Electroclinical Syndrome Research Articles

Assessing the landscape of STXBP1-related disorders in 534 individuals.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far.Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom.In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

P.103 Midline Spikes and Intractable Seizures in Pediatric Epilepsy

Background: Epileptic discharges localized to the midline vertex are rare. However, they have been associated with intractable seizures and severe long-term consequences in the developing brain. Our study aimed to understand the etiology of pediatric midline seizures and define post-surgical seizure outcomes. Methods: We reviewed charts, electroencephalography (EEG), and neuroimaging studies of ten pediatric patients with epileptic discharges localized to the midline vertex in the Comprehensive Epilepsy Program. The seizures were classified according to the International League Against Epilepsy criteria, patient age, sex, neuroimaging results, seizure etiology and outcomes were obtained. Results: Age of seizure onset was within the first 10 years of life in 90% of patients, with focal seizures being the most prevalent. Focal cortical dysplasia (FCD) was the most common etiology present in 50% of patients. These children had normal neuroimaging studies and intractable epilepsy. However, seizure freedom was achieved following surgical resection of the epileptogenic zone. Conclusions: We demonstrated that patients with midline epileptic discharges are associated with intractable focal seizures and early seizure onset. Despite normal neuroimaging reports, FCD was the most common pathology. Thus our study suggests early localization and resection of the epileptogenic zone may be beneficial for achieving seizure freedom in children with this electroclinical syndrome.

Diazepam induced sleep spindle increase correlates with cognitive recovery in a child with epileptic encephalopathy

BackgroundContinuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies.Case presentationWe describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient’s disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry.ConclusionsEpileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.

A Review of the Selected and Newer Antiseizure Medications Used in Childhood Epilepsies.

There have been additions of newer antiseizure medications in the armamentarium of clinicians for the management of epilepsy. The newer antiseizure medications have advantages of better tolerability, lesser adverse effects, and minimal drug interactions in comparison with conventional antiseizure medications. However, high cost and availability are concerns. There are also peculiar pharmacokinetic and pharmacodynamic considerations for thepediatric age, particularly in the context of age-dependent electroclinical syndromes and precision-based medicine. Thisreview attempts to provide a comprehensiveand pragmatic update on newer antiseizure medications.

Developmental and epileptic encephalopathies after negative or inconclusive genetic testing: what is next?

The redefinition of classical electroclinical syndromes and the emergence of neurogenetics has led to a revolution in the field of developmental and epileptic encephalopathies (DEEs). In this context, advances in genetic techniques are leading to the final diagnosis of a large proportion of patients with DEE. However, up to 50% of patients with DEE remain undiagnosed. For patients with uncertain genetic etiology, there is a pressing need for the implementation of new targeted treatments and precision medicine. In some undiagnosed patients, genetic reanalysis with further in-depth or reverse phenotyping are valuable diagnostic tools to clarify new variants of uncertain significance. In other cases, the implementation of new bioinformatic algorithms is required for the update and reassessment of previously generated genetic data. Moreover, many other clinical tools have been developed for the management of patients of DEEs after a negative or inconclusive genetic testing. In this review, we highlight advances and limitations of new diagnostic strategies used in DEE patients without a known genetic etiology. Finally, we provide a wide perspective on aspects that will need further research, especially in non-Mendelian inheritance DEEs, such as those related to somatic mosaicism of the central nervous system or epigenetic and oligogenic mechanisms.

An Update to Approach to the Childhood Electroclinical Syndromes.

Childhood Electroclinical Syndrome (CES) is a term which refers to distinct epilepsies of childhood which have peculiar similarities such as the age of onset, seizure semiology, EEG and prognosis. With advancements in the diagnostics and genetics, pediatric epilepsy is entering in the age of precision medicine. The present paper provides an update of CES in light of recent advances in the terminologies and classifications by International League Against Epilepsy and genetic underpinnings of epilepsy. The core features of CES for diagnosing and managing some common CES is presented here.

