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Explosion’ of New Therapies for Neurologic Conditions

There has been an “explosion of new and innovative” therapies for neurologic conditions such as stroke, epilepsy, Parkinson disease and multiple sclerosis, Loyola University Medical Center neurologist Dr. Jose Biller writes in the August issue of the journal Neurologic Clinics.

Biller is editor of the August issue, which includes 14 articles describing the latest data on new and emerging therapies for neurologic conditions. Five of the articles are written by Loyola physicians:

Sarkis Morales Vidal, MD and Sean Ruland, DO: “Platelet Antiaggregants in Stroke Prevention.”

Adriana Sofia Ploneda Perilla and Michael J. Schneck, MD: “Unanswered Questions in Thrombolytic Therapy for Acute Ischemic Stroke.”

Michael Star, MD and Murray Flaster, MD, PhD: “Advances and Controversies in the Management of Cerebral Venous Thrombosis.”

Jorge J. Asconape: “Epilepsy.”

Douglas Anderson, MD and Ninith Kartha, MD: “Deep Brain Stimulation in Nonparkinsonian Movement Disorders and Emerging Technologies, Targets and Therapeutic Promises in Deep Brain Stimulation.”

Matthew McCoyd, MD: “Update on Therapeutic Options for Multiple Sclerosis.”

In the preface, Biller writes that the August issue of Neurologic Clinics is intended to provide timely and practical information to physicians treating neurologic disorders. He concludes: “There is every reason to believe that future advances in neurologic therapy are sure to come.”

Biller is chair of the Department of Neurology of Loyola University Chicago Stritch School of Medicine.

A First in Front-Line Immunity Research

Monash University researchers have gained new insight into the early stages of our immune response, providing novel pathways to develop treatments for diseases from multiple sclerosis to cancer.

In a study published today in Nature Immunology, a team of researchers led by Professor Paul Hertzog, of the Monash Institute of Medical Research (MIMR) and Professor Jamie Rossjohn, of the School of Biomedical Sciences, have characterised for the first time how interferon beta (IFNβ) proteins bind to cells and activate an immune response.

Produced when viral and bacterial infections are detected, interferon proteins are vital to the body’s defences. They activate immune cells, such as macrophages, can interfere with virus replication, and can boost cells’ resilience to infection. They also enhance later immune responses to cancers and other stresses.

There are at least 20 subtypes of interferons that are produced at different stages of the immune response. They appear to have different functions, but these functions and their triggers are generally not well understood. The mapping of INFβ — cell interaction is a breakthrough in the field.

Professor Hertzog of MIMR’s Centre for Innate Immunity and Infectious Diseases said interferon function was vital for developing and refining therapies for incurable diseases such as lupus and multiple sclerosis.

“Interferon therapy is useful in treating a number of diseases; however these treatments have dose-limiting side effects. Further, interferons appear to drive some autoimmune diseases, raising the prospect of interferon blockers as treatment,” Professor Hertzog said.

“The more refined our understanding of interferon function, the more we can tailor treatments to optimise effectiveness — whether by boosting or blocking their actions.”

Lead author on the paper, Dr Nicole de Weerd, also of the Centre for Innate Immunity and Infectious Diseases, said the research provided new pathways for rational drug design.

“We found that when IFNβ binds to a cell, it transmits an unusual signal that seems linked to some of the toxic side effects of interferon therapy, like sepsis. This provides a promising avenue to pursue more selective activation of interferon action,” Dr de Weerd said.

Professor Rossjohn and Julian Vivian from the Department of Biochemistry and Molecular Biology collaborated closely on determining the IFNβ interactions at the molecular level.

“During this seven-year study, we have had great support from the Australian Synchrotron,” Professor Rossjohn said.

Multiple Sclerosis Research Could Help Repair Damage Affecting Nerves

Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.

A study has shed light on how cells are able to regenerate protective sheaths around nerve fibres in the brain.

These sheaths, made up of a substance called myelin, are critical for the quick transmission of nerve signals, enabling vision, sensation and movement, but break down in patients with multiple sclerosis (MS).

The study, by the Universities of Edinburgh and Cambridge, found that immune cells, known as macrophages, help trigger the regeneration of myelin.

