M. Grønning

Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.

The Committee of the European Concerted Action for Multiple Sclerosis (Charcot Foundation) organised five workshops to discuss CSF analytical standards in the diagnosis of multiple sclerosis. This consensus report from 12 European countries summarises the results of those workshops. It is hoped that neurologists will confer with their colleagues in clinical chemistry to arrange the best possible local practice. The most sensitive method for the detection of oligoclonal immunoglobulin bands is isoelectric focusing. The same amounts of IgG in parallel CSF and serum samples are used and oligoclonal bands are revealed with IgG specific antibody staining. All laboratories performing isoelectric focusing should check their technique at least annually using “blind” standards for the five different CSF and serum patterns. Quantitative measurements of IgG production in the CNS are less sensitive than isoelectric focusing. The preferred method for detection of blood-CSF barrier dysfunction is the albumin quotient. The CSF albumin or total protein concentrations are less satisfactory. These results must be interpreted with reference to the age of the patient and the local method of determination. Cells should be counted. The normal value is no more than 4 cells/microliters. Among evolving optional tests, measurement of the combined local synthesis of antibodies against measles, rubella, and/or varicella zoster could represent a significant advance if it offers higher specificity (not sensitivity) for identifying chronic rather than acute inflammation. Other tests that may have useful correlations with clinical indices include those for oligoclonal free light chains, IgM, IgA, or myelin basic protein concentrations.

Multiple sclerosis and chronic inflammatory diseases A case-control study

Introduction– Disease associations may provide useful etiological leads in relation to diseases of unknown cause. Material and methods– We conducted a hospital‐based case‐control study of 155 MS patients and 200 controls in Hordaland County, Norway to investigate the possible association between MS and autoimmune diseases. Results– The MS patients had a statistically significant more frequent coexistence of rheumatoid arthritis, psoriasis, and goitre when compared to the controls (OR = 2.96; 95% CI 1.23–7.66). This difference persisted when analysing the definite MS cases separately (OR = 2.90; 95% CI 1.10–7.96). The familial occurrence of chronic inflammatory diseases was not significantly different in cases and controls. A significant increased risk to develop MS occurred in first degree relatives of MS patients (OR = 12.58; 95% CI 1.73–552). Conclusion– Acknowledging the low figures, the uncertain estimates with large confidence intervals, and thus the obvious role of chance in this study, the results might indicate that a generalized, genetically controlled problem of the immune system could result in aggregates of the reported diseases, all of which are partly characterized by abberrations of the immune system.

EARLY PROGNOSTIC FACTORS FOR DISABILITY IN MULTIPLE-SCLEROSIS, A EUROPEAN MULTICENTER STUDY

The effects of initial clinical variables on short‐term prognosis are analyzed in a cross‐sectional study of 574 multiple sclerosis patients from 7 centers in 5 European countries. Patients with a primary progressive course had a 2.3 higher mean disability score (EDSS) than the primary remittent group after a mean duration of disease of 6.6 years. High age at onset was associated with a primary progressive course, and was also related to increased risk of a rapid shift to a secondary progressive course. Among the remittent patients without a secondary progressive course a high age at onset was significantly correlated to a higher disability score. In the whole remittent group the presence of pyramidal and cerebellar symptoms at onset predicted both a high disability score and a rapid shift to a secondary progression, while the effect was reverse for sensory and visual symptoms. No difference between the sexes was found.

An immunogenetic heterogeneity in multiple sclerosis.

Two clinical forms of multiple sclerosis (MS), primarily chronic progressive MS (PCP MS) and relapsing/remitting MS (R/R MS) have been shown to differ in several respects. The results of genomic HLA class II typing with restriction fragment length polymorphism analysis of 62 MS patients from Western Norway, 42 with R/R MS and 20 PCP MS, are reported on here. As in previous studies of Swedish patients, the haplotype DRw17(3), DQw2 was found to be five times more common in R/R MS than in PCP MS. This finding supports the hypothesis that R/R and PCP MS are immunogenetically separate entities. In contrast with a previous investigation of Norwegian MS patients, no association of MS with glutamine at position 34 of the HLA-DQ alpha chain or with defined sequences of the HLA-DQB1 gene was found.

Multiple sclerosis and cancer in Norway. A retrospective cohort study.

