MS news and research
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Teva’s Copaxone patent problems continue(01/09/14)
Teva Pharmaceuticals Industries Ltd is in trouble again for its multiple sclerosis (MS) injectable drug - Copaxone, as other drug manufacturers seek to launch their own generic versions of the drug. Teva has been fighting patent battles to ward off other pharmaceutical companies from making generic copies of Copaxone.
Copaxone makes up one-fifth of the company’s sales, but it is expected to lose 50% of its revenues by 2016, after its generic copies are launched. To deal with this impending threat, Teva introduced an improved version of the drug, with a higher dosage. But despite the introduction of the new Copaxone 40mg, troubles continue to pile up for the company.
Yesterday, Mylan Inc (MYL) and the duo of Novartis AG (ADR) (NVS)’s Sandoz unit and Momenta Pharmaceuticals, Inc (MNTA) announced that they have filed an Abbreviated New Drug Application (ANAD) for the Copaxone 40mg/mL with the US Food and Drug Administration (FDA). The ANAD, if approved, will allow the duo to manufacture and market a generic version of the drug, possibly at a low cost, which is a huge threat to the Israel-based company.
Copaxone – Teva’s Hero
Copaxone, launched in the US in 1997, is a drug for the treatment of relapsing multiple sclerosis (MS). The drug turned out to be a huge success for the company and generated $4.3 billion in sales last year, making 21% of the company’s sales. It also constitutes 42% of the company’s earnings.
However, the drug’s patent expired on May 24 this year. In order to deter launches of generic versions of the drug and to sustain its sales from Copaxone, Teva rolled out a new version of Copaxone in January - the new Copaxone is a 40 mg compared to the earlier 20 mg dose. The increased dose reduced the frequency of the drug administration significantly, from a daily dose to only three-times a week. The move worked for Teva, as in its last earnings announcement, CEO Erez Vigodman said that 51% patients had already converted to the new drug, and that the company is targeting a 65% conversion rate. The new version of the drug has patent protection until 2030.
Earlier Patent Battles
Teva, itself manufactures generic versions of many drugs, but it filed a patent infringement case against Sandoz in 2013, claiming that it was developing drugs similar to Copaxone, and violating Teva’s rights. The case was ruled against Teva, following which, Teva filed an appeal against the ruling.
Few months before Copaxone’s patent expiration, it filed a case in the US Supreme Court, seeking to delay the release of generic versions of the drug, until a ruling for the infringement case was given. Once again, the Supreme Court gave a decision against Teva’s expectations stating that any damages caused to Teva, will be recovered once the infringement case is finalised.
Teva still didn’t give up and filed a citizen petition with the FDA, asking the authority to order Mylan and Sandoz to conduct full-fledged clinical trials, which the FDA declined. In retaliation, Teva sued the FDA in Washington federal Court on May 9, claiming that the regulatory authority had wrongly rejected Teva’s appeal. Once again, Teva lost the case.
Teva’s efforts seem to have gone in vain, as yesterday Mylan and Sandoz both filed ANAD applications with the FDA for the development of generic versions of the new Copaxane 40mg, with a similar thrice a week regimen. Teva is expected to sue both companies for patent infringement, which will trigger a 30 month stay on the sale of any generic drug. But if Teva is unable to get a favorable decision before the end of the stay period, Mylan and Sandoz can launch their own biosimilar, as early as 2017.
This will be a big blow to the company, as Copaxone is a crucial part of its sales. The Copaxone 40mg has already earned $411.5 million in revenues since its launch, however cheaper versions of the drug will deeply reduce its sales. Copaxone 40mg is priced at $60,500 per year, only $1000 less than Copaxone 20mg. Any cheaper versions of the drug are expected to do well.
More importantly, Teva also faces competition from new MS oral drugs that have been launched recently. Biogen’s Tecfidera and Novartis’s Gilenya are both oral pills and can be administered more easily.
Going forward, it will be crucial for Teva to maintain sales from the MS segment, by developing new drugs for this disease. Currently, it has a MS drug called, Laquinimod, in its pipeline, which will be an oral treatment and is already in its phase 3 trials.
Teva’s stock has gained almost 30% year-to-date, as the company is trying hard to stop generic copies of its drugs from making it to the market.
Source: Bidness etc. © Bidness 2014 (01/09/14)
High dietary salt intake may worsen multiple sclerosis symptoms and boost the risk of further neurological deterioration, indicates a small observational study published online in the Journal of Neurology, Neurosurgery & Psychiatry.
Previous research has indicated that salt may alter the autoimmune response, which is implicated in the development of multiple sclerosis (MS), but it is not clear if it has any direct effect on the course of the disease itself.
The researchers assessed the blood and urine samples of 70 people with the relapsing-remitting form of MS to check for levels of salt; a marker of inflammatory activity called creatinine; and vitamin D, low levels of which have been linked to the disease.
This group were asked to provide urine samples on three separate occasions over a period of nine months to monitor changes in dietary salt intake, and their neurological health was then tracked for two years, between 2010 and 2012.
By way of comparison, urinary salt levels were measured in a second group of 52 people with the same type of MS between June and July 2013.
Salt intake averaged just over 4 g per day in both groups, but ranged from under 2 g (low) to 2-4.8 g (moderate) to 4.8 g or more a day (high), with men tending to have a higher daily intake than women.
After taking account of influential factors, such as smoking, age, gender, length of time after diagnosis, weight, treatment and circulating vitamin D, the analysis indicated a link between levels of dietary salt and worsening symptoms.
Compared with those consuming the least salt every day, those on moderate to high intake in the first group had around three more episodes of worsening symptoms, and were almost four times as likely to have these episodes.
The researchers then looked at x-rays and scans to find out if the disease had progressed further, and once again found a link between dietary salt intake and radiological evidence of further deterioration.
Those whose dietary salt intake was high were almost 3.5 times as likely to have radiological signs of further progression.
Similar results were obtained for the comparison group.
This is an observational study, so no definitive conclusions about cause and effect can be drawn. And higher levels of salt in the urine may reflect greater disease activity rather than the other way round, the authors point out.
But high salt intake is implicated in various aspects of poor health, they say. And their findings suggest further research into whether dietary salt reduction could ease MS symptoms or slow the progression of the disease might now be warranted, they add.
Source: MedicalXpress © Medical Xpress 2011-2014 (29/08/14)
Low dose naltrexone (LDN) may be on its way to becoming a new therapeutic agent for multiple sclerosis. Evidence for its efficacy in attenuating multiple sclerosis symptoms is scarce, but results of a phase 3 clinical trial, “A Randomized Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone,” suggest that LDN enhances the mental health quality of life of patients with multiple sclerosis.
The trial, initiated in 2007 by a group led by Bruce Cree, MD, PhD, at the University of California, San Francisco, sought to evaluate changes in quality of life for multiple sclerosis patients following treatment with 4.5 mg naltrexone (LDN). Eighty patients were enrolled in the trial, and treatment was administered nightly for eight weeks. Of primary interest was a difference in mean score of the multiple sclerosis quality of life inventory (MSQLI54) between LDN-treated and placebo-treated patients.
