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Purpose: Epilepsy and syncope can be difficult to distinguish, with misdiagnosis resulting in unnecessary or incorrect treatment and disability. Combined tilt-table and video EEG (vEEG) testing (tilt-vEEG) is infrequently used to parse these entities even at large centers. Because of the discovery of a rare case of epileptic seizure induced by head-up tilt (HUT) (no prior cases have been published), the authors sought to verify the rarity of this phenomenon., Methods: An observational, retrospective case series study of all combined tilt-vEEG studies performed at Stanford Health Care over a 2-year period was performed. Studies were grouped into categories: (1) abnormal tilt and normal vEEG; (2) abnormal vEEG and normal tilt; (3) abnormal vEEG and abnormal tilt; (4) normal tilt and normal vEEG, with neurologic symptoms; and (5) normal tilt and normal vEEG without neurologic symptoms., Results: Sixty-eight percent of patients had an abnormal study (categories A-C), with only 3% having both an abnormal tilt and an abnormal EEG (category C). Of these, one patient had a focal epileptic seizure induced by HUT. With HUT positioning, the patient stopped answering questions and vEEG showed a left temporal seizure; systolic blood pressure abruptly dropped to 89 mm Hg (64 mm Hg below baseline); heart rate did not change, but pacemaker showed increased firing (threshold: <60 bpm)., Conclusions: Combined tilt-table and vEEG evaluation was able to identify a previously unreported scenario-head-up tilt provocation of an epileptic seizure-and improve treatment. Combined tilt and vEEG testing should be considered for episodes that persist despite treatment to confirm proper diagnosis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 by the American Clinical Neurophysiology Society.)

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged., (© 2021 Wiley Periodicals LLC.)

Background: The aim of the present systematic revision is to analyze existing published reports about the use of home-videos recordings (HVRs) to support physicians in the differential diagnosis of paroxysmal seizure-like episodes (PSLE). We also developed practical recommendations in order to ensure adequate quality standards and safety advice for HVRs., Material and Methods: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to July 2020. All studies concerning the use of HVRs as a diagnostic tool for patients presenting PSLE were included., Results: Seventeen studies satisfied all inclusion and exclusion criteria and were considered for the review. A consistent boost in diagnostic and clinical decision-making was reported across all studies in the literature. One study found that HVRs decreased the stress level in many families and improved their quality of life. Training in performing good-quality videos is necessary and increases the diagnostic value of HVRs., Conclusions: HVRs can be of diagnostic value in epilepsy diagnosis and management. HVRs are low cost, widespread, and may provide great support for neurologists. It is important to train patients and caregivers in performing good quality videos to optimize this useful tool and to guarantee safety standards during the recording.

Background: Some epilepsy syndromes (sleep-related epilepsies [SRE]) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life., Purposes: To define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2)., Methods: The project was conducted under the auspices of the European Academy of Neurology (EAN), the European Sleep Research Society (ESRS) and the International League against Epilepsy (ILAE) Europe. The framework of the document entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For literature search a step-wise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library., Results: Scenario 1: despite a low quality of evidence, recommendations on anamnestic evaluation, tools for capturing the event at home or in the laboratory are provided for specific SRE. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizures control., Conclusions: Definitive procedures for evaluating patients with SRE are lacking. We provide advice that could be of help for standardising and improving the diagnostic approach of specific SRE. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined., (© 2020 European Academy of Neurology and European Sleep Research Society.)

