Monday, 31 August 2015

ClinicSpeak: glatiramer acetate experience and persistence

Glatiramer acetate, Teva's cash-cow, has plenty of life left in it! #ClinicSpeak #MSBlog #MSResearch

"I am often asked is there a future for the injectable DMTs. My knee jerk response is yes; the injectables are safe and there a large number of responders out there who will almost certainly want to stay on their current medication. Why? There is no data suggesting that if you are a responder to one class of drug that if you then move to a new class of therapy that you are likely to be a responder to the new class. Interestingly, the study below suggests that interferon-beta failures who switched to glatiramer acetate (GA) do better on GA than those starting the drug as naive to DMTs. Could this observation be telling us about the biology of MS and the DMTs we use to control the disease?"

"Another reason why GA is here to stay is the fact that its safety record in pregnancy is very favourable. This is based on large pregnancy registries that show GA is not teratogenic, i.e. it has not been shown to cause malformations in the foetus, it is not an abortifacient, i.e. increased loss of early pregnancies, it does not affect fertility, i.e. you ability to fall pregnant, it has not impact on labour and it is safe for breastfeeding. In short, out of all the currently licensed maintenance DMTs, GA is the only one that can make these claims."

"You are also probably aware that Teva, who manufacture GA, have now launched a 40 mg three times a week formulation (Copaxone-40), that looks to be as effective as the daily injection formulation (Copaxone-20). If you had an option why wouldn't you switch from the 20 mg daily formulation to the to 40 mg 3x per week formulation? You may not if it is due to affordability. In many countries generic versions of GA are about to be launched; in price-sensitive markets, which are most markets, cheaper versions of GA will disrupt the market."

"Finally, if we could only predict who will be a responder, or non-responder, to GA prior to them starting on treatment then GA will have plenty of life left in it. Who wouldn't you start GA if we could say your chances of responding to this drug (NEDA-3) are greater than 80% or 90%? It is all about risks and benefits; if only we can tip the ratio in favour of the benefits. May be I am wrong?"


Fernández-Fournier et al. Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon. BMC Neurol. 2015 Aug ;15:141. doi: 10.1186/s12883-015-0399-9.

BACKGROUND: In the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs' (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. 

AIMS: We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon.

METHODS: A retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004 - September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney's tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation.

RESULTS: In total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0 %) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3 %) had switched therapy: 27 patients (17.4 %) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9 %) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9 %) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4 %, 82.5 % after 12 months and 72.5 % after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 - 4.8] times greater for treatment-naive patients than for patients treated previously with interferon and this was hardly modified after adjusting for sex and age.

CONCLUSIONS: Glatiramer acetate was safe and useful with low rates of serious adverse events and low rates of break-through disease. Injection intolerance proved a major limitation to glatiramer acetate use. Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.

CoI: multiple

Fingolimod in the real world

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A. Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.
Mult Scler Int. 2015;2015:763418. doi: 10.1155/2015/763418.

Objective. The aim of this prospective observational multicenter postmarketing study was to evaluate fingolimod efficacy in a real world clinical setting. Methods. One hundred forty-two subjects with relapsing-remitting multiple sclerosis (RRMS) were enrolled in three multiple sclerosis centers throughout Central and Southern Italy between January 2011 and September 2013. After enrollment, regular visits and EDSS assessment were scheduled every 3 months, and MRI scan was obtained every 12 months. Patients were followed up from 1 to 33 months (mean 14.95 ± 9.15 months). The main efficacy endpoints included the proportion of patients free from clinical relapses, from disability progression, from magnetic resonance imaging activity, and from any disease activity. Results. Out of 142 patients enrolled in the study, 88.1% were free from clinical relapse and 69.0% were free from disability progression; 68.5% of patients remained free from new or newly enlarging T2 lesions and 81.7% of patients were free from gadolinium enhancing lesions. Overall the proportion of patients free from any disease activity was 41.9%. Conclusions. Our data in a real world cohort are consistent with previous findings that yield convincing evidence for the efficacy of fingolimod in patients with RRMS.

        Fingo in the real world gets it up their with the big boys

Sunday, 30 August 2015

Cell migration in Remyelination


In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the myelin proteolipid protein (PLP). AMPA stimulation of cultured oligodendrocyte progenitor cells (OPCs) also caused an increase in OPC migration. The current studies focused primarily on the formation of the PLP-αv integrin-AMPA receptor complex in vivo and whether complex formation impacts OPC migration in the brain. We found that in wild-type cerebellum, PLP associates with αv integrin and the calcium-impermeable GluR2 subunit of the AMPA receptor, but in mice lacking PLP, αv integrin did not associate with GluR2. Live imaging studies of OPC migration in ex vivo cerebellar slices demonstrated altered OPC migratory responses to neurotransmitter stimulation in the absence of PLP and GluR2 or when αv integrin levels were reduced. Chemotaxis assays of purified OPCs revealed that AMPA stimulation was neither attractive nor repulsive but clearly increased the migration rate of wild-type but not PLP null OPCs. AMPA receptor stimulation of wild-type OPCs caused decreased cell-surface expression of the GluR2 AMPA receptor subunit and increased intracellular Ca(2+) signaling, whereas PLP null OPCs did not reduce GluR2 at the cell surface or increase Ca(2+) signaling in response to AMPA treatment. Together, these studies demonstrate that PLP is critical for OPC responses to glutamate signaling and has important implications for OPC responses when levels of glutamate are high in the extracellular space, such as following demyelination.

What does this mean well we can let the authors explain in this journal

SIGNIFICANCE STATEMENT: After demyelination, such as occurs in multiple sclerosis, remyelination of axons is often incomplete, leading to loss of neuronal function and clinical disability. Remyelination may fail because oligodendrocyte precursor cells (OPCs) do not completely migrate into demyelinated areas or OPCs in lesions may not mature into myelinating oligodendrocytes. We have found that the myelin proteolipid protein is critical to regulating OPC migratory responses to the neurotransmitter glutamate through modulation of cell-surface expression of the calcium-impermeable GluR2 subunit of the AMPA glutamate receptor and increased intercellular Ca(2+) signaling. Altered glutamate homeostasis has been reported in demyelinated lesions. Therefore, understanding how OPCs respond to glutamate has important implications for treatment after white matter injury and disease.

GABA as a neuroprotectant

Cawley N, Solanky BS, Muhlert N, Tur C, Edden RA, Wheeler-Kingshott CA, Miller DH, Thompson AJ, Ciccarelli O Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressivemultiple sclerosis.Brain. 2015;138(Pt 9):2584-95. doi: 10.1093/brain/awv209.

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and post-synaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.

So what this study says is is the GABA (an inhibitory neurotransmitter) levels may be associated with progressive disease. If you can image GABA you will see that people with low GABA are more likely to be progressive. Is this surprising?

It has been suggested, well over a decade ago, that too much nerve excitation can cause nerve damage. This is called excitotoxicity and is one of the nerve damaging mechanisms of stroke and it also believed to be part of MS. This was suggested following EAE in studies over a decade ago.

So what did this mean? 

Well if you block glutamate the major excitable neurotransmitter then it should block excitotoxicity. The only problem is that you need nerve function to live and if you block nerve function there are side effects. In fact quiet a lot of side effects. Anyone working with animals will tell you that is you block the AMPA glutamate receptors there are side-effects.

I wonder why company efforts to use AMPA antagonists have gone no-where?  Pharma make super strong blockers and in animals these types of drugs stop the receptors functioning and so they are useless. But weak blockers are what is needed for this type of target

So the other way to block glutamate is to block NMDA glutamate receptors and again if you use super strong antagonists it will send you doolally. There are some weak anatagonists and memantine is one of them. This drug can experimentally be shown to save nerves, but in the clinic this has not really been shown and again the problem is the balance of effect verses side-effect.

So if blocking the excitatory pathway has the problem of side effects then an alternative way is to boost the inhibitory pathways and the major inhibitory nerve is GABA.

It has long been known that MS there is often an imbalance of gluatamate and GABA and this an other studies indicate that people who progress more have lost GABAergic nerves and so the balance means there is less inhibition which will lead to more excitation and could lead to more nerve damage. This could be at the level of blocking energy deficits that were found some time ago and shown that GABA could block respiratory chain deficits in the mitochondria creating less energy loss so that nerves are better able to tolerate nerve insults.

The obvious lead on from this is that you can enhance GABAergic stimulation and this should be neuroprotective.

What may shock you is that despite thousands of people taking baclofen, there is no data I am aware of on whether it slows the development of MS. This is because pharma and neuros don't follow the people to collect this type of data, because it is viewed as a symptom control drug.

If there was a registry to which people with MS signed up to like the MS register (please sign up) which had access to treatment information may get this information in a few seconds. However, people with more advanced disease are more likely to have spasticity and will therefore be more likely to take baclofen.

Is GABA agonism neuroprotective in animals, it is already known that it can be but GABA is sedating, so it has be brought into the equation as sedation is stressful for animals and this is immunomodulatory. 

Will we be seeing a neuroprotective baclofen/GABApentin etc, trial? 

I suspect that baclofen is neuroprotective may slow progression, so you may have a useful drug already...but is it enough? 

I suscpect the answer is likely to be no because progression is not stopped in people taking baclofen. What is your experience?

However remember the treatment pyramid and you want to layer neuroprotection on top of effective immunomodulation.

Saturday, 29 August 2015

ClinicSpeak: wrists weights work for cerebellar tremors

How good is your hand function? Do you need wrist weights? #ClinicSpeak #MSBlog #MSResearch


"The small study below in MSers with so called cerebellar tremor may be of interest to you. The cerebellum or 'small brain' is the structure at the back of your brain that controls motor function. It is commonly affected in MS and results in uncoordinated and slow movements. When MS lesions occur in the so called outflow pathway from the cerebellum it causes a severe tremor; this type of tremor used to be called a rubral (red) tremor as it was associated with lesions in, or near, the so called rubral (red) nucleus of the midbrain. The following YouTube video is a good example of a cerebellar outflow tremor and illustrates how disabling this type of tremor can be. This type of tremor is also socially isolating; MSers with type of tremor don't like being seen in public."


"In general this tremor responds very poorly to oral medications. The study below, however, shows that physiotherapy and the use of diving, or exercise, wrist weights improves upper limb function. This is my experience as well. By using wrist weights you dampen down the amplitude of the tremor. Increasingly we are sending patients with type of tremor for functional neurosurgery; this involves making a lesion in the thalamus (thalamotomy) using stereotactic techniques (surgical or ultrasound lesion) or inserting a stimulator into the area to block the function of an area of the thalamus. A good predictor of how well someone will be able to function after surgery is to immobilise the arm by holding it tightly, essentially to eliminate the tremor, and to then assess fine alternating finger movements. If the finger movements are still coordinated and rapid then there is a good chance that the patient will have a good result from surgery. However, if the finger movements are slow, incoordinated and inaccurate then surgery won't improve function."

"The great tragedy of this type of tremor in MS, like so many other disabilities, is that it is potentially preventable with early effective treatment."



Vishnu & Rekha. EFFECTS OF WRIST WEIGHING IN REDUCING UPPER LIMB TREMORS IN PATIENTS WITH CEREBELLAR LESIONS. Int J Physiother Res 2015, Vol 3(4):1138-41.

Background: An intentional tremor is one of the most untreated symptoms in patients with cerebellar ataxia. Upper limb tremors decreases the performance of many activities of daily life Thus treatment of patients with tremor probably implies better functional ability. It is one of the major areas of concern to improve functional independence hence, this study proposed to know the effects of wrist weighing in reducing upper limb tremors in cerebellar injury patients.

