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This page documents breaking multiple sclerosis news and research stories as they occur during the month.

For news and research for the previous 12 months please use the links on the menu on the left.

The news stories are taken from external sources and as such, MS-UK does not verify, endorse or accept responsibility for their content.

Some of these pages have been written for medical professionals and this can be reflected in the complexity of language and content. If you have any issues relating to the topics here, please call one of our advisors on 0800 7830 518.

Massage therapy can alleviate symptoms of multiple sclerosis(28/07/14)

An estimated 2.3 million people worldwide live with multiple sclerosis (MS) each day, a debilitating disease that can often cause severe pain, muscle spasms, poor circulation, anxiety, stress and clinical depression. Although not a substitute for regular MS treatment, massage therapy is an effective, complementary and alternative medicine (CAM) that can alleviate such symptoms and in turn, help to pacify the disease.

MS develops as a result of interference between the brain, spinal cord and other areas of the body. Symptoms and treatment vary widely depending on the amount of nerves that are affected. Massage therapy is an easy and affordable complement to doctor-prescribed treatments. Massage therapy may assist MS patients in managing the stress of their symptoms and to improve their quality of life.

A study reported in the Multiple Sclerosis Journal indicated lower pain levels of up to 50 percent across three months by those participants who received 10 weeks of massage therapy. Long known for its stress-busting abilities, massage has a powerful effect on health and overall well-being. And because stress may trigger or worsen MS symptoms, it is important for sufferers to find ways to relax.

"Massage therapy is a well-being approach for addressing body, mind and spirit. Along with stress reduction, massage therapy can help to increase flexibility and reduce muscle stiffness caused by spasticity," states Erin Kersanty, Regional Therapist Coordinator for Massage Envy Spas in the Greater Cleveland-Akron-Canton region. "Massage therapy is also very effective at increasing deep sleep, as touch itself has been known to create positive feelings such as comfort and care. And with more deep sleep, you have less pain," added Tiffany Field, Ph.D., of the University of Miami's Touch Research Institute.

Source: News Medical.Net (28/07/14)

Scientists one step closer to cell therapy for multiple sclerosis patients(25/07/14)

Scientists at The New York Stem Cell Foundation (NYSCF) Research Institute are one step closer to creating a viable cell replacement therapy for multiple sclerosis from a patient's own cells.

For the first time, NYSCF scientists generated induced pluripotent stem (iPS) cells lines from skin samples of patients with primary progressive multiple sclerosis and further, they developed an accelerated protocol to induce these stem cells into becoming oligodendrocytes, the myelin-forming cells of the central nervous system implicated in multiple sclerosis and many other diseases.

Existing protocols for producing oligodendrocytes had taken almost half a year to produce, limiting the ability of researchers to conduct their research. This study has cut that time approximately in half, making the ability to utilize these cells in research much more feasible.

Stem cell lines and oligodendrocytes allow researchers to "turn back the clock" and observe how multiple sclerosis develops and progresses, potentially revealing the onset of the disease at a cellular level long before any symptoms are displayed. The improved protocol for deriving oligodendrocyte cells will also provide a platform for disease modeling, drug screening, and for replacing the damaged cells in the brain with healthy cells generated using this method.

"We are so close to finding new treatments and even cures for MS. The enhanced ability to derive the cells implicated in the disease will undoubtedly accelerate research for MS and many other diseases," said Susan L. Solomon, NYSCF Chief Executive Officer.

"We believe that this protocol will help the MS field and the larger scientific community to better understand human oligodendrocyte biology and the process of myelination. This is the first step towards very exciting studies: the ability to generate human oligodendrocytes in large amounts will serve as an unprecedented tool for developing remyelinating strategies and the study of patient-specific cells may shed light on intrinsic pathogenic mechanisms that lead to progressive MS". said Dr. Valentina Fossati, NYSCF – Helmsley Investigator and senior author on the paper.

In multiple sclerosis, the protective covering of axons, called myelin, becomes damaged and lost. In this study, the scientists not only improved the protocol for making the myelin-forming cells but they showed that the oligodendrocytes derived from the skin of primary progressive patients are functional, and therefore able to form their own myelin when put into a mouse model. This is an initial step towards developing future autologous cell transplantation therapies in multiple sclerosis patients.

This important advance opens up critical new avenues of research to study multiple sclerosis and other diseases. Oligodendrocytes are implicated in many different disorders, therefore this research not only moves multiple sclerosis research forward, it allows NYSCF and other scientists the ability to study all demyelinating and central nervous system disorders.

"Oligodendrocytes are increasingly recognized as having an absolutely essential role in the function of the normal nervous system, as well as in the setting of neurodegenerative diseases,such as multiple sclerosis. The new work from the NYSCF Research Institute will help to improve our understanding of these important cells. In addition, being able to generate large numbers of patient-specific oligodendrocytes will support both cell transplantation therapeutics for demyelinating diseases and the identification of new classes of drugs to treat such disorders," said Dr. Lee Rubin, NYSCF Scientific Advisor and Director of Translational Medicine at the Harvard Stem Cell Institute.

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system, distinguished by recurrent episodes of demyelination and the consequent neurological symptoms. Primary progressive multiple sclerosis is the most severe form of multiple sclerosis, characterized by a steady neurological decline from the onset of the disease. Currently, there are no effective treatments or cures for primary progressive multiple sclerosis and treatments relies merely on symptom management.

NYSCF stem cell researcher Valentina Fossati, PhD, is the senior author and NYSCF researcher Panagiotis Douvaras, PhD, is the first author of this study.

Key collaborators on this research included Dr. Saud Sadiq and the Tisch Multiple Sclerosis Research Center of New York where patients were recruited, Dr. Fraser Sim of the State University of New York at Buffalo for the in vivo studies, and Dr. James Goldman of Columbia University Medical Center.

The New York Stem Cell Foundation research was supported by a NYSCF – Helmsley Early Career Investigator Award, The New York Stem Cell Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. The in vivo studies were supported by the Empire State Stem Cell Fund through New York State Department of Health.

Source: EurekaAlert Copyright ©2014 by AAAS, the science society (25/07/14)

Clinical features and disability progression in multiple sclerosis in Tunisia(25/07/14)

Clinical features and disability progression in multiple sclerosis in Tunisia: Do we really have a more aggressive disease course?

Sidhom Y, Damak M, Riahi A, Hizem Y, Mrissa R, Mhiri C, Gouider R.


BACKGROUND: Few epidemiological data are available on multiple sclerosis (MS) patients in North Africa (NA). Studies of immigrants from NA showed a more aggressive course compared to European patients.

OBJECTIVE: The aim of this study is to describe clinical and long term course characteristics of MS in Tunisia and to compare it to European cohorts.

METHOD: A total of 437 MS patients from three hospital based cohorts in Tunisia and having prospective follow up between 2010 and 2012 were analyzed. We considered as endpoints the time to reach EDSS scores of 3, 4 and 6 in the different clinical forms of MS and the beginning of a secondary progressive (SP) phase.

RESULTS: Sex ratio was 2.34. Mean age of onset was 30.3years. The course was relapsing-remitting (RR) in 91% of patients and primary progressive (PP) in 9%. The most frequent isolated onset symptoms were respectively motor (28%), optic neuritis (20%) and sensory (16%) dysfunction. Median time to SP onset was 19.1years. Median times from onset of multiple sclerosis to assignment of a score of 3, 4 and 6 were 8, 10.7 and 15years respectively. Benign form of MS represented 31.5%. Median interval from the onset of the disease to EDSS score of 3, 4 and 6 was shorter in PP-MS than in RR-MS. However, there was no difference between these two groups for the median time from the assignment of EDSS 4 to the assignment EDSS 6.

CONCLUSIONS: Our study shows that Tunisian MS patients have a quite similar clinical feature to European patients. Still, larger MS multicenter cohort studies in NA with longer follow-up duration could clearly respond to the issue.

Source: J Neurol Sci. 2014 Aug 15;343(1-2):110-4. doi: 10.1016/j.jns.2014.05.049. Epub 2014 Jun 2 & Pubmed PMID: 24980939 (25/07/14)

MS treatment Plegridy™ (peginterferon beta-1a) approved in the European Union(24/07/14)

Biogen Idec has announced that the European Commission (EC) has granted marketing authorization for PlegridyTM (peginterferon beta-1a) as a treatment for adults with relapsing-remitting multiple sclerosis (RRMS), the most common form of multiple sclerosis (MS). Plegridy is dosed once every two weeks and is administered subcutaneously with the Plegridy Pen, a new ready-to-use autoinjector, or a prefilled syringe.

“Plegridy offers people living with MS an interferon with compelling efficacy that requires considerably fewer injections than other platform therapies," said George A. Scangos, Ph.D., chief executive officer at Biogen Idec. “The approval of Plegridy demonstrates our commitment to improving the lives of patients by providing innovative therapies that meet their individual needs, including flexibility in managing their disease.”

Plegridy, the only pegylated interferon approved for use in RRMS, has been proven to significantly reduce important measures of disease activity, including number of relapses, MRI brain lesions, and disability progression.

The EC approval of Plegridy is based on results from one of the largest pivotal studies of a beta interferon conducted, ADVANCE1, which involved more than 1,500 patients with relapsing forms of MS.

In the ADVANCE clinical trial, Plegridy, dosed once every two weeks, significantly reduced annualized relapse rate (ARR) at one year by 36 percent compared to placebo (p=0.0007).

Plegridy reduced the risk of sustained disability progression confirmed at twelve weeks by 38 percent (p=0.0383) and at twenty four weeks by 54 percent (p=0.0069, post-hoc analysis). In addition, the number of gadolinium-enhancing [Gd+] lesions was significantly reduced by 86 percent (p<0.0001) compared to placebo.

Results over two years of ADVANCE confirm that its robust efficacy was maintained beyond the placebo-controlled first year of the study.

“The safety and efficacy that Plegridy has demonstrated, combined with its less frequent dosing schedule offers MS patients an option to put their treatment in the background for longer stretches of time,” said Professor Bernd C. Kieseier, M.D., Heinrich-Heine Universität, Dusseldorf.

The safety and tolerability profile of peginterferon beta-1a observed in ADVANCE1 was consistent with that of established MS interferon therapies. The most commonly reported adverse drug reactions with peginterferon beta-1a treatment (incidence greater-than or equal to 10% and at least 2% more frequent on peginterferon beta-1a than on placebo) were injection site reaction, flu-like illness, fever, headache, muscle pain, chills, injection site pain, weakness, injection site itching, and joint pain.

About Plegridy™

Plegridy is a subcutaneous injectable therapy for relapsing-remitting multiple sclerosis (RRMS), in which interferon beta-1a is pegylated to extend its half-life to permit a less frequent dosing schedule. Plegridy is a member of the interferon class of treatments for MS.

According to the EU Summary of Product Characteristics (SmPC), the recommended starting dose of Plegridy is 63 micrograms at dose 1, increasing to 94 micrograms at dose 2, reaching the full dose of 125 micrograms by dose 3 and continuing with the full dose (125 micrograms) every 2 weeks thereafter.

The safety and tolerability profile of Plegridy observed in ADVANCE1 was consistent with that of established MS interferon therapies. Plegridy should be administered with caution to patients with previous depressive disorders, seizures, severe hepatic impairment and severe renal impairment. Cytopenias, including rare severe neutropenia and thrombocytopenia, have been observed in patients treated with Plegridy. The following have been reported with interferon beta medicinal products including PLEGRIDY: Elevations in hepatic enzymes, serious hypersensitivity reactions, injection site reactions with subcutaneous administration, including injection site necrosis, and worsening of cardiac disease.

In addition, the EU SmPC indicates that the use of interferon beta products is associated with cases of nephrotic syndrome, thrombotic microangiopathy manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), hyper and hypothyroidism, hepatitis, autoimmune hepatitis, rare cases of severe hepatic failure, and decreased peripheral blood counts, including rare pancytopenia.

About Pegylation

Pegylation prolongs the circulation time of the molecule in the body by increasing its size, thus enabling a longer half-life, stabilizing the molecule by improving its solubility and shielding the molecule from enzymes in the body that try to break it down into smaller particles.3 Pegylation is a well-established scientific process that has been used for more than 20 years.

Source: Market Watch Copyright © 2014 MarketWatch, Inc (24/07/14)

JC virus urinary excretion and seroprevalence in natalizumab-treated MS patients(23/07/14)

The risk of developing progressive multifocal leukoencephalopathy (PML), as a consequence of infection/reactivation with JC virus (JCV), is consistent in natalizumab-treated multiple sclerosis (MS) patients, with 430 cases of PML reported so far.

The risk of PML is higher in JCV seropositive patients, and it is recommended that only MS patients without JCV antibodies should be enrolled in the treatment postulating that they do not have JCV infection.

We have studied forty-two natalizumab-treated MS patients, and urine and blood were collected monthly for up to 60 months. JCV and BK virus (BKV) DNA presence was verified using quantitative real-time PCR assays, and serum anti-JCV antibodies were measured with the Stratify and/or Stratify DxSelect tests.

JCV and BKV DNA were not found in the blood samples, whereas they were found at least once in the urine of 21 of 42 (50 %) and of 25/42 (59.5 %) patients, respectively. JCV DNA urinary shedding increased up to month 24 of natalizumab treatment (45.2 %), and the effect of time was significant for JCV (p = 0.04), but not for BKV (p = 0.39). JCV viruria and seropositivity did not completely correlate, since three patients shedding JCV DNA in the urine were seronegative according to the serological tests.

The results indicated that natalizumab therapy may increase the rate of JCV urinary shedding. Additionally, we confirmed that the identification of JCV carriers cannot solely rely on serological tests, but sensitive methods for viral DNA detection should be adopted to more precisely identify the truly JCV uninfected cases.

Source: Science Index Copyright © 2014 ScienceIndex.com (23/07/14)

Researchers discover neuroprotective role of immune cell(22/07/14)

A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer's disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.

The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.

"Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied," Dr. Trapp said. "We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer's disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection."

Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp's team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.

They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called "synaptic stripping"), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.

Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.

Source: Medical Xpress © Medical Xpress 2011-2014 (22/07/14)

Vitamin D and acute optic neuritis in Multiple Sclerosis(22/07/14)

Factors Associated With Recovery From Acute Optic Neuritis in Patients With Multiple Sclerosis

Malik MT, Healy BC, Benson LA, et al

Study Summary

Using their multiple sclerosis (MS) database, the investigators aimed to identify clinical and demographic factors linked to severity and to prediction of recovery from acute optic neuritis (AON). Malik and colleagues enrolled 253 adults and 38 children whose first symptom of MS was AON. The investigators defined a mild AON attack as visual acuity (VA) ≤ 20/40, a moderate attack as VA 20/50-20/190, and a severe attack as ≥ 20/200. At 1 year after the AON attack, complete recovery was defined as VA ≤ 20/20, fair recovery as VA 20/40, and poor recovery as VA ≥20/50.

Proportional odds logistic regression allowed the investigators to identify demographic and clinical characteristics associated with attack severity and recovery among the entire sample. To determine the association of vitamin D level with AON severity and recovery, they analyzed a subgroup of patients for whom blood samples were available within 6 months of an AON attack.

AON recovery was worse in men (adjusted odds ratio [OR], 2.28; P = .03) and in patients with severe AON attacks (adjusted OR 5.24; P < 0.001). Although children and adults had similar AON severity, recovery was significantly better in children in the unadjusted analysis (P = .041) and in the analysis adjusted for sex (P = .029).

Vitamin D level was significantly associated with AON attack severity, after adjustment for season (OR for 10-IU increase in vitamin D level, 0.47; 95% confidence interval, 0.32-0.68; P < .001). However, vitamin D level was not associated with recovery from the AON attack in univariate analysis (P = .98) or after adjustment for AON attack severity (P = .10).


Study limitations include the observational design, relatively small sample size, and inability to prove causality. In addition, vitamin D levels were available for only a subgroup of patients. Nonetheless, the findings suggest that vitamin D levels may affect AON severity, whereas younger age, attack severity, and male sex may affect AON recovery. Further clarification of the underlying pathophysiology may uncover potential therapeutic targets and strategies to limit progression of disability in MS.

Primary Source: Neurology. 2014;82:2173-2179

Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (22/07/14)

Phase I trial of ALKS 8700 to treat multiple sclerosis begins(21/07/14)

Ireland-based biopharmaceutical firm Alkermes has started a Phase I clinical trial of ALKS 8700, a novel monomethyl fumarate (MMF) molecule being developed for the treatment of multiple sclerosis (MS).

The trial will assess the safety, tolerability and pharmacokinetics of several oral formulations of ALKS 8700 compared to both placebo and active control groups in approximately 125 healthy volunteers.

ALKS 8700 is designed to rapidly and efficiently convert to MMF in the body and provide differentiated features compared to the currently marketed dimethyl fumarate, Tecfidera.

Alkermes chief medical officer Elliot Ehrich said: "We expect the results of this study to be highly informative and determine the therapeutic utility and differentiating features of ALKS 8700.

"ALKS 8700 leverages Alkermes' expertise in prodrug chemistry and oral controlled-release formulations to offer potential differentiated tolerability and dosing for patients with MS."

The randomized, double-blind trial will investigate the pharmacokinetics and pharmacodynamics of multiple formulations and doses of ALKS 8700 and is designed to determine those suitable to progress into advanced clinical testing.

The start of the Phase I trial follows the company's filing of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA), and the issuance of a composition of matter patent for ALKS 8700 from the US Patent and Trademark Office (USPTO) in March 2014, which is expected to provide patent protection into 2033.

Source: PBR Contract Research & Services © PBR 2010. Part of Progressive Digital Media Group Plc (21/07/14)

Neonatal vitamin D status and risk of multiple sclerosis(21/07/14)

Ueda P, Rafatnia F, Bäärnhielm M, Fröbom R, Korzunowicz G, Lönnerbro R, Hedström AK, Eyles D, Olsson T, Alfredsson L.


Objective: Low vitamin D status at birth may be associated with risk of adult onset multiple sclerosis, but this link has not been studied directly. We assessed the relation between neonatal vitamin D concentrations, measured in stored blood samples, and risk of multiple sclerosis.

Methods: This was a population-based case-control study in Sweden including 459 incident cases of multiple sclerosis and 663 controls, randomly drawn from a national population registry and frequency matched on sex, age and residential area.

Results: There was no association between neonatal 25-hydroxyvitamin D quintile and risk of multiple sclerosis (crude odds ratio 1.0, 95% confidence interval 0.68 to 1.44, for the highest quintile compared to the lowest). Adjusting for a number of potential confounding factors in early life (month of birth, latitude of birth, breastfeeding) and in adult life (25-hydroxyvitamin D, sun exposure, vitamin D intake from dairy products, fat fish consumption, smoking, body mass index at 20 years of age) as well as ancestry, multiple sclerosis heredity, and socioeconomic group, did not considerably affect the result.

Interpretation: At a broad population level, 25-hydroxyvitamin D at birth was not associated with risk of multiple sclerosis.

Source: Ann Neurol. 2014 Jul 1. doi: 10.1002/ana.24210. & Pubmed PMID: 24985080 (21/07/14)

Walking problems in MS associated with spasticity(21/07/14)

Leg spasticity and ambulation in multiple sclerosis.

Balantrapu S, Sosnoff JJ, Pula JH, Sandroff BM, Motl RW.


Background. Spasticity of the legs is common in multiple sclerosis (MS), but there has been limited research examining its association with ambulatory outcomes.

Objective. This study examined spasticity of the legs and its association with multiple measures of ambulation in persons with MS.

Methods. The sample included 84 patients with MS. Spasticity of the legs was measured using a 5-point rating scale ranging between 0 (normal) and 4 (contracted). Patients completed the 6-minute walk (6 MW), timed 25 foot walk (T25FW), and timed up-and-go (TUG), and O2 cost of walking was measured during the 6 MW. The patients undertook two walking trials on a GAITRite (CIR systems, Inc.) for measuring spatial and temporal parameters of gait. The patients completed the Multiple Sclerosis Walking Scale-12 (MSWS-12) and wore an accelerometer over a seven-day period.

Results. 52% (n = 44) of the sample presented with spasticity of the legs. Those with leg spasticity had significantly worse ambulation as measured by 6 MW (P = 0.0001, d = -0.86), T25FW (P = 0.003, d = 0.72), TUG (P = 0.001, d = 0.84), MSWS-12 (P = 0.0001, d = 1.09), O2 cost of walking (P = 0.001, d = 0.75), average steps/day (P < 0.05, d = -0.45), and walking velocity (P < 0.05, d = -0.53) and cadence (P < 0.05, d = -0.46).

Conclusion. Leg spasticity was associated with impairments in ambulation, including alterations in spatiotemporal parameters and free-living walking.

Source: Mult Scler Int. 2014;2014:649390. doi: 10.1155/2014/649390 & Pubmed PMID: 24999434 (21/07/14)

Sexual function in Multiple Sclerosis(17/07/14)

Correlates of Sexual Function in Male and Female Patients with Multiple Sclerosis.

Lew-Starowicz M, Rola R.


INTRODUCTION: Many factors have been suggested to contribute to sexual dysfunction (SD) in multiple sclerosis (MS) patients, but the research on their impact on sexual functioning (SF) and sexual quality of life (SQoL) remains scant.

AIM: The aim of this study was to investigate correlates of SF and SQoL in MS patients, as well as possible gender differences.

METHODS: 204 MS patients were interviewed, completed the questionnaires, and underwent neurological assessment.

MAIN OUTCOME MEASURE: Primary outcome measures included the International Index of Erectile Function, the Female Sexual Function Questionnaire, the Sexual Quality of Life Questionnaire, the Beck Depression Inventory, and the Expanded Disability Status Scale.

RESULTS: The course and duration of the disease did not predict patients' SF. Negative correlations were found for brainstem symptoms with orgasmic function and overall satisfaction in men and between cognitive functioning and the partner domain in women. Interestingly, brainstem symptoms correlated positively with the arousal domain in women. More than half (52.1%) of patients fulfilled Beck Depression Inventory criteria for depression, and these patients showed more SD than nondepressive individuals. The strongest negative correlations with depressive symptoms were found for desire, erectile function, and overall satisfaction with sexual life in men and for orgasm and sexual enjoyment in women. Deterioration in particular domains of SF was clearly related with diminished SQoL. The main gender difference was a strong influence of decreased desire on SQoL in women and no such correlation in men. Negative assessment of the relationship with partner significantly affected all domains of SF and SQoL in MS women and the desire domain in MS men.

CONCLUSIONS: Several correlates of SF in MS patients were found. The role of brainstem symptoms needs further investigation. Clinicians should pay close attention to depressive symptoms and relationship factors in MS patients who suffer from SD. Lew-Starowicz M and Rola R. Correlates of sexual function in male and female patients with multiple sclerosis.

Source: J Sex Med. 2014 Jun 26. doi: 10.1111/jsm.12622. & Pubmed PMID: 24965105 (17/07/14)

FDA lifts partial clinical hold for CTP-354, a novel drug candidate for spasticity(16/07/14)

Concert Pharmaceuticals, Inc. today announced that the FDA has provided notification that the Company has completed the necessary preclinical toxicology testing in order to administer repeated doses of CTP-354 in excess of 6 mg per day, lifting its partial clinical hold. As a result, the Company intends to initiate dosing of 12 mg per day of CTP-354 in the third quarter of this year as part of its ongoing multiple ascending dose Phase 1 trial.

