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PubMed1999

Magnetization transfer imaging to monitor the evolution of individual multiple sclerosis lesions.

In multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) is very sensitive in detecting new lesion formation and changes of lesion sizes over time. However, it lacks specificity to the heterogeneous pathological substrates of the MS lesions. This might explain the lack of correlation between MRI findings and the development of disability in MS. Magnetization transfer (MT) imaging is promising for a more accurate monitoring of the evolution of MS. MT changes indicate a reduced capacity of the macromolecules in brain tissue to exchange magnetization with the surrounding water molecules, thus reflecting matrix disorganization. The analysis of MT changes can be performed on a regional basis, thus obtaining information about individual lesions or discrete areas of the normal-appearing white matter, or on a more global basis, using MT histograms, thus estimating the amount and severity of microscopic and macroscopic disease burden in MS. The present review will summarize the major contributions given by MT for the understanding of how individual MS lesions evolve. Monitoring individual lesion evolution may be relevant not only for the understanding of the disease pathophysiology, but also as a new approach for assessing treatment efficacy in MS.

Brain↗

PubMed2006

Serum levels of soluble CD95 are not associated with amelioration of multiple sclerosis during pregnancy.

Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system. Like various other autoimmune disorders, MS normally improves during pregnancy. Pregnant MS patients experience a significant reduction in relapse rates and magnetic resonance (MR) disease activity. How sex steroid hormones affect disease course remains unclear. We hypothesized that hormonal changes during pregnancy might modulate the autoimmune response by enhancing apoptosis of autoreactive T lymphocytes. One of the most important effectors of apoptosis in T cells is the CD95/CD95L system. We have previously reported that the soluble form of CD95 (sCD95) can block CD95-mediated apoptosis and that MS patients show elevated levels of sCD95. Therefore, we considered whether gravidity might influence serum levels of sCD95 in patients, and analyzed the concentration of sCD95 in the sera of 61 patients with relapsing-remitting (RR) MS before, during and after pregnancy. We found no association between serum levels of sCD95 and pregnancy-related immune suppression in MS patients. Thus, sex steroid hormones do not seem to affect the production of anti-apoptotic sCD95.

Analysis of Variance↗

PubMed2004

Immunologic factors in primary progressive multiple sclerosis.

Primary progressive multiple sclerosis (PPMS) is clinically characterized by progression without remission or relapse, in contrast to relapsing forms of MS. Pathologic and imaging findings also indicate that PPMS differs from relapsing forms. Recent studies examining potential immunologic differences among MS forms suggest that cytokine and adhesion molecule expression profiles, but not chemokine receptor profiles, in PPMS patients resemble those in healthy controls more than those in patients with relapsing MS. However, the significance of these findings remains to be fully elucidated, and there is little additional evidence as yet of marked differences among MS forms based on immunologic characteristics. Of interest are the recent demonstrations that activated immune cells produce brain-derived neurotrophic factor (BDNF), a neuroprotective factor, in MS lesions, that BDNF receptors are located in MS tissue, and that glatiramer acetate (GA)-specific T cells produce BDNF irrespective of T helper cell Th1 or Th2 phenotype. These findings both support the concept of a protective inflammation in MS and suggest an additional mechanism of action for the clinical effects of GA therapy in MS. Whether and to what extent this mechanism is present in different MS forms remain to be clarified.

Anti-Inflammatory Agents↗

PubMed1997

Combined effect of HLA-DRB1*1501 and interleukin-1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis.

Susceptibility to multiple sclerosis (MS) is associated with HLA-DRB1*1501. Many reports have suggested associations with other loci but these results remain unconfirmed. We studied the IL-1 receptor antagonist (IL-1ra) gene polymorphism and the HLA-DR and DQ allele frequencies by DNA-based methods in both the primary chronic progressive form (PP MS) and the relapsing/remitting form (R/R MS). The frequency of DRB1*1501 and IL-1ra allele 2 were significantly higher in R/R MS. Association was more marked in the female sex and in patients with benign forms of R/R MS. On the other hand DR4 subtypes carrying a Val at position 86 in the DR beta chain were increased in PP MS. The present study indicates that MS is genetically heterogeneous and shows a combined effect of HLA-DR and IL-1ra genes in susceptibility to the R/R form of the disease.

