Long-term follow-up of benign multiple sclerosis in Hordaland County, Western Norway.

OBJECTIVE: To study the frequency of benign multiple sclerosis (MS) after 20 years disease duration and identify early clinical and demographic prognostic factors of a benign course. METHODS: A population-based cohort including all 230 MS patients with clinical disease onset during 1976-1986 in Hordaland County, Western Norway was followed up with clinical examination in 1995 and 2003. Benign MS was defined as an Expanded Disability Status Scale (EDSS) score

Relationship of cognitive impairment to psychiatric symptoms in multiple sclerosis.

Psychiatric and cognitive changes are common in patients with multiple sclerosis (MS), but their relationship has not received much attention. We studied the relationship between psychiatric symptoms and verbal memory, working memory, and mental speed in 78 patients with MS and 40 healthy control subjects using linear regression analyses. The MS group exhibited impaired performance on all cognitive tests. Apathy was associated with intrusions and depression with impaired memory and mental speed. The association between apathy and intrusions supports the hypothesis that lesions in frontal areas or frontal connections contribute to a specific neuropsychiatric syndrome in patients with MS.

FcgammaR and multiple sclerosis: an overview.

Receptors for the Fc domain of IgG (FcgammaR) play a key role in the immune system by linking the cellular and humoral immune systems. Despite extensive documentation of CNS-specific antibodies in cerebrospinal fluid and plaques in multiple sclerosis (MS) patients, the role of FcgammaR in this disease remains largely unexplored. Studies indicate however, that polymorphisms in some FcgammaR genes and treatment that induces FcgammaR on immune-competent cells could influence disease progression and treatment response.

High dose methylprednisolone induces FcgammaRI on granulocytes in MS-patients.

Immune complexes impinge on receptors for the Fc domain of IgG (FcgammaR) and may thus influence the disease course in multiple sclerosis (MS). We analyzed FcgammaR distribution on monocytes and granulocytes in twenty relapsing-remitting MS patients at baseline, immediately after a five day course of high dose intravenous methylprednisolone (IVMP) treatment and after two months. After a five day course of IVMP the proportion of granulocytes with FcgammaRI was increased, P=0,002. There was no change in FcgammaRII and FcgammaRIII expression. The effect of IVMP on FcgammaRI expression could be important for the clearance of immune complexes in MS.

Mild depression in young adults with cerebral infarction at long-term follow-up: a population-based study.

We sought to evaluate the prevalence of and risk factors for post-stroke depression (PSD) at long-term follow-up in young adults aged 15-49 years with first-ever cerebral infarction in a population-based study. Scores on Montgomery-Asberg Depression Rating Scale (MADRS) were obtained at follow-up (mean time 6.0 years after the stroke) and analysed in subgroups. MADRS scores were obtained in 196 of 209 surviving patients. PSD (MADRS>or=7) was detected in 56 patients (28.6%). None had severe PSD. Alcoholism (P=0.006), depressive symptoms any time before the index stroke (P=0.016), and severe neurological deficits on admission for the index stroke (P=0.043) were independently associated with PSD. PSD seems milder in young ischaemic stroke patients compared with older patients. Alcoholism, depression any time before the index stroke, and severity of neurological deficits on admission for the stroke increased the risk of developing PSD in the long run.

Long-term outcome of cerebral infarction in young adults.

OBJECTIVES: We analysed the long-term outcome of 232 young adults aged 15-49 years with first-ever cerebral infarction in 1988-1997 in western Norway. MATERIAL AND METHODS: Mortality, recurrence, epilepsy, functional state as evaluated by modified Rankin scale (mRS), and employment were analysed at follow-up (mean time 5.7 years). RESULTS: Twenty-three (9.9%) patients had died. Recurrence occurred in 9.9%, and post-stroke seizures developed in 10.5%. Recurrence was associated with diabetes mellitus (P = 0.005). Favourable functional outcome (mRS = 2) was found in 77.9%. The functional outcome was better in posterior than anterior circulation infarctions (P = 0.011). Unfavourable functional outcome (mRS > 2) was associated with diabetes mellitus (P = 0.001) and severity of neurological deficits on admission for the index stroke (P < 0.001). Only 58.3% were employed at follow-up. CONCLUSION: This population-based study shows that, although the majority had favourable functional outcome, cerebral infarction had major long-term impact on young adults as evaluated by mortality, recurrence and employment status.

Etiology of and risk factors for cerebral infarction in young adults in western Norway: a population-based case-control study.

