Long-term outcomes for females with early-onset dystrophinopathy.

AIM: To study long-term disease course for females with early-onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare management to support guideline development. METHOD: Twelve females with early-onset dystrophinopathy were followed for a median period of more than 17 years (range 1-36). RESULTS: One patient died owing to end-stage cardiac failure. Cardiac abnormalities were observed in three of the remaining 11 participants. Respiratory function was reduced in seven of 10 participants. Fatigue, myalgia, lower back pain, and arthralgia were reported in more than six of the participants. Functional status varied from exercise intolerance to wheelchair dependency. Most or all of the 10 participants reported restrictions in participation in work (n = 10), household duties (n = 10), sports (n = 9), and education (n = 8). Only a few participants received followed-up pulmonary (n = 2) or rehabilitation (n = 3) care. INTERPRETATION: Females with early-onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation. The whole spectrum should be acknowledged in the healthcare setting. Neuromuscular and cardiac follow-up are indispensable. Additional respiratory assessment and rehabilitation care are expected to improve health status and support daily activities and participation. WHAT THIS PAPER ADDS: No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy. Female participants with early-onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia. None of participants worked full time, all felt restricted in paid work, and most felt restricted in education. Most participants showed decreased lung function, while only one was symptomatic. Availability of rehabilitation care may improve support for daily activities and participation for females with early-onset dystrophinopathy.

Use of the experience sampling method in adolescents with Duchenne muscular dystrophy: a feasibility study.

Experience sampling methods (ESM) using mobile health (mHealth) technology with a smartphone application are increasingly used in clinical practice and research. Still, recommendations are limited in young people, and adaptations may be necessary. Patients with Duchenne muscular dystrophy (DMD) are chronically treated with steroids from a young age. However, the impact of intermittent treatment schedules on fluctuations in somatic, cognitive and behavioural symptoms is poorly investigated. Existing studies are often cross-sectional and occur in controlled clinical settings, which do not provide sufficiently detailed insights into possible correlations. ESM might alleviate these problems. ESM innovates data collection with a smartphone application, which repeatedly assesses specific symptoms and contextual factors at random moments in daily life. We aimed to evaluate its feasibility in adolescents with DMD. In three (without/with/without steroids) 4-day periods of ESM, that were nested in 10/10 or 11/9 day on/off-medication periods, we evaluated its user-friendliness and compliance, and explored its ability to objectify fluctuations in somatic, cognitive and behavioural symptom severity and their relationship with contextual factors in seven DMD patients (age range 12-18 years) using intermittent corticosteroid treatment (dosage range 0.3-0.6 mg/kg/day). Patients reported that ESM was convenient and user-friendly. We were able to capture extensive intra-individual symptom fluctuations during intermittent corticosteroid treatment that were not revealed by routine clinical assessment. Implementing ESM to evaluate symptom fluctuation patterns in relation to treatment effects shows promise in adolescents with DMD. Optimization in further research is needed.

Computerized working memory training in males with Duchenne muscular dystrophy: A single case experimental design study.

Learning disabilities (LDs) and working memory problems (WM) are common brain-related comorbidities in Duchenne muscular dystrophy (DMD). Despite growing evidence on the efficacy of computerized WM training in children with LDs, research in DMD is lacking. This exploratory study assessed whether training (1) improves dystrophin-associated WM problems in DMD, (2) effects are present at post-intervention, 3 and 8 months follow-up, and (3) improves problems that arise from their LDs. A single case non-concurrent multiple baseline across patients design evaluated the target behaviour i.e. parental reports of WM problems of four DMD participants with LDs. Additionally, participants completed cognitive tests of verbal and visual WM, academics, attention, processing speed and fluid reasoning. Parents and teachers completed behavioural questionnaires. Testing and questionnaires were administered at baseline, post-intervention (T2), 3 (T3) and 8 (T4) months follow-up. Positive effects on target behaviour were found for three of four participants, but parental bias cannot be ruled out. Short and long-term, near-and far transfer effects were found for verbal and visual WM (T2:n = 2, T3&T4:n = 1), reading (T2:n = 4,T3:n = 3,T4:n = 2), arithmetic (all T:n = 1), processing speed (all T:n = 4) and fluid reasoning (T2:n = 1,T3&T4:n = 2). Behavioural questionnaires displayed minimal changes (T2:n = 1,T3&T4:n = 2). Promising WM training results are shown in DMD that merit further research.

The Effect of Intrathecal Baclofen in Dyskinetic Cerebral Palsy: The IDYS Trial.

