[EPILEPSY SURGERY IN CHILDREN: A SUMMARY OF A DECADE AT THE SOURASKY TEL AVIV MEDICAL CENTER].

INTRODUCTION: Drug-resistant epilepsy in children is associated with morbidity, developmental regression and mortality. Over recent years, there is an increase in awareness regarding the role of surgery in the treatment of refractory epilepsy, both in the diagnostic phase and for treatment, reducing the number and magnitude of seizures. Technological advancements have enabled a minimalization of surgery, with reduction in surgical associated morbidity. METHODS: In this retrospective study, we review our experience with cranial surgery for epilepsy between the years 2011-2020. Collected data included information regarding the epileptic disorder, surgery, surgical-related complications and epilepsy outcome. RESULTS: A total of 93 children underwent 110 cranial surgeries over a decade. The main etiologies included cortical dysplasia (29), Rasmussen encephalitis (10), genetic disorders (9), tumors (7) and tuberous sclerosis (7). The main surgeries included lobectomies (32), focal resections (26), hemispherotomies (25), and callosotomies (16). Two children underwent MRI-guided laser interstitial thermal treatment (LITT). The most significant improvements following surgery were following hemispherotomy or tumor resection (100% of children, each). Following resections for cortical dysplasia led to a significant improvement in 70%. In 83% of children undergoing callosotomy, there were no additional drop seizures; 14% of the entire group underwent additional epilepsy surgery; 23% of children had an unexpected complication, in the vast majority with no permanent sequela. There was not mortality. CONCLUSIONS: Epilepsy surgery may lead to significant improvement and even cure of epilepsy. There is a wide span of epilepsy surgical procedures. Ealy referral of children with refractory epilepsy for surgical evaluation may significantly reduce the developmental injury, and improve functional outcomes.

Cardiometabolic outcomes in children and adolescents with West syndrome.

BACKGROUND: West syndrome is a convulsive disorder of infancy with unique seizures and a characteristic background electroencephalograph pattern. Adrenocorticotropic hormone (ACTH) is effective in spasm cessation, yet metabolic consequences of this therapeutic agent in childhood have not been published. METHODS: In this observational study we explored the cardiometabolic outcomes of 117 children with West syndrome (78 ACTH-treated and 39 non-ACTH-treated) monitored at a single medical center from 1995 to 2019 (median follow-up 7.2 years). Outcomes included the prevalence of cardiometabolic derangements (obesity, hypertension, and dyslipidemia) during infancy (< 2 years), early childhood (2-6 years), and childhood/adolescence (6-18 years). RESULTS: The rates of metabolic derangements during infancy in the West syndrome cohort were high compared to childhood/adolescence (obesity 27.3 % vs. 3.3 %, [p = 0.010], diastolic hypertension 48.8 % vs. 5.1 % [p < 0.001], hypertriglyceridemia 71 % vs. 40 % [p = 0.008], low high-density lipoprotein cholesterol [HDL-c] 54.2 % vs. 12.9 % [p = 0.001], and elevated triglycerides/HDL-c ratios 62.5 % vs. 12.9 % [p < 0.001]). The proportion of systolic and/or diastolic blood pressure levels categorized as hypertensive was 58.5 % during infancy, 48.1 % during early childhood, and 26.3 % during childhood/adolescence. ACTH-treated patients had higher weight and weight-to-length z-scores and higher triglyceride levels during infancy compared to non-ACTH-treated patients (p = 0.008, p = 0.001, and p = 0.037, respectively), and higher triglyceride levels during early childhood (p = 0.050), with no significant group differences during childhood/adolescence. CONCLUSIONS: Children with West syndrome apparently have an increased prevalence of cardiometabolic derangements more pronounced in infants and in ACTH-treated patients. These findings highlight the need to monitor these children for cardiometabolic derangements, even though these cardiometabolic abnormalities are transitory and tend to decrease with time. The health implications of cardiometabolic derangements during critical windows of growth and development warrant further investigation.

Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?

AIM: To evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect. METHODS: A prospective study of 92 consecutive patients (age 1-37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications. RESULTS: Mean follow-up time was 19.8 ± 12.5 months (range 3-45). Mean CBD dose was 11.3 (4-38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038). CONCLUSIONS: We report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Early prediction of encephalopathic transformation in children with benign epilepsy with centro-temporal spikes.