We sought to study the etiology of and risk factors for cerebral infarction in young adults in Hordaland County, Norway. All patients aged 15-49 years living in Hordaland County with a first-ever cerebral infarction during 1988-97 were included. Etiology was analyzed in subgroups defined by sex, age (<40 years versus >/=40 years), circulation territory (anterior versus posterior circulation) and short-term functional outcome [modified Rankin score (mRS) 2]. A questionnaire was used to evaluate possible risk factors amongst the patients compared with an age- and sex-matched control group. The distribution of etiology was significantly different in all subgroups. Atherosclerosis was frequent amongst men (22.8% vs. 4.2%) and patients >/= 40 years (20.8% vs. 2.7%). All patients with microangiopathy had favorable short-term outcome. Significant risk factors were smoking more than 15 cigarettes per day (P < 0.001), hypertension (P = 0.001), and myocardial infarction (P = 0.035). Modifiable risk factors were frequent.

Interleukin-10 promoter polymorphisms in patients with Guillain-Barré syndrome.

Interleukin-10 (IL-10) may have both pro- and anti-inflammatory effects in Guillain-Barré syndrome (GBS). The distribution of polymorphisms in the IL-10 gene (-1082 (G/A), -819 (T/C) and -592 (A/C)) was analysed to determine whether they could influence disease susceptibility or clinical course in GBS. The -592 CC and -819 CC genotypes associated with increased IL-10 response were more frequent in the GBS patients than in the controls (P=0.027), but the polymorphisms did not influence the clinical course of the disease.

Incidence and short-term outcome of cerebral infarction in young adults in western Norway.

BACKGROUND AND PURPOSE: We sought to determine the incidence and short-term outcome of people aged 15 to 49 years with first-ever cerebral infarction in 1988-1997 in Hordaland County, Norway. METHODS: Cases were found from computer search of hospital registries and detailed review of patient records. Stroke subtype was classified according to the major intracranial artery affected. Short-term outcome was evaluated by the modified Rankin Scale (mRS). RESULTS: A total of 96 women and 136 men met the inclusion criteria. The average annual incidence was 11.4/100 000. Women outnumbered men among those aged <30 years (P=0.059); men predominated among those aged > or =30 years (P=0.004). A total of 148 patients had anterior circulation infarction (64%), and 84 had posterior circulation infarction (36%) (P<0.001). Patients with posterior circulation infarction had better mRS score at discharge (P=0.005). Eighty percent had favorable outcome (mRS score < or =2). The 30-day case fatality rate was 3.4%. The recurrence rate in hospital was 2.2%. CONCLUSIONS: The incidence was in the lower range compared with other reports from western Europe. Although men predominated, there was a strong trend toward more women among patients aged <30 years. Short-term outcome was generally good. Patients with posterior circulation infarction had significantly better short-term outcome.

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction.

OBJECTIVE: Physical disability explains only part of the reduced quality of life found among multiple sclerosis (MS) patients. Bladder dysfunction and sexual disturbance are frequent and distressing problems for MS patients. We therefore estimated the relationship between the presence and degree of sexual disturbance/bladder dysfunction and the patients' quality of life as measured by the SF-36 Health Survey. METHODS: We performed a cross-sectional study of all individuals with the onset of MS between 1976 and 1986 in Hordaland County, Norway. The disease duration at examination was 9-19 years; 194 patients (94%) participated. RESULTS: Fifty-three per cent of the patients with low physical disability (Expanded Disability Status Scale (EDSS) < or = 4.0) reported disease-related sexual disturbance and 44% had bladder dysfunction according to the Incapacity Status Scale. The corresponding figures for the patients with a high physical disability (EDSS > 4.0) were 86 and 81% respectively. The patients with sexual disturbance had markedly and significantly reduced scores on all eight SF-36 scales, this was after adjustment for disease development measured by the EDSS. The patients without sexual disturbance scored 0.5 s.d. lower than a normal population on the social functioning scale, whereas those with marked sexual disturbance scored 1.5 s.d. lower. Similar results were found for the patients with bladder dysfunction. CONCLUSION: Bladder and sexual problems are associated with a marked reduction in the quality of life, also among patients with otherwise low disability. This underlines the need for identifying and treating these problems.

Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension.