OBJECTIVE: Intrathecal baclofen treatment is used for the treatment of dystonia in patients with severe dyskinetic cerebral palsy; however, the current level of evidence for the effect is low. The primary aim of this study was to provide evidence for the effect of intrathecal baclofen treatment on individual goals in patients with severe dyskinetic cerebral palsy. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was performed at 2 university medical centers in the Netherlands. Patients with severe dyskinetic cerebral palsy (Gross Motor Functioning Classification System level IV-V) aged 4 to 24 years who were eligible for intrathecal baclofen were included. Patients were assigned by block randomization (2:2) for treatment with intrathecal baclofen or placebo for 3 months via an implanted microinfusion pump. The primary outcome was goal attainment scaling of individual treatment goals (GAS T score). A linear regression model was used for statistical analysis with study site as a covariate. Safety analyses were done for number and type of (serious) adverse events. RESULTS: Thirty-six patients were recruited from January 1, 2013, to March 31, 2018. Data for final analysis were available for 17 patients in the intrathecal baclofen group and 16 in the placebo group. Mean (standard deviation) GAS T score at 3 months was 38.9 (13.2) for intrathecal baclofen and 21.0 (4.6) for placebo (regression coefficient = 17.8, 95% confidence interval = 10.4-25.0, p < 0.001). Number and types of (serious) adverse events were similar between groups. INTERPRETATION: Intrathecal baclofen treatment is superior to placebo in achieving treatment goals in patients with severe dyskinetic cerebral palsy. ANN NEUROL 2019.

Correction to: Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis.

Due to an error during the editorial phase, a correction regarding Fig. 2 is added to the original article: "Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis". Please see below correct Fig. 2.

Neurocognitive and behavioural profile in Panayiotopoulos syndrome.

AIM: To determine neurocognitive performance and behavioural problems in children with Panayiotopoulos syndrome. METHOD: All 18 children (10 females, 8 males; mean age 4y 7mo; SD 1y 10mo) diagnosed with Panayiotopoulos syndrome at the Kempenhaeghe Epilepsy Center in the Netherlands between 2010 and 2017 were analysed retrospectively. All underwent a neuropsychological/behavioural assessment, an academic assessment, and a 24-hour electroencephalogram. RESULTS: Mean full-scale IQ (93.5; range 76-123; p=0.04) and performance IQ (93.2; range 76-126; p=0.04) were within the normal range, although significantly lower compared to the normative mean. Verbal IQ (96.3; range 76-118) and processing speed (96.1; range 74-114) were not significantly lower. Simple auditory/visual reaction times, visual attention, visual-motor integration, and verbal memory were significantly lower compared to normative values. On average, patients with Panayiotopoulos syndrome were 8 months behind in arithmetic speed and 11 months behind in reading speed for the number of months in school. Behavioural questionnaires revealed significantly higher scores on reported internalizing behavioural problems. INTERPRETATION: Children with Panayiotopoulos syndrome demonstrated diffuse cognitive dysfunction in full-scale IQ, performance IQ, visual attention, visual-motor integration, and verbal memory. A high incidence of internalizing behavioural problems was reported. This strongly suggests neuropsychological and behavioural comorbidity in children with Panayiotopoulos syndrome. WHAT THIS PAPER ADDS: Children with Panayiotopoulos syndrome are at risk for cognitive deficits in various cognitive domains. Children with Panayiotopoulos syndrome are also prone to internalizing behavioural problems. Mild-to-severe academic underachievement was present in more than half of the children with Panayiotopoulos syndrome.

The expression of the distal dystrophin isoforms Dp140 and Dp71 in the human epileptic hippocampus in relation to cognitive functioning.

Dystrophin is an important protein within the central nervous system. The absence of dystrophin, characterizing Duchenne muscular dystrophy (DMD), is associated with brain related comorbidities such as neurodevelopmental (e.g., cognitive and behavioural) deficits and epilepsy. Especially mutations in the downstream part of the DMD gene affecting the dystrophin isoforms Dp140 and Dp71 are found to be associated with cognitive deficits. However, the function of Dp140 is currently not well understood and its expression pattern has previously been implicated to be developmentally regulated. Therefore, we evaluated Dp140 and Dp71 expression in human hippocampi in relation to cognitive functioning in patients with drug-resistant temporal lobe epilepsy (TLE) and post-mortem controls. Hippocampal samples obtained as part of epilepsy surgery were quantitatively analyzed by Western blot and correlations with neuropsychological test results (i.e., memory and intelligence) were examined. First, we demonstrated that the expression of Dp140 does not appear to differ across different ages throughout adulthood. Second, we identified an inverse correlation between memory loss (i.e., verbal and visual memory), but not intelligence (i.e., neither verbal nor performance), and hippocampal Dp140 expression. Finally, patients with TLE appeared to have similar Dp140 expression levels compared to post-mortem controls without neurological disease. Dp140 may thus have a function in normal cognitive (i.e., episodic memory) processes.

Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis.

Cognition in absence epilepsy (AE) is generally considered undisturbed. However, reports on cognitive deficits in AE in recent years have suggested otherwise. This review systematically assesses current literature on cognitive performance in children with AE. A systematic literature search was performed in Pubmed, Embase, Cochrane and Web of Science. All studies reporting on cognitive performance in children with AE were considered. In total 33 studies were eligible for inclusion. Neuropsychological tests were classified into the following domains: intelligence; executive function; attention; language; motor & sensory-perceptual examinations; visuoperceptual/visuospatial/visuoconstructional function; memory and learning; achievement. Random-effect meta-analyses were conducted by estimating the pooled mean and/or pooling the mean difference in case-control studies. Full-scale IQ in children with AE was estimated at 96.78 (95%CI:94.46-99.10) across all available studies and in case-control studies IQ was on average 8.03 (95%CI:-10.45- -5.61) lower. Verbal IQ was estimated at 97.98 (95%CI:95.80-100.16) for all studies and 9.01 (95%CI:12.11- -5.90) points lower in case-control studies. Performance IQ was estimated at 97.23 (93.24-101.22) for all available studies and 5.32 (95%CI:-8.27-2.36) points lower in case-control studies. Lower performance was most often reported in executive function (cognitive flexibility, planning, and verbal fluency) and attention (sustained, selective and divided attention). Reports on school difficulties, neurodevelopmental problems, and attentional problems were high. In conclusion, in contrast to common beliefs, lower than average neurocognitive performance was noted in multiple cognitive domains, which may influence academic and psychosocial development.

Dystrophin is expressed in smooth muscle and afferent nerve fibers in the rat urinary bladder.

INTRODUCTION: With increasing life expectancy, comorbidities become overt in Duchenne muscular dystrophy (DMD). Although micturition problems are common, bladder function is poorly understood in DMD. We studied dystrophin expression and multiple isoform involvement in the bladder during maturation to gain insights into their roles in micturition. METHODS: Dystrophin distribution was evaluated in rat bladders by immunohistochemical colocalization with smooth muscle, interstitial, urothelial, and neuronal markers. Protein levels of Dp140, Dp71, and smooth muscle were quantitated by Western blotting of neonatal to adult rat bladders. RESULTS: Dystrophin colocalized with smooth muscle cells and afferent nerve fibers. Dp71 was expressed two- to threefold higher compared with Dp140, independently of age. Age-related muscle mass changes did not influence isoform expression levels. DISCUSSION: Dystrophin is expressed in smooth muscle cells and afferent nerve fibers in the urinary bladder, which underscores that micturition problems in DMD may have not solely a myogenic but also a neurogenic origin. Muscle Nerve 60: 202-210, 2019.

Instruments for the Assessment of Behavioral and Psychosocial Functioning in Duchenne and Becker Muscular Dystrophy; a Systematic Review of the Literature.

OBJECTIVE: This systematic review aims to provide an overview of instruments used to assess behavioral and psychosocial functioning of patients with Duchenne and Becker muscular dystrophy, as well as to review the psychometric properties and applicability of these instruments. METHODS: Five databases (Embase, Psyc.info, ERIC, Pubmed/Medline, and Cochrane) were searched from inception to June, 2018. Potential articles were rated by two independent reviewers. A predefined PROSPERO form (CRD42017074518) was used to extract data from included articles. RESULTS: Sixty-one instruments were used in 54 studies. The Child Behavior Checklist is commonly used, but it lacks disease specific psychometric information. Sixteen instruments that contained disease specific psychometric information were included for final evaluation. The results displayed three instruments that are potentially valid for screening of psychosocial problems: The Psychosocial Adjustment and Role Skills Scale 3rd edition, the Pediatric Quality of Life Inventory Generic module, and the Life Satisfaction Index for Adolescents with Duchenne muscular dystrophy. Appropriate instruments for screening of behavioral problems may be: the Strengths and Difficulties Questionnaire, the Generalized Anxiety Disorder-7 item questionnaire, and the Patient Health Questionnaire-9 item questionnaire. CONCLUSIONS: Further research on psychometric properties of screening instruments is crucial to ascertain a gold standard for clinical and research purposes. Meanwhile, for definite diagnostics purposes we recommend a multimethod, multisource, multisetting assessment in this high-risk population.

Accelerated cognitive decline in a rodent model for temporal lobe epilepsy.

