Should every child with epilepsy undergo screening for psychiatric comorbidities?

Purpose: We aimed to build a classification system that uses resting-state (no visible scalp epileptic activity) EEG-based directed functional connectivity values to assign a patient to one of three classes: left TLE (LTLE), right TLE (RTLE) or healthy control. Methods: Twenty LTLE, 20 RTLE and 35 healthy controls underwent resting-state high-density EEG. For each subject, sixty 1-sec epochs free of artifacts or interictal spikes were selected. The source activity was obtained for 82 regions of interest using an individual head model and distributed linear inverse solution. The summed outflow and whole-brain directed functional connectivity were estimated in the theta, alpha and beta frequency bands using Granger-causal modeling. A Random Forest classifier (an ensemble of decision tree classifiers) was then used to assign the subject to one of three classes. The mean classification accuracy was computed with a leave-one-out procedure. We selected a maximum of six connectivity values for classification, using a greedy forward selection algorithm. Finally, three classifiers were built: ‘Control vs. LTLE’, ‘Control vs. RTLE’ and ‘LTLE vs. RTLE’. In the final classification system, a new subject is assigned to the class that was most voted by these three classifiers. Results: The ‘Control vs. RTLE’ classifier achieved an accuracy of 78.2% (sensitivity: 80.0%, specificity 77.2%), ‘Control vs. LTLE’ an accuracy of 83.6% (sensitivity 85.0%, specificity 82.9%) and ‘LTLE vs. RTLE’ an accuracy of 85.0% (sensitivity 85.0%, specificity 85.0%). Combining these classifiers into one system yielded that 16, 15 and 27 subjects were correctly classified as being, respectively, RTLE, LTLE and control. Conclusion: The high accuracy achieved demonstrates the potential of resting-state EEG-based directed functional connectivity for the diagnosis and lateralization of TLE. This could constitute a new clinical biomarker for surgical candidates and earlier in the course of the disease

PRRT2-related phenotypes in patients with a 16p11.2 deletion

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes

Treatment of convulsive status epilepticus in the UMCG; a retrospective, observational study.

Background: Convulsive Status Epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. Because a longer duration is associated with poor outcome, treatment is important to reduce seizure length. However, there is no golden standard yet for the treatment of CSE in childhood. Furthermore, little is known about what happens in clinical practice with respect to treatment of CSEs. Objectives: The primary objective of this retrospective, observational study was to evaluate the course of CSEs and its treatment regimes in the University Medical Centre of Groningen (UMCG). The secondary objective was to evaluate effectiveness and safety of each administered therapy. Material and methods: All children with a positive history of a febrile or non-febrile CSE were selected from a UMCG database that included all children with a first epileptic seizure or febrile convulsion before the age of 18 occurring between January 2000 and January 2010 and who were treated in the UMCG. After retrospective evaluation of their medical files, all CSEs occurring in children older than 1 month between January 2000 and October 2012 were included in this study. CSEs were excluded if no information was available about any administered therapy. Medical-files of children with included CSEs were retrospectively evaluated for parameters concerning the children themselves, their CSEs and its treatment. Results: Treatment regimes of 269 CSEs (43.9% remote symptomatic), occurring in 69 children (54.6% men, median age 4 years and 2 months), were evaluated. For cessation of CSEs, a median sum of 2.0 administrations of any therapy was needed (range 0-10, range of different therapies 0-5). Children with a CSE of acute or acute on remote symptomatic aetiology needed significantly more administrations of (different) therapies before the CSE stopped (p<0.05). Furthermore, treatment of CSEs in the presence of an individualized treatment protocols was associated with shorter total categorized duration of CSEs (p=0.002). Evaluation of treatment regimes showed that diazepam was preferred, followed by clonazepam, midazolam and phenytoin. No significant differences regarding effectiveness of these therapies were observed. Discussion and conclusion: This study highlights new fields of interest regarding an optimal treatment regime of CSEs in childhood. Treatment in the UMCG was overall in accordance with Dutch protocols and supported by evidence for efficacy in literature, except for the use of clonazepam. The use of clonazepam should therefore be reconsidered. Furthermore, further research should also focus on differences in pharmacoresistance between subtypes of CSEs, based on aetiology, and on the implementation of individualized treatment protocols in CSEs in childhood.

