Miscellaneous Research

Relying too much on brain scans appears to be one reason doctors each year misdiagnose multiple sclerosis in hundreds of patients whose symptoms are caused by some other disease.

Researchers at Oregon Health & Science University and the Portland Veterans Affairs Medical Center surveyed 242 multiple sclerosis specialists in the U.S. to find out how often they see patients who have been misdiagnosed. Among the 122 respondents, more than 95 percent said they saw at least one patient in the past year diagnosed with MS by another medical provider, but the specialist "strongly felt" the patient had some other disease. Three out of four specialists said they saw three or more misdiagnosed patients within the past year.

The authors estimate that the 122 specialists saw 600 patients in a year who had been given an incorrect diagnosis of MS. An estimated 280 of the misdiagnosed patients were receiving therapy for MS with a disease-modifying drug, which can cause serious side effects and cost $40,000 or more per patient per year.

"Some of these patients have had this diagnosis for years," says lead author Dr. Andrew Solomon, an assistant professor at the University of Vermont College of Medicine, who began the research while he was at OHSU. "All of us had seen patients like this, who had a diagnosis of MS but we felt sure they did not have MS. That's what prompted this study."

MS is a chronic disease that attacks the central nervous system. Symptoms vary from mild numbness in the limbs to severe paralysis and loss of vision. The severity and progress of the disease vary unpredictably.

Doctors have no definitive blood test or imaging scan to confirm the diagnosis. They must take into account the patient's health history and performance on tests of movement, balance, vision, and mental function. Spinal fluid tests and MRI brain scans can be helpful.

The pattern of misdiagnosis revealed by the survey suggests that doctors are leaning too much on MRI findings, Solomon says.

That fits with previous reports, including a 2003 study in which two-thirds of the 281 patients referred for possible MS had other neurological conditions. Among the patients referred because of abnormal MRI results who did not have MS, 70 percent had a more obvious explanation for the abnormal MRI, including high blood pressure, migraine, or other neurological disease.

"MRIs are not a substitute for a good history and neurological examination in the diagnosis of MS," cautioned Dr. John R. Corboy of the University of Colorado Multiple Sclerosis Center and co-authors.

'Therapeutic frenzy'

Unnecessary use of powerful MS drugs on misdiagnosed patients was underway as early as 1997. In a review of 366 cases that year, Harvard Medical School neurologist Charles Poser found that 130 patients did not have MS, and 14 of them were receiving recombinant β-interferon treatment for MS. Another 10 misdiagnosed patients said their neurologist had recommended the treatment.

Back then, Poser speculated that marketing of the newly approved β-interferon had created a "therapeutic frenzy" that further propelled misdiagnosis. "I found that some patients referred to me with the diagnosis of multiple sclerosis had already been given these drugs, irrespective of the clinical characteristics of their disease," he wrote. "I have also noted that many patients who receive β-interferon do not have multiple sclerosis, and some patients started to take the drugs even after they were told that I could not confirm the diagnosis of multiple sclerosis."

Solomon and colleagues in Portland hope their survey points the way to improving diagnostic accuracy.

"We have lot of data on all of the problems that can be mistaken for MS," he says. "This provides a snapshot of what we are actually seeing in practice." The journal Neurology is publishing the study, funded by the Department of Veterans Affairs, the National Institutes of Health and the Partners MS Fellowship Award.

About one out of seven of the surveyed MS specialists who had identified a misdiagnosis said they did not always tell the patient. They reasoned that the patient wasn't receiving MS therapy and that changing the diagnosis might cause psychological harm.

The Colorado study found that psychiatric disorders were the root of the problem for more than one-fifth of patients referred for possible MS. "These patients often go from physician to physician, using significant resources, not getting appropriate evaluation and treatment, and undergoing great emotional distress," Corboy and colleagues noted.

Dr. Dennis Bourdette, director of the OHSU Multiple Sclerosis Center and co-author of the new survey, says misdiagnosed patients remain at risk of getting a harmful treatment, while being deprived of treatment likely to help. Money wasted as a result of misdiagnosis is hard to count but would surpass $11 million a year just on medical treatment of cases identified in the survey.

Source: Oregon Live.com © 2012 Oregon Live LLC. (09/05/12)

A Case Report

Abstract (provisional)

Introduction
Tumefactive multiple sclerosis is a demyelinating disease that demonstrates tumor-like features on magnetic resonance imaging. Although diagnostic challenges without biopsy have been tried by employing radiological studies and cerebrospinal fluid examinations, histological investigation is still necessary for certain diagnosis in some complicated cases.

Case presentation
A 37-year-old Asian man complaining of mild left leg motor weakness visited our clinic. Magnetic resonance imaging demonstrated high-signal lesions in bilateral occipital forceps majors, the left caudate head, and the left semicentral ovale on fluid-attenuated inversion recovery and T2-weighted imaging, and these lesions were enhanced by gadolinium-dimeglumin.

Tumefactive multiple sclerosis was suspected because the enhancement indistinctly extended along the corpus callosum on magnetic resonance imaging and scintigraphy showed a low malignancy of the lesions. But oligoclonal bands were not detected in cerebrospinal fluid.

In a few days, his symptoms fulminantly deteriorated with mental confusion and left hemiparesis, and steroid pulse therapy was performed. In spite of the treatment, follow-up magnetic resonance imaging showed enlargement of the lesions. Therefore, emergent biopsy was performed and finally led to the diagnosis of demyelinating disease. The enhanced lesion on magnetic resonance imaging disappeared after one month of prednisolone treatment, but mild disorientation and left hemiparesis remained as sequelae.

Conclusions
Fulminant aggravation of tumefactive multiple sclerosis can cause irreversible neurological deficits. Thus, an early decision to perform a biopsy is necessary for exact diagnosis and appropriate treatment if radiological studies and cerebrospinal fluid examinations cannot rule out the possibility of brain tumors.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Source: Journal Of Medical Case Reports © 2012 BioMed Central Ltd (10/04/12)

For nearly 30 years, Tom Rogers' left hand would shake when he tried to use it, making even simple tasks such as drinking a glass of water, writing a check, or making a sandwich challenging. The tremor eventually became so disruptive that he lost use of his dominant hand. Rogers sought care and learned that his tremor was a symptom of Parkinson's disease, yet felt he was suffering from something different.

"I was familiar with Parkinson's because my father had it and I knew this wasn't the same," said Rogers, a 66-year-old retired truck driver who resides in Oswego, Ill. "It was exactly the opposite of my dad's tremor which would start when he was still or relaxed. My hand would shake when I had something in it or tried to use it."

Also convinced that her husband was suffering from something other than Parkinson's, Pam Rogers began searching the internet. Through her research the couple learned about another movement disorder called essential tremor and found their way to Northwestern's Parkinson's Disease and Movement Disorders Center. Northwestern Medicine® movement disorder specialists diagnosed Rogers with essential tremor, a neurological disorder that causes shaking in the hands, head, voice and occasionally the legs and trunk. An estimated 10 million Americans have essential tremor making it eight times more prevalent than Parkinson's, yet the two are often confused.

"Essential tremor is not a life-threatening disease, but it worsens over time and can be very debilitating," explained Joshua Rosenow, MD, director of functional neurosurgery at Northwestern Memorial Hospital and associate professor of neurosurgery at Northwestern University Feinberg School of Medicine. "Severe cases can profoundly impact a person's quality of life and limit the ability to function independently. As the condition progresses, it becomes more challenging for these patients to eat, feed themselves, write or drive. Some even become too frustrated or embarrassed to go out in public because of their tremor."

The disorder can be treated with medications, but many do not adequately control the tremor or cause negative side effects that outweigh the benefit. Patients are encouraged to eliminate any stimuli that increase their tremor, such as caffeine or life stress. When those treatments fail, deep brain stimulation (DBS) surgery is an option for some patients.

"Essential tremor is a vastly undertreated disorder, but DBS is tremendously effective, often much more so than medications," explained Rosenow. "DBS involves implanting small electrodes into very specific region deep in the brain to deliver continuous high frequency electrical impulses. Each electrode is connected to an extension wire that runs under the skin down to the chest where a battery pack is implanted. This pack acts as a 'pacemaker' for the brain and helps control the tremor."

After medication failed to control his tremor, Rogers made the decision to have DBS surgery. "It got to the point where I couldn't even sign my own name with my left hand and it was beginning to affect my right hand as well," said Rogers. "I knew if I ignored it, eventually I wouldn't be able to function on my own."

During DBS, the surgeon first plans the surgery by mapping out the best path for the electrode using detailed 3-D images of the brain. The patient is awake for part of the surgery and becomes a key member of the team as they map out the correct location for the electrode. Local anesthetic is given so that no discomfort is felt.

"The surgeon and neurophysiologist determine the exact placement for the electrode by listening to the nerve cell signals, which have a unique pattern in each area of the brain," said Rosenow, who performed Rogers' DBS surgery. "The patient's legs and arms are moved to see what effect the electrode is having and the patient is also asked to speak, look around and relate if there is any tingling or pulling in the arms, legs or face. In Tom's case, we asked him to mimic bringing a glass to his mouth because this was something that was impacted greatly by his tremor."

Rogers immediately felt a change when his surgical team found the right spot in his brain. "It was instantaneous," he recalled. "I said 'Doc, you found ground zero.' It was shaking and then all of a sudden it stopped."

A permanent electrode is placed once the correct location is found and the surgical team tests it by turning on the charge. They look for both a decrease in tremor, as well as any unwanted side effects. Once satisfied with the location, the electrode is secured and the patient is put back under general anesthesia for the remainder of the surgery. In the months following surgery, the implanted battery pack is programmed to achieve the optimal balance between stimulation and medication.

"Following surgery, we work with the patient to tailor the level of stimulation and treatment to their needs," said Cindy Zadikoff, MD, a movement disorders specialist at Northwestern Memorial and assistant professor of neurology at the Feinberg School, who helps select patients for DBS surgery and has special expertise in programming the stimulation devices. "In rare cases, the surgery itself turns off the tremor by causing what is known as a micro-lesion effect. Tom was one of these unique situations; in more than six months since surgery his device has not been turned on and his tremor has not returned."

DBS surgery allowed Rogers to regain use of his left hand and gave him the ability to do things that most people take for granted like write checks to pay his bills or drink a glass of water. "My hand is steady as a rock, it's amazing," Rogers said. "It's like I've been given back a new life."

Along with essential tremor, DBS is approved as a treatment for other movement disorders including Parkinson's and dystonia. Brain stimulation is currently being studied as a potential treatment for a wide range of disorders including chronic pain, bipolar depression, addiction, epilepsy and a number of other conditions.

"Millions of people have essential tremor and suffer without ever knowing they can explore an option such as brain stimulation surgery," said Rosenow. "This surgery can have tremendous benefit for essential tremor and allow patients to regain the ability to do things that may have been lost because of their tremor."

Source: Medical News Today © MediLexicon International Ltd 2004-2012 (02/04/12)

A University of Saskatchewan scientist plans to use the Canadian Light Source synchrotron to study the role some metals play in multiple sclerosis.

Anatomy and cell biology Prof. Bogdan Popescu wants to find out if levels of iron, copper and zinc in certain central nervous system cells can help define distinct forms of MS, or could be a target for drugs to prevent the disease’s progression.

“It’s not well-established what the connection is” between metals and MS, says Popescu, who recently secured five years of funding as a Canada Research Chair in MS.

First, a short primer: cells called oligodendrocytes manufacture a protective insulation for neurons called the myelin sheath. Although no one knows what causes MS, one result is the breakdown of this insulating sheath. The effects are similar to stripping insulation off a network of electrical wires, leading to symptoms like numbness, weakness, tingling, pain, loss of co-ordination, fatigue and paralysis.

Enzymes in oligodendrocytes working to build myelin sheath rely on iron and other elements to work, Popescu says.

“Without (iron) the cells cannot function as required, but too much can go to the opposite side of the spectrum. Too much can also be toxic.”

Whether MS patients have too much iron in those cells, researchers don’t know, and it’s what Popescu intends to find out.

He’s submitted a proposal to the CLS to use its BioXAS beamline to quantify the amount of iron in oligodendrocytes, and produce images of how the metal is distributed in the cells.

Popescu’s challenge in the interim is to round up as many brain samples as he can find from MS patients. Some samples will come from the brains of deceased MS patients, and others from brain biopsies taken from MS patients during their diagnosis.

Popescu will be working with pathologists at the U of S and beyond to find samples from patients with as many different stages and types of the disease as possible. Samples gathered when a patient was in the early stages of MS will be most informative, he says.

The studies on copper and zinc, which also play a role in myelination, will be similar.

The synchrotron is the best way to visualize and quantify the distribution of these metals, Popescu says, because current tissue-staining techniques for these elements are either tedious or provide limited information.

If metal levels do tell Popescu something new about the disease, researchers could potentially develop new MRI techniques to diagnose the disease, and possibly even determine the type of MS a patient has (such as relapsing remitting, primary or secondary progressive MS, or progressive relapsing).

An excess of metal could also be a target for drugs. Chemicals called chelators can trap and remove metals, and in some tests on mice with simulated MS, they have fewer symptoms when treated with an iron chelator.

“Why does that happen? Can we apply the same thing to patients?” Popescu asks.

The synchrotron’s BioXAS beamline is still under construction and is not expected to be open for general use until 2014, so it will be some time until Popescu can start the imaging work.

Source: The Star Phoenix © 2010 - 2012 Postmedia Network Inc (26/03/12)

Muscle endurance tests can detect abnormalities in the early stages of multiple sclerosis, Tel Aviv University researchers say

Multiple sclerosis (MS), a neurodegenerative disease, causes periodic attacks of neurologic symptoms such as limb weakness and mobility defects. And while MS patients' walking abilities and muscle strength are examined on a regular basis, doctors have yet to determine when the lower limb muscles begin to deteriorate. That's important because with earlier identification of mobility problems, doctors would be able to implement early intervention programs that could make all the difference for those with MS.

Now, Dr. Alon Kalron and his fellow researchers from Tel Aviv University's Sackler Faculty of Medicine and the Multiple Sclerosis Centre in Sheba Medical Center, Tel-Hashomer, have discovered that specific laboratory tests for leg muscle endurance and gait — the pattern of movement while walking or running — are highly effective in identifying mobility deficits at the initial stage of MS. These deficits are difficult to discover during standard neurological testing.

According to Dr. Kalron, who was supervised by Profs. Anat Achiron and Zeevi Dvir, patients in the early stages of MS had 40 percent less muscle endurance compared to their healthy counterparts. Additionally, distinct abnormalities were observed in their walking patterns. The study, which was published in the Journal of Neurologic Physiotherapy, could help researchers understand the mechanisms underlying the evolution of MS, and improve the management of patients afflicted with the disease.

One step at a time

Reduced muscle endurance may be one of the earliest signs of MS and is a common complaint among patients, but it is hard to detect, says Dr. Kalron. In order to quantify muscle fatigue, the researchers conducted a study that included 52 patients in the early stage of MS, and a control group of 28 healthy subjects.

Participants were examined using an isokinetic dynamometer, a special instrument for measuring lower limb muscle strength and endurance. They were asked to attempt to bend or straighten a knee exerting maximum effort, and maintain this position for 30 seconds. Muscle fatigue was calculated by measuring the decline in muscle strength during that period. On average, those in the early stages of MS were not able to maintain their strength — they demonstrated 40 percent less endurance compared to the healthy control group.

In addition, patients' gait was observed for factors such as how far a patient spreads his legs while walking, the length of their steps, and symmetry of movement. By examining walking patterns, the researchers discovered specific abnormalities in the MS group. Patients in the early stages of MS "tend to walk with a wider base, because walking with your legs further apart helps to improve stability. It's probably a compensation strategy due to the lower muscle endurance," explains Dr. Kalron. The participants in the MS group also walked more slowly, in an asymmetrical pattern with shorter steps.

Giving physical therapy a head start

Clinicians should be more aware of possible gait and lower limb muscle deficits very early in the disease process, especially because minor impairments are difficult to detect with regular neurological examinations. "The downside of detecting such deficits using advanced instruments is offset by the positive potential of early intervention programs," suggests Dr. Kalron. "If we find the abnormalities earlier, then we can start intervention programs when they have a chance to benefit the most."

Programs based around physical therapy and fitness can help MS patients maintain higher levels of muscle endurance and improve balance, holding off the fatigue that typically accompanies the disease.

Source: EurekaAlert! Copyright ©2012 by AAAS, the science society (27/01/12)

Abstract
Carbon monoxide (CO) is produced during the catabolism of free haem, catalyzed by haem oxygenase (HO) enzymes, and its physiological roles include vasodilation, neurotransmission, inhibition of platelet aggregation and anti-proliferative effects on smooth muscle.

In vivo preclinical studies have shown that exogenously administered quantities of CO may represent an effective treatment for conditions characterized by a dysregulated immune response.

The carbon monoxide-releasing molecules (CORMs) represent a group of compounds capable of carrying and liberating controlled quantities of CO in the cellular systems.

This review covers the physiological and anti-inflammatory properties of the HO/CO pathway in the central nervous system. It also discusses the effects of CORMs in preclinical models of inflammation.

The accumulating data discussed herein support the possibility that CORMs may represent a novel class of drugs with disease-modifying properties in multiple sclerosis.

Fagone P, Mangano K, Coco M, Perciavalle V, Garotta G, Romao CC, Nicoletti F.
Department of Bio-medical Sciences, University of Catania, Catania, Italy Alfama, Lda, Taguspark, Porto Salvo Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.

Source: Pubmed PMID: 22235993 and Clin Exp Immunol. 2012 Feb;167(2):179-87. doi: 10.1111/j.1365-2249.2011.04491.x. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology. (19/01/11)

Study finds factors that occur commonly with functional weakness.

What do we know already?
Functional weakness is a loss of strength in a part of the body, usually the arms or legs, which is caused by a person’s nervous system not working properly. Unlike other kinds of limb weakness, it is not due to damage to or a disease of the nervous system.

People with functional weakness can experience symptoms which can be disabling and frightening. It can cause difficulty walking as they may drag their feet or legs behind them, or have a feeling of a ‘heaviness’ on one side of their body. They can have trouble holding things, or can experience a feeling that a limb just doesn’t feel normal or ‘part of them’. This is called dissociative disorder.

Functional weakness can be mistaken for a stroke or symptoms of multiple sclerosis. But unlike these conditions, functional weakness can get better or even go away completely.

Doctors know some of the things that make a person more likely to have functional weakness. These are called risk factors and they include problems in childhood, or traumatic life events.

But we know much less about the circumstances during which functional weakness occurs. To find out more, specialists interviewed 107 people who had functional weakness for more than 2 years and asked them how and when it started, and how it felt for them.

What does the new study say?
Sixty-seven people said functional weakness affected one side of their body, 17 said it affected one limb, three people said three limbs and nine people said it affected all four limbs. Eleven people said it affected both of their legs.

Just under half of patients (49) said their functional weakness had started suddenly, and while they were awake. Sixteen said they first started experiencing symptoms when they woke up from sleep one morning, or having come round after being put to sleep for an operation. The remaining 42 patients said their symptoms started gradually over a period of around six hours or more.

In the group who said their symptoms started suddenly, the most ommon symptom was a panic attack, which occurred in 29 of the 49 people. A physical injury to the affected limb was next most common and happened to 10 people. Other symptoms people reported happened at the same time as the start of their symptoms were migraines and fits.

In the waking group, some people said they experienced - at around the same point in their illness - insomnia (2 people), panic attacks (4 people), or pain from the moment of waking (6 people).

In the gradual onset group, the most common symptoms were pain (in 12 people) and weakness and fatigue (in 11 people). Some people said that they began to feel that one half of their body was more tired and weak than the other.

How reliable are the findings?
Studies of this kind are valuable for finding out detailed information from individual patients about an illness. But studies like this can have limited conclusions because they tend to be small and we don’t know how widely the results apply, and whether they apply to other people with an illness.

In this study, the researchers were not able to take into account the impact of recent life events, and could not account for the context in which the symptoms occurred. Also the study is limited to what the patients were able to remember and if they were able to accurately remember situations and events, like physical injuries.

What does this mean for me?
This study means that it’s possible that the way functional weakness begins could be classed as sudden onset, from sleep, or gradual. It’s also useful to find out the symptoms and circumstances associated with the onset of functional weakness. The researchers say this could offer potential clues to understanding how functional weakness develops.

Stone J, Warlow C, Sharpe M. Functional weakness: clues to mechanism from the nature of onset. J Neurol Neurosurg Psychiatry 2012;83:67–9.

Full article

Source: Best Health © BMJ Publishing Group Limited 2012 (17/01/12)

Abstract
INTRODUCTION. Recent studies have shown the need to optimise the management of patients after a first attack suggestive of multiple sclerosis (MS). Our aim is to determine whether the results from follow-ups in these studies are reproducible within a Spanish multi-centre context.

PATIENTS AND METHODS. The PREM study (observational prospective Spanish multi-centre study at 24 months) included patients in the first three months following a first event suggestive of MS with at least two typical lesions in a magnetic resonance scan.

The Expanded Disability Status Scale (EDSS) was obtained and the presence of attacks was evaluated basally and at 3, 6, 9, 12, 18 and 24 months; a magnetic resonance scan was performed basally and at 6 and 24 months so as to be able to calculate the brain volume and the volumes of the lesions (T1, T2 and T1 after administering gadolinium). McDonald and Poser criteria were evaluated during the follow-up. A subgroup of patients was followed up for a total period of four years.

RESULTS. Altogether 110 patients (67% females) with a mean age of 30.2 years were included in the study; 22 patients dropped out of the study before it finished. Poser criteria were met by 19% and 45% of patients at 6 months and 24 months, respectively; 63% and 71% satisfied McDonald criteria. The EDSS decreased significantly (-0.94; p < 0.001) and development of atrophy was observed (-1.2%; p < 0.001) at 24 months.

CONCLUSIONS. Results of the follow-up of patients with first attacks suggestive of MS within a Spanish multi-centre context are wholly comparable with those from international clinical trials performed in these patients.

Source: Pubmed PMID: 22052172 & Rev Neurol. 2011 Nov 16;53(10):577-83 (10/11/11)

Results were presented at ECTRIMS from a survey conducted by NARCOMS which found that about one-third of patients experiencing MS relapses do not adequately respond to corticosteroid treatment. The survey included over 2,000 patients with MS who had experienced relapses and were treated with either intravenous (IV) or oral corticosteroids. Corticosteroids are generally considered to be first-line therapy for MS relapses requiring therapy by most neurologists.

Of 1,122 MS patients surveyed who had been treated with IV steroids for their relapses, 31% reported no change or a worsening of relapse symptoms following treatment. Of 894 MS patients treated with oral steroids for relapses, 39% reported no change or a worsening of symptoms following treatment.

"This NARCOMS survey helps to further our understanding about the experiences and perspectives of patients who are suffering from MS relapses," said Ruth Ann Marrie, MD, PhD, Director of the Multiple Sclerosis Clinic at the Health Sciences Centre, Winnipeg, Manitoba, Canada and NARCOMS representative. "We hope that such information can be helpful to both physicians and patients in the management of MS."

This survey was one of an ongoing series of patient surveys independently conducted by NARCOMS on a variety of important topics related to MS patient care. NARCOMS is a non-profit project of the Consortium of Multiple Sclerosis Centers and operates the largest North American MS patient self-report registry, with the ultimate goal of improving research, treatment and education.

"These findings provide a major step forward in the understanding of how MS patients who are suffering relapses view their experience with corticosteroid treatment, which has been the most widely-used first-line relapse treatment for nearly three decades," said Steve Cartt, Executive Vice President and Chief Business Officer of Questcor Pharmaceuticals, Inc. QCOR +0.25% . "The data confirm the need for additional treatment options for MS relapses. For many of these patients who do not respond adequately to corticosteroid treatment, Acthar can be a viable treatment option."

The full poster highlighting key findings from the NARCOMS survey presented at the Congress is expected to be available for viewing on the ECTRIMS website within the next 10 business days at: http://www.ectrims.eu/conferences.htm.

About H.P. Acthar® Gel

H.P. Acthar® Gel is a natural adrenocorticotropic hormone (ACTH) designed to provide a prolonged release after intramuscular or subcutaneous injection. Acthar is indicated for the treatment of acute exacerbations of multiple sclerosis in adults, and as monotherapy for the treatment of IS in infants and children under 2 years of age. It is also indicated to induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus, and for the treatment of several other diseases and disorders.

About Questcor

Questcor Pharmaceuticals, Inc. is a biopharmaceutical company whose products help patients with serious, difficult-to-treat medical conditions. Questcor markets H.P. Acthar® Gel (repository corticotropin injection), which is indicated for the treatment of acute exacerbations of multiple sclerosis in adults, and as monotherapy for the treatment of IS in infants and children under 2 years of age. It is also indicated to induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus, and for the treatment of several other diseases and disorders. The Company also markets Doral® (quazepam), which is indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Source: PR Newswire Copyright (C) 2011 PR Newswire.(21/10/11)

Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975–2009)

Abstract

Background: Recent natural history studies suggest that multiple sclerosis (MS) is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach.

Objectives: We investigated whether MS disease progression has changed over time in British Columbia, Canada.

Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration. Kaplan–Meier analysis was used to compare: the proportion of patients reaching EDSS 6 (primary analysis) and the time to EDSS 6 (secondary analysis) across the time-period groups.

Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant temporal trend was found in the proportion of patients reaching EDSS 6 within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervalsq 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09) or in survival curves for time to reach the outcome (p = 0.14).

Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

Full Article

Afsaneh Shirani Department of Medicine, University of British Columbia, Vancouver, Canada, Yinshan Zhao Department of Medicine/MS/MRI Research Group, University of British Columbia, Vancouver, Canada, Elaine Kingwell Department of Medicine, University of British Columbia, Vancouver, Canada, Peter Rieckmann Department of Medicine, University of British Columbia, Vancouver, Canada, Helen Tremlett Department of Medicine, University of British Columbia, Vancouver, Canada

Source: Multiple Sclerosis Journal Copyright © 2011 by SAGE Publications (28/09/11)

Abstract

The objective of the study was to treat fatigue in patients with multiple sclerosis (MS) by a neurocognitive rehabilitation program aimed at improving motor planning by using motor imagery (MI).

Twenty patients with clinically definite MS complaining of fatigue were treated for five weeks with exercises of neurocognitive rehabilitation twice a week.

Patients were evaluated by Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), MSQoL54, Expanded Disability Status Scale (EDSS), and MS Functional Composite (MSFC). After treatment, a decrease in fatigue was detected with both FSS, MFIS, MSFC and MSQoL54 scores improved compared to baseline.

At six-month followup, the improvement was confirmed for fatigue and for the physical subscale of MSQoL54. No differences in disability scales were found.

These results show that neurocognitive rehabilitation, based on MI, could be a strategy to treat fatigue in MS patients.

Full Article

Mauro Catalan,¹ Alessandra De Michiel,² Alessio Bratina,¹ Susanna Mezzarobba,² Lorella Pellegrini,² Roberto Marcovich,² Francesca Tamiozzo,² Giovanna Servillo,¹ Laura Zugna,¹ Antonio Bosco,¹ Arianna Sartori,¹ Gilberto Pizzolato,¹ and Marino Zorzon¹

¹Department of Medical, Surgical and Health Sciences, Cattinara Hospital, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
²School of Physiotherapy, University of Trieste, Via G. Pascoli 31, 34129 Trieste, Italy

Source: Rehabilitation Research And Practice Copyright © 2011 Mauro Catalan et al. (12/09/11)

Despite some suggestions to the contrary, using atypical symptoms of MS to identify nondemyelinating disease is more effective than using so-called “red flags”, a study indicates.

Red flags – including headache, monofocal presentation, bone lesions and seizures – are not very useful for alerting neurologists to non-demyelinating disease, the Irish researchers found, largely because of the low prevalence of red flags among patients eventually diagnosed with medically unexplained symptoms (MUS).

The study of almost 250 consecutive patients referred with suspected MS found that patients with MUS made up 20% of the referrals but only 5% of them had red flags.

In patients with other neurological diseases (not including MUS) they found 80% of patients had red flags.

Atypical symptoms predicted non-demyelinating disease with a sensitivity of 85% and a specificity of 90%. Those symptoms included those suggestive of another neurological disease, such as numbness in a glove-and-stocking distribution consistent with peripheral sensory neuropathy or non-dermatomal facial numbness and quivering.

The presence of red flags predicted non-demyelinating disease with a sensitivity of only 47% and a specificity of 88%.

"The advantage of using atypical presentations as a marker of non-demyelinating disease is that it includes the entity of MUS, which is not uncommon in the clinic,” the study authors wrote in JNNP.

“Thus, we advocate a sequential diagnostic process, using first the typicality of the presentation and then noting the presence of red flags in order to determine whether there is any better explanation than MS for the clinical presentation,” they concluded.

Sources: Neurology Update & J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2011-300679 (06/09/11)

Months or even years before demyelinating events are recognized, patients later diagnosed with multiple sclerosis often turn up in their doctors' offices complaining of fatigue, a researcher said here.

Among patients receiving MS diagnoses after 2005, records of nearly 30% indicated that they had reported fatigue to their physicians beforehand, said Joseph Berger, MD, of the University of Kentucky in Lexington, in a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

Berger noted that fatigue is a common symptom of MS, reported by many patients to be their biggest problem with the disease. Numerous previous studies have examined risk factors for fatigue and its relationship to disease progression following diagnosis.

But his study is the first to examine the presence of fatigue before a formal MS diagnosis, he said.

Berger and colleagues examined a large medical claims database maintained by Thompson Reuters, comprising records of major U.S. employers and health plans. It included 5,305 patients who were diagnosed with MS in 2005 to 2008 and who had three years of coverage prior to diagnosis as well as at least one year of coverage afterward.

Claims data for those patients during the years before MS diagnosis indicated that 1,534 (29%) had ICD-9 codes for either chronic fatigue syndrome or malaise, which were taken to indicate a patient complaint of fatigue. All but 73 of these patients were coded only for malaise.

Among these patients, records indicated that 31% experienced only fatigue without any other symptoms that might be associated with MS, Berger indicated. These included peripheral neuropathies or movement problems, visual or speech disturbances, or dizziness.

And, in the other patients with fatigue who also had other symptoms that could have been related to MS prior to formal diagnosis, records of 38% indicated that fatigue was the first symptom reported to their physicians.

Nearly one-third of the patients with fatigue had seen their physicians with the problem two to three years before diagnosis, and another quarter had reported the symptom one to two years before.

The researchers also examined drug prescriptions following these visits prior to MS diagnosis. They indicated that only 10% of patients received prescriptions for agents often given for fatigue, such amphetamines or modafinil (Provigil).

"Careful history and physical examination for features suggestive of multiple sclerosis is mandated in any patient presenting with unexplained fatigue," Berger told CMSC attendees.

He also suggested that the study's numerical findings were almost certainly underestimates of the frequency of fatigue, insofar as many physicians, including himself, rarely record it with a specific ICD-9 code on their patients' charts.

He said his group was planning additional studies to pin down the role of fatigue as a precursor to, or predictor of, MS. These include a comparative analysis of fatigue preceding other conditions such as depression, asthma, hypothyroidism, anemia, and rheumatoid arthritis as well as MS.

Also on tap is a study to see if pre-MS patients reporting fatigue as the sole symptom are otherwise different from those complaining of multiple MS-related symptoms.

And, he added, it would also be useful to compare the incidence of fatigue in patients going on to MS with the population of all patients labeled with fatigue, Berger said.

Mark Freedman, MD, of the University of Ottawa, commented during the question-and-answer session that the latter study would be especially important, insofar as most patients with such complaints in the current study were probably seen in primary care.

"You would want to know what percentage of that population with general malaise don't go on to develop multiple sclerosis," he said.

Such an analysis would shed light on the degree to which fatigue should heighten physicians' suspicions of MS, Freedman suggested.

The study was funded by Bayer.

Berger reported consulting fees, honoraria, or other payments from Asphelia, Astellas, Bayer, Biogen Idec, Genentech, GlaxoSmithKline, Millenium, Pfizer, Perseid, Teva, and EMD Serono.

Freedman reported such payments from Genzyme, Bayer, Biogen Idec, Teva, Merck Serono, Novartis, and Sanofi-Aventis.

Source: MedPage Today © 2011 Everyday Health, Inc (06/06/11)

Multiple sclerosis (MS) is a chronic, disabling, and progressive illness, representing one of the most common causes of neurological disability in young and middle-aged adults.

There is not a definitive treatment for MS yet. However, disease-modifying drugs (DMDs) for MS, which include interferon-beta and copolymer-1 have shown to be effective in reducing the frequency and severity of relapses and the progression of disability. The clinical efficacy of such therapies has been well documented in the medical literature.

Instead, the factors underlying the decision to start the pharmacological treatment, to continue it or to drop out, have not been studied so far. Adverse drug effects, as well as patients’ emotional states, therapeutic expectations, the need to assume the medicines very often, and lack of communication with medical staff, are some of the elements affecting patients’ adherence to the therapy.

Data from medical records of 567 MS patients referred to the MS Centre of the IRCCS Centro Studi Neurolesi (Messina) between the years 2001-2008 have been retrospectively analyzed in a first phase.

Factors influencing patient decision to start a pharmacological treatment with DMDs, in agreement with the neurologist suggestion, have been evaluated by applying a multinomial logit model.

The second phase of the study was cross-sectional and analyzed the data obtained through a questionnaire administered to consecutive outpatients referred to Centro Studi Neurolesi within March and May 2009 (n = 143). The probability to proceed in the treatment or to drop out was estimated through a probit model.

The present research constitutes a novelty among the existing economic and medical literature: in fact, there are no, so far, studies evaluating factors underlying MS patients’ decision to undergo a pharmacological treatment and to proceed it according to medical protocols. Moreover, a significant expenditure for health care systems is associated to MS treatment, both for patients who undergo the treatment (cost of medicines, productivity losses for patients who experience severe side effects, etc.) and for those who do not take the medicine or take it discontinuously.