According to results published in 2010 in the journal Annals of Neurology, at the end of the trial, sixty patients had completed treatment. Ten patients withdrew before the end of the first trial period, but none withdrew due to a multiple sclerosis-LDN adverse event. In fact, one patient withdrew early due to a perceived benefit of treatment. Results from the other ten patients were not available due to database management errors and incomplete quality of life surveys.
Although the diminished number of patients reduced the trial’s statistical power, a significant improvement in mental health quality of life was identified. There was a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey, a 6-point improvement on the Mental Health Inventory, a 1.6-point improvement on the Pain Effects Scale, and a 2.4-point improvement on the Perceived Low Dose Naltrexone MS research Deficits Questionnaire.
Low-dose naltrexone is thought to affect immune function by increasing the level of endorphins in the body up to 100-300%. In addition, LDN may reduce microglial activity in the brain and reduce the amount of inflammation in the central nervous system. It is inexpensive and is given as a capsule once a day at bedtime. Virtually no serious side effects are associated with LDN–only a common complaint of disrupted sleep that rarely persists past one week of treatment. Yet before LDN can be indicated for use in multiple sclerosis patients, more studies must be conducted to evaluate its continued safety and efficacy.
LDN continues to make headlines in biotech and healthcare, not only for multiple sclerosis, but also for other diseases. Recently, IBD News Today reported on how low dose naltrexone may alleviate Crohn’s Disease symptoms, while biopharmaceutical company TNI BioTech Inc. recently announced its first shipment of Lodonal, an LDN immunotherapeutic, to The Republic of Panama and The Republic of Malawi for the treatment of cancers.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (29/08/14)
Physical Disability, Anxiety and Depression in People with MS: An Internet-Based Survey via the UK MS Register.
Jones KH, Jones PA, Middleton RM, Ford DV, Tuite-Dalton K, Lockhart-Jones H, Peng J, Lyons RA, John A, Noble JG.
INTRODUCTION: People with Multiple Sclerosis are known to have a relatively high prevalence of both anxiety and depression. Studies of the relationship between physical disability and mental health in people with MS have reported mixed results, showing the need for further work.
METHODS: Between May 2011 and April 2012, 4516 people completed the MSIS-29 (v.1) and HADS scales via the dedicated internet site of the UK MS Register within a 7 day time window. These responses were linked with basic demographic and descriptive data and analysed in SPSS (v.20).
RESULTS: The proportions of people experiencing anxiety or depression increased with physical disability such that 38.0% of respondents with low, and 66.7% with high disability reported at least mild anxiety, and 17.1% of people with low, and 71.7% with high disability experienced at least mild depression. The multiple regression model explained 18.4% of the variance in anxiety with MSIS-29-PHYS score being the strongest predictor of anxiety. The model for depression explained 37.8% of the variance with MSIS-29-PHYS score being the strongest predictor. Some of the other variables included showed negative associations with anxiety and depression, indicating that the influence of physical disability on mental wellbeing could be underestimated.
CONCLUSIONS: This study indicates that there is a positive relationship between physical disability and anxiety and depression, that physical disability impacts on anxiety and depression to differing extents, and that the effects vary with gender, age, disease course and disease duration. We have shown that physical disability is a predictor of anxiety and depression, and that other factors may mask the extent of this effect. Whether the causes of anxiety and depression are reactive, organic or a combination, it is essential that mental wellbeing is given due attention in caring for people with MS so that all their health needs can be met.
Source: PLoS One. 2014 Aug 25;9(8):e104604. doi: 10.1371/journal.pone.0104604. eCollection 2014 & Pubmed PMID: 25153835 (28/08/14)
A new treatment under investigation for multiple sclerosis (MS) is safe and tolerable in phase I clinical trials, according to a study published August 27, 2014, in Neurology® Neuroimmunology & Neuroinflammation.
The phase I studies were the first to test the drug candidate in humans. Studies with animals showed that the drug, which is called anti-LINGO-1, or BIIB033, may be able to reverse the demyelination of the nerves. Anti-LINGO-1 blocks LINGO-1, a central nervous system protein that prevents myelination. Current treatments for MS work to reduce new damage to the brain, but do not repair new or past damage.
In MS, the body's immune system begins to attack the myelin that acts as insulation around the nerves in the central nervous system. This makes it more difficult for the nerves to send messages to and from the brain and spinal cord.
In the study, 72 healthy people without MS and 47 people with either relapsing-remitting MS or secondary progressive MS were given the drug or a placebo. The healthy participants received either a placebo or one dose of the drug by an infusion or an injection. The people with MS received either placebo or two intravenous doses of the drug two weeks apart. In both groups, participants received varying amounts of the drug, ranging from 0.1 mg/kg to 100 mg/kg.
The occurrence of side effects was similar for people who received the drug and those who received the placebo. Most side effects were mild to moderate and were not related to the drug. Side effects included headaches, upper respiratory infections and urinary tract infections. There were no serious side effects or deaths.
There were no significant changes in vital signs, EKGs or other safety tests of the drug.
Intravenous doses of 10 mg/kg and higher resulted in concentrations of the drug in the blood that were similar to or higher than the concentration that was associated with 90 percent of the maximum remyelination effect in studies with rats.
"With these results we have been able to start phase II studies to see whether this drug can actually repair the lost myelin in humans and have any effect on restoring physical and cognitive function and improving disability," said study author Diego Cadavid, MD, of Biogen Idec in Cambridge, Mass., which developed the drug. Cadavid is a member of the American Academy of Neurology.
Source: EurekAlert! Copyright ©2014 by AAAS (28/08/14)
Jeanne Loring and her Scripps Research Institute colleagues transplanted a set of cells into the spinal cords of mice that had lost use of their hind limbs to multiple sclerosis. As the experimentalists expected, within a week, the mice rejected the cells. But after another week, the mice began to walk.
“We thought that they wouldn’t do anything,” says Loring, who directs the Center for Regenerative Medicine at Scripps. But as her lab has since shown numerous times, and published in Stem Cell Reports, something that these particular so-called “neural precursor cells” do before the immune system kicks them out seems to make the mouse better.
The cells Loring’s team used are derived from induced pluripotent stem cells, which are mature cells, such as skin cells, that have been coaxed with a combination of chemicals to return to an earlier stage of development.
Induced pluripotent cells, also known as iPS cells, pose a number of opportunities for medicine. For instance, Loring is using iPS cells from Parkinson’s disease and multiple sclerosis patients to reconstitute cell types that may be damaged in people with those conditions. She is also using them to test how certain drugs or treatments may affect damaged cells in people with conditions such as autism spectrum disorders.
Loring says no viable long-term treatments exist for the diseases her team has been working on, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, “That’s where the need is,” she says.
The neural precursor cells that Loring has been using in the mice with MS are young cells that haven’t quite gotten to the point of being nerves yet. Only certain types of these cells have such a dramatic Lazarus-like effect on the affected mice, but Loring’s team can readily identify them based on DNA analysis.
Even so, they’re not yet ready to treat human MS patients with the approach, she says. First, the researchers want to identify what the cells produce—a protein, perhaps, or a set of proteins—that allows the mice to walk.
