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PubMed1976

Biochemical findings in multiple sclerosis. III. Immunoglobulins of restricted heterogeneity and light chain distribution in cerebrospinal fluid of patients with multiple sclerosis.

Several biochemical parameters, the most important of which are total IgG, kappa and lambda light chain distribution and thin layer isoelectric focusing, were determined in the cerebrospinal fluid of 36 multiple sclerosis patients. Their ages and the evolution period of their disease are widely spread and no sex differentiation was made.

Adult↗
PubMed2004

[Pain in multiple sclerosis--a still underestimated problem. The 1 year prevalence of pain syndromes, significance and quality of care of multiple sclerosis inpatients].

We evaluated the 1-year prevalence of pain syndromes and quality of care among 157 consecutive multiple sclerosis (MS) inpatients (90 f, 67 m) aged 19-85 years, with extended disability status scores of 1.0-8.5 and clinically definite MS. In a standardized questionnaire, only severe pain (pain intensity on visual analog scale of at least 4/10) was documented and classified which had occurred more often than three times or lasted longer than 1 week within the last year. Of 157 patients, 61% reported 176 pain syndromes: most frequent were headaches (40%), dysesthetic limb pain (19%), back pain (17%), and painful spasms (11%). Twelve percent of the pain syndromes were classified as worst symptom of MS, and in 68% insufficient care by the physicians consulted was reported. This was even true for the most frequent pain, migraine, in which clear treatment recommendations exist. There is thus an urgent need for physicians to keep this problem in mind when treating MS patients.

Adult↗
PubMed2000

CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a common disease of the central nervous system characterized by myelin loss and progressive neurological dysfunction. An underlying genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure. Full-genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS. Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS gene(s) of modest effect. Encoded here are two chemokine receptors, CCR5 and CCR2B. We examined the chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed genetic analyses of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage- and association-based tests. No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyses (ASPEX), and association testing (sib-TDT) for each locus were also not significant. However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects). Thus, chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate inflammatory demyelination.

Age of Onset↗
PubMed2006

Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration.

Hippocampal sclerosis (HS) is characterized by selective neuronal loss and gliosis in CA1 and the subiculum and has been associated with several disorders, including Alzheimer's disease, frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions (FTLD-U), vascular dementia and some tauopathies. In some cases, HS is not associated with other degenerative pathologies. Such cases are sometimes referred to as HS dementia (HSD). Differences between HSD and HS in the setting of FTLD-U have not been systematically investigated. To this end, eight cases of HSD and ten cases of HS associated with FTLD-U were studied with Nissl and periodic acid-Schiff stains to assess neuronal loss and corpora amylacea, respectively. Sections were immunostained with antibodies to glial fibrillary acidic protein, HLA-DR and synaptophysin and immunoreactivity was measured with image analysis in CA1 and the subiculum of each case. Additionally, sections were immunostained with antibodies to 4-R tau to determine the presence of argyrophilic grains. HSD was different from HS associated with FTLD-U. Specifically, it was more common in the elderly, and it was associated with more marked neuronal and synaptic loss and with greater reactive gliosis. Corpora amylacea tended to be more frequent in HSD than in FTLD-U, but there was no difference in frequency of argyrophilic grains.

Aged↗
PubMed1997

Comparative study of ubiquitin immunoreactivity of hippocampal granular cells in amyotrophic lateral sclerosis with dementia, Guamanian amyotrophic lateral sclerosis and Guamanian parkinsonism-dementia complex.