Given the documented evidence of augmenting costs (direct and indirect) with increasing disease severity, the ability of the DMDs to reduce relapse rates and slow the progression of MS may help to offset the cost of these therapies. Conversely, delayed treatment or poor compliance can dramatically increase costs and reduce benefits.

Full Article

Source: PoliEcon (19/05/11)

A worsening of the Expanded Disability Status Scale (EDSS) lasting at least six months is effective in identifying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS), according to a study published in the November issue of the Archives of Neurology.

In a retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data, Richard A. Rudick, M.D., of the Cleveland Clinic, and colleagues evaluated patients with RRMS who received at least two years of treatment and completed an EDSS evaluation eight years post-randomization.

The investigators found that 45 patients had sustained six-month EDSS progression, while 115 patients did not. Eight years after randomization, progression was the strongest predictor of reaching EDSS milestones at the follow-up visit. The investigators also found that treatment arm assignment and baseline EDSS score were other independent predictors of reaching EDSS milestones at the follow-up visit.

"In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of one point or more on EDSS from baseline lasting six months was the strongest predictor of clinically significant disability eight years after randomization into the clinical trial," the authors write.

Source: Doctors Lounge Copyright © 2001-2010 Doctors Lounge.(15/11/10)

Patients with multiple sclerosis (MS) are vulnerable to a variety of other autoimmune disorders, including thyroid abnormalities, report researchers.

Presenting at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, investigators recommended clinicians examine patients for autoimmune thyroid disease.

Previous studies have suggested that disorders such as Hashimoto's thyroiditis, diabetes mellitus, rheumatoid arthritis, and asthma are associated with MS. Investigators suspect that different autoimmune disorders share genetic tendencies that influence risk.

In the current analysis, researchers looked at 200 patients with MS and 200 control patients. The group, led by Recai Turkoglu, MD, from the Haydarpasa Numune Education and Research Hospital in Istanbul, Turkey, tested thyroid-stimulating hormone and thyroid autoantibody against peroxidase before and after immune modulatory therapy.

Investigators used the Roche Elecsys 1010/2010 and modular analytic E170 immunoassay analyzer. They considered thyroid autoantibodies positive at titers of 35 IU/mL or higher.

The researchers found significant differences in thyroid autoantibody levels between patients with MS and control subjects. Only 2 patients had positive thyroid autoantibodies after immune modulating therapy. Investigators report no significant differences on Expanded Disability Status Scale with thyroid autoantibody levels.

Asked by Medscape Medical News to comment, Talal Al-Harbi, MD, a neurologist at King Fahad Specialist Hospital in Dammam, Saudi Arabia, said he routinely examines his patients for thyroid abnormalities.

"It's still not clear whether there is a relationship, but this and other studies suggest there could be. I check my MS patients for autoimmune markers including thyroid antibodies," Dr. Al-Harbi said.

"Similar concerns were raised regarding antibodies and [amyotrophic lateral sclerosis], but we have since learned there is no relation," he added. "But I do think it's still a good idea to evaluate every patient with MS."

It is estimated that about a quarter of untreated multiple sclerosis patients have autoimmune thyroiditis or subclinical hypothyroidism.

Source: Medscape Today Copyright © 1994-2010 by WebMD LLC (21/10/10)

The present study reveals that a potential way to minimize MS exacerbation is by directly coping with the situation.

Multiple sclerosis patients who directly confronted the stress of the Second Lebanon War suffered fewer attacks than those who chose to cope with the situation by focusing on feelings. This has been shown in a new study carried out by researchers of the University of Haifa, the Technion-Israel Institute of Technology and Carmel Medical Center.

"Because there is no cure for multiple sclerosis to date, it is important to uncover all the factors that impact the recurrence of attacks," said Prof. Eli Somer of the University of Haifa, one of the authors of the study.

The study, which Prof. Somer carried out alongside Dr. Daniel Golan, Sara Dishon, Limor Cuzin-Disegni and Dr. Idit Lavi of Carmel Medical Center and Prof. Ariel Miller of the Technion, examined how MS patients living in the north of Israel coped during the Second Lebanon War. The results of the first stage of the study, which were recently published in the scientific journal Multiple Sclerosis, revealed that the ongoing stress of the war increased the number of MS attacks in patients who were exposed to rocket fire. The current stage of the study has examined 156 patients who have undergone regular therapy at the Center for Multiple Sclerosis at the Carmel Medical Center and who were living in the attacked north of Israel during the war.

The results have shown that patients who chose to use "direct coping and planning" to counter the stress factor – by preparing the shelter or protected area, stocking up on food and medications, adjusting their medical appointment schedule, and the like – suffered significantly less exacerbation of MS symptoms than patients who chose to cope with the situation on an emotional level, with relaxation techniques, requesting emotional support, or prayer.

"Patients who focused their coping on emotional wellbeing when a more direct approach was necessary, suffered more flare-ups of the disease than patients who identified the challenges that the falling missiles were presenting, and regarded the situation as an opportunity for planning and direct action," Prof. Somer noted.

The study has also found that women with MS tended to turn to emotional support, religion and willfully diverting thoughts more than men. Nevertheless, there was no difference between the numbers of men and women who chose "direct coping and planning".

"Coping directly is how a person takes real action in order to change an unwanted situation. Multiple sclerosis patients who chose to view the war as a controllable situation that requires action, instead of seeing it as an uncontrollable threat, suffered fewer attacks of the disease," said Prof. Somer, adding that now it is necessary to investigate whether the acquisition of psychological coping skills can stall the progression of this disease.

Source: Eureka Alert! (22/06/10)

There has been growing interest in the use of retinal imaging for tracking disease progression in multiple sclerosis. However, systematic and detailed pathological descriptions of retinal tissue in multiple sclerosis are lacking.

Graded, histological evaluations on eyes from 82 patients with multiple sclerosis and 10 subjects with other neurological diseases, with immunohistochemistry on a subset, were performed and correlated with clinical and pathological findings.

Multiple sclerosis cases demonstrated evidence of retinal atrophy and inflammation even in late-stage disease. Retinal ganglion cell loss was significant and remaining neurons appeared shrunken and were partially engulfed by human leukocyte antigen-DR positive cells with the phenotype of microglia in samples subjected to immunohistochemistry.

Neurofilament staining revealed variable but prominent degrees of axonal loss and injury. Neuronal loss was noted in the inner nuclear layer with focal reduction in cell density. Foamy-appearing human leukocyte antigen-DR positive cells were evident near vessels and periphlebitis was found in a small but significant number of multiple sclerosis cases. Glial fibrillary acidic protein staining showed extensive astrocyte hypertrophy and proliferation with prominent gliosis in multiple sclerosis cases.

Frequent but previously unreported abnormalities in the iris were documented in the majority of chronic multiple sclerosis cases. The injury to both iris and retina could be seen at all stages of disease.

Severity of retinal atrophy was correlated with overall brain weight at time of autopsy (P = 0.04) and a trend for increased atrophy was seen with longer disease duration (P = 0.13).

This study provides the first large-scale pathological description of retinas in multiple sclerosis, including patients with different subtypes of disease at all stages, and with variable clinical severity.

Changes were seen not only in the retinal nerve fibre layer and ganglion cell layer, but also in the inner nuclear layer, suggesting that retinal injury is more widespread than previously appreciated.

Furthermore, the human retina is devoid of myelin, but inflammation was demonstrated to be prominent in multiple sclerosis and to persist in the retina at late stages of disease.

The prominent gliosis and inflammation surrounding vessels of the inner retina could potentially impact optical coherence tomography evaluations in multiple sclerosis—as standard techniques exploit presumed differences in tissue reflectivity and utilize automated edge detection algorithms to judge axon loss in the nerve fibre layer.

Deciphering the relationships between the different types of retinal pathology may aid us in understanding the factors that drive both inflammation and tissue atrophy in multiple sclerosis.

Ari J. Green¹, Stephen McQuaid³, Stephen L. Hauser¹, Ingrid V. Allen² and Roy Lyness³

¹ Multiple Sclerosis Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA ² School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, Northern Ireland, UK ³ Tissue Pathology Laboratories, Belfast Health and Social Care Trust, Belfast BT9 7AB, Northern Ireland, UK

Source: Oxford University Press © 2010 Guarantors of Brain.(04/05/10)

Multiple Sclerosis (MS) patients present a decrease of antioxidants and neuroprotective and immunoregulatory vitamins and an increase of total homocysteine (tHcy), cholesterol (CHL), HDL-cholesterol, and of cellular stress markers, variably associated with the different phases of the disease.

