Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS):a double-blind, randomised, placebo-controlled trial

Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (>= 12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of >= 6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1.4 (95% CI 0.6-3.3; p=0.45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Multiple Sclerosis Therapy: A Practical Guide

A growing amount of evidence suggests that a disturbance of immunological function is of importance in the pathogenesis of multiple sclerosis. This is reflected in the drugs used to slow progression and to treat relapses. Immunosuppressive drugs such as azathioprine, cyclophosphamide and cyclosporin might have some potential to slow down progression of multiple sclerosis, but their use is limited by potentially serious adverse effects. Recently, it was shown that interferon-β-1b can diminish the exacerbation rate in multiple sclerosis without leading to unacceptable adverse effects. Nevertheless, symptomatic treatment remains of crucial importance in the management of multiple sclerosis patients. Spasticity, depression, fatigue and urinary, paroxysmal and sensory symptoms can all be alleviated to some extent with pharmacological interventions, although rehabilitation procedures and psychosocial consultations are no less important. Further therapeutic approaches to multiple sclerosis will be directed at either the specificity of the immune response or the grade of activation of the immune response. Magnetic resonance imaging techniques will play an important role in the evaluation of efficacy of new therapeutic agents

The role of spinal cord imaging in the diagnosis of multiple sclerosis

Background: A 29-year-old male presented with fluctuating but progressive sensory disturbances comprising tingling and dysesthesia in his right leg. MRI of the brain showed white matter lesions initially thought to be caused by multiple sclerosis. Investigations: Neurological examination, cerebrospinal fluid examination, laboratory blood testing, brain and spinal MRI scans. Diagnosis: Spinal cord schwannoma. Management: Surgical removal of the schwannoma. An algorithm is provided that clarifies the appropriate MRI work-up for cases where the clinical presentation is suggestive of multiple sclerosis

Neuromyelitis optica spectrum disorder mimicking multiple sclerosis

Background MS is a demyelinating CNS disease and has distinct clinical and radiological features. Neuromyelitis optica spectrum disorder (NMOSD) is an antibody related auto-immune disease known for invalidating episodes of myelitis and optic neuritis. Objective Reporting the case of a 29-year old woman with a disease course typical for relapsing remitting MS with consistent radiological and spinal fluid findings, who developed longitudinally extensive transverse myelitis (LETM) with positive aquaporin 4 antibodies, fulfilling the diagnostic criteria for NMOSD. Methods Case report. Results LETM is not consistent with MS. Consider NMOSD even in patients with typical MS and check for aquaporin-4 antibodies, with important treatment consequences

Patients’ expectations of autologous hematopoietic stem cell transplantation as a treatment for MS

Background: Autologous hematopoietic stem cell transplantation (aHSCT) receives increasing attention as a treatment option for MS. However, as there are no randomized controlled trials comparing aHSCT to best medical treatment as yet, aHSCT is not generally advised and implemented as a treatment option for MS. Neurologists are increasingly faced with patients asking questions regarding aHSCT and seeking commercially offered aHSCT abroad. The aim of this study is to evaluate MS patients’ knowledge and expectations of aHSCT and their actual and desired sources of information. Methods: 137 MS patients visiting the Amsterdam University Medical Center MS clinic, completed a self-developed questionnaire with items on disease history, knowledge about aHSCT, expectations of aHSCT, information sources and the role they assign to their neurologists. Results: Fifty-four percent is considering aHSCT either now or in the future, especially those who are dissatisfied with current treatment, have a shorter disease duration (≤ 10 years) or are more disabled (EDSS > 3.5). Only 25% report to have sufficient knowledge about aHSCT. Patients mainly use potentially unreliable information sources such as the internet and television, although they prefer information from their neurologist. Half of the patients think aHSCT to be superior to highly effective DMT. Expectations of efficacy in patients interested in aHSCT are significantly higher than in patients not wanting to undergo aHSCT. Only about one third of patients are able to mention at least one side effect. Conclusion: Many MS patients are considering aHSCT as a treatment option, although they think that they are not well-informed regarding aHSCT. They prefer their neurologist as a source of information. Therefore, neurologists should pro-actively inform their patients about the potential benefits and risks of aHSCT to enable them to choose the best treatment option