Introduction– During the extended course of multiple sclerosis (MS) there are ample opportunities for the patients to develop other illnesses including cancer, a potential long‐term complication of the immunosuppressive drug treatment in MS. Material and methods– A retrospective cohort study was done to estimate the relative risk of cancer in a population of MS‐patients from three Norwegian counties by record linkage with the Cancer Registry of Norway. The cohort comprised 1271 MS‐patients, 530 men and 741 women, identified in five longitudinal population‐based incidence studies. The reporting of cancer cases has been compulsory in Norway since 1952. Results– We found 73 cancer cases (standardized incidence ratio (SIR) = 0.86, 95% CI 0.68–1.09). Mean follow‐up time was 18.4 years. A significant excess of breast cancers was observed (SIR = 1.70, 95% CI 1.05–2.60). A non‐significant excess of cancer in the urinary tract was observed. No significantly increased risk in hematologic and lymphatic malignancies or malignant brain tumors was observed. The incidence of cancer of the digestive organs was significantly lower than expected (SIR = 0.51, 95% CI 0.24–0.93). Conclusion– Overall, the study indicates that an MS‐patient is not at any unusual risk for subsequent development of cancer compared to the normal population.

Incidence of Multiple Sclerosis in Hordaland, Western Norway: A Fluctuating Pattern

The incidence of multiple sclerosis (MS) was studied in the county of Hordaland, western Norway. A significant increase in incidence in the period 1958-1987, a decline followed by a gradual increase in mean age at onset, geographic differences in time trends and a biphasic pattern revealed by a birth cohort analysis support the theory of real time-space fluctuations in the incidence of MS over time.

Epileptic seizures in patients with multiple sclerosis. Is the prognosis of epilepsy underestimated

The exact prevalence of epileptic seizures in patients with multiple sclerosis (MS) is still a matter of some controversy. In a population-based, unselected group of 423 patients with MS we identified 17 (4.02%) with epileptic seizures. The mean age at onset of MS was 25.2 years and at onset of epilepsy 32.6 years. A prevalence of active epilepsy, i.e. seizures within the last 5 years, was estimated to 3.2%. The prevalence of epilepsy in our MS population is much higher than should be expected when compared to lifetime prevalence of epilepsy in corresponding age groups. The occurrence of convulsive status epilepticus is also higher than expected, and suggests a rather serious prognosis. Thus, drug treatment should be considered after the first epileptic seizure.

Elevated cerebrospinal fluid proteins in sciatica caused by disc herniation

SummaryWe carried out a study of cerebrospinal fluid (CSF) proteins in 180 patients with sciatica caused by lumbar disc herniation to elucidate further the degree and mechanisms of protein elevations. The 63 controls were patients with tension headache or migraine without aura. The CSF/serum albumin ratios were higher in the patients (mean 8.84, SD 5.16) than in the controls (mean 5.60, SD 2.33). Similar differences were found for the CSF/serum IgG ratios and the CSF-total proteins. The CSF/serum albumin ratios, CSF/serum IgG ratios and the CSF-total protein concentrations were higher in men than in women among the patients. We suggest that the significant difference in ratio parameters between patients and controls indicates a leak of plasma albumin, most likely IgG, into the CSF in patients with sciatica. The leak was more pronounced in men. Also in the control group the CSF/serum albumin and CSF/serum IgG ratios were higher in men.

Absence of HTLV-1 related sequences in MS from high prevalence areas in Western Norway

In Western Norway, long‐term follow up epidemiological studies have revealed significant increases in the incidence and prevalence rates of multiple sclerosis (MS) in stable populations, indicating the impact of exogenous factors. In this study 183 MS patients and 102 controls from high prevalence areas in Western Norway were investigated for human T‐lymphotropic virus type I (HTLV‐1) related sequences by polymerase chain reaction. Using primers targeting the gag, pol and env genes in the HTLV‐1 provirus genome, no amplification products were detected in the 183 MS patients or 102 controls. The results strongly suggest that neither HTLV‐1 nor a closely related retrovirus participate in the aetiology of MS.

Multiple sclerosis: A modifying influence of HLA class I in an HLA class II associated autoimmune disease

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system, shown to be associated with the HLA class II haplotype DRB1*15,DQB1*06. Carrying the HLA class II haplotype DRB1*15,DQB1*06 increases the risk of MS by 3.6. By adopting a polymerase chain reaction (PCR)-based typing technique for HLA class I and class II genes, 200 Swedish MS patients and 210 Swedish healthy controls were analysed for their HLA alleles. Additional HLA class I alleles that increase and decrease the genetic susceptibility to MS were identified. The HLA-A*0301 allele increases the risk of MS (odds ratio=2.1) independently of DRB1*15,DQB1*06. HLA-A*0201 decreases the overall risk (odds ratio= 0.52) and the presence of A*0201 reduces the risk of MS for DRB1*15,DQB1*06 carriers from 3.6 to 1.5. Our findings are the first to identify a major modulating effect of HLA class I alleles on the susceptibility to a human autoimmune disease; a phenomenon that has previously only been observed in animal models.