Research Updates
ROLE OF HEALTH-RELATED QUALITY OF LIFE MEASURES IN THE ROUTINE CARE OF PEOPLE WITH MULTIPLE SCLEROSISH
Solari A. Health Qual Life Outcomes. 2005 (Mar. 18;3(1):16)
Health-related quality of life instruments are expected to be of particular value in routine care of people with multiple sclerosis (MS), where they may facilitate the detection of disease aspects that would otherwise go unrecognized, help clinicians appreciate patient priorities particularly in terms of treatment goals, facilitate physician-patient communication, and promote shared decision-making. However, it appears that these instruments are little used routine clinical approaches to people with MS. To address this issue, I performed a bibliographic search of studies that evaluated the efficacy of generic or disease-specific health-related quality of life (HRQOL) instruments in MS clinical practice from clinicians' or patients' perspectives. I found only one cross-sectional study, which compared preferences for three instruments, and assessed acceptability in people with MS. Reasons for lack of transfer of HRQOL measurements to clinical practice may be cultural, methodological, or practical. With regard to MS, the proliferation of instruments seems to constitute a barrier, with no particular instrument having gained wide popularity or consensus. Other barriers are lack of resources for the administration, collection, and storage of the data, and inability of clinicians to score, interpret, and use HRQOL instruments to guide clinical care. It is therefore important to refine existing tools, extending clinical validation to wider contexts and cultures. More studies assessing acceptability and clinicians' and patients' preferences for different instruments are also required.
MS TRIAL ALERT: LIPITOR STUDY ENROLLING PATIENTS AT HIGH RISK FOR MS
Nat. M.S. Soc. (March 25, 2005)
Summary: Investigators at the University of California, San Francisco Multiple Sclerosis Center and at 13 other centers in North America are conducting a clinical trial evaluating the people at high risk for developing MS. Scott Zamvil, MD, PhD, and Emmanuelle Waubant, MD, PhD, of UCSF, are leading this effort. The study is supported by the Immune Tolerance Network, a research consortium funded by the NIH's National Institute of Allergy and Infectious Diseases.
Rationale: Previous studies have suggested that cholesterol-lowering "statins" can alter immune responses in a way that may hold promise in treating MS. Drs. Zamvil and Sawsan Youssef (Stanford University) and others reported that Lipitor prevented or reversed the MS-like disease EAE in mice (Nature, November 7, 2002). In addition, a small open-label pilot study by Timothy Vollmer, MD, and colleagues in 28 people with relapsing-remitting MS found that the cholesterol-lowering pill Zocor (simvastatin) safely reduced the number of new lesions (Lancet, May 15, 2004). The mechanism underlying the drug's possible promise appears to be immune system modulation, rather than a cholesterol-lowering mechanism.
Eligibility and Details: People eligible for participation include individuals 18-50 years of age with no previous neurological history, who experience a clinically isolated syndrome (CIS, a single demyelinating event, for example, an attack of optic neuritis in one eye, or an episode of numbness on one side) lasting at least 48 hours and magnetic resonance imaging findings suggestive of MS. Patients must receive a three-day course of intravenous steroids starting within fourteen days of onset of a CIS and must be enrolled within 48 days of onset of a CIS.
Participants will be randomly assigned to receive either Lipitor (80 mg/day) or placebo; 91 people will receive the treatment, and 61 will receive placebo for a treatment phase of 12 months. At the end of the treatment phase, all participants will be followed for an additional 6 months. If individual participants experience a clinical attack (exacerbation) or show significant MRI changes, they will be offered Avonex (interferon beta-1a), a standard treatment for MS, for the remainder of the enrollment. Participants will undergo careful neurological and MRI monitoring to detect disease activity as early as possible.
The primary objective of the study is to evaluate the effects of Lipitor to decrease or delay clinical and MRI disease activity. Secondary objectives are to determine if Lipitor is safe in patients with CIS, to determine which immune system cells or molecules are modified by Lipitor, to evaluate the effects of Lipitor on brain tissue loss, and to determine potential residual benefits after the discontinuation of therapy.
Contact: A list of sites follows. Those that are enrolling patients as of this writing include contact information. Future updates will be available in the "Trials Recruiting Patients" section of the National MS Society Web site, at:
http://www.nationalmssociety.org/Research-trialsrecruiting.asp
1. University of California, San Francisco, San Francisco, CA. Contact: Amanda Graff-Baker, 415-514-3815.
2. Yale MS Center, New Haven, CT
3. MS Center of Oregon Health & Science University, Portland, OR
4. Barrow Neurological Institute, Phoenix, AZ. Contact: Carrie Jones, CCRP, 602-406-6211
5. The University of Texas Southwestern Medical Center at Dallas, TX.
6. Virginia Mason MS Center, Seattle, WA. Contact: Dawn-Rene Becker, RN, CCRC, 206-223-6835, ext. 61814
7. Keck School of Medicine, University of Southern California, Los Angeles, CA
8. The Cleveland Clinic Foundation, Cleveland, OH. Contact: Parianne Fatica, 216-445-9419.
9. Washington University Multiple Sclerosis Center, St. Louis, MO.
10. Corrine Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, New York, NY.
11. Jacobs Neurological Institute, Buffalo, NY.
12. University of Rochester, Rochester, NY. Contact: Eileen Scheid, 585-275-6673.
13. Johns Hopkins Hospital, Baltimore, MD.
14. Montreal Neurological Institute, Montreal, Quebec, Canada.
THERAPEUTIC STRATEGIES TO PREVENT NEURODEGENERATION AND PROMOTE REGENERATION IN MULTIPLE SCLEROSIS
Chitnis T, Imitola J, Khoury SJ.(Source: Nat. Lib. of Med. 2005 Mar;5(1):11-26)
Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair or CNS components in multiple sclerosis.
MULTIPLE SCLEROSIS AND NUTRITION
Stefan Schwarz; Hans Leweling Source: Multiple Sclerosis, Feb. 2005, Vol 11, No. 1, pp. 24-32
Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however frequently stated that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a possible effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.
INFLAMMATION STIMULATES REMYELINATION IN AREAS OF CHRONIC DEMYELINATION
Foole A.K., Blakeman, W.F., Brain, 2005 Mar., 128/181,34,J Neurol Sci 2005 Feb 15;228(2):161-6.
A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demylenation, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligidodendrocyte progenitor cells (OPCs) are present. Our experiments show that i) transplanted OPCs will not population OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination-closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulation areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to regenerate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.
MOLECULES AFFECTING MYELIN STABILITY: A NOVEL HYPOTHESIS REGARDING THE PATHOGENESIS OF MULTIPLE SCLEROSIS
Mastronardi FG, Moscarello MA(Source: J Neurosci Res 2005 Feb 9)
Structural Biochemistry and Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
In this Mini-Review, we present a new hypothesis in support of the neurodegenerative theory as a mechanism for the pathogenesis of multiple sclerosis (MS). The pathogenesis of MS results from changes in two distinct CNS compartments. These are the "myelin" and "nonmyelin" compartments. The myelin compartment is where primary demyelination, amidst attempts at remyelination, is superseded in the CNS by ongoing disease. Recent evidence obtained via magnetic resonance imaging and spectroscopy techniques supports the view that the normal-appearing white matter (NAWM) in the MS brain is altered. Several biochemical changes in NAWM have been determined. These include the cationicity of myelin basic protein (MBP) as a result of the action of peptidyl argininedeiminase (PAD) activity converting arginyl residues to citrulline. The accompanying loss of positive charge makes myelin susceptible to vesiculation and MBP more susceptible to proteolytic activity. An increase of MBP autocatalysis in the MS brain might also contribute to the generation of immunodominant epitopes. Accompanying the destruction of myelin in the myelin compartment is the activation of astrocytes and microglia. These contribute to the inflammatory response and T-cell activation leading to autoimmunity. The complex environment that exists in the demyelinating brain also affects the "nonmyelin" compartment. The inappropriate un-regulation of molecules, including those of the Jagged-1-Notch-1 signal transduction pathway, affects oligodendrocyte precursor cell (OPC) differentiation. Other effectors of oligodendrocyte maturation include stathmin, a microtubule-destabilizing protein, which prevents healing in the demyelinating brain. The hypothesis we present suggests a therapeutic strategy that should 1) target the effectors within the myelin compartment and 2) enable resident OPC maturation in the nonmyelin compartment, allowing for effective repair of myelin loss. The next effect of this new therapeutic strategy is the modification of the disease environment and the stimulation of the health and repair. (c) 2005 Wiley-Liss, Inc.
TREATING LEARNING IMPAIRMENTS IMPROVES MEMORY PERFORMANCE IN MULTIPLE SCLEROSIS: A RANDOMIZED CLINICAL TRIAL
M.S. Vol. II, Issue 1 (Feb. 2005)
In this clinical trial of 29 patients with MS and learning difficulties, participants were randomized to eight sessions of the Story Memory Technique (experimental group) or eight sessions of memory exercises (control group). Assessment was completed at baseline, immediately after and 5 weeks after intervention.
WHAT EVERYONE WITH MS SHOULD KNOW ABOUT FATIGUE
Health and Wellness (MS Pathways, V1 #3)
Everybody goes through times when they feel tired and run-down. But for people living with MS, chronic, persistent fatigue is something they must deal with every day. It is one of the most common symptoms of MS; indeed, between 75% and 95% of people with MS suffer from fatigue, with as many as 50% to 60% reporting that it is the biggest problem they face in the day-to-day management of MS.
Fatigue can be related to the progression of MS. As the condition progresses, everyday activities can begin to require more energy. More often, however, a feeling of tiredness or lethargy may be wholly unrelated to the symptoms of MS. Trouble falling asleep and getting a good night's rest can deplete energy levels even further, making people feel tired during the day. Depression and stress can also impose a heavy burden upon people with MS. Fatigue can even be the result of something as simple as trying to do too many things during the course of a daily routine.
Fortunately, there are many ways that people with MS can overcome fatigue. Getting enough sleep at night can help boost energy levels during the day. Physical therapy and regular exercise can also help to restore some lost energy. In addition, there are several different medications your doctor may prescribe to help reduce the symptoms of depression common among people with MS.
Fatigue can be a difficult challenge for people with MS to overcome. But they can face that challenge by knowing their limits and by implementing some basic lifestyle changes. This can help them to gain control over their fatigue before it controls them.
HIGH INCIDENCE OF SPONTANEOUS DISEASE IN AN HLA-DR15 AND TCR TRANSGENIC MULTIPLE SCLEROSIS MODEL
J Immunol. 2005 Feb 15;174(4):1938-46.
This study seeks to characterize the role of determinant spread of T cell reactivity in MS and define the epitopes involved using a humanized transgenic mouse model. Mice strongly expressing HLA-DR15 with an MS-derived TCR even on a RAG-2 wild-type background, spontaneously develop paralysis. Disease correlates with spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. This work will develop understanding about Tcell responses in MS and provide a test bed for immunotherapies. There was a significant self-reported memory improvement in patients with MS and moderate-severe learning impairment in the experimental group compared to controls. However, in those with mild learning impairment in the experimental group, there was little improvement compared to controls.
A POSSIBLE SPATIAL AND TEMPORAL CLUSTER OF MULTIPLE-SCLEROSIS IN THE TOWN OF LINGUAGLOSSA, CICILY.
Nicoletti A, Lo Fermo S, Reggio E, Tarantello R, Liberto A, Le Pira F, Patta F, Reggio A.
