Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: A tertiary health center's experience.

OBJECTIVE: Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored. METHODS: Retrospective chart review of new onset IESS patients (January 2019-May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider-, caregiver-, disease-related). RESULTS: Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p = .021), development delay (p = .007), developmental regression/stagnation (p = .021), ES intermixed with other seizures (p = .011), and nonclustered ES at onset (p = .005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p = .004) and nonclustered ES at onset (p = .003). Sources contributing to difficulties determining date of ES onset included disease-related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver-related factors (delayed diagnosis). SIGNIFICANCE: Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences.

Infantile spasms: Assessing the diagnostic yield of an institutional guideline and the impact of etiology on long-term treatment response.

OBJECTIVE: Neuroimaging and genetic testing have been proposed for diagnostic evaluation of infantile spasms (IS), establishing etiology in ~60% of multicenter IS cohorts. A retrospective analysis of the yield of diagnostic etiology following an institutionally established guideline for investigation/treatment of IS was conducted, and the association between etiological subgroups and sustained response to standard treatment was evaluated. METHODS: Etiology of IS, neuroimaging, and genetic results were extracted from clinical records. Etiology was categorized as acquired or nonacquired, the latter including syndromic patients, nonsyndromic patients with confirmed etiology, and unknown cases. Regression analyses, using clinical variables including subtypes of etiology, were conducted to determine which factors correlated with favorable (spasm freedom at last follow-up after two or fewer standard treatments) versus unfavorable treatment outcome (refractory spasms despite two standard treatments or relapse). RESULTS: We included 127 IS patients (60% males) with a follow-up of 2.4 years (range = .6-5 years). All patients had neuroimaging, and 95% of patients in the nonacquired category (103 of 108 patients) had genetic testing. Etiology was identified in 103 of 127 (81%, 95% confidence interval = .73-.86). At last follow-up, 42 (33%) patients had favorable treatment outcome. No difference in treatment response was observed between acquired and nonacquired etiologies. Among patients with nonacquired etiologies, developmental delay prior to spasms onset increased the odds of unfavorable treatment outcome (p = .014), whereas a clearly recognizable dysmorphic/syndromic etiology was associated with a lower risk for treatment failure (p = .034). In nonacquired etiology without a recognizable dysmorphic/syndrome but with a genetic etiology, unfavorable treatment outcome was more likely (p = .043). SIGNIFICANCE: Rigorous evaluation with neuroimaging and genetic testing yields an etiological diagnosis in most patients with IS. Among patients with a nonacquired etiology, those with recognizable dysmorphic/syndromic diagnosis had a higher likelihood of a favorable treatment outcome, whereas the absence of such a finding, when associated with an identifiable genetic diagnosis, was associated with unfavorable treatment outcomes.

Mortality in infantile spasms: A hospital-based study.

OBJECTIVE: To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died. METHODS: This is a retrospective chart review of IS patients born between 2000 and 2011. We examined potential risk factors for mortality, including etiology, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement (requirement for G-tube feedings, respiratory interventions). For patients who died, we describe cause of death and resuscitation status or end-of-life care measures. RESULTS: We identified 150 IS patients with median follow-up of 12 years. During the study period, 25 (17%) patients died, 13 before 5 years of age. Univariate analysis demonstrated that developmental delay, identifiable etiology, hormonal use for IS, persistence of epileptic spasms, polypharmacy with antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a G-tube were significant risk factors for mortality. In a multivariate analysis, mortality was predicted by persistence of epileptic spasms (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 1.11-16.67, P = .035) and significant respiratory system comorbidity (OR = 12.75, 95% CI = 2.88-56.32, P = .001). Mortality was epilepsy-related in one-third of patients who died with sudden unexpected death in epilepsy (SUDEP), accounting for 88% of epilepsy-related deaths. Most deaths before age 5 years were related to respiratory failure, and SUDEP was less common (17%) whereas SUDEP was more common (45%) with deaths after 5 years. For the majority (67%) of patients with early mortality, an end-of-life care plan was in place (based on documentation of resuscitation status, comfort measures, or decision not to escalate medical care). SIGNIFICANCE: Mortality at our single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5 years of age than in those who died younger than 5 years.

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.

Seizure clustering during presurgical electroencephalographic monitoring in children.