About CTP-354

CTP-354 is a novel, potentially first-in-class, non-sedating, once-daily oral treatment for spasticity. Concert is initially developing CTP-354 for use in patients with spinal cord injury and in patients with multiple sclerosis to address significant unmet medical needs. CTP-354 is a subtype-selective GABAA receptor modulator. GABAA receptors are found in the nervous system and, when activated, reduce the transmission of certain nerve signals. Several classes of widely used drugs target GABAA receptors, including benzodiazepines, but do not have the receptor subtype selectively of CTP-354.

About Spasticity

Spasticity is a chronic condition characterised by involuntary tightness, stiffness or contraction of muscles that occurs in patients who have damage to the brain or spinal cord. Spasticity can result from a wide range of disorders, including multiple sclerosis, spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis, stroke and hereditary spastic paraplegia. Symptoms can range from mild muscle tightness to more severe symptoms, including crippling and painful inability to move limbs that can result in disability and diminished quality of life. The American Association of Neurologic Surgeons estimated in 2006 that there were 12 million patients suffering from spasticity worldwide.

Source: MarketWatch Copyright © 2014 MarketWatch, Inc (16/07/14)

MRI detects MS progression markers in white matter(16/07/14)

Magnetic resonance imaging shows the combined presence of astrogliosis and axonal damage in white matter, which has cardinal importance in multiple sclerosis (MS) severity, according to an article published in JAMA Neurology.

Researchers from the U.S. and Spain performed a study to evaluate the potential of MR markers of central nervous system injury to predict brain-volume loss and clinical disability among patients with MS.

A total of 59 patients with MS and 43 healthy controls participated in the study. There was also a confirmatory data set that included 220 patients from an independent, large genotype-phenotype research project. Participants were assessed annually over four years for outcomes, which were based on baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination.

The results showed that mI:NAA could be used as a predictor, based on NAA and mI having significant effects on brain volume. “The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: −1.68; 95 percent CI, −3.05 to −0.30; P = .02 in the preliminary study cohort and −1.08; 95 percent CI, −1.95 to −0.20; P = .02 in the confirmatory study cohort),” the authors wrote.

The mI:NAA ratio predicted clinical disability in the preliminary data set as well, they noted. Also predicted were Multiple Sclerosis Functional Composite evolution, Expanded Disability Status Scale evolution, and Expanded Disability Status Scale sustained progression in the confirmatory data set. However, there was no predictive value shown with myelin water fraction.

The authors concluded that “the mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.”

Source: Diagnostic Imaging © 1996 – 2014 UBM Medica, LLC (16/07/14)

NICE backs use of Tecfidera in adults with relapsing-remitting multiple sclerosis(15/07/14)

The National Institute for Heath and Care Excellence (NICE) issued a final appraisal determination backing the use of Tecfidera (dimethyl fumarate) in adults with relapsing-remitting multiple sclerosis (RRMS).

The decision comes after previous negative guidance from health watchdog NICE, which claimed that the drug was not a cost-effective option for the NHS in England and Wales. However, Biogen managed to change NICE's mind partly due to a patient access scheme whereby Biogen will cover part of the cost of the drug. NICE also revised Tecfidera's guidance so the drug cannot be used in patients with highly active or rapidly evolving severe RRMS.

The decision means that Tecfidera is set to become the third oral MS drug recommended by NICE, joining Novartis' Gilenya (fingolimod) and Sanofi's Aubagio (teriflunomide). Both these treatments also struggled to get through NICE's appraisal process, only succeeding once Novartis and Sanofi agreed a patient access scheme.

Gilenya was the first oral MS drug to hit the European market in 2012, and it has since managed to establish itself as a leading product for RRMS, placing in the top 50 pharmaceutical products for 2013.

Both Aubagio and Tecfidera only launched this year in the EU, although both are set to make inroads in a growing MS market. In the UK alone, about 100,000 people have MS and 50 to 60 people each week are diagnosed with the disease.

Tecfidera would have hit the European market earlier but Biogen faced a court battle, which the company won, to classify the drug's active ingredient as a New Active Substance, strengthening its patent protection.

Source: PMLive © PMGroup Worldwide Ltd 2014 (15/07/14)

KIR4.1 ruled out as possible antigen for MS(15/07/14)

Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study.

Brickshawana A, Hinson SR, Romero MF, Lucchinetti CF, Guo Y, Buttmann M, McKeon A, Pittock SJ, Chang MH, Chen AP, Kryzer TJ, Fryer JP, Jenkins SM, Cabre P, Lennon VA.


BACKGROUND: Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions.

METHODS: Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques [eight early active, eight inactive, and six remyelinated], 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases.

FINDINGS: Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosis bound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions.

INTERPRETATION: We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. The target antigen of multiple sclerosis remains elusive.

FUNDING: The National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic Robert and Arlene Kogod Center on Aging.

Source: Lancet Neurol. 2014 Jul 4. pii: S1474-4422(14)70141-3. doi: 10.1016/S1474-4422(14)70141-3. [Epub ahead of print] & Pubmed PMID: 25008548 (15/07/14)

Physical activity & associated levels of disability & quality of life in people with MS(15/07/14)

Multiple Sclerosis (MS) is a common neurodegenerative disease, which often has a devastating effect on physical and emotional wellbeing of people with MS (PwMS). Several studies have shown positive effects of physical activity (PA) on disability, health related quality of life (HRQOL), and other outcomes.

However, many studies include only people with mild disability making it difficult to generalise findings to those with moderate or severe disability. This study investigated the associations between PA and HRQOL, relapse rate (RR), disability, and demographic variables in PwMS with varying disability.

Methods: Through online platforms this large international survey recruited 2232 participants with MS who completed items regarding PA, MS and other health characteristics.

Results: PwMS who were younger (p <.001), male (p = 0.006), and with lower body mass index (BMI) (p <.001) undertook more PA, which was associated with decreased disability (p <0.001) and increased HRQOL measures (all p <0.001).

For the subsample of people with relapsing-remitting MS, PA was associated with a decreased RR (p = 0.009). Regression analyses showed that increased PA predicted clinically significant improvements in HRQOL while controlling for level of disability, age and gender.

More specifically, increasing from low to moderate and to high PA increased estimated mean physical health composite from 47.7 to 56.0 to 59.9 respectively (25.6% change), mental health composite from 60.6 to 67.0 to 68.8 (13.5% change), energy subscale from 35.9 to 44.5 to 49.8 (38.7% change), social function subscale from 57.8 to 66.1 to 68.4 (18.3% change), and overall QOL subscale from 58.5 to 64.5 to 67.7 (15.7% change).

Conclusions: For PwMS, regardless of disability level, increased PA is related to better HRQOL in terms of energy, social functioning, mental and physical health. These are important findings that should be taken into consideration by clinicians treating PwMS.

Author: Claudia H MarckEmily, J Hadgkiss,Tracey J Weiland, Dania M van der MeerNaresh, G Pereira, George A Jelinek

Credits/Source: BMC Neurology 2014, 14:143

Source: 7th Space Interactive © 2014 7thSpace Interactive (15/07/14)

Gait changes with balance-based torso-weighting in people with MS(10/07/14)

Individuals with multiple sclerosis (PwMS) often have mobility impairments that may lead to falls and limitations in activities. Physiotherapy interventions that could improve mobility typically take several weeks. Balance-based torso-weighting (BBTW), a system of strategically placing light weights to improve response to balance perturbations, has resulted in immediate small improvements in clinical measures in PwMS, but changes in spatiotemporal gait parameters are unknown. The purpose was to examine the effects of BBTW on gait parameters in PwMS and healthy controls. This study is a non-randomized controlled experiment. The study was comprised of 20 PwMS and 20 matched healthy controls.

Individuals with multiple sclerosis walked on an instrumented mat at their fastest speed for three trials each in two conditions: without BBTW then with BBTW. Healthy controls walked in both conditions at two speeds: their fastest speed and at velocities equivalent to their matched PwMS. Averaged gait trials showed that, with BBTW, PwMS had significantly increased velocity (p = 0.002), cadence (p = 0.007) and time spent in single-limb support (p = 0.014), with reduced time in double-limb support (p = 0.004). Healthy controls increased velocity (p = 0.012) and cadence (p = 0.015) and decreased support base (p = 0.014) in fast trials with BBTW; at matched velocities, step length (p = 0.028) and support base (p  = 0.006) were significantly different from PwMS. All gait variables in healthy controls at fast speeds were significantly different from PwMS walking at their fastest speeds.

All participants displayed increases in gait velocity and cadence during fast walk with BBTW. Improvements in time spent in single-limb and double-limb support by PwMS with BBTW may reflect greater stability in gait. Future research might ascertain if these immediate improvements could enhance effectiveness of longer-term physiotherapy on functional mobility in PwMS.

Abstract - http://onlinelibrary.wiley.com/doi/10.1002/pri.1595/abstract 

Source: Physiospot Copyright © 2014 Physiospot (10/07/14)

Scottish Medicines Consortium approves Lemtrada for RRMS within NHS Scotland(08/07/14)

"Scotland has one of the highest rates of multiple sclerosis in the world, and the approval of Lemtrada in Scotland is an important step forward for people with active RRMS who remain in need of new treatment options. MS treatments have come a long way in the past twenty years and the availability of Lemtrada provides an opportunity for neurologists to offer a new therapy to people with multiple sclerosis," commented Dr. Belinda Weller, Consultant Neurologist, Western General Hospital, Edinburgh.

The Scottish Medicines Consortium (SMC) today published its advice that Lemtrada has been accepted for use within NHS Scotland for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS), with active disease defined by clinical or imaging features.

"RRMS accounts for eighty-five percent of all initial diagnoses in MS. We are pleased that after many years in development, Lemtrada is now available to patients in Scotland. This provides people with MS with an important and innovative treatment option to consider in partnership with their MS specialists," said Amy Bowen, Director of Service Development at the MS Trust.

There are approximately 10,000 people living with MS in Scotland. The majority of people with RRMS experience approximately one or two relapses per year. Around half of all relapses may leave people with lingering problems and disability may accumulate over time.[

Lemtrada is the second of Genzyme's treatments for MS to receive approval for use from the SMC and become available for use within NHS Scotland.Lemtrada has also been approved by NICE and is available for NHS patients in England & Wales.

"We are thrilled by today's news that the SMC has approved Lemtrada for NHS use for people with RRMS. At Genzyme, patients at the heart of everything we do and this final milestone brings a treatment option to people with MS that could really reshape the management of their condition. We are also immensely proud of our association with Lemtrada as a home-grown product, developed and pioneered in Cambridge by a team of UK scientists. This reminds us of the UK's position at the forefront of science-led medicine, the importance of industry collaboration which brings global expertise in clinical development and our joint commitment to MS patients," commented Brendan Martin, General Manager for Genzyme UK and Ireland.

Source: Medwatch Copyright © 2014 MarketWatch, Inc (08/07/14)

Oceans of Hope leaves Portsmouth(07/07/14)

Oceans of Hope, the 20-metre yacht undertaking the first global circumnavigation by a yacht with a working crew of people with multiple sclerosis, set sail from Portsmouth yesterday following a four-day stopover.

During the 61,000-kilometre (33,000-nautical mile) voyage, which will take 17 months to complete, the Oceans of Hope project aims to inspire people with Multiple Sclerosis (MS) around the world to find a way to follow their dreams.

It hopes to create networks between the MS and sailing communities by organising sailing taster sessions in selected ports of call and on Friday, with conditions perfect, more than 20 people with MS from across the south of England came to Portsmouth to sail on the Thames barge, Alice, and a wheelchair accessible motor boat, Wet Wheels.

Each of the participants found something special in the experience: one commented that it was the first time since he had been diagnosed that he had been able to talk with others about their experiences of the disease, while a former professional sailor found he still had what it takes when the owner allowed him to helm the Thames barge back to her berth and a third said she felt for the two hours that she was on board that she was on holiday.

Oceans of Hope set sail from Portsmouth for La Rochelle, France, at midday yesterday. Phil Gowers, 46, a dentist from Gosport, Hampshire, has joined the crew for this stage of the voyage, which aims to change perceptions of MS by showing what is possible when people with a chronic disease are empowered to conquer their individual challenges.

Phil, whose wife Laura and two sons were at Gunwharf Quays to wave him off, was diagnosed with MS in 2005. Stepping on board Oceans of Hope as he and his fellow crew members prepared to set sail, he said, "I met the crew when they arrived in Portsmouth on Friday and I already feel part of the family. I have been looking forward to getting on board for months. The level of interest in the Oceans of Hope project has been amazing; it really has captured people's imaginations and I hope we inspire others to go out and follow their dreams."

People with MS from all over the world can take part and places are available on board throughout the journey. To find out more and to apply to take part, download the application forms at www.sailingsclerosis.com.

Oceans of Hope is due to arrive in the Bassin des Chalutiers in La Rochelle, France, on the afternoon of Thursday 10 July.

Source: About my area © Copyright 2005-2014 AboutMyArea (07/07/14)

Cytokine signature patterns provide insights into immunomodulatory drug effects(07/07/14)

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients.

O'Connell KE1, Mok T, Sweeney B, Ryan AM, Dev KK.


Multiple sclerosis (MS) is an inflammatory illness characterised by demyelination and axonal neurodegeneration. Here, we used serum samples from MS patients to demonstrate if "cytokine signature" patterns can separate different patient groups better than using single cytokines.

In this case, we used cytokine profiling to demonstrate if "cytokine signature" patterns can separate MS patients treated with interferon or natalizumab from drug naïve patients.

Serum levels of eight individual cytokines (TNFα, IFNγ, S100B, IL-1β, IL-6, IL-8, IL-17 and IL-23) in MS patients treated with interferons (n = 11) and natalizumab (n = 14) were measured and, in general, showed reduced levels compared to drug naïve MS patients (n = 12).

More evident changes were seen when analyzing "cytokine signatures" (i.e. summed value of all eight cytokines), which showed that patients treated with natalizumab and interferons showed significantly reduced cytokine signature levels than drug naïve MS patients.

Moreover, patients treated with natalizumab were separated from drug naïve patients by almost 100% fidelity and that patients treated with natalizumab also had reduced levels of pro-inflammatory cytokines compared to patients treated with interferon.

Overall, this study provides an example showing that the use of "cytokine signatures" may provide benefits over the analysis of single cytokines for the development of potential biomarkers.

Source: Autoimmunity. 2014 Jun 30:1-7. [Epub ahead of print] & Pubmed PMID: 24974887 (07/07/14)

Could existing common medications help restore myelin in MS patients?(07/07/14)

A common cold treatment and seven other drugs already approved for other conditions could help restore a protective coating eroded around neurons in multiple sclerosis patients, according to researchers led by a team at the University of California, San Francisco.

UCSF is spearheading a 50-patient clinical trial of the most promising drug — an over-the-counter antihistamine branded by Novartis as Tavist — that is expected to be completed by the end of the year.

Researchers warn MS patients not to rush out to buy Tavist, which also is sold generically as clemastine fumarate, because its safety and effectiveness is unknown in MS patients. What’s more, they don’t know what the proper dosage or treatment regimen of the drug might be for multiple sclerosis.

Still, the emergence of Tavist and the seven other drugs is a huge potential win for MS patients and researchers who only 14 months ago launched a new method for quickly screening 1,000 drugs already approved by the Food and Drug Administration for other conditions.

“A major unmet need in the development of therapeutics for repair in MS has been the ability to screen compounds in a high-throughput manner,” Jonah Chan, a neurology professor and senior author of a paper that appeared Sunday in the Journal Nature, said in a press release.

The research group includes scientists from Third Military Medical University in Chongqing, China, the University of Cambridge in the United Kingdom, and Trianja Technologies, north of Dallas.

Multiple sclerosis is a central nervous system disease in which the immune system attacks healthy nerve tissue, destroying the fatty myelin sheaths that are meant to protect the cells. By disrupting the electrical signals from the central nervous system to the body, MS leads to muscle weakness, worsening vision, poor balance or coordination, memory problems and other symptoms.

About 2.3 million worldwide have MS, according to the Multiple Sclerosis International Federation.

Researchers for years have focused potential treatments on soothing the inflammation caused by the intermittent and progressively worsening immune system attacks. Over the past decade, however, they have focused much of their work on stopping the erosion of myelin and, potentially, restoring myelin and protecting neurons.

Only last month drug maker Roche, the parent company of South San Francisco-based Genentech Inc., and Menlo Park-based venture capital firm Versant Ventures formed a company focused on regrowing myelin in MS patients. The basis for that company is a screening technology developed by Chan and his colleagues at UCSF.

The new automated system crafted by Chan’s research group, supported by donations to UCSF's MS Research Group, UCSF's Clinical and Translational Science Institute and the National Multiple Sclerosis Society, quickly tested if 1,000 FDA-approved drugs had any effect on oligodendrocyte precursor cells. So-called OPCs are the cells from which oligodendrocytes are derived in the brain and spinal cord, and it is those specialized oligodendrocytes that myelinate extensions of neurons that transmit signals to the brain. All eight drugs identified by the research team have a common mechanism of action — blocking a specific receptor — but clemastine was the most effective, according to UCSF. But there are five types of that receptor expressed in the nervous system and researchers want to know if clemastine blocks a single receptor of a combination.

In the ongoing Phase II trial — the second of the typically three-stage FDA drug-approval process — researchers mainly want to see if clemastine has an effect on MS patients’ vision at one, three and five months of treatment.

Patients in the trial will receive one four-milligram tablet of clemastine or a placebo twice a day for three months.

Source: San Francisco Business Times © 2014 American City Business Journals (07/07/14)

Patients with multiple sclerosis lack support in managing chronic bowel problems(04/07/14)

People with multiple sclerosis (MS) are not receiving the support they need to manage bowel problems, a report has revealed.

It is estimated that 100,000 people in the UK have MS and chronic bowel problems are a common side effect.

Patients and MS nurses were surveyed on their experiences of bowel management and the study revealed that 88 per cent of people with MS were not given any information when first diagnosed with a bowel problem, and almost half had never had the issue raised with them by a healthcare professional.

Amy Bowen, director of service development at the MS Trust, which co-produced the report with healthcare company Coloplast, said: ‘Bowel problems can have a huge impact on the lives of people with MS and can be a difficult issue to raise with the care team.’

She added that specialist nurses play a key role in this area, but services are variable and improvements need to be made.

Source: Nursing Standard © 2014 RCN Publishing Company Limited (04/07/14)

Which are the safest (and least safe) MS drugs on the market?(03/07/14)

A new comprehensive report on the safety of MS drugs may have doctors rethinking their recommendations.

The results are in, and according to a recent report comparing the safety records of all multiple sclerosis (MS) drugs on the market, Tecfidera took the top safety prize. The report reveals that newer MS drugs received high marks for safety, while older interferon drugs had more reported side effects.

California-based health informatics company AdverseEvents analyzed side effects data from the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) database. The FDA asks that doctors, consumers, and drugmakers report any serious negative health events they or their patients experience while taking an FDA-approved drug.

Using a formula called the “reporting odds ratio” (ROR), analysts compare how often an adverse event (AE) has been reported, regardless of drug, to how often the event has been reported for a specific drug in the FAERS database. This helps safety professionals identify AE and drug pairs with a higher than usual occurrence of a particular side effect, sending up a red flag.

Because the ROR is a ratio that is not affected by length of time a drug has been on the market, the analysts at AdverseEvents were able to compare the oldest MS drugs with the newest and compile accurate results, giving each drug an “RxScore.”

So, comparing the AEs reported for all MS drugs only during the time period since Tecfidera won approval did not affect the outcome, said Keith Hoffman, Vice President of Scientific Affairs at AdverseEvents, in an interview with Healthline. “We have completed that time comparison with other drug classes many times and the overall results stayed the same.”

A Few Bad Apples

The RxScore scale ranges from 0 to 100, with higher numbers indicating a greater risk of adverse events. Avonex, Rebif and Betaseron, all interferons, had the worst safety records, with scores between 53 and 55. Copaxone had the fourth highest score at 47.4.

Betaseron had the highest ratio for reports of disability or death, while Avonex users were hospitalized due to AEs the most often.

People taking Avonex reported more malignant tumors, breast cancer diagnoses, and flu-like symptoms than those taking other drugs, while Betaseron users reported more heart attacks, bacterial infections, and liver problems.

Rebif received the worst RxScore, with a higher proportion of negative events including suicidal behavior, optic nerve inflammation, and cancers of the female reproductive system.

Copaxone fared worst for life-threatening allergic reactions and psychiatric symptoms. But Copaxone, FDA-approved in 1996, scored best on measures of several side effects, including cognitive disorders and flu-like symptoms, making it the safest of the older first-line MS drugs.

The Best of the Bunch Tecfidera attained the lowest RxScore of 33 and the lowest ROR of life-threatening events, hospitalizations, disability, or death. It also scored lowest for everything from bacterial infections to optic nerve disorders and liver problems. Overall, Tecfidera had the lowest ROR for 24 out of the 58 side effects the researchers studied.

Gilenya scored second best at 39.4, but users had more cardiac-related AEs, including lowered heart rate, and the drug also scored the worst for vision disorders and skin cancers. Gilenya, FDA-approved in 2010, did not hold the lowest score for any reported AEs.

Aubagio, with the same RxScore as Gilenya, had the highest number of reports of diarrhea, but that’s the only side effect for which it scored the highest, making it among the safest of the MS therapies.

Tysabri scored relatively well but had the highest ROR for cognitive disorders, JC virus positive tests, and secondary progressive MS. The report also concluded that the relationship between Tysabri and primary multifocaleukoencephalothopy, or PML, a rare and deadly brain infection, was confirmed.

Extavia had the worst safety score of any of the new MS drugs at 44.9, and users suffered the most depression, falls, headaches, and injection site reactions.

What Does It All Mean?

The FAERS database only examines side effects, not effectiveness. And it cannot predict side effects that may emerge over time.

“We are limited by what is recorded into FAERS,” Hoffman points out. “If a safety concern takes years to manifest after a drug’s approval we will not see those reports until they are filed.”

Although this report is an effective tool for neurologists recommending drugs to their patients, doctors must also consider each drug's effectiveness. Does it have a track record for reducing relapses, preventing disability, or protecting neurons?

Weighing the risks and benefits is a crucial process when selecting a drug for an MS patient. And everyone’s MS experience is different. Nobody will have all of the reported side effects—or all of the benefits.

Source: Healthline Copyright © 2005 - 2014 Healthline Networks, Inc (03/07/14)

Increased MS relapse rates after Tysabri discontinuation (02/07/14)

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab -
Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

Marinella Clerico, MD; Irene Schiavetti, BS; Stefania F. De Mercanti, MD; Federico Piazza, MD; Dario Gned, MD; Vincenzo Brescia Morra, MD; Roberta Lanzillo, MD; Angelo Ghezzi, MD; Anna Bianchi, BS; Giuseppe Salemi, MD; Sabrina Realmuto, MD; Patrizia Sola, MD; Francesca Vitetta, MD; Paola Cavalla, MD; Damiano Paolicelli, MD; Maria Trojano, MD; Maria Pia Sormani, BS; Luca Durelli, MD


Importance: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).

Objective: To evaluate the effect of therapeutic choices on the mean annualised relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS.

Design, Setting, and Participants: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centres (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab.

Interventions: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod.

Main Outcomes and Measures: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year.

Results: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery.

Conclusions and Relevance This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.

Trial Registration Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Source: JAMA Neurology © 2014 American Medical Association (02/07/14)

CCSVI trial reports no benefit with venous angioplasty(02/07/14)

Prospective randomized trial of venous angioplasty in MS (PREMiSe).

Siddiqui AH, Zivadinov R, Benedict RH, Karmon Y, Yu J, Hartney ML, Marr KL, Valnarov V, Kennedy CL, Ramanathan M, Ramasamy DP, Dolic K, Hojnacki DW, Carl E, Levy EI, Hopkins LN, Weinstock-Guttman B.


OBJECTIVE: We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072).

METHODS: Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life.

RESULTS: No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected.

CONCLUSION: Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity.

CLASSIFICATION OF EVIDENCE: This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty. This study also includes a Class IV phase 1 study of safety in 10 patients receiving the angioplasty procedure.

© 2014 American Academy of Neurology.

Source: Neurology. 2014 Jun 27. pii: 10.1212/WNL.0000000000000638. [Epub ahead of print] & Pubmed PMID: 24975855 (02/07/14)

'Master switch' for myelination in human brain stem cells is identified(01/07/14)

Scientists at the University at Buffalo have identified the single transcription factor or "master switch" that initiates the critical myelination process in the brain. The research will be published online in Proceedings of the National Academy of Sciences (PNAS) on June 30.

The identification of this factor, SOX10, in human brain cells, brings researchers closer to the goal of treating multiple sclerosis (MS) by transplanting into patients the brain cells that make myelin.

"Now that we have identified SOX10 as an initiator of myelination, we can work on developing a viral or pharmaceutical approach to inducing it in MS patients," says Fraser Sim, PhD, senior author on the paper and assistant professor in the UB Department of Pharmacology and Toxicology in the School of Medicine and Biomedical Sciences.

"If we could create a small molecule drug that would switch on SOX10, that would be therapeutically important," he adds.

Stem cell therapy is seen as having dramatic potential for treating MS, but there are key obstacles, especially the length of time it takes for progenitor cells to turn into oligodendrocytes, the brain's myelin-making cells.

Using currently available methods, Sim explains, it can take as long as a year to generate a sufficient number of human oligodendrocyte cells to treat a single MS patient. That's partly because there are so many steps: the skin or blood cell must be turned into induced pluripotent stem cells, which can differentiate into any other type of cell and from which neural progenitor cells can be produced. Those progenitor cells then must undergo differentiation to oligodendrocyte progenitors that are capable of ultimately producing the oligodendrocytes.

"Ideally, we'd like to get directly to oligodendrocyte progenitors," says Sim. "The new results are a stepping stone to the overall goal of being able to take a patient's skin cells or blood cells and create from them oligodendrocyte progenitors," he says.

Using fetal (not embryonic) brain stem cells, the UB researchers searched for transcription factors that are absent in neural progenitor cells and switched on in oligodendrocyte progenitor cells.

While neural progenitor cells are capable of producing myelin, they do so very poorly and can cause undesirable outcomes in patients, so the only candidate for transplantation is the oligodendrocyte progenitor.

"The ideal cell to transplant is the oligodendrocyte progenitor cell," Sim says. "The question was, could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?"

To find out, they looked at different characteristics, such as mRNA expression, protein and whole gene expression and functional studies.

"We narrowed it down to a short list of 10 transcription factors that were made exclusively by oligodendrocyte progenitor cells," says Sim. "Among all 10 factors that we studied, only SOX10 was able to make the switch from neural progenitor to oligodendrocyte progenitor cell," says Sim.

In addition, the UB researchers found that SOX10 could expedite the transformation from oligodendrocyte progenitor cell to differentiation as an oligodendrocyte, the myelin-producing cell and the ultimate treatment goal for MS.

"SOX10 facilitates both steps," says Sim.

That's tantalizing, he says, because one of the biggest problems with MS is that cells get stuck in the step between the oligodendrocyte progenitor cell and the oligodendrocyte. "In MS, first the immune system attacks the brain, but the brain is unable to repair itself effectively," explains Sim. "If we could boost the regeneration step by facilitating formation of oligodendrocytes from progenitor cells, then we might be able to keep patients in the relapsing remitting stage of MS, a far less burdensome stage of disease than the later, progressive stage."

Sim is also an investigator with other scientists at UB and the University of Rochester on the $12.1 million New York State Stem Cell Science award led by SUNY Upstate Medical Center. The research will test the safety and effectiveness of implanting stem cells that can reproduce myelin into the central nervous system of MS patients.

Source: Medical Xpress © Medical Xpress 2011-2014 (01/07/14)

Regional brain damage linked to fatigue in MS(30/06/14)

Fatigue, a common symptom of multiple sclerosis, could be a result of regional damage in the brain. A study published in Radiology by a group in Italy led by Massimo Filippi, MD, from Vita-Salute San Raffaele University showed that local, rather than global, atrophy is associated with fatigue.

Sixty five patients with multiple sclerosis, 31 fatigued and 32 nonfatigued, and 35 control participants were analysed with a specialised type of brain scan: dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor magnetic resonance imaging. The degree of atrophy and damage to lesions, normal-appearing white matter, and gray matter were compared among groups.

Between both types of multiple sclerosis patients and control participants, there was more global damage to gray and white matter in multiple sclerosis patients. But compared to nonfatigued patients and control participants, fatigued multiple sclerosis patients had remarkable changes in specific regions of the brain. Regional atrophy in the right nucleus accumbens, right inferior temporal gyrus, and left frontal gyrus was associated with fatigue, measured by the Fatigue Severity Scale. Furthermore, the fatigued patients showed greater evidence of damage to the forceps major, left inferior frontoccipital fasciculus, and right anterior thalamic radiation.

To predict fatigue, the researchers were able to use right inferior temporal gyrus and right anterior thalamic radiation damage as reliable predictors of patient fatigue. According to the journal article, “This study supports the use of multimodal magnetic resonance imaging and regional analysis to assess fatigue in patients with multiple sclerosis.”

The researchers are now interested in longitudinal studies to make up for some limitations of the present study. The team is interested in knowing more about fatigue in patients with the main clinical symptoms of multiple sclerosis and how it correlates to function and structure. Specifically, they would integrate functional magnetic resonance imaging to define a pathogenetic link between atrophy and fatigue severity.

A better understanding of how fatigue develops in multiple sclerosis patients could help patients whose daily lives are affected by fatigue.

Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (30/06/14)

Spinal cord loss associated with disability in MS(30/06/14)

Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.

Lukas C, Knol DL, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Weier K, Radue EW, Gass A, Kappos L, Naegelin Y, Uitdehaag BM, Geurts JJ, Barkhof F, Vrenken H.


OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort.

METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24?months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24?months.

RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24?months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24?months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression.

CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

Source : J Neurol Neurosurg Psychiatry. 2014 Jun 27. pii: jnnp-2014-308021. doi: 10.1136/jnnp-2014-308021. [Epub ahead of print] & Pubmed PMID: 24973341 (30/06/14)

Tysabri has an effect on oligoclonal bands in the cerebrospinal fluid of MS patients(26/06/14)

Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: A longitudinal study.

Mancuso R, Franciotta D, Rovaris M, Caputo D, Sala A, Hernis A, Agostini S, Calvo M, Clerici M.


Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients.

In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy.

Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.

Source: Mult Scler. 2014 Jun 16. pii: 1352458514538111. [Epub ahead of print] & Pubmed PMID: 24948690 (26/06/14)

Cognitive impairment in multiple sclerosis: An 18-year follow-up study(25/06/14)

Researchers at Kessler Foundation and the Cleveland Clinic have published one of the longest longitudinal studies of cognition in multiple sclerosis (MS). The article, "Cognitive impairment in multiple sclerosis: An 18-year follow-up study," was epublished by Multiple Sclerosis and Related Disorders on April 13, 2014. Results provide insight into the natural evolution of cognitive changes over time, an important consideration for researchers and clinicians. Authors are Lauren B. Strober, PhD, of Kessler Foundation and Stephen M. Rao, PhD, Jar-Chi Lee, Elizabeth Fisher, PhD, and Richard Rudick, MD, of the Cleveland Clinic.

"While cognitive impairment is known to affect 40 to 65% of individuals with MS, few studies have followed the pattern of cognitive decline over time, which is important for understanding long-term care and outcomes associated with MS," said Dr. Strober, senior research scientist at Kessler Foundation. "Our study was based on a unique sample of 22 patients who underwent neuropsychological testing at entry into the original phase 3 clinical trial of intramuscular interferon beta-1a, and again at 18-year followup."

At baseline, 9 patients (41%) had cognitive impairment; at 18-year followup, 13 patients (59%), were found to be impaired. Significant declines over time were found in information processing speed, auditory attention, memory, episodic learning and visual construction. Decline was steeper in the unimpaired than in the impaired group, as indicated by the Symbol Digit Modalities Test (SDMT).

"These longitudinal data contribute substantially to our knowledge of the course of cognitive decline in MS," noted John DeLuca, PhD, VP of Research & Training at Kessler Foundation. "In light of the young age at diagnosis, this perspective is fundamental to the development of rehabilitation strategies that meet the needs of people dealing with the cognitive effects of MS."

The study was funded by Biogen Idec.

Source: Medical Xpress © Medical Xpress 2011-2014 (25/06/14)

Tapping UCSF invention, Roche and Versant dive into myelin repair(23/06/14)

When mice chew through the insulation that protects a house’s wires, an electrician can repair the wires. People with multiple sclerosis, whose immune systems malfunction and attack the insulation of their own neural wires, don’t have that option. Helping them could be a very big deal in MS care.

Swiss drug giant Roche, tapping into an unorthodox business model created by a San Francisco venture group, wants to find treatments to help. Roche and Versant Ventures have created the oddly named Inception 5—we’ll explain the name later—to house a promising new way to look for multiple sclerosis drugs, a high-throughput screen developed at the University of California, San Francisco.

Roche will contribute its vast libraries of compounds to test in the UCSF assay, and a seasoned team of drug discovery scientists in the employ of Versant’s Inception group will also try to design new compounds.

Repairing the neural insulation is called remyelination. Myelin is the substance that makes up the sheaths, and it’s also what the immune system mistakes for a pathogen. The attack leaves holes in the myelin, and like a house with faulty wiring, the patient’s nervous system starts to short-circuit, leading to a wide and unpredictable range of neurological symptoms.

While drug makers have produced improvements with drugs that tamp down the immune system’s attack, nothing is available to reverse the actual myelin damage. (Two monoclonal antibody therapies, one from Biogen Idec, Anti-LINGO-1, and another from Acorda Therapeutics, rHIgM22, are in the clinic.)

The UCSF assay, created by neurology professor Jonah Chan, is an innovative way to get at a thorny problem: It’s really hard to build tests that demonstrate remyelination. Neurons, the cells that need to be remyelinated, are finicky to grow in the lab. Also a problem: oligodendrocytes, the cells that produce myelin, don’t wrap their myelin around the axons of neurons in an easily measurable way. (Axons are the branching arms of neurons that transmit electrical signals.)

There are other reasons, too, but Chan created a work-around: Build tiny silica cones that encourage oligodendrocytes to wrap their myelin cleanly. In other words, he built axons from pure glass. And when those silica cones (which Chan calls “micropillars”) are lined up in a testing plate, their cone shape allows measurement of the myelin thickness as it wraps around. Imagine reading the myelin as if it were the rings in the cross-section of a tree.

“Jonah’s done a great job,” said Jay Tung, chief research officer of the Myelin Repair Foundation in Saratoga, CA, which has worked with Chan in the past. “We are ecstatic about pharma, academics, startups, anyone moving the field forward. This is exactly what we want to see.”

“My view is that the missing link for finding candidate therapies for myelin repair has been the lack of a platform for efficient high-throughput screening of agents,” said Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society in New York. The nonprofit funded much of Chan’s work that went into the micropillars. “The complexities of co-culture systems just don’t lend themselves to HTS. Jonah’s technology fills that critical gap.”

With the screening platform, researchers can test how thousands of drugs spur oligodendrocytes to produce myelin. That’s exactly what Inception 5 plans to do.

The group is part of a Versant initiative to keep its own drug-discovery team in-house at a company called Inception Sciences, led by a group of scientists who, at the Merck-Frosst labs in Montreal, had a string of successes including the painkiller rofecoxib (Vioxx)—later withdrawn from the market for safety concerns—and the asthma drug montekulast (Singulair). One of those scientists, Peppi Prasit, and Versant teamed up to create Amira Pharmaceuticals, which they sold in 2011 for $475 million.

Prasit and Versant managing director Brad Bolzon (right) immediately pivoted to launch Inception Sciences, which describes itself as a “small-molecule pharmaceutical incubator.” It is wholly owned by Versant and has two labs, one in San Diego, another in Vancouver. A third is about to open as well.

Instead of turning Inception Sciences into a sprawling biopharma, Versant uses a few million dollars at a time to fund Inception spin-offs that it partners with outside drug companies. (Hence the Inception 5 name; there are four other spinoffs, with more soon to be announced, according to Bolzon.) With Inception 5, Roche is paying for the research and has the option to buy the company outright once the Inception team files an IND, which is industry shorthand for asking the Food and Drug Administration permission to test a drug in humans.

Chan told Xconomy his work had drawn a lot of industry interest, but meeting the Inception scientists at their San Diego facility last year “hooked him.” Two people in particular, the medicinal chemist Brian Stearns and the biologist Daniel Lorrain, were “very impressive,” said Chan. “They’re so focused on developing products and new drugs. It made perfect sense.”

Chan also liked the idea of a third party like Inception between his work and Roche, which previously had asked him directly to screen their compounds in his lab. “That wasn’t appealing,” he said. “I didn’t want to be a service provider for companies.”

Instead, Chan and his students can get back to basic research and leave the screening work to others. “I’m just a lab rat,” he said. “It’s up to the drug hunters to take the next steps.”

Chan and his fellow UCSF neurology professor Ari Green, also an MD who treats multiple sclerosis patients, are among Inception 5’s founders and have an undisclosed equity stake. (Versant is the main owner, and Inception’s employees also take equity in each spinout.)

Even as the micropillar screen goes over to Inception 5, Green is overseeing a 50-person trial at UCSF with a drug he and Chan found with the screen. Like much of the work surrounding myelin repair, Green is taking a creative tack to measure the drug’s effect. The trial measures the speed at which light shone in a patient’s eye is converted into a signal in the brain. Myelin damage to the optic nerve slows that conversion. Patients whose speed improves during the trial might be experiencing myelin repair.

Data could be ready by the end of the year, but the trial isn’t meant to get a new drug on the market. They’re testing an off-patent, over-the-counter antihistamine, and its drowsy effect on patients rule out its potential as an MS drug. “Fatigue is the number-one issue for MS patients,” said Green. “But if this trial goes well, we’ll pursue funding for a large scale clinical trial, because even if it doesn’t lead to development of a therapeutic, it’ll help advance the field.”

It’s a field full of unknowns. As promising as Chan’s micropillars are, they’re synthetic. They only approximate how myelin would wrap around real axons, and they lack the complicating factor of inflammation in the micro-environment. Tung of the MRF says his group has an “intense focus” to move toward a high-throughput screen without using a synthetic material. Inception 5 will work on next-generation assays, too, says Green.

If Roche pulls the trigger and buys Inception 5, it will take the micropillar screen with it, which doesn’t sit well with Tim Coetzee of the NMSS. “If this platform technology got walled off from rest of the world, I’d be worried,” said Coetzee. “This is about MS, but we’re also starting to see defects in myelin in Alzheimer’s, ALS, and other diseases. It’s not as profound right now as MS, but there are other places this technology could have relevance.”

Source: Xconomy © 2007-2014, Xconomy, Inc (23/06/14)

Could the first sign of Parkinson's and multiple sclerosis be a dodgy tummy? (23/06/14)

Anxiety or anticipation can often lead to a feeling of ‘butterflies in the stomach’ – which usually dissipates along with the source of the consternation.

But scientists have discovered that the nerve pathways between the gut and the brain that cause this phenomenon may also be linked to degenerative illnesses such as Parkinson’s disease and multiple sclerosis (MS), as well as some mental health problems.

Dr Anton Emmanuel, consultant neuro-gastroenterologist at University College London and the National Hospital for Neurology, explained: ‘The gut and brain share the same nerve chemistry and have a dialogue.

'That’s why when you feel stress and other strong emotions, such as fear, it leads to gastrointestinal symptoms, like rushing to the loo.’

A new study suggests that brain disease can be caused by an unhealthy gut because these signals also travel in the opposite direction.

The study, which was published in the journal Movement Disorders, found that sufferers of Parkinson’s disease had a higher prevalence of a condition called small intestinal bacterial overgrowth, or SIBO.

In SIBO, normally harmless bacteria proliferate in large numbers in the small intestine.

Symptoms include excess gas, abdominal bloating, diarrhoea and abdominal pain. Nobody is sure how many people have it, as it often goes undiagnosed or is confused with irritable bowel syndrome, but estimates are of up to 300,000 British sufferers.

And the researchers suggest that the bacteria may produce chemicals that affect the nerves in the gut, which pass on the damage to the brain – and result in Parkinson’s and MS. Dr Emmanuel said: ‘We now think that neurological diseases such as MS and Parkinson’s are linked to the gut being more leaky, permitting pathogens into the bloodstream and causing an antibody response. Either the pathogens, directly, or the immune response, indirectly, may damage nerve tissue.’

The damaged nerves then transmit these detrimental signals to the brain.

In Parkinson’s, a small part of the brain becomes progressively damaged over many years, something that affects mainly older people. MS is the most common neurological disease in young adults and occurs when the immune system attacks the nervous system.

The two diseases affect about 100,000 and 127,00 people in the UK respectively. Both have wide-ranging symptoms, affecting movement as well as causing tiredness, pain and depression. There are drugs that can ease symptoms, but no cure or even treatments that significantly slow down progression of the diseases.

Scientists hope that this discovery will pave the way for new treatments for both these disabling conditions.

They are now mapping the ‘bacterial genome’, which will identify the bacteria in an individual’s gut – something they hope will ultimately allow doctors to prescribe tailored treatments for leakiness of the gut, improving neurological symptoms in turn.

Until then, the doctors’ body United European Gastroenterology urges people to maintain a healthy diet, including foods that boost good bacteria and encourage efficient digestion. This may have an especially positive effect on mood disorders such as anxiety and depression.

They recommend eating plenty of fibre and probiotics such as live yogurt, as well as limiting sugar, processed foods, animal fat and the use of antibiotics, antacids and anti-inflammatories, as these cause imbalances in the gut.

Source: The Daily Mail © Associated Newspapers Ltd (23/06/14)

Measuring brain shrinkage in Multiple Sclerosis(23/06/14)

Sub-Millimeter Imaging of Brain-Free Water for Rapid Volume Assessment in Atrophic Brains.

Gao KC, Nair G, Cortese IC, Koretsky A, Reich DS.


INTRODUCTION: Cerebral atrophy occurs in healthy aging, and in disease processes such as multiple sclerosis (MS), it correlates with disability accumulation. Imaging measurements of brain atrophy are commonly based on tissue segmentation, which is susceptible to classification errors and inconsistencies. High-resolution imaging techniques with strong contrast between brain parenchyma and cerebrospinal fluid (CSF) might allow fully automated, rapid, threshold-based determination of the free water in the brain. We hypothesized that total brain-free-water (BFW) volume and BFW volume expressed as a normalized fraction of the intracranial volume ("BFW fraction"), determined from heavily T2-weighted images, would be useful surrogates for cerebral atrophy and therefore would correlate with clinical measures of disability in MS.

METHODS: Whole brains of 83 MS cases and 7 healthy volunteers were imaged with a 4.7-min, heavily T2-weighted sequence on a 3T MRI scanner, acquiring 650-μm isotropic voxels. MS cases were clinically assessed on Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale (SNRS), Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HP), Symbol Digit Modalities Test (SDMT), and 25-Foot Walk. Twelve of the MS cases were rescanned within an average of 1.8months to assess reproducibility. Automated calculations of BFW volume and BFW fraction were correlated with clinical measures of disability upon adjusting for age and sex. Results were compared to data from T1-based approaches (SIENAX and Lesion-TOADS).

RESULTS AND DISCUSSION: BFW volume was automatically derived from heavily T2-weighted images with no need for separate skull stripping. BFW volume and fraction had mean scan-rescan coefficients of variation of 1.5% and 1.9%, respectively, similar to the T1-based approaches tested here. BFW fraction more strongly correlated with clinical measures than T1-derived results. Among those clinical measures, modality-specific disability scores, such as SDMT and 9HPT, were more strongly associated with BFW fraction than composite measures, such as EDSS and SNRS.

CONCLUSION: The BFW method robustly estimates cerebral atrophy in an automated, fast, and reliable manner, and as such may prove a useful addition to imaging protocols for clinical practice and trials.

Sources: Neuroimage. 2014 Jun 16. pii: S1053-8119(14)00491-1. doi: 10.1016/j.neuroimage.2014.06.014. [Epub ahead of print] & Pubmed PMID: 24945671 (23/06/14)

Jack Osbourne follows strict Paleo Diet to help his fight against MS(23/06/14)

Jack Osbourne (26) has revealed that he has turned to clean eating to try and stop the rapid deterioration of his body due to multiple sclerosis (MS).

The son of Ozzy and Sharon Osbourne was diagnosed with the debilitating condition in 2012.

Multiple Sclerosis is a chronic disease where the body attacks the myelin sheaths that protects the nerves. Patients often experience numbness in extremeties, tingling, and a loss in vision in the early stages.

Jack was diagnosed just two and a half weeks after the birth of his daughter Pearl.

He experienced losses of vision in his right eye, and sought help from a neurologist who eventually diagnosed him.

Jack told the Dr Oz Show in the US: “Diet is a big thing. I am a firm believer in you are what you eat. I juice a lot, I try and stick to a Paleo Diet.”

The Paleo or 'caveman' diet favours foods available in prehistoric times, such as meat, fish, nuts and vegetables.

“At its core, I look at MS as inflammation, so I try and eliminate foods that cause inflammation. Dairy, gluten, grains.”

He told People: “I was just angry and frustrated and kept thinking, ‘Why now?’ I’ve got a family and that’s what’s supposed to be the most important thing.”

Source: Independent.ie © Independent.ie 2014 (23/06/14)

Staring into the void: Black holes and MS prognosis(19/06/14)

Physicians commonly measure multiple sclerosis (MS) disease activity based on the appearance of new T2-weighted hyperintense MRI lesions, which arise due to edema, inflammation, gliosis, and axonal loss. Given the nonspecific disease processes leading to these lesions and the often-mediocre correlation between T2 lesions and clinical outcomes, however, the search continues for a more specific tool that lends insight into MS pathophysiology and disease activity.

In recent years, increasing attention has been paid to the possibility of measuring chronic or persistent T1-weighted lesions that appear hypointense relative to normal-appearing white matter—lesions also known as “black holes”—as a means of gauging MS-associated neurodegeneration. This approach is supported by a considerable body of histopathological evidence indicating that chronic T1 black holes reflect irreversible demyelination and axonal loss.1

“In general, knowledge of the spatial localisation and time evolution of T1-weighted lesions may help resolve some mysterious aspects of MS, which remains a largely unresolved pathology,” explained Khader M. Hasan, PhD, an Associate Professor of Radiology at the University of Texas Medical School at Houston, in an interview with MedPage Today.

Some consider the evolution of T1 lesions to be one of the most promising endpoints in phase 2 clinical trials of neuroprotective and reparative MS interventions.2 But despite this enthusiasm, a proven link between persistent black holes and clinical outcomes in MS remains elusive. Whereas a handful of studies have pinpointed a correlation between black hole volume and clinical disability as measured by the Expanded Disability Status Scale (EDSS), several others have failed to identify such ties.1

To shed more light on whether black holes can be utilised to measure clinically relevant disease progression over time, lead investigator Nicola De Stefano, MD, PhD, an Associate Professor of Neurology at the University of Siena, Italy, and his colleagues conducted a longitudinal MRI study among a small group of 57 patients with confirmed relapsing-remitting MS for an average of 5 years. The investigators obtained brain scans of patients in 2000-2001 and again 10 years later using the same MRI protocol, thus ensuring comparable image quality at both time points. The scans were then compared to evaluate how patients’ brain lesions evolved over time and the impact of these changes on long-term disability, as measured using the EDSS.3

The majority of patients—82%—experienced disease relapse over the 10-year study period, and the average EDSS score for the total cohort worsened from 1.8±1.1 (mean [SD]) at baseline to 2.5±1.7 after 10 years (P<.001).3 In tandem, over the 10-year follow-up period mean T2 lesion volume increased from 5.8 ±6.4 to 8.3±8.1 cm3 (P<.001), and mean T1 lesion volume from 2.4±3.6 to 4.4±5 cm3 (P<.001).3

The investigators found that the long-term change in EDSS score was linked to the number of new and enlarging T1 and T2 lesions, as well as to increasing lesion volume. Notably, stepwise multiple regression analysis revealed that EDSS-measured declines in clinical disability best correlated with the combined measure of baseline T1 lesion count and increase in T1 lesion volume over time.3 Together, these factors explained 37% of the variability in worsening of the EDSS score over 10 years.3

“The finding in our study that the number of black holes at baseline and their volume increase over time were the only significant brain lesion correlates of EDSS worsening over 10 years highlights the role of neurodegeneration in the pathophysiology of long-term disability in MS,” wrote Dr. De Stefano and colleagues about their results, published in the Multiple Sclerosis Journal.3

Despite these findings, Dr. Hasan still views the relationship between T1 black holes and clinical measures of disease activity as tenuous. “Yes, black hole lesions are important, but other lesion types are also important. The lesion-centered approach in MS has not provided breakthrough insights into the pathogenesis of MS, as most MS lesions remain asymptomatic,” he commented.

One of Dr. Hasan’s biggest criticisms of the study is that the investigators provided no analysis of the possible effect of therapy. Fifty of the 57 patients received disease-modifying therapy during the study period, which makes it difficult to ascertain if and how much lesion evolution was influenced by the presence of treatment and the specific type of treatment.3 Phase 3 clinical studies that measure T1 black hole evolution may provide a deeper understanding of the ongoing disease process in MS and the possible effects of treatment.

These criticisms aside, Robert T. Naismith, MD, an Assistant Professor of Neurology at Washington University School of Medicine in St. Louis, believes that the findings from the recent Italian MRI study increase our understanding of T1 black holes in MS and may help inform treatment decisions. “The presence of black holes at baseline or their appearance during treatment should be one of several factors in predicting risk and may tip the decision toward either a first-line therapeutic with relatively high efficacy, or increased monitoring if an agent is chosen based primarily on established safety,” Dr. Naismith stated in a commentary on this study published last August in NEJM Journal Watch.4


1 Sahraian MA, Radue EW, Haller S, et al. Black holes in multiple sclerosis: definition, evolution, and clinical correlations. Acta Neurol Scand. 2010;122:1-8.
2 Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5:256-266.
3 Giorgio A, Stromillo ML, Bartolozzi ML, et al. Relevance of hypointense brain MRI lesions for long-term worsening of clinical disability in relapsing multiple sclerosis. Mult Scler. 2014;20:214-219.
4 Naismith RT. “Black holes” and long-term disability in multiple sclerosis. NEJM Journal Watch. http://www.jwatch.org/na31801/2013/08/05/black-holes-and-long-term-disability-multiple-sclerosis. Published August 5, 2013. Accessed March 25, 2014.

Source: Medpage Today © 2014 Everyday Health Media, LLC (19/06/14)

Future embryonic stem cell treatment promise for multiple sclerosis(19/06/14)

Scientists in the University of Connecticut's Technology Incubation Program have identified a novel approach to treating multiple sclerosis (MS) using human embryonic stem cells, offering a promising new therapy for more than 2.3 million people suffering from the debilitating disease.

The researchers demonstrated that the embryonic stem cell therapy significantly reduced MS disease severity in animal models, and offered better treatment results than stem cells derived from human adult bone marrow.

The study was led by ImStem Biotechnology Inc. of Farmington, Conn., in conjunction with UConn Health Professor Joel Pachter, Assistant Professor Stephen Crocker, and Advanced Cell Technology (ACT) Inc. of Massachusetts. ImStem was founded in 2012 by UConn doctors Xiaofang Wang and Ren-He Xu, along with Yale University doctor Xinghua Pan and investor Michael Men.

"The cutting-edge work by ImStem, our first spinoff company, demonstrates the success of Connecticut's Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside," says Professor Marc Lalande, director of the UConn's Stem Cell Institute.

The research was supported by a $1.13 million group grant from the state of Connecticut's Stem Cell Research Program that was awarded to ImStem and Professor Pachter's lab.

"Connecticut's investment in stem cells, especially human embryonic stem cells, continues to position our state as a leader in biomedical research," says Gov. Dannel P. Malloy. "This new study moves us one step closer to a stem cell-based clinical product that could improve people's lives."

"The cutting-edge work by ImStem ... demonstrates the success of Connecticut's Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside. - Marc Lalande"

The researchers compared eight lines of adult bone marrow stem cells to four lines of human embryonic stem cells. All of the bone marrow-related stem cells expressed high levels of a protein molecule called a cytokine that stimulates autoimmunity and can worsen the disease. All of the human embryonic stem cell-related lines expressed little of the inflammatory cytokine.

Another advantage of human embryonic stem cells is that they can be propagated indefinitely in lab cultures and provide an unlimited source of high quality mesenchymal stem cells - the kind of stem cell needed for treatment of MS, the researchers say. This ability to reliably grow high quality mesenchymal stem cells from embryonic stem cells represents an advantage over adult bone marrow stem cells, which must be obtained from a limited supply of healthy donors and are of more variable quality.

"Groundbreaking research like this furthering opportunities for technology ventures demonstrates how the University acts as an economic engine for the state and regional economy," says Jeff Seemann, UConn's vice president for research.

The findings also offer potential therapy for other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and type-1 diabetes, according to Xu, a corresponding author on the study and one of the few scientists in the world to have generated new human embryonic stem cell lines.

There is no cure for MS, a chronic neuroinflammatory disease in which the body's immune system eats away at the protective sheath called myelin that covers the nerves. Damage to myelin interferes with communication between the brain, spinal cord, and other areas of the body. Current MS treatments only offer pain relief, and slow the progression of the disease by suppressing inflammation.

"The beauty of this new type of mesenchymal stem cells is their remarkable higher efficacy in the MS model," says Wang, chief technology officer of ImStem.

Source: MNT © MediLexicon International Ltd 2004-2014 (19/06/14)/p>

Lipoatrophy occurrence for MS patients using Copaxone higher than originally thought(18/06/14)

The risk of developing lipoatrophy for multiple sclerosis (MS) patients administrated with glatiramer acetate is greater than 60 percent, according to a study developed at the Riverside Medical Clinic that reviewed 73 MS patients. It was already known that the drug could cause the condition, however the rate is higher than what was originally thought, according to the study.

It is “substantially higher than previously reported and is often the sole factor prompting patients to switch to another MS disease-modifying therapy. Our data also suggest that a heightened risk of lipoatrophy is an inherent autoimmune problem and is not necessarily mitigated by vigilant injection-site rotation. The psychological consequences may be significant,” said investigator Dr. Ronald Bailey, director of the MS clinic at the Riverside Medical Clinic.

From the patients who received the glatiramer acetate (Copaxone) therapy, 63 percent, or 46 participants in the study, developed lipoatrophy. Most of the patients were women, and 55% of them were administrated the drug with an auto injector. Copaxone is a daily subcutaneous injection that works as a disease-modifying therapy, and is widely used n treatment of RRMS. Lipoatrophy is a condition characterised by the loss of subcutaneous fat, and may lead to disfiguration.

In the research, it was also noted that there was no improvement in the dents that appear on the surface of the skin associated with the condition during the 3-year observation period. Scientists also performed photographic documentation and instructive guides about the proper injection process. The reason for the correlation between Copaxone and lipoatrophy is still not fully understood, but Dr. Baily believes that perhaps ”an elevation in tumor necrosis factor–alpha causes a dedifferentiation of adipocytes in the subcutaneous tissue.”

The disease “appears to progress, even when you stop the injections. It’s a pretty impressive disfiguration. It’s important to emphasise that this isn’t necessarily going to be remedied with plastic surgery. However, if patients were stable, most of them thought that this was a small price to pay to be in remission,” Dr. Bailey said at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Some of the patients developed Lipoatrophy in the first three months of the treatment, which suggested an autoimmune reaction, according to the research. ”Upon GA treatment discontinuation, lipoatrophy remained permanent,” he noted. GA labeling alerts to a 2 percent risk with a 20-mg/mL daily dose and 0.5% with the 40-mg/mL three times weekly option. The former one is used for almost two decades, while the latter was approved this year by the Food and Drug Administration.

“Lipoatrophy is thought to be permanent. There is no known therapy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection,” according to the GA label. However, another study performed at the Riverside Clinic concluded that site rotation wouldn’t decrease the probabilities of developing the condition.

Source: Multiple Sclerosis News Today © Copyright BioNews Services, LLC 2014 (18/06/14)

Multiple sclerosis drug MIS416 benefits from compassionate use in progressive MS(18/06/14)

Innate Immunotherapeutics drug candidate for secondary progressive multiple sclerosis continues to benefit patients being treated on compassionate grounds in New Zealand.

It is also providing the company with strong data and results from use of MIS416 which show the majority of patients in the program are benefitting from its use.

Of the 24 patients using drug candidate MIS416, 15 were previously subjects in the company’s Phase 1B/2A trial and had requested ongoing access to the drug after completion of the trial.

Out of the 24 patients, 18 have SPMS while 6 have the rarer primary progressive form of multiple sclerosis.

The median time on treatment for all compassionate use patients is now approaching 24 months and these patients have received an average of 52 doses of MIS416.

While a compassionate use program cannot be used to prove the safety or efficacy of a drug, important information can still be collected from the doctors involved and the patients who are being treated in this manner.

The latest results from ongoing regular safety blood tests continue to suggest that patients can receive weekly or fortnightly injections of MIS416 on a long-term and continuous basis without experiencing significant dose intolerance or cumulative toxicity.

Analysis of the recently updated quarterly results of patient self-reported health status outcomes show that the majority of patients continue to experience significant and sustained reductions in pain and fatigue.

Immunotherapeutics continues to recruit the Australian sites required to conduct its Phase 2B efficacy trial.

This will focus on accessing the efficacy of MIS416 by using several clinical measures of neuromuscular function, backed by patient reported outcomes of treatment effect.

Secondary progressive multiple sclerosis affects walking, hand, eye sight and cognitive functions, and these disabilities will be measured regularly during the trial.


While the use of the MIS416 to treat secondary progressive multiple sclerosis patients on compassionate grounds in New Zealand cannot be used to prove the safety or efficacy of a drug, the ongoing patient and doctor reports, collated by the company, are indicative of its beneficial effects.

This is especially true given that the reported observations including that sustained improvements in SPMS related patient symptoms is unusual and that some reported improvements exceed margins of “normal” variability in the literature.

The results from the program are such that it provides a means to better recruit for its Phase 2B efficacy trial in this patient population.

Source: proactive investors Australia Copyright © proactiveinvestors.com.au 2014 (18/06/14)

Myelin repair in mice enhanced using stem cells and other novel approaches(17/06/14)

Two teams of researchers report success in stimulating the repair of nerve-insulating myelin in mouse models of MS. Myelin is a major target of immune attacks in MS, and although these are early results and further work is needed, these findings show some promise for strategies to repair damage and restore function for people with multiple sclerosis.

Background: In MS, myelin, the material that surrounds and protects nerve fibers, is damaged in the brain and spinal cord, and so are the cells that make myelin, called oligodendrocytes. Though the replacement cells that could repair myelin, called oligodendrocyte precursor cells (OPCs), exist in the brain, in MS they cannot adequately repair the damaged myelin.

Stem Cell Study: Lu Chen, PhD, Thomas Lane, PhD (University of California, Irvine) and colleagues report that administering neural precursor cells (nerve stem cells) to mice with MS-like disease reduced inflammation, decreased myelin damage, and increased myelin repair. (Stem Cell Reports, published May 15, 2014)

The team injected the stem cells into the spinal cord of mice with an MS-like disease induced by a virus. Although the stem cells were rejected by the body, and were not detectable within eight days after transplant, they were effective nevertheless in reducing the disease. Improvements in motor abilities of the treated mice were still apparent after six months.

The team noted that improvements went along with an increase in a type of immune cell called “regulatory T cells,” or “Tregs.” To test whether the Tregs contributed to the improvements, they blocked Tregs activity, which reduced the stem cells treatments’ impact.

The team speculates that the stem cells may be stimulating the immune environment in a way that activates mouse OPCs, even though the stem cells themselves do not turn into myelin-making OPCs. They are now investigating this idea further to discover the factors released by the stem cells. Ultimately, this information could contribute to the development of stem cell therapies and even cell-free therapies that stimulate recovery in people with MS.

Stimulating Resident Cells: Jessica Williams, PhD, Robyn S. Klein, MD, PhD, and colleagues (Washington University School of Medicine) report that targeting a signaling receptor (docking site) called “CXCR7” on immature oligodendrocytes in mice enhances myelin repair (Journal of Experimental Medicine, published April 14, 2014).

Dr. Klein’s team focused on a messenger protein (chemokine) that interacts with the immature OPCs. They studied mice that were given a toxin called cuprizone, which mimics myelin damage that occurs in the brain during MS. Once cuprizone is withdrawn, myelin repair occurs. The team found that CXCR7 activity increased during myelin damage, and then reduced with myelin repair. When the team administered an experimental compound that inhibits CXCR7, the numbers of OPCs, as well as mature oligodendrocytes, increased within myelin-damaged areas. Myelin repair was enhanced.

These data suggest that CXCR7 might serve as an important therapeutic target to promote myelin repair. Since these studies were conducted in mice, further research is necessary to ultimately determine whether this approach might be an effective approach for stimulating myelin repair in people with MS.

Conclusion: Achieving success in the Society’s priority area of nervous system repair would provide life-changing advances for people with MS. Read more about this research strategy.

Source: US National MS Society (17/06/14)

iPad performance testing in MS(17/06/14)

In the not-too-distant future, patients with multiple sclerosis (MS) may simply strap on an iPad to complete their balance and walking tests, without the need for a technician.

The test results would be automatically uploaded to a clinical or research database, eliminating the chance of human error.

And patients may be doing the tests in the comfort of their own home, eliminating the need to visit a clinic, a boon to those living in rural areas or with mobility issues.

"It's an entirely new way of measuring the clinical impact of MS," said Richard A Rudick, MD, who recently left the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research in Ohio to become vice president, development sciences, Value-Based Medicine, Biogen Idec."The bottom line on this is a new method to collect, display, aggregate, and analyse neurological performance data that has potential to have a major impact in MS patient care and research."

Dr. Rudick was addressing the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS).

Major Impact

The iPad is designed to simulate the standard tests administered by a technician: for example, the analogous test for the Timed 25-Foot Walk is the Walking Speed Test on the iPad, the 9-Hole Peg Test is called the Manual Dexterity Test, the Sloan Low Contrast Visual Acuity Test translates to the Low Contrast Visual Acuity, and the Symbol Digit Modalities Test to the Processing Speed Test.

The iPad is attached to a belt clip worn by the patient. A specially engineered device that sits on top of the iPad and is connected to it collects the relevant data, said Dr. Rudick.

He and his team performed a validation study that included 51 patients with MS and 49 healthy controls. Over and over, they found that the 2 methods were similar. For example, the test-retest reliability for various dimensions, including the T25FW and the 9 HPT, was "very good," said Dr. Rudick. "The correlations were mostly above .9, showing that it's highly reliable whether the technician does it or the iPad does it."

As for sensitivity to MS with tests of manual dexterity, visual acuity, and other tests, again, "what you see is that all of these tests, whether the technician or the iPad does them, distinguish MS patients from healthy controls," said Dr. Rudick.

Results were "very similar" for progressive versus relapsing types of MS, he added.

In some instances, the device was superior to a human tester. For example, with respect to how well a test distinguishes MS from healthy control, "for virtually every case, except the visual test, the iPad actually does a little bit better than the technician," said Dr. Rudick.

As for how well iPad or the technician measurements correlated with patient reports, that seemed to depend on the dimension. There was some correlation with certain lower-extremity patient reports, but not some upper-limb reports.

Dr. Rudick noted that the processing speed test correlated with just about everything except cognition. "MS patients don't recognise their cognitive dysfunction as a symptom they would call a cognitive problem," he explained. He added that the literature shows that cognition correlates better with depression than actual cognitive performance.

Easy to Use

The technology was well accepted. Patients found the applications were easy to understand and to use. "They said that completing the test on the iPad using a touch screen was easy, and they didn't have difficulty wearing the iPad for balance and walking," said Dr. Rudick.

Patients with MS, however, were more likely than healthy controls to find that the testing caused fatigue. "The way I interpret this is that it just reflects that patients have fatigue and can only tolerate so much testing," said Dr. Rudick.

The technology has several implications. The data can be transferred wirelessly to the "cloud" and scored instantly, enabling automatic entry into research and clinical databases. "You could theoretically send this right to the doctor at the time of the testing so he or she can see it, and at the same time send it to a research database," said Dr. Rudick.

This should reduce errors because there's no transcription of data, he added. "Whenever a human transcribes data there will be some error rates" which are estimated at about 1% or 2%.

The iPad data collection could lower costs of testing, too, because it lessens the need for extensive quality control of data and for human input. "If this can be transformed into a completely self-administered test, which we're working on right now, you don't need the technician," said Dr. Rudick.

"Nobody has the money for a technician to test their patients in practice," Dr. Rudick added in an interview with Medscape Medical News. "Also, a single technician can test a single patient, one at a time; with the iPad, several patients could test themselves simultaneously."

The technology could be adapted for "nontraditional" settings, such as rural areas, said Dr. Rudick. Because data could be collected at home, collection could be done more often, allowing for "trend analysis" over time, he said. Another implication, he noted, is that it allows researchers to develop a patient "profile" to determine how a patient is doing relative to healthy matched controls. "You can immediately grasp what is going on with patients over time." The technology also allows for input of additional tests the clinician might find useful, said Dr. Rudick.

The advantage of this technology, Dr. Rudick told Medscape Medical News, is that "walking speed, manual dexterity, vision function, and cognitive function information can be available to the neurologist." This, he said, "would allow the neurologist to track his or her patient over time, monitor the impact of medication, and make data-driven treatment decisions after discussion with the patient."

The technology still needs some tweaking. "We have to solve issues such as data transfer and integration with medical records, and we have to start building some databases from this," said Dr. Rudick. He said he hopes the technology will be available for widespread dissemination in about a year.

Work to Be Done

Asked for a comment, Robert P. Lisak, MD, professor and chair, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, and the new president of CMSC, said the study is very interesting and promising.

"It's nice to see modern electronics and computer technology applied to the practice of medicine in a useful manner that has the potential to enhance care and cut costs but not cut costs by reducing the amount and quality of care," Dr. Lisak told Medscape Medical News.

However, he added that "there is still some work to be done on some of the measures, and we need to see if this approach can be confirmed and validated at other centers."

The validation study was supported by Novartis Pharmaceuticals. Dr. Rudick is an employee of Biogen Idec. Dr. Lisak has disclosed no relevant financial relationships.

6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Symposium: iTechnology in MS: Transformation or Chaos? Presented May 29, 2014.

Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (17/06/14)

Could brain imaging help treat MS-related depression?(17/06/14)

Magnetic resonance imaging (MRI) can predict responses to depression treatment in patients with multiple sclerosis (MS), according to Anthony Feinstein, Professor at the Department of Psychiatry of the Sunnybrook Health Sciences Centre & the University of Toronto. In the presentation “Depression in MS: Is brain imaging helpful?” at this year’s 2014 CMSC ACTRIMS Annual Meeting in Dallas, the researcher argued that continuing to image and document brain function will help in the diagnosis and treatment of depression associated with the disease.

Feinstein believes that imaging the brain enables clinicians “to appreciate the structural brain changes” that occur in depressed MS patients in order to study the links between these changes and alterations in mood. In addition to improving diagnosis and treatment by observing lesion changes in the brain over time, Feinstein also stated the importance of MRI in determining “how the structural brain changes linked to depression differ from those seen in pseudobulbar affect.”

The pseudobulbar affect is a neurologic disorder characterized by involuntary and uncontrolled episodes of crying, without sadness, or laughing, without happiness. Although it affects up to 10% of MS patients, imaging the variance and location of the lesions in the brain can determine the pattern of the affect. The lifetime prevalence of the disease in patients with MS may be as high as 50 percent. During the annual meeting, Dr. Feinstein presented a study that analysed 115,071 Canadians that revealed a 12-month prevalence of depression in MS patients higher that in healthy subjects. Between the ages of 18 and 45 years old, the 12 month prevalence was 25.7%. Moreover, the rates have increased in relation to other neurological disorders.

“Feeling depressed mood most of the day, markedly diminished interest or pleasure in all activities, appetite change with significant weight loss or gain, psychomotor agitation or retardation, fatigue or loss of energy nearly every day, worthlessness, excessive, inappropriate guilt, having insomnia or hypersomnia nearly every day, diminished ability to think or concentrate or recurrent thoughts of death five or more times during the same two week period” may be evidence of depression, according to Dr. Feinstein.

Dr. Feinstein believes that adequately managing depression in disorders like MS cannot be overstated, since it not only impacts the clinical condition of the patient, but also the quality of life and cognitive function. A quarter of MS patients contemplate suicide, and the major factors for it include depression, social isolation, and alcohol abuse.

A new automated imaging technique was recently successfully used in a trial with women who suffered both from MS and depression. The study, led by Cedars-Sinai neurologist Nancy Sicotte‘s multicenter research team, was able to identify shrinkage of a mood-regulating brain structure. The results revealed that patients with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest — feature a reduced size of the right hippocampus.