Alleles↗

PubMed2006

Childhood multiple sclerosis: a review.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is increasingly recognized as a disease that affects children. Similar to adult-onset MS, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. A lumbar puncture can be helpful in diagnosing MS when CSF immunoglobulins and oligoclonal bands are present. White matter demyelinating lesions on MRI are required for the diagnosis; however, children typically have fewer lesions than adults. Many criteria have been proposed to diagnose MS that have been applied to children, mostly above 10 years of age. The recent revisions to the McDonald criteria allow for earlier diagnosis, such as after a clinically isolated event. However, children are more likely than adults to have monosymptomatic illnesses. None of the approved disease-modifying therapies used in adult-onset MS have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. Although children and adults with MS have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset MS require further investigation.

Anti-Inflammatory Agents↗

PubMed2006

A model for the comprehensive investigation of a chronic autoimmune disease: the multiple sclerosis CLIMB study.

Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system (CNS) resulting in various disabilities including weakness and imbalance, visual abnormalities, changes in cognition, as well as bladder and sexual dysfunction. The majority of patients begin with a relapsing-remitting course of the disease until eventually there is a progressive decline in disability. With FDA-approved disease modifying therapy now given to the majority of MS patients early in the course of the disease, the advent of MRI imaging, as well as advances in immunology and genetics, the study of MS has entered into an exciting era. Natural history studies of untreated patients have provided a guide for disease prognosis based on the clinical features of the disease but have limited utility in this new era of MS. Major questions are unanswered, including how does treatment affect the long-term clinical course of the disease and are there major subcategories of the disease with different implications for treatment and outcome. Advances in our ability to clinically measure and monitor the disease through MRI imaging technology, immunology, and genetic analysis provide the opportunity to address these critical questions.

Biomarkers↗

PubMed1986

Cytosine arabinoside induced changes in natural killer and antibody dependent cellular cytotoxicity functions in multiple sclerosis patients.

Five multiple sclerosis patients were treated weekly with cytosine arabinoside (araC) on an escalating dose schedule. The dose was initiated at 50 mg/M2 and then increased once each week by 50 mg/M2 (unless toxicity caused delay). Dosage decisions were based on whether or not the antibody-dependent cellular-cytotoxicity (ADCC) or natural killer (NK) cytotoxicity levels had been reduced to a level more than 2 standard deviations below the control range. Cytosine arabinoside treatment was discontinued in 2 of 5 subjects at doses of 500 mg/M2 due to toxicity. The 3 remaining patients demonstrated sustained reductions in the percentage of FcR+ cells in their peripheral blood. The maximum percentage reductions from the baseline values ranged from 50% to 76%. Concomitant reductions in the NK activity at the same doses ranged from 65% to 83%. ADCC activity in all 3 patients, however, was relatively resistant to suppression. The nadirs for the ADCC activity were only 16% to 44% below the baseline minimum. AraC was shown to reduce the proportion of FcR+ cells and NK cytotoxic activity in preference to ADCC activity.

Antibody-Dependent Cell Cytotoxicity↗

PubMedDate not supplied

Central auditory tests and auditory nerve-brainstem evoked responses in multiple sclerosis.

In 43 multiple sclerosis (MS) patients and an equal number of age- and sex-matched normal controls, auditory nerve-brainstem evoked responses (ABR), audiometric tests, central auditory tests (CAT) and clinical-neurological examinations were conducted. The CAT included rapid alternating speech perception, masking level differences to tones and to words and lateralization based on interaural time and intensity differences. The results in the MS group on the ABR and each of the CAT differed significantly from those in the control group. The ABR results and the lateralization test results were each abnormal in 50% of the MS patients. The ABR, CAT and clinical examination results were all mutually correlated. These findings are probably related to the fact that the demyelination in MS induces a decrease in impulse velocity, to temporal dispersion and to desynchrony of impulses in groups of affected axons and to the fact that the ABR and the CAT tests chosen are dependent on synchronous impulse firing and on the precise timing of the arrival of impulses from each ear at some brain centre. These tests may therefore contribute to neurological and to audiological diagnosis.

Adolescent↗

PubMed2003

Multiple sclerosis in children.

Multiple sclerosis (MS) is traditionally the domain of adult neurologists due to its characteristic presentation during early adult life. Although descriptions of infants with MS appeared in the beginning of the last century and the first autopsy was described even earlier, it was not until 1980 that childhood onset MS was recognized and subsequently well characterized. In spite of this, the awareness of pediatricians and pediatric neurologists to the occurrence of MS especially in infants and young children is still unsatisfactory. It is not infrequent that a meticulous, time consuming and costly search for metabolic and degenerative disorders other that MS is initiated before the diagnosis of MS is considered. This leads to a significant diagnostic and therapeutic delay in many young patients. Moreover, when the presentation is acute and characterized by confusion, seizures, CSF pleocytosis following a viral infection, a diagnosis of meningoencephalitis will be frequently reached. In this review, updated data on frequency, epidemiology, some special clinical and radiological features of childhood onset MS, outcome and treatment will be briefly discussed with the purpose of alerting physicians to the possibility of the occurrence of MS even in infants and young children.