For other diseases, however, researchers are closer to being ready to transplant working versions of reprogrammed cells into sick people.
For instance, Loring is exploring whether it’s possible to reprogram skin cells from patients with Parkinson’s disease so they turn into iPS cells and then into working dopamine neurons, which are the cells affected in the disease.
It seems to work in animals: Loring’s lab has transformed skin cells from eight human Parkinson’s disease patients into iPS cells and transplanted them as neurons into animal models.
A local Southern California Parkinson’s disease association has funded the research so far. Now Loring and colleagues are seeking additional funds to move through regulatory approval and toward the clinic.
Meanwhile, iPS cells separately suggest a way to test how disease-affected cells may or may not respond to treatment in diseases like autism, by in effect creating “dummy” cells on which drugs could be tested.
After making iPS cells from the cells of fragile X syndrome patients, a genetic condition that often co-occurs with some forms of autism, Loring’s lab turned them into cortical neurons—cells that she suspects don’t develop as they should in people with the disorder.
Indeed, the cortical neurons her lab grew from those iPS cells looked different than other cortical neurons and suffered delayed development. These neurons, she explains, could be used to test different molecules and compounds to see whether drugs could treat cells affected by autism.
This sort of approach, in which so-called “derived cells” are used for drug screening, Loring said, is the likely way that iPS cells will first be used in medicine, especially as more and more people have their genomes analyzed. Treatment with reprogrammed iPS cells will take longer to develop.
Loring says she hopes soon to be able to set up simple assays “that will allow us to find out what sort of drugs will work for people with particular genotypes.” That could offer a significant boost to drug development. iPS cells are an important new opportunity to attack diseases that otherwise have vexed researchers and doctors for decades.
Source: Techonomy © Forbes 2014 (28/08/14)
In final guidance, the National Institute for Health and Care Excellence (NICE) has recommended the use of Biogen Idec’s multiple sclerosis drug, dimethyl fumarate (also called Tecfidera).
The NHS now has a legal obligation to begin funding this treatment for eligible patients within the next 3 months.
Dimethyl fumarate is recommended as a treatment option for adults with relapsing–remitting multiple sclerosis. This is a chronic, disabling, neurological condition that, as it progresses, can be life altering and have a substantial negative impact on quality of life and activities of daily living.
The independent Appraisal Committee, which developed the guidance on behalf of NICE, considered evidence from the manufacturer, clinical experts and patient representatives. Professor Carole Longson, NICE Health Technology Evaluation Centre Director, said: “We are very pleased to be able to recommend dimethyl fumarate as an option for adults with relapsing-remitting multiple sclerosis.
“Evidence has shown that this drug is more effective in reducing relapse rates and just as effective in delaying disability progression compared with current similar treatments.
“Another advantage of dimethyl fumarate is that it is an oral treatment. It will be more convenient for patients to take than other currently available treatments, which must all be injected. It will help more people with multiple sclerosis to live a normal life.”
Dimethyl fumarate is recommended as an option for treating adults with active relapsing-remitting multiple sclerosis (normally defined as 2 clinically significant relapses in the previous 2 years), only if:
- they do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and
- the manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme.
Source: Copyright © 2014 National Institute for Health and Care Excellence. (27/08/14)
Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.
Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, Hoshi MM, Zimmer C, Hemmer B, Mühlau M.
BACKGROUND: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting.
OBJECTIVE: To determine the onset of spinal cord atrophy in the disease course of MS.
METHODS: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability.
RESULTS: Compared to HCs (76.1±6.9 mm2), UCCA was significantly reduced in CIS patients (73.5±5.8 mm2, p=0.018) and RRMS patients (72.4±7.0 mm2, p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =-0.131/0.192, p=0.044/<0.001) and disease duration (r=-0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014).
CONCLUSION: In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.
Source: Mult Scler. 2014 Aug 19. pii: 1352458514546514 & Pubmed PMID: 25139943 (27/08/14)
Sleep problems with multiple sclerosis(27/08/14)
The underdiagnosis of sleep disorders in patients with multiple sclerosis.
Brass SD, Li CS, Auerbach S.
STUDY OBJECTIVES: To report at a population level the prevalence of restless legs syndrome, insomnia, and the risk of obstructive sleep apnea in multiple sclerosis patients. Sleep patterns and associations with fatigue and daytime sleepiness were identified.
METHODS: A cross-sectional study was performed using a written survey that was mailed to 11,400 individuals from the Northern California Chapter of the National Multiple Sclerosis (MS) Society Database who self-identified as having MS. The survey included individual questions relating to demographics as well as several standard validated questionnaires related to primary sleep disorders, sleepiness, fatigue severity, and sleep patterns.
RESULTS: Among the 11,400 surveys mailed out, 2,810 (24.6%) were returned. Of these, 2,375 (84.5%) met the inclusion criteria. Among the completed surveys, 898 (37.8%) screened positive for obstructive sleep apnea, 746 (31.6%) for moderate to severe insomnia, and 866 (36.8%) for restless legs syndrome. In contrast, only 4%, 11%, and 12% of the cohort reported being diagnosed by a health care provider with obstructive sleep apnea, insomnia, and restless legs syndrome, respectively. Excessive daytime sleepiness was noted in 30% of respondents based on the Epworth Sleepiness Scale. More than 60% of the respondents reported an abnormal level of fatigue based on the Fatigue Severity Scale. Both abnormal fatigue and sleepiness scores were associated with screening positive for obstructive sleep apnea, insomnia, and restless legs syndrome.
CONCLUSION: A significant percentage of MS subjects in our sample screened positive for one or more sleep disorders. The vast majority of these sleep disorders were undiagnosed. Greater attention to sleep problems in this population is warranted, especially in view of fatigue being the most common and disabling symptom of MS.
Source: J Clin Sleep Med. 2014 Sep 15;10(9). pii: jc-00207-12. & Pubmed PMID: 25142763 (27/08/14)
An exercise component of the popular Nintendo Wii video game may help multiple sclerosis patients improve their balance by rewiring their brains, a new study suggests.
No medications exist to preserve balance in MS patients, and some drugs make balance worse, said study lead author Dr. Luca Prosperini, a neurologist at Sapienza University in Rome, Italy.
It appears that patients who use the Wii Balance Board five days a week -- moving to snowboarding or dance games, for example -- may help reduce their risk of falls and boost certain brain connections, possibly because they're coordinating their movements with a figure on a screen, Prosperini said.
There are caveats to the research, however. The study was small, and there's a risk that patients could hurt themselves by falling, although they can play seated rather than stand on the balance board.
"Patients with MS should be encouraged to start using this system only under supervision," Prosperini said. "Once well-trained, they may use it at home."
Multiple sclerosis is a nerve disorder that affects how the brain communicates with the body.
"Balance problems are quite common and arise due to the effects of MS on a number of functions that are important for balance," said Nicholas LaRocca, vice president for health care delivery and policy research with the National Multiple Sclerosis Society. Among other things, MS can disrupt vision, coordination and the body's balancing mechanism, he said.
Patients turn to a variety of strategies to support balance, he said. Canes and orthotic devices (shoe inserts) help some people, and rehabilitation can build strength and coordination. Some patients try electrical muscle stimulation to maintain or regain control of their muscles, he said.
