Clarisse Carra-Dalliere

Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Efficacy of rituximab in refractory neuromyelitis optica

Background: Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy. Objective: The purpose of this study was to assess RTX as a maintenance therapy in RNMO. Methods: Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months. Results: After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening. Conclusions: RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next‐generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini‐exome coupled to read‐depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini‐exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini‐exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

Use of quantitative susceptibility mapping (QSM) in progressive multifocal leukoencephalopathy

BACKGROUND Progressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating encephalopathy related to JC virus. Its characteristics on conventional brain MRI are well known and are important for the diagnosis. OBJECTIVE To analyze SWI hypointensities recently described in U-fibers and cortex adjacent to the white matter lesions of PML. METHODS Prospective study including four patients with an history of definite diagnosis of PML. Clinical data were collected retrospectively. Brain MRI exams were done on a 3T magnet, including FLAIR, T2 GRE sequences and SWI. RESULTS Four males were included (mean age: 47 years, mean PML duration: 24.2 months). Immunosuppression was related to AIDS (n=2), natalizumab for multiple sclerosis (n=1), B-cell lymphoma treated by chemotherapeutic agents and rituximab (n=1). All patients had SWI hypointensities in cortex and/or U-fibers adjacent to the white matter lesions. QSM always suggested a paramagnetic effect. CONCLUSION SWI and T2 GRE hypointensities in cortex and U-fibers adjacent to the white matter lesions seem highly prevalent in PML, irrespective of the delay between PML onset and the MRI. QSM data suggest a paramagnetic effect.

Quantitative susceptibility mapping suggests a paramagnetic effect in PML.

A 42-year-old man previously treated with rituximab and stem cell transplantation for B-cell lymphoma presented with subacute cerebellar ataxia and cognitive decline.

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients

Objectives To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. Methods Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. Results Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients. Conclusion RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.

Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy: [RETRACTED]

A 37-year-old man was referred for a 1-year history of word naming difficulties and progressive executive dysfunction along with anxiety. Clinical examination showed generalized hyperreflexia and bilateral Babinski sign but was otherwise normal. His brain MRI (figure, A and B) showed extensive leukoencephalopathy with multiple small cysts within the white matter changes and no gadolinium enhancement. CT identified punctate calcifications with deep frontal and juxtacortical distribution (figure, C and D). His mother died at 63 years after a 10-year history of progressive cognitive impairment of frontal type, walking difficulties, and urinary incontinence. Her brain imaging was strikingly similar to her sons (figure, E–H).

Brain magnetic resonance imaging helps to differentiate atypical multiple sclerosis with cavitary lesions and vanishing white matter disease

Multiple sclerosis (MS) patients can present with atypical cavitary lesions mimicking vanishing white matter disease (VWMD). Our objective was to identify brain magnetic resonance imaging (MRI) findings that differentiate these two disorders.

Quantitative susceptibility mapping in superficial hemosiderosis of the central nervous system.

Journal of Neuroradiology - In Press.Proof corrected by the author Available online since lundi 8 juin 2015

Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies: A Review

Importance Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)–based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes. Observations This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy. Conclusions and Relevance The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses.