Clinical Validation of Selected NIH Cognitive Toolbox Tasks in Pediatric Epilepsy.

The NIH Toolbox Cognition Battery (NIHTB-CB) is designed to assess cognitive functioning across the lifespan. We aimed to evaluate the clinical validity of two NIHTB-CB tasks as cognitive screening tools in pediatric epilepsy by comparing them to standard neuropsychological measures and their association with epilepsy characteristics. Forty-seven patients with epilepsy ages 5-18, including ten repeat evaluations, were assessed. Correlational analyses and agreement statistics were conducted to validate NIHTB-CB tasks (Flanker Inhibitory Control and Attention test (Flanker) and Pattern Comparison Processing Speed test (Pattern Comparison)) with standard clinical measures. We also examined if performance was related to epilepsy characteristics, including polytherapy, age of seizure onset, seizure type, and history of Electrical Status Epilepticus in Sleep (ESES). The NIHTB-CB tests had moderate to strong correlations with neuropsychological measures of executive functioning, processing speed, and intelligence. Agreement statistics indicated better sensitivity than specificity. Polytherapy and later age of seizure onset were associated with lower performance on Pattern Comparison. ESES patients did not significantly differ in performance on the tests compared to non-ESES patients. Pilot data from a subset of repeated measures indicated a good range of change scores. These two NIHTB tasks are feasible as a screening tool in a clinic given their correlation with clinical measures that assess executive function, processing speed, and IQ. This study supports the use of these tasks as brief, easily accessible screener tools to identify cognitive dysfunction in domains commonly impacted in patients with epilepsy and potential use for monitoring over time.

Theta-Alpha Variability on Admission EEG Is Associated With Outcome in Pediatric Cerebral Malaria.

PURPOSE: Pediatric cerebral malaria has high rates of mortality and neurologic morbidity. Although several biomarkers, including EEG, are associated with survival or morbidity, many are resource intensive or require skilled interpretation for clinical use. Automation of quantitative interpretation of EEG may be preferable in resource-limited settings, where trained interpreters are rare. As currently used quantitative EEG factors do not adequately describe the spectrum of variability seen in studies from children with cerebral malaria, the authors developed and validated a new quantitative EEG variable, theta-alpha variability (TAV). METHODS: The authors developed TAV, a new quantitative variable, as a composite of multiple automated EEG outputs. EEG records from 194 children (6 months to 14 years old) with cerebral malaria were analyzed. Independent EEG interpreters performed standard quantitative and qualitative analyses, with the addition of the newly created variable. The associations of TAV with other quantitative EEG factors, a qualitative assessment of variability, and outcomes were assessed. RESULTS: Theta-alpha variability was not highly correlated with alpha, theta, or delta power and was not associated with qualitative measures of variability. Children whose EEGs had higher values of TAV had a lower risk of death (odds ratio = 0.934, 95% confidence interval = 0.902-0.966) or neurologic sequelae (odds ratio = 0.960, 95% confidence interval = 0.932-0.990) compared with those with lower values. Receiver operating characteristic analysis in predicting death at a TAV threshold of 0.244 yielded a sensitivity of 74% and specificity of 70% for an area under the receiver operating characteristic curve of 0.755. CONCLUSIONS: Theta-alpha variability is independently associated with outcome in pediatric cerebral malaria and can predict death with high sensitivity and specificity. Automated determination of this newly created EEG factor holds promise as a potential method to increase the clinical utility of EEG in resource-limited settings by allowing interventions to be targeted to those at higher risk of death or disability.

Using EEG in Resource-Limited Areas: Comparing Qualitative and Quantitative Interpretation Methods in Cerebral Malaria.