BACKGROUND: Presurgical evaluation with antiseizure medication tapering in patients with refractory epilepsy places them at risk for seizure clustering or prolonged seizures. We looked at the occurrence of seizure clustering (3 or more seizures within 24h) and prolonged seizures and the factors that influence seizure clustering and affect length of stay (LOS) in pediatric patients during presurgical monitoring. METHODS: We retrospectively reviewed the medical records of all consecutive admissions to the epilepsy monitoring unit (EMU) and included patients undergoing noninvasive presurgical evaluation. Data were extracted regarding demographics, seizure history, details of the EMU admission including occurrence of seizure clusters, prolonged seizures, status epilepticus, treatment, and LOS. RESULTS: Sixty-nine patients met our inclusion criteria. Seizure clustering during monitoring was observed in 33 patients (48%). Prolonged seizures lasting >5min was observed in 14 (20%) patients including 2 with status epilepticus (3%). Seizure clusters necessitated rescue treatment in around 30%. History of seizure clustering at home was the only factor associated with the occurrence of seizure clustering during the EMU stay (p<0.0001). The LOS did not differ significantly between patients who had seizure clustering during monitoring versus those who did not (p=0.369). CONCLUSIONS: Seizure clustering was common in children undergoing presurgical monitoring and seen especially in those with a history of seizure clustering at home. Occurrence of seizure clustering did not prolong the LOS but necessitated the use of rescue medications in about a third of the patients with seizure clusters due to multiple seizures.

Diagnostic test utilization in evaluation for resective epilepsy surgery in children.

Epilepsy surgery is highly successful in achieving seizure freedom in carefully selected children with drug-resistant focal epilepsy. Advances in technology have aided presurgical evaluation and increased the number of possible candidates. Many of the tests employed are resource intense, and in specific cases they may be unhelpful or have adverse effects. Some standardization of the evaluation process is thus considered timely. Given the lack of class 1 or 2 evidence defining the relative utility of each test in specific clinicopathologic cohorts, a set of expert recommendations was attempted using consensus among members of the Pediatric Epilepsy Surgery Task Force of the International League Against Epilepsy (ILAE) Commissions of Pediatrics and Diagnostics These recommendations aim to limit fringe over or underutilization of use while retaining substantial flexibility in the use of various tests, in keeping with most standard practices at established pediatric epilepsy centers. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Sporadic and Periodic Interictal Discharges in Critically Ill Children: Seizure Associations and Time to Seizure Identification.

PURPOSE: We evaluated interictal discharges (IEDs) as a biomarker for the time to development of electrographic seizures (ES). METHODS: Prospective observational study of 254 critically ill children who underwent continuous electroencephalography (cEEG) monitoring. We excluded neonates and patients with known epilepsy or the sole cEEG indication to characterize events. Interictal discharges included sporadic epileptiform discharges and periodic and rhythmic patterns. Sporadic epileptiform discharges were categorized as low frequency (rare [<1/hour] and occasional [≥1/hour but <1/minute]) and high frequency (frequent, [≥1/minute] and abundant [≥1/10 seconds]). Time variables included time from cEEG start to first IED and time between first IED and ES. RESULTS: Interictal discharges were present in 33% (83/254) of patients. We identified ES in 20% (50/254), and 86% (43/50) had IEDs. High-frequency sporadic epileptiform discharges (odds ratio [OR], 35; 95% confidence interval [CI], 14.5-88; P < 0.0001) and lateralized periodic discharges (OR, 27; 95% CI, 7.3-100; P < 0.0001) were associated with ES. Mildly abnormal EEG background without IEDs or background asymmetry was associated with the absence of seizures (OR, 0.1; 95% CI, 0.04-0.3; P < 0.0001). Time from cEEG start to first IED was 36 minutes (interquartile range, 3-131 minutes), and time between first IED and ES was 9.6 minutes (interquartile range, 0.6-165 minutes). CONCLUSIONS: Interictal discharges are associated with ES and are identified in the first 3 hours of cEEG. High-frequency sporadic epileptiform discharges and periodic patterns have the highest risk of ES. Our findings define a window of high seizure risk after the identification of IEDs in which to allocate resources to improve seizure identification and subsequent treatment.

Influence of extent and age at corpus callosotomy on seizure outcomes. A single center experience.

