A multi-center comparison of surgical techniques for corpus Callosotomy in pediatric drug-resistant epilepsy.

OBJECTIVES: Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers. METHODS: Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically. RESULTS: Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant. SIGNIFICANCE: CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Responsive Neurostimulation in Drug-Resistant Pediatric Epilepsy: Findings From the Epilepsy Surgery Subgroup of the Pediatric Epilepsy Research Consortium.

BACKGROUND: Responsive neurostimulation (RNS), a closed-loop intracranial electrical stimulation system, is a palliative surgical option for patients with drug-resistant epilepsy (DRE). RNS is approved by the US Food and Drug Administration for patients aged ≥18 years with pharmacoresistant partial seizures. The published experience of RNS in children is limited. METHODS: This is a combined prospective and retrospective study of patients aged ≤18 years undergoing RNS placement. Patients were identified from the multicenter Pediatric Epilepsy Research Consortium Surgery Registry from January 2018 to December 2021, and additional data relevant to this study were retrospectively collected and analyzed. RESULTS: Fifty-six patients received RNS during the study period. The mean age at implantation was 14.9 years; the mean duration of epilepsy, 8.1 years; and the mean number of previously trialed antiseizure medications, 4.2. Five patients (9%) previously trialed dietary therapy, and 19 patients (34%) underwent prior surgery. Most patients (70%) underwent invasive electroencephalography evaluation before RNS implantation. Complications occurred in three patients (5.3%) including malpositioned leads or transient weakness. Follow-up (mean 11.7 months) was available for 55 patients (one lost), and four were seizure-free with RNS off. Outcome analysis of stimulation efficacy was available for 51 patients: 33 patients (65%) were responders (≥50% reduction in seizure frequency), including five patients (10%) who were seizure free at follow-up. CONCLUSIONS: For young patients with focal DRE who are not candidates for surgical resection, neuromodulation should be considered. Although RNS is off-label for patients aged <18 years, this multicenter study suggests that it is a safe and effective palliative option for children with focal DRE.

Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity.

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

Intravenous ganaxolone in pediatric super-refractory status epilepticus: A single hospital experience.

Synaptic GABAA receptor (GABAAR) internalization contributes to the drug resistant nature of super-refractory status epilepticus (SRSE). Ganaxolone is a 3ß-methylated synthetic analog of the endogenous neuroactive steroid, allopregnanolone, that has positive allosteric modulatory activity on synaptic and extrasynaptic GABAA receptors. Ganaxolone is currently in clinical trials to treat rare pediatric seizure disorders and established and refractory SE. Two pediatric patients with SRSE (age 17 and age 7) were treated under emergency investigational new drug (E-IND) applications with intravenous (IV) ganaxolone administered as an initial bolus and a maintenance infusion for up to 4.5 days with intermittent IV boluses as-needed followed by taper on day 5 and transitioned to chronic treatment using ganaxolone suspension. Adjunctive ganaxolone was effective in terminating SRSE in both patients, safely permitting IV anesthetics to be weaned. Seizure control has been maintained after transitioning to enteric ganaxolone. Further investigation of ganaxolone as a safe and effective treatment for SRSE is warranted.

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.

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.

Surgical evaluation in children <3 years of age with drug-resistant epilepsy: Patient characteristics, diagnostic utilization, and potential for treatment delays.

OBJECTIVE: Drug-resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young. RESULTS: The cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty-nine percent were seizure-free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001). SIGNIFICANCE: There are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections.

Palliative Epilepsy Surgery Procedures in Children.

Surgical treatment of epilepsy typically focuses on identification of a seizure focus with subsequent resection and/or disconnection to "cure" the patient's epilepsy and achieve seizure freedom. Palliative epilepsy surgery modalities are efficacious in improving seizure frequency, severity, and quality of life. In this paper, we review palliative epilepsy surgical options for children: vagus nerve stimulation, responsive neurostimulation, deep brain stimulation, hemispherotomy, corpus callosotomy, lobectomy and/or lesionectomy and multiple subpial transection. Reoperation after surgical resection should also be considered. If curative resection is not a viable option for seizure freedom, these methods should be considered with equal emphasis and urgency in the treatment of drug-resistant epilepsy.

Drug-Drug Interactions Between Cannabidiol and Lithium.

Epidiolex® (Cannabidiol- CBD) is approved for epilepsy associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients over 2 years of age. Common side effects include somnolence and diarrhea. Recent studies have demonstrated interactions between cannabidiol and several other antiseizure medications. However, little is known regarding interactions between cannabidiol and other classes of medications. We discuss an autistic patient with LGS and significant psychiatric comorbidities who was being treated with multiple antiseizure and psychiatric medications, including lithium, when CBD was added to his medical regimen. Several weeks after initiating CBD therapy, he developed hypersomnolence, ataxia and decreased oral intake and was found to have lithium toxicity. Lithium was discontinued and his symptoms resolved. He remains on CBD and 2 other antiseizure medications, seizure-free with improved behavior. We review mechanisms of action and pharmacokinetics of CBD and discuss possible explanations for lithium toxicity in this patient.

Management of Infantile Spasms During the COVID-19 Pandemic.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.

The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium.

OBJECTIVE: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. METHODS: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. RESULTS: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . SIGNIFICANCE: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.

Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet.

