Natural history of KBG syndrome in a large European cohort.

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Natural history of adults with KBG syndrome: A physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

GABRA1-Related Disorders: From Genetic to Functional Pathways.

OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

Clinical added value of interictal automated electrical source imaging in the presurgical evaluation of MRI-negative epilepsy: A real-life experience in 29 consecutive patients.

OBJECTIVE: During the presurgical evaluation, manual electrical source imaging (ESI) provides clinically useful information in one-third of the patients but it is time-consuming and requires specific expertise. This prospective study aims to assess the clinical added value of a fully automated ESI analysis in a cohort of patients with MRI-negative epilepsy and describe its diagnostic performance, by evaluating sublobar concordance with stereo-electroencephalography (SEEG) results and surgical resection and outcome. METHODS: All consecutive patients referred to the Center for Refractory Epilepsy (CRE) of St-Luc University Hospital (Brussels, Belgium) for presurgical evaluation between 15/01/2019 and 31/12/2020 meeting the inclusion criteria, were recruited to the study. Interictal ESI was realized on low-density long-term EEG monitoring (LD-ESI) and, whenever available, high-density EEG (HD-ESI), using a fully automated analysis (Epilog PreOp, Epilog NV, Ghent, Belgium). The multidisciplinary team (MDT) was asked to formulate hypotheses about the epileptogenic zone (EZ) location at sublobar level and make a decision on further management for each patient at two distinct moments: i) blinded to ESI and ii) after the presentation and clinical interpretation of ESI. Results leading to a change in clinical management were considered contributive. Patients were followed up to assess whether these changes lead to concordant results on stereo-EEG (SEEG) or successful epilepsy surgery. RESULTS: Data from all included 29 patients were analyzed. ESI led to a change in the management plan in 12/29 patients (41%). In 9/12 (75%), modifications were related to a change in the plan of the invasive recording. In 8/9 patients, invasive recording was performed. In 6/8 (75%), the intracranial EEG recording confirmed the localization of the ESI at a sublobar level. So far, 5/12 patients, for whom the management plan was changed after ESI, were operated on and have at least one-year postoperative follow-up. In all cases, the EZ identified by ESI was included in the resection zone. Among these patients, 4/5 (80%) are seizure-free (ILAE 1) and one patient experienced a seizure reduction of more than 50% (ILAE 4). CONCLUSIONS: In this single-center prospective study, we demonstrated the added value of automated ESI in the presurgical evaluation of MRI-negative cases, especially in helping to plan the implantation of depth electrodes for SEEG, provided that ESI results are integrated into the whole multimodal evaluation and clinically interpreted.

Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy.

AIM: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants. METHODS: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles. RESULTS: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%. CONCLUSION: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation.

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

Perioral myoclonia with absences and myoclonic status aggravated by oxcarbazepine.

Perioral myoclonia with absences belongs to the "idiopathic generalised epilepsy syndromes in development", currently not yet cited in the ILAE classification. This epilepsy syndrome is associated with a seizure type that appears to be specific. Here, we report polygraphic recordings of this seizure type in a young boy, previously misdiagnosed with focal epilepsy. EEG and clinical features were useful to differentiate diagnosis of his seizures from other absence or myoclonic seizures. Interestingly, some seizures were associated with neck myoclonia. Home video recording of myoclonic status aggravated by inappropriate treatment is also presented. [Published with video sequences].

Automated electrical source imaging with scalp EEG to define the insular irritative zone: Comparison with simultaneous intracranial EEG.

OBJECTIVE: To evaluate the accuracy of automatedinterictallow-density electrical source imaging (LD-ESI) to define the insular irritative zone (IZ) by comparing the simultaneous interictal ESI localization with the SEEG interictal activity. METHODS: Long-term simultaneous scalp electroencephalography (EEG) and stereo-EEG (SEEG) with at least one depth electrode exploring the operculo-insular region(s) were analyzed. Automated interictal ESI was performed on the scalp EEG using standardized low-resolution brain electromagnetic tomography (sLORETA) and individual head models. A two-step analysis was performed: i) sublobar concordance betweencluster-based ESI localization and SEEG-based IZ; ii) time-locked ESI-/SEEG analysis. Diagnostic accuracy values were calculated using SEEG as reference standard. Subgroup analysis wascarried out, based onthe involvement of insular contacts in the seizure onset and patterns of insular interictal activity. RESULTS: Thirty patients were included in the study. ESI showed an overall accuracy of 53% (C.I. 29-76%). Sensitivity and specificity were calculated as 53% (C.I. 29-76%), 55% (C.I. 23-83%) respectively. Higher accuracy was found in patients with frequent and dominant interictal insular spikes. CONCLUSIONS: LD-ESI defines with good accuracy the insular implication in the IZ, which is not possible with classical interictalscalpEEG interpretation. SIGNIFICANCE: Automated LD-ESI may be a valuable additional tool to characterize the epileptogenic zone in epilepsies with suspected insular involvement.

