Diffusion tensor imaging in multiple sclerosis at different final outcomes.

OBJECTIVES: Methods to evaluate the relative contributions of demyelination vs axonal degeneration over the long-term course of MS are urgently needed. We used magnetic resonance diffusion tensor imaging (DTI) to estimate degrees of demyelination and axonal degeneration in the corpus callosum (CC) in cases of MS with different final outcomes. MATERIALS AND METHODS: We determined DTI measures mean diffusivity (MD), fractional anisotropy (FA), and axial (AD) and radial (RD) diffusivities in the CC of 31 MS patients, of whom 13 presented a secondary progressive course, 11 a non-progressive course, and seven a monophasic course. The study participants were survivors from an incidence cohort of 254 attack-onset MS patients with 50 years of longitudinal follow-up. As reference, we included five healthy individuals without significant morbidity. RESULTS: In patients with secondary progression, compared to all other groups, the corpus callosum showed increased RD and reduced FA, but no change in AD. None of the parameters exhibited differences among non-progressive and monophasic course groups and controls. CONCLUSION: Increased RD was observed in secondary progressive MS, indicating significant myelin loss. Normal RD values observed in the clinically isolated syndrome and non-progressive groups confirm their benign nature. AD was not a characterizing parameter for long-term outcome. Demyelination revealed by increased RD is a distinguishing trait for secondary progression.

Clinically isolated syndromes with no further disease activity suggestive of multiple sclerosis at the age of population life expectancy.

The proportion of patients with clinically isolated syndrome (CIS) reported to convert to clinically definite multiple sclerosis varied between 30 and 75%. We studied the lifetime probability of remaining in the "CIS only" condition. The study was based on the longitudinally followed Gothenburg 1950-1964 incidence cohort (n = 306). Survival analysis revealed that 17.8% of 236 attack onset patients remained "CIS only". Patients with afferent (optic and sensory) symptoms had a better prognosis with approximately 30% of these patients remaining "CIS only". Patients who had experienced no relapse during the first 25 years remained "CIS only" for the subsequent 25 years of follow-up.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

Prediction of outcome in multiple sclerosis based on multivariate models.

An incidence cohort of 308 multiple sclerosis patients was followed up repeatedly during at least 25 years of disease. In the patients with acute onset, multivariate survival analyses were performed and predictive models created. The endpoints DSS 6 and start of progressive disease were used. A number of variables were tested. The most important of these for prediction and therefore included in these models were: age at onset, sex, degree of remission after relapse, mono- or polyregional symptoms, type of affected nerve fibres, number of affected neurological systems. The relapse rate did not correlate with prognosis. In the predictive models, coefficients and risk ratios are provided that can be used for calculating the risk of progression and DSS 6 or to predict the median time for these endpoints in individual patients. It was also found that the risk of progression is not constant, but has a maximum a certain time after disease onset. For a patient with early onset, the risk is low in the beginning, but reaches a maximum level, which is several times higher, after about 15 years. The patient with a late onset has a much higher risk of endpoint immediately after onset, but reaches the maximum in a few years, and after that the risk decreases.

HLA and prognosis in multiple sclerosis.

The patients of a multiple sclerosis (MS) incidence cohort with 25 years of longitudinal follow-up were typed for HLA-DR and DQ. This type of cohort provides reliable data for gene frequencies and prognostic studies. The influence of sampling bias, mainly due to mortality during the long follow-up, was accounted for. A positive association between MS and DR15,DQ6 was confirmed, but this haplotype did not influence prognosis. There was no difference in haplotype frequency between relapsing-remitting and primary chronic progressive MS. DR17,DQ2 was significantly over-represented in the quartile with the most malignant course. The haplotype DR1,DQ5, which was found rather less frequently in MS patients, also tended to be associated with a poorer prognosis.

Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis.

The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.

Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up.

An incidence cohort consisting of 308 multiple sclerosis patients was followed up repeatedly during at least 25 years of disease. A number of clinical factors were analysed with respect to their validity in assessing the long-term prognosis. Of the onset characteristics, the type of course was the most important, with primary progressive patients experiencing a much more severe course. In patients with an acute onset, low onset age, high degree of remission at first exacerbation, symptoms from afferent nerve fibres and onset symptoms from only one region (as compared with polyregional symptoms) of the central nervous system, were factors significantly associated with a favourable long-term prognosis. Of factors known 5 years after onset, a low number of affected neurological systems, a low neurological deficit score and a high degree of remission from the last bout were the most important favourable prognostic factors.