Evaluation of pediatric patients in new-onset seizure clinic (NOSc)

AimWe evaluated the clinical and demographic features of children presenting with unprovoked seizures at a regional new-onset seizure clinic (NOSc). MethodsWe retrospectively reviewed charts of 492 consecutive patients evaluated in the NOSc at the Childrne’s Healthcare of Atlanta ResultsNonepileptic events (NEE) were diagnosed in 102 (24%) and epileptic seizures in the remaining 326 (76%). Patients with NEE were younger than patients with epileptic seizure (5.0 vs. 7.4 years). Except for headache which occurred more frequently in NEE (14% vs. 6%), frequencies of comorbidities were similar in groups with NEE and epileptic seizure. Electroencephalogram (EEG) was performed in 98%, and finding was abnormal in 51%. Brain magnetic resonance imaging (MRI) was performed in 55%, and finding was abnormal in 15%. An electroclinical epilepsy syndrome was diagnosed in 42%. Antiseizure medication was started in 25% with first seizure and in 77% with recurrent seizures. InterpretationFor children with newly-presenting seizures, a regional NOSc provided efficient, timely diagnosis and appropriate evaluations and treatment. Timely recognition of NEE resulted in fewer unnecessary evaluations and treatment for a quarter of referred patients whereas identification of the specific types of seizures and epilepsy allowed appropriate use, including deferral, of neuroimaging and guided treatment selection.

EEG in genetic generalized epilepsies

Genetic, or idiopathic, generalized epilepsies (GGEs or IGEs) includes childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures alone (GTCS-a).Aim. to characterize the capabilities of electroencephalography (EEG) for the diagnosis of various forms of genetic generalized epilepsyMaterials and methods. Literature data in Pubmed, Google Scholar was analyzed. In addition, own observations and clinical cases were systematized.Results. The article presents the data of morphology and topography of spike-wave discharges, as well as other patterns of EEG in the GGE – poly-spike activity, photoparoxysmal response, occipital intermittent rhythmic delta activity (OIRDA), fixation-off sensitivity and generalized paroxysmal fast activity (GPFA), as well as epileptiform K-complexes, the allocation of which in an independent pattern is questioned by a number of neurophysiologists. The differences between interictal and ictal activity in the GGE are discussed in detail; electroencephalogram (EEG) informativity modifiers are considered. The morphology of atypical features in the GGE is considered. The role of EEG in the differential diagnosis of CAE, JAE, JME, GTCS alone with the description of typical, atypical features, study scenarios and diagnostic criteria for each form are considered.Conclusions. Typical EEG features of GGE significantly simplify the differential diagnosis of electroclinical syndromes. There are “non-classical” features of EEG in the GGE, which do not contradict the diagnosis. To reveal the peculiarities of epileptiform discharges distribution, video EEG monitoring with night-time sleep and the use of several modality stimuli is preferable. Incorrect interpretation of EEG is dangerous for the patient.

Use of the International League Against Epilepsy (ILAE) 1989, 2010, and 2017 Classification of Epilepsy in children in a low-resource setting: A hospital-based cross-sectional study.

ObjectivesThis cross‐sectional study was designed to test the applicability of the 1989, 2010, and 2017 International League Against Epilepsy (ILAE) classification of epilepsy in children from a resource‐limited setting in India.MethodsClassification of seizure types and syndromes was done through parental interviews and review of medical records in children with epilepsy aged one month to 18 years. Available investigations including EEG, MRI, and metabolic/genetic tests were used in classifying patients as per the 1989, 2010, and 2017 ILAE (level II‐epilepsy type) classification. We compared the proportion of children remaining unclassified by each scheme.ResultsSeven hundred and twenty‐six children (436 males, mean age 6.4 ± 4.6 years) were enrolled. Using the 1989 ILAE classification, we were able to classify 95.7%, and 82.6% children by the 2010 scheme. The 2017 ILAE classification could classify all 726 children at level I (seizure type), 664 (91.0%) children at level II (epilepsy type), and an electroclinical syndrome could be identified in 409 (56.1%) of the children. An etiology could be identified in 75%, perinatal brain injury being the most frequent. West syndrome was the most common electroclinical syndrome, identified in 22.7% patients. The 1989 ILAE classification system was superior to the 2010 system (P = .01) in epilepsy classification. There was no difference between the 1989 and 2017 schemes (P = .31) or the 2010 and 2017 schemes (P = .10).SignificanceThe 2017 ILAE classification, being multidimensional, allowed classification of children who could not undergo extensive evaluation due to economic constraints and also provided room for overlapping etiologies.

