A Comparison of Automatically Extracted Quantitative EEG Features for Seizure Risk Stratification in Neonatal Encephalopathy.

PURPOSE: Seizures occur in up to 40% of neonates with neonatal encephalopathy. Earlier identification of seizures leads to more successful seizure treatment, but is often delayed because of limited availability of continuous EEG monitoring. Clinical variables poorly stratify seizure risk, and EEG use to stratify seizure risk has previously been limited by need for manual review and artifact exclusion. The goal of this study is to compare the utility of automatically extracted quantitative EEG (qEEG) features for seizure risk stratification. METHODS: We conducted a retrospective analysis of neonates with moderate-to-severe neonatal encephalopathy who underwent therapeutic hypothermia at a single center. The first 24 hours of EEG underwent automated artifact removal and qEEG analysis, comparing qEEG features for seizure risk stratification. RESULTS: The study included 150 neonates and compared the 36 (23%) with seizures with those without. Absolute spectral power best stratified seizure risk with area under the curve ranging from 63% to 71%, followed by range EEG lower and upper margin, median and SD of the range EEG lower margin. No features were significantly more predictive in the hour before seizure onset. Clinical examination was not associated with seizure risk. CONCLUSIONS: Automatically extracted qEEG features were more predictive than clinical examination in stratifying neonatal seizure risk during therapeutic hypothermia. qEEG represents a potential practical bedside tool to individualize intensity and duration of EEG monitoring and decrease time to seizure recognition. Future work is needed to refine and combine qEEG features to improve risk stratification.

MRI and pathology comparisons in Rasmussen's encephalitis: a multi-institutional examination of hemispherotomy outcomes relative to imaging and histological severity.

PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution's review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.

Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation. CITATION: Dominguez D, Rudock R, Tomko S, Pathak S, Mignot E, Licis A. Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon. J Clin Sleep Med. 2024;20(4):657-662.

Surgical outcomes of open and laser interstitial thermal therapy approaches for corpus callosotomy in pediatric epilepsy.

OBJECTIVE: Corpus callosotomy (CC) is a palliative surgical intervention for patients with medically refractory epilepsy that has evolved in recent years to include a less-invasive alternative with the use of laser interstitial thermal therapy (LITT). LITT works by heating a stereotactically placed laser fiber to ablative temperatures under real-time magnetic resonance imaging (MRI) thermometry. This study aims to (1) describe the surgical outcomes of CC in a large cohort of children with medically refractory epilepsy, (2) compare anterior and complete CC, and (3) review LITT as a surgical alternative to open craniotomy for CC. METHODS: This retrospective cohort study included 103 patients <21 years of age with at least 1 year follow-up at a single institution between 2003 and 2021. Surgical outcomes and the comparative effectiveness of anterior vs complete and open versus LITT surgical approaches were assessed. RESULTS: CC was the most common surgical disconnection (65%, n = 67) followed by anterior two-thirds (35%, n = 36), with a portion proceeding to posterior completion (28%, n = 10). The overall surgical complication rate was 6% (n = 6/103). Open craniotomy was the most common approach (87%, n = 90), with LITT used increasingly in recent years (13%, n = 13). Compared to open, LITT had shorter hospital stay (3 days [interquartile range (IQR) 2-5] vs 5 days [IQR 3-7]; p < .05). Modified Engel class I, II, III, and IV outcomes at last follow-up were 19.8% (n = 17/86), 19.8% (n = 17/86), 40.2% (n = 35/86), and 19.8% (n = 17/86). Of the 70 patients with preoperative drop seizures, 75% resolved postoperatively (n = 52/69). SIGNIFICANCE: No significant differences in seizure outcome between patients who underwent only anterior CC and complete CC were observed. LITT is a less-invasive surgical alternative to open craniotomy for CC, associated with similar seizure outcomes, lower blood loss, shorter hospital stays, and lower complication rates, but with longer operative times, when compared with the open craniotomy approach.

Macroperiodic Oscillations: A Potential Novel Biomarker of Outcome in Neonatal Encephalopathy.