Researchers found that following loss of or damage to myelin, macrophages can release a compound called activin-A, which activates production of more myelin.

Dr Veronique Miron, of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh, said: “In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.

“Approved therapies for multiple sclerosis work by reducing the initial myelin injury — they do not promote myelin regeneration. This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.”

The study, which looked at myelin regeneration in human tissue samples and in mice, is published in Nature Neuroscience and was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.

Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.

Dr Susan Kohlhaas, Head of Biomedical Research at the MS Society, said: “We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin. We look forward to seeing this research develop further.”

Dr Karen Lee, Vice-President, Research at the MS Society of Canada, said: “We are pleased to fund MS research that may lead to treatment benefits for people living with MS. We look forward to advances in treatments that address repair specifically, so that people with MS may be able to manage the unpredictable symptoms of the disease.”

Cannabis Constituent Has No Effect On Multiple Sclerosis Progression, Study Shows

The first large non-commercial clinical study to investigate whether the main active constituent of cannabis (tetrahydrocannabinol or THC) is effective in slowing the course of progressive multiple sclerosis (MS), shows that there is no evidence to suggest this; although benefits were noted for those at the lower end of the disability scale.

The study is published in The Lancet Neurology.

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study was carried out by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry. The study was funded by the Medical Research Council (MRC), the Multiple Sclerosis Society and the Multiple Sclerosis Trust, and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

CUPID enrolled nearly 500 people with MS from 27 centres around the UK, and has taken eight years to complete. People with progressive MS were randomised to receive either THC capsules or identical placebo capsules for three years, and were carefully followed to see how their MS changed over this period. The two main outcomes of the trial were a disability scale administered by neurologists (the Expanded Disability Status Scale), and a patient report scale of the impact of MS on people with the condition (the Multiple Sclerosis Impact Scale 29).

Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes. However, there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of enrolment but, as the benefit was only found in a small group of people rather than the whole population, further studies will be needed to assess the robustness of this finding.

One of the other findings of the trial was that MS in the study population as a whole progressed slowly, more slowly than expected. This makes it more challenging to find a treatment effect when the aim of the treatment is to slow progression.

As well as evaluating the potential neuroprotective effects and safety of THC over the long-term, one of the aims of the CUPID study was to improve the way that clinical trial research is done, by exploring newer methods of measuring MS and using the latest statistical methods to make the most of every piece of information collected. This analysis continued for several months and has provided important information about conducting further large scale clinical trials in MS.

Professor John Zajicek, Professor of Clinical Neuroscience at Plymouth University Peninsula Schools of Medicine and Dentistry, said: “To put this study into context: current treatments for MS are limited, either being targeted at the immune system in the early stages of the disease or aimed at easing specific symptoms such as muscle spasms, fatigue or bladder problems. At present there is no treatment available to slow MS when it becomes progressive. Progression of MS is thought to be due to death of nerve cells, and researchers around the world are desperately searching for treatments that may be ‘neuroprotective’. Laboratory experiments have suggested that certain cannabis derivatives may be neuroprotective.”

He added: “Overall our research has not supported laboratory based findings and shown that, although there is a suggestion of benefit to those at the lower end of the disability scale when they joined CUPID, there is little evidence to suggest that THC has a long term impact on the slowing of progressive MS.”

Enhanced White Blood Cells Heal Mice With MS-Like Disease

Genetically engineered immune cells seem to promote healing in mice infected with a neurological disease similar to multiple sclerosis (MS), cleaning up lesions and allowing the mice to regain use of their legs and tails.

The new finding, by a team of University of Wisconsin School of Medicine and Public Health researchers, suggests that immune cells could be engineered to create a new type of treatment for people with MS.

Currently, there are few good medications for MS, an autoimmune inflammatory disease that affects some 400,000 people in the United States, and none that reverse progress of the disease.

Dr. Michael Carrithers, assistant professor of neurology, led a team that created a specially designed macrophage — an immune cell whose name means “big eater.” Macrophages rush to the site of an injury or infection, to destroy bacteria and viruses and clear away damaged tissue. The research team added a human gene to the mouse immune cell, creating a macrophage that expressed a sodium channel called NaVI.5, which seems to enhance the cell’s immune response.

