Archive for October, 2013
While it’s been known for over a century that iron deposits in the brain play a role in the pathology of Multiple Sclerosis (MS), new imaging research from Western University (London, Canada) helps to answer the question of whether these accumulations are a cause or consequence of the disease. The study led by Ravi Menon, PhD, of the Robarts Research Institute found iron deposits in deep gray matter, suggesting the accumulation occurs very early in the disease course. The researchers also found evidence casting further doubt on the controversial liberation therapy for MS. The research is in early publication online in Multiple Sclerosis and Related Disorders.
Menon and PhD candidate Matthew Quinn used 3-Tesla Magnetic Resonance Imaging (MRI) to scan 22 patients with clinically isolated syndrome (CIS). These are patients who’ve had a single clinical attack, at least half of whom will go on to be diagnosed with MS. The others may have a different disease. Sixteen age and sex matched controls were also studied.
“We wanted to know if the iron deposits happen early in the process, or whether it’s something that accumulates with time as the disease progresses,” says Menon, who holds a Canada Research Chair in Functional Magnetic Imaging. “We also studied the veins that drain from the brain and looked for a correlation between the diameter of of these veins and iron accumulation. One of the reasons to do this, of course was the hypothesis proposed by Paolo Zamboni that if you had narrow jugular veins, this would give rise to additional iron and in turn cause MS.”
The scientists found iron deposits in the CIS group were well above the amounts found in the control group. The MRIs also revealed for the first time, subtle damage to the brain’s white matter even at this early stage. The researchers also found no correlation between the iron deposits and diameter of the veins.
“So while the iron in the brain correlates with the disability of the subjects, the iron in the brain does not correlate with the actual diameter of the jugular veins. So the Zamboni hypothesis is incorrect as far as the iron being related to some kind of obstruction.” Menon found narrowed veins in the control group as well as the CIS group, and both groups had narrower veins on one side compared to the other.
Menon hopes this imaging research will lead to the earlier diagnosis of MS. He plans to follow the patients every four months for the next two years, to see retrospectively, what characterizes those patients that go on to be diagnosed with MS compared to those who do not.
“We’re looking at a couple of different approaches to diagnostics using this imaging research. In suspected MS cases -the very first time they appear in clinic, if they have an abnormally high amount of iron in the frontal cortex of the brain -that’s probably a pretty good sign they have MS or some other white matter disease.” This research was funded primarily by the Canadian Institutes of Health Research.
MS is the most common neurological disease affecting young adults, with symptoms that include loss of balance, impaired speech, double vision, extreme fatigue and paralysis.
New classification criteria for systemic sclerosis have just been published and are more sensitive than the 1980 criteria, enabling earlier identification and treatment of this disabling autoimmune disease. The 2013 criteria, developed by a joint committee commissioned by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR), are published in the ACR journal, Arthritis & Rheumatism.
Systemic sclerosis, also known as scleroderma, is a connective tissue disease that is characterized by sclerodermatous skin changes-a hardening of tissue due to increased collagen deposits; Raynaud’s phenomenon-spasms of small blood vessels in response to cold or stress that cause color changes in fingers or toes, to obliteration of blood vessels (vasculopathy) leading to tissue death; and internal organ fibrosis-formation of excess tissue that scars organs. The ACR estimates that systemic sclerosis affects 49,000 U.S. adults.
The joint ACR-EULAR committee was led by Dr. Janet Pope from Western University, St. Joseph’s Health Care London in Ontario, Canada, and Dr. Frank van den Hoogen from St. Maartenskliniek in The Netherlands. The committee’s intent was to improve the classification of systemic sclerosis by clustering items and simplifying the weighting of the different criteria. The new criteria set was tested for specificity and sensitivity by comparing scleroderma cases with controls (patients with disorders similar to scleroderma), and validated by experts viewing cases with and without the disease.
“There is a need for improved classification criteria for systemic sclerosis,” explains Dr. van den Hoogen. “The 1980 ACR criteria were not sensitive enough to identify patients with early disease or limited cutaneous system sclerosis. Our efforts with the joint committee addressed this sensitivity issue, resulting in the 2013 classification criteria for systemic sclerosis.”
Based on the new criteria, a patient with thickening of the skin in the middle part of the fingers (from proximal to the metacarpophalangeal joints) would be classified as having systemic sclerosis, regardless of other features. If this criterion was not met, however, then seven items with varying weights would need to be assessed in order to obtain a scleroderma classification: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, pulmonary arterial hypertension and/or interstitial lung disease, Raynaud’s phenomenon, and SSc-related antibodies.
