Damien Biotti

Therapeutic use of CCR5 antagonists is supported by strong expression of CCR5 on CD8(+) T cells in progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome.

therapy (ART) [3], and two non-HIV-infected patients who developed PML after chemotherapy or natalizumab, one who developed PML-IRIS, and the other at high risk of PML-IRIS (supplementary table and figure). Biopsies were performed before any steroid therapy and before maraviroc was introduced for the two non-HIV-infected patients to treat or prevent PML-IRIS, with a highly favorable outcome. As a control, we collected brain autopsies from 4 HIV-infected patients who developed classic PML (without IRIS). Consistent with previous reports [3, 6], CD8+ T cells dominate the inflammatory response in HIV-infected as well as non-HIV-infected patients with inflammatory PML (Fig. 1a). In patient 2, CD68+ macrophagic/microglial cells (1,480/mm), CD20+ B cells (55/mm) and CD138+ plasma cells (241/mm) were also present in the biopsied lesion, while in patient 1, who was treated by rituximab, cells of the B cell lineage were totally absent, arguing against a necessary role for B cells and antibodies in the pathogenesis of PML-IRIS (Fig. 1i–k and data not shown). Brain lesions displayed strong infiltration by CCR5+ cells Therapeutic strategies that modulate the deleterious immune response underlying progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) are warranted [5]. Maraviroc, an antagonist of the CCR5 chemokine receptor that entered recently the HIV armamentarium, has been suggested to be beneficial in preventing or treating PMLIRIS [1, 4]. Since chemokine receptors play an important role in inflammatory cell migration, we investigated whether the molecular target of maraviroc is expressed on pathogenic T cells infiltrating PML-IRIS lesions. Paraffinembedded brain specimens of inflammatory PML, obtained through diagnostic stereotactic brain biopsy, were analyzed from five previously described HIV-infected patients who developed PML-IRIS after initiation of antiretroviral

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study

Objective To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.

NeuroépidémiologieLes accidents vasculaires cérébraux : ce qui a changé au début du xxie siècleWhat has changed for stroke at the beginning of the 21st century

INTRODUCTION Striking developments in stroke epidemiology, initially based on the results of the Framingham study, have greatly improved our neuroepidemiological knowledge of the disease. STATE OF ART The development of stroke registries has made it possible to evaluate the descriptive epidemiology of stroke and its evolution. With the increasing use of CT-scan, MRI, and either cardiac or vascular imaging, the diagnosis of stroke and its subtypes has been made easier. Over the last 20 years, a decrease in the incidence and mortality of stroke has been observed in Western countries. In contrast, in Dijon, which has the only population-based stroke registry in France, stable incidence rates have been reported. However, over the same period, age at stroke onset has risen by five years in men and eight years in women, which is probably related to both population aging and improvements in primary prevention and general health. The reported decrease in case-fatality rates suggests better acute management of stroke patients, and explains in part the increase in the prevalence of stroke. In addition, the assessment of vascular risk factors has demonstrated that high blood pressure remains the principal risk factor for both ischemic and hemorrhagic stroke, and that antihypertensive treatment is able to reduce stroke incidence. PERSPECTIVES Epidemiology studies could make it possible to measure the impact of new therapeutic strategies applied in both primary and secondary prevention. CONCLUSION Prevention, diagnosis, and acute treatment of stroke have considerably improved, but cerebrovascular diseases together with myocardial infarction remain the leading cause of death. Despite the absence of a rise in the incidence of stroke, its prevalence has increased. This is due to the decrease in case-fatality rates. As a consequence, there is an urgent need to organize health networks around stroke. Moreover, the rise in stroke-free life expectancy is a positive finding that reflects improvements in prevention.

Multiple sclerosis broke my heart

We report 5 cases of acute heart failure (AHF) related to multiple sclerosis (MS) relapses. AHF was inaugural in 3 patients, always preceded or accompanied by signs of brainstem dysfunction; it was severe, requiring intensive care management. Echocardiography showed left ventricular hypokinesis. No other cause of AHF has been found. All patients showed a new medullary lesion on brain magnetic resonance imaging. All had rapid and complete recovery of ventricular function after intravenous corticosteroids. We concluded that the cases represent a takotsubo phenomenon. Physicians should be aware of rare cases of takotsubo cardiomyopathy in MS relapses. Ann Neurol 2017;81:754–758

Fingolimod treatment after natalizumab-related progressive multifocal leukoencephalopathy: Three new cases

Case 1 This patient was diagnosed with MS at the age of 32. She was first treated with interferon IM and was switched to NTZ in 2009. Expanded Disability Status Scale (EDSS) was 2.5 and retrospective analysis showed positive JC virus with gen1 ELISSA3. After 43 infusions (November 2012), she experienced progressive nystagmus, gait ataxia and fatigue. PML was suspected on MRI because of the cerebellum (pedoncular) signal. PML was confirmed4 at NIH laboratory USA with a positive JC virus DNA detection on CSF at 1500 copies. Plasma exchange (Plex) was performed, followed by steroids because of gadolinium enhanced lesions seen in December 2012. Interferon (IFN) sub-cutaneous (s.c.) was re-introduced but, five months later, she had a relapse. PML re-activation was excluded by MRI and negative JC virus detection in the CSF. FGL was started in September 2013 and she has had no new neurological signs after nine months’ follow up.