Materials and Methods: A total number of 21 patients with various abnormalities of cerebellar function were selected. These patients were randomly divided into two groups. One group was treated with wrist weighing by using Velcro weight cuffs for 15 minutes along with conventional physiotherapy for 5 days a week for 2 months & the other group was treated with conventional physiotherapy for 5 days in a week for 2 months. The subjects were tested by using tremor rating scale and nine hole peg test. The values are collected before and after the treatment

Results: In the group treated with wrist weighing the improvement in the tremor rating scale is very significant (p: 0.0001) and in nine hole peg test is extremely significant (p: 0.0001). In conventional therapy group the improvement in the tremor rating scale was significant (p: 0.0051) and in nine hole peg test is very significant (p: 0.0002).

Conclusion: Incorporation of wrist weighing along with conventional therapy reduced the intensity of upper limb tremors in patients with cerebellar injuries but both the treatments are effective in improving upper limb function.

imaging grey matter loss


Freeman L, Garcia-Lorenzo D, Bottin L, Leroy C, Louapre C, Bodini B, Papeix C, Assouad R, Granger B, Tourbah A, Dollé F, Lubetzki C, Bottlaender M, Stankoff B. The neuronal component of gray matter damage in multiple sclerosis: A [11C]-flumazenil positron emission tomography study.
Ann Neurol. 2015 Aug. doi: 10.1002/ana.24468

OBJECTIVE:Using positron emission tomography (PET) with [11 C]flumazenil ([11 C]FMZ), an antagonist of the central benzodiazepine site located within the GABA-A receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric.
METHODS:A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [11 C]FMZ PET imaging and brain magnetic resonance imaging. [11 C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis.
RESULTS: [11 C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([11 C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [11 C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [11 C]FMZ cortical binding correlated with cognitive performance.
INTERPRETATION: This pilot study showed that PET with [11 C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS


Positron Emission Tomography is a method of imaging radio-active substances. Carbon 12 is the  non-radio active variant but carbon 11 is a  rapidly degraded radioactive isotope. Here they make a drug called flumazenil with carbon 11 and this will bind to the GABA-A receptor on  nerves.

The benzodiazepines had already been in wide use as anxiolytics and anticonvulsants for more than ten years before their site of action in the central nervous system, the benzodiazepine receptor, was discovered. Simultaneously, a binding site in the peripheral organs, e.g. heart, lungs and kidneys, was found. Although some benzodiazepines, such as diazepam, bind to both central and peripheral benzodiazepine receptors with a high affinity, these two binding sites exhibit quite different properties. It is already clear that the central benzodiazepine receptors are in many regions of the brain coupled with the receptors for gamma-amino butyric acid (GABA), and they mediate the acute actions of benzodiazepines in the central nervous system. 
The peripheral-type receptors are present on microglia and PET ligands against the peripheral benzodiazepine receptor are used for imaging microglia.

This study shows that grey matter nerves are lost in MS and this is associated with loss of flumazenil binding in both RR and SPMS.

Co-ordinated production and loss of factors are needed for remyelination

Zhao C, Ma D, Zawadzka M, Fancy SP, Elis-Williams L, Bouvier G, Stockley JH, de Castro GM, Wang B, Jacobs S, Casaccia P, Franklin RJ. Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination. J Neurosci. 2015 19; 35:11482-99. 


The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination.
SIGNIFICANCE STATEMENT: Understanding the mechanisms of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced in chronic demyelinating diseases such as multiple sclerosis. In this study, we describe the role of Sox2, a transcription factor widely implicated in stem cell biology, in CNS myelination and remyelination. We show how Sox2 is expressed in oligodendrocyte progenitor cells (OPCs) preparing to undergo differentiation, allowing them to undergo proliferation and priming them for subsequent differentiation. Although Sox2 is unlikely to be a direct therapeutic target, these data nevertheless provide more information on how OPC differentiation is controlled and therefore enriches our understanding of this important CNS regenerative process.

SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells. For repair to occur after demyelination you have to clear up the debris from the damage then the oligoprecursor cells  have to migrate into the areas of damage and you may need to proliferate and then the precursor cells have to differentiate into mature oligodendrocytes and become myelin forming cells. This is co-ordinated and things are turned on an off in the process. This shows that Sox2 is important in in the repopulation of demyelinated areas and gets them ready for  becoming oligodendrocytes, but this needs to be switched off before cells begin remyelinating. This shows that it may not always be a simple case of switch-on things to get effective remyelination.

Friday, 28 August 2015

ResearchSpeak: Vitamin D and MS risk

The best time to plant a tree is twenty years ago. The second best time is now. #ResearchSpeak #MSBlog #MSResearch

"The study below on vitamin D (vD) and MS risk confirms what we already know that low vD levels increase your risk of getting MS. What is really very neat is how the investigators' did this study; they used a very cool method called Mendelian Randomization. Yes, Mendelian comes from Gregor Mendel the monk and father of modern genetics. What you need to remember  that vD levels in your blood are not only related to recent sun exposure and diet, there are several genetic variants that also contribute to your blood levels of vD. For example, a variation the function of a vD activating enzyme will affect your vD levels; if you happen to inherit the variant that is less active your vD levels will be lower than someone with a more active enzyme. These genetic variants are inherited and pass from parents to offspring according to the laws of Mendelian genetics. Mendelian randomization is simply the method of using the genetic variants as a proxy for the biological process under study; it allows you examine the causal effect of a modifiable exposure on disease in a non-experimental way."


"What this study showed that four genetic variants in the genome were significantly associated with vD levels, specifically the 25-hydroxy, or 25OHD, form of vD. Using a Canadian population from an osteoporosis study they found that the number of vD decreasing variants was strongly associated with lower vD levels. Using this information they were able to impute genetically low vD levels based on the number of genetic variants. In short, for each genetically determined one-standard-deviation decrease in vD level (log-transformed) conferred a 2.0-fold increase in the odds of getting MS. In summary genetic causes of low vD levels increase your risk of getting MS. This confirms other evidence linking low vD levels to MS risk."

"How important is this study? Very! It also suggests that is specifically low vD levels, and not lack of sunlight exposure, that is the risk factor for getting MS. What should we do about? We should start an International MS Prevention Study, or possibly two, ASAP. A great disappoint was the output, or more correctly lack of output, of the NMSS vD Prevention Task Force meeting I attended in April 2011 (see programme below). All the MS vD Experts were invited to attend the taskforce meeting with the hope of designing an International Trial vD prevention trial. Unfortunately, there was no consensus and the output of the meeting never saw the light of day; tragically no trial was ever started."