The results of the validation testing show that sensitivity and specificity were both greater than 90% for the 2013 systemic sclerosis classification criteria compared to 75% for the 1980 ACR criteria. “The new systemic sclerosis classification criteria should correctly classify more patients with the disease,” concludes Dr. Pope. “Criteria that are more specific will allow for earlier identification and better treatment for those with systemic sclerosis.”
Scientists of the International Multiple Sclerosis Genetics Consortium (IMSGC) have identified an additional 48 genetic variants influencing the risk of developing multiple sclerosis. This work nearly doubles the number of known genetic risk factors and thereby provides additional key insights into the biology of this debilitating neurological condition. The genes implicated by the newly identified associations underline the central role played by the immune system in the development of multiple sclerosis and show substantial overlap with genes known to be involved in other autoimmune diseases.
Published online September 29 in the journal Nature Genetics, the study, “Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis,” is the largest investigation of multiple sclerosis genetics to date. Led by the University of Miami Miller School of Medicine, this study relied upon an international team of 193 investigators from 84 research groups in 13 countries and was funded by more than 40 local and national agencies and foundations.
Multiple sclerosis (MS) is a chronic disabling neurological condition that affects over 2.5 million individuals worldwide. The disease results in patchy inflammation and damage to the central nervous system that causes problems with mobility, balance, sensation and cognition depending upon where the damage to the central nervous system occurs. Neurological symptoms are often intermittent in the early stages of the disease but tend to persist and progressively worsen with the passage of time for the majority of patients. The risk of developing multiple sclerosis is increased in those who have a family history of the disease. Research studies in twins and adopted individuals have shown that this increased risk is primarily the result of genetic risk factors.
The findings released in this study nearly double the number of confirmed susceptibility loci, underline the critical role played by the immune system in the development of multiple sclerosis, and highlight the marked similarities between the genetic architecture underlying susceptibility to this and the many other autoimmune diseases.
The present study takes advantage of custom designed technology known as ImmunoChip — a high-throughput genotyping array specifically designed to interrogate a targeted set of genetic variants linked to one or more autoimmune diseases. IMSGC researchers used the ImmunoChip platform to analyze the DNA from 29,300 individuals with multiple sclerosis and 50,794 unrelated healthy controls, making this the largest genetics study ever performed for multiple sclerosis. In addition to identifying 48 new susceptibility variants, the study also confirmed and further refined a similar number of previously identified genetic associations. With these new findings, there are now 110 genetic variants associated with MS. Although each of these variants individually confers only a very small risk of developing multiple sclerosis, collectively they explain approximately 20 percent of the genetic component of the disease.
Explaining the significance of the work and the nature of the collaboration, the Miller School’s Jacob McCauley, Ph.D., who led the study on behalf of the IMSGC, said, “With the release of these new data, our ongoing effort to elucidate the genetic components of this complex disease has taken a major step forward. Describing the genetic underpinnings of any complex disease is a complicated but critical step. By further refining the genetic landscape of multiple sclerosis and identifying novel genetic associations, we are closer to being able to identify the cellular and molecular processes responsible for MS and therefore the specific biological targets for future drug treatment strategies. These results are the culmination of a thoroughly collaborative effort. A study of this size and impact is only possible because of the willingness of so many hard working researchers and thousands of patients to invest their time and energy in a shared goal.”
Using mice, lab-grown cells and clues from a related disorder, Johns Hopkins researchers have greatly increased understanding of the causes of systemic sclerosis, showing that a critical culprit is a defect in the way certain cells communicate with their structural scaffolding. They say the new insights point the way toward potentially developing drugs for the disease, which affects approximately 100,000 people in the United States.
Until now we’ve had little insight and no effective treatment strategies for systemic sclerosis, and many patients die within a year of diagnosis,” says Hal Dietz, M.D., the Victor A. McKusick Professor of Genetics and Medicine in the Johns Hopkins’ Institute of Genetic Medicine, director of the Smilow Center for Marfan Syndrome Research at Johns Hopkins and Howard Hughes Medical Institute investigator. “Our group created mouse models that allowed us to learn about the sequence of events that leads to the disease’s symptoms, and we hope drugs can be developed that target one or more of these events.” The Dietz team’s results are described in the Oct. 10 issue of Nature.
Patients with systemic sclerosis, also known as systemic scleroderma, experience a sudden hardening, or fibrosis, of the skin. For some patients, this hardening occurs only in limited areas, but for others, it quickly spreads across the body and to organs such as the heart, intestines and kidneys. It is this fibrosis of the internal organs that is often fatal.
