Catherine Lubetzki

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

BACKGROUND Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING Teva Pharmaceutical Industries, Israel.

Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study

Objective: To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS). Methods: Patients with MS with stable disability, and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35. Results: A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 ± 9 in the placebo group and 63 ± 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern. Conclusions: There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.

Neurofascin Is a Glial Receptor for the Paranodin/Caspr-Contactin Axonal Complex at the Axoglial Junction

In myelinated fibers of the vertebrate nervous system, glial-ensheathing cells interact with axons at specialized adhesive junctions, the paranodal septate-like junctions. The axonal proteins paranodin/Caspr and contactin form a cis complex in the axolemma at the axoglial adhesion zone, and both are required to stabilize the junction. There has been intense speculation that an oligodendroglial isoform of the cell adhesion molecule neurofascin, NF155, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex, particularly since paranodin/Caspr and NF155 colocalize to ectopic sites in the CNS of the dysmyelinated mouse Shiverer mutant. We report that the extracellular domain of NF155 binds specifically to transfected cells expressing the paranodin/Caspr-contactin complex at the cell surface. This region of NF155 also binds the paranodin/Caspr-contactin complex from brain lysates in vitro. In support of the functional significance of this interaction, NF155 antibodies and the extracellular domain of NF155 inhibit myelination in myelinating cocultures, presumably by blocking the adhesive relationship between the axon and glial cell. These results demonstrate that the paranodin/Caspr-contactin complex interacts biochemically with NF155 and that this interaction is likely to be biologically relevant at the axoglial junction.

Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-11C]-2-(4′-methylaminophenyl)- 6-hydroxybenzothiazole

Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine‐T derivative 2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker.

Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system

Oligodendrocyte precursor cells, which persist in the adult central nervous system, are the main source of central nervous system remyelinating cells. In multiple sclerosis, some demyelinated plaques exhibit an oligodendroglial depopulation, raising the hypothesis of impaired oligodendrocyte precursor cell recruitment. Developmental studies identified semaphorins 3A and 3F as repulsive and attractive guidance cues for oligodendrocyte precursor cells, respectively. We previously reported their increased expression in experimental demyelination and in multiple sclerosis. Here, we show that adult oligodendrocyte precursor cells, like their embryonic counterparts, express class 3 semaphorin receptors, neuropilins and plexins and that neuropilin expression increases after demyelination. Using gain and loss of function experiments in an adult murine demyelination model, we demonstrate that semaphorin 3A impairs oligodendrocyte precursor cell recruitment to the demyelinated area. In contrast, semaphorin 3F overexpression accelerates not only oligodendrocyte precursor cell recruitment, but also remyelination rate. These data open new avenues to understand remyelination failure and promote repair in multiple sclerosis.

Axonal signals in central nervous system myelination, demyelination and remyelination

Axonal signals are key players in central nervous system myelination. During development, the onset of myelination depends on a balance between positive and negative axonal signals. Among negative signals are inhibitory adhesion molecules that need to be removed from the cell surface for the myelination process to proceed. Positive signals necessary to initiate myelination consist of both interactions with specific adhesion molecules and electrical activity-induced release of promyelinating factors. In multiple sclerosis, demyelination induces major modifications of axonal surface components. The disruption of these factors might participate to the failure of the myelin repair process.

Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy.

ObjectiveTo examine the impact of highly active antiretroviral therapy (HAART) on the outcome of HIV-1-related cognitive impairments using a neuropsychological (NP) battery to assess separately the psychomotor, executive function and memory fields. DesignA longitudinal study of HIV-1-infected patients based on serial NP tests in a Paris University Hospital. MethodsA group of 91 HIV-1-infected patients, of whom 47 were already taking HAART at their first NP examination, were initially categorized as cognitively impaired (n = 53) or non-impaired (n = 38) and underwent one to six serial NP batteries (mean follow-up 12.3 ± 8.3 months). Generalized estimating equations (GEE) were used to evaluate performance in a given NP test according to the number of days on HAART. ResultsDespite a 25% mortality rate among patients who had cognitive impairment at their first NP examination, GEE showed a positive relationship between the duration of HAART and cognitive performance. Performance in psychomotor tests (e.g. Purdue Pegboard dominant hand) improved continuously during the study period, while memory test performance (e.g. Grober and Buschke free recall) tended to reach a plateau. ConclusionsHAART improves subcortical cognitive functions during the first year of treatment. Distinct neuropathological mechanisms appear to underlie psychomotor and memory dysfunctions in AIDS.

Myelin/oligodendrocyte glycoprotein (MOG) expression is associated with myelin deposition

We investigated the onset of expression of the myelin/oligodendrocyte glycoprotein (MOG) mRNA and protein in the developing mouse central nervous system. In situ hybridization on brain sections at different stages of embryonic and postnatal development showed that MOG transcripts were first detected at birth in the medulla oblongata. During the first week after birth, cells expressing MOG mRNA were located in the ventral longitudinal funiculus. During the second postnatal week, the pattern of MOG mRNA expression extended rostrally to the mid‐forebrain regions and reached completion by the beginning of the third week. MOG transcription was delayed by several days with respect to myelin basic protein (MBP), and it appeared that while the MBP probe labeled both non‐myelinating and myelinating oligodendrocytes, only the latter were MOG‐positive. In vitro, immunocytochemical analysis of MOG protein expression, performed on myelinating cultures derived from mouse brain embryos at 15 days of gestation, confirmed the strict restriction of MOG expression to myelinating oligodendrocytes. In particular, oligodendrocytes lining up their processes along axons, but not yet having started to deposit a myelin sheath, were still MOG negative. However, in the same cultures, pseudo‐myelinating oligodendrocytes (i.e., cells not associated with neurites, but forming whorls of myelin‐like figures) were MOG positive. Similarly, rat CG4 cells, an oligodendrocyte‐like cell line, expressed MOG only after they had extended sheet‐like processes, which suggested that the activation of MOG transcription depends more on an intrinsic oligodendroglial maturation program of myelination than on a neuronal signal.

Clinical and spectroscopic improvement in HIV-associated cognitive impairment.

To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.