The spectrum of movement disorders in young children with ARX-related epilepsy-dyskinesia syndrome.

Children with developmental and epileptic encephalopathies often present with co-occurring dyskinesias. Pathogenic variants in ARX cause a pleomorphic syndrome that includes infantile epilepsy with a variety of movement disorders ranging from focal hand dystonia to generalized dystonia with frequent status dystonicus. In this report, we present three patients with severe movement disorders as part of ARX-associated epilepsy-dyskinesia syndrome, including a patient with a novel pathogenic missense variant (p.R371G). These cases illustrate diagnostic and management challenges of ARX-related disorder and shed light on broader challenges concerning epilepsy-dyskinesia syndromes.

Diagnostic Yield of CSF Testing in Infants for Disorders of Biogenic Amine Neurotransmitter Metabolism.

BACKGROUND AND OBJECTIVES: Biochemical testing of CSF for neurotransmitter metabolites and their cofactors is often used in the diagnostic evaluation of infants with neurologic disorders but requires an invasive, labor-intensive procedure with many potential sources of error. Our aim was to determine the diagnostic yield of CSF testing for biogenic amines (serotonin, norepinephrine, epinephrine, and dopamine) and their cofactors in identifying inborn errors of neurotransmitter metabolism among infants. METHODS: We evaluated all infants aged 1 year or younger who underwent CSF biogenic amine neurotransmitter (CSFNT) testing at Children's Hospital of Philadelphia (CHOP) and Boston Children's Hospital (BCH) between 2008 and 2017 in this cross-sectional study. The primary outcome was the proportion of individuals who received a diagnostic result from CSFNT testing. Secondary assessments included the proportion of infants who obtained a diagnostic result from other types of diagnostic testing. RESULTS: The cohort included 323 individuals (191 from CHOP and 232 from BCH). The median age at presentation was 110 days (range 36-193). The most common presenting features were seizures (71%), hypotonia (47%), and developmental delay (43%). The diagnostic yield of CSFNT testing was zero. When CSF pyridoxal-5-phosphate level was assayed with CSFNT testing, 1 patient had a diagnostic result. An etiologic diagnosis was identified in 163 patients (50%) of the cohort, with genetic testing having the highest yield (120 individuals, 37%). DISCUSSION: Our findings support the case for deimplementation of CSFNT testing as a standard diagnostic test of etiology in infants aged 1 year or younger presenting with neurologic disorders.

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.

Delays to care in infantile epileptic spasms syndrome: Racial and ethnic inequities.

OBJECTIVE: Non-Hispanic (NH) Black children are less likely to receive a standard treatment course for infantile epileptic spasms syndrome (IESS) than White/NH children at pediatric tertiary care epilepsy centers in the United States. However, if inequities exist in time to diagnosis is unknown. Diagnostic delays as little as 1 week can be associated with worse developmental outcomes. METHODS: Diagnostic delays were evaluated in a retrospective cohort of 100 children with new onset IESS between January 2019 and May 2022. RESULTS: Children with Black, Indigenous, and People of Color (BIPOC) caregivers were more likely to experience clinically significant delays in referral from first provider to neurologist, when compared to White/NH children, even after controlling for other demographic and clinical variables (odds ratio = 4.98, confidence interval = 1.24-19.94, p = .023). SIGNIFICANCE: Disproportionate diagnostic delays place BIPOC children at risk of adverse developmental and epilepsy outcomes. Further interventional prospective and qualitative studies are needed to address inequities in care.

Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.

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.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

OBJECTIVE: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

Clinical characteristics of children with infantile epileptic spasms syndrome from a tertiary-care hospital in Dhaka, Bangladesh.