Systemic sclerosis rarely runs in families, Dietz says, making the gene for the disease, if it exists, very difficult to find. Without a known genetic mutation, researchers had not been able to create a genetically altered mouse with which to study the condition. But Dietz’s group was struck by the similarities between systemic sclerosis and a less severe, much rarer condition called stiff skin syndrome (SSS), which does run in families, and they suspected that learning more about SSS would also shed light on systemic sclerosis.
In a previous experiment , they pinpointed the genetic mutation responsible for SSS in a gene for a protein called fibrillin-1, which plays a role in other connective tissue disorders. In certain types of tissues, including skin, fibrillin-1 helps make up the scaffolding for cells. The specific changes in fibrillin-1 seen in SSS patients were predicted to impair the ability of cells to make contact with fibrillin-1 through bridging molecules called integrins.
In the current study, M.D./Ph.D. student Elizabeth Gerber created a line of mice with a genetic variant similar to that found in SSS patients. To test the group’s hypothesis, Gerber also created a line of mice with a variant the team knew would prevent fibrillin-1 from interacting with integrin. As the team expected, both groups of mice developed patches of stiff skin, along with elevated levels of proteins and cells involved in the immune response — much like humans with SSS or systemic sclerosis. “It seemed we were right that the SSS mutation causes the condition by blocking fibrillin’s interaction with integrin,” Dietz says. “Something else we found was that both types of mice had high levels of integrin in their skin, which made us think their cells were trying to compensate for the lack of fibrillin-integrin interaction by making more and more integrin.”
This still left open the question of what was ultimately causing fibrosis, however: Was it the integrin levels or the immune response? Dietz’s group delved deeper into the question by creating mice that had both the SSS mutation and artificially low levels of integrin, and found that the mice never developed fibrosis or an abnormal immune response. “They looked normal,” Dietz says.
The team next tried waiting until mice with the SSS mutation had developed fibrosis, then treating them with a compound known to block a key molecule with known connections to both fibrosis and the immune response. This reversed the mice’s skin fibrosis and immunologic abnormalities. The team also tested the compounds on lab-grown human skin cells with systemic sclerosis, with the same results. This raises the possibility that systemic sclerosis patients could eventually be treated with similar compounds in humans, Dietz says. A number of the compounds that proved effective in SSS mice and systemic sclerosis cells are currently being explored by drug companies for the treatment of other conditions, prominently including cancer.
The results raised another big question for the team: Which of the several types of skin cells were responsible for the runaway immune response and fibrosis? They traced the activity to so-called plasmacytoid dendritic cells, or pDCs, a cell type known to either tamp down or ramp up immune response, depending on the circumstances.
“Dietz’s work gives scleroderma patients hope that we have gained fundamental insights into the process of fibrosis in scleroderma. In particular, I am confident that within a relatively short time, novel therapies can be tested in patients, and I am optimistic that such treatments will have a profound effect,” says Luke Evnin, Ph.D., chairman of the board of directors of the Scleroderma Research Foundation and a scleroderma patient.
Other authors on the study were Elizabeth E. Gerber, Elena M. Gallo, Stefani C. Fontana, Fredrick M. Wigley and David L. Huso, all of the Johns Hopkins University School of Medicine, and Elaine C. Davis of McGill University.
The study was funded by the Scleroderma Research Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers RO1-AR41135 and PO1-AR049698), the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research, and the Howard Hughes Medical Institute.
Loyola University Health System has begun a Driver Rehabilitation program that provides a comprehensive evaluation on whether a patient can safely drive a car.
The program is intended for elderly patients and patients with conditions such as stroke, brain injury, Parkinson’s disease, multiple sclerosis and low vision.
The clinical evaluation takes 1.5 hours. It includes a medical history and tests of the patient’s visual skills, perceptual skills, cognition, reaction time, physical ability and motor function.
A report will be sent to the patient’s physician and shared with the patient and family members. It will recommend whether the patient is:
Fit to drive.
Should participate in a behind-the-wheel assessment.
Is not fit to drive due to significant impairments.
At the end of testing, this delicate issue is discussed in a careful and sensitive way, helping drivers and family members understand the risks and explore other transportation options if needed.
In some cases, Driver Rehabilitation will recommend adaptations to the car to enable patients to keep driving. Patients also may benefit from follow-up treatments such as occupational therapy or vision care.
When ordered by a physician, Driver Rehabilitation usually is covered by Medicare and most insurance plans.
There is no evidence that impaired blood flow or blockage in the veins of the neck or head is involved in multiple sclerosis, says a McMaster University study.
The research, published online by PLOS ONE today, found no evidence of abnormalities in the internal jugular or vertebral veins or in the deep cerebral veins of any of 100 patients with multiple sclerosis (MS) compared with 100 people who had no history of any neurological condition.