Ictal EEG source imaging and connectivity to localize the seizure onset zone in extratemporal lobe epilepsy.

PURPOSE: To evaluate the yield of Functional Connectivity (FC) in addition to low-density ictal Electrical Source Imaging (ESI) in extratemporal lobe epilepsy (ETLE), using an automated algorithm for analysis. METHOD: Long-term EEG monitoring of consecutive ETLE patients who underwent surgery was reviewed by epileptologists, and seizure onsets characterized by rhythmical activity were identified. A spectrogram-based algorithm was developed to select objectively the parameters of ESI analysis. Two methods for SOZ localization were compared: i) ESI power, based on LORETA exclusively; ii) ESI + FC, including a Granger causality-based connectivity analysis. Results were determined at a sublobar level. The resection zone, in relation to 1-year follow-up surgical outcome, was considered as reference standard for diagnostic accuracy analyses. RESULTS: Ninety-four seizures from 24 patients were analyzed. At seizure-level, ESI power showed 36 % sensitivity and 72 % specificity (accuracy: 45 %). ESI + FC significantly improved the accuracy, with 52 % sensitivity and 84 % specificity (accuracy: 61 %, p = 0.04). Results of ESI + FC were equally valuable in patients with lateralized or bilateral/generalized visual interpretation of ictal EEG. In a patient level sub-analysis, upon blinded clinical interpretation, ESI + FC showed a correct localization in 67 % of patients and substantial inter-rater agreement (kappa = 0.64), against 27 % achieved by ESI power, with fair inter-rater agreement (kappa = 0.37). CONCLUSION: FC significantly improves SOZ localization compared to ESI solely in ETLE. Ictal ESI + FC could represent a novel option in the armamentarium of presurgical evaluation, aiding also in patients with visually non-localizable scalp ictal EEG. Prospective studies evaluating the clinical added value of automated low-density ictal ESI may be justified.

Additional clinical value of voxel-based morphometric MRI post-processing for MRI-negative epilepsies: a prospective study.

Magnetic resonance imaging is of paramount importance in the presurgical evaluation of drug resistant epilepsy. Detection of a potentially epileptogenic lesion significantly improves seizure outcome after surgery. To optimize the detection of subtle lesions, MRI post-processing techniques may be of essential help. In this study, we aimed to evaluate the detection rate of the voxel-based morphometric analysis program (MAP) in a prospective trial. We aimed to study the MAP+ findings in terms of their clinical value in the decision-making process of the presurgical evaluation. We included, prospectively, 21 patients who had negative MRI by visual analysis. In a first step, results of the conventional non-invasive presurgical evaluation were discussed, blinded to the MAP results, in multidisciplinary patient management conferences to determine the possible seizure onset zone and to set surgical or invasive evaluation plans. Thereafter, MAP results were presented, and the change of initial clinical plan was recorded. All MAP detections were reaffirmed by a neuroradiologist with epilepsy expertise. For the 21 patients included, mean age at the time of patient management conference was 26 years (SD 15 +/- years, range: 5-54 years). In total, 4/21 had temporal lobe epilepsy and 17/21 had extra-temporal lobe epilepsy. MAP was positive in 10/21 (47%) patients and in 6/10 (60%) a diagnosis of focal cortical dysplasia was confirmed after neuroradiologist review, corresponding to a 28% detection rate. MAP+ findings had a clear impact on the initial management in 7/10 patients (7/21, 33% of all patients), which included an adaptation of the intracranial EEG plan (6/7 patients), or the decision to proceed directly to surgery (1/7 patients). MRI post-processing using the MAP method yielded an increased detection rate of 28% for subtle dysplastic lesions in a prospective cohort of MRI-negative patients, indicating its potential value in epilepsy presurgical evaluation.

Electrophysiological characterisation of myoclonic-atonic seizures in symptomatic continuous spike-waves during slow sleep syndrome.

Sudden epileptic falls are frequently reported in continuous spike-waves during slow sleep (CSWS) syndrome. Inhibitory seizures are usually considered as the underlying mechanism. However, published polygraphic recordings are rare. We report the case of a 22 month-old boy suffering from a symptomatic CSWS syndrome associated with a perinatal stroke involving the right middle cerebral artery territory. He presented with psychomotor regression and daily multiple falls related to myoclonic-atonic seizures. Neurophysiological examination showed secondary generalized myoclonus systematically correlated with a bilateral spike spreading from the right central area. This confirms that positive myoclonus, in addition to negative myoclonus, may be responsible for epileptic falls in CSWS syndrome. [Published with video sequences].

Adult-onset Rasmussen encephalitis associated with focal cortical dysplasia.