BACKGROUND: Most children with Benign epilepsy with centro-temporal spikes (BECTS) undergo remission during late adolescence and do not require treatment. In a small group of patients, the condition may evolve to encephalopathic syndromes including epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), or Landau-Kleffner Syndrome (LKS). Development of prediction models for early identification of at-risk children is of utmost importance. AIM: To develop a predictive model of encephalopathic transformation using data-driven approaches, reveal complex interactions to identify potential risk factors. METHODS: Data were collected from a cohort of 91 patients diagnosed with BECTS treated between the years 2005-2017 at a pediatric neurology institute. Data on the initial presentation was collected based on a novel BECTS ontology and used to discover potential risk factors and to build a predictive model. Statistical and machine learning methods were compared. RESULTS: A subgroup of 18 children had encephalopathic transformation. The least absolute shrinkage and selection operator (LASSO) regression Model with Elastic Net was able to successfully detect children with ECSWS or LKS. Sensitivity and specificity were 0.83 and 0.44. The most notable risk factors were fronto-temporal and temporo-parietal localization of epileptic foci, semiology of seizure involving dysarthria or somatosensory auras. CONCLUSION: Novel prediction model for early identification of patients with BECTS at risk for ECSWS or LKS. This model can be used as a screening tool and assist physicians to consider special management for children predicted at high-risk. Clinical application of machine learning methods opens new frontiers of personalized patient care and treatment.

Whole-exome and HLA sequencing in Febrile infection-related epilepsy syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new-onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient-parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors.

Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.

OBJECTIVE: Experiential phenomena (EP), such as illusions and complex hallucinations, are vivid experiences created in one's mind. They can occur spontaneously as epileptic auras or can be elicited by electrical brain stimulation (EBS) in patients undergoing presurgical evaluation for drug-resistant epilepsy. Previous work suggests that EP arise from activation of different nodes within interconnected neural networks mainly in the temporal lobes. Yet, the anatomical extent of these neural networks has not been described and the question of lateralization of EP has not been fully addressed. To this end, an extended number of brain regions in which electrical stimulation elicited EP were studied to test whether there is a lateralization propensity to EP phenomena. METHODS: A total of 19 drug-resistant focal epilepsy patients who underwent EBS as part of invasive presurgical evaluation and who experienced EP during the stimulation were included. Spatial dispersion of visual and auditory illusions and complex hallucinations in each hemisphere was determined by calculation of Euclidean distances between electrodes and their centroid in common space, based on (x, y, z) Cartesian coordinates of electrode locations. RESULTS: In total, 5857 stimulation epochs were analyzed; 917 stimulations elicited responses, out of which 130 elicited EP. Complex visual hallucinations were found to be widely dispersed in the right hemisphere, while they were tightly clustered in the occipital lobe of the left hemisphere. Visual illusions were elicited mostly in the occipital lobes bilaterally. Auditory illusions and hallucinations were evoked symmetrically in the temporal lobes. CONCLUSIONS: These findings suggest that complex visual hallucinations arise from wider spread in the right compared to the left hemisphere, possibly mirroring the asymmetry in the white matter organization of the two hemispheres. These results offer some insights into lateralized differences in functional organization and connectivity that may be important for functional mapping and planning of surgical resections in patients with epilepsy.

Development of Ontology for Self-limited Epilepsy with Centrotemporal Spikes and Application of Data Mining Algorithms to Identify New Subtypes.

BACKGROUND: Benign rolandic epilepsy or benign childhood epilepsy with centrotemporal spikes (BCECTS) is a common childhood epileptic syndrome. The syndrome resolves in adolescence, but 1-7% of patients have an atypical presentation, some of which require aggressive medical treatment. Early treatment may prevent complications and neurocognitive deterioration. Variants include Landau-Kleffner syndrome (LKS) and electrical status epilepticus during sleep (ESES). OBJECTIVES: To determine data driven identification of risk factors and characterization of new subtypes of BCECTS based on anontology. To use data mining analysis and correlation between the identified groups and known clinical variants. METHODS: We conducted a retrospective cohort study comprised of 104 patients with a diagnosis of BCECTS and a minimum of 2 years of follow-up, between the years 2005 and 2017. The medical records were obtained from the epilepsy service unit of the pediatric neurology department at Dana-Dwek Hospital, Tel Aviv Sourasky Medical Center. We developed a BCECTS ontology and performed data preprocessing and analysis using the R Project for Statistical Computing (https://www.r-project.org/) and machine learning tools to identify risk factors and characterize subgroups. RESULTS: The ontology created a uniform and understandable infrastructure for research. With the ontology, a more precise characterization of clinical symptoms and EEG activity of BCECTS was possible. Risk factors for the development of severe atypical presentations were identified: electroencephalography (EEG) with spike wave (P < 0.05), EEG without evidence of left lateralization (P < 0.05), and EEG localization (centrotemporal, frontal, or frontotemporal) (P < 0.01). CONCLUSIONS: Future use of the ontology infrastructure for expanding characterization for multicenter studies as well as future studies of the disease are needed. Identifying subgroups and adapting them to known clinical variants will enable identification of risk factors, improve prediction of disease progression, and facilitate adaptation of more accurate therapy. Early identification and frequent follow-up may have a significant impact on the prognosis of the atypical variants.

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study.

INTRODUCTION: Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time. METHODS: This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests. RESULTS: Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved. CONCLUSIONS: PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

Improved quality of life and cognition after early vagal nerve stimulator implantation in children.

OBJECTIVE: In patients with drug-resistant epilepsy, reduction of seizure duration and frequency at an early age is beneficial. Vagal nerve stimulator (VNS) was shown to reduce seizure frequency and duration in children; however, data in children under the age of 12 years are sparse. The aim of this study was to compare seizure outcome and quality of life after early (≤5 years of age) and late (>5 years of age) implantation of VNS in children. METHODS: This study reviewed 45 consecutive children undergoing VNS implantation. Primary outcome measure was the reduction of seizure frequency. Secondary outcome measures were epilepsy outcome assessed by the McHugh and Engel classifications, reduction of antiepileptic drugs (AEDs), psychomotor development, and quality of life measured by the Pediatric Quality of Life (PEDSQL™) questionnaire and caregiver impression (CGI) scale. The mean follow-up time was 72.3 months (±39.8 months). RESULTS: Out of 45 patients included, in 14 (31.1%), VNS was implanted early and in 31, (68.9%) late. Reduction of seizure frequency, McHugh and Engel classifications, and reduction of AED were comparable in both groups. Quality of life measured by the CGI scale (2.1 ±â€¯1.7 in the early group vs. 3.6 ±â€¯1.6 in the late group; p = 0.004), as well as the difference of total PEDSQL™ Core scores (12.0 ±â€¯24.0 in the early group vs. -5.2 ±â€¯14.9 in the late group; p = 0.01) and cognitive PEDSQL™ Core (30.6 ±â€¯32.0 in the early group vs. 2.4 ±â€¯24.3 in the late group; p = 0.03) between preoperative and follow-up was significantly higher in the early implantation group. CONCLUSION: Early VNS implantation in children leads to a significantly better quality of life and cognitive outcome compared with late implantation while reduction of seizure frequency and epilepsy outcome seems comparable. Therefore, in children with drug-resistant epilepsy, VNS implantation should be considered as early as possible.

Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents - An observational, longitudinal study.

The objective of this observational study was to evaluate the efficacy of medical cannabis for the treatment of refractory epilepsy. Fifty-seven patients (age 1-20 years) with epilepsy of various etiologies were treated with Cannabis oil extract (CBD/THC ratio of 20:1) for at least 3 months (Median follow up time-18 months). Forty-Six Patients were included in the efficacy analysis. Average CBD dose was11.4 mg/kg/d. Twenty-six patients (56%) had ≤50% reduction in mean monthly seizure frequency. There was no statistically significant difference in response rate among various epilepsy etiologies, and cannabis strain used. Younger age at treatment onset (<10 years) and higher CBD dose (>11 mg/kg/d) were associated with better response to treatment. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation. Our results suggest that adding CBD-enriched cannabis extract to the treatment regimen of patients with refractory epilepsy may result in a significant reduction in seizure frequency according to parental reports. Randomized controlled trials are necessary to assess its true efficacy.

