Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.

OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel. RESULTS: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. INTERPRETATION: We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.

Surgery for infants with catastrophic epilepsy: an analysis of complications and efficacy.

PURPOSE: Infants with epilepsy often have a catastrophic course. There is a reluctance to operate in the very young, due to the perception of an unacceptable risk of morbidity with early operations. The purpose of this investigation was to better characterize the efficacy and safety of epilepsy surgery in infants. METHODS: Epilepsy operations performed on children under 1 year old, between 2002 and 2013, were reviewed for demographic information, epilepsy characteristics, surgical approach, outcomes, and surgical complications. RESULTS: Twenty-five patients, ages 11 days to 11.5 months (mean 4.7) at operation, were identified. All had daily seizures. Twenty-two (88%) had an abnormal magnetic resonance imaging (MRI). Sixteen (64%) patients underwent hemispherotomy at initial operation. Seven (28%) infants had grid placement followed by focal resection. Focal cortical dysplasia was the most common pathology (40%) followed by hemimegalencephaly (32%). Complications occurred in 36% of patients. These included hydrocephalus in five patients (20%). Two patients had significant intra-operative complications which required unplanned staging of their operations. Both recovered without permanent injury. Mean follow-up was 62.4 months. Twenty patients (80%) are seizure-free, and 10 (40%) are off anticonvulsant medication. Two patients are Engel class 2, and the remaining three patients were Engel class 4, one of whom died with status epilepticus from the contralateral hemisphere. CONCLUSION: Infants with localization-related catastrophic epilepsy can have excellent outcomes from early epilepsy surgery. Complications are common in this patient group and proper diagnosis can be challenging. Young age should not exclude infants with catastrophic epilepsy from consideration for early surgical intervention.

New antiepileptic drugs: lacosamide, rufinamide, and vigabatrin.

OPINION STATEMENT: The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms.

Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities.

PURPOSE: Evidence for a poor psychiatric, social, and vocational adult outcome in childhood absence epilepsy (CAE) suggests long-term unmet mental health, social, and vocational needs. This cross-sectional study examined behavioral/emotional, cognitive, and linguistic comorbidities as well as their correlates in children with CAE. METHODS: Sixty-nine CAE children aged 9.6 (SD = 2.49) years and 103 age- and gender-matched normal children had semistructured psychiatric interviews, as well as cognitive and linguistic testing. Parents provided demographic, seizure-related, and behavioral information on their children through a semi-structured psychiatric interview and the child behavior checklist (CBCL). RESULTS: Compared to the normal group, 25% of the CAE children had subtle cognitive deficits, 43% linguistic difficulties, 61% a psychiatric diagnosis, particularly attention deficit hyperactivity disorder (ADHD) and anxiety disorders, and 30% clinically relevant CBCL broad band scores. The most frequent CBCL narrow band factor scores in the clinical/borderline range were attention and somatic complaints, followed by social and thought problems. Duration of illness, seizure frequency, and antiepileptic drug (AED) treatment were related to the severity of the cognitive, linguistic, and psychiatric comorbidities. Only 23% of the CAE subjects had intervention for these problems. CONCLUSIONS: The high rate of impaired behavior, emotions, cognition, and language and low intervention rate should alert clinicians to the need for early identification and treatment of children with CAE, particularly those with longer duration of illness, uncontrolled seizures, and AED treatment.

Children with ESES: variability in the syndrome.