Background: We describe patient characteristics and response to initial treatment in a large case series of children presenting with infantile epileptic spasms syndrome to a tertiary-care hospital with a pediatric neurology service in Bangladesh. The purpose of the study was to add to the growing body of literature on infantile epileptic spasms syndrome in low- and middle-income countries. Methods: We enrolled 212 infants with new-onset infantile epileptic spasms syndrome (IESS) at the time of initial presentation to the National Institute of Neurosciences and Hospital (NINS) in Dhaka, Bangladesh, between January 2019 and August 2021. We collected data about seizure type and frequency, etiology, medication dosage, and available neuroimaging. Results: Median age at initial presentation to NINS was 9 months. Developmental delay and regression prior to presentation were found in 83% and 36%, respectively. Prior to their presentation at NINS, 197 (93%) patients had received anti-seizure medication to treat spasms, of whom only 8 (4%) had received standard therapy with ACTH, prednisolone, or vigabatrin. At NINS, 207 (98%) of patients received standard therapy, most frequently ACTH in 154 (73%). Median time between seizure onset to receipt of first-line therapy was 5 months. Of the 169 patients who were seen in follow-up at average of 5 weeks, 92 (54%) reported absence of clinical epileptic spasms. No serious adverse events requiring hospitalization were reported. Conclusions: This study highlights the long lead times to treatment for IESS in a low- and middle-income country, and the need for early referral of children with suspected epileptic spasms to epilepsy care centers.

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.

Temporal trends in the cost and use of first-line treatments for infantile epileptic spasms syndrome.

OBJECTIVE: To describe the temporal trends in the cost and use of adrenocorticotropic hormone (ACTH), oral prednisolone, and vigabatrin, the first-line treatments for infantile epileptic spasms syndrome (IESS). METHODS: Retrospective observational study using the MarketScan Commercial database from 2006 to 2020. We identified patients with IESS diagnosed between birth and 18 months of age who received at least one of the first-line treatments within 60 days of diagnosis. Costs were adjusted for inflation using the Gross Domestic Product Implicit Price Deflator. RESULTS: A total of 1131 patients received at least one first-line treatment (median [p25 -p75 ] age: 6.3 [4.5-8.3] months, 55% male), of whom 592 patients received ACTH, 363 patients received oral prednisolone, and 355 patients received vigabatrin. After adjusting for inflation, the median average wholesale price of a 14-day course of treatment increased for ACTH from $3718 in 2006 to $100 457 in 2020, ~2700% (by a factor of 27), whereas it decreased for oral prednisolone from $169 in 2006 to $89 in 2020, ~50% (by a factor of 0.5), and increased for vigabatrin from $1206 in 2009 (first year with data on vigabatrin used for IESS) to $4102 in 2020, ~340% (by a factor of 3.4). During the first 60 days after diagnosis, inpatient admission days and costs where higher for ACTH than for oral prednisolone and vigabatrin-5.0 (3.0-8.3) days vs 2.0 (0.0-5.0) days vs 2.0 (0.0-6.0) days, p < .0001; and $32 828 ($14 711-$67 216) vs $16 227 ($0-$35 829) vs $17 844 ($0-$47 642), p < .0001. ACTH use decreased from representing 78% of first-line treatments in 2006 to 18% in 2020 (p < .0001). Sensitivity analyses confirmed the robustness of the results. SIGNIFICANCE: The gap between the cost of ACTH and the cost of oral prednisolone or vigabatrin has widened markedly from 2006 to 2020, whereas the relative proportion of ACTH use has decreased.

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.

Association of Time to Clinical Remission With Sustained Resolution in Children With New-Onset Infantile Spasms.

