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PubMed2001

The effect of corticosteroids on serum and cerebrospinal fluid nitric oxide levels in multiple sclerosis.

Multiple sclerosis is a disease characterized by perivascular infiltrates and demyelination of the white matter in the central nervous system. In this study, we compared the serum and cerebrospinal fluid nitric oxide levels before and after methylprednisolone therapy, and during remission period, and investigated the relationship of nitric oxide to the activity of multiple sclerosis. Cerebrospinal fluid and serum nitric oxide levels were measured blind as nitrite plus nitrate, using the nitrate reductase and Griess reaction method in 20 patients with multiple sclerosis before and after corticosteroid therapy, and during remission period, and in 20 control subjects. Mean cerebrospinal fluid and serum nitric oxide levels were highest in the pretreatment group and lowest in the control group. There was no correlation with nitric oxide levels in these two groups. Although corticosteroid therapy did not have any great effect on Expanded Disability Status Scales, it led to a decrease in nitric oxide levels. The possible cause of this might be the inhibition of nitric oxide synthesis by methylprednisolone, or a decrease in multiple sclerosis activity. We conclude that serum or cerebrospinal fluid nitric oxide levels do not reflect the activity in multiple sclerosis.

Adolescent↗
PubMed2004

Disease-modifying drugs for the early treatment of multiple sclerosis.

The introduction of new immunomodulatory therapies such as, interferon-beta, glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) and mitoxantrone (Ralenova, Wyeth Pharma; Novantrone, Immunex Corp.) has considerably improved the therapeutic options for patients with multiple sclerosis. These agents have been shown to reduce relapse rate, slow down progression of disability and prevent the accumulation of magnetic resonance imaging lesion load in clinically definite multiple sclerosis. Moreover, two formulations of interferon-beta delayed conversion into clinically definite multiple sclerosis in patients with clinically isolated syndromes suggestive of multiple sclerosis. Since axonal damage leading to irreversible neurological disability is already present early at the onset of the disease, immunomodulatory therapy should start as soon as possible. This article reviews the arguments for the early initiation of therapy and provides an overview of clinical studies dealing with the early treatment of multiple sclerosis.

Adjuvants, Immunologic↗
PubMed2005

Interferon-beta1b for multiple sclerosis.

Interferon-beta1b (Betaseron/Betaferon) was the first approved therapy for relapsing-remitting multiple sclerosis. The US Food and Drug Administration has expanded the indication to include relapsing forms of multiple sclerosis which encompasses secondary-progressive multiple sclerosis if relapses are present. In one scientifically sound head-to-head comparison (Independent Comparison of Interferon trial), interferon-beta1b was shown to be clinically superior to low-dose interferon-beta1a (Avonex). Current studies are underway to compare it with a double dosage of interferon-beta1b [corrected] as well as glatiramer acetate. Neutralizing antibodies are more likely to occur with interferon-beta1b, but their clinical significance has shown conflicting and confusing results making the utility of measuring neutralizing antibodies uncertain. Up to 12 years of follow-up data suggest that the drug remains effective on T2 magnetic resonance imaging burden of disease in those who stay on therapy. Initially, the major problem with interferon-beta1b was a lack of tolerability due to high incidents of skin reactions and influenza-like side effects. Patient adherence has improved dramatically with the introduction of autoinjectors and protocol changes including initial dose escalation, prophylactic ibuprofen or acetaminophen, evening administration of drug and an attentive nurse support system. Interferon-beta1b remains a first-line treatment for relapsing-remitting multiple sclerosis and relapsing forms of secondary-progressive multiple sclerosis based on robust efficacy data and a long-term safety profile.

Adjuvants, Immunologic↗
PubMed2005

Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis.

Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-beta, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Humans↗
PubMed2006

Glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis.

Glucocorticoids exert a variety of immunomodulatory activities. Since changes in glucocorticoid homeostasis impact on susceptibility to autoimmune diseases, and synthetic glucocorticoids are widely used in the treatment of multiple sclerosis, a detailed understanding of their mechanism of action is desirable. Experimental autoimmune encephalomyelitis is a common animal model that mirrors many hallmarks of multiple sclerosis, a chronic inflammatory disease of the CNS with presumed autoimmune origin. Experimental autoimmune encephalomyelitis has been instrumental for many years in studying multiple sclerosis, revealing the blood-brain barrier, the microglia and T-cell apoptosis as major targets of glucocorticoids in this disease. Despite the great advances in the field, the answers to many questions concerning the mechanism of glucocorticoids; for example, the contribution of nongenomic effects or the cell-type specificity of their action, remain elusive. This review will critically discuss what we have learned so far from the analysis of animal models of the molecular mode of therapeutic and endogenous glucocorticoid action in multiple sclerosis. With this knowledge in mind, we should be able to further improve the management of multiple sclerosis using this class of drugs.