"The next generation of MSers will almost certainly look back at us and say: 'You knew about the link between low vD levels and MS risk and you did nothing about it. Why? I now have MS because of your inactivity'. I will respond: 'guilty as accused!'."




“The best time to plant a tree is twenty years ago. The second best time is now. We really have no excuse not to do an International vD MS Prevention Trial.” 


Mokry et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2015; 12:e1001866.

BACKGROUND: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.


METHODS AND FINDINGS: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple SclerosisGenetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

CONCLUSIONS: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

Low L-selectin as a risk factor for PML

Spadaro M, Caldano M, Marnetto F, Lugaresi A, Bertolotto A.
Natalizumab treatment reduces L-selectin (CD62L) in CD4(+) T cells. J Neuroinflammation. 2015 Aug;12(1):146. doi: 10.1186/s12974-015-0365-x.

BACKGROUND: The purpose of this research was to validate the low expression of L-selectin (CD62L) in natalizumab (NTZ)-treated patients. CD62L is involved in rolling and transmigration of leukocyte cells. A correlation between CD62LCD4(+) T cells low expression and progressive multifocal leukoencephalopathy (PML) development has been suggested in multiple sclerosis (MS) patients treated with NTZ.
METHODS: We performed a flow cytometric analysis on peripheral blood mononuclear cells (PBMC); we collected from 23 healthy donors and 225 MS patients: untreated (n = 19) or treated with NTZ (n = 113), interferon-beta (n = 26), glatiramer acetate (n = 26), fingolimod (n = 23) and rituximab (n = 18). We have also analysed two PML/IRIS (immune reconstitution inflammatory syndrome) patients and four longitudinal samples of a NTZ-treated patients before and during the development of a clinical asymptomatic magnetic resonance imaging (MRI) lesion confirmed as PML by cerebrospinal fluid (CSF) examination. Thirty-five NTZ-treated patients were studied longitudinally with three samples taken 4 months apart.
RESULTS: The NTZ-treated patients showed a lower percentage of CD62L (33.68 %, n = 113) than first-line treated patients (44.24 %, n = 52, p = 0.0004). NTZ effect was already clear during the first year of treatment (34.68 %; p = 0.0184); it persisted in the following years and disappeared after drug withdrawal (44.08 %). Three percent of longitudinally analysed patients showed a percentage of CD62LCD4(+) T cells under a hypothetical threshold and one patient with asymptomatic PML belongs to a group which expressed low percentage of CD62LCD4(+) T cells.
CONCLUSIONS: Our research confirms that NTZ has a specific effect on CD62LCD4(+) T cells consisting in decreasing of the number of positive cells. The low level of CD62L found in a clinically asymptomatic PML patient strengthens its potential usefulness as a biomarker of high PML risk in NTZ-treated patients. A larger study is required to better confirm the data.

MEL14  is antibody name for anti-CD62L

In this study they confirm a previous study that indicates that low levels of CD62Lon T cells is a marker of risk for PML http://multiple-sclerosis-research.blogspot.com/2013/08/finding-marker-of-risk-of-pml.html.

This is related to a recent post where it was reported that soluble CD62L, which is presumably shed by the T cells links to a PML risk. http://multiple-sclerosis-research.blogspot.com/2015/07/to-correlate-or-not-correlatethat-is.html


Flow cytometry is a technique often used to count cells. You stain the cells with a flourescent dye and put them in the flow cytometer it shines a laser onto the cells and if they have the dye they glow and the machine detects this. Non-expressing cells do not glow.

This study highlights a risk that you need to be aware of when you read papers. In a cell sorting machine it normally looks at say 10,000 events or 10,000 cells and does this in a few seconds, so if we get the result that say 20% are type X so in sample there are 2,000 cells. This may mean that in 100,000 cells in the body there are 20,000 cells X.  So we do it again after Natalizumab and there are now 10% positive cells there are 1,000 X cells in the sample. So there is a reduction in cell type X. 

Now, because Natalizumab is stopping cell type Y from entering the CNS rather than stopping cell type X getting into the lymph gland rather than there being 100,000 cells in the blood there are 200,000 cells but still only 20,000 type X cells because they have not been affected.  So you do the same experiment on the flow cytometer and in the 10,000 cell sample you would now only have 1,000 cells X and 10% type X cells. However, it is not cell type X that has gone down but that other cell types have gone up that is the important result.

CD62L is a molecule (a carbohydrate) that helps T cells exit the blood and travel into lymph glands. This molecule is expressed on virgin T cells that have not been activated. They are made in the thymus and then you want them to travel to the lymph glands because that is where sensitizing antigens (infectious agents) are going to be brought by the antigen presenting cells. In the lymph glands if these naive cells see their target antigen, they will divide and expand so on next encounter with the target there are lots of cells there to fight the infection. They then change their surface markers to that of an activated cell. 

One thing is to down regulate CD62L and upregulate CD49d and CD44. This because when there is inflammation in tissues the blood vessels produce vascular cell adhesion molecule (VCAM) bound by CD49d and hyalouronic acid bound by CD44 as a marker to get activated cells into sites of infection. You don't want the virgin cells entering the site of infection as they have not been primed to destroy the infection and there are not many of them. 

So natalizumab works by blocking CD49d on the white blood cells so that they can't bind to VCAM  on the blood vessel and so they get stuck in the blood and increase in number, so it is low CD62L that is marker of how good the antibody is at stopping the CD49d cells getting into the brain and if they can't do this then there is a risk of developing PML.

So as a biomarker is perhaps does not matter in this instance but it is worth thinking about when you read papers with flow cytometry and percentages. For this reason it is often helpful to work in whole cell numbers. 

If there are say 5% CD4 T regs in normal blood with 100,000 cells per microlitre but 40% T regs after Alemtuzumab is this the reason for benefit in MS?.

