There is growing evidence of activated microglia and inflammatory processes in the cerebral cortex in amyotrophic lateral sclerosis (ALS). Activated microglia is characterized by increased expression of the 18 kDa translocator protein (TSPO) in the brain and may be a useful biomarker of inflammation. In this study, we evaluated neuroinflammation in ALS patients using a radioligand of TSPO, 18F-DPA-714. Ten patients with probable or definite ALS (all right-handed, without dementia, and untreated by riluzole or other medication that might bias the binding on the TSPO), were enrolled prospectively and eight healthy controls matched for age underwent a PET study. Comparison of the distribution volume ratios between both groups were performed using a Mann-Whitney’s test. Significant increase of distribution of volume ratios values corresponding to microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of 18F-DPA-714 was increased in ALS patients during the “time of diagnosis” phase of the disease. This finding might improve our understanding of the pathophysiology of ALS and might be a surrogate marker of efficacy of treatment on microglial activation.

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter defibrillator (ICD) implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as a) sudden cardiac death or b) ICD-treated or hemodynamically unstable VTA. The prognostic model was derived using Fine-Gray's regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (standard deviation) or medians [interquartile range]. Results: We included 444 patients 40.6 (14.1) years of age in the derivation sample and 145 patients 38.2 (15.0) years in the validation sample, of whom 86 (19.3%) and 34 (23.4%) suffered LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, non-missense LMNA mutation, 1st degree and higher atrioventricular block, non-sustained ventricular tachycardia, and left ventricular ejection fraction. In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842) and calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959) and calibration slope 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA compared with the guidelines-based approach. Conclusions: Compared to the current standard of care, this risk prediction model for LTVTA in laminopathies facilitated significantly the choice of ICD candidates. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03058185.

BackgroundPathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by 1H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS.MethodologyCSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional 1H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses.Principal FindingsFifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time.Conclusion/SignificanceCSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

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Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a treatable brainstem encephalitis recently described by Pittock et al. [1]. We report a case with clinical, radiological, and pathological signs of CLIPPERS but with final diagnosis of type B primary central nervous system lymphoma (PCNSL).In March 2010, a 33-year-old man with unremarkable personal history was first seen in the internal medicine unit for isolated vomiting with weight loss of 5 kg. The clinical and paraclinical examinations were unremarkable. In June, he was admitted to our unit for subacute gait ataxia, dysphagia, and binocular diplopia. Clinical examination revealed bilateral sixth nerve palsy and gait ataxia with pyramidal signs. Brain magnetic resonance imaging (MRI) showed hyperintense lesions on T2-weighted and fluidattenuated inversion recovery (FLAIR) sequences within the pons, medulla, and upper cervical cord, with enhancement after gadolinium administration. Cerebrospinal fluid (CSF) analysis showed elevated levels of proteins (1.10 g/l) with normal electrophoretic pattern and without abnormal cell count (2/mm 3 ). Extensive laboratory investigations were normal. Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET), and labial salivary gland biopsies were negative, including aquaporin-4 water channel and onconeural antibodies. Biopsy of pons revealed perivascular lymphocyte infiltrates without any findings of sarcoidosis, lymphoma, glioma, or lymphomatoid granulomatosis (Fig. 1d). CLIPPERS syndrome was suspected, and the patient was treated for five consecutive days with 1,000 mg intravenous methylprednisolone followed by oral prednisone 60 mg (1 mg/kg/day) every day, with dramatic recovery except for persistence of moderate gait ataxia. In August 2010, a second brain MRI showed a reduction in the number and size of brainstem lesions. Localized proton magnetic resonance spectroscopy (MRS) examination showed a slight decrease of N-acetyl-aspartate/creatine (NAA/Cr) ratio (1:52) and an increase in choline/creatine (Cho/Cr) ratio (1:58) in the brain and medulla (Fig. 1a). The dose of steroids was reduced by 10 mg/week until 30 mg/ day was reached. In September 2010, he complained of numbness in all four limbs with worsening gait ataxia. A third brain MRI showed enlargement of the pontine lesions with necrosis. The MRS showed a slightly elevated Cho/ NAA ratio, as well as strong resonance of lipids and lactates (Fig. 1b). The patient was then treated with 1,000 mg intravenous methylprednisolone for 5 days; this was followed by double-filtration plasmapheresis. Because no further clinical improvement was observed, monthly intravenous cyclophosphamide was added. In October, the fourth brain MRI revealed radiological progression of brainstem lesions with the appearance of gadoliniumenhanced lesions localized close to the left lateral ventricle.

Summary:Purpose: The aim of this study was to determine the clinical, social, and/or professional and cognitive outcomes in adulthood of the continuous spike-waves during slow sleep (CSWS) and Landau-Kleffner syndromes, which are two rare epileptic syndromes occurring in children.Methods: We enrolled seven young adults, five who had a CSWS syndrome, and two, a Landau-Kleffner syndrome in childhood. We evaluated their intellectual level as well as their oral and written language and executive functions.Results: This study confirmed that the epilepsy associated with these syndromes has a good prognosis. Only one patient still had active epilepsy. However, the neuropsychological disorders particular to each syndrome persisted. Only two patients had followed a normal pathway in school. Three of the five patients with a CSWS syndrome during childhood remained globally and nonselectively mentally deficient. We found no evidence of the persistence of a dysexecutive syndrome in this study group. The intellectual functions of the two patients with Landau-Kleffner syndrome were normal; however, their everyday lives were disrupted by severe, disabling language disturbances. We discuss the role of some prognostic factors such as the location of the interictal electric focus and the age at onset of CSWS.Conclusions: These two epileptic syndromes of childhood are very similar in many respects, but their clinical outcomes in adulthood are different.

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