New and emerging pharmacologic treatments for developmental and epileptic encephalopathies.

PURPOSE OF REVIEW: Summarize evidence on Developmental and Epileptic Encephalopathies (DEEs) treatments focusing on new and emerging pharmacologic therapies (see Video, http://links.lww.com/CONR/A61, Supplementary Digital Content 1, which provides an overview of the review). RECENT FINDINGS: Advances in the fields of molecular genetics and neurobiology have led to the recognition of underlying pathophysiologic mechanisms involved in an increasing number of DEEs that could be targeted with precision therapies or repurposed drugs, some of which are currently being evaluated in clinical trials. Prompt, optimal therapy is critical, and promising therapies approved or in clinical trials for tuberous sclerosis complex, Dravet and Lennox-Gastaut Syndromes including mammalian target of rapamycin inhibitors, selective membrane channel and antisense oligonucleotide modulation, and repurposed drugs such as fenfluramine, stiripentol and cannabidiol, among others, may improve seizure burden and neurological outcomes. There is an urgent need for collaborative efforts to evaluate the efficacy and safety of emerging DEEs therapies. SUMMARY: Development of new therapies promise to address unmet needs for patients with DEEs, including improvement of neurocognitive function and quality of life.

Time to electroencephalography is independently associated with outcome in critically ill neonates and children.

OBJECTIVE: To identify factors associated with in-hospital mortality in neonates and children undergoing continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU). METHODS: We performed a retrospective observational study in patients from birth to 21 years of age who underwent clinically indicated cEEG in the ICU from 2011 to 2013. The main outcome measure was in-hospital mortality. RESULTS: Six-hundred and twenty-five patients (54.2% male) met eligibility criteria, of whom 211 were neonates (55% male, 24.8% premature) and 414 were pediatric patients (53.9% male). Electrographic seizures occurred in 176 patients (28.2%) and status epilepticus (SE) occurred in 20 (11.4%). The time from ICU admission to cEEG initiation was 16.7 (5.1-94.4) h. Eighty-nine patients (14.2%) (30 [14.2%] neonates, and 59 [14.3%] pediatric patients) died in the hospital. In neonates-after controlling for gender and prematurity-independent factors associated with mortality were prematurity (odds ratio [OR] 2.63. 95% confidence interval [CI] 1.06-6.5, p = 0.037), presence of status epilepticus (SE); OR 8.82, 95% CI 1.74-44.57, p = 0.008), and time from ICU admission to initiation of cEEG (OR 1.002, 95% CI 1.001-1.004 per hour, p = 0.008]. In pediatric patients-after controlling for gender and age-independent factors associated with mortality were the absence of seizures factors associated with mortality were absence of seizures (OR = 4.3, (95% CI: 1.5-12.4), p = 0.007), the presence of SE (OR 7.76, 95% CI 1.47-40.91, p = 0.016), and the time from ICU admission to initiation of cEEG (OR 1.001, 95% CI 1.0002-1.001, per hour, p = 0.005]. SIGNIFICANCE: Both presence of electrographic SE and time from ICU admission to cEEG initiation were independent factors associated with mortality in neonates and pediatric patients with cEEG in the ICU.

Temporal Encephalocele: A Treatable Etiology of Drug-Resistant Pediatric Temporal Lobe Epilepsy.