However this is 40% of 150 cells per microlitre after Alemtuzumab (figures are not accurate) and is there infact less regulation. As this means there were 5,000 per microlitre to start verses  60 cells after treatment and they can't control the B cells (20% of population) which have gone-up in number by 200% in the same period, so 20,000 B cells have become 40,000 B cells and T reg to B cell ratio has gone from 5,000:20,000 (1 in 4 ratio) to 60:40,000 (1 in 333ratio). Is this why we get B cell autoimmunity after alemtuzumab. 

Improved walking with medical cannabis

Coghe G, Pau M, Corona F, Frau J, Lorefice L, Fenu G, Spinicci G, Mamusa E, Musu L, Massole S, Massa R, Marrosu MG, Cocco E.J 
Walking improvements with nabiximols in patients with multiple sclerosis. Neurol. 2015 Aug 5. [Epub ahead of print]

Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion-extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.

You can read the conclusions if interested. If the drug helps spasticity you would hope that it improves mobility. 

Thursday, 27 August 2015

ClinicSpeak: does time matter?

What will it take for us to treat MS more actively? More wheelchairs? #MSBlog #MSResearch #ClinicSpeak

"Does the aphorism 'Time is Brain' apply to MS? Yes, I think it does. When we were attempting to get alemtuzumab licensed as a firstline treatment in Europe, I used the following two case studies to illustrate what the potential price is of delaying access to a highly-active treatment; an 18 month delay and two relapses later is the difference between the two narratives (EDSS 0.0 vs. EDSS 3.5)."

"Both these patients kindly agreed to have their case studies presented and ultimately written-up. Both are out of the MS closet and have published lay summaries of their experiences (see below). I appreciate them doing so; a story, or narrative, makes the trial data relevant and come alive. The following slideshow is a precis of their case reports and tries to put their stories into a contemporary context of treating-2-target of NEDA with a choice of an induction therapy in the hope that it results in long-term remission and possibly an MS cure."

"Why I am I rehashing this theme? Simply because I am currently looking after a patient who clearly illustrates 'Time Matters'. This patient has highly-active RRMS and is JCV seropositive. Whilst she was waiting for her NHS alemtuzumab infusion slot she has had a devastating spinal cord relapse. If she had had her alemtuzumab the week after we had made the decision to go the induction route this relapse would probably have been prevented. She is now EDSS 7.0 with bilateral sphincter involvement. At present she requires a urinary catheter. Although she is likely  to make a recovery from this attack the recovery may be incomplete. I sincerely hope she doesn't pay the price of an NHS delay."

"When you analyse how much time is wasted in MS care pathways you quickly realise that we, the MS community, need to change our attitude to  the management of MS. This is why I am leading on a MS policy document focusing on the issues 'time matters' and 'brain health'. Only after we change our management philosophy and treat MS focusing on long-term brain and spinal cord health will maximise the promised improvements in outcome that our therapies offer relapsing MSers in 2015. May be you disagree?" 


McCarthy et al. Timing is everything in the treatment of multiple sclerosis. BMJ Case Rep. 2015 Apr 15;2015.

We present two similar cases of relapsing-remitting multiple sclerosis, both of whom received treatment with the monoclonal antibody alemtuzumab, but had significantly different long-term outcomes. Patient A is 12 years into his illness and was treated early in his disease course, he has no disability and continues to perform at a high level as a professional golfer. Patient B was initially started on interferon-β1a therapy and went on to have two disabling relapses on this treatment which resulted in a degree of fixed disability prior to the start of alemtuzumab. 10 years into his disease course he has moderate disability and daily symptoms of spasticity in his legs which impair his quality of life. These two contrasting cases highlight the difficult decision of when to start potent immune modulating therapies for multiple sclerosis in young adults who appear well early in their disease but have the potential to rapidly accrue irreversible disability from future relapses.


CoI: multiple and I am a co-author on this paper

Speed makes processing faster.

Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study.
Psychopharmacology (Berl). 2015 Aug. [Epub ahead of print]

RATIONALE:Multiple sclerosis (MS) commonly affects cognitive function, most frequently presenting as impaired processing speed (PS). There are currently no approved treatments for PS in this population, but previous studies suggest amphetamines may be beneficial.
OBJECTIVE: The objective of this study is to determine if mixed amphetamine salts, extended release (MAS-XR) has the potential to improve impaired PS in MS patients in a randomized controlled pre- and post-dose testing study.
METHODS:  Fifty-two MS patients demonstrating PS impairment on either the Symbol Digit Modalities Test (SDMT) or Paced Auditory Serial Addition Test (PASAT) were randomized to a single dose of 5 mg MAS-XR (n = 18), 10 mg MAS-XR (n = 20), or placebo (n = 14). Subjects were evaluated a second time, after taking the blinded medication.
RESULTS: At baseline, the mean SDMT score was 43.3 ± 7.2 and the mean PASAT was 34.8 ± 13.4, with 47 (90.4 %) and 25 (48.1 %) categorized as impaired on the SDMT and PASAT, respectively. The change in SDMT scores from baseline to post-treatment demonstrated significant improvement for the MAS-XR 10-mg dose compared to placebo, increasing by 5.2 ± 4.5 vs. 0.6 ± 4.4 points (p = 0.043), with a medium effect size of 0.47. Change on the PASAT was not significantly different in either treatment group.
CONCLUSIONS: This study supports MAS-XR 10 mg as a potential treatment for MS patients with demonstrated PS impairment, warranting a larger longitudinal study
.



Many years ago in my student days, I used to work in a bar and one of my work colleagues used to take Amphetamine. They talked a mile a minute and I used to watch them clean the bar, collect all the empty glasses and stock the shelves all night long as they could not stand still.  Fighter pilots can fly for along time without sleep after taking amphetamines. 

In this study there was an affect on processing activity,  surprise, surprise no wonder amphetamines are called "Speed".

Killing CD20 T cells

Holley JE, Bremer E, Kendall AC, de Bruyn M, Helfrich W, Tarr JM, Newcombe J, Gutowski NJ, Eggleton P. CD20+inflammatory T-cells are present in blood and brain of multiple sclerosis patients and can be selectively targeted for apoptotic elimination. Mult Scler Relat Disord. 2014;3(5):650-8.

