, some CIS never develop MS. The identification of patients at risk of MS conversion is crucial as early treatment may improve their outcome. Free kappa chains (FKC) are increased in cerebrospinal fluid (CSF) of MS patients. We studied the accuracy of CSF FKC level measurement to predict conversion of CIS patients to MS.

METHODS: We quantified the FKC in CSF from 25 patients with non-inflammatory neurological diseases (NIND) and 78 consecutive CIS patients. We assessed whether high CSF FKC levels associate with CIS conversion to clinically definite MS, defined as the onset of new relapses during follow-up.

RESULTS: Between 0.1 and 5mg/l the FKC test showed linearity of 0.98 and inter-assay correlation coefficient of =0.99. A cut-off value of 0.53mg/l (mean+2SD of NIND group CSF FKC values) was calculated. CIS patients with CSF FKC above this value showed earlier conversion to MS in univariate and multivariate Cox analysis (HR=6.41; 95%CI=1.88-21.78, p=0.003).

CONCLUSION: High CSF FKC levels accurately predict CIS patient conversion to MS.

Antibodies are made up of a heavy and a light chain. The light chain are made from either lamda or kappa gene variants.  There are normally joined to the heavy chains by disulphide bonds where a sulphur on one chain binds to a sulphur on the other chain.  However the light chains can occur as free molecules. When people presented with their first neurological sign, those with free light chains had a greater chance of developing MS. Given that their are a increasing number of trials aimed at treating people at the CIS stage this may be an additional test that may indicate the chances of subsequently developing MS.

Rebound in MS disease activity on fingolimod withdrawal

Epub: Hakiki et al. Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases. Mult Scler. 2012 Jul.

The objective of this study is to report the limited experience on fingolimod suspension in MSers. The clinical and MRI outcomes are presented in 6 MSers after fingolimod discontinuation. Within three months from fingolimod suspension, 5 MSers returned to pre-treatment disease activity; one MSer , however, exhibited a clear rebound of clinical and MR activity. These findings suggest that clinical and MR outcomes after fingolimod suspension can vary among MSers. Systematic collection of clinical, laboratory and imaging data is highly advisable to identify subjects who are at higher risk of rebound and to define effective management strategies in these subjects.

"What this early experience is telling us is that if your MS is well controlled on fingolimod and you stop fingolimod your disease rebounds about 3 months later. This fits with the timing of the drug washing out of your body."

"These observations of rebound is not surprising as fingolimod does not work by rebooting our immune system; it works by trapping white blood cells in lymph nodes. If you remove this block the white blood cells are then able to move out of the lymph nodes and into the brain and spinal cord and trigger clinical attacks and new MRI lesions. This same thing happens with natalizumab."

Research: vitamin D and the main MS genetic risk factor

Epub: Nolan et al. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk.  Neurology. 2012 Jul 11.

"This research is what I call hard-core functional genomics and supports other studies already published. All genes have an area upstream of the protein coding reading that controls whether they are switched ON or OFF. The area that controls on the ON function is called the promoter. The major group of genes that control the risk of MS, called the HLA-DRB1*1501, has a a vitamin D ON switch. This switch is not an all or nothing switch but acts as a dimmer switch. If vitamin D levels are high it switches this gene ON very bright and if vitamin D levels are low this switch is set on ON low or dim. Interestingly other genes in this family don't have a vitamin D switch and are therefore are unaffected by vitamin D levels and some of these vitamin D non-responsive genes protect you from MS. What is important is that this family of genes that are linked to MS risk play a vital role in controlling the immune system and have to be switched on brightly early in life to educate the developing immune system. We believe low levels of vitamin D in utero or in early in life, results in the MS at-risk gene been set on DIM; as a result the immune system is wrongly educated and this then puts you at risk of MS when you get older. This is the main reason why we believe that vitamin D supplementation as a preventative strategy for MS needs to be given early in life, possibly in utero. If you are under my care I stress this, which is why I always talk about planning your pregnancies, getting your children onto vD supplements and to educate your siblings and their children. I wish public health officials would do this instead - I becoming an accidental public health doctor. Don't worry I like doing it; in fact if I knew what I know now when I was in medical school, I would almost certainly have specialised in public health and health economics."

OBJECTIVE: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk.

METHODS: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls.

RESULTS: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)).

CONCLUSIONS: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.

Thursday, 26 July 2012

Research: Another action for Gilenya

Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-α treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-α treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration.

The blood brain barrier keeps stuff out of the brain to maintianin its health, it consists of speciallised blood vessel cells that bind together tightly to make them inpenetrable. This is facilitated by factors produced by astrocytes that contact the blood vessel. This group finds that Gilenya may act on astrocytes to increase the production of a molecule that helps make the blood brain barrier less leaky to monocytes, which are macrophages in the blood. This suggests that Gilenya may not only stop (lymphocytes) white blood cells from entering the blood during MS but may also interfer with white blood cell (monocyte) entry into the brain also so a double whammy of benefit.

Grand Challenges in MS (3): changing sex ratio

Why is the incidence of MS increasing amongst woman?

To prove that MS is caused by a single factor or the interaction of several factors it has to explain everything we know about the epidemiology of the disease.

Epidemiology = the branch of medicine involved with the study of disease in the population; epidemiology deals with the study of the causes, distribution, and control of disease in populations.

One observation that is being noticed across several populations, but not all, is the increasing incidence of MS in woman. Why is this occurring? Some of it may be due to the changing in smoking prevalence amongst woman, which has been increasing relative to males. Another is cultural factors, for example the addition of UV blockers in cosmetics over the last 15 years. Other have suggested the use of oral contraceptive pill (OCP) or change in work environment. However, the change in sex ratio appears to go back to the beginning of the 20th century so it predates the change in work environment associated with World War 2 or the introduction of the OCP in the '60s.

Other posts of interest:

Research: the MS diagnosis just got better in the Netherlands, 26 July 2012; "The increasing incidence amongst woman can be seen with a change in the sex ratio. Why this is occurring is not clear. Some of the increasing incidence can be explained by changes in the rate of smoking amongst woman ...

Research: Sex Ratio with MS increasing in Women, 24 May 2012; METHODS: Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset.

Research: More women than men have MS in Sweden, 22 Jun 2012; Methods:Data from the Swedish MS Register and data from the Swedish National Statistics Office were used to estimate sex ratio by year of birth and year of onset. Results:In the analysis of sex ratio by year of birth there were ...

Article of interest (1): change in sex ratio of MS - Multiple Sclerosis ..., 11 Jun 2011; 2006 Nov;5(11):932-6. This study showed that the female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada. "The incidence of MS is increasing; particularly in woman.

Multiple Sclerosis Research: Research:MS in Women
, 23 May 2012; At the turn of the 1900's Canadian data indicate that the sex ratio of female to males was around is 1 to 1 it is now nearer to 3 to 1. In Iran the ratio is 6:1. MS is increasing in women and staying constant in men. Why is this the ...

Research: the MS diagnosis just got better in the Netherlands

Epub: Kramer et al. Incidence of Multiple Sclerosis in the General Population in the Netherlands, 1996-2008. Neuroepidemiology. 2012 Jul 17;39(2):96-102.

: These investigators estimated the MS incidence (number of cases per year) in the Netherlands in relation to vaccine safety.

Methods: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases.

Results: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005).

Conclusions: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

 "The results of this study are interesting and confirm what we know about MS is other countries; the incidence is increasing in woman and the time to diagnosis has decreased."

"The increasing incidence amongst woman can be seen with a change in the sex ratio. Why this is occurring is not clear. Some of the increasing incidence can be explained by changes in the rate of smoking amongst woman (increased relative males) and cultural changes (addition of UV blockers in cosmetics). However, the sex ratio changes remains largely unexplained."

"The lag time diagnosis relates to wider access to neurological services and in particular MRI scans. Another driver is the change in the diagnostic criteria that allows the diagnosis of MS to occur much earlier for example after the first attack. The latter has implications in that more MSers are being diagnosed with less active disease, which is why the overall prognosis of MS is changing, i.e. getting better. The latter is referred to be statisticians as the Will Rogers effect; i.e. changing the diagnostic boundary between CIS and RRMS, by moving the boundary to the left, improves the outcome of both groups. Interesting? I find the Will Rogers effect or phenomenon fascinating!"

Research: MS and cancer risks in women

Epub: Hemminki et al. Effect of autoimmune diseases on risk and survival in female cancers. Gynecol Oncol. 2012 Jul 18.

OBJECTIVES: People with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited.

METHODS: The investihgators analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIR) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008.

RESULTS: For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma.

CONCLUSIONS: Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks.

"These results indicated that female MSers are at increased risk of ovarian cancer. I suggest this data is confirmed or refuted in another population before we start speculating about potential mechanisms. It is interesting nevertheless."