OBJECTIVE: Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy. METHODS: Neurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance. RESULTS: Rats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits. SIGNIFICANCE: The effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy.

Efficacy of working memory training in children and adolescents with learning disabilities: A review study and meta-analysis.

The effectiveness of working memory (WM) training programmes is still a subject of debate. Previous reviews were heterogeneous with regard to participant characteristics of the studies included. To examine whether these programmes are of added value for children with learning disabilities (LDs), a systematic meta-analytic review was undertaken focusing specifically on LDs. Thirteen randomised controlled studies were included, with a total of 307 participants (age range = 5.5-17, Mean age across studies = 10.61, SD = 1.77). Potential moderator variables were examined, i.e., age, type of LD, training programme, training dose, design type, and type of control group. The meta-analysis indicated reliable short-term improvements in verbal WM, visuo-spatial WM, and word decoding in children with LDs after training (effect sizes ranged between 0.36 and 0.63), when compared to the untrained control group. These improvements sustained over time for up to eight months. Furthermore, children > 10 years seemed to benefit more in terms of verbal WM than younger children, both immediately after training as well as in the long-term. Other moderator variables did not have an effect on treatment efficacy.

Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia.

BACKGROUND: Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates.Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. RESULTS: We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. CONCLUSIONS: This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection.

Fetal brain genomic reprogramming following asphyctic preconditioning.

BACKGROUND: Fetal asphyctic (FA) preconditioning is effective in attenuating brain damage incurred by a subsequent perinatal asphyctic insult. Unraveling mechanisms of this endogenous neuroprotection, activated by FA preconditioning, is an important step towards new clinical strategies for asphyctic neonates. Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of preconditioning. Therefore we investigated whole genome differential gene expression in the preconditioned rat brain. FA preconditioning was induced on embryonic day 17 by reversibly clamping uterine circulation. Male control and FA offspring were sacrificed 96 h after FA preconditioning. Whole genome transcription was investigated with Affymetrix Gene1.0ST chip. RESULTS: Data were analyzed with the Bioconductor Limma package, which showed 53 down-regulated and 35 up-regulated transcripts in the FA-group. We validated these findings with RT-qPCR for adh1, edn1, leptin, rdh2, and smad6. Moreover, we investigated differences in gene expression across different brain regions. In addition, we performed Gene Set Enrichment Analysis (GSEA) which revealed 19 significantly down-regulated gene sets, mainly involved in neurotransmission and ion transport. 10 Gene sets were significantly up-regulated, these are mainly involved in nucleosomal structure and transcription, including genes such as mecp2. CONCLUSIONS: Here we identify for the first time differential gene expression after asphyctic preconditioning in fetal brain tissue, with the majority of differentially expressed transcripts being down-regulated. The observed down-regulation of cellular processes such as neurotransmission and ion transport could represent a restriction in energy turnover which could prevent energy failure and subsequent neuronal damage in an asphyctic event. Up-regulated transcripts seem to exert their function mainly within the cell nucleus, and subsequent Gene Set Enrichment Analysis suggests that epigenetic mechanisms play an important role in preconditioning induced neuroprotection.

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy.

PURPOSE: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. METHODS: Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. KEY FINDINGS: Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. SIGNIFICANCE: Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE.

Attainment of personal goals in the first year of intrathecal baclofen treatment in dyskinetic cerebral palsy: a prospective cohort study.

PURPOSE: To assess attainment of individual treatment goals one year after intrathecal baclofen (ITB) pump implantation in individuals with dyskinetic cerebral palsy (CP). MATERIALS AND METHODS: A multi-center prospective cohort study was conducted including 34 non-walking individuals with severe dyskinetic CP, classified as Gross Motor Function Classification System (GMFCS) IV/V, aged 4-24 years, 12 months after pump implantation. The main outcome measure was Goal Attainment Scaling (GAS). Predictors of GAS results were analyzed. Complications were registered systematically. RESULTS: Seventy-one percent of individuals with dyskinetic CP fully achieved one or more treatment goals. One or more treatment goals were partially achieved in 97% of individuals. Two factors were found to be associated with attainment of goals: Dyskinesia Impairment Scale (DIS) score at baseline and the difference in pain score between baseline and follow-up. These two variables explain 30% of the variance in the outcome. CONCLUSIONS: Intrathecal baclofen is effective in achieving individual treatment goals in children and young adults with dyskinetic CP after nine to 12 months of ITB treatment. A positive outcome on treatment goals is, for a small part, associated with higher severity of dystonia at baseline and with improvement of pain during treatment. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, number NTR3642.Implications for rehabilitationIntrathecal baclofen treatment is effective in attainment of personal treatment goals, one year after pump implantation in patients with dyskinetic cerebral palsy.A positive outcome on treatment goals is, for a small part, related to higher severity of dystonia at the start and on improvement of pain during treatment.