But because macrophages can also be part of the autoimmune response that damages the protective covering (myelin) of the nerves in people with MS, scientists weren’t sure whether the NaV1.5 macrophages would help or make the disease worse.

When the mice developed experimental autoimmune encephalomyelitis — the mouse version of MS — they found that the NaV1.5 macrophages sought out the lesions caused by the disease and promoted recovery.

“This finding was unexpected because we weren’t sure how much damage they would do, versus how much cleaning up they would do,” Carrithers says. “Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case.”

In follow-up experiments, regular mice that do not express the human gene were treated with the NaV1.5 macrophages after the onset of symptoms, which include weakness of the back and front limbs. The majority of these mice developed complete paralysis of their hindlimbs. Almost all of the mice that were treated with the Na1.5 macrophages regained the ability to walk. Mice treated with placebo solution or regular mouse macrophages that did not have NaV1.5 did not show any recovery or became more ill. In treated mice, the research team also found the NaV1.5 macrophages at the site of the lesions, and found smaller lesions and less damaged tissue in the treated mice.

Because the NaV1.5 variation is present in human immune cells, Carrithers says, “The questions are, ‘Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?’ ” He says the long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS.

Carrithers is a neurologist who treats patients with multiple sclerosis at University of Wisconsin Hospital and Clinics and the William S. Middleton Veterans’ Hospital in Madison. His research team includes Kusha Rahgozar, Erik Wright and Lisette Carrithers. The research was supported by a prior National MS Society research grant and a current VA Merit Award from the Biomedical Laboratory Research and Development service of the Department of Veterans Affairs (7784115).

Interleukin 17F Level and Interferon Beta Response in Patients With Multiple Sclerosis

A study by Hans-Peter Hartung, M.D., of Heinrich-Heine-Universität, Düsseldoft, Germany, and colleagues examines the association between IL-17F and treatment response to interferon beta-1b among patients with relapsing-remitting multiple sclerosis.

Serum samples were analyzed with an immunoassay from 239 randomly selected patients treated with interferon beta-1b, 250 micrograms, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study. Researchers measured the levels of IL-17F at baseline and month 6, as well as the difference between the IL-17F levels at month 6 and baseline were compared between: (1) patients with less disease activity versus more disease activity; (2) patients with no disease activity versus some disease activity; and (3) responders versus nonresponders.

According to study results,levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging (MRI) criteria. Relapses and new lesions on MRI were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change.

“We found that serum concentrations of IL-17F alone did not predict response to interferon beta-1b therapy in patients with relapsing-remitting multiple sclerosis.” The study concludes, “Given the multifaceted pathophysiology associated with disease progression and response to treatment by patients with relapsing-remitting multiple sclerosis, using extreme patient cohorts in combination with immune-based biomarker signatures may actually be the most efficient way of initially identifying response markers.”

Alternative Medicine Use by MS Patients Now Mapped

A major Nordic research project involving researchers from the University of Copenhagen has, for the first time ever, mapped the use of alternative treatment among multiple sclerosis patients — knowledge which is important for patients with chronic disease and the way in which society meets them.

People with multiple sclerosis (MS) often use alternative treatments such as dietary supplements, acupuncture and herbal medicine to facilitate their lives with this chronic disease. This is the result of a new study of how MS patients use both conventional and alternative treatments which has been carried out by researchers from five Nordic countries. The results have been published in two scientific journals, the Scandinavian Journal of Public Health and Autoimmune Diseases.

“What we see is that patients do not usually use alternative treatments for treating symptoms, but as a preventative and strengthening element,” says Lasse Skovgaard, industrial PhD candidate from the Faculty of Health and Medical Sciences and the Danish Multiple Sclerosis Society, who has been involved in conducting the questionnaire-based study among 3,800 people with MS in Denmark, Sweden, Norway, Finland and Iceland.

Multiple sclerosis is a chronic disease which attacks the central nervous system, and which can lead to a loss of mobility and sight. Denmark is one of the countries with the highest incidence of the disease worldwide, with approx. 12,500 MS patients. At the same time, the number of MS patients in the West is increasing, posing considerable challenges in respect of treatment, prevention and rehabilitation.