Corpus callosotomy (CC) is a palliative treatment for drop seizures in patients with drug-resistant nonlocalizable epilepsy. We compared drop seizure outcomes between patients undergoing anterior CC versus complete CC and examined factors impacting outcomes for drop seizures including age at CC and duration of epilepsy. A retrospective review of patients who underwent CC between 2003 and 2022 with a minimum of 6 months postsurgical follow-up was included. Outcome measure for drop seizures included seizure reduction ≥50% from baseline as well as elimination of drop seizures. Thirty-eight patients were included. Overall, ≥50% reduction in drop seizures occurred in nearly 70% (23 out of 33) patients with complete elimination in 58% (19 out of 33). Compared with anterior CC (n = 13), patients undergoing complete CC (n = 25) had increased likelihood of ≥50% reduction (p = 0.006) or elimination (p = 0.024) of drop seizures. Regression analysis showed that complete CC was the primary predictor for improved drop seizure outcomes (elimination, p = 0.014 or ≥50% reduction, p = 0.006), while age at CC and duration of epilepsy did not impact the outcomes. Compared to anterior CC, complete CC was significantly more likely to lead to improvement/freedom from drop seizures. Age at CC or duration of epilepsy did not influence drop seizure outcomes.

Hospital readmissions in children with new-onset infantile epileptic spasms syndrome.

OBJECTIVE: To describe inpatient resource use in the 2 years following infantile epileptic spasms syndrome (IESS) diagnosis, examine the association between clinical/demographic variables and incidence of readmission, and identify risk factors/reasons for frequent readmissions. METHODS: Retrospective cohort analysis of readmissions (scheduled/unscheduled) within the first 2 years following IESS diagnosis, details of readmissions (number/time between rehospitalizations, and length of stay), demographic/clinical variables, and reasons for readmissions were collected. Negative binomial regression analysis evaluated associations between incidence of readmissions (both scheduled/unscheduled and unscheduled alone) and demographic/clinical factors. Logistic regression assessed the risk of having recurrent readmissions (≥5 readmissions). RESULTS: Among 93 (60% males) new-onset IESS patients, there were 394 readmissions (56% scheduled and 44% unscheduled) within 2-years following IESS diagnosis. Mean length of stay was 3.5 days (SD: 5.9). Readmissions occurred in 82 patients (88%) and 37 (40%) experienced ≥5 readmissions. On multivariate regression analysis, readmissions were increased with use of multiple first-line treatments for IESS (P = 0.006), technology assistance (P ≤ 0.001), and multispecialty care (P = 0.01); seizure freedom (P = 0.015) and known etiology (P = 0.011) lowered the incidence of readmissions. Examining unscheduled readmissions separately, increased readmissions occurred with public insurance (P = 0.013), technology use (P ≤ 0.0.001), and multispecialty care (P = 0.013); seizure freedom decreased unscheduled readmissions (P = 0.006). Technology assistance (G-tube, NG tube, VP shunt, and tracheostomy use) increased the odds (P = 0.007) for recurrent readmissions. Reasons for readmissions included EEG monitoring (protocol driven for verification of IESS remission/characterization of events/EEG surveillance/presurgical monitoring) (51%), acute medical issues (21%), and seizure exacerbation (15%). Protocol-driven readmissions declined an estimated 52% following protocol modification during the study. SIGNIFICANCE: In the 2 years following IESS diagnosis, there is substantial inpatient resource use with nearly 40% experiencing ≥5 readmissions (mostly epilepsy related). Since readmissions are increased by intrinsic patient characteristics such as medical complexity (technology use and multispecialty care) or epilepsy-related issues, the preventability of readmissions is uncertain, except for protocol-driven ones.

Interictal Connectivity Revealed by Granger Analysis of Stereoelectroencephalography: Association With Ictal Onset Zone, Resection, and Outcome.