Prosperini was inspired to study a video game treatment for MS when he saw patients in rehabilitation using a balance-boosting system that reminded him of an old Atari video game. Then a commercial about the Wii Balance Board caught his attention. The balance board, shaped a bit like a weight scale, detects a person's movements and allows them to be translated into action on a TV screen.
Prosperini tried to get a grant from Nintendo to support research. The company wasn't interested, he said, but he obtained funding from the Italian MS Society.
His previous research has supported the idea that patients regain balance when they use the Wii Balance Board. The new study aimed to understand what's happening in their brains.
In the new study, published online Aug. 26 in Radiology, 27 MS patients were split into two groups. One group spent three months doing nothing special while the other group played with the Wii Balance Board for 30 to 40 minutes daily, five days a week. Then the groups reversed roles: Those who had done nothing special used the balance board for three months, while the others stopped using it.
Another 15 healthy people tried the system, too.
All participants had specialised MRI scans to detect any physiological changes in the brain.
The researchers found that patients regained some balance, presumably by using the board, and their brains actually changed. Using the video game was tied to improvements in the protective sheath around nerves, leading to better conduction of impulses between the body and brain, Prosperini said.
It's not clear if other kinds of training might also help MS patients regain balance, he said. But video games like those that use the balance board might have similar benefits because they require patients to mimic movements that they see on screen, potentially providing an extra brain boost.
LaRocca, of the MS Society, said the study is valid but has limitations. For one, it's difficult to interpret what the brain changes mean, he said. Also, he added, the research suggests that the improvements in balance aren't permanent, requiring patients to keep at it to make the benefits last.
"Training needs to be ongoing, just like any other form of exercise," LaRocca said.
While the study found an association between the video-game balance board and balance-enhancing brain changes, it did not establish a cause-and-effect relationship. Prosperini said more research is needed, especially since the study was so small.
"There is increasing evidence of the clinical benefit of playing with the balance board, and more in general with highly interactive video games," he said. But researchers don't know enough about why the patients are getting better, he added.
Souce: healthfinder.gov Copyright © 2014 HealthDay (27/08/14)
Persons with MS may be able to improve self-awareness via task-oriented cognitive rehabilitation(26/08 14)
A new study of self-awareness by Kessler Foundation researchers shows that persons with multiple sclerosis (MS) may be able to improve their self-awareness through task-oriented cognitive rehabilitation. The study was epublished ahead of print on July 2 in NeuroRehabilitation. (Yael Goverover, Helen Genova, Hali Griswold, Nancy D. Chiaravalloti & John DeLuca: Metacognitive knowledge and online awareness in persons with multiple sclerosis doi: 10.3233/NRE-141113). Self-awareness is one's ability to recognise cognitive problems caused by brain injury. This is the first study of self-awareness in MS that includes assessment of online awareness, as well as metacognitive awareness.
Yael Goverover, PhD, OT, is a visiting scientist at Kessler Foundation. She is an associate professor at New York University. Dr. Goverover is a recipient of the National Institute on Disability and Rehabilitation Research Fellowship award (Mary Switzer Award). Drs. Genova, Chiaravalloti and DeLuca are MS researchers at Kessler Foundation.
The researchers assessed 18 people with MS and 16 healthy controls for 2 types of self-awareness - metacognitive knowledge of disabilities (or intellectual awareness) and online awareness (emergent or anticipatory awareness). They also looked at the relationships among self-awareness, functional performance and quality of life (QoL). Assessment involved the Functional Behavior Profile, questionnaires administered before and after functional tasks (purchasing cookies and airline tickets via the Internet) and the Functional Assessment of Multiple Sclerosis measure.
"Results showed that compared with controls, people with MS assessed their actual performance more realistically following completion of a task. This suggests that individuals may be able to improve their self-awareness through more experience with tasks," noted Nancy Chiaravalloti, PhD, director of Neuropsychology & Neuroscience Research at Kessler Foundation. "Research that leads to better understanding of types of self-awareness, functional outcomes and QOL will aid the development of effective assessments and rehabilitation interventions," said Dr. Chiaravalloti. "The association between online awareness and task performance in this study, for example, may have implications for cognitive rehabilitation strategies in the MS population."
Source: News-Medical.Net Copyright AZoM.com Limited 2000-2014 (26/08 14)
Non-parametric analysis of seasonality in birth and MS risk in second generation of migrants in Kuwait(26/08 14)
There are inconsistent reports about multiple sclerosis (MS) risk among migrants from low to high MS risk geographical regions. This study assessed the overall MS incidence and evaluated seasonality in birth and subsequent MS risk later in the life in second generation of migrants born and lived in Kuwait.
Methods: We assessed the overall and gender-specific MS risk in second generation of migrants born and lived in Kuwait between January 1, 1950 and April 30, 2013.
Data on migrant MS patients diagnosed and registered in Kuwait National MS Registry were used. Hewitt's non-parametric test was carried out to evaluate the seasonality in migrant MS births in comparison with the second generation migrant births in general population.
Results: During the study period, an overall risk of migrant MS births (per 100,000 non-Kuwaiti births in general population) as 23.8 (95% CI: 20.8 - 27.0).
Gender-specific MS risk showed that non-Kuwaiti female had statistically significant (p=0.003) higher risk (28.6; 95% CI: 24.2 - 33.7) than non-Kuwaiti males (18.7; 95% CI: 15.1-23.0). The month-specific distribution of migrant MS births compared with migrant births in general population did not differ significantly (2 goodness-of-fit test statistic=9.51, p=0.575).
Hewitt's non-parametric test revealed an evidence of slight but statistically non-significant (p=0.090) increased tendency of migrant MS births during September through February.
Conclusions: The proportion of migrant MS births (per 100,000 migrant births in general population) over the study period was 23.8 (95% CI: 20.8 - 27.0), which was statistically significantly higher than the previously reported Kuwaiti national MS births (16.2; 95% CI: 15.1-17.4) in Kuwait. Non-parametric analysis showed slight but statistically non-significant increased tendency of migrant MS births from September through February.
Knowledge of MS risk factors and how and when they act among genetically vulnerable individuals from gestation to early adulthood will help design prevention strategies.
Author: Saeed AkhtarRaed AlroughaniAhmad Al-ShammariJarrah Al-AbkalYasser Ayad
Credits/Source: BMC Neurology 2014, 14:170
Source: 7thSpace Interactive © 2014 7thSpace Interactive (26/08 14)
A growing body of evidence suggests that early control of disease activity in patients with multiple sclerosis (MS) plays a key role in preventing disability, prolonging the period of being active and engaged, and protecting quality of life.
For that reason, MS experts are calling for early and full access to all disease-modifying therapies (DMTs) for patients with MS.
The experts recommend initiation of these therapies as soon as possible following a diagnosis of relapsing MS. They also advise these agents for patients with a first clinical event and MRI features consistent with MS in whom other possible causes have been excluded, and for those with secondary progressive MS who continue to demonstrate clinical relapses and/or demonstrate inflammatory changes on MRI.