Adolescent↗

PubMed2003

[Diagnosis and treatment of multiple sclerosis. Update, 2003].

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. The etiology of MS is not yet fully understood. Besides of genetic predisposition and environmental factors autoimmune mechanisms seem to play a major role in the pathogenesis of MS. Therapy of MS therefore comprises mainly immunomodulatory and immuno-suppressive therapeutic concepts. Interferon beta (Avonex, Rebif, Betaferon/Betaseron) and Glatirameracetate (Copaxone) offer effective therapeutic options for the long-term treatment of relapsing-remitting MS. With Mitoxantron (Ralenova) being recently approved by the EMEA for the treatment of secondary-progressive and progressive-relapsing MS an effective therapeutic option is now available also for this group of patients. The standard treatment for acute MS continues to be the intravenous administration of high-dose methylprednisolone. Several promising new agents (Antegren, Statins) are currently under clinical examination and could expand the spectrum of available therapeutic strategies soon. Recent and ongoing trials as well as upcoming studies on MS therapy are summarized in this review.

Acute Disease↗

PubMedDate not supplied

Adherence to disease-modifying therapy in multiple sclerosis: Part II.

Multiple sclerosis (MS) is a chronic, debilitating disease for which there is no cure; however, the recent introduction of injectable immunomodulating agents has reduced the rate of relapsing episodes and possibly slowed the progression of the disease. These disease-modifying agents are recommended by the National MS Society, but their true potential cannot be realized if patients do not accept them and healthcare professionals do not promote them. Since MS has an unpredictable course, and treatments can produce side effects, adherence to the recommended therapy is a complex and challenging issue. Improved understanding of the obstacles to adherence and the identification of possible solutions should be of value to nurses, who have numerous opportunities to encourage patients to initiate and continue therapy. Part I of this article, published in the September/October 2001 issue of Rehabilitation Nursing, described the particular problems of treatment adherence in MS. Part II proposes that the transtheoretical model of behavior change can be a useful tool in achieving both patient acceptance and treatment goals. This model is founded upon the concept that readiness for change is crucial, and that attempts at intervention should be sensitive to the patients' changing conditions and states of mind.

Humans↗

PubMed2006

PECAM-1 and gelatinase B coexist in vascular cuffs of multiple sclerosis lesions.

In multiple sclerosis (MS), the matrix metalloprotease (MMP) gelatinase B/MMP-9 and platelet endothelial cell adhesion molecule (PECAM)-1 have both been implicated in trans-endothelial infiltration of leucocytes into the brain, but their functional connection has not yet been investigated. We investigated the expression of gelatinase B and PECAM-1 in post mortem brains of MS patients by immunohistochemistry. Because increased soluble PECAM-1 serum levels have been observed in MS patients, we also tested in vitro whether this could be due to cleavage of PECAM-1 by gelatinase B or matrilysin-1/MMP-7. Constitutive expression of PECAM-1 was found on brain endothelial cells, whilst in active MS lesions cell-bound PECAM-1 was highly up-regulated on foamy macrophages in perivascular infiltrates and co-localized with gelatinase B. However, human THP-1 monocyte-bound or soluble recombinant PECAM-1 were both resistant to proteolytic cleavage by gelatinase B or matrilysin-1 in vitro, as demonstrated by Western blot analysis and flow cytometry. These results suggest that PECAM-1 and gelatinase B may complement each other during the transmigration of the blood-brain barrier by mononuclear cells.

Blotting, Western↗

PubMed2004

Effect of drugs in secondary disease progression in patients with multiple sclerosis.

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN beta) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN beta-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN beta-1a) in MS (SPECTRIMS), the North American Study of IFN beta-1b in SPMS (NASPMS), and the International MS Secondary Progressive Avonex Clinical Trial (IMPACT). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN beta has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly i.v. Ig were disappointing, positive effects on disease progression have been reported with the application of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

Adjuvants, Immunologic↗

PubMed2004

Effect of gender on T-cell proliferative responses to myelin proteolipid protein antigens in patients with multiple sclerosis and controls.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women.

Amino Acid Sequence↗

PubMed2006

Gait variability in people with multiple sclerosis.