The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures.

PURPOSE: Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more "subtle" short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children. METHODS: A cross-sectional study of 188 children with epilepsy. Electroencephalography (EEG)-video recordings and cognitive testing were performed simultaneously. The results of children with short nonconvulsive seizures during a 2-h testing session were compared with all children with epilepsy without seizures during the 2-h cognitive testing session and with controls without epilepsy. In a second analysis the cognitive effects of frequency of epileptiform EEG discharges were analyzed. KEY FINDINGS: The cognitive effects of short nonconvulsive seizures were large, ranging from 0.5 to 1 standard deviation and concerned global cognitive function, speed of central information processing, and memory function. In children without seizures during cognitive testing, the occurrence of frequent epileptiform discharges showed more subtle effects. These effects were independent from the occurrence of short nonconvulsive seizures. SIGNIFICANCE: We concluded that although the effect is less pronounced in number of areas involved and magnitude, the type of association between frequent epileptiform activity (>1% of the time) and cognitive function in children with epilepsy is comparable to the association between short nonconvulsive seizures and cognitive function.

Microstructural and functional MRI studies of cognitive impairment in epilepsy.

Cognitive impairment is the most common comorbidity in children with epilepsy, but its pathophysiology and predisposing conditions remain unknown. Clinical epilepsy characteristics are not conclusive in determining cognitive outcome. Because many children with epilepsy do not have macrostructural magnetic resonance imaging (MRI) abnormalities, the underlying substrate for cognitive impairment may be found at the microstructural or functional level. In the last two decades, new MRI techniques have been developed that have the potential to visualize microstructural or functional abnormalities associated with cognitive impairment. These include volumetric MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and functional MRI (fMRI). All of these techniques have shed new light on various aspects associated with, or underlying, cognitive impairment, although their use in epilepsy has been limited and focused mostly on adults. Therefore, in this review, the use of all these different MRI techniques to unravel cognitive impairment in epilepsy is discussed both in adults and children with epilepsy. Volumetric MRI and VBM have revealed significant volume losses in the area of the seizure focus as well as in distant areas. DTI adds evidence of loss of integrity of connections from the seizure focus to distant areas as well as between distant areas. MRS and fMRI have shown impaired function both in the area of the seizure focus as well as in distant structures. For this review we have compiled and compared findings from the various techniques to conclude that cognitive impairment in epilepsy results from a network disorder in which the (micro)structures as well as the functionality can be disturbed.

Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial.

AIM: The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. METHOD: In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo-17y 8mo) were included. Thirty-five participants had localization-related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high-output VNS (maximally 1.75mA) and the other half received low-output stimulation (0.25mA). Finally, all participants received high-output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi-structured interviews. RESULTS: At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase The overall seizure severity also improved (p<0.001). INTERPRETATION: VNS is a safe and well-tolerated adjunctive treatment of epilepsy in children. Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well-being makes this treatment worth considering in individual children with intractable epilepsy.

Cognitive and behavioral functioning in two neurogenetic disorders; how different are these aspects in Duchenne muscular dystrophy and Neurofibromatosis type 1?

The presence of neurocognitive and behavioral problems are common features in various neurogenetic disorders. In Duchenne muscular dystrophy (DMD), these problems have been linked to mutations along the dystrophin gene affecting different brain dystrophin isoforms. However, comparable cognitive and behavioral problems have been found in Neurofibromatosis type 1 (NF1). This study aims to assess disorder specific differences in cognition and behavior between DMD and NF1. Retrospective data of 38 male patients with DMD were aged-matched with data of 38 male patients with NF1. Patients of both groups underwent neurocognitive assessment for regular clinical care. Intellectual abilities, sequential and simultaneous processing, verbal memory and sustained attention were evaluated. In addition, parents and teachers completed behavioral questionnaires. Males with DMD exhibited low intellectual abilities and sequential processing problems, but these outcomes not significantly differed from males with NF1. Simultaneous processing, verbal memory and sustained attention outcomes were equal for both groups. Outcomes of questionnaires displayed higher rates of aggressive behavior (13.2%) in DMD, whereas in NF1 higher rates of problems with thinking (15.8%), withdrawn (10.5%) and social behavior (10.5%) were noticed. In the neurogenetic disorders DMD and NF1, on average overlapping cognitive and behavioral problems are noticed, suggesting that these are not only caused by gene mutations resulting in a lack of one specific protein.