OBJECTIVE: To evaluate disability and prognosis in an untreated population-based incidence cohort of multiple sclerosis (MS) patients. METHODS: The Expanded Disability Status Scale (EDSS) score was recorded in 220 MS patients. Disease progression was assessed by life table analysis with different endpoints and multivariate Cox regression analysis was performed for evaluation of prognostic factors. RESULTS: The probability of being alive after 15 years was 94.8 +/- 1.8% (s.e.), of managing without a wheelchair (EDSS < 7.0) 75.8 +/- 3.2%, of walking without walking assistance (EDSS<6.0) 60.3 +/- 3.6%, and of not being awarded a disability pension 46.0 +/- 3.7%. The probability of still having a relapsing-remitting (RR) course after 15 years was 62.0 +/- 4.1%. A RR course and long interval between the initial (onset) and second episode (> 3 years) predicted favorable outcome. There was also a trend towards favorable outcome in patients with optic neuritis, sensory symptoms and low age at onset but these factors were associated with the RR course. Motor symptoms and high age at onset indicated unfavorable outcome, but these factors were associated with the primary progressive course. CONCLUSIONS: A RR course and long inter-episode intervals in the early phase of the disease were associated with a better outcome. Other onset characteristics indicating a favorable outcome were associated with the RR course while characteristics indicating an unfavorable outcome were associated with the PP course.

Neutralizing antibodies to interferon (IFN) alpha-2a and IFN beta-1a or IFN beta-1b in MS are not cross-reactive.

Sera from patients with MS treated with recombinant interferon (rIFN) alpha-2a, rIFNbeta-1a, or rIFNbeta-1b were analyzed for cross-reacting neutralizing antibodies (NAB). Because cross-reactivity was not found, switching treatment from rIFNbeta-1a or rIFNbeta-1b to rIFNalpha-2a might provide a secondary treatment response in patients with NAB to rIFNbeta-1a or rIFNbeta-1b. A positive treatment response also might be achieved by switching NAB rIFNalpha-2a-positive patients to rIFNbeta-1a or rIFNbeta-1b.

Performance of the SF-36, SF-12, and RAND-36 summary scales in a multiple sclerosis population.

BACKGROUND: Multiple sclerosis (MS) patients accumulate both physical and mental health problems along with disease progression. Valid and sensitive outcome measures are important to measure disease effects and the effect of treatment. OBJECTIVE: The objective of this study was to test the performance of the physical and mental summary scales of SF-36, SF-12, and RAND-36. METHODS: The scales were evaluated by comparing the scores of a cohort of 194 MS patients with general population data and using the Expanded Disability Status Scale (EDSS) and the Incapacity Status Scale-mental as criterion variables for physical functioning and mental health. RESULTS: All 3 physical summary scales were markedly reduced and correlated highly with the EDSS. The SF-36 mental summary score was only slightly reduced among MS patients (0.2 SD) compared with the general population, despite significantly reduced scores on all 4 health scales being most related to mental health and despite a high prevalence of mental health problems. This results from the poor physical functioning (mean scale score, 2.3 SD below the general population) and the orthogonal factor rotation used to derive independent measures of physical and mental health. Similar results were found for the SF-12. The nonorthogonal RAND-36 physical and mental summary scores were both markedly reduced. This is more compatible with the disease progression in MS and the results of the other measures of physical and mental health used in the study. CONCLUSIONS: The SF-36 and SF-12 mental health summary scales appear to overestimate mental health in people with MS.

Quality of life as a predictor for change in disability in MS.

OBJECTIVE: To investigate the predictive value of quality of life on changes in disability measured by the Expanded Disability Status Scale (EDSS). BACKGROUND: There are few good prognostic factors for disease development in MS. Quality of life and self-rated health have been shown to be highly predictive of morbidity and disease development in heart disease and cancer. METHODS: Data on quality of life (SF-36 Health Survey) were ascertained at baseline for 97 relapsing-remitting patients with MS participating in a short-term clinical trial on interferon alpha-2a. These scores were correlated with change in EDSS scores 1 year later, 6 months after treatment ended. RESULTS: Low scores on the SF-36 mental health scale were correlated with increased (worsened) EDSS scores 1 year later (r = -0.29, p = 0.006). The results were not altered by adjusting for disease activity at baseline, which was measured by the number gadolinium-enhanced MRI lesions, relapse rate for the preceding 2 years, and baseline EDSS score. Similar results were found for self-rated health (according to the first question of the SF-36). CONCLUSIONS: These findings reinforce the importance of incorporating the patients' evaluation of their quality of life during treatment. Further, assessing such measures is important in evaluating effects in treatment trials in MS.

Interferon-alpha2a effects on complement activation and regulation in MS patients.

OBJECTIVES: To evaluate the treatment effect of recombinant interferon-alpha2a (rIFN-alpha2a) on complement activation and regulation in MS patients. MATERIAL AND METHODS: Plasma levels of the complement activation products C3bc and terminal complement complex (TCC) and serum levels of the complement regulatory proteins, complement receptor 1, CR1 (CD35) and the membrane inhibitor of reactive lysis, protectin (CD59), were determined by enzyme-linked immunosorbent assay (ELISA) in MS patients treated with IFN-alpha2a (14 patients) or placebo (7 patients). RESULTS: The level of soluble CD35 decreased while the level of TCC and to a lesser degree C3bc increased in the IFN-alpha2a treated patients during the initial part of the treatment. There was also a concomitant reduction of leukocytes in the same patients. CONCLUSIONS: The results indicate that complement is activated during the initial phase of rIFN-alpha2a treatment. This could partly be due to a concomitant reduction in soluble CD35.