The aim of this report was to refine the genotypes and phenotypes of chromodomain helicase DNA-binding protein 2 (CHD2)-related epilepsy. Seventeen patients with CHD2 mutations were enrolled. CHD2 mutations were identified by application of next-generation sequencing of epilepsy or whole exome sequencing. Sixteen mutations were identified, among which 15 have not yet been reported. Thirteen mutations were de novo. Age at seizure onset ranged from 3 months to 10 years 5 months. Seizures observed were generalized tonic-clonic, myoclonic, atonic, atypical absence, focal, and myoclonic-atonic. Epileptic spasms occurred in two patients. Developmental disability was present in 14 patients. Autism features were observed in seven patients. Video electroencephalogram was abnormal in 15 patients. Five patients were diagnosed with non-specific epileptic encephalopathy, two with epilepsy with myoclonic-atonic seizures, two with Lennox-Gastaut syndrome, two with febrile seizures plus, and one with West syndrome. Seizures were controlled in nine patients. Q1392TfsX17 may be a hot-spot mutation of CHD2. West syndrome was observed as a new phenotype of CHD2 mutation. The severity of the phenotypes of CHD2 mutations ranged from mild febrile seizures to severe epileptic encephalopathy. WHAT THIS PAPER ADDS: Q1392TfsX17 maybe the hot-spot mutation of CHD2. West syndrome could be a new phenotype of CHD2 mutation., (© 2019 Mac Keith Press.)

Background and purpose: Some epilepsy syndromes (sleep‐related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2). Methods: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library. Results: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control. Conclusions: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined. [ABSTRACT FROM AUTHOR]

The chromodomain helicase DNA-binding (CHD) family of proteins are ATP-dependent chromatin remodelers that contribute to the reorganization of chromatin structure and deposition of histone variants necessary to regulate gene expression. CHD proteins play an important role in neurodevelopment, as pathogenic variants in CHD1, CHD2, CHD4, CHD7 and CHD8 have been associated with a range of neurological phenotypes, including autism spectrum disorder (ASD), intellectual disability (ID) and epilepsy. Pathogenic variants in CHD2 are associated with developmental epileptic encephalopathy (DEE) in humans, however little is known about how these variants contribute to this disorder. Of the nine CHD family members, CHD2 is the only one that leads to a brain-restricted phenotype when disrupted in humans. This suggests that despite being expressed ubiquitously, CHD2 has a unique role in human brain development and function. In this review, we will discuss the phenotypic spectrum of patients with pathogenic variants in CHD2, current animal models of CHD2 deficiency, and the role of CHD2 in proliferation, neurogenesis, neuronal differentiation, chromatin remodeling and DNA-repair. We also consider how CHD2 depletion can affect each of these biological mechanisms and how these defects may underpin neurodevelopmental disorders including epilepsy. [ABSTRACT FROM AUTHOR]

Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay. [ABSTRACT FROM AUTHOR]

Deletions of the 15q26 region encompassing the chromodomain helicase DNA binding domain 2 (CHD2) gene have been associated with intellectual disability, behavioral problems, and several types of epilepsy. Including the cases mentioned in ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations) and DECIPHER (database of genomic variation and phenotype in humans using ensembl resources), so far, a total of 13 intellectually disabled patients with a genetically proven deletion of the CHD2 gene are described, of whom eleven had a history of severe forms of epilepsy starting from a young age. In this article, a moderately intellectually disabled 15-year-old male with a 15q26.1-q26.2 interstitial deletion is reported, who was referred for analysis of two recent short-lasting psychotic episodes that were nonresponsive to antipsychotic treatment and recurrent disinhibited behaviors since early infancy. Careful interdisciplinary assessment revealed that the psychotic phenomena originated from a previously unrecognized absence epilepsy. Treatment with valproic acid was started which resulted in full remission of psychotic symptoms, and consequently, substantial improvement of behavior. It was concluded that in case of (rare) developmental disorders with genetically proven etiology, a detailed inventory of anamnestic data and description of symptomatology over time may elucidate epilepsy-related psychopathology for which a specific treatment regimen is needed. [ABSTRACT FROM AUTHOR]

Muscle–eye–brain disease (MEB, OMIM 253280) is an autosomal recessive disorder characterized by a distinct triad of congenital muscular dystrophy, structural eye abnormalities, and cobblestone lissencephaly. Clinically, MEB patients present with early onset muscular hypotonia, severely compromised motor development, and mental retardation. Magnetic resonance imaging reveals a lissencephaly type II with hypoplasia of the brainstem and cerebellum. MEB is associated with mutations in the gene for protein O-mannose beta-1,2- N-acetylglucosaminyltransferase ( POMGnT1, OMIM 606822). In this paper, we report the clinical findings of nine MEB patients from eight families. Eight of the nine patients presented typical features of MEB. However, a broad phenotypic variability was observed, ranging from two patients with severe autistic features to another patient with an unusually mild phenotype, initially diagnosed as congenital muscular dystrophy. Furthermore, severe hydrocephalus was reported in two families during a previous pregnancy, emphasizing the phenotypic overlap with Walker–Warburg syndrome. In addition to three previously reported mutations, we identified six novel POMGnT1 mutations (one missense, five truncating) in the present patient cohort. Our data suggest mutational hotspots within the minimal catalytic domain at arginine residue 442 (exon 16) and in intron 17. It is interesting to note that all mutations analyzed so far result in a complete loss of enzyme activity. Therefore, we conclude that the type and position of the POMGnT1 mutations are not of predictive value for the clinical severity. This supports the notion that additional environmental and/or genetic factors may contribute to the observed broad spectrum of POMGnT1-associated phenotypes. [ABSTRACT FROM AUTHOR]

Two commentaries on a study that asserts the effective application of ocular compression during electroencephalography (EEG) in distinguishing breath-holding spells and syncope from epileptic seizures in children are presented. The first commentary points out that the proposed approach is not sufficient to come to a diagnosis. The second supported the first comment by claiming that increased attention to the clinical history and adequate follow-up of the patient are more important than EEG.

Periventricular nodular heterotopia (PNH) is a rare neuronal migration disorder in which immature neurons fail to undergo a directed migration from the ventricular and subventricular zones to the cerebral cortex. Classic PNH occurs predominantly in females and is associated with periods of epilepsy and near-normal intelligence. One gene associated with PNH was mapped to chromosome Xq28. PNH with learning disability is reported in 15 male patients with several syndromes and various congenital abnormalities such as craniosynostosis, frontonasal malformation, and agenesis of the corpus callosum. We present a 26-year-old male patient who was followed up with the diagnosis of epilepsy from the age of 1 year. Additionally the patient had severe learning disability, obesity, and hypogonadism. Imaging of his brain demonstrated PNH. Klinefelter syndrome was clinically suspected, and analysis of his chromosomes revealed a karyotype 46,XY,der(19)t(X;19) (q11.1–11.2;p13.3). Molecular techniques, such as subtelomere-specific fluorescent in-situ hybridization and multicolour banding, were also used. The same translocation was demonstrated in his mother and his maternal grandmother. This family might help to explain the gene localization of X-linked recessive PNH. In our patient, PNH is associated with familial (X;19) translocation. To our knowledge, this unique combination has not been reported in the medical literature. [ABSTRACT FROM AUTHOR]

The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin ( RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive. [ABSTRACT FROM AUTHOR]

Aims: To describe a large series of children with anoxic-epileptic seizures (AES)—that is, epileptic seizures induced by syncopes. Methods: Retrospective case-note review in a tertiary paediatric neurology unit. For all 27 children seen with a definite diagnosis of AES between 1972 and 2002, a review of clinical histories, videotapes, and EEG/ECG studies was undertaken. Main outcome measures were: age of onset, frequency and type of syncopes; age of onset and frequency of AES; type and duration of induced epileptic seizures; effect of treatment of syncopal and epileptic components. Results: Median age of onset of syncopes was 8 months (range 0.2-120), frequency 2 in total to 40/day, median total -200. Syncopes were predominantly reflex asystolic (RAS), prolonged expiratory apnoea (cyanotic breath-holding spells), or of mixed or uncertain origin; there was one each of ear piercing and hair grooming vasovagal syncope and one of compulsive Valsalva. Median age of onset of AES was 17 months (range 7-120), frequency from total 1 to 3/day, median total 3. The epileptic component was almost always bilateral clonic; three had additional epilepsy, one each with complex partial seizures, myoclonic absences, and febrile seizures plus. Median duration of epileptic component was 5 minutes (range 0.5-40, mean 11). Cardiac pacing prevented RAS in two patients: most other anti-syncope therapies were ineffective. Diazepam terminated the epileptic component in 6/8. Valproate or carbamazepine abolished AES in 5/7 without influencing syncope frequency. Conclusions: Although uncommon compared with simple syncopes, syncope triggered epileptic seizures (AES) are an important treatable basis of status epilepticus. [ABSTRACT FROM AUTHOR]