At the University of Calgary’s Hotchkiss Brain Institute, new techniques are also being studied to improve diagnosis and treatment using MRI by sensing small changes in patterns of the MS patients’ brains. Using an algorithm, the researchers hope to find a parameter called MRI texture heterogeneity and clearly identify patterns and changes in the tissue.

Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (17/06/14)

Oceans of Hope sets sail on circumnavigation for MS(17/06/14)

The Danish yacht, Oceans of Hope, has set sail from Copenhagen on a historic global voyage. It is the first ever circumnavigation of the world by a yacht crewed by people with multiple sclerosis (MS).

Oceans of Hope is the flagship of a campaign by the same name, organised by the Sailing Sclerosis Foundation. The aim of the 17-month project is to change perceptions of MS by showing what is possible when people with a chronic disease are empowered to conquer their individual challenges.

The crew who set sail from Amaliehaven this afternoon on the 61,000-kilometre (33,000-nautical mile) voyage have been involved in establishing an active network across Denmark of groups of people with MS who sail on a regular basis. Through sailing events organised during stopovers in the 20 ports of call they want to widen those networks between the MS and the sailing worlds and help create a valuable legacy for the Oceans of Hope project.

The route will take the yacht from Copenhagen to Kiel, Germany, for the first stopover from 19-22 June, followed by Amsterdam, Netherlands (26-29 June), Portsmouth, UK (3-6 July), La Rochelle, France (10-14 July), Lisbon, Portugal (25 July ñ 2 August) and across the Atlantic Ocean to Boston, Massachusetts, USA, where the crew is due to arrive on 8 September. Oceans of Hope will take centre stage at the joint ACTRIMS-ECTRIMS conference, the world's largest annual international conference devoted to basic and clinical research in multiple sclerosis.

Source: mysailing.com.au copywrite Yaffa Publishing Group 2014 (17/06/14)

Biogen to reapply for Irish HSE funding for MS drug Fampyra(17/06/14)

The makers of a drug that helps people with multiple sclerosis to walk are to make a fresh application to have it covered by the Health Service Executive-funded drug schemes. People with MS, who say Fampridine (known commercially as Fampyra) has greatly increased their mobility, have criticised the HSE for not reimbursing the cost of the drug on the long-term illness scheme.

In 2012, regulatory authorities concluded that Fampyra was not demonstrably cost-effective for the treatment of MS. The HSE said the manufacturers, Biogen Idec, had failed to demonstrate or provide any formal justification of the prices proposed, but did not rule out a revised application.

The National Centre for Pharmaco-economics (NCPE), which rules on the cost-effectiveness of new drugs, said Fampyra would cost nearly €7,000 a patient each year. It said the €20 million annual cost to the State over five years would take money from other areas. Biogen later made the drug available free of charge to some patients as part of a late-stage clinical trial.

Since Fampyra was licensed for sale and became commercially available here this year, Biogen started charging for the product, leaving patients facing a €500 monthly bill to continue treatment.

One of these is Rosaleen Rafter, from Ballina, Co Mayo, whose daughter Caitríona Redmond says it will be impossible for her mother to afford the drug on her pension. Ms Redmond has been running a campaign through Facebook to highlight her mother’s battle to continue getting “the only treatment that has improved and stabilised her symptoms of MS”. “My mum retired early because of the illness and her loss of mobility and loss of power in her arms and hands. She uses a rollator to walk and has a hand-controlled adapted car as her legs have severely reduced power. She has foot drop and has had two falls, one of which took me and my brother ages to get her off the ground and resulted in a fractured shoulder.

“Watching the effects that her condition has on her has been awful and, without her medication, things will progress sooner.”

Last week, Minister of State for Primary Care Alex White told the Dáil he understood Biogen had told the HSE it intended to submit a revised application to the NCPE. The HSE would then reconsider the application “in line with the agreed procedures and timescales for the assessment of new medicines”.

Mr White said he was aware that studies were ongoing to assess the wider impact of the drug on both walking and quality of life for people with MS.

Their results would contribute to the evidence base demonstrating the clinical effectiveness of the product, which could be used to support future applications for inclusion on HSE drugs schemes.

Biogen said it was working with the authorities to make Fampyra available to all patients. It said it provided the drug free for 2½ years to qualifying patients and continued to provide the first four weeks of treatment free, so that patients who responded to it could be identified.

Source: The Irish Times © 2014 THE IRISH TIMES (17/06/14)

Positive top-line results in phase III Daclizumab high-Yield process study in MS(16/06/14)

Biogen Idec and AbbVie ABBV announced positive top-line results from the Phase 3 DECIDE clinical trial, designed to evaluate the superiority of once-monthly, subcutaneous daclizumab high-yield process (DAC HYP) when compared to intramuscular interferon beta-1a (IFN β-1a), as a potential treatment for relapsing-remitting multiple sclerosis (RRMS), the most common form of multiple sclerosis (MS). Results showed that DAC HYP was superior on the study’s primary endpoint, demonstrating a statistically significant 45 percent reduction in annualized relapse rate (ARR) compared to IFN β-1a (p<0.0001).

“The results of the DECIDE study are compelling, with DAC HYP demonstrating robust efficacy compared to a current standard of MS care,” said Gilmore O’Neill, vice president, Global Neurology Clinical Development, Biogen Idec. “As a potential once-monthly therapy with a novel mechanism of action, we believe that, if approved, DAC HYP will be an important treatment option for people living with MS.”

“The positive results in the DECIDE study represent achievement of an important milestone in the development of DAC HYP as a potential new treatment option for MS patients,” said Michael Severino, M.D., executive vice president, Research and Development and chief scientific officer, AbbVie. “Together, the companies are committed to working with regulatory agencies on filing plans for DAC HYP.”

DAC HYP showed superiority on the first secondary endpoint, number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54 percent reduction relative to IFN β-1a (p<0.0001). On the second secondary endpoint, DAC HYP reduced the risk of three month confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS) by 16 percent over IFN β-1a, which was not statistically significant (p=0.16). Using a pre-specified sensitivity analysis that accounted for 67 patients who did not have a confirmatory disability assessment, DAC HYP showed a 21 percent reduction in the risk of sustained disability progression (p=0.047).

The safety profile of DAC HYP in the study was consistent with what has been observed in prior studies. The overall incidence of adverse events was comparable across the DAC HYP and IFN β-1a treatment groups. In patients treated with DAC HYP compared to IFN β-1a, there was an increased incidence of serious infections (4 percent vs. 2 percent), serious cutaneous reactions (2 percent vs. < 1 percent), and elevations of liver transaminases greater than 5 times the upper limit of normal (6 percent vs. 3 percent). There were 4 deaths in the IFN β-1a group and 1 death in the DAC HYP group, none of which was considered treatment related.

Biogen Idec and AbbVie plan to work with regulatory agencies to determine appropriate timelines for filing. The companies intend to present detailed results from DECIDE at a future medical conference.


DECIDE was a two to three year, Phase 3, global, randomized, double-blind, multicenter study designed to determine if DAC HYP would provide superior outcomes for certain clinical endpoints compared to treatment with IFN β-1a. The study enrolled more than 1,800 people with RRMS in 28 countries. DECIDE was an active comparator study with two groups: 150 mg of subcutaneous DAC HYP every four weeks was compared to IFN β-1a 30 mcg intramuscular injection once weekly.

The primary endpoint in DECIDE was the reduction in ARR. Secondary endpoints included the number of new or newly enlarging T2-hyperintense lesions, the proportion of patients with sustained disability progression (EDSS), the proportion of relapse-free patients and the proportion of patients who experienced a worsening physical impact score on the Multiple Sclerosis Impact Scale (MSIS-29).

After completing the DECIDE study, patients have the option to participate in an open-label extension study called EXTEND.

The DAC HYP development program also includes the previously completed pivotal, placebo controlled, double-blind SELECT study.

About Daclizumab High-Yield Process

DAC HYP is a new form of humanized monoclonal antibody that binds to CD25, a receptor subunit that is expressed at high levels on T-cells that become abnormally activated in MS. DAC HYP modulates IL-2 signaling without causing general immune cell depletion. DAC HYP is believed to work by decreasing abnormally-activated T-cells and pro-inflammatory lymphoid tissue inducer cells, and increasing CD56bright natural killer (NK) cells, important cells that help regulate the immune system.

Biogen Idec and AbbVie are jointly developing DAC HYP.

Source: MarketWatch Copyright © 2014 MarketWatch, Inc (16/06/14)

Is it time to rethink the MS immune cell theory?(16/06/14)

Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients.

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC.


In multiple sclerosis (MS), B cell-depleting therapy using monoclonal anti-CD20 Abs, including rituximab (RTX) and ocrelizumab, effectively reduces disease activity.

Based on indirect evidence, it is generally believed that elimination of the Ag-presenting capabilities and Ag nonspecific immune functions of B cells underlie the therapeutic efficacy.

However, a small subset of T lymphocytes (T cells) was shown to also express CD20, but controversy prevails surrounding the true existence of this T cell subpopulation. Using single-cell imaging flow cytometry and expression profiling of sorted lymphocyte subsets, we unequivocally demonstrate the existence of CD3+CD20dim T cells.

We show that in MS patients, increased levels of CD3+CD20dim T cells are effectively depleted by RTX. The pathological relevance of this T cell subset in MS remains to be determined.

However, given their potential proinflammatory functionality, depletion of CD20-expressing T cells may also contribute to the therapeutic effect of RTX and other mAbs targeting CD20.

Sources: J Immunol. 2014 Jun 13. pii: 1400118. [Epub ahead of print] & Pubmed PMID: 24928997 (16/06/14)

Parasitic worm in pigs could help relieve symptoms of multiple sclerosis(16/06/14)

The pig whipworm could help treat people suffering from arthritis, multiple sclerosis, diabetes and autism.

Medical experts are excited at the unlikely new hope a parasitic worm found in pigs could offer across a suite of illnesses and ailments.

University of Melbourne has for the first time mapped the genes of the pig whipworm, which could lead to new drugs and treatments for auto-immune disorders.

The pig whipworm causes death in livestock, but it does not harm humans, and there is even evidence it can lessen symptoms in people with multiple sclerosis and inflammatory bowel disease.

In auto-immune disorders the immune system mistakenly attacks their body’s own tissues.

Already the pig whipworm is being used as medicine for treating inflammatory bowel diseases.

“It seems to affect the immune system by suppressing some of the inflammation,” the university’s Faculty of Veterinary Science Dr Aaron Jex said.

“The goal is to see if we can identify what it is doing in the body and how you could mimic that with a drug.”

Understanding the genetic make up of the parasite that infects animals will also help scientists better understand the human whipworm, which infects an estimated one billion people worldwide.

Dr Jex said people can become infected with the human form of the parasite after ingesting food or water with the eggs in it.

It can lead to dysentery, malnourishment and, in children in particular, it can lead to problems in physical and mental development.

The whipworm, which is between 2cm and 4cm in length, implants it’s front end in the intestinal wall and its body sticks out, like the handle of a whip.

“The long thin head is what it uses to feed in the intestinal wall,” Dr Jex said.

The adult worm secretes enzymes that breaks down cells in their host.

For the past two years Dr Jex has been sequencing the pig whipworm’s genome, working in collaboration with 11 institutions in six countries.

The paper, published in the journal Nature Genetics today, states that understanding the worm’s genetic make-up should enable the design of urgently needed drugs to treat the human form of the disease.

Dr Jex said the human whipworm is predominately found in south east Asia in rural or remote areas, particularly where there are inadequate sewerage systems.

There is one treatment that is currently being distributed to children in countries most at risk, but alternatives are needed to prevent drug resistance.

Source: Herald Sun Copyright News Ltd 2014 (16/06/14)

Concern at shortfall of MS specialist nurses in UK(13/06/14)

The new report has highlighted the need for more multiple sclerosis specialist nurses in the UK and fears over future funding.

The analysis, launched by the MS Trust, is based on a record 97% of the 245 MS specialist nurses in the country responding to a survey. It notes that there is “a high level of variation in the availability of nurses” between England, Wales, Scotland and Northern Ireland. In England, more than 40% cover three or more clinical commissioning groups (CCGs), compared to MS specialist nurses in Scotland who generally cover only one health board.

The MS Trust adds that “there is a clear shortfall of MS specialist nurses” for the more-than 100,000 people with the disease in the UK, and between 126 and 214 more posts are “needed to provide an acceptable caseload level”. This would equate to 300 MS cases per nurse and currently, the caseload sits at around 550 people each.

The report notes that nearly 90% of MS specialist nurses are solely funded by the NHS - Only 18 posts are funded by charities or pharmaceutical companies across the UK. Also, although MS nursing has grown steadily over the past twenty years “and is well-established and highly valued by the MS community”, the study notes that “recent and ongoing changes in the NHS could potentially lead to new complexities in how services are commissioned and funded”.

Amy Bowen, director of service development at the MS Trust, said that “we now look forward to following up this initial research and getting to the heart of the issues facing MS nursing, particularly with regards to funding and commissioning, and presenting these results later this year”.

Source: PharmaTimes Copyright PharmaTimes 2014 (13/06/14)

Vitamin D status may relate to severity of acute optic neuritis in MS(13/06/14)

A new study published in Neurology has found that in patients with multiple sclerosis, vitamin D status may relate to acute optic neuritis severity but not to recovery.

Acute optic neuritis (AON) is an inflammatory condition that occurs in the nerve fibers that communicate information between the eye and the brain. It is characterised by color blindness, vision loss, and pain in the eye.

AON is common in people with multiple sclerosis, a disease in which the immune system mistakenly attacks the covering of the body’s nerves. AON is often the first symptom that is present in those with multiple sclerosis, where the immune system attacks the optic nerves.

Vitamin D’s role in multiple sclerosis is well-established. Research suggests that maintaining healthy vitamin D levels helps slow progression of multiple sclerosis and help manage some aspects of the condition.

To further explore the diverse roles that vitamin D plays in multiple sclerosis, researchers recently conducted a study to determine if vitamin D status was related to AON.

For this study, the researchers were interested in evaluating factors that may relate to severity and recovery of AON, such as age, gender and vitamin D status. For vitamin D, they looked at 101 patients who had their vitamin D levels tested within six months of an AON attack.

The researchers found that 52.5% of the patients had a moderate attack and 35.6% had a severe attack. They also found that 90.1% of this group had a full recovery from the attack.

According to their results, vitamin D status was significantly related to the severity of attack. Male gender, more severe attacks, and older age were related to worse recovery from AON, while vitamin D status was not related to recovery.

“No previous study has specifically investigated the importance of vitamin D in severity of AON, and our results support the hypothesis that low vitamin D levels are related to worse multiple sclerosis disease course,” the researchers stated.

The researchers call for future studies using larger samples to further evaluate the role that vitamin D may play in AON attack severity.

Malik, M. et al. Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis. Neurology, 2014.

Source: Vitamin D Council (13/06/14)

Modified approach to the treatment of autonomic dysfunction in MS patients(13/06/14)

A new study sheds light on the positive effect of a venous procedure upon the sympathetic nervous system. Researchers were able to pinpoint how the procedure improved the abnormal sympathetic function found in patients with many chronic conditions including Multiple Sclerosis. Additionally, the study may offer insight on the beneficial effects of Chronic Cerebrospinal Venous Insufficiency (CCSVI) treatment.

Newport Beach Interventional Radiologist, Michael Arata, MD, has co-authored the study, which will be published in the June 2014 issue of Journal of Endovascular Therapy. The study, performed by Dr. Arata and his research associate, Zohara Sternberg, PhD, found that using an angioplasty balloon to stimulate vein-associated nerves increased sympathetic activity. This treatment for autonomic dysfunction shows promise for patients who suffer from Multiple Sclerosis, an inflammatory disease that causes damage to the central nervous system and can lead to paralysis.

Dr. Arata has spent more than a decade performing angioplasty and has been at the forefront of research for CCSVI, a venous condition in which blood flow from the brain is restricted. "There is a possibility that improved autonomic function may diminish symptoms and have an impact on the course of the disease," explained Dr. Arata, who serves as Medical Director at Synergy Health Concepts in Newport Beach and has performed more than 2000 procedures on patients with autonomic-associated disease, maintaining a high clinical (patient response) success rate in excess of 90% in a recent study group.

"The current study demonstrates the procedure's effect on autonomic function, offering an explanation for why patients may see symptom improvement with venous ballooning even though separate studies have failed to show a relationship between venous obstruction and Multiple Sclerosis. The mechanism of symptom improvement is improved autonomic tone rather than relief of flow obstruction," he said.

About Michael Arata, M.D.

A graduate of UCSF School of Medicine, Dr. Arata completed his four year residency at Duke University Medical Center. Dr. Arata is certified by the American Board of Venous and Lymphatic Medicine. He has been caring for patients with autonomic dysfunction for four years, and he established the first endovascular treatment center focused on treating autonomic dysfunction, located in Newport Beach, CA.

Source: Digital Journal copyright © 2014 digitaljournal.com (13/06/14)

Study suggests MS drug Tysabri treatment can be safely continued past 24 months(13/06/14)

A recent study suggests that treatment with natalizumab (Tysabri) beyond 2 years compared with switching to other drugs can control relapsing-remitting multiple sclerosis (RRMS) with adequate safety.

The longer a patient with RRMS is treated with natalizumab, the greater the risk of developing progressive multifocal leukoencephalopathy (PML), especially in patients who are infected with JC virus after 2 years of monthly treatments.

"Our study provides evidence to support the choice of continuing treatment with natalizumab after the 24th administration," Luca Durelli, MD, from the Department of Clinical and Biological Sciences at the University of Torino and the San Luigi Gonzaga University Hospital in Obassano, Italy, reported here at the 24th Meeting of the European Neurological Society (ENS).

Between 2005 and May 2014, among 125,800 patients with MS treated in the postmarketing setting, 462 cases of PML have been reported, of which 23% were fatal, for an incidence of 3.6 cases/1000 treated. The highest prevalence has been in patients receiving natalizumab for 2 to 3 years.

In this present prospective, multicenter, observational Tysabri discontinuation study after the 24th natalizumab administration (TY-STOP), 130 adult patients with clinically and radiologically stable RRMS were stratified according to their choices of treatment after the 24th dose of natalizumab, 300 mg every 28 days, and observed every 3 months for 1 year.

Treatment options presented to the patients after the 24th natalizumab dose were to continue receiving natalizumab ("continuers"), to start treatment with a different therapy ("switchers"), or to stop any disease-modifying therapy ("quitters").

First-line therapy options were interferon β-1a, interferon β-1b, or glatiramer acetate. Second-line options were fingolimod (since December 2011), natalizumab, or mitoxantrone (only 2 patients).

Of the 130 patients, Professor Durelli reported on 124 (95.4%) who had completed the entire 1-year follow-up, which consisted of 43 (35%) who continued natalizumab and 81 (65%) who interrupted it.

The following baseline characteristics did not significantly differ between the patients who continued natalizumab and those who did not: age, body mass index, age at disease onset, sex, disease duration at baseline, disability scores, annual relapse rates, MRI activity, and disease-modifying therapies before natalizumab initiation.

The as-treated population consisted of 73 (59%) quitters, 16 (13%) switchers, and 35 (28%) continuers.

For the intention-to-treat population, after 1 year of observation following the decision to stay on natalizumab or not, there was no significant difference in the mean Expanded Disability Status Scale scores, but the annualized relapse rate had tripled (0.24 ± 0.48 for those remaining on natalizumab vs 0.73 ± 0.85 for those not; P = .004) and the presence of MRI activity in the previous year had doubled (26.8% vs 51.3%, respectively; P = .018).

Results were similar for the as-treated population, with no significant differences in disability scores but a higher annualized relapse rate among quitters and switchers compared with continuers. MRI activity during the follow-up year was higher among quitters but not among switchers compared with continuers.

Professor Durelli said that in the as-treated population, the overall frequency of adverse effects was similar among the patients treated with the different therapies, and "during the period of observation no new safety issues emerged."

Among the continuers, there was 1 case of pyelonephritis and 1 acute myocardial infarction. Among switchers, 1 case of PML occurred in a patient who had been receiving natalizumab for 28 months. The patient made a full recovery after being treated with plasma exchange and mirtazapine.

In no patient who stopped natalizumab did disease activity return worse than it had been before natalizumab therapy.

Professor Durelli concluded that in patients with relapsing-remitting MS, "interruption of treatment with natalizumab after the first 24 courses exposes [patients] to an increased risk of clinical and/or MRI MS disease activity." He added the study results can support a choice of continuing natalizumab beyond 24 months.

Relapse Activity Increase

Session chairman Kjell-Morten Myhr, MD, PhD, professor of neurology at the University of Bergen, Norway, told Medscape Medical News that the study "very well showed the efficacy of Tysabri. When stopping Tysabri and starting them on a less potent treatment, the relapse activity will increase."

Infection with JC virus is a major risk factor for PML in patients treated with natalizumab, and 60% to 80% of adults in the United States and Europe are positive for antibodies to it, indicating exposure. "Of course, it would be best for the treatment of the disease itself continuing with the Tysabri, but it's a difficult issue with the risk of PML," he said.

He commented that he had the impression that the study patients had not been screened for JC virus before natalizumab initiation, probably because screening was not yet available.

"For those that are JC virus negative, there is no reason to stop after 24 months. They should continue," he said. "These patients that could be considered for stopping or switching are JC virus positive after 24 months." In keeping with usual practice, he recommended that JC virus–negative patients be tested every 6 months because they can become infected at any time.

Dr. Myhr said in his experience, when the risks of PML are explained to patients and they elect to continue natalizumab, sometimes they come back in a few months and have decided to switch to another drug because they say that they are continuously thinking about the risk.

"It's difficult for patients to make decisions, and I think they need time to make their decisions. So we really need good biomarkers to differentiate the risk for this serious complication," he said, noting that the JC virus index will be 1 biomarker "to identify those with a low risk but still a risk but lower than those with a high index."

Professor Durelli had no disclosures. Dr. Myhr has received honoraria for lecturing; participation in advisory boards or pharmaceutical company–sponsored clinical trials; and travel support from Allergan, Almiral, Bayer Schering, Biogen Idec, Novartis, Merck-Serono, Roche, and Sanofi-Aventis.

24th Meeting of the European Neurological Society (ENS). Abstract OS1115. Presented May 31, 2014.

Source: Medscape Medical News © 2014 WebMD, LLC (13/06/14)

Wider use of MS drug Gilenya approved in Europe(12/06/14)

The European Commission has endorsed the recent Committee for Medicinal Products for Human Use (CHMP) positive opinion recommending the expanded use of Swiss drug major Novartis’ drug Gilenya (fingolimod) for adult patients with highly active relapsing-remitting multiple sclerosis (RRMS).

The indication expansion will now give clinicians the flexibility to use fingolimod in the highly active RRMS group, for patients needing to switch from interferons as well as glatiramer acetate (Teva’s Copaxone) and other DMTs.

Prior to the indication expansion, fingolimod, which generated sales of nearly $2 billion last year, was limited for use in those patients with highly active RRMS not responding to an interferon.

The European Commission approval was based on a favourable review of the long-term efficacy and safety data for fingolimod and comes three years after the initial licence was granted in March 2011. Fingolimod is now approved in 80 countries and it is estimated that more than 91,500 patients have been treated with fingolimod in clinical trials and in the post-marketing setting.