Treatment of convulsive status epilepticus in the UMCG: A retrospective, observational study

Objectives: Little is known about clinical practice with respect to the application of guidelines in the treatment of Convulsive Status Epilepticus (CSE). This retrospective, observational study evaluated treatment of episodes of CSE in children at the University Medical Centre Groningen (UMCG). Material and methods: Episodes of CSE were derived from the UMCG database of children with epilepsy aged 1 month. Treatments used in the UMCG were compared with recommendations from two most recent Dutch treatment guidelines for CSE in children aged >1 month. Results: 269 episodes of CSE occurring in 69 children (53.6% male, median age 4.3 years; range 0.1-16.3 years) were included; 219 (81.4%) of the episodes started outside the hospital, 118 (43.9%) had remote symptomatic aetiology, 96 (35.7%) were accompanied by fever. Half of the CSE episodes laste

Genotype-phenotype correlations in patients with GRIN2A variants

Objective: The GRIN2A gene has been associated with both benign childhood epilepsies and severe epileptic encephalopathies. This study evaluates the genotype-phenotype correlations in patients with GRIN2A variants. Methods: A systematic literature search was performed, identifying all patients reported before May 2014 with GRIN2A variants. Patients were classified in two groups based on their GRIN2A genotype. Group I genotypes had an expected detrimental effect on protein expression: nonsense, frameshift, splice site, or initiation codon sequence variants, translocations with breakpoints within GRIN2A, or deletions comprising GRIN2A. Group II genotypes were expected to result in an altered protein structure or function: missense or in-frame sequence variants. Results: Of 136 patients, 74 were included in group I and 62 in group II. Epilepsy was diagnosed in 86% of patients in both groups, with focal seizures being most common (82%). Benign epilepsy with centrotemporal spikes (BECTS) was significantly more often diagnosed in group II than in group I (51% versus 27%, p=0.03). Continuous spikes and waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) occurred more often in group I than in group II (50% versus 37%), although not statistically significant (p=0.29). Mild to severe developmental problems related to speech and language (80%), cognition (66%), and motor skills (48%), and behavioural problems (61%) were present in both groups. Speech and language problems were significantly more often reported in group I than in group II (90% versus 69%, p=0.02), also in patients with no LKS/CSWS (94% versus 50%, p=0.01). Conclusion: GRIN2A variants are associated with a spectrum of epilepsies, mainly accompanied by language developmental problems. This epilepsy-aphasia syndrome spectrum ranges from relatively mild BECTS to more severe LKS/CSWS. This study shows that GRIN2A genotypes with an expected milder effect on protein function are associated with a relatively more benign phenotype including BECTS without language problems

Early predictors of long-term cognitive, emotional and behavioural outcome in children with ESES: A retrospective study

Objectives: Long-term outcome of Electrical Status Epilepticus during Sleep (ESES) is generally unfavourable but hard to predict in individual children. Longer duration of ESES and younger age at onset of ESES have been reported to be predictors of poor outcome, whereas any treatment response is associated with a relatively better prognosis. This study aimed at determining possible other early predictors of long- term outcome. Material and methods: We retrospectively studied a cohort of 35 children with ESES, treated at the University Medical Centre Groningen (UMCG) and the Epilepsy Clinic of SEIN, Zwolle. We examined possible early predictors including duration between onset of clinical symptoms and definite diagnosis of ESES (diagnostic delay), and spike-wave-index (SWI). To evaluate long-term outcome, school performance as well as cognitive, emotional and behavioural functioning was assessed with the parent- reported Brain Injury Alert - adapted for children with ESES. Results: Mean age at onset of epilepsy was 4.2 years; at onset of symptoms suggestive of ESES 6.5 years; and at diagnosis of ESES 7.6 years. SWI >85% was present in 40.0%, SWI 75-85% in 34.3%, and SWI 85% was overall associated with a less favourable outcome: categorized SWI differed significantly between children with and without a negative change in three parameters of the questionnaire: understanding language (p=0.013), depressive feelings (p=0.007), and indifference (p=0.049). Conclusions: In this retrospective study, both prolonged diagnostic delay and higher SWI are associated with unfavourable long-term outcome and might therefore be early predictors for cognitive, emotional and behavioural outcome in children with ESES

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Item does not contain fulltextPURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants