Relationship between emotion recognition and cognition in multiple sclerosis: a meta-analysis protocol.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterised by a broad and unpredictable range of symptoms, including cognitive and socio-cognitive dysfunction. Alongside the well-known deficits in information processing speed (IPS), executive functioning and episodic memory, recent evidence also highlighted socio-cognitive impairments in MS, such as emotion-recognition deficits. Recently, several studies investigated the association between emotion-recognition and cognitive impairment to assess whether social cognition is parallel to (or even dependent on) general cognitive dysfunction. Yet, there have been inconsistent findings, raising the need for a meta-analysis of the literature. Objectives: The aim of the present paper is to outline the protocol for an upcoming meta-analysis we designed to clarify these conclusions. Methods and analysis: We plan to estimate combined effect sizes for the association between emotion-recognition and cognitive impairment in MS across three cognitive domains (IPS, executive functions and episodic memory) and 7 emotion scores of interests (total and by 6-basic emotions subscores). Further, we plan to investigate whether identified variables are the cause for heterogeneity in any combined association. To that end, we will conduct additional meta-regression analyses to explore whether overall correlations differ according to clinical characteristics of MS patients (ie, disease duration, MS-phenotype, severity of depression and disability). Ultimately, this study will provide support either for an association of these disorders (in which emotion-recognition deficits might result from more fundamental cognitive dysfunction), or for two distinct sets of symptoms which may occur independently, for targeted patient profiles.

Improving cognition in people with multiple sclerosis: study protocol for a multiarm, randomised, blinded trial of multidomain cognitive rehabilitation using a video-serious game (E-SEP cognition).

Introduction: Multiple sclerosis (MS) is a prevalent neurological disease characterised by disseminated areas of demyelination and atrophy within the central nervous system, inducing cognitive disorders in 45%-65% of persons with MS (PwMS). Neuropsychology and neuroimaging studies provide evidence of the effectiveness of cognitive rehabilitation interventions, including memory and attention. Recently, serious game therapy (SGT) has been used in rehabilitation to improve cognitive processing speed. The aim of this study is to describe the protocol of a randomised controlled trial (RCT) to test the efficacy of a tablet-based cognitive home intervention among ambulatory PwMS, in comparison to a standardised neuropsychological rehabilitation. Methods and analysis: This will be a parallel-assignment, double-blinded, RCT. One hundred and fifty (75 per arm) PwMS will be randomly assigned to receive cognitive rehabilitation session over 4 months (four 20-min sessions/week) of either: (1) tablet-based SGT or (2) conventional cognitive exercises. The same assessor will evaluate outcome measures at three points: at baseline (T0), after the 16 therapy sessions weeks (T1), and 6 months after the end of treatment (T2). The primary outcomes were the scores from the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Data analysis will be performed to compare the efficacy of the two treatments. We expect superior efficiency of tablet-based SGT in contrast to conventional cognitive exercises, based on BICAMS measures of speed processing information and episodic memory. Ethics and dissemination: The trial protocol is registered on ClinicalTrials.Gov (NCT04694534) and benefits from a favourable opinion from an ethics committee (RC-P0066-2018-A00411-54).

Assessing cognitive changes in multiple sclerosis: criteria for a reliable decision.

INTRODUCTION: Quantifying a significant cognitive change on a neuropsychological battery is essential to assess patients' decline or recovery and offer appropriate care. The reliability of change indices is particularly important in multiple sclerosis (MS), as the course of cognitive impairment is quite unpredictable, due at least in part to substantial interindividual variability. The main objective of this study was to compare six different methods for assessing cognitive change in an MS sample: the SD method, two reliable change indices, two standardized regression-based methods (SRB), and the generalized regression-based method (GSRB). METHOD: One hundred and twenty-three patients with clinically definite MS and 89 healthy controls underwent a battery of standardized neuropsychological tests assessing cognitive functions that are frequently affected in this disease (i.e., verbal episodic memory, working memory, processing speed and verbal fluency). RESULTS: We observed fairly similar proportions of improvement, decline or stability in the control group whatever the method. By contrast, in the MS sample, regression-based methods with one predictor (i.e., score at T1) and four predictors (i.e., score at T1 and demographic factors: age, sex, education level) detected a significant worsening more often than the reliable change indices while the GSRB method was more consistent with the RCI methods in tasks associated with ceiling effects. CONCLUSIONS: The interpretation of a patient's cognitive changes depends on which method is used. The (G)SRB methods appear to be relevant indicators for assessing cognitive change in MS. The addition of demographic factors does not seem to play an important role in the prediction of significant worsening in the MS sample, regardless of cognitive domain. For clinicians, an easy-to-use free shiny app is provided.

Corpus callosum damage to account for cognitive, affective, and social-cognitive dysfunctions in multiple sclerosis: A model of callosal disconnection syndrome?

