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.

Safety & feasibility of responsive neurostimulation in children with refractory epilepsy: A single-center experience.

OBJECTIVES: Responsive neurostimulation (RNS) is a relatively recent addition to the epilepsy surgery armory, gaining FDA approval in 2013 for use in adults with intractable focal epilepsy. Data for the use of RNS system in patients less than 18 years of age is limited. We aim to determine the safety and feasibility of RNS in children with refractory epilepsy. METHODS: A retrospective chart review was conducted for all patients who underwent RNS implantation at an urban tertiary children's hospital. Demographics of the patients were obtained, including age at the time of implant, MRI findings, seizure onset zone identification, and RNS targets. RESULTS: Out of a fourteen patient cohort, one patient had a post-operative complication of infection at surgical site requiring explantation. Thirteen out of 14 patients had immediate post-operative head imaging that was negative for hemorrhage, infarction, or skull fracture; one patient did not undergo head imaging. No patients reported a worsening clinical seizure frequency at a 6-month follow up visit. In the subset of patients who were implanted with RNS and did not undergo concurrent resections, there was a statistically significant reduction in the average number of long episodes at the most recent visit when compared to the 1-month post-operative visit (p = 0.0268). CONCLUSIONS: RNS is a feasible and safe option for children as young as six years with refractory epilepsy when appropriate seizure focus identification has been performed with stereo CT and stereo EEG evaluations, and can be used in conjunction with other surgical epilepsy treatment modalities. Two canister RNS placement is achievable for patients with a broad epileptogenic network or multifocal seizure onset zones.

Sleep and Epilepsy.

The relationship between sleep and epilepsy is both intimate and bidirectional. The molecular mechanisms which control circadian rhythm and the sleep/wake cycle are dysregulated in epileptogenic tissue and are themselves effected by molecular pathways for epilepsy. Sleep affects the frequency of interictal epileptiform discharges and recent research has raised new questions regarding the impact of discharges on sleep function and cognition. Epileptiform discharges themselves affect sleep architecture and increase the risk of sleep disorders. Several sleep-related epilepsy syndromes have undergone changes in their classification which highlights their intimate relationship to sleep and novel screening tools have been developed to help clinicians better differentiate epileptic seizures from sleep-related paroxysmal events. Improving sleep and addressing sleep disorders has been associated with improved seizure control and increased well-being in people with epilepsy. These interactions are discussed in detail in this review.

The Relationship Between Sleep, Epilepsy, and Development: a Review.

PURPOSE OF REVIEW: To review the relationship between sleep, neurodevelopment, and epilepsy and potential underlying physiological mechanisms. RECENT FINDINGS: Recent studies have advanced our understanding of the role of sleep in early brain development and epilepsy. Epileptogenesis has been proposed to occur when there is a failure of normal adaptive processes of synaptic and homeostatic plasticity. This sleep-dependent transformation may explain the cognitive impairment seen in epilepsy, especially when occurring early in life. The glymphatic system, a recently discovered waste clearance system of the central nervous system, has been described as a potential mechanism underlying the relationship between sleep and seizures and may account for the common association between sleep deprivation and increased seizure risk. Epilepsy and associated sleep disturbances can critically affect brain development and neurocognition. Here we highlight recent findings on this topic and emphasize the importance of screening for sleep concerns in people with epilepsy.

A late presentation of TPM3 myopathy presenting as sleep hypoventilation in the setting of acute demyelinating encephalomyelitis.

Central hypoventilation is a rare cause of respiratory failure that has been associated with multiple underlying disorders, including congenital central hypoventilation syndrome, obesity hypoventilation syndrome, and several neuromuscular conditions. We report the case of an adolescent who presented with respiratory failure in the setting of acute demyelinating encephalomyelitis whose clinical history was consistent with a congenital myopathy and whom we found to have a Tropomyosin 3 (TPM3) genetic variant on further genetic testing. This case expands the clinical spectrum of causes for late-onset central hypoventilation in the setting of a neuromuscular disorder. CITATION: Stringel V, Bizargity P, Laureta E, Kothare S. A late presentation of TPM3 myopathy presenting as sleep hypoventilation in the setting of acute demyelinating encephalomyelitis. J Clin Sleep Med. 2022;18(11):2695-2698.

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.

The Interaction Between Sleep and Epilepsy.

