High frequency oscillation network dynamics predict outcome in non-palliative epilepsy surgery.

High frequency oscillations are a promising biomarker of outcome in intractable epilepsy. Prior high frequency oscillation work focused on counting high frequency oscillations on individual channels, and it is still unclear how to translate those results into clinical care. We show that high frequency oscillations arise as network discharges that have valuable properties as predictive biomarkers. Here, we develop a tool to predict patient outcome before surgical resection is performed, based on only prospective information. In addition to determining high frequency oscillation rate on every channel, we performed a correlational analysis to evaluate the functional connectivity of high frequency oscillations in 28 patients with intracranial electrodes. We found that high frequency oscillations were often not solitary events on a single channel, but part of a local network discharge. Eigenvector and outcloseness centrality were used to rank channel importance within the connectivity network, then used to compare patient outcome by comparison with the seizure onset zone or a proportion within the proposed resected channels (critical resection percentage). Combining the knowledge of each patient's seizure onset zone resection plan along with our computed high frequency oscillation network centralities and high frequency oscillation rate, we develop a Naïve Bayes model that predicts outcome (positive predictive value: 100%) better than predicting based upon fully resecting the seizure onset zone (positive predictive value: 71%). Surgical margins had a large effect on outcomes: non-palliative patients in whom most of the seizure onset zone was resected ('definitive surgery', ≥ 80% resected) had predictable outcomes, whereas palliative surgeries (<80% resected) were not predictable. These results suggest that the addition of network properties of high frequency oscillations is more accurate in predicting patient outcome than seizure onset zone alone in patients with most of the seizure onset zone removed and offer great promise for informing clinical decisions in surgery for refractory epilepsy.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

The accuracy of quantitative EEG biomarker algorithms depends upon seizure onset dynamics.

OBJECTIVE: To compare the performance of different ictal quantitative biomarkers of the seizure onset zone (SOZ) across many seizures in a cohort of consecutive patients with a variety of seizure onset patterns. METHODS: The Epileptogenicity Index (EI, a measure of fast activity) and Slow Polarizing Shift index (SPS, a measure of infraslow activity) were calculated for 212 seizures (22 patients). After stratification by onset pattern, median index values inside and outside the SOZ were compared in aggregate and for each of the onset patterns. Receiver Operating Characteristic (ROC) curves were constructed to compare the performance of each index. RESULTS: Median values of EI (0.056 vs 0.0087), SPS (0.27 vs 0.19), and CI (0.21 vs 0.12) were significantly higher for contacts inside the SOZ, all p < 0.0001. Analysis of AUC showed variable performance of these indices across seizure types, although AUC for EI and SPS was generally greatest for seizures with fast activity at onset. CONCLUSIONS: All indices were significantly higher for contacts inside the SOZ; however, the performance of these indices varied depending on the pattern of seizure onset. SIGNIFICANCE: These findings suggest that future studies of quantitative biomarkers of the SOZ should account for seizure onset pattern.

Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid.

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients' epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.

Genetic testing in a cohort of patients with potential epilepsy with myoclonic-atonic seizures.

Epilepsy with myoclonic-atonic seizures (EMAS) accounts for 1-2% of all childhood-onset epilepsies. EMAS has been shown to have an underlying genetic component, however the genetics of this disorder is not yet well understood. The purpose of this study was to review genetic testing results for a cohort of EMAS patients. A retrospective chart review was conducted for 77 patients evaluated at Children's Hospital Colorado with a potential diagnosis of EMAS. Genetic testing and biochemical testing was reviewed. Family history data was also collected. Seventy-seven percent of the cohort had at least one genetic test performed, and a molecular diagnosis was reached for six patients. Thirty-seven patients had a microarray, six of which identified a copy number variant. Only one was felt to contribute to the phenotype (2p16.3 deletion including NRXN1). Fifty-one patients had an epilepsy panel, two of which were positive (likely pathogenic variant in SCN1A, pathogenic variant in GABRG2). Of the six patients who had whole exome sequencing, two were negative, three were positive or likely positive, and one had multiple variants not felt to explain the phenotype. While EMAS is widely accepted to have a strong genetic component, the diagnostic yield of genetic testing remains low. This may be because several genes now thought to be associated with EMAS are not included on the more commonly ordered epilepsy panels, or have only recently been added to them.

Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures.

INTRODUCTION: There is overlap in the electroclinical features of many childhood epilepsy syndromes, especially those presenting with multiple seizure types, such as epilepsy with myoclonic-atonic seizures (EMAS) and Lennox-Gastaut syndrome (LGS). This study aimed to determine the frequency of diagnosis switching and the factors influencing epilepsy syndrome diagnosis in a cohort of children with possible EMAS, as well as to explore the relationship between epilepsy syndrome diagnoses, key electroclinical features, and clinically relevant outcomes. METHODS: This is a cross-sectional retrospective chart review of children treated at the Children's Hospital of Colorado with a potential diagnosis of EMAS. RESULTS: There were 77 patients that met eligibility criteria, including 39% (n = 30) with an initial diagnosis of EMAS and 74% (n = 57) with a final diagnosis of EMAS. On average, for the 65% of patients who received more than one epilepsy diagnosis, the first, second, and third diagnoses were received within one year, three years, and ten years after epilepsy onset, respectively. Final diagnosis was significantly related to obtaining at least a six-month period of seizure freedom, p = 0.03. Classic LGS traits, including paroxysmal fast activity, slow spike-and-wave, and tonic seizures were present in 50% of the overall cohort, although a minority of these patients had a final diagnosis of LGS. However, the presence of more LGS traits was associated with a higher likelihood of ongoing seizures. Adjusted for age of epilepsy onset, seizure freedom was half as likely for every additional LGS trait observed (0.49[0.31, 0.77], p = 0.002). CONCLUSION: Current epilepsy syndrome classification has reduced applicability due to overlapping features. This results in diagnosis switching and limited prognostic value for patients with an overlapping clinical phenotype. Future studies should attempt to stratify patients based not only on epilepsy syndrome diagnosis, but also on the presence of various electroclinical traits to more accurately predict outcome.

Ketogenic Diet in Super-Refractory Status Epilepticus.

Researchers from the Children's National Health System in Washington, D.C. studied the feasibility, rate of complications, and effect on seizures of initiating the Ketogenic Diet (KD) in pediatric patients with Super-Refractory Status Epilepticus (SRSE).