de Jacques Keyser

Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors

Background: In MS, T cells reactive to myelin proteins can cross the blood–brain barrier and release proinflammatory cytokines, such as interferon γ. These can induce glial cells to express class II major histocompatibility complex (MHC) molecules, which are required to present myelin antigens to the T cells in order to mount a proper autoimmune response. Both microglia and astrocytes can function as antigen-presenting cells. In contrast to microglia, endogenous suppressors, including norepinephrine, regulate astrocytic class II MHC expression. The effects of norepinephrine are mediated through activation of β2 adrenergic receptors. Objective: To investigate β2 adrenergic receptors in astrocytes in MS. Methods: Immunocytochemical techniques were applied in postmortem brain tissue from 10 patients with MS, three patients with a cerebral infarction, and six controls, and in spinal cord from three patients with ALS. Results: β2 adrenergic receptors were visualized on astrocytes in white matter of controls, and they were prominently expressed in reactive astrocytes at the boundary of cerebral infarctions and in the lateral corticospinal tract in ALS. In MS, β2 adrenergic receptors could neither be visualized on astrocytes in normal-appearing white matter nor in reactive astrocytes in chronic active and inactive plaques, whereas they were normally present on neurons. MHC class II–positive astrocytes were only visualized in chronic active plaques. Conclusions: Because astrocytic β2 adrenergic receptors are involved in suppressing inducibility of MHC class II molecules, we suggest that their lack of expression may play an important role in the induction or perpetuation of autoimmune reactions in MS.

Benign course in multiple sclerosis: a review

Since the 1950s, it has been recognized that a subgroup of multiple sclerosis (MS) patients exists that shows little or no progression in the severity of the disease over time. This group is referred to as ‘benign’ MS. Although a substantial amount of research in MS indicates a multifactorial background in disease severity, to date it is still difficult to predict whether the course will be benign at onset and it is difficult to find factors that influence the course of the disease over time. Maintaining or restoring neural conduction inside a central nervous system lesion seems to be the essence of staying ‘benign’.

Efficacy of desmopressin in patients with multiple sclerosis suffering from bladder dysfunction: a meta-analysis

Objectives –  The current review evaluates the safety and efficacy of desmopressin in patients with multiple sclerosis (MS) who suffer from both daytime and nocturnal voiding frequency and from incontinence.

Early prediction of a benign course of multiple sclerosis on clinical grounds: a systematic review

Background: There is growing consensus that neurologists should consider disease-modifying therapies early in multiple sclerosis (MS). However, there is a subgroup with a natural benign course, in which treatment could be postponed. We sought to determine the frequency of benign MS and early clinical factors that may predict a benign course. Methods: We performed a systematic review of the existing literature on benign MS, which was defined as minimal or no disability equivalent to a score on the Expanded Disability Status Scale (EDSS) 43.0 at least 10 years after disease onset. Results: Only a small number of studies of adequate quality was available. In total there were nine published studies representing 2204 patients. The estimated frequency of benign MS was 26.7%. Onset with optic neuritis, onset before the age of 40 years, absence of pyramidal signs at presentation, duration of first remission more than 1 year, and only one exacerbation in the first 5 years after onset of MS, were associated with a benign course. Conclusions: From the existing literature a set of unrelated clinical characteristics emerged that was associated with a benign course of MS. However, there is a need for prospective studies to define more precisely clinical and paraclinical predictors of benign MS.

Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study

Background: Suppressing the antigen-presenting capacity of glial cells could represent a novel way of reducing inflammatory activity in multiple sclerosis (MS). Aims: To evaluate the effects of fluoxetine on new lesion formation in patients with relapsing MS. Methods: In a double-blind, placebo-controlled exploratory study, 40 non-depressed patients with relapsing remitting or relapsing secondary progressive MS were randomised to oral fluoxetine 20 mg or placebo daily for 24 weeks. New lesion formation was studied by assessing the cumulative number of gadolinium-enhancing lesions on brain MRI performed on weeks 4, 8, 16 and 24. Results: Nineteen patients in both groups completed the study. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine group and 5.16 (8.6) in the placebo group (p = 0.15). The number of scans showing new enhancing lesions was 25% in the fluoxetine group versus 41% in the placebo group (p = 0.04). Restricting the analysis to the past 16 weeks of treatment showed that the cumulative number of new enhancing lesions was 1.21 (2.6) in the fluoxetine group and 3.16 (5.3) in the placebo group (p = 0.05). The number of patients without enhancing lesions was 63% in the fluoxetine group versus 26% in the placebo group (p = 0.02). Conclusions: This proof-of-concept study shows that fluoxetine tends to reduce the formation of new enhancing lesions in patients with MS. Further studies with this compound are warranted. Trial registration: Number: ISRCTN65586975