Animals↗
PubMed1995

Multiple sclerosis therapy. A practical guide.

A growing amount of evidence suggests that a disturbance of immunological function is of importance in the pathogenesis of multiple sclerosis. This is reflected in the drugs used to slow progression and to treat relapses. Immunosuppressive drugs such as azathioprine, cyclophosphamide and cyclosporin might have some potential to slow down progression of multiple sclerosis, but their use is limited by potentially serious adverse effects. Recently, it was shown that interferon-beta-1b can diminish the exacerbation rate in multiple sclerosis without leading to unacceptable adverse effects. Nevertheless, symptomatic treatment remains of crucial importance in the management of multiple sclerosis patients. Spasticity, depression, fatigue and urinary, paroxysmal and sensory symptoms can all be alleviated to some extent with pharmacological interventions, although rehabilitation procedures and psychosocial consultations are no less important. Further therapeutic approaches to multiple sclerosis will be directed at either the specificity of the immune response or the grade of activation of the immune response. Magnetic resonance imaging techniques will play an important role in the evaluation of efficacy of new therapeutic agents.

Adjuvants, Immunologic↗
PubMed2005

From cannabis to endocannabinoids in multiple sclerosis: a paradigm of central nervous system autoimmune diseases.

An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of multiple sclerosis, including spasticity and pain. Endogenous molecules with cannabinoid-like activity, such as the "endocannabinoids", have been shown to mimic the anti-inflammatory properties of cannabinoids through the cannabinoid receptors. Several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis. Indeed, they can down regulate the production of pathogenic T helper 1-associated cytokines enhancing the production of T helper 2-associated protective cytokines. A shift towards T helper 2 has been associated with therapeutic benefit in multiple sclerosis. In addition, cannabinoids exert a neuromodulatory effect on neurotransmitters and hormones involved in the neurodegenerative phase of the disease. In vivo studies using mice with experimental allergic encephalomyelitis, an animal model of multiple sclerosis, suggest that the increase of the circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects could open new strategies for the treatment of multiple sclerosis.

Animals↗
PubMed1992

Relapsing-remitting multiple sclerosis: sequential enhanced MR imaging vs clinical findings in determining disease activity.

OBJECTIVE: Sequential MR imaging frequently shows disease activity (clinically silent new brain lesions) in subgroups of patients with multiple sclerosis and therefore is valuable in monitoring the effects of treatment. Monitoring of disease activity in patients being treated for relapsing-remitting multiple sclerosis will increase in importance as new and safe therapies are developed. We studied sequential enhanced MR images of patients with early relapsing-remitting multiple sclerosis to define the MR features that indicate disease activity in this subgroup of patients and to compare MR imaging and clinical findings for this purpose. SUBJECTS AND METHODS: Seven patients with relapsing-remitting definite multiple sclerosis were examined monthly for 4-12 months. For each image, a standard repositioning protocol consisting of three images was used to ensure reproducibility of axial (double oblique) image planes, planned according to internal landmarks. A total of 58 unenhanced T2-weighted and enhanced T1-weighted MR images were obtained. RESULTS: MR images showed new enhancing lesions in six of the seven patients. On 25 (43%) of the 58 enhanced T1-weighted MR images, a total of 50 new enhancing lesions were observed, and on one image a reenhancing lesion was seen. The unenhanced T2-weighted images showed corresponding abnormalities for 92% of the new enhancing lesions. At follow-up, most lesions (86%) were enhanced on only one occasion: 4% were enhanced on more than two consecutive monthly MR examinations. Forty-nine percent of the lesions seen on T2-weighted images "disappeared" (beyond the resolution of the imaging system) after a mean follow-up of 3.5 months, especially lesions that were initially smaller than 5 mm. During the study, only five clinical relapses occurred in three patients (all at times when MR images showed contrast-enhancing lesions), and fixed disability did not increase. On 21 additional occasions, MR images showed new enhancing or reenhancing lesions in patients who were clinically stable at the time (4.2 times more clinically silent disease activity). CONCLUSION: Our results suggest that contrast-enhanced MR imaging is more sensitive than clinical monitoring for detecting new disease activity in patients with relapsing-remitting multiple sclerosis and that MR imaging might be useful in the evaluation of therapeutic regimens.