PURPOSE: Neonatal encephalopathy (NE) is a common cause of neurodevelopmental morbidity. Tools to accurately predict outcomes after therapeutic hypothermia remain limited. We evaluated a novel EEG biomarker, macroperiodic oscillations (MOs), to predict neurodevelopmental outcomes. METHODS: We conducted a secondary analysis of a randomized controlled trial of neonates with moderate-to-severe NE who underwent standardized clinical examination, magnetic resonance (MR) scoring, video EEG, and neurodevelopmental assessment with Bayley III evaluation at 18 to 24 months. A non-NE cohort of neonates was also assessed for the presence of MOs. The relationship between clinical examination, MR score, MOs, and neurodevelopmental assessment was analyzed. RESULTS: The study included 37 neonates with 24 of whom survived and underwent neurodevelopmental assessment (70%). The strength of MOs correlated with severity of clinical encephalopathy. MO strength and spread significantly correlated with Bayley III cognitive percentile (P = 0.017 and 0.046). MO strength outperformed MR score in predicting a combined adverse outcome of death or disability (P = 0.019, sensitivity 100%, specificity 77% vs. P = 0.079, sensitivity 100%, specificity 59%). CONCLUSIONS: MOs are an EEG-derived, quantitative biomarker of neurodevelopmental outcome that outperformed a comprehensive validated MRI injury score and a detailed systematic discharge examination in this small cohort. Future work is needed to validate MOs in a larger cohort and elucidate the underlying pathophysiology of MOs.

Detecting slow narrowband modulation in EEG signals.

BACKGROUND: We observed an unusual modulatory phenomenon in the electroencephalogram (EEG) of pediatric patients with acquired brain injury. The modulation is orders of magnitude slower than the fast EEG background activity, necessitating new analysis procedures to systematically detect and quantify the phenomenon. NEW METHOD: We propose a method for analyzing spatial and temporal relationships associated with slow, narrowband modulation of EEG. We extract envelope signals from physiological frequency bands of EEG. Then, we construct a sparse representation of the spectral content of the envelope signal across sliding windows. For the latter, we use an augmented LASSO regression to incorporate spatial and temporal filtering into the solution. The method can be applied to windows of variable length, depending on the desired frequency resolution. RESULTS: The sparse estimates of the envelope power spectra enable the detection of narrowband modulation in the millihertz frequency range. Subsequently, we are able to assess non-stationarity in the frequency and spatial relationships across channels. The method can be paired with unsupervised anomaly detection to identify windows with significant modulation. We validated such findings by applying our method to a control set of EEGs. COMPARISON WITH EXISTING METHODS: To our knowledge, no methods have been previously proposed to quantify second order modulation at such disparate time-scales. CONCLUSIONS: We provide a general EEG analysis framework capable of detecting signal content below 0.1 Hz, which is especially germane to clinical recordings that may contain multiple hours worth of continuous data.

ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD.

OBJECTIVE: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD. METHODS: Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively. RESULTS: Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed. INTERPRETATION: Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.

Resolving and characterizing the incidence of millihertz EEG modulation in critically ill children.

OBJECTIVE: We analyze a slow electrographic pattern, Macroperiodic Oscillations (MOs), in the EEG from a cohort of young critical care patients (n = 43) with continuous EEG monitoring. We construct novel quantitative methods to quantify and understand MOs. METHODS: We applied a nonparametric bilevel spectral analysis to identify MOs, a millihertz (0.004-0.01 Hz) modulation of 5-15 Hz activity in two separate ICU patient cohorts (n = 195 total). We also developed a rigorous measure to quantify MOs strength and spatial expression, which was validated against surrogate noise data. RESULTS: Strong or spatially widespread MOs appear in both high clinical suspicion and a general ICU population. In the former, patients with strong or spatially widespread MOs tended to have worse clinical outcomes. Intracranial pressure and heart rate data from one patient provide insight into a potential broader physiological mechanism for MOs. CONCLUSIONS: We quantified millihertz EEG modulation (MOs) in cohorts of critically ill pediatric patients. We demonstrated high incidence in two patient populations. In a high suspicion cohort, MOs are associated with poor outcome, suggesting future potential as a diagnostic and prognostic aid. SIGNIFICANCE: These results support the existence of EEG dynamics across disparate time-scales and may provide insight into brain injury physiology in young children.