BACKGROUND: Our goal was to compare the strength of association and predictive ability of qualitative and quantitative electroencephalographic (EEG) factors with the outcomes of death and neurological disability in pediatric cerebral malaria (CM). METHODS: We enrolled children with a clinical diagnosis of CM admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2012 and 2017. A routine-length EEG was performed within four hours of admission. EEG data were independently interpreted using qualitative and quantitative methods by trained pediatric neurophysiologists. EEG interpreters were unaware of patient discharge outcome. RESULTS: EEG tracings from 194 patients were reviewed. Multivariate modeling revealed several qualitative and quantitative EEG variables that were independently associated with outcomes. Quantitative methods modeled on mortality had better goodness of fit than qualitative ones. When modeled on neurological morbidity in survivors, goodness of fit was better for qualitative methods. When the probabilities of an adverse outcome were calculated using multivariate regression coefficients, only the model of quantitative EEG variables regressed on the neurological sequelae outcome showed clear separation between outcome groups. CONCLUSIONS: Multiple qualitative and quantitative EEG factors are associated with outcomes in pediatric CM. It may be possible to use quantitative EEG factors to create automated methods of study interpretation that have similar predictive abilities for outcomes as human-based interpreters, a rare resource in many malaria-endemic areas. Our results provide a proof-of-concept starting point for the development of quantitative EEG interpretation and prediction methodologies useful in resource-limited settings.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

OBJECTIVE: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Electrical status epilepticus in sleep (ESES) - Treatment pattern and EEG outcome in children with very high spike-wave index.

OBJECTIVE: The objective of the study was to determine electrical status epilepticus in sleep (ESES) outcome in children with very high spike-wave index (SWI; ≥85%), and assess treatment pattern. METHODS: Medical records of children 1-17 years old with ESES were reviewed. In this study, ESES is defined as SWI in non-rapid eye movement (non-REM) sleep of ≥85%. Electrical status epilepticus in sleep resolution is defined as reduction of SWI to <50%. RESULTS: Complete data were available in 33 children. Age at ESES diagnosis ranged from 32 to 165 months, median 76 months. The median duration of follow-up was 33 months. Two-thirds of the children were on one or more antiepileptic drugs (AED) at ESES diagnosis. Antiepileptic drugs were used as first treatment for ESES in 24/33 (73%). Electrical status epilepticus in sleep initially resolved in 76%, but 56% had subsequent relapse. The relapse rate was higher for steroids (89%) and benzodiazepines (60%) as compared with nonbenzodiazepine AEDs (29%). At last follow-up, ESES resolved in 21 children (64%). Electrical status epilepticus in sleep resolution was associated with seizure freedom (Fisher's exact, p < 0.05). SIGNIFICANCE: Using electroencephalogram (EEG) criteria, ESES resolved in 64%. We found high failure rate of first-line AEDs in preventing ESES, and high relapse rate. Standardization of ESES management is urgently needed.

Measure thrice, cut twice: On the benefit of reoperation for failed pediatric epilepsy surgery.

OBJECTIVE: To determine whether clinical outcomes are improved after repeat surgery for medically refractory epilepsy in children. METHODS: This is a single-center retrospective cohort analysis of all patients who received repeat resective surgery for ongoing seizures from 2000-2017. From a total of 251 consecutive individual epilepsy surgical patients for focal resection, 53 patients met study inclusion criteria and had adequate follow-up documented. RESULTS: Median age of seizure-onset was 2.0-years-old (IQR 0.3-5.5 years). The median age at first epilepsy surgery was 6.3-years-old (IQR 2.9-9.2 years) and at second epilepsy surgery was 8.4-years-old (IQR 4.7-12.6 years). Overall, 53 % (n = 28) of this series achieved Engel Class I (seizure freedom); with improved seizure control (Engel Class I-II) in 83 % (n = 44) of the cohort. 64 % (n = 34) had one reoperation; 26 % (n = 14) had two; and 9% (n = 5) had three. Pathology: 58 % (n = 31) had focal cortical dysplasia; 13 % (n = 10) tumor; 9% (n = 5) encephalitis; 6% (n = 3) gliosis; 4% (n = 2) mesial temporal sclerosis; and 2% (n = 1) hemimegalencephaly. Tumor pathology was associated with increased chance (p = 0.01) for seizure freedom (90 % of tumor patients had Engel Class I outcome). MTS had worse outcome with both patients having ongoing seizures (Engel II-IV). There were 6 patients who developed post-operative hemiparesis; one was unplanned but resolved. SIGNIFICANCE: Reoperation for pediatric epilepsy surgery can lead to seizure freedom in many cases and improved seizure control in most cases. Reoperation for brain tumor pathology is associated with a high rate of seizure freedom.