Multiple sclerosis patients show a highly significant decrease in alpha band interhemispheric synchronization measured using MEG

MEG data were acquired from a group of relapsing-remitting multiple sclerosis (MS) patients and a group of healthy controls, using an eyes-closed no-task condition. An interhemispheric coherence measure (IHCM), reflecting the synchronization between the left and right hemispheres, showed a decrease in the patients, particularly in the alpha band. No comparable differences were seen in the alpha band power or its distribution over the head. The observed difference is in agreement with a reduced long-range connectivity in the brains of MS patients. The IHCM was found to be reproducible in controls over a period of more than 15 months. Further studies should investigate whether MEG derived synchronization measures may be useful as markers for MS disease load

Increased production of tumor necrosis factor α, and not of interferon γ, preceding disease activity in patients with multiple sclerosis

Objective: To study whether tumor necrosis factor (TNF) α or interferon (IFN) γ production by stimulated white blood cells precedes or accompanies clinical and magnetic resonance imaging signs of disease activity in patients with multiple sclerosis. Design: Prospective study with a follow-up of 9 months. Setting: Patients visiting an outpatient university clinic. Patients: The 30 Amsterdam-based patients (28 completing all evaluations) participating in a multicenter, randomized, placebo-controlled, double-blind trial of a chimeric anti-CD4 antibody in the treatment of active relapsing-remitting and secondary progressive multiple sclerosis. Patients in both treatment arms were included, because for these patients anti-CD4 treatment in this study did not affect TNF-α and IFN-γ production and did not reduce signs of disease activity on magnetic resonance imaging. Main Outcome Measure: Distribution of classes of TNF-α and IFN-γ production (expressed as z scores) in patients with or without clinical or magnetic resonance imaging signs of disease activity. Results: One month preceding exacerbations of multiple sclerosis, there was a shift toward higher z scores of TNF-α production (P<05), but not of IFN-γ production. There was no statistically significant relationship between IFN-γ and TNF-α production and magnetic resonance imaging markers of multiple sclerosis activity. Conclusion: The production of TNF-α, and not of IFN-γ, is significantly higher in patients with multiple sclerosis before exacerbations than in patients with stable disease. Although present, this relationship is too weak to use TNF-cα production as a surrogate marker of disease activity in multiple sclerosis

Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis: Relation to inflammatory activity

Objective: To evaluate whether degree of inflammatory activity in multiple sclerosis, expressed by frequency of gadolinium enhancement, has prognostic value for development of hypointense lesions on T1-weighted spin- echo magnetic resonance images, a putative marker of tissue destruction. Design: Cohort design with long-term follow-up. Thirty-eight patients with multiple sclerosis who in the past had been monitored with monthly gadolinium-enhanced magnetic resonance imaging for a median period of 10 months (range, 6-12 months) were reexamined after a median period of 40.5 months (range, 33-80 months). Setting: Magnetic Resonance Center for Multiple Sclerosis Research, Amsterdam, the Netherlands, referral center. Main Outcome Measures: The new enhancing lesion rate (median number of gadolinium- enhancing lesions per monthly scan) during initial monthly follow-up; hypointense T1 and hyperintense T2 lesion load at first and last visit. Results: The number of enhancing lesions on entry scan correlated with the new enhancing lesions rate (r = 0.64; P<.001, Spearman rank correlation coefficient). The new enhancing lesion rate correlated with yearly increase in T1 (r = 0.42; P<.01, Spearman rank correlation coefficient) and T2 (r= 0.47; P<.01, Spearman rank correlation coefficient) lesion load. Initial T1 lesion load correlated more strongly with yearly increase in T1 lesion load (r = 0.68; P<.01, Spearman rank correlation coefficient). Conclusions: Degree of inflammatory activity only partially predicted increase in T1 (and T2) lesion load at long-term follow-up. Initial T1 lesion load strongly contributed to subsequent increase in hypointense T1 lesion load, suggesting that there is a subpopulation of patients with multiple sclerosis who are prone to develop destructive lesions