PURPOSE OF REVIEW: To review the mutual interactions between sleep and epilepsy, including mechanisms of epileptogenesis, the relationship between sleep apnea and epilepsy, and potential strategies to treat seizures. RECENT FINDINGS: Recent studies have highlighted the role of functional network systems underlying epileptiform activation in sleep in several epilepsy syndromes, including absence epilepsy, benign focal childhood epilepsy, and epileptic encephalopathy with spike-wave activation in sleep. Sleep disorders are common in epilepsy, and early recognition and treatment can improve seizure frequency and potentially reduce SUDEP risk. Additionally, epilepsy is associated with cyclical patterns, which has led to new treatment approaches including chronotherapy, seizure monitoring devices, and seizure forecasting. Adenosine kinase and orexin receptor antagonists are also promising new potential drug targets that could be used to treat seizures. Sleep and epilepsy have a bidirectional relationship that intersects with many aspects of clinical management. In this article, we identify new areas of research involving future therapeutic opportunities in the field of epilepsy.

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.

Patients Diagnosed with Multisystem Inflammatory Syndrome in Children Have Persistent Neurologic, Sleep, and Psychiatric Symptoms After Hospitalization.

Background: Acute neurological complications from COVID-19 have been reported in both pediatric and adult populations. Chronic symptoms after recovery have been reported in adults and can include neuropsychiatric and sleep symptoms. Persistent symptoms in children with the multisystem inflammatory syndrome in children (MIS-C) have not been studied. Methods: We conducted a single-center retrospective chart review and cross-sectional survey of patients diagnosed with MIS-C. Patients and parents were surveyed on symptoms before the COVID-19 pandemic, upon admission, and 23 weeks (interquartile range 20-26 weeks) after discharge. Age and gender-matched patients requiring intensive care unit (ICU) care for status asthmaticus were surveyed as a control group. Results: In this cohort of 47 patients, 77% reported neurological, 60% psychiatric, and 77% sleep symptoms during hospitalization. Prior to hospitalization, 15% reported neurological, 0% psychiatric, and 7% sleep symptoms. Eighteen (50%) of the 36 patients who had neurological symptoms during hospitalization continued to have symptoms on follow-up (odds ratio [OR] = ∞, p = .003]). Similarly, 16 (57%) of 28 patients with psychiatric symptoms reported persistence at follow-up (OR = 5.00; p = .02). Fifteen (42%) of the 18 patients reporting sleep disturbance during hospitalization had persistence on follow-up (OR = 1.9; p = .49). The aggregate of neurological, psychiatric, and sleep symptoms during admission and at follow-up was significantly higher for MIS-C patients requiring ICU care when compared to the control group (p = .01). Conclusions: In this cohort of patients with MIS-C, a majority of patients reported new-onset neuropsychiatric and sleep symptoms. Almost half of these patients had persistent symptoms on a follow-up survey.

Evaluating vagus nerve stimulation treatment with heart rate monitoring in pediatric patients with intractable epilepsy.

PURPOSE: Vagus nerve stimulators (VNS) have emerged as an effective treatment modality for pediatric patients suffering from intractable, drug-resistant epilepsy. Newer devices, AspireSR™ Model 106 and the SenTiva™ Model 1000 (VNS TherapyⓇ, LivaNova™), contain an "auto-stimulation" feature that detects ictal tachycardia and transmits pulsations to attenuate seizures. However, the exact benefits of auto-stimulation compared to its risks still merit further exploration. This study evaluates the utility of these specific devices in a heterogeneous population of pediatric and young adult patients with intractable epilepsy. METHODS: This is a retrospective chart review of 55 patients who underwent either VNS insertion with or without an auto-stimulation-enabled VNS device at a single level four epilepsy center. Seizure frequency, seizure subtype, side effects, and change in anti-seizure medication load both before and after VNS implantations were collected from patient self-reporting at the time of VNS insertion and 12 months following implantation. Information regarding output current, auto-stimulation current, duty cycling, and auto-stimulation threshold of the device was obtained from documented VNS interrogation for patients with auto-stimulation-enabled VNS devices. RESULTS: Patients with auto-stimulation-enabled VNS devices had a mean 56.0% (SD = 0.414) seizure frequency reduction 12 months post-VNS insertion, while patients without auto-stimulation-enabled VNS devices had a mean 41.6% (SD = 0.456) seizure frequency reduction during the same interval. The mean seizure frequency reduction 12 months post-VNS insertion for patients with a SenTiva™ 1000 model was 66.0% (SD = 0.426). For patients with auto-stimulation-enabled VNS devices, post-treatment seizure reduction was significantly correlated with daily auto-stimulation activation (R = 0.432, p = 0.025). CONCLUSION: This study supports the clinical safety and utility of auto-stimulation-enabled VNS models, specifically the SenTiva™ 1000, in treating pediatric patients with intractable epilepsy of various subtypes and etiologies. Further research is needed to evaluate the sustained impact of auto-stimulation on long-term outcomes (≥ 2 years follow-up post-VNS).

Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome.

PURPOSE: To assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). METHODS: In this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. RESULTS: A total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43-7) for persons with DS receiving standard-of-care. CONCLUSION: All-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk. CLINICAL TRIAL REGISTRATION: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.