OBJECTIVE: We undertook a retrospective study of children who present with significant activation of paroxysmal discharges during sleep to examine the clinical spectrum of disorders that present with such an EEG abnormality. BACKGROUND: Electrical status epilepticus in sleep (ESES) is an electrographic pattern characterized by nearly continuous spike-wave discharges in slow wave sleep, usually with a frequency of 1.5-3 Hz and usually diffuse and bilateral in distribution. A variety of neurocognitive and behavioral problems have been associated with this EEG pattern. METHODS: We conducted a retrospective review of 1497 EEG records of patients admitted to University of California, Los Angeles (UCLA) for overnight video-EEG monitoring during a 5 year interval. Demographic, clinical and electroencephalographic variables were evaluated. RESULTS: EEG records for 102 patients meeting criteria were identified. Clinical information was available for 90 of those patients. Eighteen of these patients could be diagnosed with Landau-Kleffner syndrome (LKS). Key findings include: (1) neuroimaging abnormalities were uncommon in our LKS patients; (2) among children who do not fit the specific diagnostic criteria for LKS, a spike-wave index (SWI) >50% was more likely to be associated with global developmental disturbances than SWI < or =50% (p<0.05); (3) Children with generalized discharges were more likely to experience severe or global developmental disturbance than those with focal abnormalities, without reaching statistical significance (p=0.07). CONCLUSIONS: Severity of ESES can vary over time between and within patients and clinical status does not always directly correlate with SWI. However, the prognosis of LKS is substantially better than CSWS and these two disorders could be classified in a dichotomous manner rather than be seen as two points along a continuum.

Assessing the similarity of surface linguistic features related to epilepsy across pediatric hospitals.

OBJECTIVE: The constant progress in computational linguistic methods provides amazing opportunities for discovering information in clinical text and enables the clinical scientist to explore novel approaches to care. However, these new approaches need evaluation. We describe an automated system to compare descriptions of epilepsy patients at three different organizations: Cincinnati Children's Hospital, the Children's Hospital Colorado, and the Children's Hospital of Philadelphia. To our knowledge, there have been no similar previous studies. MATERIALS AND METHODS: In this work, a support vector machine (SVM)-based natural language processing (NLP) algorithm is trained to classify epilepsy progress notes as belonging to a patient with a specific type of epilepsy from a particular hospital. The same SVM is then used to classify notes from another hospital. Our null hypothesis is that an NLP algorithm cannot be trained using epilepsy-specific notes from one hospital and subsequently used to classify notes from another hospital better than a random baseline classifier. The hypothesis is tested using epilepsy progress notes from the three hospitals. RESULTS: We are able to reject the null hypothesis at the 95% level. It is also found that classification was improved by including notes from a second hospital in the SVM training sample. DISCUSSION AND CONCLUSION: With a reasonably uniform epilepsy vocabulary and an NLP-based algorithm able to use this uniformity to classify epilepsy progress notes across different hospitals, we can pursue automated comparisons of patient conditions, treatments, and diagnoses across different healthcare settings.

Pediatric epilepsy: Five new things.

Epilepsy in children can be very different from epilepsy in adults, both in seizure type and epilepsy syndrome. The goal in treating children is seizure freedom, no treatment side effects, and function that is no different from the general population. In a significant percentage of patients, this goal remains unachievable, but many aspects of epilepsy are becoming clearer. This review will highlight 5 areas where progress is being made to achieve these goals in pediatric epilepsy. Specific research animal models are being developed to reflect the unique features of different pediatric epilepsies. As genetic syndromes are better identified, for some patients this has led to improved treatment. New advances in drug therapy have led to 3 new medications approved for children. More effective drug choices can now be recommended due to comparative drug trials and better overall care of children can be provided due to awareness of the comorbidities of epilepsy.

Paroxysmal fast activity: an interictal scalp EEG marker of epileptogenesis in children.

PURPOSE: High-frequency oscillations (>100Hz) have been proposed as localized markers of epileptic networks, but require intracranial electroencephalographic (EEG) recordings. This study explored if beta- and gamma-frequency paroxysmal fast activity (PFA), recorded interictally during non-REM sleep, could be used as a scalp EEG marker of epileptogenesis in children. METHODS: The presence and scalp location of PFA was visually identified in 681 patients with overnight video-EEG (age 0-18 years), and compared with ictal onset sites. The clinical features of patients with PFA were compared with patients without PFA along with evidence of PFA evolution in 35 patients who had multiple video-EEG records. RESULTS: PFA was present in 16% of all patients and in 28% of those with seizures. PFA was more frequently observed in EEGs from patients 3 years of age or younger (>40%), and children with infantile spasms (85%). When present, PFA predicted if the patient had epilepsy with 97% accuracy, and was not found in individuals with non-epileptic events. PFA localized with EEG-ictal onset sites with 91% sensitivity and 82% accuracy. Ictal scalp EEG events began with beta- and gamma-frequencies in 80% of patients with PFA, and they had increased seizure frequencies compared with non-PFA cases. In patients with multiple video-EEG studies, PFA showed progression over increased numbers of electrodes in 74%, improvement in 15%, and remained unchanged in 12% and correlated with seizure evolution. PFA was not associated with other seizure types, anatomic location, type of antiepileptic drug, etiology, or histopathology. CONCLUSIONS: While relatively infrequent, interictal PFA was specific in identifying younger children with epilepsy, co-localized with the ictal onset sites on scalp video-EEG, and progressed and correlated with seizure severity. We propose that PFA is a scalp EEG marker of epileptic networks with the advantage of being recorded non-invasively during interictal non-REM sleep.