Characterization of Anti-seizure Medication Treatment Pathways in Pediatric Epilepsy Using the Electronic Health Record-Based Common Data Model.

The purpose of this pilot study was to analyze treatment pathways of pediatric epilepsy using the common data model (CDM) based on electronic health record (EHR) data. We also aimed to reveal whether CDM analysis was feasible and applicable to epilepsy research. We analyzed the treatment pathways of pediatric epilepsy patients from our institute who underwent antiseizure medication (ASM) treatment for at least 2 years, using the Observational Medical Outcomes Partnership (OMOP)-CDM. Subgroup analysis was performed for generalized or focal epilepsy, varying age of epilepsy onset, and specific epilepsy syndromes. Changes in annual prescription patterns were also analyzed to reveal the different trends. We also calculated the proportion of drug-resistant epilepsy by applying the definition of seizure persistence after application of two ASMs for a sufficient period of time (more than 6 months). We identified 1,192 patients who underwent treatment for more than 2 years (mean ± standard deviation: 6.5 ± 3.2 years). In our pediatric epilepsy cohort, we identified 313 different treatment pathways. Drug resistance, calculated as the application of more than three ASMs during the first 2 years of treatment, was 23.8%. Treatment pathways and ASM resistance differed between subgroups of generalized vs. focal epilepsy, different onset age of epilepsy, and specific epilepsy syndromes. The frequency of ASM prescription was similar between onset groups of different ages; however, phenobarbital was frequently used in children with epilepsy onset < 4 years. Ninety-one of 344 cases of generalized epilepsy and 187 of 835 cases of focal epilepsy were classified as medically intractable epilepsy. The percentage of drug resistance was markedly different depending on the specific electro-clinical epilepsy syndrome [79.0% for Lennox-Gastaut syndrome (LGS), 7.1% for childhood absence epilepsy (CAE), and 9.0% for benign epilepsy with centrotemporal spikes (BECTS)]. We could visualize the annual trend and changes of ASM prescription for pediatric epilepsy in our institute from 2004 to 2017. We revealed that CDM analysis was feasible and applicable for epilepsy research. The strengths and limitations of CDM analysis should be carefully considered when planning the analysis, result extraction, and interpretation of results.

Management of epilepsy in elderly

The prevalence of seizures and epilepsy in the elderly is generally underestimated. Epileptic seizures are not a rare occurrence in the elderly and their prevalence increases with age. The clinical manifestations of seizures, the aetiology, the treatment and the psychosocial impact of the epilepsy diagnosis may differ in the elderly. Differential diagnosis with episodes of unconsciousness and/or fall or other non-epileptic manifestations is often difficult. The presence of comorbidities, the polypharmatherapy and the age-related pharmacokinetic changes can represent a problem for the treatment of epilepsy in the elderly, with a higher risk of adverse effects and potentially inappropriate drug interactions. Epileptic seizures in the elderly can have semiological characteristics similar to those of other age groups. On the other hand, the richness of the electroclinical syndromes of childhood and adolescence is not found in the elderly, and, in particular, idiopathic generalized epilepsies are rarely expressed at this age. Symptomatic seizures related to acute structural injury or metabolic causes are particularly frequent. Therapy management of the elderly with an epileptic seizure should concern not only neurologists, but also general practitioners, geriatricians, and cardiologists, therefore involving a wide range of clinical specialties. This review aims to summarize the management of epilepsy in the elderly, reporting also differences in epidemiology, electroclinical features, aetiology and diagnostic procedures.