Febrile infection-related epilepsy syndrome (FIRES) is a newly recognized epileptic encephalopathy in which previously healthy school-aged children present with prolonged treatment-resistant status epilepticus (SE). Survivors are typically left with pharmacoresistant epilepsy and severe cognitive impairment. Various treatment regimens have been reported, all with limited success. The ketogenic diet (KD) is an alternative treatment of epilepsy and may be an appropriate choice for children with refractory SE. We report 2 previously healthy children who presented with FIRES and were placed on the KD during the acute phase of their illness. Both children experienced resolution of SE and were maintained on the KD, along with other anticonvulsant medications, for several months. Both were able to return to school, with some academic accommodations. These cases highlight the potential value of the KD as a preferred treatment in FIRES, not only in the acute setting but also for long-term management. Early KD treatment might optimize both seizure control and cognitive outcome after FIRES.

Subdural hemorrhages associated with antithrombotic therapy in infants with cerebral atrophy.

Low-molecular-weight heparins, such as enoxaparin, are often used to treat thrombosis in infants. We present 4 infants with diffuse brain injury who developed cerebral venous sinus thrombosis or deep vein thrombosis and were treated with enoxaparin. These infants subsequently developed subdural hemorrhages, and enoxaparin was stopped. In 3 cases, the subdural hemorrhages were found on routine surveillance brain MRI, and in 1 case imaging was urgently obtained because of focal seizures. Two patients needed urgent neurosurgical intervention, and all subdural hemorrhages improved or resolved on follow-up imaging. Each infant developed severe neurologic deficits, probably from the coexisting diffuse brain injury rather than from the subdural hemorrhages themselves. The risk of intracranial hemorrhage from enoxaparin may be accentuated in patients with diffuse brain injury, and careful consideration should be given before treatment in this population.

Advanced treatments for childhood epilepsy: beyond antiseizure medications.

A substantial minority of children with epilepsy have continued seizures despite adequate trials of standard antiseizure medications. To maximize seizure control and thereby optimize their neurodevelopmental outcomes, alternate nonmedication therapies should be considered for these patients. Dietary therapies, including the ketogenic diet and its variations, have been available for years. With a recent resurgence in popularity and expansion of indications, these treatments can lead to freedom from seizures or a significantly reduced seizure burden for a large number of patients. For carefully selected individuals, resective epilepsy surgery may offer the best hope for a cure. For others, palliation may be achieved through additional surgical approaches, such as corpus callosotomy and multiple subpial transections, or through neurostimulation techniques, such as the vagus nerve stimulator. In this review, we present these nonmedication approaches to treatment-resistant childhood epilepsy, with attention to patient selection and the potential risks and benefits.

Seizures in acute childhood stroke.

OBJECTIVES: To describe the risk of seizures in children with acute stroke and identify factors predicting their later risk of epilepsy. STUDY DESIGN: Data for patients >3.5 years of age at a tertiary care children's hospital with acute stroke were collected and reviewed. RESULTS: Seventy-seven patients were identified (mean age, 8.4 years); 21% had clinical seizures. An additional 10% of patients had a clinical seizure during the acute hospitalization. Status epilepticus was common in infants and patients with cortical strokes. Non-convulsive status epilepticus was captured only in patients with prolonged electroencephalograms and always within 24 hours of monitoring. Six months after their stroke, 24% of our patients had epilepsy, all of whom experienced seizures at initial presentation with stroke. CONCLUSION: In our series of pediatric patients with stroke, most of the clinical seizures occurred within the first 24 hours of presentation and did not vary in stroke subtype. Status epilepticus was common, especially in infants. Epilepsy had a high likelihood of developing in the next 6 months in children with seizures in the first 24 hours of stroke onset. Prolonged electroencephalogram monitoring was useful in detecting non-convulsive status epilepticus, but not in predicting the risk of epilepsy at 6 months.

Hallucinations and reversed cerebral dominance in mesial temporal sclerosis.

The localizing value of experiential phenomena in temporal and occipital lobe epilepsy has become increasingly elucidated. We describe complex visual and auditory hallucinations in a right-handed adolescent and review the localization value of ictal visual and auditory auras in partial epilepsy. A 15-year-old right-handed girl with 2 previous secondarily generalized seizures manifested a new semiology of complex visual and auditory hallucinations, characterized by seeing a school bus full of children and then hearing a male voice tell her to "feed the children." Feeling compelled, she "fed" the children, and they reboarded the bus and the bus drove away. Video electroencephalogram monitoring demonstrated fluent language during her seizures. Magnetic resonance imaging was compatible with left mesial temporal sclerosis. Fluorodeoxyglucose positron emission tomography demonstrated left temporal hypometabolism. An ictal single-photon emission computed tomography study demonstrated left anterior temporal hyperperfusion; Wada testing revealed reversed cerebral dominance. The patient underwent left anterior temporal lobectomy without complication and remains seizure-free. Complex auditory and visual hallucinations can occur in occipitotemporal and anteromedial temporal epilepsy. Reversed cerebral dominance is more common in children than adults and should be considered in any dextral person with fluent ictal speech with a left-sided epileptogenic lesion.

Isolated cranial nerve enhancement in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder with an estimated incidence of 1:40,000. Magnetic resonance imaging at time of diagnosis often shows symmetric white matter involvement, sparing the arcuate fibers. A 25-month-old female child presented with a cranial neuropathy, a spastic gait, decreased leukocyte arylsulfatase-A activity, and elevated urinary sulfatides. Magnetic resonance imaging revealed multiple cranial nerve enhancement, without intraparenchymal white matter involvement.