BACKGROUND AND OBJECTIVES: Standard therapies (adrenocorticotropic hormone [ACTH], oral steroids, or vigabatrin) fail to control infantile spasms in almost half of children. Early identification of nonresponders could enable rapid initiation of sequential therapy. We aimed to determine the time to clinical remission after appropriate infantile spasms treatment initiation and identify predictors of the time to infantile spasms treatment response. METHODS: The National Infantile Spasms Consortium prospectively followed children aged 2-24 months with new-onset infantile spasms at 23 US centers (2012-2018). We included children treated with standard therapy (ACTH, oral steroids, or vigabatrin). Sustained treatment response was defined as having the last clinically recognized infantile spasms on or before treatment day 14, absence of hypsarrhythmia on EEG 2-4 weeks after treatment, and persistence of remission to day 30. We analyzed the time to treatment response and assessed clinical characteristics to predict sustained treatment response. RESULTS: Among 395 infants, clinical infantile spasms remission occurred in 43% (n = 171) within the first 2 weeks of treatment, of which 81% (138/171) responded within the first week of treatment. There was no difference in the median time to response across standard therapies (ACTH: median 4 days, interquartile range [IQR] 3-7; oral steroids: median 3 days, IQR 2-5; vigabatrin: median 3 days, IQR 1-6). Individuals without hypsarrhythmia on the pretreatment EEG (i.e., abnormal but not hypsarrhythmia) were more likely to have early treatment response than infants with hypsarrhythmia at infantile spasms onset (hazard ratio 2.23, 95% CI 1.39-3.57). No other clinical factors predicted early responders to therapy. DISCUSSION: Remission after first infantile spasms treatment can be identified by treatment day 7 in most children. Given the importance of early and effective treatment, these data suggest that children who do not respond to standard infantile spasms therapy within 1 week should be reassessed immediately for additional standard treatment. This approach could optimize outcomes by facilitating early sequential therapy for children with infantile spasms.

Inequities in Therapy for Infantile Spasms: A Call to Action.

OBJECTIVE: The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. METHODS: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. RESULTS: Of 555 children, 324 (58%) were non-Hispanic white, 55 (10%) non-Hispanic Black, 24 (4%) non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non-Hispanic Black children had lower odds of receiving a standard treatment course compared with non-Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20-0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21-0.84; p = 0.01). INTERPRETATION: Non-Hispanic Black children were more often treated with non-standard IS therapies than non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32-44.

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.

Comparison of Cosyntropin, Vigabatrin, and Combination Therapy in New-Onset Infantile Spasms in a Prospective Randomized Trial.

Objective: In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1 mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 years) with new-onset infantile spasms syndrome and hypsarhythmia were randomized into 3 arms: cosyntropin, vigabatrin, and cosyntropin and vigabatrin combined. Daily seizures and adverse events were recorded, and EEG was repeated at day 14 to assess for resolution of hypsarhythmia. The primary outcome measure was the composite of resolution of hypsarhythmia and absence of clinical spasms at day 14. Fisher exact test was used to compare outcomes. Results: 37 children were enrolled and 34 were included in the final efficacy analysis (1 withdrew prior to treatment and 2 did not return seizure diaries). Resolution of both hypsarhythmia and clinical spasms was achieved in in 9 of 12 participants (75%) treated with cosyntropin, 1/9 (11%) vigabatrin, and 5/13 (38%) cosyntropin and vigabatrin combined. The primary comparison of cosyntropin versus vigabatrin was significant (64% [95% confidence interval 21, 82], P < .01). Adverse events were reported in all 3 treatment arms: 31 (86%) had an adverse event, 7 (19%) had a serious adverse event, and 15 (42%) had an adverse event of special interest with no difference between treatment arms. Significance: This randomized trial was underpowered because of incomplete enrollment, yet it demonstrated that cosyntropin was more effective for short-term outcomes than vigabatrin as initial treatment for infantile spasms.

Confirmation of infantile spasms resolution by prolonged outpatient EEGs.