Outcome of West Syndrome: A Critical Review

AbstractWest syndrome is a genetically heterogeneous electro-clinical syndrome starting in early infancy. Short-term goal of therapy is spasm control and with standard hormonal or vigabatrin treatment, spasms can be controlled in 60 to 80% of patients in 2 weeks to 3 months period. Hormonal treatment with oral steroid is an alternative therapy to injectable adrenocorticotropin hormone, especially in low resource areas. Vigabatrin is preferred in tuberous sclerosis patients. Long-term aim of treatment is sustained remission of seizures and better neurodevelopmental outcome. About 50 to 70% of children are spasm free for prolonged duration, but epilepsy with multiple seizure types including Lennox–Gastaut syndrome is evident in 20 to 40% of children in long-term follow-up. Though hypsarrhythmia is helpful for the diagnosis, prognostic role of the resolution of electroencephalographic abnormalities is still uncertain. Seizures can be controlled in 40 to 60% of the patients, but only 12 to 40% children have normal neurodevelopmental outcome and a third of children are left with severe disabilities. Children with unknown etiology and normal development at spasm onset have better clinical outcome. Young age at onset, nonstandard therapy have less favorable outcome. Surgery is helpful for spasm control in patients with structural lesions and refractory spasms even in the absence of structural lesions.

Status Epilepticus Manifested as Continuous Epileptic Spasms.

Objective: The etiology and outcome of status epilepticus with continuous epileptic spasms have not been fully understood; and only rare cases have been reported in the literature. Here, we described 11 children, who manifested continuous epileptic spasms with various etiologies and different outcomes.Methods: This is a case series study designed to systematically review the charts, video-electroencephalography (video-EEG), magnetic resonance images, and longitudinal follow-up of patients who presented continuous epileptic spasms lasting more than 30 min.Results: Median age at onset was 2 years old, ranging from 2 months to 5.6 years. The etiology of continuous epileptic spasms for these 11 cases consisted of not only some known electro-clinical epilepsy syndromes like West Syndrome and Ohtahara Syndrome, but also secondary symptomatic continuous epileptic spasms, caused by acute encephalitis or encephalopathy, which extends the etiological spectrum of continuous epileptic spasms. The most characteristic feature of these 11 cases was prolonged epileptic spasms, lasting for a median of 13.00 days (95% CI: 7.26–128.22 days). The interictal EEG findings typically manifested as hypsarrhythmia or its variants, including burst suppression. Hospital stays were much longer in acute symptomatic cases than in primary epileptic syndromic cases (59.67 ± 50.82 vs. 15.00 ± 1.41 days). However, the long-term outcomes were extremely poor in the patients with defined electro-clinical epilepsy syndromes, including severe motor and intellectual developmental deficits (follow-up of 4.94 ± 1.56 years), despite early diagnosis and treatment. Continuous epileptic spasms were refractory to corticosteroids, immuno-modulation or immunosuppressive therapies, and ketogenic diet.Conclusion: Continuous epileptic spasms were associated with severe brain impairments in patients with electro-clinical syndromes; and required long hospital stays in patients with acute symptomatic causes. We suggest to include continuous epileptic spasms in the international classification of status epilepticus, as a special form. Further investigations are required to better recognize this condition, better understand the etiology, as well as to explore more effective treatments to improve outcomes.

Clinical characteristics of children with epilepsy managed at an urban hospital in Africa: a retrospective study

Background&#x0D; Most children with epilepsy reside in resource-limited regions such as sub-Saharan Africa, where the majority of studies have been conducted in rural areas with limited investigations. Medical records from children with epilepsy seen at an urban hospital in Kenya were examined to provide a comprehensive description of epilepsy in children from this hospital.&#x0D; &#x0D; Methods&#x0D; A retrospective observational study was conducted which involved reviewing medical records of 426 epilepsy patients (260 males and 166 females) aged 0 - 18 years, seen at Aga Khan University Hospital, Nairobi, Kenya between February 2011 and December 2014.&#x0D; &#x0D; Results&#x0D; The most frequent age at presentation; documented in 29% was in infancy. Generalized seizures due to structural brain abnormalities were the most common form of epilepsy (28%). Lennox-Gastaut Syndrome was the most common electroclinical syndrome (7%). Focal seizures and focal seizures with loss of awareness were identified in 12% of the population. There were no cases of childhood absence epilepsy in this group. Brain atrophy was the most common MRI finding, occurring in a fifth of the population (20%), while cystic encephalomalacia occurred in 13%. Half (50%) of all EEG recordings performed for this cohort were abnormal. Generalized seizures due to structural brain abnormalities and Lennox-Gastaut Syndrome (LGS) were significant predictors of a treatment history of three or more AEDs. At the conclusion of the review period, 16% of the patients had not visited the clinic for more than 12 months and were considered to be lost to follow-up.&#x0D; &#x0D; Conclusion&#x0D; The highest frequency of epilepsy cases was documented in children less than one year of age. Generalized seizures due to structural abnormalities and Lennox-Gastaut syndrome were the most common seizure type and syndrome. Improvement of public awareness of different types of seizures in children may increase identification of children with childhood absence epilepsy.