.Fingolimod is the only established oral therapy approved by the UK’s drugs watchdog the National Institute for Health and Care Excellence (NICE) for the treatment of highly active RRMS that is effective across four key measures of MS disease activity – relapses, MRI lesions, brain volume loss and disability progression, the drugmaker noted. Novartis says it will work with the relevant European funding bodies to ensure that patients who meet these new criteria are able to access fingolimod in the near future.

Source: thepharmaletter(12/06/14)

Researchers develop better way to track MS(10/06/14)

What if an MRI scan could detect damage caused by Multiple Sclerosis at an early stage?

Researchers at Western University have developed a way to better track MS progression in patients by looking at damage in brain areas common to all MS patients.

The technique is called Quantitative Susceptibility Magnetic Resonance Imaging (MRI).

While MRI scans are a vital part of diagnosing Multiple Sclerosis, they are often not conclusive until a patient is relatively late in the progression of the disease. However, the brain changes long before symptoms begin.

MRIs are able to detect spots on the brain, but using Quantitative Susceptibility MRI data, doctors can see damage areas of the brain that otherwise would go unnoticed until symptoms were farther advanced.

Currently a standard MRI will detect lesions in the brain but, until now, there was no correlation between lesions and the extent of a patient's disability. While lesions can appear or disappear over time, the damage caused is still apparent in QS image testing even after the patient's first episode.

Research leader at UWO, Ravi Menon, noted the changes are subtle – on the parts per billion level – but by using QS they are able to measure when tissues begin to degenerate or as iron accumulates in the brain. Iron accumulation happens naturally as a person ages, however, Menon explained that for an MS patient, they have levels that are likened to that of a person three years older.

Early detection and treatment can stop or slow down the disease.

Menon said if every current MS patient were diagnosed early and treated with low doses of prescription drugs the number of cases would drop four to five fold. He estimated about $100 billion dollars would be saved in drug costs alone.

The next stage, he said, is to have QS work on a single subject.

The university is equipped with a 7T MRI machine – the only one in Canada - but the tests were performed on the less sensitive 3T machine, meaning they can be reproduced in any hospital in the country.

That, Menon said, is a sign of hope.

The QS test group consisted of 25 patients with recurring or remitted MS or clinically isolated syndrome, which leads to the disease, as well as 15 age and sex-matched participants. The QS mapping showed the same damage areas in brains of all MS patients.

The progression of Multiple Sclerosis is measured using an Extended Disability Status Score, and QS results from the MS patients correlated to individual scores very well.

The diagnostic benefits of QS imaging has great potential, as some patients have to wait between six months to twenty years for their MS to become apparent.

For those with low disability scores or those who have not been diagnosed, the difference is life-changing. The wait, Menon said, is the hardest part for many patients. Early detection and treatment of MS can save much heartache for patients waiting on diagnosis, as well as save lives and long term healthcare costs.

Source: thelondoner.ca © 2014 Londoner (10/06/14)

Positive phase 2 results reported for RPC1063 in relapsing Multiple Sclerosis(10/06/14)

Receptos, Inc. announced that the Phase 2 portion of the RADIANCE trial of its selective S1P1 receptor modulator, RPC1063, in relapsing multiple sclerosis (RMS) met the primary endpoint, reduction in MRI brain lesion activity. The overall safety profile of RPC1063 was consistent with the results of prior trials, and continues to support the differentiation of the drug candidate against other oral agents for treatment of RMS on the market or in clinical development.

The randomized, double-blind study assessed the efficacy, safety and tolerability of two orally administered doses (0.5 mg and 1.0 mg) of RPC1063 against placebo in 258 patients with RMS across 77 sites in 13 countries. The primary endpoint of the trial was the reduction in the cumulative number of total gadolinium-enhancing (GdE) lesions determined by MRI from week 12 to week 24 of study treatment, a standard endpoint for Phase 2 trials in this indication. Patients on RPC1063 experienced a statistically significant reduction in GdE lesions of 86% at both 0.5 mg and 1.0 mg compared to patients on placebo (p-values <0.0001 for each dose group compared to placebo). Secondary endpoints measuring effects on other MRI parameters were also positive and statistically significant (p<0.0001 for each dose group compared to placebo). Although this Phase 2 portion of the trial was not powered to detect a statistically significant difference between RPC1063 treatment arms and placebo on annualized relapse rate (ARR), there was a favourable trend for both RPC1063 dose groups. The detailed results of the Phase 2 portion of the RADIANCE trial are expected to be presented at a major scientific meeting in coming months.

Safety and tolerability data from the trial provide support for a differentiated, potential best-in-class profile. The overall adverse event profile appeared relatively similar between the RPC1063 dose groups and placebo with no concerning safety signals for patients receiving RPC1063. First dose changes in heart rate in patients receiving RPC1063 were generally modest (maximum mean reduction).

"The results of this trial demonstrated a significant treatment effect of RPC1063 at both doses, consistent with other molecules in the class," said Jeffrey Cohen, M.D., Principal Investigator of the RADIANCE trial and director of the Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research. "The results also showed a favourable overall safety profile, particularly in the critical areas of cardiovascular and hepatic side effects. The ongoing Phase 3 trial has been designed to confirm and extend these results."

Receptos initiated the Phase 3 portion of the RADIANCE trial under a Special Protocol Assessment (SPA) with the FDA in December 2013. The Phase 3 portion of the trial, which is currently enrolling patients, is a randomized, double-blind study designed to compare 0.5 mg and 1.0 mg of RPC1063 against interferon beta-1a (Avonex®) in 1,200 patients with RMS.

"The positive results of the Phase 2 portion of RADIANCE exceeded our expectations with respect to the differentiation thesis for RPC1063," said Faheem Hasnain, President and Chief Executive Officer of Receptos. "Based on our analysis of the Phase 2 dataset, we believe that RPC1063 has the opportunity to be the best-in-class S1P receptor modulator. Our Phase 3 program is now well underway, positioning the program as the most advanced S1P receptor modulator in development for relapsing multiple sclerosis. In addition, we believe that RPC1063 may have promise in other therapeutic areas, and we continue to look forward to the results of TOUCHSTONE, our Phase 2 trial of RPC1063 in ulcerative colitis, in the fourth quarter of 2014."

Source: MarketWatch Copyright © 2014 MarketWatch, Inc (10/06/14)

MS patients blocked from 'life-changing' drugs Fampyra and Sativex(10/06/14)

People with multiple sclerosis are on the verge of being denied two drugs that help alleviate pain as a result of new NHS recommendations.

Fampyra and Sativex have been licenced in recent years to help people who experience mobility problems and muscle spasms.

However, the National Institute of Health and Care Excellence (NICE) is due to reject the drugs as treatments for MS, with experts saying they are not cost-effective.

In a letter to the Daily Telegraph, a group of experts including the head of the MS Society and seven neurologists say NICE has not taken full account of the "life-changing" differences the two drugs make to sufferers' lives.

"NICE is proposing to block access to two potentially life-changing MS treatments which are licensed and proven to be effective at helping people walk more easily and control painful muscle spasms," they wrote.

"If this guideline remains unchanged, people will be forced to pay privately, or face the agonising daily frustration of living with painful and debilitating symptoms, knowing there are drugs that may help them, but that they can't get access to."

Fampyra helps treat mobility problems, while sativex can be used to treat muscle spasms. On a private prescription, they would cost an MS surferer between £200 and £350.

The experts said NICE has over-estimated how much medication people would need for the drugs to be effective.

It is estimated that of the 100,000 people in the UK with MS, 40,000 would benefit from Fampyra and Sativex.

Michelle Mitchell, chief executive of the MS Society, told the Telegraph: "We understand that NICE has to make difficult decisions which balance cost to the NHS with the efficacy of a given treatment. But we don't understand why NICE deliberately excluded organisations that represent people with MS from a process which resulted in a proposal that two relatively affordable drugs with proven efficacy should be not be used in the NHS."

Willy Notcutt, Consultant in Pain Management at James Paget University Hospital, Norfolk, added: "Many people, including doctors, don't really understand how unpleasant symptoms such as spasms are - for example someone screaming in pain whenever someone tries to wash them.

"For many of them these treatments are invaluable and make life worth living again."

NICE said organisations will have their chance to comment and that the guidelines will be revised if new evidence emerges in support of Fampyra and Sativex.

Source: International Business Times © Copyright 2014 IBTimes Co., Ltd (10/06/14)

Studies stress the importance of vitamin D intake during first year of life(09/06/14)

Everyone seems to agree that vitamin D is important throughout life. This is certainly as true in the first year of life as it is later on. For it is during the first year that, in addition to its role in calcium metabolism, this critical nutrient reduces both the risk of current infections and the late-life development of such autoimmune diseases as multiple sclerosis and type 1 diabetes.

Both the Institute of Medicine (IOM) and the American Academy of Pediatrics (AAP) agree that vitamin D intake during the first year of life should be 400 IU/d. My own estimation of the requirement (for different ages and body sizes) is 65-75 IU/kg body weight per day. For average body weights in infants during the first year of life that rule of thumb computes to somewhere between 300 and 500 IU/d for infants. So, while there is still contention with respect to the optimal intake for adults, there really is no disagreement about how much is needed for infants, either among various authoritative sources or arising from different approaches to the evidence. With respect to infants, 400 IU/d seems to be just about right.

The question is, how is the infant to get that vitamin D? Human milk, in most nursing mothers, contains very little vitamin D. Infant formulas, from various manufacturers, all contain some added vitamin D in amounts calculated to be sufficient to meet an infant's needs. But extensive studies during the first year of life reveal that less than one-fifth of all infants ever get as much as the recommended 400 IU/d from any source, and fewer than one out of 10 breast-fed infants meet the requirement. As a result, the AAP urges that all infants, regardless of whether they are breast or formula fed, receive their 400 IU/d as pediatric drops. Unfortunately, this recommendation, while appropriate, is not often followed. Most babies are just not getting the vitamin D they need. The late-life consequences of this shortfall could be enormous.

It must seem strange that on the one hand we stress that human milk is the best source of nourishment for our babies, and on the other seem to ignore the fact that human milk doesn't contain the vitamin D those babies need. The explanation, very simply, is that the disconnect is artificial. Nursing mothers have so little vitamin D in their own bodies that there is little or none left over to put into their milk. But it has not always been this way. We know that the vitamin D blood concentrations that are regularly found today in Africans living ancestral lifestyles are high enough to support putting into breast milk all the vitamin D an infant needs. But the bulk of the world's population today is not living on the high equatorial plains of East Africa nor exposing much of its skin for most of the day.

Fortunately, we don't have to return to East Africa. It turns out that, if we give nursing mothers enough vitamin D to bring their blood levels up to the likely ancestral levels, then they automatically put all of the vitamin D their baby needs into their own milk, thereby ensuring that the infant gets total nutrition without the need to resort to vitamin D drops.

How much vitamin D does the mother need so as to ensure an adequate amount in her milk? As with everything else related to vitamin D, there is a lot of individual variation, but it appears that the daily intake must be in the range of 5,000-6,000 IUs. As no surprise, that's just about the amount needed to reproduce the vitamin D blood levels in persons living ancestral lifestyles today. And while 5,000-6,000 IU may initially seem high, it is important to remember how much the sun produces for us. A single 15 minute whole body exposure to sun at mid-day in summer produces well over 10,000 IU.

There is one important proviso for nursing mothers concerning the needed intake. Those who live in North America and have to rely on supplements should be certain that they take their supplements every day. While for other purposes it is possible to take vitamin D intermittently (e.g., once a week), that doesn't work for putting vitamin D into human milk. The residence time of vitamin D in the blood is so short that, if the mother stops taking her vitamin D supplement for a day or two, vitamin D in her milk will be low (or absent altogether) on the days she skips.

There is a glaring disconnect here between these well-attested physiological facts and the official IOM recommendation for nursing mothers, i.e., only 400 IU/d - the same intake for her as IOM recommends for her baby (whose body weight is less than 10% of her own). The IOM, if it were to be explicit about its current recommendations, would be telling nursing mothers something like this:

"The evidence we analyzed indicates that your own body needs only 400 IU of vitamin D each day. Unfortunately, that won't allow you to put any vitamin D into your breast milk. Sorry about that . . . So, if you want to ensure that your baby is adequately nourished, you are going to have to resort to giving your infant vitamin D drops."

That would be a hard message to sell, and clearly, it makes little sense on its face. As I have already noted, women living ancestral lifestyles (whether or not they are nursing an infant) have far higher blood levels of vitamin D than contemporary urban Americans. Milk production (and its optimal composition) are simply two of the many functions that vitamin D supports in a healthy adult. This breast-feeding example is not a special case; it is just one of the many pieces of evidence that point to the fact that current vitamin D recommendations for adults are too low - way too low.

Vitamin D supplements - and in this case vitamin D drops - are literal lifesavers for infants today. But what about two or three generations back - before nutritional supplements come into existence, but long after migration out of Africa? Ninety years ago vitamin D had not yet been discovered, and there certainly were no vitamin D supplements that could have been used. How did we get by through those thousands of years? There are two answers. Most of us, living in temperate latitudes, got a lot more sun exposure than we do today, and of course there were no sunscreens, so there was no blocking of the solar radiation that produces vitamin D in our skin. Those of us living in far northern latitudes survived mostly by depending upon diets that were very high in seafood, which is naturally a rich source of vitamin D. And those of us who got vitamin D by neither route were at increased risk of a whole host of vitamin D-related disorders, most obvious and most easily recognized being rickets.

The bony deformities of rickets were common a century ago in Europe, North America, and East Asia, and were largely eradicated in growing children by use of cod liver oil and, in the US, by the introduction of vitamin D fortification of milk in the 1930s. Fortunately, growing children can repair some of the bone deformities of rickets if they are given vitamin D soon enough. But, repairing rickets, while a good and necessary thing to do, is not sufficient. It is too late, by the time we recognize the deformities of rickets, to ensure maximal protection against the autoimmune diseases (for example), for which susceptibility is mainly determined in the first year of life.

To sum up, we now better recognize the importance of vitamin D in the earliest stages of life. Furthermore, there is, as noted earlier, quite good agreement on how much an infant needs. Where we lack consensus is how to make certain that all of our babies get the amount they need. Why not rely on giving nursing infants vitamin D drops, as the AAP recommends? Two reasons: 1) It's been tried and has failed; and, 2) When it does work in individual infants, it provides no benefit for the mother. By contrast, ensuring an adequate vitamin D input to the mother during pregnancy and lactation is almost certainly the best way to meet the needs of both individuals.

An "adequate" intake for nursing mothers, as noted earlier, is not the 400 IU/d the IOM recommends, but is instead in the range of 5,000-6,000 IU/d, taken daily. If they get that much, they will meet not only their own needs, but their infant's as well. And they will have the satisfaction of knowing that they are supplying all their baby's needs, the natural way.

Source: News-Medical.Net Copyright 2000-2014 AZoM.com Limited (09/06/14)

Compassion fatigue fighting through self care (09/06/14)

The first step to effective caregiving for those with Multiple Sclerosis is caring for oneself, according to researchers Marie Namey, a clinical nurse specialist in Multiple Sclerosis at the Cleveland Clinic Main Campus, and Ellen Reardon, a dietitian at Walden Behavioral Care. The presentation “Compassion Fatigue: Caring for the Caregiver,” presented at this year’s 2014 CMSC ACTRIMS Annual Meeting in Dallas, demonstrates how to fight the condition known as “compassion fatigue,” which gradually decreases the feeling of compassion within people who work directly with those suffering from chronic or progressive diseases such as MS, and often found in nurses, psychologists and first responders.

“If you don’t care for yourself physically, emotionally, and spiritually then eventually there will not be enough of you left to care for anyone else,” the researchers noted during the presentation. The condition was first identified in nurses in the 1950s, which presented with feelings of hopelessness, incompetency and self-doubt; decrease in feeling pleasure; constant stress; anxiety; and decrease in productivity.

Therefore, the researchers consider it crucial for caregivers who are tasked with treating or supporting those with MS to balance the care of both the body and the mind. To deal with the trauma experienced by patients, caregivers may need to have a calm and safe retreat where they can retreat to, as well as a strategy to deal with loss and grief. “Stay clear with commitment to career goals or your personal mission, know how to focus on what you can control and look at situations as entertaining challenges and opportunities, not problems or stresses,” they recommend.

However, recovery from stress, anxiety, and trauma associated with caring for those with chronic illness also depends on keeping the physical self strong through exercise, relaxing, adequate sleep habits, good nutrition, and medical and preventive care.

Specific advice for self caring includes breathing exercises, having some sort of a treat before talking to people, sitting calmly at a desk and cupping the eyes with the hands, engaging in joyful thoughts, keeping in touch with loved ones during the day, and meditation. “Put joy, love, hope, laughter and gratitude in each day,” they summarize.

For those caregivers who are seeking to recover from the effects of compassion fatigue, researchers recommend compassion cultivation training, during which patients may perform traditional contemplative practices as well as search for contemporary psychology and scientific help. It is also important to redevelop empathy and kindness for oneself and others.

Compassion fatigue is a combination of physical, emotional, and spiritual exhaustion experienced by those who help others in distress. The condition can be identified by indicators like anxiety, irritability, mood swings and difficulty concentrating. It leads to detrimental effects in individuals, both professionally and personally, since caregivers may also experience a decrease in their self esteem, distrust, changes in appetite, sleep, and other habits. However, some cases can even cause depression, which can lead to self medication.

Caregivers who experience compassion fatigue go through a series of stages that begin with what Namey and Reardon term as the zealot phase, in which the person still feels committed and enthusiastic. The second stage, the irritability phase, turns enthusiasm into displeasure, and complaints about work begin, as well as inappropriate use of humor. In the withdrawal phase, the person begins to start avoiding the patients, feeling lapses of concentration, and even avoids family and friends.

The fourth phase is the zombie phase, in which the rage begins, the relation between coworkers may be conflictual, and patience is at a minimum level among caregivers. This pattern leads to some people feeling overwhelmed and leaving the profession, sometimes associated with somatic illness and the endurance of the symptoms, while others feel resilient and transform their attitude. In either case, the effects of caring for those with progressive diseases such as Multiple Sclerosis are indeed real. Both Namey and Reardon’s presentation at the 2014 CMSC ACTRIMS on the subject serves as starting point for identifying how to avoid and deal with the difficulties of caregiving in MS, which in the end benefits both patient and caregiver alike.

Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (09/06/14)

MS rebound after stopping Tysabri(09/06/14)

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis.

Gueguen A, Roux P, Deschamps R, Moulignier A, Bensa C, Savatovsky J, Heran F, Gout O.


OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.

METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.

RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9?months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.

CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

Source: J Neurol Neurosurg Psychiatry. 2014 May 29. pii: jnnp-2014-307591. doi: 10.1136/jnnp-2014-307591 & Pubmed PMID: 24876183 (09/06/14)

Age and it's effects on response to MS treatment Tysabri(06/06/14)

Age-dependent effects on the treatment response of natalizumab in MS patients.

Matell H, Lycke J, Svenningsson A, Holmén C, Khademi M, Hillert J, Olsson T, Piehl F.


BACKGROUND: Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18-50 years. The effect of natalizumab has not been specifically studied in older patients.

OBJECTIVE: We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program.

METHODS: In three MS centers registry data for patients aged >50 years were validated.

RESULTS: At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients.

CONCLUSION: These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.

Source: Mult Scler. 2014 May 27. pii: 1352458514536085. & Pubmed PMID: 24866201 (06/06/14)

Mechanism of cell death unraveled—perspectives for treating inflammatory diseases(05/06/14)

Researchers at VIB and Ghent University have unraveled the mechanism of necroptosis. This is a type of cell death that plays a crucial role in numerous diseases, from viral infections and loss of auditory nerve cells to multiple sclerosis, acute heart failure and organ transplantation. Having detailed knowledge of the cell death process enables a targeted search for new drugs.

Peter Vandenabeele (VIB/UGent): "The molecular mechanism of necroptosis was a complete mystery for a long time. Cells explode. But exactly how they do this was unclear. Now we have found that cells activate pore-forming molecules that make holes in the membrane. This basic research provides entirely new perspectives for the treatment of numerous chronic and acute inflammatory and degenerative diseases where necroptosis needs to be blocked. But it can also be useful to stimulate necroptosis in a controlled way, for example to circumvent the resistance of cancer cells to chemotherapy or to resensitize cancer cells to cell death."

Inflammatory reactions due to cell death

Many diseases are associated with dying cells. That is why understanding the cell death process is essential for the search for new medications. Peter Vandenabeele has many years of expertise in researching cell death, including with 'necroptosis'. In this type of cell death the cell explodes, as it were, and the cell content is released. This causes inflammatory reactions in the surrounding tissue.

Prior research shows that necroptosis occurs with a number of diseases, including viral infections, septic shock, detached retina, loss of auditory nerve cells, multiple sclerosis, acute heart failure, stroke, kidney failure and organ transplant complications. It also occurs in the presence of bad blood circulation and oxygen deficiency in the extremities or organs such as with atherosclerosis or type II diabetes.

A new therapeutic strategy: counteracting pore formation

Yves Dondelinger and Peter Vandenabeele discovered that the cellular explosion during necroptosis is paired with the formation of pores consisting of MLKL proteins. These MLKL pores are formed on the cell surface and cause the cells to absorb too much water. Because of this the cells ultimately explode. Detailed knowledge about how MLKL proteins create pores offers possibilities for developing medications for combatting or tolerating cell death by preventing or temporarily blocking this process.

Source: Medical Xpress © Medical Xpress 2011-2014 (05/06/14)

MS drug Tecfidera's gastrointestinal side-effects influence ongoing use(05/06/14)

Large proportions of patients starting on dimethyl fumarate (Tecfidera) for multiple sclerosis appear to need additional medications to manage the drug's gastrointestinal and other adverse effects, and a substantial minority are ultimately unable to tolerate the drug, multiple studies reported here found.

These findings were confirmed in the manufacturer's own studies -- for example, more than half of patients in an open-label study took over-the-counter medications to control stomach upset and diarrhea -- although symptoms eventually abated in those who stayed on the drug beyond 2 months.

On the other hand, one-quarter of patients switching to dimethyl fumarate from another MS medication in an independent study had stopped the drug within 3 months.

These and other reports on dimethyl fumarate's safety were presented during a poster session at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS).

The drug's safety has always been a concern. Serious adverse events have been rare -- no cases of progressive multifocal leukoencephalopathy (PML) have been reported with dimethyl fumarate in MS patients, although a handful of cases have been seen with a close chemical cousin marketed for many years in Europe for psoriasis.

But more mundane side effects such as flushing, gastrointestinal complaints, and itching were common in the MS trials and, according to the studies reported at CMSC-ACTRIMS, in real-world experience as well.

Groups at three major medical centers -- in Los Angeles, the Boston area, and here in Dallas -- each reported their experiences in patients starting on dimethyl fumarate either de novo or after switching from some other medication.

University of California Los Angeles

Kirstin Nygren, NP, and Barbara Giesser, MD, reviewed outcomes in 30 patients starting on dimethyl fumarate from April 2013 (immediately after its FDA approval) through January of this year. All patients were switched to the drug because they were failing on other therapies.