These recommendations, based on a comprehensive review of current evidence, appear in the paper,"The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence," produced by the Multiple Sclerosis Coalition, a group of MS organisations including the Accelerated Cure Project for Multiple Sclerosis, Can Do Multiple Sclerosis, the Consortium of Multiple Sclerosis Centers, the International Organization of Multiple Sclerosis Nurses, the Multiple Sclerosis Association of America, the Multiple Sclerosis Foundation, the National Multiple Sclerosis Society, and the United Spinal Association.
The document, written by a 5-member team and vetted by more than 50 experts in the field, has been endorsed by Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Not Carved In Stone
There's currently no algorithm for the order in which DMTs should be prescribed, said Kathleen Costello, MS, associate vice president clinical care, National Multiple Sclerosis Society, and one of the paper's authors. "It's not carved in stone which one you should start with, which one should be the next treatment or the 3rd treatment."
Because of this, said Costello, experts believe that "access needs to be available for all the therapies so decision-making on which therapy to use can be made on an individual basis." Factors to consider include patients' MRI findings, their clinical presentation, their risk tolerance, and their ability to adhere to a therapy.
Access to all the DMTs is all the more important as MS is a such a variable disease, added Rosalind Kalb, PhD, vice president, clinical care, advocacy, services and research department, also at the National Multiple Sclerosis Society. "Not only does the disease present and progress differently in different people, but individuals respond very differently for a variety of reasons to the available medications."
At the time of writing the document, 10 DMTs had been approved by the US Food and Drug Administration (FDA), all of which primarily target inflammation; however, none are fully effective in stopping MS disease activity or disease progression, the authors noted. An 11th agent (Plegridy, Biogen Idec Inc), a long-acting interferon β-1a, was just approved last week.
Although there are a growing number of approved treatment choices, patients sometimes have difficulty accessing them. In the past, it wasn't uncommon for providers to tell patients, "you don't need to be on that (β interferon); you're not 'bad enough' yet," said Costello. "But over the years, evidence has mounted showing that the better outcomes occur when treatment is initiated as early in the disease process as possible."
Early treatment can affect a range of disease factors, including delayed conversion to clinically definite MS, the document notes. The authors cited 4 phase 3 studies showing that in patients with clinically isolated syndrome, defined as the first episode of neurologic symptoms lasting at least 24 hours and caused by inflammation and demyelination in 1 or more sites in the central nervous system, conversion was delayed by about 45% at 2 to 3 years in patients taking glatiramer acetate or interferon compared with placebo.
As well, said the authors, early treatment may result in reduced relapse rates and slowed progression of disability. Reduced loss of mobility may improve the ability to carry out important activities of daily living.
Such benefits, they added, "may not be equaled in those who start treatment later in the disease course," who may never "catch up" with those who start treatments immediately. However, a 10-year follow-up found no difference in disability outcomes between the early and delayed groups treated with intramuscular interferon β-1a, possibly indicating the delayed treatment group did catch up in this case.
"It remains to be determined the extent to which the older medications — and the newer medications for which we do not yet have any long-term data — impact longer-term disability outcomes for people with MS," the authors write.
The course of MS varies, with 85% to 90% of patients demonstrating a relapsing-remitting pattern at onset, which transitions over time in most untreated patients to a pattern of progressive worsening with few or no relapses (secondary progressive MS). The authors stressed that the optimal window for reducing long-term disability is during the early relapsing phase of the disease, with the goal being to slow the accumulation of lesion volume, decrease the number of relapses and prevent disability from both unresolved relapse and disease progression.
Patients without this relapsing pattern might demonstrate a steady progression of symptoms over time. This primary progressive disease presentation is generally diagnosed at an older age.
The paper includes an informative table listing the proposed mechanisms of action, adverse effects, and warnings/precautions of each MS agent. Another table shows the effect of self-injected, oral and intravenous agents on annualized relapse rate compared to placebo, and their effects on disability progression compared to placebo. A third table illustrates the effect of the various drugs on gadolinium-enhancing lesions and on new and enlarging T2 lesions.
An MS diagnosis often comes with other comorbidities. Some 60% of patients with MS will experience cognitive impairment, 36% to 54% will have a major depressive disorder, and up to 92% will endure substantial fatigue, which contributes to increased disability and reduction in quality of life.
There are an estimated 450,000 people with MS in the United States. Women are affected at least 2 to 3 times more than men, except for primary progressive MS, which is equally distributed between the sexes, and whites are affected more than other racial groups. Although some research shows a high incidence of MS farther away from the equator, recent studies have not demonstrated such a North-South gradient.
The Coalition will distribute the paper to delegates attending the upcoming joint ACTRIMS-ECTRIMS meeting in Boston, Massachusetts (September 10-13), and will post it on the Web sites of the participating MS groups. It will be updated at least every 6 months, something that is necessary because the MS treatment landscape changes so frequently, said Dr. Kalb.
Limited Therapy Options?
Asked for comment, Lily Jung Henson, MD, an MS neurologist, Swedish Medical Center, Seattle, Washington, said that the new paper nicely "summarizes the current level of evidence and knowledge around the management of MS."
"The fact that this is created by a coalition of MS groups stresses the consensus amongst MS specialists," she told Medscape Medical News.
The coalition's call for full access to DMTs is likely in response to some insurers trying to limit therapy options based on pricing, commented Dr. Jung Henson.
"A lot of the payers will, for example, insist that you use several of the interferons and glatiramer before you can use a more expensive pill. Or, patients have to fail several drugs before they can use the one that their neurologist thinks may be the best for them."
Although most MS neurologists do initiate treatment as soon as a diagnosis is made, "a lot of general neurologists are amazingly passive in their use of DMTs and their willingness to tolerate breakthrough disease without making a change," said Dr. Jung Henson.
Funding for the document was provided by member societies of the MS Coalition with no external support. Ms. Costello and Dr. Kalb have disclosed no relevant financial relationships. Dr. Jung Henson reports receiving honoraria from Biogen, Teva, EMD Serono, Pfizer, Novartis, and Genzyme and research funding from Biogen, Novartis, Genzyme, and Opexa.
Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (21/08/14)
Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study.
Durrenberger PF, Fernando FS, Kashefi SN, Bonnert TP, Seilhean D, Nait-Oumesmar B, Schmitt A, Gebicke-Haerter PJ, Falkai P, Grünblatt E, Palkovits M, Arzberger T, Kretzschmar H, Dexter DT, Reynolds R.
Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations.
Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration.
We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues.
The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms.
Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases.
The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases.
This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
Source: J Neural Transm. 2014 Aug 13. [Epub ahead of print] & Pubmed PMID: 25119539 (21/08/14)
Testicular hypofunction and multiple sclerosis risk: A record-linkage study.
Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ.
The influence of gonadal hormones on multiple sclerosis is not well characterised and has thus far been investigated primarily in animal models or as a proposed therapeutic approach.
We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and multiple sclerosis risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011.
We report a strong positive association between testicular hypofunction and subsequent multiple sclerosis, rate ratio 4.62 (95% confidence interval 2.3-8.24, p<0.0001).
Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females.