Wednesday, 25 July 2012

Asssessing infection before steroids

Epub: Rakusa et al. Testing for urinary tract colonisation before high-dose corticosteroid treatment in acute multiple sclerosis relapses: prospective algorithm validation. Eur J Neurol. 2012. doi: 10.1111/j.1468-1331.2012.03806.x

: To evaluate a dipstick algorithm for urinary tract colonisation, prior to high-dose corticosteroid treatment in acute relapses of MS.

: Prospective cohort study of 267 consecutive MSers with MS relapses requiring corticosteroid treatment in a hospital-based, ambulatory, acute MS relapse clinic. A total of eighteen participants met the exclusion criteria, leaving 249 for analysis. Main outcome measures were urinary dipstick sensitivity, specificity, positive predictive value, negative predictive value and safety of antibiotic co-treatment with high-dose corticosteroids.

: Significant bacteriuria (≥10(5) colonies ml) rate in this population was 11% (95% CI, 7.1-14.9). Specificity and sensitivity of positive leucocyte esterase or nitrite were 78% and 65%. Negative predictive value of urine dipstick was 96%. No clinical adverse events occurred in the 3% (95% CI, 0.9-5.1) of patients with a false-negative dipstick. Eighteen per cent of patients were unnecessarily treated with antibiotics for 48h.

: Urinary dipstick testing allows for rapid and safe management of patients suffering from an acute MS relapse. The algorithm is conservative, and future work is needed to reduce the false-positive rate.

This study illustrates two things the problem with diagnostic tests and the issue of bladder infections and the use of steroids. No diagnostic test is 100% accurate this is why we discuss the issue of sensitivity (the chance of a true positive test being positive) and specificity (the chance of a true negative test being negative). The other metrics we often refer to is the positive and negative predictive value of a test; these vary depending on how common the condition is in the population you are applying the test to. The reason why the dipstick test for urinary infection is not ideal is that it mainly relies on the detection of nitrite in the urine; bacteria make an enzyme called nitrate reductase that converts nitrate to nitrite. The problem with this test is that not all bacteria that commonly cause bladder infections make nitrate reductase; in fact only about 70-80% do."

"It is advisable that if someone is about to receive high-dose steroids for a relapse that we make sure they don't have an infection. Steroids suppress the immune system and put MSers at high-risk of developing septicaemia as a complication of the infection. This is why I personally make sure everybody is infection free before prescribing high-dose steroids."

"As you may be aware that infections often exacerbate preexisting MS symptoms that are often then misinterpreted as being a relapse. This why our contemporary definition of a relapse in clinical trials states that the relapse has to occur in the absence of an infection."

MS Register

Epub: Ford et al.The feasibility of collecting information from people with Multiple Sclerosis for the UK MS Register via a web portal: characterising a cohort of people with MS. BMC Med Inform Decis Mak. 2012;12(1):73.

BACKGROUND: A UK Register of people with Multiple Sclerosis has been developed to address the need for an increased knowledge-base about MS. The Register is being populated via: a web-based portal; NHS neurology clinical systems; and administrative data sources. The data are deidentified and linked at the individual level. At the outset, it was not known whether people with MS would wish to participate in the UK MS Register by personally contributing their data to the Register via a web-based system. Therefore, the research aim of this work was to build an internet-mounted recruitment and consenting technology for people with Multiple Sclerosis, and to assess its feasibility as a questionnaire delivery platform to contribute data to the UK MS Register, by determining whether the information provided could be used to describe a cohort of people with MS.
METHODS: The web portal was developed using VB.net and JQuery with a Microsoft SQL 2008 database. UK adults with MS can self-register and enter data about themselves by completing validated questionnaires. Descriptive statistics were used to characterise the respondents.
RESULTS: The web portal was launched in May 2011, and in first three months 7,279 individuals registered on the portal. The ratio of men to women was 1:2.4 (n = 5,899), the mean self-reported age at first symptoms was 33.8 (SD 10.5) years, and at diagnosis 39.6 (SD 10.3) years (n = 4,401). The reported types of MS were: 15% primary progressive, 63% relapsing-remitting, 8% secondary progressive, and 14% unknown (n = 5,400). These characteristics are similar to those of the prevalent MS population. Employment rates, sickness/disability rates, ethnicity and educational qualifications were compared with the general UK population. Information about the respondents' experience of early symptoms and the process of diagnosis, plus living arrangements are also reported.
CONCLUSIONS: These initial findings from the MS Register portal demonstrate the feasibility of collecting data about people with MS via a web platform, and show that sufficient information can be gathered to characterise a cohort of people with MS. The innovative design of the UK MS register, bringing together three disparate sources of data, is creating a rich resource for research into this condition.

The study gives a report of some of the analysis of people who have joined the MS register, which aims to increase the knowledge base of  UK Msers. It had respondents from 18-95. The study reports that there are more professional people with MS than the UK average, but only approximately 42% of our potential MS workforce were in employment. This provides new information about the lives of  people with MS in the UK from their own perspective but as it is open access so that you can read the whole thing if you want. 

If you want to find out more about the MS register or even join it click here

Activated Microglia can kill Oligodendrocytes

Yeo et al. CD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen species. J Neuroinflammation. 2012 16;9(1):173.

CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the mouse microglia cells lines BV-2 and N9, as well as primary mouse microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established mouse model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kills oligodendrocytes.

CD137 is a molecule expressed on T cells with is stimulated by CD137 ligand CD137L. This is found on antigen presenting cells that stimulate T cells and loss of this molecule reduces microglial function. Stimulation by CD137Ligand triggers microglia to kill oligodendrocyte therefore blocking this pathway may be a way to stop damagaing microglia. However we need repairing microglia to repair.

Research: urinary incontinence is common

Murphy AM et al. Prevalence of stress urinary incontinence in women with multiple sclerosis. Int Neurourol J. 2012;16(2):86-90.

PURPOSE: The purpose of this study was to determine the prevalence of stress urinary incontinence (SUI) in women MSers and to what degree these women are bothered by their SUI, since there is a paucity of literature regarding the nature of SUI in this unique population of women.

"SUI is the passing of urine when coughing or straining; in general SUI is not due to MS, but another problem."

METHODS: Women scheduled for outpatient follow-up appointments at a dedicated MS centre were asked to complete a questionnaire regarding urinary incontinence. Urgency urinary incontinence (UUI) and SUI were defined as an answer of slightly, moderately or greatly to the Urogenital Distress Inventory (UDI-6) question #2 and question #3, respectively. Impact of SUI on physical activity was determined by Incontinence Impact Questionnaire (IIQ-7) question #2.

RESULTS: A total of 55.9% (80/143) women had SUI, 70.6% (101/143) women had UUI, and 44.8% (64/143) women had mixed urinary incontinence. The mean age was 45.8 years old (range, 20 to 72 years). Women with SUI were significantly older (mean, 47.2 vs. 41.9; P=0.023) and there was a trend towards a greater body mass index (mean, 29.3 vs. 26.5; P=0.057). Women with SUI had significantly higher IIQ-7 scores compared to women without SUI (P<0.001). Impact of urinary incontinence on physical activity was also found to be significantly greater in women with SUI (mean IIQ-7 question #2, 0.96 vs. 0.35; P<0.001).

CONCLUSIONS: The prevalence of SUI in women with MS is 55.9% and the presence of SUI has a significant impact on their quality of life. A comprehensive urologic evaluation of a woman with MS should include assessment of SUI.

"This is figure is unbelievable; I ask most, if not all, of the MSers who see in clinic about incontinence and I have never seen figures of stress incontinence that were this high. May be I am wrong. I will need to run an audit about this!"

"I am beginning to believe that bladder problems are the indicator symptoms from which a lot of MSers problems start, in other words it is the first domino in the impairment and disability cascade. Once you have moderate bladder problems, frequency, urgency, urgency incontinence and/or hesitancy with incomplete emptying it has a major impact on your QoL and then the course of your MS."

"MSers with bladder problems have difficulty with sleep; they have to get up frequently to go to the toilet. This results in day-time fatigue that then prevents them functioning properly in the day. Bladder problems causes severe anxiety! Were is the next toilet? Will I make it to the toilet? Should I go out? This often leads to MSers becoming socially isolated; they avoid going out because of their bladder problems. This has implications for work."

"Once there is incomplete bladder emptying there is the risk of recurrent infections. There is mounting evidence that recurrent infections may speed up MS disease progression."

"Drugs we use for treating bladder problems have side effects; the older ones that enter the brain make cognition worse, they all make constipation worse and they cause dryness of the mouth. Once there is incomplete emptying MSers have to generally start using intermittent self-catheterising; most MSers don't like doing this - another negative."

"Bladder problems increase health-care utilisation; more doctor appointments more interventions, etc."

"I think one of the quality indicators that should be used for assessing the quality of the MS Services in the UK is how well we judge our management of MS-related bladder dysfunction. What do you think?"