Bilateral periventricular nodular heterotopia (BPNH) is a neuronal migration disorder that is characterized by subependymal nodules of gray matter. Recently, a causative gene for BPNH, filamin 1, has been identified, and possible roles of the translated protein in cell migration and blood vessel development have been proposed. We report here the histopathological features of an autopsy case of BPNH with widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex, in whom we found a novel exon 11 (Val528Met) filamin 1 mutation. Within the periventricular nodules, well-differentiated pyramidal neurons were randomly oriented. A small proportion of neurons were immunolabeled with antibodies raised against calbindin D-28k, parvalbumin, or calretinin. We used a carbocyanine dye (DiI) tracing technique to investigate the extent of fiber projections within and outside the nodules. The labeled fibers formed bundles that extended into the surrounding white matter. Connections between adjacent nodules were evident. Connections between the nodules and the cerebral cortex were also seen, with a small number of labeled fibers reaching the cortex. In the cerebral cortex, small closely packed vessels ran in a parallel fashion throughout all of the layers. Immunohistochemically, the inner rim of individual vessel lumina was labeled by an antibody against factor VIII, and the vessel walls were labeled by antibodies against actin and laminin. Astrocyte processes, labeled with an antibody to glial fibrillary acidic protein, invaded these vascular channels. Ultrastructurally, a network of basal lamina-like materials lined with endothelial cells was evident. The cytoarchitecture of the cerebral cortex was disturbed, in that the columnar neuronal arrangement was distorted around the malformed vessels. This case appears to represent an example of BPNH manifesting widespread developmental anomalies within the blood vessels and the cortical cytoarchitecture in the cerebrum. [ABSTRACT FROM AUTHOR]

Rationale: Cortical dysplasia (CD) designates a diverse group of malformations resulting from one or more abnormalities in the development of the cerebral cortex. The clinical manifestations of CD are varied, probably depending on the type, location and extent of CD. Epilepsy is a potential late manifestation of any cortical malformation. To our knowledge, however, no study has focused specifically on late onset of epilepsy in patients with localized CD. Material and Methods: We studied patients with localized CD confirmed by MRI. Patients were divided into 2 groups according to age at onset of epilepsy. Group 1 included patients in whom the first seizure occurred up to the age of 12 (early-onset group) and group 2 included patients in whom the first seizure occurred after the age of 12 (late-onset group). The two groups were compared with regard to the type of CD, clinical findings and EEG findings. Results: Thirty-three patients with various forms of CD were studied. Onset of epilepsy occurred in adolescence or adulthood in 9 cases (37%). In 6 of these (17% overall), the first seizure occurred in adulthood. CD were posterior bilateral pachygyria (1), unilateral polymicrogyria (3), focal dysplasia with subcortical gray matter heterotopia (1), perisylvian bilateral polymicrogyria (1), bioccipital polymicrogyria (1) and bilateral nodular periventricular gray matter heterotopia (2). The incidence of neurological signs was lower in the late-onset group. Mental retardation was moderate or absent, thus allowing a fairly normal lifestyle. All patients presented partial seizures with a lower incidence of drug resistance (p < 0.01). EEG demonstrated preservation of background activity and absence of diffuse or multifocal abnormalities. Conclusion: Onset of epilepsy with various forms of CD may be delayed until adolescence or adulthood. Prognosis of epilepsy is usually more favorable in these cases. [ABSTRACT FROM AUTHOR]

Discusses key issues concerning the occurrence of disturbances of neuronal migration and its implications for the onset of bipolar disorders. Molecular mechanisms involving filamin 1; Causes of neuronal migration and alterations in the electric stability in areas of neural tissue; Clinical manifestations of epilepsy and bipolar disorders.