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report.

PURPOSE: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG-PET/MRI coregistration and diffusion-tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients. METHODS: FDG-PET/MRI coregistration and/or DTI for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were utilized in 15 TSC patients. Presurgery scalp EEG and postsurgery seizure control identified epileptogenic tubers (n = 27) and these were compared with nonepileptogenic tubers (n = 204) for MRI tuber volume, volume of FDG-PET hypometabolism on MRI coregistration, DTI, ADC, and FA values. RESULTS: Compared with nonepileptogenic tubers, epileptogenic regions had increased volume of FDG-PET hypometabolism (p < 0.0001), and increased ADC values in subtuber white matter (p < 0.0001). In contrast, the largest MRI identified tuber (p = 0.046) and decreased FA values (p = 0.58) were less accurate in identifying epileptogenic regions. Larger volumes of FDG-PET hypometabolism correlated positively with increased ADC values (p = 0.029), and localized to areas of cortical dysplasia adjacent to the tuber in four cases. CONCLUSIONS: Larger volumes of FDG-PET hypometabolism relative to MRI tuber size and higher ADC values identified epileptogenic tubers and adjoining cortex containing cortical dysplasia in TSC patients with improved accuracy compared with largest tuber by MRI or lowest FA values. Used in conjunction with ictal scalp EEG and interictal magnetoencephalography, these newer neuroimaging techniques should improve the noninvasive evaluation of TSC patients with intractable epilepsy in distinguishing epileptogenic sites for surgical resection.

Social competence in pediatric epilepsy: insights into underlying mechanisms.

This study compared parent-based Child Behavior Checklist (CBCL) social competence scores of 90 children with complex partial seizures (CPS) and 62 with absence epilepsy (CAE) of average intelligence with scores of 91 healthy children. It also examined the role of seizure-related, cognitive, behavioral, linguistic, social communication, and demographic variables on these measures. When differences in cognitive, linguistic, and demographic variables were controlled for, the CPS and CAE groups had significantly lower scores in the school, but not in the social interaction and activities domains compared with the healthy control group. Among the patients, lower Full Scale IQ externalizing behaviors, disruptive disorders, minority status, and impaired social communication, but not seizure variables, predicted lower social competence scores. These findings demonstrate the importance of controlling for cognitive, behavioral, and demographic variables in social competence studies of children with CPS and CAE and the need to assess cognition and behavior when parents report school and social problems in these children.

Status epilepticus and frequent seizures: incidence and clinical characteristics in pediatric epilepsy surgery patients.