This report concerns an investigation on ubiquitin immunoreactivity in the neuronal perikarya of hippocampal granular cells in Guamanian amyotrophic lateral sclerosis (G-ALS) and Guamanian parkinsonism-dementia complex (G-PDC). Specimens from two non-Guamanian cases of ALS with dementia (ALS-D) were included for comparison. Histologically normal hippocampi from five adults served as controls. Antibodies to ubiquitin and tau protein were used throughout. Most Guamanian patients examined had granular cells with perikaryal ubiquitin immunoreactivity in the dentate gyrus, but in comparison to ALS-D, the frequency of ubiquitin-positive neurons was significantly lower. Tau-positive granular cells were detected in most Guamanian patients, but not in ALS-D. There was a relationship between the numbers of ubiquitin-positive and tau-positive neurons in the dentate granular cell layer of G-ALS and G-PDC patients. This was verified on sections double immunostained for tau protein and ubiquitin. The present findings suggest that the ubiquitin-positive materials observed in the perikarya of the dentate granular cells of patients with G-ALS or with G-PDC seem to be Alzheimer's neurofibrillary tangles rather than the typical ubiquitin-positive intracytoplasmic neuronal inclusions, characteristics of ALS-D. Our data would indicate that different mechanisms are involved in the geneses of cortical neuronal degeneration and decline in cognitive function in ALS-D, G-ALS and G-PDC.

Adult↗
PubMed2005

Interferon beta in relapsing-remitting multiple sclerosis. An eight years experience in a specialist multiple sclerosis centre.

BACKGROUND AND OBJECTIVE: Long-term observational studies may provide additional information about the behaviour of different drugs in the post-marketing period. We present the data of our cohort of relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon beta (IFNbeta). METHODS: We analysed RRMS patients followed for at least 2 years. From 1995, we initiated therapy with IFNbeta. As they became available, patients were allocated to one of the IFNs at standard doses (IFNbeta-1b, IFNbeta-1a i.m. or IFNbeta-1a s.c.). Each patient was included in a follow-up protocol containing demographic and baseline clinical data. RESULTS: Between 1995 and 2004, 382 patients have completed at least 2 years of follow-up. Significant differences at entry were observed. Patients on IFNbeta-1b had a higher disease activity and disability at baseline than those on IFNbeta-1a i.m. or IFNbeta-1a s.c. A significant reduction in the relapse rate was observed for the three drugs (70% for IFNbeta-1b, 64% for IFNbeta-1a i.m. and 74% for IFNbeta-1a s.c.). We observed a sustained progression of disability in 11% of patients on IFNbeta-1b, 17% on IFNbeta-1a i.m. and 19% on IFNbeta-1a s.c.; and at four years of follow-up in 24% of patients on IFNbeta-1b, 23% on IFNbeta-1a i.m. and 35% on IFNbeta-1a s.c. No unexpected major adverse events were observed with any of the drugs. CONCLUSIONS: Interferon beta is safe and well tolerated. The various registered interferon beta drugs provide a comparable efficacy in a large non-selected cohort of RRMS patients.

Adjuvants, Immunologic↗
PubMed2000

Patients with amyotrophic lateral sclerosis and cancer do not differ clinically from patients with sporadic amyotrophic lateral sclerosis.

We examined whether patients with both amyotrophic lateral sclerosis (ALS) and cancer differ from classical ALS patients, and whether motor neuron disease responds to oncological therapy. We analyzed clinical and immunological features of 14 patients (9 men, 5 women; mean age 65.3 years) with pure/definite ALS and cancer. Patients with solid tumor cancer and definite ALS were selected according to the E1 Escorial criteria; cases with ALS plus were excluded. Four patients had breast cancer, three lung adenocarcinoma, and three bowel tumor; hepatocarcinoma, kidney cancer, and mesothelioma were observed in one case each, and in one patient the primary tumor was unidentified. Patients' sera were examined for antinervous system antibodies by means of immunohistochemistry and western blot analysis. Of five patients who underwent surgical therapy, two worsened during the procedure, while the other three had no benefit. The remaining two patients did not improve after chemotherapy and radiotherapy. In none of our cases did the oncological disease progress. Death was a consequence of ALS in all eight patients who died. Median survival was 18 months and did not differ from that of 28 ALS patients matched for age, sex, and onset features (bulbar or spinal). Anti-nervous system antibodies were never detected. We conclude that our group of pure ALS patients with cancer do not significantly differ from patients with classical ALS. They usually die as a consequence of the motor neuron syndrome in the absence of cancer progression. To date we have not observed any response of ALS to antitumor therapy.

Aged↗
PubMed1993

Ubiquitin-positive inclusion in anterior horn cells in subgroups of motor neuron diseases: a comparative study of adult-onset amyotrophic lateral sclerosis, juvenile amyotrophic lateral sclerosis and Werdnig-Hoffmann disease.

This report concerns the expression of ubiquitin in anterior horn cells of various subgroups of adult and infantile motor neuron disease (MNDs); immunohistochemical techniques were employed. Ubiquitin-positive skein-like inclusions (SLIs) were found in all cases of adult-onset amyotrophic lateral sclerosis (ALS), including 16 cases with sporadic ALS, two cases of familial ALS with posterior column degeneration and Lewy body-like hyaline inclusions (LBHIs), two sporadic ALS cases with LBHIs, and three cases of sporadic ALS with dementia. SLIs were not found in anterior horn cells of 5 cases with Werdnig-Hoffmann disease (WHD). However, granular ubiquitin-positive deposits were seen in ballooned neurons of WHD patients. No ubiquitinated materials were found in the perikarya of two sporadic juvenile ALS patients with basophilic inclusions (BIs), but granular ubiquitin-immunoreactive deposits were occasionally observed in the BIs. These results suggest that ubiquitin-positive SLIs are characteristic features of various forms of adult-onset ALS and that aggregated ubiquitinated granules are characteristic of ballooned neurons of WHD. Ubiquitinated structures and their distribution patterns may reflect degenerative processes of anterior horn cells, and may be useful for classifying subgroups of motor neuron diseases.

Adult↗
PubMed1995

Geographic similarities between varicella and multiple sclerosis: an hypothesis on the environmental factor of multiple sclerosis.

The environmental factor causing multiple sclerosis (MS) is unknown. Kurtzke et al. (Neurology 1979; 29: 1228-1235) depicted a north to south diminishing gradient in the case/control ratios for MS among American veterans in the United States. A similar, but less precise, gradient emerged when the incidence rates of varicella from 37 states during 1978-91 were compared. A loose correlation appears to exist between the mean incidence of varicella and the MS risk ratio (n = 0.344 Spearman rank correlation coefficient, p = 0.037). Further, the data on the fat of migrants moving from a high risk MS country to a low risk country and the reverse, plus the great importance of the age at migration, raise the question of a possible connection between the two diseases. Because of these epidemiological and other similarities between the two diseases a further comparative study was suggested.

Adolescent↗
PubMed2006

Perspectives in multiple sclerosis health care: special focus on the costs of multiple sclerosis.

Brain disorders are amongst the leading causes of disease and disability worldwide, accounting for 35% of the burden of all diseases in Europe. Despite their enormous personal and national impact the knowledge of the financial and economic impression of brain disorders has been relatively little researched. Recently it has been estimated that there are nearly 400,000 multiple sclerosis (MS) patients in Europe, which is 0.003% of all brain disease patients in the continent. In MS economic consequences are predominantly the early loss of work capacity and the impact of physical and psychological disabilities in a population of young adults, hospitalization during severe disease exacerbations and the need for assistance in activities of daily living. In the last decade the introduction of new immunomodulatory treatments led to an increase in direct costs due to the cost of these drugs, but also led to a more intensive management of patients. However, most studies of MS costs were carried out prior to the widespread use of newer treatments. In the present study we estimated the economic impact of MS in Israel and compared the traditional-vertical management model with the integrated-multidisciplinary model of health service delivery following the introduction of immunomodulatory treatments. Mean direct health cost was 8,554 euros and 5,599 euros in the traditional and integrative models, respectively (p<0.01). After 1-year follow-up, full-time employment decreased by 10% in the traditional model and increased by 17% in the integrated model (p<0.05). Analysis of variance demonstrated that the model of service delivery explained most of the difference in cost between the two models. Compared to mean annual costs in Europe that are estimated at 23,695 euros per case the cost of health services in Israel by MS patients is significantly lower. MS represents a high economic burden to society. In line with the findings from 15 studies published in Europe, we can conclude that studies agree with the following findings: a) costs outside the healthcare system, non-medical costs and informal care dominate the costs of MS, b) costs increase with increasing severity of the disease and c) an integrated service delivery model that is satisfying to patients on the one hand and cost effective on the other is to be recommended.