Antiepileptic Drugs in Pediatrics.

Epilepsy affects approximately 1% of the population. First-line treatment for epilepsy is the administration of anti-seizure medication, also referred to as antiepileptic drugs (AEDs), although this nomenclature is erroneous as these medications typically do not impact underlying epileptogenic processes; the goal of these medications is to control symptoms. Over 30% of patients are classified as having "medically refractory" epilepsy, i.e., lack of adequate seizure control despite trials of two or three AEDs (Kwan and Brodie, N Engl J Med 342:314-9, 2000). Epilepsy is associated with worse quality of life in children, adolescents, and their families (Cianchetti et al., Seizure 24:93-101, 2015). Patients with epilepsy have a two to three times greater risk of death than the general population, by various causes including sudden unexplained death in epilepsy patients (SUDEP) (Abdel-Mannan et al., Epilepsy Behav 90:99-106, 2019). It is these factors, among others, that have motivated the continued development of AEDs. This chapter will review the history and evolution of AED development, features of specific AEDs with a focus on the newest generation, and examples of AEDs in development.

Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy.

Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy.

Resective surgery for focal cortical dysplasia in children: a comparative analysis of the utility of intraoperative magnetic resonance imaging (iMRI).

PURPOSE: Seizure freedom following resection of focal cortical dysplasia (FCD) correlates with complete resection of the dysplastic cortical tissue. However, difficulty with intraoperative identification of the lesion may limit the ability to achieve the surgical objective of complete extirpation of these lesions. Intraoperative magnetic resonance imaging (iMRI) may aid in FCD resections. The objective of this study is to compare rates of postoperative seizure freedom, completeness of resection, and need for reoperation in patients undergoing iMRI-assisted FCD resection versus conventional surgical techniques. METHODS: We retrospectively reviewed the medical records of pediatric subjects who underwent surgical resection of FCD at Children's National Medical Center between March 2005 and April 2015. RESULTS: At the time of the last postoperative follow-up, 11 of the 12 patients (92 %) in the iMRI resection group were seizure free (Engel Class I), compared to 14 of the 42 patients (33 %) in the control resection group (p = 0.0005). All 12 of the iMRI patients (100 %) achieved complete resection, compared to 24 of 42 patients (57 %) in the control group (p = 0.01). One (8 %) patient from the iMRI-assisted resection group has required reoperation, compared to 17 (40 %) patients in the control resection group. CONCLUSION: Our results suggest that the utilization of iMRI during surgery for resection of FCD results in improved postoperative seizure freedom, completeness of lesion resection, and reduction in the need for reoperation.

Pediatric status epilepticus: identification and evaluation.

PURPOSE OF REVIEW: Status epilepticus is an acute neurologic emergency, the incidence of which is increasing in the United States as the definition evolves and our detection abilities improve. We will present the current definition of status epilepticus, including a recently modified operational definition for use in the clinical setting. We will also provide updates on identifying children in status epilepticus, etiologic considerations, and the rationale for diagnostic testing. RECENT FINDINGS: Recent data reveal the benefits of MRI vs. computed tomography in new-onset status epilepticus, as well as high rates of identification of electrographic seizures in patients with unexplained acute encephalopathy in pediatric ICU settings. Genetic testing should be considered in young children with recurrent status epilepticus. SUMMARY: Prompt recognition and diagnostic evaluation of the child in status epilepticus will help identify causes, which may require specific treatment, and help in the management of this life-threatening condition. Laboratory work, neuroimaging, electroencephalogram or continuous video electroencephalogram, lumbar puncture, and genetic testing may be considered in the evaluation of the child in status epilepticus.

The ketogenic diet: initiation at goal calories versus gradual caloric advancement.