Optic neuritis in patients with anti-MOG antibodies spectrum disorder: MRI and clinical features from a large multicentric cohort in France

Between May 2014 and December 2016, all patients with a MOG-SD and at least one ON event were included from four medical sites in France. MOG-Abs were determined by cell-based assay, as recommended [1, 2]. Data collected included demographics, neuro-ophthalmological and biological parameters, brain, and orbital MRI features. A visual score (VS) was determined as follows [3] normal (0); scotoma but with a VA of better than 20/30 (1); a VA of 20/30 to 20/59 (2); a VA of 20/60 to 20/199 (3); a VA of 20/200 to 20/800 (4); counting fingers (5); light perception only (6) and no light perception (7). Baseline scores obtained were compared to those obtained 3 months later. All of the MRI scans were retrospectively reviewed by a neuro-radiologist. The extension of the optic nerve lesion was determined by the sum of the contiguous segments involved, among which intra-orbital/pre-orbital, intra-orbital/retro-orbital, canalicular, intra-cranial, chiasmal, and optic tracts, as previously described [4]. Statistical analyses were performed using Statistica®10.0 software. T test and Pearson’s Chi-square test measured continuous and categorical variables, respectively. Forty-seven patients were included, 24 of which were female (51.1%, SR = 1.04), 65% were Caucasian. The mean age at ON onset was 37.0 years. 19 patients (40.4%) were included who presented with bilateral simultaneous ON and 66 affected eyes (AE). Nine patients had a prior history of ON but did not receive treatment. None of the patients met MS diagnostic criteria. At the onset, ON events were painful (89.4%) and were accompanied by optic nerve head swelling in 70.2% of cases. Peripapillary hemorrhages were observed in four eyes (four patients) accompanied, in two cases, by punctuate perimacular hemorrhages (Fig. 1). The median VS was 3[0–7] and the VA was less than 20/200 (score ≥4) in 34.8% of AE. At baseline, the mean defect of the AE in automated perimetry was −15.6 ± 10.2 dB (versus Dear Sirs,

Leukocyte Telomere Length: A Focus on Cerebrovascular Events

Telomeres are specialized DNA structures located at the ends of chromosomes. Their length is reduced at each cell cycle, especially when the cumulative burden of oxidative stress is high. The purpose of this study was to determine the associations between telomere length and clinical and biological risk factors in ischemic stroke patients. A total of 215 stroke patients hospitalized in the Dijon, France, stroke unit were prospectively and continuously included from January to September, 2004. The telomere length measured from peripheral blood leukocytes--leukocyte telomere length (LTL)--was determined by real-time quantitative polymerase chain reaction. The results were compared with clinical and biological variables of interest collected at admission to find significant associations. Possible relationships between LTL and stroke subtypes were evaluated. A multiple regression that included all the variables significantly associated (p<0.20) with LTL in univariate analysis and age and subtypes of stroke confirmed a significant association with age (p<0.001), homocysteinemia (p=0,049), and levels of both antiphospholipid antibodies (p=0.019) and triglycerides (p=0.007). Linearity was verified and confirmed for each variable. The subtype of stroke did not significantly affect telomere length. We were able to highlight significant associations between LTL and certain cerebrovascular risk factors in a general population of stroke patients. These associations did not depend on the ischemic stroke subtype.

Late-onset neutropenia and neurological relapse, during long-term rituximab therapy in myelin oligodendrocyte glycoprotein-antibody spectrum disorder:

Late-onset neutropenia after rituximab therapy (LONART) is defined as a fall in the absolute neutrophil count below 500/mm3 at least 3 weeks after rituximab infusion, in the absence of any other explanation. LONART is rare during dysimmune conditions but can be life-threatening. We report on two patients with LONART and associated neurological relapse occurring in myelin oligodendrocyte glycoprotein (MOG)-antibody spectrum disorders. Rituximab was reintroduced in one patient, while the second patient was switched to tocilizumab. LONART can occur during anti-MOG spectrum disorders. Neurologists should be aware of this rare and treatable complication. Regular monitoring of blood cell counts is needed, and patients should be informed of the need to consult their physician if symptoms of infection appear.

Teaching NeuroImages: Painful diplopia and Crohn disease: Think about orbital myositis.

A 34-year-old man with Crohn disease (CD) treated with infliximab was seen for a 2-month history of painful binocular horizontal diplopia. Pain initially appeared in the right eye, then switched to the left eye 1 month later. Neuro-ophthalmologic testing revealed a painful limitation of the left eye during adduction and periorbital edema. Thyroid tests were normal. Orbital MRI showed features of orbital myositis (figure).