BACKGROUND: Stereoelectroencephalography (sEEG) facilitates electrical sampling and evaluation of complex deep-seated, dispersed, and multifocal locations. Granger causality (GC), previously used to study seizure networks using interictal data from subdural grids, may help identify the seizure-onset zone from interictal sEEG recordings. OBJECTIVE: To examine whether statistical analysis of interictal sEEG helps identify surgical target sites and whether surgical resection of highly ranked nodes correspond to favorable outcomes. METHODS: Ten minutes of extraoperative recordings from sequential patients who underwent sEEG evaluation were analyzed (n = 20). GC maps were compared with clinically defined surgical targets using rank order statistics. Outcomes of patients with focal resection/ablation with median follow-up of 3.6 years were classified as favorable (Engel 1, 2) or poor (Engel 3, 4) to assess their relationship with the removal of highly ranked nodes using the Wilcoxon rank-sum test. RESULTS: In 12 of 20 cases, the rankings of contacts (based on the sum of outward connection weights) mapped to the seizure-onset zone showed higher causal node connectivity than predicted by chance ( P ≤ .02). A very low aggregate probability ( P < 10 -18 , n = 20) suggests that causal node connectivity predicts seizure networks. In 8 of 16 with outcome data, causal connectivity in the resection was significantly greater than in the remaining contacts ( P ≤ .05). We found a significant association between favorable outcome and the presence of highly ranked nodes in the resection ( P < .05). CONCLUSION: Granger analysis can identify seizure foci from interictal sEEG and correlates highly ranked nodes with favorable outcome, potentially informing surgical decision-making without reliance on ictal recordings.

Hippocampal Involvement With Vigabatrin-Related MRI Signal Abnormalities in Patients With Infantile Spasms: A Novel Finding.

BACKGROUND: In a subset of infants exhibiting typical vigabatrin-related magnetic resonance imaging (MRI) changes, the authors observed additional hippocampal signal abnormalities. The authors investigated occurrence and significance of additional signal abnormalities. METHODS: A retrospective review of infantile spasms patients with typical vigabatrin-related MRI abnormalities was performed. Atypical features included signal changes unilaterally or at previously unreported sites. Comparisons were made between patients with and without atypical features. RESULTS: In all, 26/55 (47%) exhibited typical vigabatrin-related MRI changes, with additional signal abnormalities in the hippocampi in 6 of 26. On follow-up, evolution of hippocampal signal changes paralleled changes at typical locations in 4 patients. Two patients, clinically well, without follow-up MRI. Patients with and without additional hippocampal signal changes did not differ with respect to clinical factors, including seizure status. One patient had unilateral thalamic/cerebral peduncle signal abnormality along with typical vigabatrin changes. CONCLUSIONS: Hippocampal changes seen in subset of patients with typical vigabatrin-related changes may be attributable to vigabatrin exposure in the appropriate circumstance.

EEG features of brain injury during extracorporeal membrane oxygenation in children.

OBJECTIVE: To examine EEG features of major pathophysiology in children undergoing extracorporeal membrane oxygenation (ECMO). METHODS: This was a single-center, retrospective study of 201 pediatric patients on ECMO, using the first 24 hours of continuous EEG (cEEG) monitoring, collating background activity and electrographic seizures (ES) with imaging, ECMO type, and outcome. RESULTS: Severely abnormal cEEG background occurred in 12% (25/201), and was associated with death (sensitivity 0.23, specificity 0.97). ES occurred in 16% (33/201) within 3.2 (0.6-20.3) hours (median [interquartile range]) of cEEG commencement, and higher ES burden was associated with death. ES was always associated with ipsilateral injury (p = 0.006), but occurred in only one-third of cases with abnormal imaging. In 28 patients with isolated hemisphere lesion, type of arterial ECMO cannulation was associated with side of injury: right carotid cannulation was associated with right hemisphere lesions, and ascending aorta cannulation with left hemisphere lesions (odds ratio, 0.29 [95% confidence interval, 0.08-0.98], p = 0.03). CONCLUSIONS: After starting ECMO, cEEG background activity has the potential to inform prognosis. Type of arterial (carotid vs aortic) ECMO correlates with side of focal cerebral injury, which in ≈33% is associated with presence of ES. We hypothesize that the differential distribution reflects abnormal flow dynamics or embolic injury.

Effects of dexmedetomidine sedation on the EEG in children.