Dept. of Neuroscience, Univ. of Catania, Catania, Italy
Source: J Neurol. 2005 Mar 24
We carried out an epidemiological survey to determine prevalence and incidence of multiple sclerosis in the little town of Linguaglossa in the Province of Catania. We calculated prevalence rate as point prevalence at 1 January 2001 and incidence during 1991-2000. We studied the frequency of multiple sclerosis in the community of Linguaglossa in a population of 5,422 inhabitants in the 2001 census. The primary sources for the case ascertainment were the general practitioners of Linguaglossa, the local Italian Multiple Sclerosis Association and the neurological departments, Multiple Sclerosis Centers and private neurologists of the province of Catania. We considered as prevalent and incident cases all patients who satisfied the Poser's diagnostic criteria. We detected 11 patients with multiple sclerosis who had had the onset of disease on prevalent day (P.D.). The onset-adjusted prevalence rate was 203/100,000 (95% CI 107-352). Prevalence was higher in women (247/100,000) than in men (154/100,000). From 1991 to 2000, 10 subjects with MS had clinical onset of disease. The mean annual incidence risk was 18.2/100,000 (C.I. 95% 5.9-42.5). Conversely in the same population prevalence on 1 January 1991 was 37/100,000 while the onset adjusted annual incidence risk during the previous decade (1981-1991) was 3.6/100,000. Prevalence and incidence rates of MS during the last decade in the little town of Linguaglossa are higher than those found in the same area during the previous ten years ands also those reported in other Sicilian and Italian surveys suggesting a possible cluster of MS.
IS OPTIC NEURITIS MORE BENIGN THAN OTHER FIRST ATTACKS IN MULTIPLE SCLEROSIS?
Ann. Neurol. 2005 Feb;57(2):210-5.
This prospective study on 320 patients looks at whether optic neuritis has a better prognosis than other clinically isolated syndromes (CISs). Optic neuritis patients had lower rates of conversion to clinically definite multiple sclerosis and a smaller proportion of patients fulfilling MRI dissemination in space, time, or both. Nevertheless, when only patients with abnormal cranial MRI results at baseline were selected, no differences for clinical or MRI conversion were found. MRI at baseline, not CIS topography, appears to be the crucial issue at multiple sclerosis presentation
SUBJECTIVE COGNITIVE COMPLAINTS RELATE TO MILD IMPAIRMENT OF COGNITION IN MULTIPLE SCLEROSIS
Ruth Ann Marrie; Gordon J. Chelune; Deborah M. Miller; Jeffrey A. Cohen
Multiple Sclerosis, V. 11, Issue 1, Feb. 2005
The lack of correlation between cognitive and physical impairment in MS can be misleading, and symptoms may be erroneously attribute to depression. In this study, a number of neuropsychological tools were applied to measure cognitive impairment subjectively and objectively, adjusted for mood. There were subtle declines in Processing Speed Index (PSI) and Immediate Memory in patients reporting subjective impairment, and patients with normal or severely reduced PSI were far less likely to report. The authors therefore suggest that cognitive complaints should be pursued and should not be assumed to be mood-related.
INTRATHECAL ANTIBODY (IgG) PRODUCTION AGAINST HUMAN HERPESVIRUS TYPE 6 OCCURS IN ABOUT 20% OF MULTIPLE SCLEROSIS PATIENTS AND MIGHT BE LINKED TO A POLYSPECIFIC b-CELL RESPONSE
Derfuss T., Hohlfeld, R., Meinl E., J. Neurol. 2005 Mar 21.
Human herpesvirus 6 (HHV-6) is one of the many infectious agents that have been implicated in the pathogenesis of multiple sclerosis (MS). Intrathecal immunoglobulin (Ig) production with oligoclonal CSF bands are hallmarks of both MS and infections of the CNS. In neuroinfections, the intrathecal Ig production is directed largely against the respective agent, while MS patients mount an intrathecal Ig production against different pathogens. In this study,. a total of 77 serum/CSF pairs were first analyzed for an intrathecal immune response against HHV-6. We found that 21% of the MS patients, but none of the control donors, showed an intrathecal immunoglobulin (Ig) response against HHV-6 (p=0.017). Patients with such an intrathecal Ig production had a significantly higher total amount of Ig (p = 0.007) and a higher cell number of the CSF (p = 0.03). In a second step, four of the MS-patients who showed a strong intrachecal Ig production against HHV-6 were examined for immune reactivity against other viruses (human herbesvirus type 1, measles virus, human cytomegalovirus, rubella virus, varicella zoster virus). All of these patients had an intreathecal Ig production against at least one other, unrelated virus. Together our findings strongly argue that in the majority of MS patients without an intrathecal Ig response to HHV-g (about 80% in our study), this virus is not involved in the pathogenesis. In the other 20% the intrathecal Ig production to HHV-56 might reflect reactivation of HHV-6 or could be part of a polyspecific B cell activation.
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