Rasmussen encephalitis is a rare, devastating condition, typically presenting in childhood. Cases of adult-onset Rasmussen have also been described, but the clinical picture is less defined, rendering final diagnosis difficult. We present a case of adult-onset Rasmussen encephalitis with dual pathology, associated with focal cortical dysplasia and encephalitis. We interpreted the Rasmussen encephalitis to be caused by severe and continuous epileptic activity due to focal cortical dysplasia. The best therapeutic approach for such cases remains unclear.

Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity.

Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

Current and emerging treatments for absence seizures in young patients.

In this report, we review the pharmacological and non-pharmacological treatments of the different absence seizure types as recently recognized by the International League Against Epilepsy: typical absences, atypical absences, myoclonic absences, and eyelid myoclonia with absences. Overall, valproate and ethosuximide remain the principal anti-absence drugs. Typical absence seizures exhibit a specific electroclinical semiology, pathophysiology, and pharmacological response profile. A large-scale comparative study has recently confirmed the key role of ethosuximide in the treatment of childhood absence epilepsy, more than 50 years after its introduction. No new antiepileptic drug has proven major efficacy against typical absences. Of the medications under development, brivaracetam might be an efficacious anti-absence drug. Some experimental drugs also show efficacy in animal models of typical absence seizures. The treatment of other absence seizure types is not supported with a high level of evidence. Rufinamide appears to be the most promising new antiepileptic drug for atypical absences and possibly for myoclonic absences. The efficacy of vagal nerve stimulation should be further evaluated for atypical absences. Levetiracetam appears to display a particular efficacy in eyelid myoclonia with absences. Finally, it is important to remember that the majority of antiepileptic drugs, whether they be old or new, may aggravate typical and atypical absence seizures.

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.

Development of an electronic decision tool to support appropriate treatment choice in adult patients with epilepsy--Epi-Scope(®).

BACKGROUND: Given the continuous knowledge progression and the growing number of available antiepileptic drugs (AEDs), making appropriate treatment choices for patients with epilepsy is increasingly difficult. While published guidelines help for separate clinical aspects, patients with a combination of specific characteristics may escape proper guidance. This study aimed to determine the appropriateness of AEDs for particular clinical variables and to offer treatment recommendations for adult patients with epilepsy in a user-friendly format for practicing neurologists. METHODS: Using the RAND/UCLA Appropriateness Method, the appropriateness of AEDs as initial/second mono-therapy and combination therapy was assessed in relation to selected clinical variables by a Belgian panel of 13 experts in epilepsy. Panel recommendations for particular patient profiles were determined by the outcome of these separate ratings. RESULTS: The appropriateness outcome of individual AEDs was not substantially different between first and second mono-therapy; valproate was considered appropriate for all types of generalised and partial seizures. The outcome for combination therapy was highly dependent on the type of AED and seizures. With respect to co-morbidities and co-treatments, levetiracetam and pregabalin proved to have the least contra-indications. For the elderly and with respect to factors related to the female reproductive system the appropriateness of AEDs showed a more diffuse pattern. Although caution was deemed necessary for some combinations, the AEDs were never considered inappropriate regarding their drug interaction profile. CONCLUSIONS: The Epi-Scope(®) tool that displays appropriateness recommendations for highly specific, possibly complex cases, supports optimal treatment choices for adult patients with epilepsy in daily practice.

Language-induced epilepsy, acquired stuttering, and idiopathic generalized epilepsy: phenotypic study of one family.

PURPOSE: Language-induced epilepsy involves seizure precipitation by speaking, reading, and writing. Seizures are similar to those of reading epilepsy (RE). The nosologic position of language-induced epilepsy is not clear. We performed a clinical and neurophysiological study in a multigenerational family with the association of idiopathic generalized epilepsy (IGE) with ictal stuttering as a manifestation of reflex language-induced epilepsy. METHODS: Nine members on three generations were studied. All patients underwent video-polygraphic EEG recordings (awake and during sleep). A standardized protocol was applied to test the effect of language and non-language-related tasks. RESULTS: Six patients presented language-induced jaw jerking that mimicked stuttering and corresponded to focal myoclonus involving facial muscles. This was associated with an IGE phenotype in four of these patients. Focal EEG spikes were found in all six patients by visual analysis and/or back-averaging techniques. The focal spikes were either asymptomatic (when followed by a slow wave) or symptomatic of facial myoclonia (when isolated). Levetiracetam, used as add-on or monotherapy in four patients, suppressed ictal stuttering. One additional case only had a phenotype of IGE without focal features. CONCLUSIONS: This family study demonstrates the phenotypic heterogeneity of the association of IGE phenotype with ictal stuttering (language-related reflex seizure). Our data suggest that this particular form of reflex epilepsy related to language has more similarities with generalized epilepsies than with focal ones. Neurophysiological investigations should be performed more systematically in patients with acquired stuttering, especially if there is family history of IGE.