PURPOSE: The literature suggests that pediatric epilepsy surgery cases that present in status epilepticus (SE) are an unusual occurrence. However, this concept is based on case reports, and the incidence and clinical characteristics of these patients have not been systematically assessed. METHODS: The cohort consisted of resective epilepsy surgery cases from 2000 to 2005 (n = 115), and they were classified as presenting with continuous SE requiring medical suppression therapy (n = 6) or intermittent SE (greater than 3 seizures/hour; n = 17). The SE categories were compared with extratemporal surgery patients without SE (non-SE; n = 64) for differences in clinical variables abstracted from the medical record. RESULTS: Continuous SE was noted in 5% and intermittent SE in 15% of resective surgery cases, and all had extratemporal cortical involvement. Compared with continuous SE and non-SE cases, intermittent SE patients were younger at surgery with shorter duration of seizures, and had an increased incidence of active infantile spasms during video scalp EEG monitoring. Compared with non-SE cases, the continuous and intermittent SE groups required a larger number of antiepileptic medications presurgery and 6-months postsurgery, underwent hemispherectomy more frequently, and had an increased incidence of hemimegalencephaly and Rasmussen encephalitis and a lower occurrence of infarct/ischemia and infectious etiologies. Seizure control was over 71% up to 2 years postsurgery, and there were no differences between patient groups. Finally, seizure frequency per hour was greater in continuous SE cases compared with the intermittent SE group. CONCLUSIONS: Children presenting with continuous or intermittent SE are not rare in pediatric epilepsy surgery centers, and such cases are more commonly associated with infantile spasms, Rasmussen's syndrome, and hemimegalencephaly pathologies. Seizure outcome after surgery was not altered in pediatric patients because they had presented with continuous or intermittent SE.

Behavioral disorders in pediatric epilepsy: unmet psychiatric need.

PURPOSE: This study examined the relation between psychiatric diagnosis and mental health services in children with epilepsy and the associated demographic, cognitive, linguistic, behavioral, and seizure-related variables. METHODS: The Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), the Child Behavior Checklist, the Test of Language Development, and the Wechsler Intelligence Scale for Children-Revised (WISC-R) were administered to 114 children, aged 5 to 16 years, with either complex partial seizures (CPS) or primary generalized with absence (PGE, petit mal). A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis and information regarding mental health services were derived from the K-SADS. RESULTS: Although approximately 60% of the subjects had a DSM-IV psychiatric diagnosis, >60% received no mental health treatment. Absence of mental health care was associated with younger age, less parental education, limited number of antiepileptic drugs (AEDs; i.e., one or none), and higher verbal IQ. In addition, children with PGE and a single psychiatric diagnosis were less likely to have a history of mental health treatment. CONCLUSIONS: This is the first study to demonstrate unmet mental health need in a large sample of children with CPS and PGE. The study's findings suggest that parents and clinicians should be aware of the mental health needs of children with epilepsy, particularly if they have one or more of the identified risk factors.

Five or more acute postoperative seizures predict hospital course and long-term seizure control after hemispherectomy.

PURPOSE: Acute postoperative seizures (APOSs) are those that occur in the first 7 to 10 days after surgery, and previous studies in temporal lobe epilepsy patients support the notion that APOSs may foretell failure of long-term seizure control. It is unknown whether APOSs also predict seizure outcome or hospital course after hemispherectomy. METHODS: Hemispherectomy patients (n = 114) were studied retrospectively and subdivided into the following groups: No APOSs, 1 to 5 APOSs, or >5 APOSs. Intensive care unit (ICU) nursing staff or family members reported and described the APOS events. APOS categories were compared with pre- and postsurgery clinical variables abstracted from the medical record. RESULTS: APOSs occurred in 22.6% of hemispherectomy patients. Compared with the 0 and 1 to 5 APOS groups, patients with >5 APOS showed (a) longer seizure durations before surgery, (b) longer hospitalizations, (c) later oral food intake, (d) more frequent lumbar punctures, (e) worse seizure control at 0.5 and 1 year after surgery, (f) more antiepileptic drug (AED) use at 2 and 5 years after surgery, and (g) higher reoperation rate. No similar differences were found between the 0 and 1 to 5 APOS groups. The day of the APOS, whether the APOS was typical of preoperative seizures, and postsurgery scalp EEG did not predict long-term seizure control. APOS patients in the 1 to 5 and >5 groups had lower pre- and postsurgery Vineland developmental quotients compared with those without an APOS. CONCLUSIONS: Hemispherectomy patients with >5 APOSs had a more prolonged and complicated hospital course and worse postsurgery seizure control, more AED use, and higher reoperation rate than did patients with 0 or 1 to 5 APOSs. Thus the number of APOSs was a predictor of postsurgery seizure control and can be used to counsel patients and families about prognosis after hemispherectomy.