Cost of Illness↗
PubMed2005

Cross-cultural adaptation and validation of multiple sclerosis quality of life questionnaire (MSQOL-54) in a Turkish multiple sclerosis sample.

OBJECTIVE: Multiple sclerosis (MS) is a chronic progressive disease with multiple neurological impairments. The disease can also dramatically affect the health-related quality of life of patients. The objective of this study was to investigate the validation of the translated and cross-culturally adapted MSQOL-54 in 183 Turkish MS patients. METHODS: 183 adults classified as having definite MS patients were enrolled into the study. Patients were classified into four severity groups according to the expanded disability status scale (EDSS); group I (EDSS 0-4), group II (EDSS 4.5-5.5), group III (EDSS 6-6.5) and group IV (EDSS 7-8). MSQOL-54 questionnaire were translated and culturally adapted into Turkish. Associations between age, gender, disease duration, EDSS score, marital status, education and health insurance and the MSQOL-54 physical and mental health composite scores were determined. RESULTS: The mean age of the 183 patients (138 female and 45 male) was 39+/-10 years. The questionnaire was well accepted but small cultural adaptations were required. EDSS scores showed significant associations with the MSQOL-54 physical and mental health composite scores. From the different EDSS groups only, the group I (EDSS 0-4) score was significantly associated with the physical health composite as well as the disease duration showed significant correlation with the physical and mental composite scores. None of the other EDSS groups and the other parameters showed correlation with physical health composite or mental health composite. CONCLUSION: Assessment of quality of life of MS patients in addition to disease severity and disability level is important, because it provides unique information that is important to patients and to clinicians. A translation of an existing MS-targeted HRQOL measure from US English into Turkish was easily administered and well accepted in a Turkish MS sample.

Adolescent↗
PubMed2005

Clinical multiple sclerosis occurs at one end of a spectrum of CNS pathology: a modified threshold liability model leads to new ways of thinking about the cause of clinical multiple sclerosis.

Multiple sclerosis (MS) is a complex trait, the causes of which are elusive. A threshold liability model influences thinking about the causes of this disorder. According to this model, a population has a normal distribution of genetic liability to MS. In addition, a threshold exists, so that MS begins when an individual's liability exceeds the MS threshold; environmental and other causative factors may increase or decrease an individual's MS liability. It is argued here, however, that this model is misleading, as it is based on the incorrect assumption that MS is a disorder that one either has or does not have. This paper hypothesizes, instead, that patients with a diagnosis of MS share identical CNS pathology, termed MS pathology, with some individuals who have a diagnosis of possible MS and with some apparently healthy individuals, who may never have a diagnosis of MS. In order to accommodate this hypothesis, the current threshold liability model is modified as follows. (1) In addition to a normal distribution of MS liability within a population, a spectrum of MS pathology occurs in some who have a high MS liability. (2) A clinical MS threshold exists at a point on this liability distribution, where the burden and distribution of MS pathology permits a diagnosis of clinical MS. (3) Additional thresholds exist that correspond to a lower MS liability and a lesser burden of MS pathology than occur at the clinical MS threshold. This modified threshold model leads to the postulate that causes act at various time points to increase MS liability and induce MS pathology. The accumulation of MS pathology sometimes leads to a diagnosis of clinical MS. One implication of this model is that the MS pathology in clinical MS and in some with possible MS differs only in the extent but not in the type of CNS injury. Thus, it may be possible to obtain insight into the causative environmental factors that increase MS liability and induce MS pathology by focusing on patients who have clinical MS; some environmental factors that induce new lesions in patients with clinical MS may be identical to those that induce MS pathology in genetically susceptible individuals who do not have clinical MS. Identification of these causative factors has importance, as specific treatment may prevent the accumulation of MS pathology that leads to the significant CNS damage associated with clinical MS.