Cooling garment treatment in MS: Clinical improvement and decrease in leukocyte NO production

Ten heat-sensitive patients with MS were randomly allocated in a cross-over study to wear a cooling garment for 60 minutes at 7 °C (active cooling) and 26 °C (sham cooling). In contrast to sham cooling, active cooling improved fatigue and postural stability with eyes closed and muscle strength. There was no decrease in tympanic temperature, but active cooling was associated with a 41% decrease in mean leukocyte nitric oxide (NO) production (p = 0.004). This effect on NO could be relevant because it blocks conduction in demyelinated axons.

Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis

BackgroundThe role of oxidative stress in patients with multiple sclerosis (MS) is poorly understood.ObjectiveTo investigate oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of MS.MethodsDiene conjugate (DC) levels (a measure of lipid peroxidation), total antioxidative activity (AOA) and total antiradical activity (ARA) were measured in serum and peripheral blood leukocytes from 30 patients with benign relapsing remitting MS (BMS), 27 with secondary progressive MS (SPMS), 29 with primary progressive MS (PPMS), and 30 healthy controls. All MS patients were in a clinically stable phase.ResultsSerum DC levels were elevated in patients with BMS (p <0.05), SPMS (p <0.01) and PPMS (p <0.001). Serum total AOA and ARA were not different between MS patients and controls. Compared to controls, leukocyte DC levels were not different in each MS subgroup, but total ARA was elevated. There was a strong correlation, both in controls and MS patients, between leukocyte DC levels and leukocyte total ARA (p <0.0001) and leukocyte total AOA (p <0.0001).ConclusionOxidative stress occurs in progressive as well as benign MS. The finding that cells withstand oxidative stress, due to upregulated cellular antioxidant defence mechanisms, suggests that reactive oxygen species (ROS) formation in MS is not necessarily deleterious.

Plasma lipid peroxidation and progression of disability in multiple sclerosis

Oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS), but its relation to disease progression is uncertain. To evaluate the relationship of plasma lipid peroxidation with progression of disability in MS, we measured blood plasma fluorescent lipid peroxidation products (PFLPP) levels in 23 patients with RRMS with a benign course, 32 with secondary progressive MS, 24 with primary progressive MS and 30 healthy controls. None of the patients had a relapse within the previous 3 months. Progression of disability was evaluated during a follow‐up period of 5 years by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). We found plasma PFLPP levels elevated in patients with MS compared with controls (P < 0.0001), but there was no difference between patients with a benign and progressive disease course. There was no correlation between PFLPP levels and worsening of disability on the EDSS and speed of progression on the MSSS. Our data suggest that there is no relation between the degree of oxidative stress in plasma and progression of disability in MS.

A randomized crossover study of bee sting therapy for multiple sclerosis

Background: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. Methods: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy’s Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). Results: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. Conclusions: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

Parity and secondary progression in multiple sclerosis

Background: Pregnancy has a well-documented effect on relapses in multiple sclerosis (MS), whereas little is known about the impact of pregnancy and childbirth on the risk of secondary progression. Objective: To investigate the association of parity and secondary progression in women with MS. Methods: The association of the number of births and secondary progression was studied in a hospital-based cohort of 277 women with MS. Data were analysed in a multivariable logistic regression model, with adjustment for possible confounders. Results: Parity was not independently associated with secondary progression, while the factors disease duration (OR per year increase: 1.05, 95% CI 1.03 to 1.09) and use of immunomodulatory treatments (OR 0.23, 95% CI 0.08 to 0.65) were independently associated with secondary progression. Conclusion: We found no evidence that parity influences the risk of secondary progression in MS. Further population-based studies on the association of pregnancy and childbirth on the long-term prognosis of MS are needed.