Vaccine-associated measles in a patient treated with natalizumab: a case report

Safety of live vaccines in patients treated with immunosuppressive therapies is not well known, resulting in contradictory vaccination recommendations. We describe here the first case of vaccine-associated measles in a patient on natalizumab treatment. A young female patient with relapsing-remitting multiple sclerosis on natalizumab treatment received the live attenuated measles, mumps, and rubella vaccine in preparation for a change in her treatment in favour of fingolimod, with established immunosuppressive qualities. Seven days after receiving the vaccine, our patient experienced diffuse muscle pain, fatigue, and thereafter developed a fever and then an erythematous maculopapular rash, compatible with vaccine associated measles. This was later confirmed by a positive measles RT-PCR throat swab. The patient's symptoms resolved without any sequelae. In this case report we review the immunosuppressive qualities of natalizumab and the evidence in favour and against live vaccines in patients on this treatment. Our findings reveal the insufficient understanding of the immunosuppressive effects of new immunomodulators, and thus of the safety of live vaccines in patients on such medications. While this case triggers precaution, there is insufficient evidence to conclude that natalizumab treatment could favor the onset of vaccine-associated measles

Discussing Challenges in Diagnosis of Tuberculous Meningitis and Neurosarcoidosis.

Isolated chronic granulomatous meningitis remains a diagnostic challenge for the physician. Symptoms are often nonspecific and ancillary tests have low-sensitivity rates, which may delay targeted treatment and lead to increased morbidity and mortality. Here, we discuss the challenges in diagnosing and treating patients with chronic meningitis by reporting two cases of previously healthy patients who presented with granulomatous meningitis on brain biopsy

Intravenous Corticosteroids as an Adjunctive Treatment for Refractory and Super-Refractory Status Epilepticus: An Observational Cohort Study.

Status epilepticus (SE) represents a neurological emergency that leads to considerable morbidity and mortality. Following failure of first-line therapy, usually with benzodiazepines, there is no clear evidence to guide treatment of refractory SE, although a wide variety of approaches has been described anecdotally. The aim of this study was to assess the clinical response to corticosteroids in adults with refractory and super-refractory SE, describing, to the best of our knowledge, the first adult SE cohort treated with corticosteroids. We retrospectively analysed our adult SE registry (2006-2017), identifying 15 out of 987 episodes (1.5%) in which corticosteroids were prescribed de novo as adjuvant therapy to a variety of antiepileptic drug regimens. We analysed incident episodes and defined clinical response as SE ceasing within 1 week of administration, without any other medical intervention. Out of 987 SE episodes, 15 (1.5%) were treated with de novo corticosteroids, corresponding to 12 patients, with increasing prevalence as the SE became refractory (10/411; 2.4% of episodes) and super-refractory (5/108; 4.6% of episodes). One patient (a woman with Rasmussen encephalitis) presented with four SE episodes over a period of 3 years, so only her index SE episode was included in subsequent analyses. The episodes treated were predominantly of inflammatory origin (6/12), such as autoimmune or Rasmussen encephalitis. In five out of 12 (42%) of the considered incident episodes, SE resolved following corticosteroids (all within 3 days). The outcome was better in this responders group (for 2/5 episodes, patients did not have a new handicap at discharge, versus 0/7 in non-responders). In patients with inflammatory and acute symptomatic causes, global prognosis was better than in those with progressive or neurodegenerative aetiologies (6/8 vs. 4/4 had a new handicap at discharge or died). Our observations seem to support the use of corticosteroids, especially for acute SE of putative inflammatory origin; these compounds, however, were prescribed infrequently

Environmental factors in multiple sclerosis [Environmental factors in multiple sclerosis]

Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual genetic susceptibility seems to influence MS onset and clinical expression, as well as therapeutic responsiveness. Multiple human epidemiological and animal model studies have evaluated the effect of different environmental factors, such as viral infections, vitamin intake, sun exposure, or still dietary and life habits on MS prevalence. Previous Epstein-Barr virus infection, especially if this infection occurs in late childhood, and lack of vitamin D (VitD) currently appear to be the most robust environmental factors for the risk of MS, at least from an epidemiological standpoint. Ultraviolet radiation (UVR) activates VitD production but there are also some elements supporting the fact that insufficient UVR exposure during childhood may represent a VitD-independent risk factor of MS development, as well as negative effect on the clinical and radiological course of MS. Recently, there has been a growing interest in the gut-brain axis, a bidirectional neuro-hormonal communication system between the intestinal microbiota and the central nervous system (CNS). Indeed, components of the intestinal microbiota may be pro-inflammatory, promote the migration of immune cells into the CNS, and thus be a key parameter for the development of autoimmune disorders such as MS. Interestingly most environmental factors seem to play a role during childhood. Thus, if childhood is the most fragile period to develop MS later in life, preventive measures should be applied early in life. For example, adopting a diet enriched in VitD, playing outdoor and avoiding passive smoking would be extremely simple measures of primary prevention for public health strategies. However, these hypotheses need to be confirmed by prospective evaluations, which are obviously difficult to conduct. In addition, it remains to be determined whether and how VitD supplementation in adult life would be useful in alleviating the course of MS, once this disease has already started. A better knowledge of the influence of various environmental stimuli on MS risk and course would certainly allow the development of add-on therapies or measures in parallel to the immunotherapies currently used in MS

Maladies neuro-inflammatoires

Les nouvelles possibilités thérapeutiques ont changé l’évolution et la prise en charge des patients souffrant des maladies neuro-inflammatoires, permettant dans de nombreux cas de ralentir la progression de la maladie. Une collaboration étroite entre neurologue et médecin de famille est donc plus que jamais essentiel afin d’assurer un diagnostic précoce, une introduction rapide et sécuritaire du traitement immunomodulateur et un suivi régulier de leur toxicité potentielle

First-ever treatment in multiple sclerosis.