Source: ANN NEUROL 2014. © 2014 American Neurological Association & Pubmed 25131454 (21/08/14)
Europe's drug safety regulator said multiple sclerosis treatments known as interferon beta need stronger label warnings because some patients treated with the drugs have suffered side effects affecting the kidney and other organs.
A spokeswoman for the European Medicines Agency said the label change would affect all countries in the European Union.
In a statement posted on its website on Wednesday, German regulator BfArM said cases of a condition called thrombotic microangiopathy, or TMA, have occurred after weeks or even several years of treatment with interferon beta, some of them fatal.
Neither agency said how many patients could be affected.
The drugs in question are Biogen Idec's Avonex and Plegridy drugs, Merck KGaA's Rebif, Bayer's Betaferon and Novartis's Extavia.
Interferon beta drugs, which are injected, have been in use for more than 10 years.
TMA affects the kidney and a range of other organs, and BfArM said its symptoms included high blood pressure, fever, disorientation, impaired kidney function and a low count of coagulation cells in the blood.
It added that patients diagnosed with TMA should be taken off interferon beta and should be treated immediately.
Cases of another condition, nephrotic syndrome, have also been reported among interferon beta users and will be included in the label change, the European and German regulators said, again without saying how many patients could be affected.
Source: Reuters © Thomson Reuters 2014 (21/08/14)
U.S. health regulators on Friday approved Biogen Idec Inc’s Plegridy, a long-acting multiple sclerosis drug that the company expects will eventually replace its older big-selling Avonex treatment.
Some other MS treatments from the interferon class of medicines, such as Pfizer Inc’s Rebif, are dosed more frequently than Avonex.
Biogen said it will continue to support Avonex, which has compiled global sales of more than $1.5 billion in the first half of this year, for patients who are comfortable with the treatment and not looking to switch. Avonex has U.S. patent protection until 2026, Biogen said.
Source: Felix medical group © 2014 Felix Medical Group, Inc (19/08/14)
Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research(19/08/14)
Amy Waldman MD, Prof Angelo Ghezzi MD, Amit Bar-Or MD, Yann Mikaeloff MD, Prof Marc Tardieu PhD, Prof Brenda Banwell MD
The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years.
National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis.
The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume.
Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis.
Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
Source: The Lancet Neurology, Volume 13, Issue 9, Pages 936 - 948, September 2014 Copyright © 2014 Elsevier Ltd (19/08/14)
EAE is not a useful model for demyelinating disease
Peter O. Behanemail, Abhijit Chaudhuri
Experimental allergic encephalomyelitis (EAE) is the commonest, readily induced, organspecific, autoimmune disorder of laboratory animals of its kind.
It is an artificial disorder brought about by the immunisation of susceptible animals with brain antigens in complete Freund?s adjuvant (CFA).
Variations can be induced by altering the nature of the antigen and the conditions involving immunisation.
Whilst it is often described as a demyelinating disease, in strict terms it is not, since the primary pathologic process is not demyelination but rather an encephalomyelitis that is immunologically induced. Rather, the prototype demyelinating disease is multiple sclerosis and its variants.
In this paper, the central question we ask is whether the data gleaned from the EAE model contributes to our understanding of the pathological events in MS.
Towards answering this, we describe the historical development of EAE and its hyperacute form, and discuss the findings studied extensively in the non-human primate which show that ordinary EAE is an exact model for ADEM in the human, and that the hyperacute form of EAE is represented by AHLE in the human. Additionally, we shall comment on the latest research on new variants of EAE, and explain our opinion regarding the use of EAE models in research aiming to understand the pathogenesis of multiple sclerosis.
Source: Multiple Sclerosis and related disorders Copyright © 2014 Elsevier Inc (19/08/14)
Progressive multiple sclerosis CSF induces inflammatory demyelination, axonal loss, and astrogliosis in mice(15/08/14)
Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA.
Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS.
Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS.
We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice.
We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF.
Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.
Source: Exp Neurol. 2014 Aug 8. pii: S0014-4886(14)00248-9. doi: 10.1016/j.expneurol.2014.07.020. [Epub ahead of print] & Pubmed PMID: 25111532 (15/08/14)
New Zealand researchers have been given the green light to trial new treatments on multiple sclerosis patients using anti-psychotic drugs.
The researchers from Victoria University believe they may be able to reduce the symptoms of this debilitating disease using commonly prescribed drugs.
They say a lower dosage of Clozapine and Risperidone, which treat depression and schizophrenia, can be used to treat MS.
Victoria University researcher Dr Laura Green says the study shows that using the drugs are reducing inflammation and even stopping inflammation in its tracks.
Dr Anne La Flamme says while there are drugs for people who suffer relapses, there has been nothing for those whose condition is progressive.
"It's a different pathway, different way that they are treating MS as to how they would be treating schizophrenia," she says.
"To be able to do something that may benefit them directly is invaluable."
Multiple-sclerosis (MS) is a disease that inflames the nerve cells in the brain and spinal cord and affects 3,000 New Zealanders. Some of the symptoms of MS are blurred vision and chronic pain.
Source: TVNZ Copyright © 2014, Television New Zealand Limited (14/08/14)
Evidence found in both human multiple sclerosis patients and experimental mouse models, according to research published in the American Journal of Pathology.
A new study published in The American Journal of Pathology identifies a novel gene that controls nerve conduction velocity. Investigators report that even minor reductions in conduction velocity may aggravate disease in multiple sclerosis (MS) patients and in mice bred for the MS-like condition experimental autoimmune encephalomyelitis (EAE).
A strong tool for investigating the pathophysiology of a complex disease is the identification of underlying genetic controls. Multiple genes have been implicated as contributing to the risk of developing MS. Unlike studies that have focused on genetic regulators of inflammation, autoimmunity, demyelination, and neurodegeneration in MS, this study focused on nerve conduction velocity. Investigators found that polymorphisms of the inositol polyphosphate-4-phosphatase, type II (Inpp4b) gene affect the speed of nerve conduction in both mice with EAE and humans with MS.
"Impairment of nerve conduction is a common feature in neurodegenerative and neuroinflammatory diseases such as MS. Measurement of evoked potentials (whether visual, motor, or sensory) is widely used for diagnosis and recently also as a prognostic marker for MS," says lead investigator Saleh M. Ibrahim, MD, PhD, of the Department of Dermatology, Venereology, and Allergology of the University of Lubeck (Germany).
Using several genomic approaches, the investigators narrowed their search to the genetic region controlling the enzyme inositol-polyphosphate-4-phosphatase II (INPP4B), the product of which helps to regulate the phosphatidyl inositol signaling pathway. Enzymes in this family are involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular communication.
In one series of experiments, the researchers analyzed the genetic locus EAE31, which previously had been shown to control the latency of motor evoked potentials and clinical onset of EAE in mice. Using advanced techniques including congenic mapping, in silico haplotype analyses (computer simulations), and comparative genomics (from rats, mice and humans), they were able to "finemap" the focus to Inpp4b as the quantitative trait gene for EAE31.
When the investigators analyzed this region in eight different strains of mice, they found they could divide the strains into two groups based on differences in amino acid sequences. The strains with the longer-latency SJL/J allele had the two amino acids (arginine and proline), whereas those with the shorter-latency C57BL/10S allele had others (serine and histidine). "These data suggest that Inpp4b structural polymorphism is associated with the speed of neuronal conduction," comments Dr. Ibrahim.