Of these, five (17%) stopped the drug, primarily because of its adverse GI effects, the researchers said. One of these patients developed splenomegaly within a week of starting on the agent, which resolved after it was withdrawn.

Of the remaining 25, 12 reported either minimal or no adverse effects. The other 13 indicated significant side effects, mainly nausea, vomiting, bloating, and/or diarrhea, but not severe enough that they stopped taking the drug. These were treated with dietary strategies (e.g., taking the medication with fat-containing foods and use of probiotics) as well as over-the-counter medications such as simethicone.

Nygren and Giesser indicated that, midway through the study period, they adopted a slower up-titration schedule than the 1-week period currently recommended in the drug's label (starting dose 120 mg twice daily, then 240 mg thereafter). Their new strategy involved starting patients at 120 mg once daily for the first week and gradually stepping the dose up to 240 mg twice daily over 4 weeks. The researchers indicated that this seemed to reduce the incidence of side effects.

They also reported a novel finding -- in three patients who discontinued and for whom lab data were available, all showed high eosinophil counts. This was not seen in other patients (number unspecified) who found the drug more tolerable.

Lahey Outpatient Center, Lexington, Mass.

Claudia Chaves, MD, and colleagues tracked 104 patients who were put on dimethyl fumarate. They found that 57% developed GI symptoms during the first month of treatment, but when reevaluated after 3 months, only 11% were still reporting such effects.

Flushing, another common side effect of dimethyl fumarate, was seen in 51% during month one, declining by about half in subsequent months.

More seriously, grade 2 leukopenia or grade 3-4 lymphopenia was detected at month six in 25%, after only a small percentage had shown such effects in earlier evaluations.

Treatment was discontinued in 13 patients, "the vast majority due to the GI side effects," Chaves and colleagues reported.

University of Texas Southwestern Medical Center

In this chart review, researchers led by Elliott Frohman, MD, PhD, examined adverse effects in 66 patients starting on dimethyl fumarate following its approval.

They found that only 18% had no adverse effects. Flushing affected 44%, while 51% reported GI symptoms. Another 12% reported itching.

These were generally treated with OTC medications -- low-dose aspirin for flushing, bismuth agents or loperamide for abdominal discomfort, and antihistamines for pruritus.

In patients with persistent side effects, medications were stepped up to the prescription category, including montelukast (Singulair) for itching and glycopyrrolate for GI symptoms, the researchers indicated.

Nevertheless, they reported, 26% eventually stopped dimethyl fumarate because of intolerability.

Manufacturer-Sponsored Studies

The drug's manufacturer, Biogen Idec, funded a series of post-marketing analyses of dimethyl fumarate's safety reported at CMSC-ACTRIMS. One of these, called MANAGE, focused specifically on GI effects.

Led by Edward Fox, MD, of Central Texas Neurology Consultants in Round Rock, Texas, the open-label study recruited 233 MS patients (mean disease duration 9 years, SD 7) who agreed to start on dimethyl fumarate.

Nearly all -- 206 -- reported some type of GI event during the 16-week study -- and 126 took some type of OTC medication to treat GI symptoms, the researchers found. Most of these uses occurred early in treatment, as fewer than 10% of patients were still taking such medications when asked at week 12.

Fox and colleagues reported that 10% discontinued dimethyl fumarate because of adverse effects, of whom three-quarters cited GI problems as the main reason.

Patients in MANAGE were asked to keep daily diaries during the first 12 weeks of the study, recording among other things whether they had taken the drug with food as recommended. Severe GI events appeared to be more common in participants whose diaries indicated that they didn't always follow the instruction -- these were seen in 15.5% of such patients, versus 7.7% of those always taking the drug with meals -- but compliance with the food instruction did not seem to affect the risk of either "extreme" GI difficulties or mild-moderate symptoms.

Interim results from a longer, larger study called ENDORSE generally followed the same pattern. This is a planned 5-year extension study involving some 1,700 participants in earlier pivotal trials, including some originally assigned to placebo or glatiramer acetate (Copaxone) and therefore new to dimethyl fumarate.

Discontinuation rates in those patients because of adverse effects have ranged from 14% to 23%, according to investigators led by J. Theodore Phillips, MD, of Baylor Institute for Immunology Research in Dallas. Among those continuing on dimethyl fumarate after 2 or more years on the drug during the placebo-controlled trials, discontinuations because of adverse effects were in the range of 4%-6%.

In the patients continuing on the drug from the earlier trials, MS relapse was the most common reason for discontinuing. But for those who switched from placebo or glatiramer acetate, reasons were mostly the same as in the other studies, led by GI complaints and flushing.

Another analysis sponsored by Biogen Idec confirmed that lymphopenia incidence grew with extended treatment (up to 3.6% of patients staying on the drug for 96 weeks).

Limitations to these analyses, especially the retrospective "real-world" studies, included variable and often unspecified methods for diagnosing and categorizing adverse effects, as well as reliance on patient reports for those with subjective symptoms.

The retrospective chart reviews had no external funding. Authors of the Lahey and UCLA reviews declared they had no relevant financial interests. Some authors of the UT Southwestern study reported relationships with Biogen Idec, Teva, Acorda, Genzyme, Novartis, and Abbott.

The Biogen Idec-sponsored studies included company employees as authors. Other authors reported extensive relationships with commercial entities, including Biogen Idec as well as Acorda, Genzyme, Novartis, Teva, XenoPort, Roche, Synthon, Merck Serono, and others.

Source: MedPage Today © 2014 MedPage Today, LLC (05/06/14)

Some MS patients resist physical activity boost(04/06/14)

Multiple sclerosis (MS) patients who would benefit the most from an increase in physical activity were, unfortunately, those for whom an intervention designed to boost it was least effective, a researcher said here.

In a secondary analysis of data from an earlier, overall successful trial of an Internet-based exercise intervention, factors associated with the strongest responses included mild versus moderate disability, body weight in the normal range versus obesity, and relapsing-remitting versus progressive MS, according to Robert Motl, PhD, of the University of Illinois in Urbana-Champaign.

There is "value in modifying and refining interventions" to improve their chances of success in difficult populations, he suggested at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Separately, another analysis of the same trial data indicated that, in the overall study sample, the improvements seen in measures of physical activity were accompanied by reductions in time spent sitting.

Rachel Klaren, a graduate student in Motl's laboratory, reported that mean sitting time among all study participants (including dropouts) was lower by 1.6 hours per day compared with a wait-listed control group; and among those completing the study per protocol, the difference was 2.1 hours per day.

The results confirmed that participants did indeed get up out of their chairs to achieve the increased step counts seen in the primary study results, reported at the CMSC-ACTRIMS meeting in 2013.

Motl and colleagues had developed a 6-month intervention geared to increasing physical activity in MS patients. It included a website providing information on how MS patients can become more physically active using social cognitive therapy techniques, as well as one-on-one live video coaching conducted over the Internet. Participants wore pedometers and had goals for the number of steps, recording their actual step counts in a diary.

At the 2014 meeting, Motl explained that physical activity is known to be beneficial in preserving mobility for MS patients, which typically diminishes over time even in those who remain in the relapsing-remitting phase.

The trial randomized 82 patients either to the intervention or to a wait-listed control. While on the wait-list, participants received no encouragement or coaching; they then entered the program at the trial's conclusion.

Who Responds, Who Doesn't

Overall, mean step counts increased from baseline by nearly 40% in the intervention group. But Motl said that the investigators noted that not every participant showed such an increase. In fact, some had marked decreases.

Relative to the wait-listed controls, only those in the intervention group with mild disability on the basis of Expanded Disability Status Scale scores showed increases in step counts, whereas the intervention had no effect for those classified with moderate disability (P<0.01 for the effect of disability status).

Similarly, the intervention was effective only in those with relapsing-remitting disease, not in those with progressive forms of MS (P<0.01 for the effect of clinical course) -- and it was effective only for those with body mass index values of 25 kg/m2 or less, not for those with higher values (P<0.05 for the effect of obesity status).

As it happens, the subgroups not benefiting from the intervention were those at the greatest risk for continued or accelerated disability progression, and therefore those for whom an increase in physical activity would have the greatest health benefit. Motl concluded that his, or other interventions, may need to be tailored more specifically to these patients to increase the chances of success.

Other factors, including whether patients were taking disease-modifying drugs or medications for specific MS symptoms, did not affect the intervention's impact, Motl indicated.

Effect on Sedentarism

Klaren noted that time spent sitting "has been described as 'the new smoking'" because of its adverse effects on a host of health outcomes.

Although the increase in step counts seen in the trial's primary results might logically entail a commensurate decrease in sitting times, it can't be assumed. Consequently, Klaren analyzed data on sitting time specifically collected in the trial.

As part of the baseline and 6-month follow-up evaluations, participants were asked to estimate their average daily time spent sitting down over the past 7 days. The analysis covered 70 participants who had provided baseline data (intent-to-treat sample), of whom 13 did not complete the intervention.

In the overall group and after adjusting for baseline differences, the mean daily sitting time in the intervention group at follow-up was 7.2 hours (SE 3.3), compared with 8.8 (SE 3.3, P<0.05) for the wait-listed controls.

For the per-protocol group, mean daily sitting time at follow-up was 6.8 hours (SE 3.5) with the intervention versus 8.9 (SE 3.5, P<0.05) for controls, Klaren reported.

She said these were the first data specifically addressing the effect on sitting time of an exercise intervention in MS patients.

Next steps, she added, would be to examine whether reductions in sitting time really do lead to demonstrable health benefits, and to identify factors associated with sedentarism in MS patients.

The study was supported by the National Multiple Sclerosis Society.

Motl reported relationships with Biogen Idec and Acorda. Klaren declared she had no relevant financial interests.

Primary source: Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis
Source reference: Motl R, et al, "Does the effect of a physical activity behavior intervention vary by clinical characteristics of people with multiple sclerosis?" CMSC-ACTRIMS 2014; Abstract RH05.

Additional source: Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis
Source reference:Klaren R, et al "Efficacy of a behavioral intervention for reducing sedentary behavior in people with multiple sclerosis" CMSC-ACTRIMS 2014; Abstract RH04.

Source: MedPage Today © 2014 MedPage Today, LLC (04/06/14)

No easy answers for managing secondary progressive MS(04/06/14)

For multiple sclerosis patients who have transitioned to secondary progressive disease despite use of disease-modifying treatments (DMTs), their management must still rely on physicians' instincts and the patients' wishes, clinicians here agreed.

Evidence-based medicine has almost nothing to say about whether DMTs continue to offer a benefit to patients who have moved from relapsing-remitting to secondary progressive MS (SPMS) because the existing trials were badly flawed, said Olaf Stüve, MD, PhD, of the University of Texas Southwestern Medical Center here.

Taking the "stop DMTs" side in a point-counterpoint debate at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, Stüve argued that the lack of demonstrable benefit and the adverse effects of DMTs militates against continuing them.

But his opposite number on the debate platform -- Michael Carrithers, MD, PhD, of the University of Wisconsin in Madison -- as well as audience members countered that there are some biological reasons to believe that DMTs could be beneficial, even if the hard trial evidence is lacking.

And, Stüve admitted (to the audience's murmured approval), stopping DMTs "is a difficult decision because patients feel like you're abandoning them."

Several clinicians in the packed meeting room agreed that, purely from a patient engagement perspective, it's necessary to give them some kind of treatment. For example, one said he routinely adds methotrexate.

"You have to do something," another said. If the clinician has nothing to offer, added a third, patients "think you're giving up." But nobody advocated mitoxantrone -- the only FDA-approved treatment for SPMS -- the evidence for which has been criticized.

In the end, Stüve lost an electronically recorded vote by a landslide -- only about 10 of the nearly 100 attendees indicated they would stop DMTs in a hypothetical patient with progressing disability, no relapses in 20 years, and no significant adverse effects from his long-standing DMT.

The only current evidence backing DMTs such as interferon-beta for SPMS comes from three trials conducted in the 1990s and early 2000s with interferon-beta.

For all three of them -- one conducted in Europe and two in the U.S.  -- the topline results indicated a benefit. But Stüve called attention to these trials' inclusion criteria and the resulting sample characteristics. Patients experiencing relapses within the past year were accepted, mean disease durations were under 10 years, and time since SPMS diagnosis was just 2 years.

All of which, he suggested, indicates that many of the patients in these trials probably did not have true SPMS. One of the trials actually reported a reduction in relapse rates as one of the favorable outcomes -- even though SPMS patients aren't supposed to be having relapses.

As a result, the overall benefits seen in the trial probably were concentrated in those who still had substantial inflammatory activity not consistent with SPMS, Stüve suggested.

But Carrithers and some audience members responded that inflammation does not always die down completely when a patient transitions to SPMS.

Carrithers pointed to a small study published in 2005 in which SPMS patients who had interferon-beta withdrawn showed accelerated disability progression and, importantly, new MRI lesions.

On the other hand, he noted that many of the patients in the earlier "successful" trials of interferon-beta in SPMS had not received the drug previously. Hence, the results can't be generalized to those currently on such medications, for whom the question is whether to withdraw them.

One audience member insisted that inflammation remains a feature in SPMS but is "locked behind the blood-brain barrier" where it is less apparent in standard tests. She argued that it is vital to keep treating patients with DMTs in order to keep these smoldering inflammatory processes in check.

During the electronic vote, most of the audience indicated that they would like to switch a hypothetical patient who had been on interferon-beta to another type of DMT. About two-thirds of those voters wanted specifically to try natalizumab (Tysabri), a very potent drug for relapsing-remitting MS but with unclear benefits in progressive forms.

Debate moderator Dennis Bourdette, MD, of Oregon Health and Science University in Portland, tried to canvas the audience for an explanation of that choice. He never got one, but some in the room complained that health system and insurer policies would prevent it anyway. Natalizumab is relatively expensive and since it is not approved for SPMS, most payers won't cover it.

A phase III trial of natalizumab in SPMS is now underway -- with enrollment criteria more to Stüve's liking -- and both he and Carrithers indicated that its results would go at least part way toward settling the now-unanswered question of DMTs for the condition.

Carrithers said that a trial specifically aimed at withdrawal of DMTs in SPMS patients is needed as well. Bourdette pointed out that just such a trial was reported last month at the American Academy of Neurology's annual meeting -- it found that 90% of those stopping DMTs remained stable after a median of 3 years off treatment, but a few showed renewed MRI lesion activity.

Until the evidence is clearer, though, panelists and audience members seemed to agree that physicians will have to base their clinical decision-making on their own experience and individual patients' characteristics and wishes.

Stüve and Carrithers both said MRI scans are vital. Patients should continue to be treated as long as they still show lesion activity, they agreed.

The debate was organized with support from the Department of Veterans Affairs, with which Bourdette, Carrithers, and Stüve are affiliated.

Carrithers reported research funding from Biogen Idec. Bourdette and Stüve declared they had no relevant financial interests.

Source: MedPage Today © 2014 MedPage Today, LLC (04/06/14)

New updated electronic injection RebiSmart for self-administration of Rebif(04/06/14)

Merck Serono, the biopharmaceutical division of Merck, has introduced its updated electronic injection RebiSmart for self-administration of Rebif (interferon beta-1a). Rebif is the disease-modifying treatment of the company, which is used as basic therapy for the treatment of relapsing-remitting form of multiple sclerosis (MS).

The new RebiSmart allows patients to inject Rebif themselves, and may also collect information about injection times, dates and doses administered and store and wirelessly send the safe MSdialog server. But only the new RebiSmart must be inserted into a corresponding transmitter and then a button to be pressed.

Together with the new RebiSmart, Merck Serono also conducts a the new, web-based software system MSdialog. This allows people with MS to become actively involved in the management of their disease by being regularly called upon to fill abstracts of health-related questionnaires that are based on established procedures and standardized scales - such as the MSQLI (Multiple Sclerosis Quality of Life Inventory) - and the MusiQoL (Multiple Sclerosis International Quality of Life) questionnaire. In addition, doctors and MS nurses can monitor patient compliance as well as the course of their health on the basis of regular questionnaires.

"To encourage patients through knowledge and technologies and to enable, may have the potential to improve patient outcomes, as it allows the patient, even to contribute to document their disease," said Dr. Gavin Giovannoni, Professor of Neurology at the Barts and The London School of Medicine and Dentistry. "This new RebiSmart and MSdialog platform can provide physicians access to certain therapy data of their patients in real time, so that the time can be used during the doctor visit to discuss important patient-specific topics and issues. Moreover, these technologies enable the patient to more indepth knowledge of their own disease."

Patients who use MSdialog, have the choice between E-mail and SMS reminders for the self-application of their medication. Moreover, they can MSdialog share with their MS nurse between visits to the doctor to document their adherence to therapy, and patient-related indicators. This information may be able to save time, which is available during the practice visit for the doctor-patient interaction.

"We worked at Merck Serono is continuously working to improve our product portfolio and taking advantage of the latest medical and technological advances to meet the needs of patients over years," said Belén Garijo, Head of the Merck Serono division. "With the introduction of MSdialog we rely on digital technologies to provide people with MS a management system that can help them become more involved in the treatment of their disease and to lead a more open dialogue with their treatment team."

RebiSmart was the first injection device in MS, the date, time and dosage stores each injection. This may be an accurate recording of doses administered retrieved and discussed with the patient, which allows the physician to monitor patient compliance and improve. The new RebiSmart offers improvements over the original device-including a larger display, a new guide on the screen, a graphical representation of adherence to therapy and a transmitter for wireless data transmission.

The new RebiSmart is used with Rebif multidose cartridges, each containing the drug store for a week. An interactive, on-screen instructions and signals guide patients through the injection process. Customizable settings give more flexibility with injection duration and depth, helping discomfort and pain can be reduced to a minimum.

The new RebiSmart and MSdialog are from May 2014 in the UK, Ireland, France, Italy, Switzerland, Austria, Finland, Portugal , Germany, Belgium, Canada, Denmark, Luxembourg available, Netherlands and Sweden. Other markets will follow. Two versions of the multidose cartridge, 132 micrograms (three doses of 44 micrograms) and 66 micrograms (three doses of 22 micrograms), were in January 2009, the approval by the European Medicines Agency (EMA).

Source: PHARMABIZ.com Copyright © 2010 Saffron Media Pvt. Ltd (04/06/14)

US FDA accepts MS drug Lemtrada resubmission for review(03/06/14)

The US Food and Drug Administration (FDA) has accepted for review the Genzyme's resubmission of supplemental Biologics License Application (sBLA) seeking approval of Lemtrada (alemtuzumab) for the treatment of relapsing forms of multiple sclerosis. A six-month review period has been assigned for the Lemtrada sBLA. Genzyme expects FDA action on the sBLA in the fourth quarter.

This resubmission is based on data from the same clinical studies included in the original sBLA, and provides supplemental analyses and additional information to specifically address issues previously noted by the FDA in its December 27, 2013 Complete Response Letter. The company resubmitted the sBLA earlier this month following constructive discussions with the agency.

Source: PHARMAbiz.com Copyright © 2010 Saffron Media Pvt. Ltd (03/06/14)

Cognitive problems and white matter loss in SPMS(03/06/14)

Extensive White Matter Dysfunction in Cognitively Impaired Patients with Secondary-Progressive Multiple Sclerosis.

Francis PL, Chia TL, Jakubovic R, O'Connor P, Lee L, Feinstein A, Aviv RI.


BACKGROUND AND PURPOSE: Cognitive impairment is a common, disabling symptom of MS. We investigated the association between cognitive impairment and WM dysfunction in secondary-progressive multiple sclerosis using DTI.

MATERIALS AND METHODS: Cognitive performance was assessed with a standard neuropsychological battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Cognitive impairment was defined as scoring >1.5 standard deviations below healthy controls on ≥2 subtests. Fractional anisotropy maps were compared against cognitive status using tract-based spatial statistics with threshold-free cluster enhancement.

RESULTS: Forty-five patients with secondary-progressive multiple sclerosis (median age: 55 years, female/male: 27/18, median Expanded Disability Status Scale Score: 6.5) were prospectively recruited. Cognitively impaired patients (25/45) displayed significantly less normalized global GM and WM volumes (P = .001, P = .024), more normalized T2-weighted and T1-weighted WM lesion volumes (P = .002, P = .006), and lower WM skeleton fractional anisotropy (P < .001) than non-impaired patients. Impaired patients also had significantly lower fractional anisotropy (pcorr < .05) in over 50% of voxels within every major WM tract. The most extensively impinged tracts were the left posterior thalamic radiation (100.0%), corpus callosum (97.8%), and right sagittal stratum (97.5%). No WM voxels had significantly higher fractional anisotropy in patients with cognitive impairment compared with their non-impaired counterparts (pcorr > .05). After the inclusion of confounders in a multivariate logistic regression, only fractional anisotropy remained a significant predictor of cognitive status.

CONCLUSIONS: Cognitively impaired patients with secondary-progressive multiple sclerosis exhibited extensive WM dysfunction, though preferential involvement of WM tracts associated with cognition, such as the corpus callosum, was apparent. Multivariate analysis revealed that only WM skeleton fractional anisotropy was a significant predictor of cognitive status.

Source: AJNR Am J Neuroradiol. 2014 May 15 & Pubmed PMID: 24831599 (03/06/14)

Cognitive-behavioral therapy improves fatigue in MS patients(03/06/14)

Fatigue, often linked to insomnia, is one of the most common complaints of patients with multiple sclerosis (MS), so anything that controls this debilitating condition would be a welcome relief.

Cognitive-behavioral therapy (CBT), a psychotherapeutic treatment that helps patients understand the thoughts and feelings that influence their behaviors, appears to be a viable option. A small, new study showed that it increases sleep time and reduces fatigue and depression in MS patients suffering insomnia.

It is hard to tease out whether the intervention first has an effect on the fatigue or on the depression and then perhaps has a kind of snowball effect, said lead author Megan Clancy, PhD, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, in Ohio.

"We don't know if it's the chicken or the egg," Dr. Clancy said, that is, whether the problem with insomnia started with depression or with fatigue, and then made the other problem worse. In any case, CBT appears to work on both.

Dr. Clancy discussed the data at a poster presentation here at the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Chicken or Egg

According to a recent survey of about 7700 MS patients, more than half (56%) reported sleep disturbances, including insomnia, which can have negative effects on physical and mental health. These sleep problems often overlap with depression, Dr. Clancy noted. Patients with MS are at 26% to 51% increased risk for depression compared with the general population, she said.

The new study was a retrospective analysis of 11 MS patients who participated in individual or group CBT at the Sleep Disorders Center at the Cleveland Clinic Foundation between January 2008 and December 2013. The 1 male and 10 female participants ranged in age from 36 to 69 years; 8 were white, and 3 were African American.

Researchers assessed depression, fatigue, and insomnia before and after the treatment intervention using the Patient Health Questionnaire (PHQ-9), the Fatigue Severity Scale (FSS), and the Insomnia Severity Index (ISH), respectively. The tests all use self-reported measures.

The CBT, which took place over an average of 4 to 6 sessions, targeted specific behaviors and thoughts related to sleep. Components included the following: stimulus control (going to bed only when sleepy, limiting activities in bed to sleep and sex, getting out of bed at the same time every morning, and arising if not asleep within 20 minutes); sleep hygiene (for example, limiting use of caffeine and other simulants before retiring and having no technology within reach while in bed); relaxation training; and cognitive therapy.