Patients with multiple sclerosis (MS) present with varying symptoms that can differ between and within individuals. As new interventions and drug treatments become available to MS patients, it is essential to understand the relationship between fatigue and the variability of functional mobility measures in order to define a meaningful change due to treatment within the MS population. The purpose of this study was to examine the within-day and between-day changes in gait variability for subjects with MS in fresh and fatigued conditions. Walking gait parameters were measured from 20 subjects diagnosed with MS and eight healthy control subjects. Standard deviations of hip, knee and ankle kinematic and kinetic variables were quantified as the measure of variability and analysed with a two-way (group by condition) ANOVA. Results indicated MS subjects had significantly greater hip (P <0.020), knee (P <0.011) and ankle (P <0.034) joint angle variability than control subjects, but variability was not different between conditions. Kinetic variability was not different between groups or conditions. MS subjects in this study walked more slowly than the healthy controls and they also reported more fatigue. Research examining treatment effects within the MS population should account for increased levels of kinematic gait variability.

Adult↗

PubMed2005

Short communication: impairment of membrane markers on peripheral blood mononuclear cells and imbalance of cytokine secretion in the pathogenesis of multiple sclerosis active phases.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In active disease, a transmigration of autoreactive T cells to myelin antigens recruited from the peripheral blood (PBMC) to the CNS occurs, and there these cells prolong their survival and contribute to the perpetuation of the inflammation. In the active local lesions of MS patients, these cells display activation and apoptosis surface markers and secrete a range of cytokines. The aim of this research is to study on PBMCs and in the serum of stable and active MS subjects (1) the behavior of the CD40/CD40L system and the consequent balance of Th1 and Th2 cytokines and (2) the apoptosis marker system CD95/CD95L and tumor necrosis factor (TNF)- binding receptors, TNFRI and TNFRII. A possible excess of activation marker expression affecting and driving Th1 cytokine production or a parallel impairment of apoptosis may contribute to MS relapses. Our results may indicate that a dysregulation of early activation and apoptosis receptor systems and a profound and complex imbalance of cytokine production occurred in the peripheral blood of MS patients. This impairment could account for active phases of the disease.

Adult↗

PubMedDate not supplied

[Genetic epidemiology of multiple sclerosis].

INTRODUCTION: Although multiple sclerosis (EM) has the characteristics of a disorder which is complex to study epidemiologically, many papers have been published on its genetic epidemiology, and these have given a great deal of information regarding the aetiological factors of the disorder. METHOD: These epidemiological investigations have also studied the incidence and prevalence of EM in each zone, the different geographical distribution, its variation with immigration, relation to race and sex, the existence of possible epidemics or groups and its family aggregation. They have supported the environmental aetiological factor of EM, the geographical gradient of the frequency, possible epidemics or groups, changes with migrations and concordance in identical twins of less than 100%. However, arguments in favour of a genetic aetiological factor have been supported by racial differences in the frequency of this disorder, the existence of resistant ethnic groups in spite of the migrations and the increased concordance in monozygotic twins. CONCLUSION: The results of studies on the genetic epidemiology of EM support the multifactorial nature of its aetiology, with a polygenic type of genetic susceptibility, although this alone does not justify the development of EM. Some environmental factor, as yet unknown, is necessary for the disease to develop in a genetically susceptible person. Molecular genetic studies are adding further knowledge about this genetic susceptibility, although the genes involved have not yet been conclusively identified because of the complexity of EM.

Humans↗

PubMed1991

Immunoglobulin producing cells in bone marrow and blood of patients with multiple sclerosis and controls.

Multiple sclerosis (MS) is characterised by intrathecal synthesis of IgG, less frequently of IgA and IgM. Local production of antibodies to myelin basic protein (MBP) and other myelin components has also been reported, and autoimmune pathogenesis has been postulated. Whether MS is accompanied by a systemic B cell response is less clear. To elucidate this question, we examined bone marrow and peripheral blood from patients with MS and controls for cells secreting IgG, IgA and IgM, as well as anti-MBP antibodies of these three isotypes. Patients with MS without any signs of concurrent infections had higher numbers of IgG + IgA + IgM secreting cells both in bone marrow and peripheral blood compared with healthy controls. The same abnormalities were observed in patients with other inflammatory neurological diseases (OIND). When analysing individual isotypes, patients with MS and OIND had higher numbers of IgA secreting cells both in bone marrow and blood compared with healthy controls. Only one of 13 MS patients examined had anti-MBP antibody secreting cells in bone marrow and blood. The systemic B cell response registered in MS is also present in other inflammatory neurological diseases and its specificity and possible role in the pathogenesis of MS remains unknown.

Adult↗