Recurrence of disease activity during pregnancy after cessation of fingolimod in multiple sclerosis

Background: Fingolimod is an effective treatment for active relapsing-remitting multiple sclerosis (MS). Discontinuation of therapy may be followed by recurrence of disease activity. Thus, female MS patients may be at risk of relapse during pregnancy after stopping fingolimod. Objectives and methods: To report the disease course during pregnancy of five women who interrupted therapy with fingolimod for pregnancy. Results: All patients experienced relapses during pregnancy and/or postpartum after stopping fingolimod. Conclusion: The risk of recurrence of disease activity during pregnancy after stopping fingolimod may be substantial. This should be considered and discussed with MS patients who are planning to become pregnant

An expanded parenchymal CD8+ T cell clone in GABAA receptor encephalitis

The role of T cells in autoimmune encephalitis syndromes with autoantibodies against cell surface antigens is still enigmatic. Here we analyzed the T cell receptor repertoires of CD8+ and CD4+ T cells in a patient with “idiopathic” gamma‐aminobutyric‐acid‐A receptor (GABAA‐R) encephalitis by next‐generation sequencing and single‐cell analyses. We identified a CD8+ T cell clone that was strongly expanded in the cerebrospinal fluid and in the hippocampus but not in the operculo‐insular cortex. By contrast, CD4+ T cells were polyclonal in these tissues. Such a strong clonal expansion suggests that CD8+ T cells may play a significant role in the pathogenesis

Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis

Objective CD8+ T cells are the most prevailing lymphocyte population in inflammatory lesions of patients with multiple sclerosis (MS) but it is not even known whether they are merely passive bystanders or actively communicate with other cells in the brain. To identify their potential interaction partners, we analyzed CD8+ T cells that contained vectorially oriented cytotoxic granules and analyzed the areas to which the granules pointed. Methods We stained cryo‐sections of active MS lesions of an index patient with antibodies to CD8 and perforin, searched for vectorially oriented perforin granules, and isolated target areas opposing the granules and control areas by laser‐microdissection. From both areas, we analyzed cell‐type specific transcripts by next‐generation sequencing. In parallel, we stained samples from the index‐patient and other patients by four‐color immunohistochemistry (IHC). Results We found transcripts of the mononuclear phagocyte (MP) specific markers CD163 and CD11b only in the microdissected target areas but not in control areas. We validated the finding that MPs are communication partners of CD8+ T cells in MS lesions by classical IHC in samples from the index‐patient and other patients with acute and progressive MS and other inflammatory neurological diseases. Interpretation Because CD163 and CD11b are specifically expressed in MPs, our findings suggest that CD8+ T cells communicate with local MPs. Although it is still unclear if these interactions lead to killing of the communication partners by CD8+ T cells, our data underline that CD8+ T cells play an active role in the pathogenesis of MS

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Suggests Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis

Objectives: Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. Materials and Methods: The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects. In an institutional review board-approved study, patients with RR-MS (n = 24;mean age, 36 years;17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16;mean age, 49 years;9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence;2.1 seconds temporal resolution;44 slices;spatial resolution, 1.7 x 1.7 x 3 mm). Regions were defined manually in the middle cerebral artery;in the frontal, periventricular, and occipital NAWM;in the pons;and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model. Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. Results: For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P 0.25) in all evaluated regions. Conclusions: Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies

Review: ‘Gimme five’: future challenges in multiple sclerosis. ECTRIMS Lecture 2009

This article is based on the ECTRIMS lecture given at the 25th ECTRIMS meeting which was held in Düsseldorf, Germany, from 9 to 12 September 2009. Five challenges have been identified: (1) safeguarding the principles of medical ethics; (2) optimizing the risk/benefit ratio; (3) bridging the gap between multiple sclerosis and experimental autoimmune encephalitis; (4) promoting neuroprotection and repair; and (5) tailoring multiple sclerosis therapy to the individual patient. Each of these challenges will be discussed and placed in the context of current research into the pathogenesis and treatment of multiple sclerosis