Adult↗
PubMed2007

Use of International Classification of Functioning, Disability and Health (ICF) to describe patient-reported disability in multiple sclerosis and identification of relevant environmental factors.

OBJECTIVE: To use the International Classification of Functioning, Disability and Health (ICF) to describe patient-reported disability in multiple sclerosis and identify relevant environmental factors. METHODS: Cross-sectional survey of 101 participants in the community. Their multiple sclerosis-related problems were linked with ICF categories (second level) using a checklist, consensus between health professionals and the "linking rules". The impact of multiple sclerosis on health areas corresponding to 48 ICF categories was also assessed. RESULTS: A total of 170 ICF categories were identified (mean age 49 years, 72 were female). Average number of problems reported was 18. The categories include 48 (42%) for body function, 16 (34%) body structure, 68 (58%) activities and participation and 38 (51%) for environmental factors. Extreme impact in health areas corresponding to ICF categories for activities and participation were reported for mobility, work, everyday home activities, community and social activities. While those for the environmental factors (barriers) included products for mobility, attitudes of extended family, restriction accessing social security and health resources. CONCLUSION: This study is a first step in the use of the ICF in persons with multiple sclerosis and towards development of the ICF Core set for multiple sclerosis from a broader international perspective.

Activities of Daily Living↗
PubMed1998

Assessment of memory in multiple sclerosis patients using the Memory Assessment Scale.

Previous assessment of memory function in multiple sclerosis patients has yielded mixed findings regarding the type and severity of memory deficits, which may be due to (1) differential selection of scales for memory assessment; (2) limited, inconsistent or weak reliability and validity data for the memory scales employed; (3) poor standardization techniques; (4) lack of theoretical foundation for the measure; and (5) limited control of confounding variables, e.g., education, age and the use of nonverbal memory tests. The purpose of the present study was to assess memory function in multiple sclerosis subjects using the verbal subtests of the Memory Assessment Scale, a relatively new measure designed to overcome many of the aforementioned problems. Participants included 57 patients diagnosed as relapsing-remitting, 47 diagnosed as chronic progressive (two generally recognized types of multiple sclerosis), and 132 control participants. A multivariate analysis controlling for age and verbal IQ was significant (Wilks = 5.64, p < .001). One way follow-up tests showed both groups with multiple sclerosis had significantly diminished performance across all memory variables when compared with controls, with the exception of List Clustering Acquisition. This indicated that the patients used clustering (mentally grouping similar words together) as often as controls did. These findings provide support for the presence of significant and consistent verbal memory impairment in multiple sclerosis patients and the particular importance of using psychometrically sound measures in the assessment of this population.

Adolescent↗
PubMed1994

Defective CD3 mediated proliferation and LPS responsiveness in multiple sclerosis.

Multiple sclerosis [MS] is a chronic inflammatory disease of the central nervous system which has been postulated to be a T cell mediated disease. We examined proliferation of mononuclear cells to OKT3 mAb, Con A, ionomycin plus PMA and human myelin basic protein in subjects with relapsing-remitting and chronic progressive multiple sclerosis. Age and sex matched controls demonstrated a good proliferation to anti-CD3 mAb whereas subjects with relapsing-remitting multiple sclerosis showed a significantly decreased anti-CD3 mAb response. There was no difference in mitogen, ionomycin plus PMA or human MBP proliferation between controls and MS subjects. There was also a trend for decreasing anti-CD3 mAb proliferation in patients with chronic progressive multiple sclerosis compared to controls. LPS significantly decreased anti-CD3 mAb proliferation in controls but not in the MS subjects. An abnormality of signal transduction via the CD3 T-cell receptor complex in T cells and responsiveness to the immunomodulatory effect of IFN inducers may exist in multiple sclerosis.

CD3 Complex↗
PubMedDate not supplied

Insulinoma in a patient with tuberous sclerosis: is there an association?