Genotype-phenotype correlation on 45 individuals with West syndrome.

West syndrome is an epilepsy syndrome characterized by repetitive epileptic spasms (ES) and hypsarrhythmia, typically leading to developmental delay/intellectual disability (DD/ID). It is considered a classic epileptic encephalopathy (EE). We designed a diagnostic sequencing panel targeting 131 genes associated with epilepsy and/or EE and screened a cohort of 45 individuals with clinical diagnosis of West syndrome. We identified disease-causing single nucleotide variants in 11 out of 45 individuals affecting genes commonly associated with West syndrome (such as CDKL5, ARX) but also in genes predominantly linked to other epileptic disorders (such as DEPDC5, SCN1A, WDR45, AARS). Panel analysis revealed copy number variants in two additional cases, comprising a 6,7Mb Duplication on chromosome 2 including SCN2A and SCN3A and a supernumerary marker chromosome 15 leading to an overall diagnostic yield of 29% (13/45). In our cohort, individuals with a disease-causing variant had significantly more severe phenotypes with respect to DD/ID, therapy resistant epilepsy and cerebral atrophy compared to genetically unclarified cases. In addition to investigating the genotypic spectrum of West syndrome, we compared the phenotypic spectrum of clarified versus unclarified cases. Our study illustrates that West syndrome is an electroclinical syndrome caused by various genetic disorders. Individuals without detectable genetic cause might have less encephalopathy leading to a less severe course.

The natural history of seizures and neuropsychiatric symptoms in childhood epilepsy with centrotemporal spikes (CECTS)

ObjectiveChildhood epilepsy with centrotemporal spikes (CECTS) (formally benign epilepsy with centrotemporal spikes, BECTS) is a common childhood epilepsy syndrome characterized by psychiatric, behavioral, and cognitive abnormalities and self-limited seizures. Although CECTS is one of the most well-characterized electroclinical epilepsy syndromes, the natural history of neuropsychiatric outcomes is poorly understood. We report the psychiatric, behavioral, and cognitive profiles over the course of disease from a large, prospectively-enrolled, longitudinal cohort of children with CECTS. We further characterize the detailed seizure course and test the relationship between several proposed risk factors and neuropsychiatric and seizure outcomes in these children. MethodsPatients diagnosed with CECTS were enrolled as part of a community-based study and followed from diagnosis through disease resolution (16.0 ± 3.1 years, N = 60). Twenty sibling controls were also recruited. We report the natural history of premorbid neuropsychiatric concerns, postmorbid neuropsychiatric diagnoses, long-term neuropsychological performance, seizure course, antiseizure medication (ASM) treatment response, and the relationship between duration seizure-free and remission. Age at onset and premorbid neuropsychiatric concerns were tested as predictors of seizure count, epilepsy duration, postmorbid neuropsychiatric diagnoses, and long-term neuropsychological performance. Antiseizure medication treatment duration, seizure count, and epilepsy duration were tested as predictors of postmorbid neuropsychiatric diagnoses and long-term neuropsychological performance. ResultsChildren with CECTS had a high incidence of ADD/ADHD symptoms (18.3%) or learning difficulties (21.7%) before diagnosis. New or persistent ADHD (20%), mood disorders (23.6%), learning difficulties (14.5%), and behavioral disorders (7.3%) were common after CECTS diagnosis. At 9-year follow-up, performance on formal neuropsychological testing was comparable to population statistics and sibling controls. More than two-thirds of treated children experienced at least one seizure during treatment. Most children (61.7%) had entered terminal resolution after 12 months seizure-free. Among all children, for each month seizure-free, there was a 6–7% increase in the probability of achieving terminal remission (p < 1e-10). The presence of a premorbid neurodevelopmental concern predicted a longer epilepsy duration (p = 0.02), higher seizure count (p = 0.02), and a postmorbid psychiatric or neurodevelopmental diagnosis (p = 0.002). None of the tested features predicted long-term neuropsychological performance. SignificanceChildren are at high risk of neuropsychiatric symptoms along the course of the disease in CECTS, however, long-term cognitive performance is favorable. The majority of children had a seizure while being treated with ASMs, suggesting that CECTS is not as pharmacoresponsive as assumed or that treatment approaches are not optimized. Among treated and untreated children, future seizure-risk can be estimated from duration seizure-free. The presence of a premorbid neuropsychiatric concern predicted a more severe disease course in CECTS.

Risk factors for recurrence after drug withdrawal in childhood epilepsy

BackgroundSeveral studies have been conducted to determine the risk of recurrence after withdrawal of antiepileptic drugs (AEDs) in recent years. There is no consensus concerning the circumstances affecting discontinuation of AEDs. This study was designed to determine the recurrence rate of epilepsy after withdrawal of AEDs and the risk factors related with recurrence. MethodsChildren with epilepsy onset between 1 month and 16 years of age who were followed up at least 3 years after AED treatment withdrawal were enrolled. Patients were classified into groups according to defined risk factors for recurrence. ResultsA total of 284 patients, 137 (48.2%) girls and 147 (51.8%) boys were included, and seizures recurred after withdrawal in 51 patients (18%). Thirty-three (64.7%) patients had recurrence in the first year after withdrawal. The recurrence risk was calculated based on the electro-clinical syndromes classification; the recurrence risk was the highest in the juvenile myoclonic/absence group and lowest in the benign infantile seizure group. No recurrence was observed in the infantile spasm group. Data evaluated by multivariable analysis showed that having the structural-metabolic and unknown epilepsy and <3 years seizure free period before withdrawal of AEDs were the main risk factors for recurrence after AED withdrawal in our study. ConclusionWe suggest a seizure-free period of at least 3 years under AED medication and we must be cautious in patients with structural-metabolic and unknown epilepsy before AED withdrawal.

Antiepileptic Effects of a Novel Non-invasive Neuromodulation Treatment in a Subject With Early-Onset Epileptic Encephalopathy: Case Report With 20 Sessions of HD-tDCS Intervention.

The current clinical investigation examined high-definition transcranial direct current stimulation (HD-tDCS) as a focal, non-invasive, anti-epileptic treatment in a child with early-onset epileptic encephalopathy. We investigated the clinical impact of repetitive (20 daily sessions) cathode-centered 4 × 1 HD-tDCS (1 mA, 20 min, 4 mm ring radius) over the dominant seizure-generating cortical zone in a 40-month-old child suffering from a severe neonatal epileptic syndrome known as Ohtahara syndrome (OS). Seizures and epileptiform activity were monitored and quantified using video-EEG over multiple days of baseline, intervention, and post-intervention periods. Primary outcome measures were changes in seizure frequency and duration on the last day of intervention versus the last baseline day, preceding the intervention. In particular, we examined changes in tonic spasms, tonic-myoclonic seizures (TM-S), and myoclonic seizures from baseline to post-intervention. A trend in TM-S frequency was observed indicating a reduction of 73% in TM-S frequency, which was non-significant [t(4) = 2.05, p = 0.1], and denoted a clinically significant change. Myoclonic seizure (M-S) frequency was significantly reduced [t(4) = 3.83, p = 0.019] by 68.42%, compared to baseline, and indicated a significant clinical change as well. A 73% decrease in interictal epileptic discharges (IEDs) frequency was also observed immediately after the intervention period, compared to IED frequency at 3 days prior to intervention. Post-intervention seizure-related peak delta desynchronization was reduced by 57%. Our findings represent a case-specific significant clinical response, reduction in IED, and change in seizure-related delta activity following the application of HD-tDCS. The clinical outcomes, as noted in the current study, encourage the further investigation of this focal, non-invasive neuromodulation procedure in other severe electroclinical syndromes (e.g., West syndrome) and in larger pediatric populations diagnosed with early-onset epileptic encephalopathy.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02960347, protocol ID: Meiron 2013-4.

Concurrent recording of neurometabolic changes and local field potential in the central nervous system of awake-behaving rodent models of epilepsy

Introduction: Temporal lobe epilepsy (TLE) is a form of acquired epilepsy characterized as an electro-clinical syndrome in which seizures emanate from the limbic system [1,2]. TLE is particularly disabling due to the unpredictable and recurrent nature of seizures and incidence of antiepileptic drug resistance [3] many times an indication for resection surgery [4,5]. Pre-surgical identification of the seizure onset zone relies on multimodal methods based on different pathophysiological principles. The golden standard technique is long-term intracranial electroencephalogram (EEG) [6] combined neuroimaging techniques, which explore brain hemodynamics as a surrogate signal for brain activity [7,8]. To date, no single sensor approach allows simultaneous and seamless recording of electrical and hemodynamic responses. Materials and methods: We used multisite ceramic-based Pt microelectrode arrays (MEAs) to perform high-frequency amperometric recording of pO2 and local field potential (LFP)-related currents in the CNS of chronically implanted freely-moving rats during pilocarpine-evoked status epilepticus. Using fast Fourier transform (FFT) filtering of the raw electrochemical signal we separated into the low frequency component (<1 Hz), corresponding to the electrochemical reduction of O2 and high (>1 Hz) frequency component, corresponding to the LFP currents. Results: We determined the mean resting level of pO2 in two subregions of the hippocampus as well as in the striatum and the cortex of freely moving rats. The hippocampal DG showed lowest (p < 0.01) resting pO2 level (6.6 ± 0.7 μM) when compared to CA1 (22.1 ± 3.4 μM), striatum (17.2 ± 1.7 μM), and cortex (22.1 ± 4.9 μM). Evoked changes in interstitial pO2 in vivo we performed a 5 min tail pinch stress paradigm test, which induced a transient increase pO2 in the hippocampus of 15 ± 4% from baseline, corresponding to an average Δ[O2] of 3.7 ± 0.6 μM. Induction of status epilepticus induced biphasic changes in pO2 in the hippocampus. The initial dip at seizure onset (−4.5 ± 0.7 µM) was followed by a prolonged hyperoxygenation phase (+10.4 ± 2.9 µM). Analysis of high-frequency component of the amperometric signal allowed the simultaneous monitoring LFP at the site of pO2 recording. This has high potential for translation into the clinical setting supported on intracranial grid or strip electrodes. Discussion and conclusions: This strategy revealed that a single sensor can simultaneously report chemical (pO2) and electrophysiological (LFP currents) information, allowing concurrent monitoring of electrical and neurovascular/neurometabolic activities.

Electroclinical insights into autoimmune epilepsy

PurposeChronic autoimmune epilepsy is an increasingly recognised entity however its clinical and electrographic features remain poorly understood. We present a case undergoing diagnostic Stereo-electroencephalography implantation that was found to have a multifocal perisylvian epilepsy with unique electrographic features and is now seizure free with immunotherapy. MethodsThe patient had antibody negative refractory perisylvian epilepsy and underwent implantation of the perisylvian-temporal networks. Immunomodulatory treatment was administered during SEEG. ResultsSEEG demonstrated a multifocal perisylvian epilepsy with strong involvement of the posterior insula. There was almost continuous spiking seen interictally from multiple foci within the right hemisphere and independent seizures were generated from 5 locations. After treatment with intravenous methylprednisone and immunoglobulin during SEEG, spiking and seizures terminated while still off anti-seizure medications. The patient remains seizure free on immunotherapy. ConclusionThis case highlights the importance of considering autoimmunity in the differential diagnosis of refractory epilepsy, especially perisylvian epilepsy. It also highlights the need to define a clinical phenotype associated with autoantibodies in epilepsy, as there are likely many cases who are not positive for one of the commercially available tests. This case also provides insights into the possible features of an electroclinical syndrome associated with autoimmunity.