Prevalence and characteristics of dysarthria in a multiple-sclerosis incidence cohort: relation to neurological data.

Few attempts have been made to use degree and type of multiple sclerosis (MS) dysarthria in neurological evaluation. In the present study, 77 individuals drawn from an MS population were examined both by a speech pathologist and a neurologist, and data from three sources of information were subsequently combined: (1) a clinical dysarthria test procedure, (2) a perceptual analysis of speech characteristics in continuous speech, and (3) neurological deficit scoring. The speech of 15 age- and gender-matched healthy control subjects was also investigated. It was concluded that: (1) the prevalence of mild to severe dysarthria in this cohort was 51% and occurred in all components of speech production: respiration, phonation, prosody, articulation and nasality. (2) The clinical dysarthria test was sensitive in detecting subclinical speech signs. The prevalence of pathologic speech signs found on the basis of the test was found to be 62%. The prevalence of dysarthria based on the neurological evaluation alone was 20%. (3) The dysarthria of MS was a predominantly mixed dysarthria, with both ataxic and spastic speech signs frequently present in the speech of a given individual. (4) Furthermore, when a predominant type of dysarthria existed, it was not generally associated with a characteristic profile of neurological deficits. Rather, severity of speech deviation was positively correlated to overall severity of neurological involvement, type of disease course, and number of years in progression.

Temporal speech characteristics of individuals with multiple sclerosis and ataxic dysarthria: 'scanning speech' revisited.

'Scanning speech' has been used as a description of a prominent characteristic of the dysarthria of multiple sclerosis (MS) as well as of ataxic dysarthria in general. It is thought to be measurable as equalized syllable durations. There are seemingly contradictory prosodic-temporal characteristics of ataxic dysarthria: perceptually characterised as prosodic excess as well as phonatory-prosodic insufficiency and acoustic characteristics including signs of isochrony as well as variability. This study investigates the temporal characteristics at two levels, duration and variability of syllable durations and the durations of interstress intervals. A group of 14 individuals with MS and ataxic dysarthria as well as 15 control subjects were studied. It was concluded that individuals with ataxic dysarthria and MS showed (a) for syllables: significantly increased durations and decreased intrautterance variability (more isochrony or syllable equalization) as well as significantly increased interutterance variability; (b) for interstress intervals: significantly increased durations and increased variability (less isochrony). The results point to inflexibility as well as instability of temporal control, which could contribute to the explanation of why the perceptual characteristics are contradictory.

Incidence of MS during two fifteen-year periods in the Gothenburg region of Sweden.

The average annual incidence of definite and probable MS in Gothenburg was re-investigated. For 1950-1954, 1955-1959 and 1960-1964 it was 4.2, 4.2 and 4.3/100,000/year. For the five-year periods between 1974 and 1988 it was 3.0, 2.7 and 2.0/100,000/year. If possible MS was included, the corresponding incidence for 1950-1964 was 5.2, 5.3 and 5.1, and for 1974-1988 it was 3.9, 3.9 and 4.3/100,000/year. Neurological methods and diagnostic criteria were constant throughout the period. The 1950-1964 incidence was based on personally investigated cases, while the 1974-1988 incidence was based partly on review of Gothenburg neurology records. It is concluded that there has been a significant decrease in the incidence of MS in this area. However, the notified decrease may partly be explained by alterations in the case ascertainment procedure. Since the Swedish measles vaccination program started in 1971, the occurrence of measles has been declining and has practically ceased during the 1980s. The time when a possible influence of mass vaccinations against childhood diseases on MS incidence can be monitored is discussed.

Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis.

By matching a cohort of 494 infectious mononucleosis (IM) cases with a multiple sclerosis (MS) register, 3 MS cases were retrieved. The interval between IM and MS was 12 years. This corresponds to a relative risk of 3.7 for MS to occur subsequent to IM (p = 0.05). This relationship between a manifestation of a relatively late Epstein-Barr virus infection and MS may indicate that a microbiologically shielded environment is important in the pathogenesis of MS.