Central Nervous System Diseases↗
PubMed2000

Benefits of glatiramer acetate on disability in relapsing-remitting multiple sclerosis. An analysis by area under disability/time curves. The Copolymer 1 Multiple Sclerosis Study Group.

New immunomodulatory therapies for relapsing-remitting multiple sclerosis (RRMS) have well-documented effects in reducing relapses, but it has been difficult to demonstrate their benefits on disability in relatively short treatment trials. Commonly utilised disability outcome measures are problematic both in usefulness and clinical interpretation when applied to MS subjects with fluctuating and variable disease courses. An alternative technique is to use the summary measure 'area under the disability/time curve' (AUC) to index the total in-trial morbidity experienced by patients. In this study, we applied AUC analyses to the serial Expanded Disability Status Scale (EDSS) scores from the U.S. multicentre, Phase III, two-year core study of glatiramer acetate in 251 RRMS patients. When all available EDSS evaluations were analysed with AUC(CHANGE) ('combined data', including relapse-related assessments), active treatment was significantly superior to placebo (P=0.018). The benefits of glatiramer acetate persisted when transient relapse effects were reduced by using 'scheduled visit data' only (P=0.021). With the more conservative AUC(SUM) measure, significant active treatment effects remained (P=0.029 and 0.046, for both 'combined' and 'scheduled visit' data, respectively). Subgroup calculations performed with baseline disability stratified at EDSS 3.5 also showed benefits of treatment over placebo, but statistical significance was not reached. This analysis of data from a Phase III treatment trial illustrates the AUC summary measure technique and provides further evidence of the efficacy of glatiramer acetate in RRMS.

Disability Evaluation↗
PubMed1996

Glial transforming growth factor (TGF)-beta isotypes in multiple sclerosis: differential glial expression of TGF-beta 1, 2 and 3 isotypes in multiple sclerosis.

We studied glial transforming growth factor (TGF)-beta isotype expression in 14 cases of multiple sclerosis. Acute active lesions exhibited selective TGF-beta 2 immunoreactivity of lesion encircling ramified microglia. In contrast, astrocytes within chronic active white matter lesions expressed all three isotypes. Chronic active lesions which extended into cortex exhibited selective cortical astrocyte TGF-beta 2 expression. This isotype was also selectively expressed by astrocytes in apparently normal white matter. A similar pattern of glial TGF-beta expression was seen in the pathological control, progressive multifocal leukoencephalopathy. The results suggest that TGF-beta cytokines are locally expressed in demyelination and that the beta 2 isotype may be uniquely regulated.

Humans↗
PubMed1999

Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

BACKGROUND AND OBJECTIVE: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Adjuvants, Immunologic↗
PubMed2000

Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach. French Multiple Sclerosis Genetics Group.

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

Cytokines↗
PubMed1983

Multiple sclerosis: immunogenetic analyses of sib-pair double case families. II. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6, and GLO polymorphisms.

The complement component polymorphisms of C2, C4, BF, C3, C6, and the enzyme polymorphism GLO were studied in 13 sib-pair double case families with multiple sclerosis. A significant association was seen between MS patients and the C4 haplotype A4,B2 as compared with their healthy siblings. This finding seems to parallel reports on C2 hypocomplementemia in MS patients since C4 A4,B2 in normal individuals was also seen to be in linkage disequilibrium with the C2 deficiency allele (C2QO) by other investigators.

Complement C2↗