OBJECTIVE: To describe a patient with tuberous sclerosis who, on initial assessment, had neurologic symptoms, which were ultimately found to be caused by an insulinoma. METHODS: We present a case report with clinical, laboratory, and radiologic data. The literature is reviewed relative to tuberous sclerosis and islet cell tumors, and a possible association is discussed. RESULTS: A 43-year-old man with a history of tuberous sclerosis required medical attention because of mental confusion and slurred speech and was found to have hypoglycemia. Neuroradiologic imaging showed no new lesions to account for his symptoms. His physical examination was striking for a large abdominal mass, which showed increased uptake on octreotide scanning. After surgical resection, the mass measured 21 cm and was found to be an insulinoma. Blood glucose values were normal postoperatively and on follow-up, and the patient had no recurrence of the symptoms. CONCLUSION: From this report, we emphasize two findings. First, we draw clinicians' attention to the possibility of an association between islet cell tumors and tuberous sclerosis and suggest consideration of this diagnosis in patients with tuberous sclerosis who have new or worsening neurologic symptoms. Second, the insulinoma we describe is, to our knowledge, the largest to be reported thus far in the literature.

Adult↗
PubMed1999

Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis.

In the genetically homogeneous Scandinavian population, we have investigated chromosome 5 and the HLA (human leukocyte antigen) region on chromosome 6p21 by applying linkage and association analyses on 106 white sibling pair families with multiple sclerosis. The importance of genes within the HLA region for the susceptibility of multiple sclerosis has previously been reported. More recently, findings have suggested importance of regions on chromosome 5. Half of chromosome 5 was analyzed by using 14 microsatellite markers and a susceptibility region with a maximum LOD score of 1.1 was identified. Chromosome 6 was analyzed by HLA-DR typing and using the TNF alpha microsatellite marker. A peak maximum LOD score of 2.0 was found at the HLA-DR marker. Association studies were made for all the markers, comparing 106 probands from the sibling pairs with 100 unrelated controls. None of the markers on chromosome 5 showed significant association with multiple sclerosis, whereas strong association between multiple sclerosis and DR2 was found, with an odds ratio of 3.7 (p < 10(-5)). It is surprising that association was not seen for any of the TNF alpha alleles including the 121-bp allele, although this allele was in positive linkage disequilibrium with DR2 in both patients and controls. Our results support the existence of multiple sclerosis susceptibility loci on chromosomes 5p and 6p21.

Chromosome Mapping↗
PubMed1999

[Multiple sclerosis: one or several diseases?].

The various clinical courses of multiple sclerosis (relapsing-remitting, primary progressive, secondary progressive, progressive-relapsing) are likely related to different severity or distribution of the main lesions that constitute the plaques (inflammation, demyelination, axonal injury and loss, necrosis). They might lead to different therapeutic approaches. Some cases of the other clinico-radiological or clinico-pathological variants (pseudo-tumoral, concentric sclerosis of Baló, acute disseminate encephalomyelitis, Devic's neuromyelitis optica) obviously share similar mechanisms with multiple sclerosis. Other cases are, on the contrary, linked to different diseases. Do the variants of multiple sclerosis could be the consequence of different diseases? This is, today, a highly speculative conjecture. The prevalent hypothesis suggests that the clinico-pathological heterogeneity of multiple sclerosis is linked to the variability of the reaction of the nervous tissue to an initial injury. This different vulnerability, that depends on unknown factors, would explain the variants of the disease.

Diagnosis, Differential↗
PubMed1999

[Mortality due to multiple sclerosis in Spain, 1951-1992].

UNLABELLED: FOUNDATIONS: In this work, multiple sclerosis mortality trend in Spain from 1951 to 1992 is displayed. The purpose is to identify the pattern of age-adjusted mortality evolution and to measure the effect of environmental factors. METHODS: Multiple sclerosis mortality is standardized by age using the world standard population. In each year from 1951 to 1992, age-specific mortality rates are transversely fitted to the Gompertz law. The Longitudinal Gompertzian analysis is applied to the obtained coefficients to quantify the effects of competing risks and environmental factors. RESULTS: Multiple sclerosis age-adjusted mortality increased from 1951 to 1968; a step-down is produced in 1969 (coinciding with change from 7th to 8th revision of the International Classification of Diseases) and a stability from 1970 on. Multiple sclerosis in Spain is a Gompertzian disease. Adjusting mortality for R0 (which in the Gompertz function represents the addition of the environmental factors acting in a point near the beginning of the life and the competing risks of death) the result was almost constant throughout the whole analyzed period. CONCLUSIONS: It is suggested that multiple sclerosis mortality trend in Spain is due to changes in some environmental factor acting early and in a point; on the other hand, diet or other environmental factors acting for long time or genetic factors have and little or no influence in this trend.

