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.

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.

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.

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.

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).

Time-dependent transformations of memory representations differ along the long axis of the hippocampus.

Research has shown that sleep is beneficial for the long-term retention of memories. According to theories of memory consolidation, memories are gradually reorganized, becoming supported by widespread, distributed cortical networks, particularly during postencoding periods of sleep. However, the effects of sleep on the organization of memories in the hippocampus itself remains less clear. In a 3-d study, participants encoded separate lists of word-image pairs differing in their opportunity for sleep-dependent consolidation. Pairs were initially studied either before or after an overnight sleep period, and were then restudied in a functional magnetic resonance imaging (fMRI) scan session. We used multivariate pattern similarity analyses to examine fine-grained effects of consolidation on memory representations in the hippocampus. We provide evidence for a dissociation along the long axis of the hippocampus that emerges with consolidation, such that representational patterns for object-word memories initially formed prior to sleep become differentiated in anterior hippocampus and more similar, or overlapping, in posterior hippocampus. Differentiation in anterior hippocampal representations correlated with subsequent behavioral performance. Furthermore, representational overlap in posterior hippocampus correlated with the duration of intervening slow wave sleep. Together, these results demonstrate that sleep-dependent consolidation promotes the reorganization of memory traces along the long axis of the hippocampus.

Sleep Spindles Promote the Restructuring of Memory Representations in Ventromedial Prefrontal Cortex through Enhanced Hippocampal-Cortical Functional Connectivity.

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when restudying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex for scene-word pairs. Using multivariate pattern analyses, we also show that fast spindle density during postlearning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest that fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENT How new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity among memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

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.

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.

Length of stay linked to neurodiagnostic workup for seizures presenting to the pediatric emergency department.

INTRODUCTION: Patients presenting to the pediatric emergency department (ED) often undergo unnecessary testing that leads to prolonged ED visits. Lower ED length of stay has been linked to improved patient experience and may reduce ED overcrowding, a costly burden on a health system. METHODS: This is a retrospective cohort study involving patient records over the period of 6 months at an urban tertiary children's hospital who presented with seizures. Febrile seizures, seizures associated with trauma, and charts of patients who did not present initially through our ED were excluded. RESULTS: 328 charts were obtained through this search criteria. Head imaging was performed in 52 (16%) patients and consisted of 81% CT (n = 42) and 19% (n = 10) magnetic resonance imaging (MRI). Obtaining an MRI was associated with a 3.5 h longer ED visit (p = 0.07); obtaining a CT was associated with a 1.5 h longer ED visit (p = 0.005). An Electroencephalogram (EEG) was obtained for 67 (20%) visits and was associated with a 3.0 h longer ED length of stay (p < 0.001). Ten % of the CT scans showed new or progressive findings and 40% of the MRIs done provided useful information for management. Thirty-seven % of EEGs performed in new onset seizure patients revealed epileptiform findings and 5% of EEGs in established seizure patients provided meaningful findings important to management. CONCLUSION: Obtaining neurodiagnostic studies significantly prolongs duration of stay in the ED. Electroencephalograms appear to have the greatest yield in new onset seizure patients and can help make a diagnosis of an epilepsy syndrome 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.

Laser interstitial thermal therapy for gyrus rectus cortical dysplasia in a child: a technical note.

Laser interstitial thermal therapy (LITT) has become a popular tool in the treatment of tumors and epilepsy. While most commonly used for the treatment of mesial temporal lobe epilepsy, it can be used as a minimally invasive option for the treatment of any seizure focus but has very rarely been discussed in the setting of cortical dysplasia. Here, we discuss the case of a 5-year-old girl with medically refractory epilepsy secondary to a right medial orbital gyrus and gyrus rectus cortical dysplasia successfully treated with LITT. After confirmation of seizure focus using stereo electroencephalography (SEEG), the patient underwent thermal ablation of the focus through an eyebrow incision with use of a single laser fiber. She has been seizure-free 6 months postoperatively, only on one anti-seizure medication, with normal EEG. The use of LITT in this case was successful because of the cylindrical shape of the cortical dysplasia, making it easily accessible via a single laser fiber in the absence of a yet to develop fontal sinus. While open resection would have also been appropriate, the use of LITT provided a minimally invasive alternative approach that allowed for an excellent outcome with limited risks.

Robot-assisted stereoelectroencephalography electrode placement in twenty-three pediatric patients: a high-resolution analysis of individual lead placement time and accuracy at a single institution.