Access to knowledge bank

Together with researchers from the five other Nordic countries, Lasse Skovgaard has spent three years gathering the new data, and he is delighted at what it offers: “Within the field of health research, it is often a question of studying the extent to which a particular type of drug affects a particular symptom. However, it is equally as important to look at how people with a chronic disease, for example, use different treatments to cope with their situation. Here, MS patients offer valuable experience. Their experiences constitute a knowledge bank which we must access and learn from,” he says.

Lasse Skovgaard draws attention to the significance of this new knowledge because, if people with chronic disease are better able to manage their lives, it can potentially save society large sums of money.

“There is a lot of talk about ‘self-care competence’, in other words patients helping themselves to get their lives to function. Here, many people with a chronic disease find they benefit from using alternative treatments, so we should not ignore this possibility,” says Lasse Skovgaard.

At the same time, he emphasises that knowing more about why patients choose particular treatments is important in relation to improving patient safety because of the possible risks involved in combining conventional and alternative medicine.

Growing use of alternative treatments

According to the latest Health and Sickness Study from the Danish National Institute of Public Health (NIPH) in 2010, one in four Danes say that they have tried one or more types of alternative treatments within the past twelve months. Among MS patients, the use of alternative medicine has been growing steadily over the past fifteen years. In the researchers’ latest study, more than half of the respondents say that they either combine conventional and alternative medicine or only use alternative medicine.

“We cannot ignore the fact that people with chronic disease use alternative treatments to a considerable extent, and that many of them seem to benefit from doing so. It doesn’t help to only judge this from a medical point of view or say that alternative treatments are nonsense — rather, we must try to understand it,” says Lasse Skovgaard.

Highly qualified women top the list

The study shows that, among MS patients using alternative treatments, there is a significantly bigger proportion of people with a high level of education compared to those who do not use alternative treatments. There is also a larger proportion of highly paid people and of younger women.

“Some critics are of the opinion that when alternative treatments are so popular, it is because they appeal to naïve people looking for a miraculous cure. But our results indicate that it is primarily the well-educated segment that is subscribing to alternative treatments. And that using alternative treatments is part of a lifestyle choice,” says Lasse Skovgaard.

He hopes that the new knowledge will improve communication regarding how the chronically ill use alternative treatments in combination with conventional medicine:

“We see that so many people are combining conventional medicine with alternative treatment that it should be taken seriously by the health service. Until now, there hasn’t been much focus on the doctor-patient dialogue in relation to the alternative methods used by the chronically ill to manage their lives,” says Lasse Skovgaard. He says that the research group is continuing to analyse the results and, among other things, is conducting several interview studies based on the results of the questionnaires. The interview studies will, for example, provide additional knowledge on how patients perceive the risks associated with using alternative medicine and explore why some patients turn their backs completely on conventional medicine.

Atrophy in Key Region of Brain Associated With Multiple Sclerosis

Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.

MS develops as the body’s immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk.

Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.

“For some time we’ve been trying to understand MRI biomarkers that predict MS development from the first onset of the disease,” said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. “In the last couple of years, research has become much more focused on the thalamus.”

The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients.

“Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it,” Dr. Zivadinov said.

For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.

“One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack,” he said. “No one has really looked at this over the long term in a clinical trial.”

The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.

“First, these results show that atrophy of the thalamus is associated with MS,” Dr. Zivadinov said. “Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions.”

The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients.

“Thalamic atrophy is an ideal MRI biomarker because it’s detectable at very early stage,” Dr. Zivadinov said. “It has very good predictive value, and you will see it used more and more in the future.”

The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS.

“The next step is to look at where the lesions develop over two years with respect to the location of the atrophy,” Dr. Zivadinov said. “Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus.”

MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.

Common Multiple Sclerosis Drugs Taken Together Do Not Reduce Relapse Risk

A recent clinical trial found that interferonβ-1a (INF) and glatiramer acetate (GA), two of the most commonly prescribed drugs for multiple sclerosis (MS), provide no additional clinical benefit when taken together. While findings published today in Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society, suggest that taking both INF and GA together was not superior to GA monotherapy in reducing relapse risk; the combination therapy does appear to reduce new lesion activity and total lesion volume.