OBJECTIVES: To examine the effects of dexmedetomidine sedation on EEG background and epileptiform activity in children, comparing it to natural sleep. AIM: To provide quantitative and qualitative descriptions of the effect of dexmedetomidine sedation on the EEG of children. BACKGROUND: Children with intractable epilepsy admitted for surgery undergo 5 days of continuous EEG monitoring as well as nuclear medicine imaging studies with dexmedetomidine for sedation. Continuous EEG monitoring of each child during both natural sleep and dexmedetomidine-induced sedation provides a unique opportunity to evaluate the effects of dexmedetomidine on the EEG of children. MATERIALS/METHODS: Sixteen children undergoing dexmedetomidine sedation for nuclear medicine studies and simultaneous continuous EEG monitoring were studied. EEG segments during sedation were compared to samples of naturally occurring stage II sleep from the same child. Standard visual EEG analysis, quantification of delta, theta, alpha, beta, and total RMS power, number and location of spike foci, and frequency of spike activity were compared. RESULTS: The EEG during dexmedetomidine sedation resembled stage II sleep. During sedation, statistically significant increases in power of 16% for theta (P = 0.01), 21% for alpha (P = 0.03), and 40% for beta (P < 0.01) were observed, but not for delta (P = 0.63) or total EEG power (P = 0.61). Spike frequency increased by 47% during sedation but no new spike foci or seizures were observed. CONCLUSION: Dexmedetomidine sedation elicited an EEG pattern similar to that of Stage II sleep with modest increases in theta, alpha, and beta activity. Dexmedetomidine does not hinder interpretation of the EEG, suggesting that it may be a uniquely useful agent for EEG sedation in children.

Continuous EEG in Pediatric Critical Care: Yield and Efficiency of Seizure Detection.

PURPOSE: Our goal was to define the duration of continuous EEG (cEEG) monitoring needed to adequately capture electrographic seizures and EEG status epilepticus in the pediatric intensive care unit using clinical and background EEG features. METHODS: Retrospective study of patients aged 1 month to 21 years admitted to a tertiary pediatric intensive care unit and undergoing cEEG (>3 hours). Clinical data collected included admission diagnosis, EEG background features, and time variables including time to first seizure after initiation of cEEG. RESULTS: Four hundred fourteen patients aged 4.2 (0.75-11.3) years (median, interquartile range) were included. With a median duration of 21 (16-42.2) hours of cEEG monitoring, we identified electrographic seizure or EEG status epilepticus in 25% of subjects. We identified three features that could improve the efficiency of cEEG resources and provide a decision-making framework: (1) clinical history of acute encephalopathy is not predictive of detecting electrographic seizure or EEG status epilepticus, whereas a history of status epilepticus or seizures is; (2) normal EEG background or absence of epileptiform discharges in the initial 24 hours of recording informs the decision to discontinue cEEG; (3) failure to record electrographic ictal events within the first 4 to 6 hours of monitoring may be sufficient to predict the absence of subsequent ictal events. CONCLUSIONS: Individualized monitoring plans are necessary to increase seizure detection yield while improving resource utilization. A strategy using information from the clinical history, initial EEG background, and the first 4 to 6 hours of recording may be effective in determining the necessary duration of cEEG monitoring in the pediatric intensive care unit.

Factors predictive of seizures and neurologic outcome in perinatal depression.

To identify which early clinical variables are predictive of outcome in newborns with perinatal depression, we prospectively examined newborns with persistently abnormal neurologic examinations at 48 hours and (1) arterial pH

The stability of spike counts in children with interictal epileptiform activity.

PURPOSE: Little is known about the stability of serial measures of spike counts in children or whether spike counts are an inherently stable or unstable measure. We investigated the variation in first- and second-night spike counts in children undergoing 48-h ambulatory EEG recording. METHODS: We analyzed 40 consecutive 48-h ambulatory EEGs performed at Boston Children's Hospital that manifested spikes but no seizures. Distinct spike foci in the same child were counted separately. We visually counted all spikes in the first 20min after the first sleep spindle during nighttime sleep, comparing the first and second nights. RESULTS: Fifty-five unique spike foci were counted in 40 children (age range: 9 months to 19 years; median: 8.4 years). Considerable variation was seen when comparing Night 1 and Night 2 spike counts: for all foci, Night 1 mean and median spike counts were 304.5 and 126 and Night 2 counts were 309.5 and 148, respectively. For each focus, the mean change in spike frequency between Night 1 and Night 2 was 42.1% (median=28.3%, IQR 19.0-50.0%). The coefficient of variation of 0.94 suggested a large amount of variation. The percentage change weighted according to high or low spike frequency was 25.1%. CONCLUSION: In 40 children with 55 unique spike foci, significant variability in spike frequency was seen between consecutive nights of sleep, suggesting significant natural variation in spike frequency. A quarter of spike foci varied by 50% or more. Spike counts separated by longer intervals may show even more dramatic natural variation.