PURPOSE: We describe a detailed evaluation of predictors associated with individual lead placement efficiency and accuracy for 261 stereoelectroencephalography (sEEG) electrodes placed for epilepsy monitoring in twenty-three children at our institution. METHODS: Intra- and post-operative data was used to generate a linear mixed model to investigate predictors associated with three outcomes (lead placement time, lead entry error, lead target error) while accounting for correlated observations from the same patients. Lead placement time was measured using electronic time-stamp records stored by the ROSA software for each individual electrode; entry and target site accuracy was measured using postoperative stereotactic CT images fused with preoperative electrode trajectory planning images on the ROSA computer software. Predictors were selected from a list of variables that included patient demographics, laterality of leads, anatomic location of lead, skull thickness, bolt cap device used, and lead sequence number. RESULTS: Twenty-three patients (11 female, 48%) of mean age 11.7 (± 6.1) years underwent placement of intracranial sEEG electrodes (median 11 electrodes) at our institution over a period of 1 year. There were no associated infections, hemorrhages, or other adverse events, and successful seizure capture was obtained in all monitored patients. The mean placement time for individual electrodes across all patients was 6.56 (± 3.5) min; mean target accuracy was 4.5 (± 3.5) mm. Lesional electrodes were associated with 25.7% (95% CI: 6.7-40.9%, p = 0.02) smaller target point errors. Larger skull thickness was associated with larger error: for every 1-mm increase in skull thickness, there was a 4.3% (95% CI: 1.2-7.5%, p = 0.007) increase in target error. Bilateral lead placement was associated with 26.0% (95% CI: 9.9-44.5%, p = 0.002) longer lead placement time. The relationship between placement time and lead sequence number was nonlinear: it decreased consistently for the first 4 electrodes, and became less pronounced thereafter. CONCLUSIONS: Variation in sEEG electrode placement efficiency and accuracy can be explained by phenomena both within and outside of operator control. It is important to keep in mind the factors that can lead to better or worse lead placement efficiency and/or accuracy in order to maximize patient safety while maintaining the standard of care.

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.

Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients.

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy diagnosed in childhood that persists through adolescence and into adulthood. While the characteristics of LGS in pediatric patients are well defined, including "drop attacks", interictal slow spike and wave electroencephalogram (EEG) activity, and intellectual disability, these features can evolve over time, and different EEG activities may be present in adult patients with LGS. This may result in missed diagnoses in these patients and subsequent challenges for the adequate treatment of their seizures. Based on discussions held during the LGS Transition of Care advisory board meeting and thereafter, we developed proposed diagnostic and treatment algorithms for LGS in adult patients. We highlight readily available assessments to facilitate diagnosis of LGS, based on past medical history and physical examination. The LGS diagnostic algorithm recommends that clinicians consider the occurrence of wider seizure types and abnormal EEG activities to be potentially indicative of LGS. Seizure types may include atypical absence seizures, myoclonic seizures, focal seizures, and tonic-clonic seizures, and EEG may demonstrate background slowing, focal or multifocal epileptiform discharges, and diffuse fast rhythms during sleep, among other activities. Extended EEG during sleep and video-EEG should be used in equivocal cases. Treatment of LGS in adult patients should incorporate both antiseizure drug (ASD) therapy and nonpharmacologic approaches. Frequent reassessment of patients is considered a central aspect. ASDs were categorized based on order of preference for use in the treatment of LGS; Tier 1 comprises recommended first-line ASDs, and includes valproate, clobazam, lamotrigine, rufinamide, topiramate, and cannabidiol. Other treatment options include diet, neurostimulation, and surgical approaches. Developments with the potential to improve diagnosis in the future include genetic screening, while novel ASDs and advances in neurostimulation techniques may provide valuable treatment options. These algorithms should be frequently revisited to incorporate improved techniques and therapies.

Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.

Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder.

A randomized controlled trial of levodopa in patients with Angelman syndrome.

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.

Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression.

Patients with epilepsy have 20-fold risk of sudden death when compared to the general population. Uncontrolled seizures is the most consistent risk factor, and death often occurs at night or in relation to sleep. We examined seizure-related respiratory disturbances in sleep versus wakefulness, focusing on periictal oxygen saturation. Respiratory measures were examined in 48 recorded seizures (sleep, n = 23, wake, n = 25) from 20 adult patients with epilepsy. Seizures from sleep were associated with lower saturation, as compared to seizures from wakefulness, both during ictal (sleep median = 90.8, wake median = 95.5; p < 0.01) and postictal periods (sleep median = 94.3, wake median = 96.9; p = 0.05). Compared to wake-related seizures, seizures from sleep were also associated with a larger desaturation drop (sleep median = -4.2, wake median = -1.2; p = 0.01). Postictal generalized electroencephalography (EEG) suppression (PGES) occurred more frequently after seizures from sleep (39%), as compared to wake-related seizures (8%, p = 0.01). Our findings suggest that nocturnal seizures may entail a higher sudden unexpected death in epilepsy (SUDEP) severity burden, as they are associated with more severe and longer hypoxemia events, and more frequently followed by PGES, both factors implicated in sudden death.

Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience.

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500 mg (mean: 1800 ± 900 mg). The duration of therapy ranged from 1 month to 20 years (mean duration: 35 ± 45 months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved ≥ 50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.