Type I interferons and the quality of life of multiple sclerosis patients. Results from a clinical trial on interferon alfa-2a.

The objective of the study was to examine whether the beneficial effect of treatment of interferon alfa-2a on multiple sclerosis seen by magnetic resonance imaging is reflected in a corresponding improvement in the quality of life (QoL) and to address the impact of adverse events related to this treatment on the QoL. The study was a randomised double-blinded placebo-controlled treatment trial including 97 relapsing-remitting multiple sclerosis patients. Thirty-two patients received 4.5 MIU recombinant interferon alfa-2a, 32 patients received 9.0 MIU recombinant interferon alfa-2a and 33 patients received placebo treatment for 6 months. All patients were followed up 6 months after end of treatment. QoL was assessed according to the eight scales of the SF-36 Health Survey and measured at baseline, month 3, 6 and 12. The effect found on MRI was not reflected in a corresponding change in the QoL. We found a relationship between the presence of new enhancing lesions and reduced QoL among the placebo patients, whereas this was not found among the patients treated with interferon. The presence of the adverse events fatigue, myalgia, headache and weakness were significantly negatively correlated to several of the QoL dimensions. Conclusively, the treatment with interferon alfa-2a does not seem to improve the patients' QoL after 6 months of treatment, in spite of a marked effect measured by MRI. The treatment is followed by adverse events that negatively affected the QoL.

Quality of life in multiple sclerosis: measuring the disease effects more broadly.

OBJECTIVE: To compare the Expanded Disability Status Scale (EDSS) and self-rated quality of life scores (SF-36 Health Survey) as measures of disease impact in a representative sample of MS patients. BACKGROUND: The EDSS is the most common outcome measure of impairment/disability for MS patients but is heavily weighted toward mobility. Sensitive outcome measures are needed that also capture other aspects of the effects of MS. METHODS: The authors performed a cross-sectional study of the cohort of all individuals with onset of MS between 1976 and 1986 who were diagnosed before 1995 in Hordaland County, Norway. A total of 194 patients (94%) participated. RESULTS: The patients had lower mean scores for all eight SF-36 health dimensions compared with sex- and age-adjusted scores in a general population. EDSS scores correlated highly with physical functioning (r = -0.86, R2 = 0.73), and explained some of the variation in social functioning (r = -0.48, R2 = 0.23) and general health (r = -0.46, R2 = 0.21) but little for the other dimensions. CONCLUSIONS: The SF-36 captures the broad effects of MS, and the results showed that patients also are bothered frequently with health problems such as bodily pain and low vitality. These problems, which are not reflected in the Expanded Disability Status Scale, should be given more attention in the treatment of MS and when evaluating interventions.

Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of interferon-alpha2a (IFN-alpha2a) in relapsing-remitting MS (RRMS). BACKGROUND: Several immune-modulating therapy regimens of IFN-alpha have shown varying results in MS. A recent pilot study suggested benefits from IFN-alpha2a. METHODS: Ninety-seven patients were randomized to receive subcutaneous injections of placebo (33 patients) or 4.5 million international units (mIU) (32 patients) or 9.0 mIU (32 patients) of IFN-alpha2a three times weekly for 6 months, with a further 6 months of follow-up. Monthly gadodiamide-enhanced MRI was the primary method of evaluating efficacy. RESULTS: IFN-alpha2a treatment resulted in fewer new MRI lesions during the treatment period (p < 0.003). The probability of no new lesions during treatment was >2.5 times higher with 9.0 mIU IFN-alpha2a than with placebo (p < 0.005). The median number of lesions at the end of treatment was lower with IFN-alpha2a treatment than with placebo (p = 0.0004), but the difference disappeared during follow-up. The total number of lesions (mean) increased by 4.78 with placebo, 0.86 with 4.5 mIU IFN-alpha2a, and 0.28 with 9.0 mIU IFN-alpha2a during treatment (p = 0.030). No treatment effect on exacerbation rate, progression of disability, or quality of life was detected. Nine patients discontinued treatment, five because of adverse events. CONCLUSIONS: IFN-alpha2a treatment significantly reduced disease activity as measured by MRI, but the efficacy disappeared within 6 months after discontinuation of treatment. A long-term study of more patients using disability as a primary outcome measure is needed to evaluate the clinical impact.