Adult↗
PubMedDate not supplied

[Multiple sclerosis incidence in the Alcoi Health district. 12-year-long study (1986-1997)].

INTRODUCTION: To date, epidemiological studies on multiple sclerosis in Spain have been basically prevalence studies, and the data on incidence recorded have been the result of different methodologies, with no definition of the criteria for inclusion. OBJECTIVE: To carry out a study of incidence with prospective collection/review of cases over a prolonged period of time. PATIENTS AND METHODS: Over 12 years, between 1 March 1986 and 31 December 1997, we collected data prospectively for patients with a definite diagnosis of multiple sclerosis. The year of incidence was considered to be when the patient fulfilled clinical criteria for diagnosis of the disease. RESULTS: On 31 December 1997 in the Alcoi Health District there were 54 patients with clinically defined multiple sclerosis (a prevalence of 41.28 cases per 100,000 inhabitants). Of these, 45 patients were diagnosed during the period studied, with an average incidence of 2.82 cases per 100,000 inhabitants per year. Only 15 patients were confirmed before 1986. CONCLUSIONS: This is the most prolonged study of the incidence of multiple sclerosis carried out in Spain. The figures found for incidence are in contrast to those found in previous years for prevalence and incidence. Analysis of the data suggests that the incidence of multiple sclerosis in the Alcoi district has changed and has increased since the second half of the 1980s.

Adolescent↗
PubMed2000

[Detection of viral genomes of the Herpesviridae family in multiple sclerosis patients by means of the polymerase chain reaction (PCR)].

BACKGROUND: The multiple sclerosis seems to be the junction between genetics alteration and an unknown environmental factor, that they would originate an autoimmune alteration, that they would be the reason of the inflammation and demyelinization responsible of the disease. Our objective has been the determination of this possible environmental factor and to reach it, we have studied the appearance of Herpesviridae family viruses. MATERIALS AND METHODS: 204 blood samples were studied: 102 from relapsing-remitting multiple sclerosis patients (43 were undergoing beta-interferon treatment), and 102 from blood donors with the same age and sex than multiple sclerosis patients. From this samples, we extracted the DNA of peripheral blood mononuclear cells (PBMCs), and we analyzed by polymerase chain reaction (PCR) to detect the appearance of herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6 (HHV-6), human herpesvirus 7 and human herpesvirus 8. RESULTS: a) we only found significative difference (p = 0.0001) in HHV-6: 21.5% donors positive samples (22/102), opposite to 49.02% of positivity in mulytiple sclerosis patients (50/102); b) we didn't found significative differences in none of other viruses studied, between patients treated with beta-interferon and non-treated ones. CONCLUSIONS: Our results suggest us that HHV-6 can play an important role in the multiple sclerosis development. The beta-interferon treatment doesn't affect to DNA prevalence of none of studied viruses.

Adult↗
PubMedDate not supplied

[A review of the epidemiology of multiple sclerosis in Mexico].

OBJECTIVE: To review the epidemiological information on multiple sclerosis in Mexico. DEVELOPMENT AND CONCLUSIONS: The results of the few epidemiological studies on multiple sclerosis show a prevalence of 1.5/100,000 inhabitants, a figure which is not in concordance with studies carried out by institutions, which indicates an increase in the frequency of new cases. This information is not necessarily due to a true increase in prevalence. Possibly this increase is related to improved methodology for clinical and paraclinical diagnosis, especially the use of magnetic resonance. There is a need for descriptive and analytical epidemiological studies to obtain precise data on this. At present, the Mexican Group for the study of Multiple Sclerosis and The Mexican Association for the study of Multiple Sclerosis are using a questionnaire designed and validated for Mexico in order to determine the clinical characteristics and the prevalence of multiple sclerosis. The results will be available in the near future to improve knowledge regarding the epidemiology of this disorder and its economic impact on the Mexican health systems.

Humans↗