The current treated MS population is very different from that of patients in randomized clinical trials. To study the long-term efficacy and tolerance of fingolimod (FTY) and dimethyl fumarate (DMF), both available as first-line treatment in early-treated treatment-naïve MS patients. Retrospective analysis of 75 patients from our prospective MS registry fulfilling the inclusion criteria: FTY or DMF as first-line treatment, treatment initiation within 36months of disease onset and treatment duration>12months. Demographics and MRI characteristics at baseline were similar in both groups (FTY 55 patients, DMF 20), but patients on FTY had higher pretreatment clinical activity (P=0.008). Twenty-two percent of patients in the FTY group and 15% in the DMF group had highly active disease. At last follow-up (mean: 44.2, SD: 17.3months), the majority of the patients were still on treatment while 54.5% of FTY and 65% of DMF patients reached NEDA 3 status (P=0.444). Both treatments significantly decreased relapses and occurrence of new T1 Gd-enhancing lesions (P<0.001). The main reason for discontinuation was disease activity without severe side effects on either treatment. Our findings support efficacy and tolerance of both drugs in early-treated treatment-naive MS patients, arguing in favour of efficient early immunomodulation in MS patients. Both drugs significantly reduced the incidence of new relapses and Gd-enhancing lesions on treatment with FTY being more frequently prescribed than DMF, especially in patients with evidence of higher clinical disease activity

Interaction between Neurons and the Oligodendroglial Lineage in Multiple Sclerosis and Its Preclinical Models

International audienceMultiple sclerosis (MS) is a complex central nervous system inflammatory disease leading to demyelination and associated functional deficits. Though endogenous remyelination exists, it is only partial and, with time, patients can enter a progressive phase of the disease, with neurodegeneration as a hallmark. Though major therapeutic advances have been made, with immunotherapies reducing relapse rate during the inflammatory phase of MS, there is presently no therapy available which significantly impacts disease progression. Remyelination has been shown to favor neuroprotection, and it is thus of major importance to better understand remyelination mechanisms in order to promote them and hence preserve neurons. A crucial point is how this process is regulated through the neuronal crosstalk with the oligodendroglial lineage. In this review, we present the current knowledge on neuron interaction with the oligodendroglial lineage, in physiological context as well as in MS and its experimental models. We further discuss the therapeutic possibilities resulting from this research field, which might allow to support remyelination and neuroprotection and thus limit MS progression

Recurrence of disease activity after fingolimod discontinuation in older patients previously stable on treatment.

Discontinuing fingolimod (FTY) in older patients is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal. To estimate the incidence of recurrence of disease activity (RDA) and rebound after FTY withdrawal in patients older than 50 years. Retrospective analysis of all MS patients in our clinic who discontinued FTY after at least 6 months of treatment, according to disease activity on FTY and age at discontinuation. RDA was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal and rebound when the levels of disease activity surpassed pretreatment activity. From the 128 patients who discontinued FTY since 2011, up to 35.2% of patients experienced evidence of disease activity and 12.5% had a rebound. The incidence of both RDA and rebound was not different among individuals who had persistent disease activity on FTY to those who stopped FTY for other reasons than inefficacy (RDA: 25.5% vs 20.5%, p = 0.353 rebound: 14.5% vs 11%, p = 0.596). Negative predictive factors for RDA were younger age at disease onset (p = 0.036), highly active disease at baseline (p = 0.003) and previous treatment with NTZ (p = 0.013). Older age at FTY discontinuation did not reduce the risk of RDA in patients previously stable on treatment (OR 0.972, 95% CI 0.871-1.085, p = 0.613), although the incidence of RDA/rebound was half less in the older patients (36.5% in the <50 vs 19% in the ≥50 year-old, p = 0.174) and none of the patients over 60 experienced RDA. Although there is a tendency for a lower risk of disease reactivation in the older patients, the incidence of RDA, and even rebound, is not negligible between the age of 50 and 60 years, even in patients with previously stable MS on FTY

Is disease activity prior to fingolimod initiation predictive of response? Fingolimod as a "common" first line treatment.

In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity. We retrospectively analysed the data of RRMS patients treated with FTY, focusing on 2 groups: 17 highly active patients (HA) defined as follows: ≥2 relapses in the year before treatment initiation and either≥1 Gd-enhancing T1 lesion or a significant increase in T2 lesion load from a baseline MRI; and 37 "not highly active" (NHA). We reviewed treatment efficacy (defined as NEDA-3), reasons for discontinuation and treatment tolerance in both groups. Mean follow-up duration was 48.2 months, SD 18.4. Fingolimod efficiently reduced relapses (NHA 90.3% reduction, P<0.001, HA 84.9%, P<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, P=0.019, HA 92.3%, P=0.043). The proportion of patients reaching NEDA-3 status was higher in the NHA group (NHA: 80% at 2 years and 66% at 4 years, HA: 58% at 2 years and 38% at 4 years, P=0.042). Fingolimod was discontinued in 20 cases, mainly because of lack of efficacy (n=15). FTY is efficient in reducing relapses and new Gd enhancing lesions in both HA and NHA patients although the probability of achieving NEDA-3 over time is higher in early-treated treatment-naive NHA patients