BACKGROUND: A subset of T-cells expresses the B-cell marker CD20 and in rheumatoid arthritis secretes Interleukin (IL)-17. IL-17 secreting T-cells (Th17) have also been implicated in the inflammatory response in the central nervous system in multiple sclerosis (MS) and may be a potential target for elimination by biologic therapeutics. ScFvRit:sFasL comprises of a rituximab-derived antibody fragment scFvRit genetically fused to human soluble FasL that specifically eliminated T-cells.
OBJECTIVE: To determine the presence and phenotype of CD20+T-cells in blood and brain of MS patients. Second, to determine whether scFvRit:sFasL can selectively eliminate CD20+T-cells. After CD20-selective binding, scFvRit:sFasL is designed to trigger FasL-mediated activation-induced cell death of T-cells, but not B-cells.
METHODS: Flow cytometry and immunohistochemistry were used to screen for CD20+inflammatory T-cells in MS blood and brain tissue. ScFvRit:sFasL pro-apoptotic activity was evaluated by Annexin-V/PI staining followed by flow cytometry assessment.
RESULTS:Peripheral blood (n=11) and chronic but not active lesions of MS patient brains (n=5) contained CD20+inflammatory T-cells. Activated CD20+T-cells were predominantly CD4+and secreted both IL-17 and INF-γ. ScFvRit:sFasL triggered CD20-restricted FasL-mediated activation-induced cell death in peripheral blood CD20+T-cells, but not CD20+B-cells.
CONCLUSION: CD20+inflammatory T-cells are present in blood and chronic brain lesions of MS patients. ScFvRit:sFasL selectively eliminated CD20+T-cells and may eliminate pathogenic T-cells without B-cell depletion.


It is clear that anti-CD20 antibodies are very effective at inhibiting relapsing MS. This causes a problem for the dogma of MS in that people say it is a T cell-mediated disease. effective drugs for MS target the B cell.

We know that EAE is a T cell mediated disease but it is claimed that anti-CD20 inhibits EAE also, so EAE is like MS..Problem is it is not. Anti-CD20 B cell depleting antibodies have only a marginal effect on EAE and reduce the severity of disease a little bit and this is believed to workk through affecting antigen presentation to T cells. Rituximab is however very effective in human CD20 expressing transgenic mice. However there it is affecting T cell that must be expressing the transgene.

So if we stick with dogma and MS is caused by T cells and anti-CD20 is very effective then if we only kill the CD20 expressing T cells then it should stop MS, but have fewer side effects because it won't be killing B cells. How can this be done?

Well here they take the anti-CD20 binding part of rituximab formed by the variable region of the heavy and light chains of antibody (click) and make a single chain fragment variable (scFV) construct which is the antigen binding bit of the heavy chain linked to a bit on the light chain. This will bind to the B cells and the CD20-expressing T cells. To this they have attached FAS Ligand, this binds to FAS (CD95) expressed on activated T cells. The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis) so kills the cell. So now they have done this and killed CD20 expressing T cells.

The question is what would happen if this was administered to humans would relapsing MS disappear?  Is it safe?

Wednesday, 26 August 2015

NeuroSpeak: reversible cerebral vasoconstriction syndrome and fingolimod

Another possible vascular complication of fingolimod; reversible cerebral vasoconstriction syndrome #NeuroSpeak #MSBlog

"Reversible cerebral vasoconstriction syndrome (RCVS) is a relatively new condition. I have my first patient admitted under me a few months ago with this condition. She presented with a thunderclap headache whilst running on a treadmill and was admitted with a subarachnoid haemorrhage. An angiogram showed diffuse cerebral vasoconstriction and no aneurysm.  We managed her with nimodipine and she made a good recovery from the acute crisis. A repeat angiogram after discharge was normal. Unfortunately, when I reviewed her in clinic a few weeks ago she has developed migraine headaches and has persistent fatigue, both relatively common complications of a subarachnoid haemorrhage. Her only risk factor for RCVS was borderline hypertension. RVCS has been strongly associated with stimulants (cocaine and amphetamines), serotonin reuptake inhibitors, triptans, tacrolimus and pregnancy states. I was therefore fascinated to read that an MSer on fingolimod had RVCS 3 months post-partum. I can only assume that fingolimod is a risk factor for RVCS. Fingolimod is vasoactive and has been linked to several vascular complications, i.e. macular oedema, hypertension and posterior reversible encephalopathy syndrome  or PRES. I would be interested to see if there have been any more reports of RCVS in MSers on fingolimod?"

"Please note that NeuroSpeak posts are a new feature on this blog and are targeted at neurologists reading this blog. However, if you are an MSer on fingolimod you need to be aware of the vascular complications of fingolimod. Based on this case study and others I would recommend you try and avoid vasoactive stimulants (cocaine, amphetamines, ephedrine, pseudoephedrine, etc.). Please note that pseudoephedrine is the active ingredient in many nasal decongestants and is widely used as an appetite suppressant."


Kraemer et al. Reversible cerebral vasoconstriction syndrome associated with fingolimod treatment in relapsing-remitting multiple sclerosis three months after childbirth. Mult Scler. 2015 Aug . pii: 1352458515600249.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by acute thunderclap headache, evidence of vasoconstriction in conventional angiography or magnetic resonance angiography and reversibility of these phenomena within 12 weeks. Some triggering factors, for example drugs such as selective serotonin reuptake inhibitors, sumatriptan, tacrolimus, cyclophosphamide and cocaine, or states such as pregnancy, puerperium or migraine have been described. We describe the case of a 29-year-old woman with RCVS associated with fingolimod three months after childbirth. This case represents the first report of RCVS in fingolimod treatment.

Are you being sold a curve ball when trying to explain your genes

Explaining, not just predicting, drives interest in personal genomics. Meisel SF, Carere DA, Wardle J, Kalia SS, Moreno TA, Mountain JL, Roberts JS, Green RC; PGen Study Group.
Genome Med. 2015;7(1):74. doi: 10.1186/s13073-015-0188-5. eCollection 2015.