In another experiment, the scientists compared motor conduction velocity in genetically modified mice with a mutant Inpp4b gene to that of control mice. The nerve conduction in this group was slower than in the control group.
Finally, the investigators studied INPP4B polymorphisms in MS patients. They looked at two cohorts: one from Spain (349 cases and 362 controls) and a second from Germany (562 cases and 3,314 controls). The association between the INPP4B polymorphisms and susceptibility to MS was statistically significant when the cohorts were pooled. However, although the Spanish cohort showed a strong association between INPP4B and MS, the association was weaker in the German cohort. "The exact reason for the diverging effect across these populations remains unresolved," states Dr. Ibrahim.
In an accompanying commentary, Hans Lassmann, MD, of the Center for Brain Research of the Medical University of Vienna (Austria) notes, "This study represents an interesting example of how minor changes in conduction velocity, which do not result in a clinical phenotype in control populations, may aggravate disease in conditions such as EAE or MS." In other words, impaired nerve conduction may have a greater impact on those with MS compared to healthy individuals. Noting that the study reported no major loss of myelin in animals carrying the mutant allele, Dr. Lassmann comments that it is still unclear which neurobiological mechanisms underlie the INPP4B-associated impaired conduction. One suggestion is that INPP4B may be involved in calcium ion signaling within synapses, affecting neurotransmitter release.
Source: EurekaAlert! Copyright ©2014 by AAAS (13/08/14)
Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.
Yamamoto S, Gotoh M, Kawamura Y, Yamashina K, Yagishita S, Awaji T, Tanaka M, Maruyama K, Murakami-Murofushi K, Yoshikawa K.
Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterised by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies.
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death.
In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis.
Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction.
Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction.
These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis.
cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease.
Source: Eur J Pharmacol. 2014 Jul 30. pii: S0014-2999(14)00577-9. doi: 10.1016/j.ejphar.2014.07.040. [Epub ahead of print] & Pubmed PMID: 25084219 (12/08/14)
A latest study debunked the association between vitamin D levels in newborns and the risk of developing multiple sclerosis in adulthood.
This study was conducted by researchers at the Karolinska Institutet. Over the recent years, it was widely accepted that low levels of vitamin D in newborn babies increase the risk of multiple sclerosis (MS) in adulthood. This is based on the studies that highlighted infants born in spring have a high risk of developing the disease as compared to those born during autumn. It was believed that low levels of sun exposure during pregnancy doubles the risk of MS in children born after winter.
This is the first time that this hypothesis has been tested; till date it was assessed through indirect observations.
Multiple sclerosis (MS) is one of the most disabling neurological diseases that affect 250,000-350,000 people in the U.S. It is diagnosed in people aged between 20 and 40 years. It is estimated that nearly 2.5 million people worldwide have MS. It is not an inherited disorder, but researchers assume that there is a genetic predisposition to the development of the disease.
"There are several reasons why the link between vitamin D at birth and later risk of MS has not been directly assessed previously," explains Peter Ueda.
The levels of vitamin D at birth of MS sufferers were measured and compared with a control group. It included 459 participants with MS and 663 healthy control subjects. These participants were part of the EIMS project led by the Institute. Each participant with MS gave blood sample and was made to answer a questionnaire.
Using PKU register that contains blood samples from newborn Swedish babies from 1975 onwards, the researchers determined the levels of vitamin D from time of birth of MS patients and their controls. They developed a new technique to measure vitamin D levels in dried blood samples.
"We could not see any association between levels of vitamin D at birth and risk of MS in adulthood," said Peter Ueda. "However a weaker link cannot be ruled out, nor can the link be ruled out for people with certain genes. However, our results do not support the hypothesis of such a possibility for reducing MS risk."
The results have been published in the journal Annals of Neurology.
Source: Science World Report Copywrite Science World Report 2014 (12/08/14)
Researchers have recently discovered that the fatigue that patients with multiple sclerosis (MS) experience is not the same kind of fatigue that healthy people feel from time to time, nor is it caused by the same factors. The National Multiple Sclerosis Society reports that around 80% of people who suffer from MS experience ongoing fatigue, and that the symptom has a major impact on daily life and work. As a result, fatigue is directly associated with the rate of early retirement reported among MS patients.
Those with Multiple Sclerosis often experience episodes of fatigue every day. Onset of the symptom can come suddenly, almost like an attack or exacerbation. Early research into MS-related fatigue by Dr. Victoria M. Leavitt, a noted neuropsychologist and a co-founder of the New York-based Manhattan Memory Center, revealed that outdoor heat aggravates both the disease and fatigue-related symptoms. The previous study also indicated that an MS patient’s internal temperature may affect the disease progression.
In a new study led by Leavitt along with Dr. James F. Sumowski, a senior research scientist in neuropsychology and neuroscience at the Kessler Foundation, the researchers studied fifty patients with RRMS, as well as twenty-two patients with secondary progressive MS (SPMS) and forty healthy patients as controls in the experiment. The study, entitled, “Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure,” was published in the Archives of Physical Medicine and Rehabilitation.
As a result of this new study, more extreme fatigue was observed in RRMS patients with warmer body temperatures. However, they could not reach a conclusion on whether body temperature played a role in secondary progressive MS patients because the patients did not present with a fever in the study.
Sumowski commented that body temperature issues in MS patients — including low-grade fevers, which are frequently reported as well — may be the result of the internal inflammatory process associated with the disease. He went on to say that, “Rather than chronic inflammation, however, we think that body temperature may fluctuate with day-to-day fluctuations in inflammation among RRMS patients, although this still needs to be investigated directly.”
These new research insights into inflammation, body temperature, and fatigue may give researchers and pharmaceutical companies a new angle for treating inflammation in MS in order to curtail body temperature fluctuations and ultimately control fatigue symptoms.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (12/08/14)
Peptides naturally produced by parasitic intestinal worms could help treat auto-immune diseases such as multiple sclerosis and rheumatoid arthritis, say researchers at Monash University.
Peptides naturally produced by intestinal worms could help treat auto-immune diseases such as multiple sclerosis, rheumatoid arthritis, lupus and psoriasis. That is the finding of a Monash University study, published in the journal of the Federation of American Societies for Experimental Biology.
Professor Ray Norton, lead researcher at Monash Institute of Pharmaceutical Sciences, said the research was possible through the "wonders of the genome era". His team had been working on molecules from a sea anemone that can suppress the effects of auto-immune diseases.
Prof Norton said scientists in the USA had identified that parasitic worms had the capability to produce similar molecules.
"We went looking to see if these molecules really were in the worms," he said.
"Sure enough, these molecules can actually suppress the sorts of white blood cells that cause all the damage in auto-immune diseases."
The research could be seen as supporting the "hygiene hypothesis" that developed societies are too clean for their own good.
"There's no doubt that as our environment gets cleaner and we're exposed to fewer and fewer infections that allergies and, to a lesser extent, auto-immune diseases are on the rise," said Prof Norton.