We compared the blood levels of uric acid, folic acid, vitamins B12, A, and E, tHcy, CHL, HDL-cholesterol, and triglycerides in forty MS patients during a phase of clinical inactivity with those of eighty healthy controls, matched for age and sex.

We found higher levels of tHcy (p = 0.032) and of HDL-cholesterol (p = 0.001) and lower levels of vitamin E (p = 0.001) and the ratio vitamin E/CHL (p = 0.001) in MS patients.

In conclusion, modifications of some biochemical markers of cell damage were detected in MS patients during a phase of clinical inactivity.

Authors: Giuseppe SalemiMaria Concetta GueliFrancesco VitaleFloriana BattaglieriEgidio GuglielminiPaolo RagoneseAngela TrentacostiMaria Fatima MassentiGiovanni SavettieriAntonino Bono

Source: 7thSpace Interactive © 2010 7thSpace Interactive (19/02/10)

While gripping, lifting or manipulating an object such as drinking from a cup or placing a book on a shelf is usually easy for most, it can be challenging for those with neurological diseases such as multiple sclerosis or Parkinson’s, or for people who had a stroke. For them, the tight gripping can cause fatigue, making everyday tasks difficult.

A team of University of Illinois at Chicago physical therapists report this month in the journal Neurorehabilitation and Neural Repair that persons with multiple sclerosis use excessive force when they are lifting objects. In an earlier finding reported in the journal Clinical Neurophysiology, they reported that regaining control and coordination may be as easy as applying a gentle touch to the affected hand from a finger of the opposite hand.

“We studied how this light touch application changes the way people apply force to an object they want to grip,” said Alexander Aruin, professor of physical therapy. The study compared eight adults with multiple sclerosis to eight without the disease, gender-matched and of comparable age. “In each case, the grip force required to lift an object decreased,” said Aruin.

He found similar results in an earlier study he did of people with arm weakness caused by a stroke.

Why the simple light finger touch application works so well is not fully understood, but Aruin offers a hypothesis.

“It could be due to auxiliary sensory information from the contra-lateral arm,” he said. “When we use our second hand and touch the wrist of the target hand, available information to the central nervous system about the hand-object interaction may increase. Without the touch, the information needed to manipulate an object comes only through vision and sensory input from just the target arm and hand.”

Aruin and his colleagues tested subjects griping and lifting a variety of objects that they moved in several different ways, directions and velocities. The gentle finger touch always helped to reduce grip force, making the task easier.

The UIC researcher said he and his colleagues plan to test the approach on those with other neurological and muscular diseases to examine the effects.

“We look forward to developing training and rehabilitation procedures on how to use this,” said Aruin. “We know that MS patients are prone to fatigue and muscle weakness. This finding may enable them to perform daily activities more independently to improve their quality of life.”

Source: Armenian Medical Network © 2000 - 2009 Armenian Medical Network Inc (15/10/09)

To the background hum of freezers Dr Steve Gentleman, a neuropathologist at Imperial College, is performing a dissection.

"It is a detective game, I need to find out what has gone wrong in the brain so I can pass that information onto researchers who are using the tissues," he explains.

The University houses two brain tissue banks, one for multiple sclerosis and the other for Parkinson's disease. They are funded by charity and rely on brain donors.

Dr Gentleman creates a series of diagnostics blocks which are then processed into microscopic sections for structural analysis.

"In a multiple sclerosis brain, what we are looking for is signs of disruption to the normal wiring of the brain, so the white matter becomes discoloured, this is a sign something has gone wrong with the normal insulation of the nerve fibre," he says.

Damage to the spinal cord might indicate motor-neurone disease, while lesions in the limbic system, the memory part of the brain, could suggest Alzheimer's.

Discoveries made using brain tissue include the now well-described role of dopamine in Parkinson's disease, a chemical where depletion results in poor co-ordination, and the presence of amyloid deposits in Alzheimer's disease, which results in the death of brain cells.

Central database

It is now hoped that deeper inroads into brain research can be made due to the announcement of a UK-wide Brain Bank Network. This will coordinate the 12 major brain banks in the UK, from London to Edinburgh.

The network, led by the Medical Research Council (MRC), will make the processing of brains from donor to lab more efficient, giving researchers speedier access to the tissue they need.

All samples will be entered into a central database and scientists across the UK, as well as those overseas, will be able to request certain tissues according to disease, region of the brain and age.

Professor James Ironside, Director of the UK Brain Banks Network says: "The UK is leading the world with this system. Many diseases, like Alzheimer's, are becoming more common as the population ages.

"In order to help clinicians and families we need to know more. The network will help speed up research so people in the field can use the results."

Donation

Through sharing, the network also hopes to make use better use of the available control samples, normal brains that can be used as a yardstick against which to measure.

Recent research has shown that while many people are prepared to donate other organs, there is reluctance about brain donation.

Imperial College brain bank has approximately one control brain for every diseased brain. Brain banks for other conditions, like autism, may have even fewer controls, as a disease that is predominant in children.

Dr Shaun Griffin, from the Human Tissue Authority (HTA), says: "Anyone giving tissue for research can be confident their donation will be treated with respect and dignity.

"This area is tightly regulated by the HTA, we are an independent watchdog that protects public confidence by making sure that human tissue is used ethically and with proper consent."

Source: BBC News © British Broadcasting Corporation 2009 (05/06/09)

Background: Chaperonin 10 (Cpn10) is a mitochondrial molecule involved in protein folding. The aim of this study was to determine the safety profile of Cpn10 in patients with multiple sclerosis (MS).

Methods: A total of 50 patients with relapse-remitting or secondary progressive MS were intravenously administered 5 mg or 10 mg of Cpn10 weekly for 12 weeks in a double-blind, randomized, placebo controlled, phase II trial. Clinical reviews, including Expanded Disability Status Scale and magnetic resonance imaging (MRI) with Gadolinium, were undertaken every 4 weeks. Stimulation of patient peripheral blood mononuclear cells with lipopolysaccharide ex vivo was used to measure the in vivo activity of Cpn10.

Results: No significant differences in the frequency of adverse events were seen between treatment and placebo arms. Leukocytes from both groups of Cpn10-treated patients produced significantly lower levels of critical proinflammatory cytokines. A trend toward improvement in new Gadolinium-enhancing lesions on MRI was observed, but this difference was not statistically significant. No differences in clinical outcome measures were seen.

Conclusions: Cpn10 is safe and well tolerated when administered to patients with MS for 3 months, however, a further extended phase II study primarily focused on efficacy is warranted.

Broadley S, Vanags D, Williams B, Johnson B, Feeney D, Griffiths L, Shakib S, Brown G, Coulthard A, Mullins P, Kneebone C.

School of Medicine, Gold Coast Campus, Griffith University, Queensland, Australia; Gold Coast Hospital, Southport, Queensland, Australia.

Source: Pubmed PMID: 19039022 (02/12/08)

A new centre for the research of Multiple Sclerosis has been set up in Scotland - the MS Society and Edinburgh University Centre for Translational Research has been established with the support of JK Rowling.

The project will be funded for six years initially and will build on the university's track record in translational research and relevant disciplines, for including neuroscience, inflammation and stem cells.

A National Clinical Audit or register of MS in Scotland is also being established. The Scottish Government recently announced a grant of £70,000 to support the set-up costs and pilot the national audit in Edinburgh, Glasgow and Aberdeen. It will enable MS to be accurately mapped for the first time by establishing the incidence of the condition and providing answers to many of the other unknowns about MS. (31/07/08)

Researchers at Cornell University showed that giving mice the equivalent of six to eight cups of coffee a day protected them against experimental autoimmune encephalomyelitis (EAE), the animal model of MS.

It is known that caffeine is a popular adenosine receptor blocker and the findings show that this molecule plays a vital role in permitting the infiltration of immune cells into the central nervous system of patients with MS.

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that occurs when the body’s immune system attacks and damages nerves in the brain and spinal cord. While the infiltration of immune cells into brain and other CNS tissue is a rare sight in healthy individuals without MS, the researchers are sure that the molecule adenosine is responsible for this infiltration.

Adenosine is widely present in the body and is vital to many biochemical processes, like energy transfer and the promotion of sleep and suppression of arousal.

Initial studies led the researchers to discover that mice lacking CD73, the enzyme necessary for synthesizing extracellular adenosine, were protected from developing the mouse form of MS (experimental autoimmune encephalomyelitis or EAE). Subsequent studies dealing with immune cells from such mice made them believe that normal CD73’s ability to synthesize extracellular adenosine governed the development and progression of the MS-like disease.