A novel missense SNAP25b mutation in two affected siblings from an Israeli family showing seizures and cerebellar ataxia.

SNAP25 is a core component of the soluble N-ethylmaleimide-sensitive factor attachment receptor complex, which plays a critical role in synaptic vesicle exocytosis. To date, six de novo SNAP25 mutations have been reported in patients with neurological features including seizures, intellectual disability, severe speech delay, and cerebellar ataxia. Here, we analyzed an Israeli family with two affected siblings showing seizures and cerebellar dysfunction by whole-exome sequencing, and identified a novel missense SNAP25 mutation (c.176G > C, p.Arg59Pro) inherited from their unaffected father. Two SNAP25 isoforms are known, SNAP25a and SNAP25b, which each contain a different exon 5. The c.176G > C mutation found in this study was specific to SNAP25b, while five previously reported mutations were identified in exons common to both isoforms. Another was previously reported to be specific to SNAP25b. Comparing clinical features of reported patients with SNAP25 mutations, the current patients demonstrated apparently milder clinical features with normal intelligence, and no magnetic resonance imaging abnormality or facial dysmorphism. Our results expand the clinical spectrum of SNAP25 mutations.

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and ß-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. METHODS: To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes. RESULTS: Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications. CONCLUSION: Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.

CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

PURPOSE: To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil. METHODS: A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. RESULTS: CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients. CONCLUSIONS: The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.

Multiplex families with epilepsy: Success of clinical and molecular genetic characterization.

OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. RESULTS: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. CONCLUSION: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.

Benign childhood epilepsy with Centro-Temporal spikes (BCECTSs), electrical status epilepticus in sleep (ESES), and academic decline--how aggressive should we be?

Since many of the children with BCECTSs display electrical status epilepticus during sleep and many present with different comorbidities, mainly ADHD and behavioral disturbances, clinicians are often confronted with the dilemma of how aggressive they should be with their efforts of normalizing the EEG. We conducted a retrospective study by screening medical records of all consecutive patients with BCECTSs, spike-wave index (SWI) >30%, and ADHD/ADD that were evaluated in our pediatric epilepsy service and were followed up for at least two years. Patients with neurocognitive deterioration detected by formal testing were excluded. A total of 17 patients with mean age of 6.9years at BCECTS diagnosis were identified. The patients' mean SWI was 60% and that dense electrical activity lasted 1.5years on average (range: 1-4.5years). Six children were formally diagnosed with learning disabilities in addition to ADD/ADHD. All of them were treated with an average of three antiepileptic medications, mainly for the purpose of normalizing the EEG, but none of them was treated with steroids or high-dose diazepam. The mean duration of follow-up was 5.5years. A cognitive or behavioral deterioration was not detected in any of them. Our data suggest that when treating a child with BCECTSs, high SWI, and school difficulties, the most critical parameter that determines the necessity of using second-line antiepileptic agents such as steroids or high-dose diazepam is a formal psychological evaluation that proves cognitive (I.Q.) decline. Otherwise, these agents may be avoided.

Emergence of sensory patterns during sleep highlights differential dynamics of REM and non-REM sleep stages.

Despite the profound reduction in conscious awareness associated with sleep, sensory cortex remains highly active during the different sleep stages, exhibiting complex interactions between different cortical sites. The potential functional significance of such spatial patterns and how they change between different sleep stages is presently unknown. In this electrocorticography study of human patients, we examined this question by studying spatial patterns of activity (broadband gamma power) that emerge during sleep (sleep patterns) and comparing them to the functional organization of sensory cortex that is activated by naturalistic stimuli during the awake state. Our results show a high correlation (p < 10(-4), permutation test) between the sleep spatial patterns and the functional organization found during wakefulness. Examining how the sleep patterns changed through the night highlighted a stage-specific difference, whereby the repertoire of such patterns was significantly larger during rapid eye movement (REM) sleep compared with non-REM stages. These results reveal that intricate spatial patterns of sensory functional organization emerge in a stage-specific manner during sleep.