BACKGROUND: Temporal lobe encephaloceles (TEs) are a rare cause of drug-resistant temporal lobe epilepsy (DR-TLE), with head trauma and obesity identified as risk factors in adults. This study evaluated the clinical characteristics of childhood-onset DR-TLE due to TE. METHODS: This is a single-institution retrospective review of childhood-onset DR-TLE with radiographic TE identified between 2008 and 2020. The epilepsy history, brain imaging features, and surgical outcomes were collected. RESULTS: Eleven children with DR-TLE due to TE were included (median age at epilepsy onset was 11 years, interquartile range 8.5 to 13.5 years). Median latency between epilepsy diagnosis and TE detection was 3 years (range of 0 to 13 years). None had history of head trauma. Body mass index greater than 85 percentile for age and sex was seen in 36% of the children. No patient had bilateral TE identified. TEs were diagnosed based on epilepsy surgery conference re-review of imaging in 36% of cases. All herniations were contained defects without osseous dehiscence. Regional fluorodeoxyglucose (FDG) hypometabolism ipsilateral to the encephalocele was seen in all children who had FDG-positron emission tomography (PET) of the brain. Of the children who had surgery, 70% were seizure free or had nondisabling seizures at last follow-up (mean follow-up 52 months). CONCLUSIONS: TE is a surgically remediable etiology of DR-TLE in childhood. TEs are often overlooked at pediatric epilepsy diagnosis, calling for the need to increase awareness of this entity. FDG-PET temporal hypometabolism in children with presumed nonlesional DR-TLE should be carefully examined for occult TEs.

Impact of Antiseizure Medications on Appetite and Weight in Children.

There are numerous potential factors that may affect growth in children with epilepsy, and these must be evaluated in any child with appetite and weight concerns. Antiseizure medications (ASMs) have potential adverse effects, and many may affect appetite, thus impacting normal growth and weight gain. The aim of this review is to focus on the impact of both epilepsy and ASMs on appetite and weight in children. We systematically reviewed studies using Medline assessing the impact of ASMs on appetite and weight in children. Eligible studies included randomized controlled trials and open-label studies (open-label extension and interventional) that targeted or included the pediatric population (0-18 years of age). Each study was classified using the American Academy of Neurology (AAN) Classification of Evidence for Therapeutic Studies, and the level of evidence for impact on appetite and weight in children was graded. ASMs associated with decreased appetite and/or weight loss include fenfluramine, topiramate, zonisamide, felbamate, rufinamide, stiripentol, cannabidiol, brivaracetam and ethosuximide; ASMs with minimal impact on weight and appetite in children include oxcarbazepine, eslicarbazepine, lamotrigine, levetiracetam, lacosamide, carbamazepine, vigabatrin and clobazam. The ASM most robustly associated with increased appetite and/or weight gain is valproic acid; however, both pregabalin and perampanel may also lead to modest weight gain or increased appetite in children. Certain ASMs may impact both appetite and weight, which may lead to increased morbidity of the underlying disease and impaired adherence to the treatment regimen.

Time to continuous electroencephalogram in repeated admissions to the pediatric intensive care unit.

PURPOSE: Describe timing from intensive care unit (ICU) admission to initiation of continuous electroencephalogram (cEEG) in repeated ICU admissions. METHOD: We performed a retrospective observational study in pediatric patients who underwent repeated ICU admissions with cEEG from 2011 to 2013. The main outcome measure was time from ICU admission to cEEG. RESULTS: There were 41 patients (54% males) with at least 2 ICU admissions with cEEG (median (p25-p75) age at first admission: 3.3 (0.3-8.4) years, at second admission: 3.9 (1.1-9.4) years), 7 patients (57% males, 9.9 (2.9-11.5) years) with at least 3 ICU admissions, and 5 patients (60% males, 10.1 (4-10.5) years) with at least 4 ICU admissions. One patient had 21 ICU admissions. The median (p25-p75) time from ICU admission to cEEG was not different during the first and second ICU admissions [10.7 (1.9-22.9) hours versus 13 (0.2-36.7) hours; p=0.908]. Among patients with electrographic seizures on first admission, time to cEEG was not different during the first and second admissions [7.9 (0.5-23.4) hours versus 14.5 (-2 to 44.5) hours; p=0.636]. Among patients with status epilepticus during the first admission, time to cEEG was not different between the first and second admissions [15.3 (9-79) hours versus 40.7 (19.3-42.6) hours; p=0.75]. CONCLUSIONS: The time from ICU admission to the initiation of cEEG did not decrease in second or subsequent ICU admissions, even in patients with seizures or status epilepticus on the first admission.