OBJECTIVE: There is no consensus on the type or duration of the posttreatment EEG needed for assessing treatment response for infantile spasms (IS). We assessed whether outpatient electroencephalograms (EEGs) are sufficient to confirm infantile spasms (IS) treatment response. METHODS: Three-year retrospective review identified new-onset IS patients. Only presumed responder to IS treatment at 2 weeks with a prolonged (>90 minutes) outpatient EEG to assess treatment response and at least 3-month follow-up were included. Hypsarrhythmia, electroclinical spasms, and sleep were evaluated for the first hour and for the duration of the EEG. RESULTS: We included 37 consecutive patients with new-onset IS and presumed clinical response at 2 weeks posttreatment. Follow-up outpatient prolonged EEGs (median: 150 minutes, range: 90-240 minutes) were obtained 14 days (IQR: 13-17) after treatment initiation. EEGs detected ongoing IS in 11 of 37 (30%) presumed early responders. Prolonged outpatient EEG had a sensitivity of 85% (confidence interval [CI] 55%-98%) for detecting treatment failure. When hypsarrhythmia and/or electroclinical spasms were not seen, EEG had a negative predictive value 92% (CI: 75%-99%) for confirming continued IS resolution. Outpatient EEG combined with clinical assessment, however, identified all treatment failures at 2 weeks. Compared with the entire prolonged EEG, the first-hour recording missed IS in 45% (5/11). While sleep was captured in 95% (35/37) of the full EEG recording, the first hour of recording captured sleep in only 54% (20/37). SIGNIFICANCE: Infantile spasms treatment response can be confirmed with a clinical history of spasm freedom and an outpatient prolonged EEG without evidence for ongoing spasms (hypsarrhythmia/electroclinical spams on EEG). Outpatient prolonged EEG, but not routine EEGs, represents an alternative to inpatient long-term monitoring for IS posttreatment EEG follow-up.

Comparative Effectiveness of Initial Treatment for Infantile Spasms in a Contemporary US Cohort.

OBJECTIVE: Compare the effectiveness of initial treatment for infantile spasms. METHODS: The National Infantile Spasms Consortium prospectively followed children with new onset infantile spasms that began at age 2-24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations. RESULTS: Freedom from treatment failure rates were: ACTH 88/190 (46%), oral steroids 42/95 (44%), vigabatrin 32/87 (37%), and non-standard therapy 4/51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% CI 34-54]). Changing from non-standard therapy to ACTH would improve response from 8% to 39 [17-67]%, and to oral steroids from 8% to 38 [15-68]%. There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42 [15-75]%), vigabatrin to oral steroids (29% to 42 [28-57]%), and non-standard therapy to vigabatrin (8% to 20 [6-50]%). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p<0.05) CONCLUSION: Compared to non-standard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between ACTH / oral steroids and non-standard therapy, though the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children with new onset infantile spasms, ACTH or oral steroids were superior to non-standard therapies.

Subclinical seizures detected on intracranial EEG: Patient characteristics and impact on surgical outcome in a single pediatric epilepsy surgery center.

OBJECTIVE: Subclinical seizures (SCS) are often captured during intracranial EEG monitoring of pediatric patients with refractory focal epilepsy. However, their clinical significance remains uncertain. We aimed to characterize features associated with SCS and whether their presence impacts epilepsy outcomes post-surgically. METHODS: A single center retrospective chart review of patients with refractory focal epilepsy who underwent intracranial EEG monitoring at Boston Children's Hospital between 2004 and 2014 was conducted. Patient and seizure characteristics as well as post-operative outcome data were collected. RESULTS: Of the 104 patients included in the study, SCS were recorded in 66 (63%). Fifty-eight had electroclinical seizures (ECS) and SCS (ECS + SCS), and eight patients only had SCS. There were no significant patient characteristics associated with the presence of SCS. One hundred one of the 104 patients (97%) underwent surgical resection after the intracranial EEG monitoring, 53 of which had Engel 1 outcomes (52%). Incomplete resection (OR 0.15, 95% confidence interval (CI) [0.06, 0.40], p < 0.001) or presence of temporal plus epilepsy (OR 0.23, 95% CI [0.06, 0.80], p = 0.04) was associated with poor Engel outcomes (Engel 2-4). Presence of SCS was not associated with epilepsy surgical outcomes (p = 0.99). SIGNIFICANCE: Nearly 2/3 of patients in our study had SCS captured on intracranial EEG monitoring, and arose in overlapping regions with the ictal onset zone of ECS. Completeness of resection remains the most important predictor of seizure outcome, regardless of the presence of SCS. In the absence of ECS during intracranial EEG monitoring, SCS onset zones may provide useful localization information to guide surgical resection plans. This is the largest cohort reported in the literature describing characteristics associated with the presence of SCS and the impact of SCS on pediatric epilepsy surgery outcomes.

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.