The study contradicts a controversial theory that says that MS, a chronic, neurodegenerative and inflammatory disease of the central nervous system, is associated with abnormalities in the drainage of venous blood from the brain. In 2008 Italian researcher Paolo Zamboni said that angioplasty, a blockage clearing procedure, would help MS patients with a condition he called chronic cerebrospinal venous insufficiency (CCSVI). This caused a flood of public response in Canada and elsewhere, with many concerned individuals lobbying for support of the ‘Liberation Treatment’ to clear the veins, as advocated by Zamboni.
“This is the first Canadian study to provide compelling evidence against the involvement of CCSVI in MS,” said principal investigator Ian Rodger, a professor emeritus of medicine in the Michael G. DeGroote School of Medicine. “Our findings bring a much needed perspective to the debate surrounding venous angioplasty for MS patients.”
In the study all participants received an ultrasound of deep cerebral veins and neck veins as well as a magnetic resonance imaging (MRI) of the neck veins and brain. Each participant had both examinations performed on the same day. The McMaster research team included a radiologist and two ultrasound technicians who had trained in the Zamboni technique at the Department of Vascular Surgery of the University of Ferrara.
The research was funded by a collection of private donors including the Harrison McCain Foundation, W. Garfield Weston Foundation, Charity Intelligence and St. Joseph’s Healthcare Foundation as well as many concerned individuals.
A study led by Dr. Anthony Traboulsee of the University of British Columbia and Vancouver Coastal Health to see whether narrowing of the veins from the brain to the heart could be a cause of multiple sclerosis has found that the condition is just as prevalent in people without the disease.
The results, published in the U.K. medical journal The Lancet, call into question a controversial theory that MS is associated with a disorder proponents call chronic cerebrospinal venous insufficiency (CCSVI).
The study used both ultrasound and catheter venography (an x-ray of the vein after injecting it with a dye) to examine the veins of people with MS, their unrelated siblings and unrelated healthy volunteers. Catheter venography is considered the most accurate, “gold standard” technology for revealing the size and shape of veins, says Traboulsee, an associate professor of Neurology at UBC and director of the MS Clinic at UBC Hospital of Vancouver Coastal Health.
By comparing the width of veins between the brain and the heart with a normal reference point taken from below the jaw, the researchers showed that at least two-thirds of each of the groups had narrowing of the extracranial veins that was greater than 50 per cent. Differences in rates of venous narrowing between the groups were not statistically significant.
“Our results confirm that venous narrowing is a frequent finding in the general population, and is not a unique anatomical feature associated with multiple sclerosis,” Traboulsee says. “This is the first study to find high rates of venous narrowing in a healthy control group, as well as the first to show that the ultrasound criteria usually used to ‘diagnose’ CCSVI are unreliable. The connection between venous narrowing and MS remains unknown, and it would certainly appear to be much more complicated than current theories suggest.”
The CCSVI theory, first put forth by Dr. Paolo Zamboni of Italy in 2009, holds that narrowing of the extracranial veins between the brain and the heart leads to MS, and that angioplasty to widen those veins — sometimes called the “liberation procedure” — can be an effective treatment for some people with the disease.
The researchers examined the extracranial veins of 79 people with MS, 55 of their unaffected siblings, and 43 unrelated healthy volunteers (controls), using both ultrasound and catheter venography.
Venous narrowing was present in 74 per cent of people with MS, 66 per cent of their unaffected siblings, and 70 per cent of the unrelated controls. Catheter venography found venous narrowing to be more widespread than Zamboni’s criteria for measuring the condition with ultrasound. Ultrasound found narrowing in fewer than half of the cases that were detected by catheter venography.
In a related commentary in The Lancet, Dr. Friedemann Paul of Germany and Dr. Mike Wattjes of the Netherlands suggest that the new results sound a “death knell” for the hypothesis of CCSVI as a disease entity. “If chronic cerebrospinal venous insufficiency actually existed, the ultrasound findings of this study and previous studies would suggest that up to half of the general and otherwise healthy population should be judged to be seriously ill because of venous insufficiency of the cervical veins,” they write. “The fact that some changes in the venous system have been described in association with multiple sclerosis does not imply causality.”
Traboulsee, a member of the Brain Research Centre of UBC and Vancouver Coastal Health, is leading another pan-Canadian study focused on angioplasty, or “liberation therapy.” His team is providing both angioplasty and a sham treatment to 100 MS patients; each group will “cross over” to the other treatment after a year, so all patients will receive the angioplasty at some point. Results from the trial are expected in late 2015. “Despite the negative findings of our diagnostic study, many patients want to know if the venous dilation procedure could be beneficial,” Traboulsee says. “We are committed to evaluating this treatment with robust methods and utilizing patient-focused outcomes.”