BACKGROUND: There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic aetiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT.
METHODS: Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression.
RESULTS: We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were 'very interested' in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis.
CONCLUSIONS: PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory.

In the age of genomics one can now be genome sequenced for about $1,000 and a few weeks. Maybe we should all be sequenced a birth, it would aid the issue of matching people for transplants, aid in crime prevention, such as rape.  But who holds the information and what will the information be used for such as assessing your risk of developing disease in 50 years time and affecting your insurance premium

So is it good to know your genome make up and will it help predict your medical future? In time maybe and for some things like he Huntingdon mutation, which is dominant maybe..but for MS at present one has to say dream on.

So far about 150 gene variants have been found out of 30,000 genes and none of the genetic variants is an absolute requirement. The other 250 or so genes variants to be found all will all have minor influences, just like the other 149 genes found. The most important is cluster is the human leucocyte antigen,  notably HLA-DR2, which is common in Northern European Stock  In fact if you have 100% of the genes of someone with MS, identical twin studies show that there is a 75% chance you will not get MS. So as a predictive tool is is simply not good enough at present.

Does it help explain your disease? Again it may in the future but for many genes we do not understand what the genetic variants are doing and many of them will mean you have a good immune response to get rid of infections

Next, a problem is having the computational power to work out what it all means as many of the genes will work in networks. I have a genome sequence of a mouse strain. The question is where to start and what to do.

So by all means get yourself genotyped, but it will be some time before it explains your MS.

Genes and response to interferons

Bertoli D, Serana F, Sottini A, Cordioli C, Maimone D, Amato MP, Centonze D, Florio C, Puma E, Capra R, Imberti L.Less Frequent and Less Severe Flu-Like Syndrome in Interferon Beta-1a Treated Multiple Sclerosis Patients with at Least One Allele Bearing the G&C Polymorphism at Position -174 of the IL-6 Promoter Gene.
PLoS One. 2015;10(8):e0135441

One of the most common adverse event of interferon beta (IFNβ) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-α -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFNβ-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-α -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFNβ-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-α had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/anti-pyretic therapy for a more effective FLS prevention.


The promoter region of a gene contains regulatory elements that influence secretion of a protein. In this study they found that if you have a certain gene variant in the interleukin 6 gene that you were less likely to have flu like symptoms after beta interferon injection. Interleukin 6 is produced in response to infection and is known as an endogenous pyrogen (heat) and can induce fever, as heat can help destroy some bacteria. In this study they found that one gene variant was associated with more IL-6.

So now you say you are full of mushroom food MD, because if  you were genotyped it could tell you if you were going to get flu-like symptoms and explain why this is happening. While this may be part of the explanation, some one with the associated gene variant may make less IL-6 than someone without the gene variant because there is overlap as can be seen in figure B above and people without the variant get flu like symptoms. So at present it is a small piece of a bigger jigsaw.

Tuesday, 25 August 2015

ResearchSpeak: could cognitive fatigue be linked to specific neuronal pathways?

Have we found the brain's fatigue pathway? #ResearchSpeak #MSBlog #MSResearch 

"I have been very interested in the neural substrate that underpins fatigue in people in general and in people with MS. Unlike other symptoms there is not a specific area of the brain where the percept of fatigue lies. What I mean is that unlike other sensory percepts (a conscious awareness of sensations) that have a specific area of the cerebral cortex allocated to them there is no area that has been identified for fatigue. Why? I am not sure and this is why we think fatigue is similar to alertness or wakefulness and is controlled by a distributed network that comes from the brainstem."

"The study below suggests that in MSers with fatigue there is a disruption of the projections linking the posterior hypothalamus to the brain stem. This is very interesting; if fatigue can be made worse by focal brainstem or hypothalamic pathology it could explain the disconnect between fatigue and physical disability. Not everyone who is physically disabled necessarily has pathology in this pathway. Similarly, people with 'benign MS' may have a lesion in this pathway and have profound fatigue and no physical or cognitive disabilities. Clearly this study needs to be repeated and some basic science done in this area. Who knows it may lead to a new treatment for MS-related fatigue."

"Did you know fatigue comes out on top of the list of symptoms that MSers would like to get rid of?"

"Please note that the negative affect, or low mood, associated with chronic fatigue is controlled by an area of the brain located the frontal lobe called the anterior cingulate gyrus. This area controls mood and not fatigue. If you lesion this area you potentially remove, or neutralise, the negative emotions that are associated with several unpleasant percepts, for example chronic intractable pain."

"I hope you are beginning to realise that although the central nervous system is modular, it is a highly connected network, which makes decoding its function at a molecular, cellular or network level so interesting. You can't say neuroscience and neurology are boring."



Hanken et al. On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network. Eur J Neurol. 2015 Aug. doi: 10.1111/ene.12815.

BACKGROUND AND PURPOSE: Various causes have been suggested for multiple sclerosis (MS) related fatigue. Hypothalamus-brainstem fibres play a role in sleep-wake regulation and in hypothalamic deactivation during inflammatory states. Hence, they may play a role for experiencing fatigue by changing bottom-up hypothalamic activation.

METHODS: Multiple sclerosis patients with and without self-reported cognitive fatigue and healthy controls were analysed with respect to the integrity of hypothalamus-brainstem fibres using diffusion-tensor imaging based tractography, focusing on the anterior, medial and posterior hypothalamic areas, controlling for clinical impairment and excluding participants with depressive mood.

RESULTS: Multiple sclerosis patients without self-reported cognitive fatigue showed increased axial and radial diffusivity levels specifically for fibres connecting the right posterior hypothalamus with the right locus coeruleus, but not for the medial hypothalamus and the corpus callosum. Moreover, there were no differences between MS patients with and without fatigue in brain atrophy and lesion load, which could explain our results.

CONCLUSION: Multiple sclerosis patients not experiencing fatigue show increased axial and radial diffusivity for fibres connecting the posterior hypothalamus and the brainstem, which might prevent bottom-up activation of the posterior hypothalamus and therefore downregulation of structures responsible for wakefulness and exploratory states of mind.

