Harald Nyland

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers C D3, C D4, C D8, C D45RO, and C D20. The highest density of C D3- positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P B-0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the C D4, C D8, and C D45RO markers. C D20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.

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.

Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions

Tissue sections of brains from patients with multiple sclerosis (MS) and from control individuals were immunostained with MHC class II and glial or vascular endothelial cell antibodies and analyzed by confocal microscopy. MHC class II was abundant in and around actively demyelinating MS lesions and was detected on microglia, phagocytic macrophages, and perivascular macrophages. Astrocytes and vascular endothelial cells were MHC class II-negative. Changes in the size and shape of MHC class II-positive cells associated with MS lesions suggest that microglia transform into phagocytic macrophages, and that they are actively involved in demyelination. Many MHC class II-positive perivascular macrophages within MS lesions contained abundant intracellular MHC class II immunoreactivity; these cells may be involved in antigen presentation and in T cell activation.

Effect of dietary advice and n‐3 supplementation in newly diagnosed MS patients

Objective– To investigate whether supplementation with fish oil given together with dietary advice and vitamin supplementation influenced the clinical outcome in newly diagnosed multiple sclerosis (MS) patients. Material and methods– Sixteen consecutive, newly diagnosed patients with multiple sclerosis were recruited to an open intervention study. They were given dietary advice and supplemented with 0.9 g/day of long‐chain marine fatty acids and vitamins. The patients were followed for 2 years with respect to dietary habits, blood parameters and neurological assessment including exacerbation rate. Results– There was a significant reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale (EDSS) as compared to pre‐study values. The plasma total phospholipid n‐3 fatty acids increased and n‐6 fatty acids decreased significantly. Conclusions– The results suggest that fish oil supplementation given together with vitamins and dietary advice can improve clinical outcome in patients with newly diagnosed MS.

Prevalence of bladder, bowel and sexual problems among multiple sclerosis patients two to five years after diagnosis:

Most multiple sclerosis (MS) patients experience some sexual, bladder and/or bowel dysfunction during the course of the disease - one of MS most disabling features. This study estimated the frequency of these problems among patients, two to five years after diagnosis, and investigated how these problems are associated with health-related quality of life (using the Multiple Sclerosis Quality of Life-54 questionnaire). The study population comprised a cohort of patients (n=56), diagnosed in a three-year period, in Hordaland County, Norway. The patients were examined clinically, including scoring of the Expanded Disability Status Scale (EDSS), and completed questionnaires related to bowel and bladder dysfunction, sexual problems and health-related quality of life. More than half the patients had bladder and sexual problems. The frequency of self-reported bladder problems corresponded to the relatively high levels of residual urine found. The presence of these problems was associated with lower scores on the quality of life scales. Further, the bowel problems reported were markedly associated with the quality of life scores. Since treatments and preventive strategies can manage many of these problems, we suggest increasing the focus on these aspects of the disease when consulting patients, including at early stages.

Reactive microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of IgG

Receptors for the Fc part of IgG, FcRI (CD64), FcRII (CD32), and FcRIII (CD16) were studied by indirect immunoperoxidase staining of cryostat sections from normal and multiple sclerosis (MS) brains. Microglia in the parenchyma of normal white matter had a dendritic morphology, and were weakly stained by monoclonal antibodies (mAbs) to FcRI, FcRII, and FcRIII. In active MS lesions reactive microglia were strongly stained by the mAbs 32.2 (FcRI), IV-3 (FcRII), and 3G8 (FcRIII). Perivascular macrophages were stained by all anti-FcR mAbs in both normal white matter and in MS lesions, whereas endothelial cells were stained by the anti-FcRIII mAb only. The FcR on microglia and perivascular macrophages may be of functional importance in antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and local immunoregulation. FcR on endothelium may be of importance in binding and transportation of immune complexes into the CNS. FcR mediated functions may consequently be highly relevant to the pathogenesis of MS.

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 (EDSS57.0) 75.8+3.2%, of walking without walking assistance (EDSS56.0) 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 (43 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.

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.

Fc receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets.

We have utilized surgically resected human central nervous system (CNS) tissue to determine the expression and functions of Fc receptors (FcyR) on individual cell types found within the CNS. We observed all three classes of FcyR on microglial cells in situ and in vitro, but not on astrocytes or oligodendrocytes. Incubation of cultured microglia with immune complexes (antibody-coated red blood cells) induced phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and oxidative bursts. We also found that microglia have the capability to produce T cell stimulatory soluble mediators after FcyR crosslinking. These functional responses were enhanced by pretreatment of the microglia with interferon-y (IFN-y). Our results implicate microglial effector responses triggered by interaction of FcyR with opsonized antigens as potential mediators of tissue injury within the CNS. Such injury may be particularly applicable to multiple sclerosis, an inflammatory demyelinating disease characterized by intrathecal production of immunoglobulins and cytokines.

Health-Related Quality of Life Among Young Adults With Ischemic Stroke on Long-Term Follow-Up

Background and Purpose— We sought to compare health-related quality of life (HRQoL) in young adults with ischemic stroke on long-term follow-up with controls and to evaluate HRQoL in clinically relevant patient subgroups. Methods— HRQoL was determined with the use of the 8 subscales of the Short-Form General Health Survey (SF-36). Subgroups of patients were defined by sex, age, functional status (modified Rankin Scale), marital status, education, depression (Montgomery-Åsberg Depression Rating Scale), and fatigue (Fatigue Severity Scale). SF-36 scores among patients were compared with SF-36 scores among age- and sex-matched controls and SF-36 scores available from the general Norwegian population. Results— SF-36 scores were obtained after a mean follow-up of 6.0 years among 190 young adults with ischemic stroke during 1988–1997 and among 215 responding controls (55%). The difference in HRQoL between patients, controls, and the general Norwegian population was restricted mainly to the 3 subscales physical functioning, general health, and social functioning (P<0.001). Subgroup analysis showed significantly reduced scores for all SF-36 items among patients who were depressed, suffered from fatigue, or unemployed. Linear regression analysis showed that fatigue and depression were major independent variables correlated with low HRQoL. Conclusions— Compared with controls and the general Norwegian population, low level of HRQoL among young adults with ischemic stroke was most pronounced in regard to physical functioning. Early identification and treatment of depression, fatigue, and physical disability may potentially improve HRQoL among stroke patients.