Macroperiodic Oscillations Are Associated With Seizures Following Acquired Brain Injury in Young Children.

PURPOSE: Seizures occur in 10% to 40% of critically ill children. We describe a phenomenon seen on color density spectral array but not raw EEG associated with seizures and acquired brain injury in pediatric patients. METHODS: We reviewed EEGs of 541 children admitted to an intensive care unit between October 2015 and August 2018. We identified 38 children (7%) with a periodic pattern on color density spectral array that oscillates every 2 to 5 minutes and was not apparent on the raw EEG tracing, termed macroperiodic oscillations (MOs). Internal validity measures and interrater agreement were assessed. We compared demographic and clinical data between those with and without MOs. RESULTS: Interrater reliability yielded a strong agreement for MOs identification (kappa: 0.778 [0.542-1.000]; P < 0.0001). There was a 76% overlap in the start and stop times of MOs among reviewers. All patients with MOs had seizures as opposed to 22.5% of the general intensive care unit monitoring population ( P < 0.0001). Macroperiodic oscillations occurred before or in the midst of recurrent seizures. Patients with MOs were younger (median of 8 vs. 208 days; P < 0.001), with indications for EEG monitoring more likely to be clinical seizures (42 vs. 16%; P < 0.001) or traumatic brain injury (16 vs. 5%, P < 0.01) and had fewer premorbid neurologic conditions (10.5 vs. 33%; P < 0.01). CONCLUSIONS: Macroperiodic oscillations are a slow periodic pattern occurring over a longer time scale than periodic discharges in pediatric intensive care unit patients. This pattern is associated with seizures in young patients with acquired brain injuries.

Immediate Postoperative Electroencephalography Monitoring in Pediatric Moyamoya Disease and Syndrome.

BACKGROUND: Moyamoya disease and syndrome are progressive steno-occlusive cerebrovascular diseases that manifest clinically with ischemic episodes. There is evidence for the use of electroencephalography (EEG) in preoperative and long-term postoperative evaluation of these patients, as well as in the intraoperative period to monitor for changes correlated with perioperative ischemic events. However, the utility of EEG in the immediate postprocedure time period has not previously been described. METHODS: We review six patients who underwent pial synangiosis from 2017 to 2019. EEGs from the preoperative, intraoperative, and immediate postoperative period were evaluated, as well as clinical examination changes and subsequent interventions. RESULTS: Six patients with postoperative EEG monitoring following pial synangiosis were included. EEG data was collected preoperatively, intraoperatively, and continuously postoperatively. Preoperatively, five of six patients had normal background activity on EEG, whereas one of six had hemispheric asymmetry. Three patients had new or worsening hemispheric intracerebral asymmetry on EEG during the immediate postsurgical period. Two of these had no clinical manifestations of ischemia, and one had transient left facial weakness. All three underwent blood pressure augmentation with improvement in the asymmetry on EEG and clinical improvement in the symptomatic patient. CONCLUSIONS: Although widely accepted as a useful tool during the preoperative and intraoperative periods of evaluation and management of moyamoya disease and syndrome, we propose that the use of continuous EEG in the immediate postoperative period may have potential as a useful adjunct by both detecting early clinical and subclinical intracranial ischemia.

Continuous Electroencephalography Monitoring in Critically Ill Infants and Children.

Continuous video electroencephalography (CEEG) monitoring of critically ill infants and children has expanded rapidly in recent years. Indications for CEEG include evaluation of patients with altered mental status, characterization of paroxysmal events, and detection of electrographic seizures, including monitoring of patients with limited neurological examination or conditions that put them at high risk for electrographic seizures (e.g., cardiac arrest or extracorporeal membrane oxygenation cannulation). Depending on the inclusion criteria and clinical characteristics of the population studied, the percentage of pediatric patients with electrographic seizures varies from 7% to 46% and with electrographic status epilepticus from 1% to 23%. There is also evidence that epileptiform and background CEEG patterns may provide important information about prognosis in certain clinical populations. Quantitative EEG techniques are emerging as a tool to enhance the value of CEEG to provide real-time bedside data for management and prognosis. Continued research is needed to understand the clinical value of seizure detection and identification of other CEEG patterns on the outcomes of critically ill infants and children.