However, Prof Norton said that while "it's a good correlation" the causal effect of the link is "very much up for debate."
In fact one of the key scientists in the Monash study is sceptical of the hypothesis.
"He accepts the link but he doesn't accept the current explanation."
The researchers hope that their work could lead to a pill that mimics the benefits of parasitic worm infection.
Professor Norton believes producing a pharmaceutical is preferable to infecting people with worms.
"There are people culturing worms on huge scales for clinical trials in the US.
"The question will still be is the worm infection just doing you good, or is it potentially causing some problems as well."
He said given the choice he would prefer to take a pill than be given intestinal worms.
"A pure pharmaceutical might actually be much cleaner and more effective."
Source: ABC Melbourne © 2014 ABC (12/08/14)
Sativex, a cannabis-derived drug for treating muscle spasms in multiple sclerosis, could be available in Wales but blocked in England.
GW Pharmaceuticals, the British company that develops cannabis-based medicines, is facing the prospect of having its multiple sclerosis treatment blocked in England but available in Wales.
The Welsh medicines board has recommended the use of Sativex to treat medium to severe muscle spasms in multiple sclerosis and is awaiting final approval from the devolved Government, The Sunday Telegraph has learnt.
Sativex could, however, be blocked from routine use in England. Draft guidelines from the National Institute of Health and Care Excellence (Nice), issued in April, recommended against the use of Sativex in multiple sclerosis. If this remains unchanged in the final guidelines, expected in October, Sativex will not be available on the NHS in England.
Justin Gover, chief executive of GW Pharmaceuticals, said it was a “travesty” that different parts of the UK could have different guidelines on Sativex, a mouth spray made from compounds derived from the cannabis plant.
“We very much hope that it [Nice] will indeed endorse use of the medicine – it would make little sense if you could drive to Wales and get the drug but not in England,” he added.
The draft guidelines have also attracted criticism from neurologists and patient groups, who say Sativex and Famprya, another drug which could be blocked, can stop patients “screaming out” in pain.
Experts have questioned Nice’s cost-benefit methodology, saying it had vastly overestimated the doses needed for the effective management of symptoms.
Sativex has been licensed for use in the UK since 2010, but did not undergo a clinical assessment until this year, with Nice due to update its multiple sclerosis guidelines for the first time in a decade.
About 100,000 people in the UK currently have MS.
Source: The Daily Telegraph © Copyright of Telegraph Media Group Limited 2014 (11/08/14)
A team of researchers has pinpointed a small molecule responsible for nerve cell damage and other symptoms tied to neurological diseases, including multiple sclerosis (MS).
In a study published in the June 2014 issue of The Federation of American Societies for Experimental Biology Journal, investigators at The Open University (OU) in the United Kingdom and colleagues from Sheffield, London, and Amsterdam highlighted the behavior of MicroRNA-155 (miR-155) and its activity during inflammation.
According to a statement released by the OU, inflammation in the molecule creates gaps in tissue cells, leading to toxins entering the brain from the bloodstream. In comparison, unaffected individuals’ cells create a barrier that prevents molecules from invading the brain.
“We have identified miR-155 as a critical miRNA in neuroinflammation at the blood-brain barrier (BBB),” the authors noted. “miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis.”
The statement also noted that cells that line blood vessels and control molecules’ brain access when inflamed become “leaky” due to neurological immunity. This inflammation, the study noted, has been observed with several conditions such as MS, HIV, dementia, and bacterial infections of the blood.
The investigators said that while BBB dysfunction was recognised in MS and stroke patients, molecular activity behind the dysfunction is still a mystery.
"This research has helped us to gain a better understanding of how toxins and other blood-borne molecules are leaked into the brain in inflammatory conditions,” lead author Ignacio Romero, MD, senior lecturer in Cellular Neuroscience in Open University’s Department of Life, Health and Chemical Sciences, said in a statement.“This is crucial, not only for helping to explain the molecular underpinnings of neurological diseases such as Alzheimer’s and MS, but also for opening up new possibilities for developing treatments to reduce the flow of these unwanted molecules to the brain and also for delivering life-saving drugs.”
Source: HCP Live Copyright HCPLive 2006-2014 (06/08/14)
Drugs taken by HIV patients could also be used to prevent and treat multiple sclerosis, scientists say.
Researchers have discovered that people with HIV have a significantly lower risk of developing MS, a debilitating neurological condition. It is not yet clear whether the lowered risk is caused by the HIV virus itself, or by the antiretroviral drugs taken by sufferers. But if future research shows antiretrovirals to be key, it raises the possibility that they could one day be used to help MS patients.
The conditon affects nerves in the brain and spinal cord, causing a wide range of symptoms including problems with muscle movement, balance and vision. The unexpected potential benefits of drugs usually given to people with HIV are revealed in a study published today in the Journal of Neurology, Neurosurgery & Psychiatry. The research was prompted by the discovery of a patient who had HIV and MS, and who stayed clear of any MS symptoms for more than 12 years. British and Australian researchers from Oxford University, Queen Mary University of London and the Prince of Wales Hospital in Sydney discovered that HIV patients were significantly less likely to get MS than the general public.
An analysis of English Hospital Episode Statistics of HIV sufferers between 1999 and 2011 found a “negative association between HIV and MS” which was “statistically significant”. Data for more than 21,000 people infected with HIV was analysed and compared against a wider group of more than five million non-HIV patients. Those with HIV were 62 per cent less likely to develop MS than those who did not have the virus.
The researchers reported: “If subsequent studies demonstrate there is a causal protective effect of HIV [and/or its treatment], and if the magnitude of it proves to be similar to our rate ratio of 0.38, this would be the largest protective factor yet observed in relation to MS.”
They suggested that the weakening of immune systems in those with HIV “may prevent development of MS” and that “antiretroviral medications” could “suppress other viral pathogens implicated in MS”. Researchers concluded that having HIV and being on antiretroviral drugs “provided a significant and potentially protective effect”.
In an editorial published with the research, Mia van der Kop, an epidemiologist at the University of British Columbia in Vancouver, Canada, described the study as providing “further evidence to support the hypothesis that there is an association between HIV (or its treatment) and a reduced risk of MS”.
The news was welcomed yesterday by Dr Emma Gray, the research communications manager at the MS Society, who said: “This is a valuable and intriguing new study. Much more research is needed to definitively prove whether having HIV or being treated for HIV with antiretrovirals, or even a combination of the two, reduces the risk of someone developing MS.”
The study “provides some encouragement that antiretrovirals could be a potential future option” for MS sufferers in search of new treatments, Dr Gray said, adding: “Clinical trials are the only way to determine this, and the good news is there is a London-based trial aimed at testing one such drug [at the Royal London Hospital and the Institute of Neurology, University College London].”
Source: The Independent © independent.co.uk 2014 (05/08/14)
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 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: 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)
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.
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.
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)
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)
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)
Factors Associated With Recovery From Acute Optic Neuritis in Patients With Multiple Sclerosis
Malik MT, Healy BC, Benson LA, et al
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)
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)
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)
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)
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.
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.
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)
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)
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)
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)
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)
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)
"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)
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)
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)
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)
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)
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)
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)
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)