The National Institute of Neurological Disorders and Stroke (NINDS) describes MS as a neuroinflammatory disease, which affects the central nervous system by attacking myelin, a substance found in nerve fibers. NINDS estimates that up to 350,000 individuals in the U.S. are diagnosed with MS, which affects twice as many women as men, with most symptoms appearing between the ages of 20 and 40. Experts believe this complex autoimmune disease may be caused by genetic and environmental factors.

“While there are a number of drugs to treat MS, our study is the first to investigate if the concurrent use of two drugs with different modes of action would provide any additional clinical benefit without side effects,” explains lead author Dr. Fred Lublin, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York. “The CombiRx study was designed to assess whether IFN and GA in combination was more effective than either alone in reducing relapse of MS.”

The research team enrolled 1,008 participants from 68 sites in this double-blind, randomized, controlled phase III trial. Participants received IFN plus GA (499), IFN alone (250), or GA alone (259), with 30µg IFN administered intramuscularly weekly and/or 20 mg of GA injected daily. The groups were followed for three years to assess if the combination therapy reduced MS relapse rates.

Trial results found that the IFN plus GA combination did not lessen disease progression according to the Expanded Disability Status Scale (a measure of disability caused by MS) or show change in the Multiple Sclerosis Functional Composite (measure used during clinical trials to assess leg, arm, and cognitive function in MS patients) better than the individual agents over a three-year period. The combination therapy and GA alone were significantly better than IFN in reducing relapse risk. MRI findings also suggested that the IFN plus GA together were better in reducing new lesions (plaques) and total lesion accumulation than either drug alone.

Dr. Lublin concludes, “Combining two of the most commonly prescribed MS therapies did not produce significant clinical benefit, reducing relapse risk, during the three-year study period. We will continue to monitor this group to determine if the combination therapy displays positive results, particularly in reducing lesion activity, beyond the initial trial timeframe.”

In a related editorial, Dr. Stephen L. Hauser, Department of Neurology Chair at University of California, San Francisco and Editor-in-Chief of Annals adds, “In the end, CombiRx was essentially a negative study, with the combination therapy doing no better than monotherapy in reducing MS relapse rate over three years. However, the continued follow-up of this group by Dr. Lublin and colleagues provides an opportunity to develop a comprehensive long-term history of MS — assessing response to first-generation therapies, possibly predicting individual disease trajectories, and understanding of treatment response. CombiRx could emerge as a model for long-term assessment, not only in MS, but across clinical neuroscience.”

This CombiRx study was funded by a grant from the NINDS — a part of the National Institutes of Health.

Can Hormone Help Treat Multiple Sclerosis Long-Term?

A new study suggests that treatment with adrenocorticotropic hormone (ACTH) may be helpful for people whose multiple sclerosis (MS) is not well-controlled through their regular treatment. The study was released today and will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013.

The study involved 23 people with MS who were taking beta-interferon treatment and had at least one relapse or brain scan showing new disease activity within the previous year. They were considered to have “breakthrough” MS, which means that their treatment that had been working previously stopped being effective, leading to worsening disability and more frequent relapses, as well as increased evidence of disease activity on brain scans.

The study participants were given either ACTH or methylprednisolone as pulse therapy monthly in addition to their regular treatment for one year. The people with MS knew which treatment they were receiving, but the researchers examining them did not.

The participants were tested every three months for 15 months. Over that time, those receiving ACTH had fewer relapses, or 0.08 cumulative relapses per patient compared to 0.8 relapses per patient for those receiving methylprednisolone. Those taking ACTH also had no cases of psychiatric side effects, while those taking methylprednisolone had a cumulative number of 0.55 psychiatric episodes per patient.

“These results are of interest because few treatments are available for people with breakthrough MS,” said study author Regina Berkovich, MD, PhD, of Keck Medical Center of USC in Los Angeles. “Further studies, including randomized controlled trials, are needed to validate these preliminary findings, but the results suggest a potential benefit of ACTH pulse therapy in breakthrough MS.”

While ACTH has been approved for use in MS relapses for many years, its cost has limited its use to only those patients who are in need of a relapse treatment alternative to corticosteroids. This is believed to be the first study to have been done on its use as a chronic treatment for MS. ACTH is not FDA-approved for use as chronic treatment for MS.

The study was supported by a research grant from Questcor Pharmaceuticals, Inc., maker of ACTH