BACKGROUND: Inpatient initiation of the ketogenic diet has historically involved fasting followed by gradual advancement of calories and/or diet ratio. Complications during this initiation period are common. We sought to determine if the initiation of the diet at goal calories would reduce these complications while maintaining efficacy. METHODS: Sixty patients were admitted to a tertiary care hospital for elective initiation of the ketogenic diet between October 2007 and January 2013. All patients were placed on a ketogenic diet initiation pathway. In 2010, the pathway was modified from gradual caloric advancement to initiation at goal calories. We selected 30 consecutive patients before and after the change for comparison. Each child's record was reviewed for the occurrence of hypoglycemia, number of days to reach full ketosis (defined as 4 + urine ketones), acidosis requiring commencement of sodium citrate, length of admission, and long-term efficacy. RESULTS: Both methods of initiation had similar rates of dehydration, vomiting, lethargy, and irritability. More patients initiated at goal received sodium citrate (P = 0.005); however, mean daily values of carbon dioxide were not significantly different. Onset of ketosis was slightly delayed (P = 0.009) in patients initiated at goal, but length of stay was not affected (P > 0.1). Hypoglycemia was uncommon and rates were similar between the groups. Efficacy at 3 months was better in patients initiated at full calories (P < 0.05). CONCLUSION: Initiation of the ketogenic diet full calories is a reasonable alternative to the current standard practice of gradual advancement of calories and/or diet ratio.

Continuous video EEG for patients with acute encephalopathy in a pediatric intensive care unit.

OBJECTIVES: In this study, we aimed to determine the incidence of electrographic seizures among patients in a pediatric intensive care unit (PICU) presenting with acute encephalopathy. Risk factors and duration of continuous EEG monitoring needed to capture electrographic seizures were also assessed. STUDY DESIGN: Based on a NeuroICU clinical care pathway, all patients with acute encephalopathy admitted to the PICU are monitored with continuous video electroencephalogram (cVEEG) for 48 h or until the encephalopathy improves. Ninety-four consecutive patients included on the pathway over a year were identified. Mean age was 6.7 years (range 32 days-17.9 years). Data pertaining to patient clinical information and electrographic seizures, including non-convulsive seizures (NCS) and non-convulsive status epilepticus (NCSE), were extracted from a prospective database. RESULTS: Thirty percent (28/94) had seizures captured on cVEEG including 17 patients (18%) with NCSE. Variables associated with electrographic seizures were age <24 months and clinical seizure(s) prior to EEG placement. The first seizure captured on cVEEG occurred in the first 24 h for the majority of patients (97%). Acute brain injury and electrographic seizures were associated with worse outcome. CONCLUSIONS: Electrographic seizures are common in pediatric patients with acute encephalopathy. This study supports the practice of cVEEG monitoring for at least 24 h in pediatric patients with acute encephalopathy, particularly if they are less then 24 months of age and/or if a clinical event suspicious for seizure precedes the encephalopathy.

Treatment of epilepsy in children with developmental disabilities.

Children with developmental disabilities are at increased risk for epilepsy with a prevalence rate higher than the general population. Some of the more common developmental disorders in childhood and the features of epilepsy in these conditions are discussed. Specifically, autism, cerebral palsy, mental retardation, and attention deficit and hyperactivity disorder are reviewed. Ideal treatment for developmentally-disabled children with epilepsy entails maximal seizure control without any significant adverse effects from the anti-epileptic drugs and good quality of life. Antiepileptic drugs' cognitive and behavioral adverse effects tend to occur more frequently in these children. Careful selection of the appropriate medication and close monitoring for drug adverse effects is important. The specific adverse effects of the older and newer antiepileptic drugs are also reviewed.

Identification and evaluation of the child in status epilepticus.

Status epilepticus (SE) is an acute neurologic emergency that requires prompt recognition and initiation of treatment. Recognition can be difficult because SE comes in many forms and has been defined differently over the past decade. We present the general consensus definition of SE and how to use the definition, including a modified operational definition, to guide management. Furthermore, evaluation of the child who presents in SE is important to determine the etiology and identify underlying causes that may require additional treatment. Evaluation may include measurement of electrolytes, lumbar puncture, drug levels, electroencephalography, and/or neuroimaging. Recent data are presented that update the current practice parameter guidelines and also indicate that neuroimaging is important in cases of new-onset SE and can help significantly in the diagnosis and management.