Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

Child Neurology: Initial Presentation of PCDH19-Related Epilepsy With New-Onset Refractory Status Epilepticus and Treatment With Anakinra.

PCDH19-related epilepsy is a developmental and epileptic encephalopathy typically presenting with epilepsy and varying degrees of intellectual disability. Seizures typically present in clusters of focal or generalized seizures, sometimes in the setting of fever. We present the case of a 7-month-old girl presenting with new-onset refractory status epilepticus that followed routine vaccine administration and ensuing cytokine storm. She was diagnosed with a pathogenic variant in PCDH19 The patient required 5 antiseizure medications and pentobarbital-induced burst suppression for control of seizures. She was noted to have elevated serum cytokine levels (interleukin [IL]-2, IL-4, IL-10, IL-13, IL-17, IL-1, IL-1ß, and IL-8) and CSF cytokine levels (IL-6 and IL-13). Anakinra was initiated and titrated based on serial cytokine levels, with doses ranging from 5 to 20 mg/kg/d resulting in reduction in cytokine levels and seizure reduction. By age 14 months, she was able to be maintained on 3 active antiseizure medications and ketogenic diet for seizure control.

18F-FDG Brain PET Findings in Narcolepsy Type 2.

ABSTRACT: A 16-year-old adolescent boy with extensive travel throughout West Africa presented with a 6-year history of social withdrawal, anhedonia, and daytime sleepiness. The patient's electroencephalography was normal. Initial MRI revealed small pituitary gland and left temporal developmental venous anomaly. Subsequently obtained 18F-FDG brain PET was notable for markedly severe hypometabolism in the brainstem. Further workup revealed a normal orexin, autoimmune encephalitis panel, and negative titers for Trypanosoma brucei and cruzi in the CSF. Outpatient sleep study showed mild obstructive sleep apnea, and multiple sleep latency test revealed reduced mean sleep latency at 7 minutes with sleep-onset REM in 3/5 naps, findings consistent with narcolepsy type 2.

Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: A single-center retrospective study.

OBJECTIVE: We explored the efficacy and safety profile of cenobamate as an adjunctive therapy in patients with refractory focal-onset epilepsy in the pediatric population. METHODS: This was a retrospective, single-center study of cenobamate used as an adjunctive medication in pediatric patients with refractory focal-onset epilepsy . We measured seizure reduction, median reduction in seizure frequency, median dose, responder rate, and treatment-emergent adverse events. RESULTS: We studied the efficacy and safety profile of cenobamate in 21 pediatric patients (mean age 15.9). Cenobamate was up titrated using the prescribed starter pack with final doses ranging from 100 mg to 400 mg daily. The mean and median dose of cenobamate was 209.8 mg (±98.87 mg) and 200 mg (175-275), respectively. For patients weighing less than 50 kg, mean and median dose was 4.0 mg/kg/day (3.20-4.63) and 4.32 mg/kg/day, respectively. Mean and median baseline seizure frequency per month in this cohort was 15.38 and 16, respectively, prior to the introduction of cenobamate. After the adjunctive use of cenobamate, mean and median seizure frequency per month reduced to 7.29 and 1, respectively; median reduction in seizure frequency was 93.7%. Seizure reduction of at least 50% (responder rate) was noted in 13 (62.5%) patients and a seizure reduction of at least 75% noted in 11 (52.4%) patients, similar to that seen in adults. Four patients (19%) achieved seizure freedom. Of the 21 pediatric patients, 9 (42.8%) patients had treatment-emergent adverse events (TEAE) with the most commonly reported symptom being ataxia (5, 23.8%) and sedation (2, 9.5%). Three (14.3%) patients discontinued early due to these side effects. No children developed drug rash with eosinophilia and systemic symptoms (DRESS). CONCLUSION: Cenobamate demonstrates similar efficacy rates and safety profile within the pediatric population when compared to the published adult data, making it an effective, safe, and tolerable adjunctive medication for children with refractory focal-onset epilepsy, even at the maximum daily dose.

Sleep Disorders in Traumatic Brain Injury.

SUMMARY: Sleep disorders are common after traumatic brain injury (TBI). This study will review the spectrum and proposed mechanisms of TBI-associated sleep disorders and discuss the clinical approach to diagnosis and management of them. Disordered and fragmented sleep with insomnia and daytime sleepiness is very common after TBI. Sleep disruption contributes to morbidity and neurocognitive and neurobehavioral deficits and prolongs the recovery phase after injury. Early recognition and correction of these problems may limit the secondary effects of TBI and improve patient outcomes. Evaluating sleep disorders in TBI should be an important component of TBI assessment and management. Finally, newer research techniques for early diagnosis, prognosis, and improved outcomes after TBI will also be addressed.

A Role for Electroconvulsive Therapy in the Management of New Onset Refractory Status Epilepticus (NORSE) in a Young Child.

New-onset refractory status epilepticus (NORSE) describes prolonged or recurring new onset seizures which fail to respond to antiseizure medications. NORSE poses a challenge in diagnosis and treatment, and limited high-quality evidence exists to guide management. The efficacy of Electroconvulsive therapy (ECT) in aborting refractory status epilepticus has been described in case reports, but its application remains uncommon, particularly in young children. We describe a case of NORSE in a 3-year old child in which ECT played an important role in aborting status epilepticus, facilitating the diagnosis and surgical excision of an underlying focal cortical dysplasia. Although further research is needed, our case suggests that ECT can be a valuable tool in the treatment of refractory status epilepticus in children.