Though this discovery did help the researchers to explain the presence of adenosine near the cells, but they were unaware of the mechanism that made the compound enter into the CNS cells. As adenosine is supposed to bind to its receptor in order to affect a cell, the researchers thought that adenosine receptor activation would have allowed for entry of immune cells into the brain and spinal cord and thus they turned to caffeine.

Caffeine’s stimulatory effects on the CNS are mainly due to its ability to bind to the same receptors as adenosine, thus blocking adenosine’s ability to affect CNS cells. When mice consumed caffeine in their drinking water, they were protected against development of EAE, the MS model.

Thus it was concluded that CD73 and adenosine receptor signalling are required for the efficient entry of immune cells into the CNS during the initiation and progression of EAE in mice and, quite possibly, during the development of MS in humans.

“These results might mark the first in a series of discoveries from our lab that could spawn the impetus for the development of adenosine-based therapies for the treatment of MS,” said Bynoe.

The study was presented at Experimental Biology 2008 which was a part of the scientific programs of the American Society of Immunologists and published in the Proceedings of the National Academy of Sciences in July

Source: First reported by MSRC 08/04/08, updated 04/07/08

"Inpatient rehab works in MS patients, and we have seen in this study in detail that it works, especially ameliorating fatigue, function of upper limbs and cognition, " said lead investigator Stephan Bamborschke, MD, professor of neurology, Charité Hospital, Berlin, and head of rehabilitation, Brandenburg Clinic, Bernau, Germany.

The purpose of the study was to assess the efficacy of neurological rehabilitation in MS patients, using the Multiple Sclerosis Functional Composite (MSFC, Cutter 1999) scale and measuring fatigue using the Fatigue Severity Scale (FSS, Krupp 1989), given to patients before and after rehabilitation.

"We also looked for parameters which possibly could predict the improvement of fatigue," the research team wrote in their poster presentation.

They enrolled 35 men and 103 women, age 22 to 61 years with a mean age of 44.1, who were in a stable phase of the disease.

Disease course among the subjects was primary progressive in 4%, relapsing-remitting in 69% and secondary progressive in 24%.

(Expanded Disability Status Scale (EDSS) scores ranged from 1.0 to 7.0, with a mean of 4.1.

The variety of ongoing treatments included: interferon beta 1b (27%), subcutaneous interferon beta 1a (17%), intramuscular interferon beta 1a (11%), glatiramer-acetate (16%), azathioprine (4%) and mitoxanthrone (2%).

Researchers performed the FSS with 101 of the 138 patients, and the MSFC with 128 of the 138 patients. Both were done at the beginning and the end of rehabilitation.

Patients received a diagnosis of fatigue with FSS values higher than 23 (possible range 9-63).

All subjects also took the Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire (SF36) quality of life questionnaire at the beginning of rehabilitation.

During 4 weeks of neurological inpatient rehabilitation all patients underwent individually-modified treatment with physiotherapy, ergotherapy, aerobic physical exercise, and, when appropriate individually, neuropsychological training.

The investigators reported that mean FSS score was 45.0 +/- 1.5 at the beginning of rehabilitation and 42.2 +/- 1.6 at the end. Mean MSFC score was -0.38 +/- 0.07 at the beginning of rehabilitation and -0.24 +/- 0.09 at the end.

They observed significant improvement of fatigue (P = .002) and MSFC score (P = .000035).

"The improvement of fatigue could not be predicted by gender, age, EDSS, initial MSFC values, quality of life measurement or extent of depression," they noted.

[Presentation title: Efficacy of Neurological Inpatient Rehabilitation Measured By Fatigue Severity Scale and Multiple Sclerosis Functional Composite in Multiple Sclerosis Patients. Abstract P431]

Source: Doctor's Guide Channels All contents Copyright (c) 1995-2006 Doctor's Guide Publishing Limited. All rights reserved.

The authors surmised that MHC-I+ mutant oligodendrocytes were targeted by T-cells. Flow cytometry experiments confirmed that the brain CD8+ cells were activated mature effector cells. The authors crossed the PLP mice with mice deficient for recombination activating gene-1 (RAG-1) that lack mature T- and B-lymphocytes.

Demyelination was reduced in these mice, an effect that was reversed by implantation of CD8+/CD4− bone marrow, indicating that the CD8+ lymphocytes are important to the secondary immune response. The authors suggest that this pattern of secondary, rather than primary, inflammatory/immune response may also underlie some subtypes of multiple sclerosis.

Authors: Chi Wang Ip, Antje Kroner, Martin Bendszus, Christoph Leder, Igor Kobsar, Stefan Fischer, Heinz Wiendl, Klaus-Armin Nave, and Rudolf Martini

Source: News tips from the Journal of Neuroscience

The study involved 245 paraplegic or quadriplegic men who received penile prostheses between 1980 and 1996. Other prostheses used besides the inflatable 3-piece type (AMS 700), included semirigid (Jonas) and self-contained inflatable types (Dynaflex).

The average patient age was 40.8 years old. The causes of spinal cord injury were trauma (80 percent), spina bifida (7 percent), tumors (6 percent), central nervous system infections (5 percent) and multiple sclerosis (2 percent).

The majority of patients -- 134 -- received the prosthesis to control urinary incontinence to improve "urinary drainage when penile retraction has made this difficult," lead author Dr. Dirk-Henrik Zermann, from Friedrich-Schiller-University Jena in Germany, and colleagues note. Sixty patients received the device for erectile dysfunction and 51 received the implant for both problems.

After an average follow-up period of 7.2 years, urinary incontinence has resolved in 90.3 percent of the patients and erectile dysfunction was successfully treated in 82.6 percent of the patients.

Forty-three revisions, due to technical issues or infections, were performed, the report indicates. The overall infection rate was 5 percent.

The number of perforations associated with the implant varied by the type of device, ranging from none with the inflatable 3-piece device to 18.1 percent for the semi-rigid type.

The results of long-term follow-up indicate that the inflatable 3-piece prosthesis has the lowest risk of complications, the authors conclude. A successful outcome for penile implant surgery requires special preoperative and postoperative care, they add, particularly in men with neurologic impairments.

SOURCE: The Journal of Urology, March 2006.

The findings could also be significant for developing new ways to help patients with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or juvenile diabetes.

The study, which was published in the February 16 issue of the online journal Science Express, showed that these injections caused a massive selective increase in the immune system's two main types of T cells.

"Our study shows that different cytokine-antibody complexes such as IL-2/IL-2 mAb could be clinically useful to selectively boost or inhibit the immune response in vivo," said Onur Boyman, a member of the Scripps Research Department of Immunology and lead author of the study.

The type of monoclonal antibody that was injected was specific to interleukin-2 (IL-2), a naturally occurring protein and a known immunotherapy for metastatic melanoma and renal cancer. The researchers showed that the anti-IL-2 monoclonal antibody (IL-2 mAb) expands the proliferation of specific T cells in vivo by increasing the biological activity of naturally occurring IL-2 through the formation of immune complexes. When combined with recombinant IL-2, some IL-2/IL-2 mAb complexes cause more than a 100-fold proliferation in CD8+ T cells, which can target virally infected cells or tumor cells.

Interleukin-2 increases the number of a subset of CD8+ T cells (referred to as antigen-experienced or memory T cells) in circulation and is often used for tumor immunotherapy and vaccination. However, IL-2 also stimulates CD4+ T regulatory cells, which can suppress those same memory T cells. Therefore, the prevailing view was that administration of IL-2 mAb removes the IL-2-dependent CD4+ T regulatory cells, which in turn leads to an expansion of CD8+ T cells.

"In the study, however, we noticed that the enhancing effect of IL-2 mAb correlated with naturally occurring levels of IL-2," Boyman said. "We concluded that, despite its reported neutralizing effect, IL-2 mAb actually expanded the proliferation of CD8+ T cells simply by increasing the biological activity of pre-existing IL-2 through the formation of antibody-cytokine immune complexes in vivo. We next combined recombinant IL-2 with IL-2 mAb, which led to an even more dramatic expansion. This expansion effect also extended to other types of antibody-cytokine complexes, such as IL-4/IL-4 mAb and IL-7/IL-7 mAb."

Despite these findings, Boyman noted, no one yet knows why these antibody-cytokine complexes are such potent immune response boosters in vivo.

"A few studies have suggested that injecting a cytokine together with the right antibody increases the half-life of the cytokine in vivo, accompanied by a very mild immune activation," he said. "But our study suggests a different mechanism and that joining a cytokine to its specific antibody opens the way for selective and vigorous stimulation of T cell subsets. With some types of antibodies, injecting IL-2/IL-2 mAb complexes might be clinically useful for tumor immunotherapy and for expanding T cell numbers after bone marrow transplantation. On the other hand, expansion of CD4+ T regulatory cells by IL-2 combined with another type of IL-2 mAb might provide a basis for treating autoimmune disease."