Now you see and now you don't - Neurofilament predicts visual outcome

Mult Scler. 2015 Aug 17. pii: 1352458515599074. [Epub ahead of print]

Cerebrospinal fluid neurofilament light chain levels predict visual outcome after optic neuritis.

Modvig S, Degn M, Sander B, Horwitz H, Wanscher B, Sellebjerg F, Frederiksen JL

Abstract


BACKGROUND:

Optic neuritis is a good model for multiple sclerosis relapse, but currently no tests can accurately predict visual outcome.

OBJECTIVE:

The purpose of this study was to examine whether cerebrospinal fluid (CSF) biomarkers of tissue damage and remodelling (neurofilament light chain (NF-L), myelin basic protein, osteopontin and chitinase-3-like-1) predict visual outcome after optic neuritis.
METHODS:

We included 47 patients with optic neuritis as a first demyelinating episode. Patients underwent visual tests, optical coherence tomography (OCT), magnetic resonance imaging (MRI) and lumbar puncture. Biomarkers were measured in CSF by enzyme-linked immunosorbent assay (ELISA). Patients were followed up six months after onset and this included visual tests and OCT. Outcome measures were inter-ocular differences in low contrast visual acuity (LCVA), retinal nerve fibre layer (RNFL) and ganglion cell layer+inner plexiform layer (GC-IPL) thicknesses.
RESULTS:

CSF NF-L levels at onset predicted inter-ocular differences in follow-up LCVA (β=13.8, p=0.0008), RNFL (β=5.6, p=0.0004) and GC-IPL (β=4.0, p=0.0008). The acute-phase GC-IPL thickness also predicted follow-up LCVA (β=12.9, p=0.0021 for NF-L, β=-1.1, p=0.0150 for GC-IPL). Complete/incomplete remission was determined based on LCVA from 30 healthy controls. NF-L had a positive predictive value of 91% and an area under the curve (AUC) of 0.79 for incomplete remission.
CONCLUSION:

CSF NF-L is a promising biomarker of visual outcome after optic neuritis. This could aid neuroprotective/regenerative medical advancements.

So the key here is that there are no available tests (biological or imaging wise) which can predict visual outcome following optic neuritis at the time of onset of the disease. Jette Frederikesen's group suggest that CSF (cerebrospinal fluid) NF-L (light chain, heavy chain was not tested here but there is work in the literature suggesting similar outcomes) can predict this in 91% of cases. Equally, as the patients recover, the NF-L levels also dropped, providing proof-of-concept. What I find interesting is the relative load of NF-L in the CSF compartment following optic neuritis (see figures below, 10,000 ng/L is the top standard in the assay) - should we be worried?


Figure: Associations between baseline cerebrospinal fluid (CSF) neurofilament light chain (NF-L) levels and visual outcome parameters after optic neuritis (ON).Associations between CSF NF-L levels measured in the acute phase of optic neuritis and inter-ocular differences in visual outcome measures: (a) low contrast visual acuity (LCVA) function (b) retinal nerve fibre layer (RNFL) thickness and (c) ganglion cell layer+inner plexiform layer (GC-IPL) thickness. A high value on the y-axis thus indicates a poor clinical outcome and high degree of neuronal loss. Correlation coefficients (r=Spearman’s rho) and p-values as calculated by Spearman’s rank correlation analysis are given at the top of each panel.

Nerves affecting colour vision

Lampert EJ, Andorra M, Torres-Torres R, Ortiz-Pérez S, Llufriu S, Sepúlveda M, Sola N, Saiz A, Sánchez-Dalmau B, Villoslada P, Martínez-Lapiscina EH. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. J Neurol. 2015 Aug. [Epub ahead of print]

Multiple Sclerosis (MS) results in color vision impairment regardless of optic neuritis (ON). The exact location of injury remains undefined. The objective of this study is to identify the region leading to dyschromatopsia in MS patients' NON-eyes. We evaluated correlations between color vision and measures of different regions in the afferent visual pathway in 106 MS patients. We evaluated color vision with Hardy-Rand-Rittler plates and retinal damage using Optical Coherence Tomography. 
We found moderate, significant correlations between color vision and macular retinal nerve fiber layer (rho = 0.289, p = 0.003), ganglion cell complex (GCC = GCIP) (rho = 0.353, p < 0.001), thalamus (rho = 0.361, p < 0.001), and lesion volume within the optic radiations (rho = -0.230, p = 0.030). Only GCC thickness remained significant (p = 0.023) in the logistic regression model. In the final model including lesion load and NBPV as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia [OR = 0.88 95 % CI (0.80-0.97) p = 0.016]. This association remained significant when we also added sex, age, and disease duration as covariates in the regression model. Dyschromatopsia in NON-eyes is due to damage of retinal ganglion cells (RGC) in MS. Color vision can serve as a marker of RGC damage in MS.
Again we see a very modest correlation on colour (Color=US Engrish) vision and retinal ganglion damage. 

Have you noticed any influence in colour vision?

Monday, 24 August 2015

Competition to redesign MS Journal cover

The Journal “Multiple Sclerosis and Related Disorders” (MSARD) is inviting artists and designers to improve its front cover with the winning design receiving a prize of £500.

This is what the journal cover currently looks like....


The journal editors are accepting submissions of original artworks or designs for the front cover that are inspired or reference multiple sclerosis or a related disorder. All entries must be emailed to bartsmsblog@gmail.com in a high resolution PDF file.

Each submission can be either a front cover design, including relevant journal information (Journal title, Editors etc.) or an artwork that can be placed alongside this information.

Application process:
  • Application system open August 2015
  • Application deadline Friday 2nd October 2015
  • Winner announced and notified by email Friday 9th October 2015
  • First print and online issue of MSRD Journal will new cover January 2016 
The winning design will be chosen at the ECTRIMS conference on the 6-10th October 2015 by the journal editors. It will be used on the first issue of 2016. There are a number of further print requirements which will communicated to the winning design when it is selected.