The corpus callosum (CC) is the major commissure interconnecting the two hemispheres and is particularly affected in multiple sclerosis (MS). In the present review, we aimed to investigate the role played by callosal damages in the pathogenesis of MS-related dysfunctions and examine whether a model of callosal disconnection syndrome is a valid model for MS. For this purpose, we will first review structural and functional evidence of callosal pathology in MS. Second, we will account for the potential role of CC abnormalities in MS-related dysfunctions. Finally, we will report data concurring with a "multiple disconnection hypothesis" that has been proposed to explain those dysfunctions, and we will examine evidence pointing toward MS as a "callosal disconnection syndrome." We will end by discussing the contribution of this interpretation to the understanding of MS and MS-related deficits.

Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants.

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.

CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability.

OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145). RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

EVASEP: A Noninterventional Study Describing the Perception of Neurologists, Patients, and Caregivers on Caregivers' Role in the Support of Patients Suffering from Multiple Sclerosis Treated with Subcutaneous Interferon Beta 1a.

Background. The perception of the role of caregivers for people with multiple sclerosis (MS) is important but poorly studied, particularly in patients with low levels of disability. Objectives. To describe the perceptions of the role of caregivers from the perspective of the caregiver, the patient, and neurologists. Methods. This observational study was conducted in France on patients with relapsing remitting MS treated with subcutaneous (SC) interferon-ß-1a (IFN-ß-1a) for more than 24 months. Results. Caregiver, patients, and neurologists all considered providing moral support and fighting against the disease as the most important role of the care provider. Moral support was considered significantly more important by caregivers than the patients and neurologists (p = 0.002) and caregivers considered their role in helping patients to fight disease more important than did the neurologists (p = 0.006). Knowledge of disease and available treatments were less important among support providers than patients (p = 0.007 and p = 0.001). Conclusion. There are many unmet needs in the perception of the role of caregivers for people with MS which need to be addressed to deliver the most effective care package for patients and to support the needs of the support provider.

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

Treatment discontinuation in multiple sclerosis: The French Web-based survey ALLIANCE.

BACKGROUND: In multiple sclerosis (MS), treatment discontinuation leads to a higher risk of relapse, poorer quality of life and greater economic impact. OBJECTIVE: The objective of this work is to evaluate treatment discontinuation in MS, the reasons for this and the reasons for treatment resumption. METHODS: A French national Web-based survey was carried out between May and August 2011. A total of 602 MS patients answered a questionnaire on sociodemographic data, medical follow-up, disease-modifying therapies (DMTs), symptomatic treatments, care given, factors involved in treatment discontinuation and reasons for resuming treatment. RESULTS: Among 413 patients using DMTs, 54% have considered discontinuing their treatment, primarily because of anger (61%), side effects (61%) and fatigue (57%). Sixty-eight patients have actually discontinued their treatment because of side effects (43%), lack of observed outcomes (32%), exasperation (29%) or fatigue (29%). The reasons for symptomatic treatment discontinuation were fear of addiction (32%-46%) and lack of efficacy (28%-45%). Physiotherapy was discontinued because of fatigue (37%), stress (34%) or inefficiency (31%). According to patients, treatment discontinuation could have been prevented by psychological support, care team empathy and support from family. CONCLUSION: The major factor that could prevent treatment discontinuation is psychological support. Initiating and monitoring treatment in MS leads to emotional and personality changes, requiring adaptations that may improve compliance.

Decrease of mutual information in brain electrical activity of patients with relapsing-remitting multiple sclerosis.

The disturbance of cortical communication has been hypothesized as an important factor in the appearance of cognitive impairment in (MS). Cortical communication is quantified here in control subjects and patients with relapsing-remitting multiple sclerosis (RRMS) on the basis of mean coherence in the δ, θ, α, ß and γ bands and using mutual information computed between pairs of bipolar EEG signals recorded during resting condition. Each patient received also a cognitive assessment using a battery of neuropsychological tests specific to cognitive deficits in MS. No difference was observed for the coherence indices whereas inter-hemispheric and right hemisphere mutual information is significantly lower in patients with MS than in control subjects. Moreover, inter-hemispheric mutual information decrease significantly with illness duration and right mutual information differentiate cognitively deficient and non-deficient patients. Mutual information allows to quantify the cortical communication in patients with RRMS and is related to clinical characteristics. Cortical communication quantified in a resting state might be a potential marker for the neurological damage induced by RRMS.

A 5.3Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay.

Interstitial 18q deletions encompassing band 18q12.3 define the del(18)(q12.2q21.1) syndrome. Usual manifestations are mild dysmorphic features, mental retardation, behaviour abnormalities and lack of serious malformation. Seizures have also been found. Recently, more specifically, impairment of expressive language has been reported. We report on two patients with de novo 18q interstitial deletions characterized by oligonucleotide array CGH. The smallest, a 5.3Mb deletion (35.7-40.9Mb) within band q12.3, was found in a 4-year-old girl who suffered mainly from expressive dysphasia. A larger 9.5Mb deletion (34.6-43.9Mb) was observed in a 20-year-old man with a more severe clinical picture including seizures and limited speech. Among the four genes located in the 5.3Mb region, RIT2 (Ras-like without CAAX 2) and SYT4 (synaptotagmin IV), both strongly expressed in the brain, are pointed out as likely candidate genes for language development.