Other authors of the study include Marek Kovar, Mark Rubinstein, and Charles D. Surh of the Scripps Research Department of Immunology and Jonathan Sprent of the Scripps Research Department of Immunology and the Garvan Institute of Medical Research, Darlinghurst, Australia.

The study was supported by the National Institutes of Health, the Swiss National Science Foundation and the Novartis Foundation.

About The Scripps Research Institute 

The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.

Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.

Source: Scripps Research Institute Press Release

Geneva's university hospital treated 30 patients with transcranial magnetic stimulation (TMS), and reported impressive results.

The patients in the Geneva trial were selected because of their strong resistance to conventional treatments, such as drugs and psychotherapy.

"Half of them responded well to this alternative therapy and have remained in a stable condition for several months", said Dr Rachid Fady, one of the doctors responsible for the Geneva programme.

The technique, which stimulates the cerebral cortex with equipment sending out magnetic impulses, is also used in Spain (a pioneer in this field), the United States, France, Germany, Britain, Finland and Austria.

Though still experimental in Switzerland, TMS is a recognised treatment in Canada and Israel, and is covered by their national health insurance schemes.

TMS is also used in neurology, and in treating Parkinson's, multiple sclerosis, epilepsy and chronic pain.

Alternative

"In France, TMS is already used as an alternative to drugs," explained Fady. "It is good to have a number of options, even on patients who respond well to drug-based therapies."

He added that the therapy was never likely to replace completely anti-depressant drugs, which are among the most widely prescribed medicines in the western world.

There are concerns that magnetic fields – such as electrosmog from mobile phone antennae - could be damaging to the brain.

TMS uses a magnetic field very similar to the type used in magnetic resonance imaging - very strong, but far less rapid than the field required to operate a mobile phone.

"The frequencies we use for TMS are much higher than those used in mobile phones or microwave ovens, but they are applied to the patient's brain in a very localised and selective way," explained Fady's colleague, Jean Golaz. "We irradiate a cone of just a few cubic centimetres under the cranium.

"We certainly do not burn the brain, which must be intact if it is to respond to the therapy, but we enable it to clear blockages."

Deaths

"Since magnetic resonance imaging was developed – added Fady – millions of scans have been performed all over the world.

"And yet there have been only seven deaths due to misuse of the equipment. The victims were people who should never have undergone an examination of this kind because, for example, they had metal objects lodged in their brains as a result of surgery."

TMS has also aroused interest as a possible way of enhancing mental faculties. Because it activates certain areas of the brain, some think it could conceivably improve the processing power of the mind, speeding up learning or performing complicated mathematics.

"In Australia, there has in fact been some research of this kind, and a number of scientific papers have been published in the United States," said Jean Golaz. "But it is not really advisable, in our opinion; it smacks of science fiction and could be dangerous."

Source: Swissinfo © Copyright swissinfo SRI

Inflammation is a process by which the white blood cells and chemicals of the immune system rally to protect the body from infection and foreign substances such as bacteria and viruses. In autoimmune diseases, however, this defense system triggers an inflammatory response when there are no foreign substances to fight off, or the defense system goes into "overdrive" and forgets how to turn off. In these diseases, the body's normally protective immune system attacks and damages its own healthy tissues.

UCSD researcher Mark H. Ginsberg, M.D., professor of Medicine at the University of California, San Diego (UCSD) School of Medicine, and his colleagues have identified a mechanism to selectively disrupt signaling to recruit lymphocytes and monocytes – white blood cells sent to sites of inflammation to fight infection – while maintaining the body's other essential immune system functions. Their findings appear online on February 9 in advance of print publication in the March issue of the Journal of Clinical Investigation.

In the case of certain autoimmune diseases, the alpha 4 integrins cause white blood cells to accumulate at the site of the disease, resulting in inflammation. An integrin is a surface molecule found on the exterior of cells that helps cells adhere and migrate. It is also believed to be responsible for a role in cell signaling, which allows cells to communicate with the extracellular environment.

One of the promising treatments for disorders such as multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis – the alpha 4 integrin antagonist – works by blocking cell adhesion. However, this anti-inflammatory therapy could cause adverse side effects, such as impairment of the immune system and the patient's ability to develop new red and white blood cells in the bone marrow, a process called hematopoiesis.

"Our goal was to identify a more specific target of alpha 4 integrin molecules in order to interfere with their roles in disease progression while sparing alpha4 functions required for normal health," said David M. Rose, D.V.M., Ph.D., assistant professor of medicine at UCSD, and co-author of the study.

The research team created mutant mice known as "alpha4(Y991A) mice," in which the alpha4 integrin can no longer bind to a signaling protein inside the cell called paxillin. Previously generated alpha4 integrin deficient mutant mice died at birth because too many aspects of alpha4 function were changed. The new alpha4(Y991A) mice have an impairment only in the interaction between alpha4 and paxillin, and thus have fewer effects on development. The researchers discovered that, in contrast to normal mice, alpha4(Y991A) mice exposed to an inflammatory stimulus recruited fewer circulating white blood cells (B and T cells) to the region of exposure. However, the development of new B and T cells was unaffected.

The authors suggest that these mice are a valuable tool to test models of inflammatory and autoimmune diseases of humans, and that a new class of pharmaceutical agents that target the specific interaction of paxillin and alpha4 integrin could be important future treatments of inflammatory disease.

"We were surprised to find that the mutation actually had very little effect on the animal's development of lymphocytes, the white blood cells that fight infection," said Rose. "This could prove to be an important first step in development of a more effective drug to target alpha4 integrins in autoimmune and inflammatory disease of humans."

Additional co-authors include Kenneth Kaushansky, M.D., Chloé C. Féral, Jaewon Han, Norman Fox and Gregg J. Silverman, UCSD Department of Medicine.

Source: Public release - University of California - San Diego

The animal model of MS, EAE, has been successfully prevented and improved in mice by using oral compounds known as 'PPAR-gamma ligands'. Some of these are used to treat diabetes. If successful, they could lead the way to a new class of treatments for MS.

PPAR-gamma ligands attach to a specific receptor (a molecular docking site), called PPAR-gamma, and modulate its anti-immune activity. In MS, immune activity causes damage to myelin, the substance that insulates nerve fibres.

Dr Douglas L. Feinstein of the University of Illinois, Chicago, tested three different types of PPAR-gamma ligands, including ones that are currently being used to treat Type II diabetes.

The drugs reduced the incidence and severity of both chronic and relapsing EAE, and also decreased immune system activity and damage to myelin.

Ref: The National Multiple Sclerosis Society, US

First modifiable risk factor for disease advancement identified Boston, MA – Researchers from the Harvard School of Public Health (HSPH) recently discovered that cigarette smoking may contribute to the progression of multiple sclerosis (MS), suggesting that quitting smoking could limit or delay central nervous system deterioration.

This is the first time that a modifiable risk factor for MS progression has been identified, providing a new strategy for patients hoping to control neurological damage from the disease. Study results appear in the March 9, 2005 issue of Brain.

Miguel Hernán, lead author of the study and an assistant professor of epidemiology at HSPH, noted that "the findings are interesting because no modifiable risk factors for the progression of MS are known. This was the first prospective study that identified a potential intervention (quitting smoking) for reducing the risk of progression of MS."

Analyzing over 2,000 medical records in the General Practice Research Database (GPRD), researchers identified 179 British patients who were originally diagnosed with relapsing-remitting MS, a form of the disease in which symptoms fade and recur in unpredictable patterns. Patients who were current or past smokers were 3.6 times as likely as patients who had never smoked to develop secondary progressive MS, a later stage of the disease marked by steady deterioration of the central nervous system. This disease progression also occurred more quickly in patients who were identified as current or past smokers.

The study also supported earlier research showing that smoking may increase the risk of initial MS diagnosis. Current and past smokers were 30% more likely to be diagnosed with MS than those who had never smoked.

While more research is needed to understand the mechanisms behind these findings, Hernán and his colleagues speculate that nitrous oxide, a chemical present in cigarette smoke, may play a role in hastening the degeneration of nerve fibers. Alternatively, chemicals in cigarette smoke could damage the cells that create myelin, a protective coating for neurons, or may predispose smokers to autoimmune responses.

According to Hernán, "Our findings raise a number of other questions that future research needs to address. Does a dose-response relation between cumulative exposure to tobacco and risk exist? How long does the tobacco effect last? Is second-hand smoking associated with an increased risk as well?"