Electrographic Seizures in Preterm Neonates in the Neonatal Intensive Care Unit.

OBJECTIVE: Characterize clinical and electroencephalography (EEG) characteristics of preterm neonates undergoing continuous EEG in the neonatal intensive care unit. METHODS: Retrospective study of preterm neonates born less than 37 weeks' gestational age undergoing continuous EEG in the neonatal intensive care unit at Boston Children's Hospital over a 2-year period. RESULTS: Fifty-two preterms (46% male) had a mean gestational age of 32.8 weeks (standard deviation = 4.17). Seizures were detected in 12/52 (23%), with EEG seizures detected in 4/12 (33%). The median time from EEG to the first seizure was 0.5 hours (interquartile range 0.24-4). Factors associated with seizures were male gender (odds ratio = 4.65 [95% confidence interval = 1.02-21.24], P = .047) and lack of EEG state change (odds ratio = 0.043 [95% confidence interval = 0.005-0.377], P = .04). CONCLUSION: Twenty-three percent of preterms undergoing continuous EEG had EEG seizures or electrographic seizures with no clear clinical correlate. This confirms recent American Clinical Neurophysiology Society guidelines suggesting that preterm neonates are at high risk for seizures.

Increasing Ketamine Use for Refractory Status Epilepticus in US Pediatric Hospitals.

Ketamine is an emerging therapy for pediatric refractory status epilepticus. The circumstances of its use, however, are understudied. The authors described pediatric refractory status epilepticus treated with ketamine from 2010 to 2014 at 45 centers using the Pediatric Hospital Inpatient System database. For comparison, they described children treated with pentobarbital. The authors estimated that 48 children received ketamine and pentobarbital for refractory status epilepticus, and 630 pentobarbital without ketamine. Those receiving only pentobarbital were median age 3 [interquartile range 0-10], and spent 30 [18-52] days in-hospital, including 17 [9-28] intensive care unit (ICU) days; 17% died. Median cost was $148 000 [81 000-241 000]. The pentobarbital-ketamine group was older (7 [2-11]) with longer hospital stays (51 [30-93]) and more ICU days (29 [20-56]); 29% died. Median cost was $298 000 [176 000-607 000]. For 71%, ketamine was given ≥1 day after pentobarbital. Ketamine cases per half-year increased from 2 to 9 ( P < .05). Ketamine is increasingly used for severe pediatric refractory status epilepticus, typically after pentobarbital. Research on its effectiveness is indicated.

ZEB2 gene mutation and duplication of 22q11.23 in Mowat-Wilson syndrome.

Mowat-Wilson syndrome is a recently delineated multiple congenital anomaly syndrome characterized by a distinctive facial appearance in association with intellectual disability, microcephaly, agenesis of the corpus callosum, seizures, congenital heart disease, Hirschsprung disease, short stature, and genitourinary anomalies. We report a 2-year-10-month-old white female with this syndrome caused by mutations in the ZEB2 gene, and in addition a duplication of the 22q11.23, a previously undocumented occurrence.

Relapse of multiple myeloma presenting as extramedullary plasmacytomas in multiple organs.

Multiple myeloma is a neoplastic plasma cell disorder. It is characterized by collections of abnormal plasma cells accumulating in the bone marrow, where they interfere with the production of normal blood cells. It usually presents as a multisystemic involvement, whose symptoms and signs vary greatly. Some patients have slowly progressive disease while others have aggressive clinical behavior by extramedullary involvement. In addition to renal failure, anemia, hypercalcemia, lytic bone lesions, and immunodeficiency, it also affects multiple organ system, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, lymph nodes, and bone. To raise awareness of the variable presentations of this disease, we report a 53-year-old male patient, with multiple myeloma in his first remission who relapsed with extramedullary plasmacytomas (EMPs) involving multiple organs, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, and lymph nodes.