The study showed that patients reported improvements across all domains. A majority (73%) reported an increase in total sleep time ? an overall increase of 1.25 hours.

About 60% of the patients reported a reduction in fatigue (mean change, 1.9), but all patients continued to have a clinical level of fatigue.

"We used a scale for fatigue that just rated a patient as having clinical fatigue or not having clinical fatigue," explained Dr. Clancy. "Everybody reduced their level of fatigue, but they were still clinically fatigued, which is not surprising given that it's MS."

Half of the patients reported improvement in depression measure (mean change, 1.2), and they reported an overall decrease in depression severity. About 86% of the group reported improvement in insomnia, and 43% reported an overall reduction in severity of insomnia.

Root Cause

Asked to comment, Robert Lisak, MD, professor and chair, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, and new president of the CMSC, said that CBT can be helpful for fatigue in MS patients, but it depends on the root cause of the fatigue.

For example, it will not do much for fatigue caused by "getting up 3 times during the night to go to the bathroom to urinate" because of a bladder problem, but it may be useful if the fatigue is linked to depression, said Dr. Lisak. "You can try to fish out the cause, but it's my experience that it's almost never just 1 factor."

Obesity, which increases risk for obstructive sleep apnea, may contribute to insomnia and fatigue in MS patients, noted Dr. Lisak.

In addition to CBT, doctors may turn to pharmacologic approaches to treat fatigue, including amantadine (Symadine, Solvay Pharmaceuticals, Inc), a drug originally used to prevent flu. Another approach, usually done in collaboration with physiotherapists or occupational therapists, is "economy of effort," said Dr. Lisak. This involves encouraging patients to plan ahead with respect to daily activities ? for example, going upstairs only once to fetch things instead of going up and down 4 times.

Dr. Clancey and Dr. Lisak have reported no relevant financial relationships.

6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Abstract CG26. Presented May 29, 2014.

Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (03/06/14)

MS bladder problems show up early and often(03/06/14)

Nearly 80% of multiple sclerosis patients in a large registry reported overactive bladder symptoms, and more than one-third of newly diagnosed patients in a different cohort also had urinary dysfunction, researchers reported here.

Analysis of questionnaires returned by 8,380 participants in the registry operated by the North American Committee on MS (NARCOMS) indicated that 6,392 of them reported overactive bladder -- including 5,159 who said they had urgency-related leakage, according to Stacey S. Cofield, PhD, of the University of Alabama at Birmingham, and colleagues.

However, barely half had ever seen a urologist for their symptoms, the researchers reported during a poster session at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS).

In part because a recent history of urinary tract infections was relatively common in patients with "wet" overactive bladder -- who had a mean of 0.85 infections in the past 6 months, compared with 0.56 on average among those with "dry" symptoms and 0.47 without any -- Cofield and colleagues suggested that patients with urgency-related leakage "may benefit from more specialty care."

In the study of newly diagnosed patients, Emily Riser, MD, and colleagues at the Tanner Center for MS in Birmingham found that 38% (13 of 34 recruited at initial MS diagnosis) had post-voiding urinary retention (at least 50 mL after urinating) as measured by ultrasound scan.

The same 13 patients all showed some degree of ambulatory impairment as well, with 25-foot walk times greater than the "normal" of 2.2 seconds. Four of these patients had 25-foot walk times in excess of 5 seconds, indicating significant impairment, Riser and colleagues reported.

Cofield and colleagues had also found that other disabilities frequently accompanied the overactive bladder. Moderate to severe overall disability as rated with the 8-point Patient Determined Disease Steps scale was reported by 80.7% of NARCOMS participants with overactive bladder plus leakage, 65.4% of those with overactive bladder but no leakage, and 48.4% of those with no urinary symptoms (P<0.001 for wet overactive bladder versus no symptoms).

Together, the two studies' results confirm that bladder dysfunction is a common feature of MS, even in its earliest stages.

A third study reported at the CMSC-ACTRIMS meeting examined whether routine ultrasound bladder scans would aid in clinical management -- with results suggesting the answer is "hardly ever."

Ellen Lathi, MD, and colleagues at St. Elizabeth's Hospital in Boston performed scans on 101 consecutive consenting MS patients (70 with relapsing-remitting disease, 31 with primary or secondary progressive MS). Patients were also asked about urination problems such as frequency, urgency, and leakage.

Patients were considered symptomatic if they reported two or more symptoms with at least minimal severity or one symptom of at least moderate severity.

Most symptomatic patients showed normal (less than 50 mL) post-voiding retention with the scans. Of 20 patients deemed asymptomatic, only one (with relapsing-remitting MS) had a positive scan, and the measurement of 51 mL in this patient just barely exceeded the necessary threshold.

"For symptomatic patients, measurement of post-voiding retention did not alter clinical decision-making or provide additional useful information," Lathi and colleagues concluded.

But they stopped short of suggesting that the scans were completely useless. The single asymptomatic patient with a positive scan may represent "a small but meaningful percentage of patients with relapsing-remitting MS, and measurement of post-retention voiding is most valuable for identifying this group," they argued.

The NARCOMS analysis was supported by Allergan. Study authors reported relationships with Teva, MedImmune, Ortho Biotech, GlaxoSmithKline, Bayer, EMD Serono, and Sanofi. Two co-authors were Allergan employees.

The other two studies had no external funding and the authors declared they had no relevant financial interests.

Additional source: CMSC-ACTRIMS
Source reference:Cofield S, et al "Severity and characteristics of overactive bladder condition in multiple sclerosis: an ancillary analysis of the NARCOMS registry data" CMSC-ACTRIMS 2014; Abstract SX08.

Additional source: CMSC-ACTRIMS
Source reference:Tracy T, et al "Bladder dysfunction and disability in people newly diagnosed with multiple sclerosis" CMSC-ACTRIMS 2014; Abstract SX22.

Source: MedPage Today © 2014 MedPage Today, LLC (03/06/14)

Brain volume changes in patients with relapsing-remitting MS treated with Interferon Beta-1a(03/06/14)

The reductions in brain volume often seen in patients with chronic relapsing–remitting multiple sclerosis may be reduced by treatment with interferon beta-1a, though treatment may be affected by the patient’s immunologic status, according to data presented by Michael G. Dwyer, PhD, at the 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Dwyer is an assistant professor of neurology in the Department of Neurology at the University of Buffalo School of Medicine and Biomedical Sciences, and the technical imaging director of the Buffalo Neuroimaging Analysis Center, Buffalo, NY.

According to Dwyer, chronic relapsing-remitting multiple sclerosis (RRMS) progression is often associated with decreased brain volume. “We know there are volume changes, but we don’t have a ‘smoking gun,’” he said.

In the study write-up, the authors noted that “Over the short term, brain volume may change, via inflammation-related hydrodynamic changes, which subside following anti-inflammatory therapy,” known as pseudoatrophy.

Dwyer presented data from a study, titled “Relapsing-Remitting Multiple Sclerosis Treated with Interferon Beta-1a: Immunologic and Short-term Volume Changes,” that compared percent brain volume change between 23 patients with relapsing-remitting multiple sclerosis who were treated for 24 weeks with subcutaneous injections of interferon beta-1a three times per week, and 15 healthy controls.

Patients were evaluated via magnetic resonance imaging (MRI) at baseline, and at months 3 and 6. Researchers also assessed immunologic markers (CD4+ T cells producing interleukin (IL)-17F) at baseline and again at 6 months.

Researchers assessed percent brain volume change from baseline to month 3, from month 3 to month 6, and from baseline to month 6 and compared differences both within and between groups. The study found that the percent brain volume change between baseline and 3 months was -0.95% (SD= 1.712%) among patients with relapsing-remitting multiple sclerosis (P=0.03) and 0.24% (SD 1.068%) among healthy controls (P=0.36).

The difference was significant between groups (P=0.02).

However, the researchers found no significant difference in percent brain volume change within or between either group from months 3 to 6, or from baseline to month 6.

The authors reported that decreased percentage of CD4+ T cells producing IL-17F from baseline to month 6 “was significantly correlated with reduced brain volume over months 0 to 6 (r = 0.51, P=0.02)” in patients with relapsing-remitting multiple sclerosis.

Treatment with subcutaneous interferon beta-1a was associated with reduced brain volume over the first 3 months of treatment, but there were no differences in brain volume seen in treated patients from month 3 to month 6, or from baseline to month 6.

The authors noted “the correlation between decreased percentage of CD4+ T cells producing inflammatory IL-17F and volume reduction is supportive of an early anti-inflammatory effect” of treatment with subcutaneous interferon beta-1a.

Source: HCPLive Copyright HCPLive 2006-2014 Intellisphere, LLC (03/06/14)

Unique solutions for MS gait problems(03/06/14)

With impaired walking ability generally considered the number one functional problem for multiple sclerosis (MS) patients, new approaches to assistive devices were described here, ranging from the mechanical to the furry.

In the former category, PhD student Morgan Boes and colleagues at the University of Illinois in Urbana-Champaign (UIUC) have designed a self-contained, pneumatic-powered ankle-foot orthosis (AFO) aimed at boosting a patient's ability to push off while walking or climbing stairs.

In the latter category is Bamse, a 6-year-old boxer dog trained by Cecilie Fjeldstad, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City, to provide both physical and psychological support to moderately disabled MS patients as they walk.

Both researchers described their progress to date with their respective approaches at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS).

Pneumatic Powered AFO

Boes, who is completing her doctoral studies in the UIUC lab of Robert Motl, PhD, showed her device's design at two CMSC-ACTRIMS poster sessions.

It's powered by bottled CO2 gas worn on a belt, which is connected to an AFO that includes positional and force sensors and a pneumatic actuator that flexes the foot while increasing joint stability and motion control.

The primary goal, Boes explained, is to provide "directional powered assistance during each phase of the gait."

Passive AFOs are already widely available to support the foot and ankle in MS patients and others with weakened lower-extremity muscle function. A common problem in MS is drop foot -- impairment in the strength of ankle-foot flexion, depriving patients of the power needed to move forward while walking.

These devices stabilize the joint and hold the foot in a neutral position, which helps patients with drop foot to walk but cannot provide an actual strength boost.

The UIUC device provides up to 100 lbs per square inch (PSI) of force during three of the four gait stages: initial contact when the foot strikes the ground (stage 1), forward propulsion (stage 3), and leg advancement (stage 4). No power is delivered at the second stage, known as loading response, when the weakened foot is flat on the ground and the walker has not yet begun to push off on it.

Pilot studies with healthy people in the lab have indicated that it should perform more or less as desired, but testing in MS patients has not yet begun. Boes's group is gearing up for a trial with planned enrollment of about 30 patients already using an AFO or for whom it has been recommended. The trial will use the 6-minute walk test as the primary endpoint.

Boes admitted that the prototype's design was somewhat awkward looking (although when this was suggested to her, she laughed and said it was "sleek" relative to an earlier model). But she pointed out that it was constructed from readily available and inexpensive components and the pneumatic system was known to be both robust and safe. She said her group had considered an electromechanical design and decided it would have more minuses than pluses.

Service Dog for Walking Assistance

Fjeldstad reported on an initial trial with Bamse (Norwegian for "stuffed teddy bear," she explained, pronouncing it as "bom-suh") in 36 patients with pronounced walking impairment but who did not currently require an assistive device such as a cane or walker.

She personally trained the animal (already a certified therapy dog) to walk beside a person without pulling ahead or lagging behind, and designed a special harness with a flexible handle. Hence, the patient cannot and should not lean on the dog like a cane.

The intent is similar to that of a guide dog for the blind, Fjeldstad indicated. The person may gain some physical steadying from having a hand on the dog's harness, but the support is primarily psychological in giving the patient more confidence in walking.

In the trial, the 36 patients underwent a total of four timed 25-foot walk (T25W) tests with Bamse -- an unassisted walk followed 3 minutes later with a second walk with Bamse. After a 15-minute rest, each patient then repeated the two T25W tests but in reverse order (assisted followed by unassisted).

The mean unassisted time to complete the 25-foot walks was 9.3 seconds (SD 0.4), well in excess of the 8-second threshold for substantial impairment proposed in a Neurology paper last year by several researchers including Motl.

Bamse's assistance improved the T25W times only a little -- to a mean of 8.7 second (SD 0.3), which was statistically significant at P=0.014 -- but then, the participants had not trained with the dog before and one might expect that the confidence boost would increase with practice.

Fjeldstad said that these results should encourage more research into the use of service animals as an aid to ambulation in MS patients.

The study by Boes' group was supported by the CMSC Foundation and the National Science Foundation Research Center for Compact and Efficient Fluid Power.

The study by Fjeldstad's group had no external funding.

Authors of both studies declared they had no relevant financial interests.

Primary source: CMSC-ACTRIMS
Source reference: Boes M, et al. "Evaluation of a portable powered ankle-foot orthosis on gait function in persons with multiple sclerosis" CMSC-ACTRIMS 2014.

Additional source: CMSC-ACTRIMS
Source reference:Fjeldstad C, et al. "Does using a service dog help ambulation in MS individuals with gait dysfunction?" CMSC-ACTRIMS 2014; Abstract RH07.

Source: MedPage Today © 2014 MedPage Today, LLC (03/06/14)

Canadian study finds no link between blocked veins, MS(03/06/14)

A new Canadian study is casting doubt on the link between blocked neck veins and multiple sclerosis, after finding no difference in the proportion of abnormalities in the veins of MS patients and healthy controls.

The study, published Monday in The Canadian Medical Association Journal, found no link between chronic cerebrospinal venous insufficiency (CCSVI) and MS.

Using ultrasound and MRI technology, University of Calgary neurologist Dr. Fiona Costello and her colleagues tested the criteria used to diagnose a patient with CCSVI on a group of MS patients and healthy controls.

They compared the ultrasound results of 120 patients and 60 controls and found a "high" proportion of both groups met one or more of the criteria required for a CCSVI diagnosis. Their results showed that 58 per cent of MS patients and 63 per cent of the healthy controls met one or more of the proposed criteria. "We detected no differences in the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls," the study's authors conclude. "Moreover, our study revealed significant methodologic concerns regarding the proposed diagnostic criteria for chronic cerebrospinal venous insufficiency that challenge their validity."

Dr. Paolo Zamboni first put forth his theory that constricted veins in the head and neck were linked to MS in 2009. Zamboni also postulated that a vein-widening procedure, which he called the "liberation treatment," could improve the symptoms of MS patients.

Since that time, hundreds of MS patients have sought the treatment, often paying to have it done overseas. As well, several studies have examined Zamboni's theory, with many poking holes in his work.

A recent study published last October in The Lancet also found that a narrowing of the veins leading from the brain was just as prevalent in healthy individuals as it was in patients with MS.

Meanwhile, a separate survey found that a group of Canadian MS patients who left the country to get the controversial "liberation treatment" were relatively satisfied with the results, despite receiving sub-optimal care.

Of the 124 participants, nearly 60 per cent said they received no follow-up investigations at the centre where they had received the procedure. More than 40 per cent said they had no follow-up care of any kind.

Jamie Greenfield, a data analyst at the University of Calgary's MS Research Program, said only 6 per cent of the survey respondents reported that they had not been told of potential adverse side effects. Some potential risks, such as stent migration or kidney damage resulting from the dyes used to help locate blocked veins, were rarely raised, she said.

Despite these findings, 50 per cent of the patients rated their overall satisfaction with the procedure as good or better. As well, 122 of the 124 participants said their procedure was successful, with 79 per cent reporting no complications and 19 per cent saying it was "successful with some trouble."

Greenfield presented the results of the survey at the joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis in Dallas over the weekend. The results of her presentation were published in MedPage Today.

Barrie, Ont. resident Steve Garvie opted to have the liberation treatment in 2010. He told CTV News that it was only because of the procedure that he was able to attend his daughter's recent wedding in Boston.

"I walked her down the aisle and had the father and daughter dance with her," he said. "I feel truly blessed. Without the procedure I would be either cheering her on from my wheelchair in government housing, or I would not be on this earth to have this joy."

Source: CTV © 2014 Bell Media (03/06/14)

Pregnancy hormone may reduce multiple sclerosis symptoms(02/06/14)

For decades, women with multiple sclerosis have noticed that they tend to do better while they are pregnant. That has led to an experimental drug for the disease that's based on a hormone associated with pregnancy.

The hormone is a form of estrogen called estriol. It's abundant in a woman's body only when she is pregnant. Adding estriol to treatment with an existing MS drug cut relapses by 47 percent in a study of 158 women presented at the American Academy of Neurology meeting in April.

The result is "quite remarkable," says Rhonda Voskuhl, an author of the study and a neurologist at the University of California, Los Angeles. It suggests that estriol could greatly enhance the effectiveness of current MS drugs, Voskuhl says. Those drugs, which are designed to modulate the immune system, can cost up to $60,000 a year.

Multiple sclerosis is a disease that damages the myelin sheath covering nerve fibers. Researchers believe the damage is caused at least in part because the body's own immune cells begin attacking myelin. About 400,000 people in the United States have multiple sclerosis, with symptoms ranging from muscle weakness or paralysis to difficulty thinking.

The new research on estriol was inspired by decades of anecdotal reports from women like Melissa Sherak Glasser of Woodland Hills, Calif. Glasser is 41 now, but was diagnosed with MS when she was just 15.

She remembers putting one hand into a tub of bathwater to check the temperature and being surprised that it felt cold. "Then I put my other hand in and it was burning hot and I thought OK, something's wrong," she says.

An MRI scan showed that Glasser had MS. But Glasser didn't let the disease slow her down much. She was a cheerleader in high school, then went to college and graduate school and got married, despite relapses that caused temporary blindness, vertigo and difficulty walking.

When Glasser was in her mid-20s, she got pregnant. And one day, during an episode of morning sickness, she realized something surprising: her MS symptoms had gone away. "I felt so horrible with all the pregnancy hormones, and I had to laugh," she says.

Glasser reported this to neurologists at UCLA who had been monitoring her MS since she was diagnosed more than a decade earlier. They weren't surprised. They'd heard stories like that before from women with MS. And pregnancy's effect on MS symptoms had been confirmed by a large scientific study in 1998.

So by the time Glasser became pregnant for the first time (she has four children now and was free of MS symptoms during all four pregnancies), Voskuhl and other researchers were already hard at work trying to identify the factor that was protecting pregnant women with MS. "If we could just figure it out, we would have an inroad to a major discovery," Voskuhl says.

The researchers knew that during pregnancy, a woman's immune system changes. "Pregnancy involves a fetus, which has half of the father's proteins on it," Voskuhl says. "So it's half foreign. In order to not reject that half-foreign fetus, the mother's immune system shifts."

Voskuhl figured that whatever was causing that shift was also protecting the woman's nerve fibers from MS. And she suspected a key factor was the hormone estriol.

So the researchers gave estriol to mice with multiple sclerosis and waited to see whether it would help them. "And indeed it did," Voskuhl says. "The mice were not paralyzed, they were walking around fine. It was just a dramatic reduction in their disease." Doses of the pregnancy hormone even worked in male mice.

Voskuhl was confident that estriol could help people with MS. But it took more than a decade to find out.

Drug companies weren't interested in estriol because it isn't a patented chemical, Voskuhl says. So she turned to the National Institutes of Health, the National Multiple Sclerosis Society and foundations, including one set up by the family of Melissa Sherak Glasser.

Ultimately, Voskuhl got the millions of dollars she needed to conduct a two-year trial of estriol in women who also were taking the widely used MS drug Copaxone. The success of that trial clears the way for a much larger study that can be submitted to the Food and Drug Administration for approval.

Glasser is confident that estriol will ultimately be approved as a treatment for MS and hopes to be one of the first people in the U.S. to get a prescription.

Source: Copyright 2014 NPR (02/06/14)

Alemtuzumab: Do the benefits outweigh the risks in treating multiple sclerosis? (01/06/14)

Serious questions remain regarding the side effects and benefits associated with the use of alemtuzumab for the treatment of multiple sclerosis.

The 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) concluded Saturday with “Controversies in the Treatment of Multiple Sclerosis,” a debate-style session that focused on discussion of several hot-button issues in current practice. The third and final segment, “Controversy III: Alemtuzumab is Too Toxic to Use in Most Patients with MS,” featured a debate over the benefit vs. risk profile of alemtuzumab, an anti-CD52 monoclonal antibody that is currently approved for the treatment of several forms of leukemia and lymphoma and is being studied for the treatment of multiple sclerosis.

Late last year, the FDA rejected the drug for the treatment of multiple sclerosis, saying that more evidence from high-quality clinical trials was need regarding the benefits and risks of the drug in this patient population.

One participant in the debate session, Olaf Stüve, MD, PhD, said “there is a need for more effective yet safe therapies; currently available treatment options are only partially effective and have potentially life-threatening side effects.”

Stüve is associate professor in the Department of Neurology and Neurotherapeutics and associate professor in the Department of Immunology at University of Texas Southwestern Medical Center, and chief of the Neurology Section at VA North Texas Health Care Systems.

The clinical phase II CAMMS223 study (which was not an open-label study) compared alemtuzumab with interferon beta-1a in patients with early, active relapsing-remitting multiple sclerosis. Over five years of follow up, researchers found that treatment with alemtuzumab lowered the risk of sustained accumulation of disability by 72% compared with interferon beta-1a. Treatment with alemtuzumab also lowered relapse rate by 69% compared with interferon beta-1a. In the CARE-MS I trial, treatment with alemtuzumab led to a 55% risk reduction in relapses compared with interferon beta-1a.

Stüve also noted that in CARE-MS II the secondary co-primary endpoint (sustained accumulation of disability) was met and there was a 42% improvement in risk reduction in the alemtuzumab group compared with the interferon beta-1a group.

“Alemtuzumab is highly effective; with it patients can be treated early to prevent accumulation of disability,” he said.

“There is no need to treat patients long-term, sides effects are mostly mild to moderate, disease and organ specific, and a pharmacovigilance program could be established to screen patients,” said Stüve.

Fellow debater, Mitchell Wallin, MD, MPH, disagreed, pointing out that there are “serious GI side effects” associated with treatment with alemtuzumab, including abdominal pain and flushing.

Wallin is Clinical Associate Director of the Multiple Sclerosis Center of Excellence based in the Baltimore Veterans Affairs (VA) Medical Center/University of Maryland, and associate director of Clinical Care and associate professor of medicine at Georgetown University.

Safety issues potentially preventing the approval of alemtuzumab “include autoimmune cytopenias, nephropathy, serious infections, and malignancies,” said Wallin.

He noted there are also concerns over treatment adherence and challenges of maintaining long term injection. Adherence to self-administered disease-modifying therapies in multiple sclerosis has been the subject of several papers. Based on study results, between 12-87% of patients with multiple sclerosis do not adhere to their disease-modifying therapies.

In addition, because of the risk for life-threatening infections, rapid diagnosis of autoimmune cytopenias is imperative. He said the company had recommended monitoring complete blood count in patients.

If approved for the treatment of multiple sclerosis, the drug would have to have labeling regarding the risks, said Wallin.

Source: Copyright HCPLive 2006-2013 Intellisphere, LLC. All Rights Reserved. (01/06/14)

Critical review of outcomes used in MS clinical trials

Prof. George Ebers