A journey into the unknown: An ethnographic examination of drug-resistant epilepsy treatment and management in the United States.

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed.

Neurodevelopmental outcomes in congenital heart disease through the lens of single ventricle patients.

PURPOSE OF REVIEW: This review aims to summarize and organize the current body of literature on this contemporary topic, alongside a more general discussion of neurodevelopmental complications of congenital heart disease. RECENT FINDINGS: It is theorized that the causes of the neurodevelopment disabilities are multifactorial resulting from structural central nervous system abnormalities, haemodynamic alterations and/or biochemical changes. It is therefore imperative that all patients with single ventricle anatomy and physiology receive long-term neurologic and developmental assessments in addition to their cardiac monitoring. SUMMARY: Advancements in surgical techniques and medical management have improved survivorship of these medically complex patients. Neurodevelopmental sequelae are one of the most common comorbidities affecting this patient population leading to long-term challenges in motor, language, social and cognitive skills.

Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes.

BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Sudden unexpected death in children: myth or reality?

PURPOSE OF REVIEW: Despite many years of study, sudden unexplained death remains a tenuous diagnosis of exclusion. Here, we discuss the current science behind the uncertainties of sudden death, as well as the questions that still remain. RECENT FINDINGS: Failure in any part of the complex interplay between peripheral sensors and central cardiorespiratory regulation can result in sudden death. Diagnostic testing with electrocardiograms, electroencephalogram, sleep studies, or even genetic studies have increased our ability to identify patients at the highest risk. SUMMARY: Advances in the understanding of sudden unexplained death in children may show common pathways leading to sudden death from multiple different diseases. Although rare, the devastating implication prioritizes the importance in educating patients about how to live with the risk of sudden death.

Migraine and Sleep in Children: A Bidirectional Relationship.

Migraine and sleep disorders in children exhibit a bidirectional relationship. This relationship is based on shared pathophysiology. Migraine involves activation of the trigeminal vascular system. Nociceptive neurons that innervate the dura release various vasoactive peptides. Calcitonin gene-related peptide is the most active of these peptides. Neural pathways that are involved in sleep generation are divided into those responsible for circadian rhythm, wake promotion, non-rapid eye movement, and rapid eye movement sleep activation. Sleep state switches are a critical component of these systems. The cerebral structures, networks, and neurochemical systems that are involved in migraine align closely with those responsible for the regulation of sleep. Neurochemical systems that are involved with both the pathogenesis of migraine and regulation of sleep include adenosine, melatonin, orexin, and calcitonin gene-related peptide. Sleep disorders represent the most common comorbidity with migraine in childhood. The prevalence of parasomnias, obstructive sleep apnea, and sleep-related movement disorders is significantly greater in children migraineurs. Infantile colic is a precursor of childhood migraine. Treatment of comorbid sleep disorders is important for the appropriate management of children with migraine. Sleep-based behavioral interventions can be of substantial benefit. These interventions are particularly important in children due to limited evidence for effective migraine pharmacotherapy.

Autism: considerations for transitions of care into adulthood.

PURPOSE OF REVIEW: The steady rise in number of youth diagnosed with autism spectrum disorder (ASD) has led to the need to examine transition of care considerations specific to ASD. Improved understanding and guidance addressing these needs will allow pediatric and adult providers to work together to optimize social, medical, and occupational outcomes for these patients. RECENT FINDINGS: Health-care transition is a delicate time when children with ASD outgrow the services of pediatric programs and enter a fragmented healthcare system that is unfamiliar, insufficiently knowledgeable, and underfunded for their needs. SUMMARY: Increasing autism prevalence and an aging population with autism lend urgency to improve outcomes in children transitioning to adult-care. Research reveals poor consequences in social support, education, vocational training and employment, housing, and healthcare. Specific considerations to address these issues and ensure successful transition from pediatric to adult care are needed.

Doxepin in children and adolescents with symptoms of insomnia: a single-center experience.

STUDY OBJECTIVES: Pediatric insomnia is a widespread problem and especially difficult to manage in children with neurodevelopmental disorders. There are currently no US Food and Drug Administration-approved medications to use once first-line therapy fails. The objective of this study was to evaluate the efficacy and tolerability of doxepin in pediatric patients. METHODS: This is a retrospective single-center chart review of children and adolescents (2-17 years of age) whose sleep failed to improve with behavioral intervention and melatonin who were then trialed on doxepin. Treatment was initiated at a median starting dose of 2 mg and slowly escalated to a median maintenance dose of 10 mg. Improvement in sleep was recorded using a 4-point Likert scale reported by parents on follow-up visits. RESULTS: A total of 29 patients were included in the analysis. Mean follow-up duration was 6.5 ± 3.5 months. Of 29 patients, 4 (13.8%) patients discontinued doxepin because of lack of efficacy or side effects. Eight (27.6%) patients showed significant improvement of their insomnia, 8 (27.6%) showed moderate improvement, 10 (34.5%) showed mild improvement, and 3 (10.3%) showed minimal to no improvement on treatment with doxepin (P < .05) Only 2 patients (6.9%) experienced adverse effects in the form of behavioral side effects (aggression) and enuresis. CONCLUSIONS: Results of our studies suggest that low-dose doxepin is both effective and well tolerated in pediatric patients with insomnia.