Intractable Seizures and Limbic Encephalitis, Unaccounted Complications of Type 1 Diabetes Autoimmunity

Glutamic acid decarboxylase 65kD autoantibody (GAD65Ab) is frequently detected in patients with refractory epilepsy and stiff person syndrome (SPS). In contrast to T1D, the pathological role of GAD65Ab in neurological disorders is still debatable. As a result, the implementation of possible immunotherapy is usually delayed. This report presents two cases of GAD65Ab associated brain autoimmunity and their different management. We present clinical data and discuss management based on available evidence in the reviewed literature. Both cases presented with acute on chronic neurological symptoms and were GAD65Ab positive. Case 1, a 30-year-old man with a history of early-onset T1D at 14 months, followed by cryptogenic temporal epilepsy at 11 years of age, presented with intractable seizures. Case 2, a 48-year-old woman, presented with a history of recurrent severe headaches, cognitive impairment, decreased memory, and behavioral symptoms. GAD65Ab was detected in both patients’ sera. CSF GAD65Ab was only checked and positive in case 1. Case 2 was diagnosed with limbic encephalitis, treated with immunotherapy, and showed a remarkable clinical improvement. Case 1 with refractory epilepsy failed multiple AEDs and Responsive-Stimulator System (RNS) treatments. He was finally diagnosed with autoimmune epilepsy. The delay in diagnosis resulted in a lost opportunity for early immunotherapy. In conclusion, autoantibody screening and early initiation of immunotherapy should be considered to manage GAD65Ab associated neurological disorders.

GABRB3 mutation as a cause of Ohtahara syndrome: A case report

Ohtahara syndrome (OS) is a rare early infantile epileptic encephalopathy that is characterized by an abnormal electroencephalogram (EEG) and intractable seizures. The patient of this reported case is a 4-month-old male infant delivered by cesarean section with an uneventful antenatal and neonatal period. At 2 months of age, he developed seizures that were refractory to anticonvulsants. Prolonged video EEG showed a characteristic suppression-burst pattern. We report an infant OS associated with heterozygous mutation in the GABRB3 gene.

Clinical Characteristics and Treatment Experience of Individuals with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE): Findings from an Online Caregiver Survey

ABSTRACT Purpose: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. Variants in the SCN8A gene are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8Arelated epilepsies. Methods: A 36-question online survey was developed to obtain de-identified data from caregivers of children with SCN8A-related epilepsy. The survey included questions on genetic diagnosis, disease manifestations/comorbidities, seizure severity/type, current/prior use of antiseizure medicines (ASMs), and best/worst treatments per caregiver perception. Results: In total, 116 survey responses (87 USA, 12 Canada, 12 UK, 5 Australia) were included in the quantitative analysis. Generalized tonic/clonic was the most common seizure type at onset and time of survey; absence and partial/focal seizures were also common. Most patients (77%) were currently taking ≥2 ASMs; 50% had previously tried and stopped ≥4 ASMs. Sodium channel blockers (oxcarbazepine, phenytoin, lamotrigine) provided the best subjective seizure control and quality of life. Conclusion: The SCN8A-DEE patient population is heterogeneous and difficult to treat, with high seizure burden and multiple comorbidities. The high proportion of patients who previously tried and stopped ASMs indicates a large unmet treatment need. Further collaboration between families, caregivers, patient advocates, clinicians, researchers, and industry can increase awareness and understanding of SCN8A-related epilepsies, improve clinical trial design, and potentially improve patient outcomes.

AS3MT Polymorphism: A Risk Factor for Epilepsy Susceptibility and Adverse Drug Reactions to Valproic Acid and Oxcarbazepine Treatment in Children From South China

Epilepsy is a common neurologic disorder characterized by intractable seizures, involving genetic factors. There is a need to develop reliable genetic markers to predict the risk of epilepsy and design effective therapies. Arsenite methyltransferase (AS3MT) catalyzes the biomethylation of arsenic and hence regulates arsenic metabolism. AS3MT variation has been linked to the progression of various diseases including schizophrenia and attention deficit or hyperactivity disorder. Whether genetic polymorphism of AS3MT contributes to epilepsy remains unclear. In this study, we investigated the association of AS3MT gene polymorphism with susceptibility to epilepsy in children from south China. We also explored the effect of AS3MT variation on the safety of antiepileptic drugs. Genotypic analysis for AS3MT rs7085104 was performed using samples from a Chinese cohort of 200 epileptic children and 244 healthy individuals. The results revealed a genetic association of AS3MT rs7085104 with susceptibility to pediatric epilepsy. Mutant homozygous GG genotype exhibited a lower susceptibility to childhood epilepsy than AA genotype. Carriers of AS3MT rs7085104 AA genotype exhibited a higher risk of digestive adverse drug reactions (dADRs) in children when treated with valproic acid (VPA) or oxcarbazepine (OXC). Additionally, bioinformatics analysis identified eight AS3MT target genes related to epilepsy and three AS3MT-associated genes in VPA-related dADRs. The effects of AS3MT on epilepsy might involve multiple targets including CNNM2, CACNB2, TRIM26, MTHFR, GSTM1, CYP17A1, NT5C2, and YBX3. This study reveals that AS3MT may be a new gene contributing to epileptogenesis. Hence, analysis of AS3MT polymorphisms will help to evaluate susceptibility to pediatric epilepsy and drug safety.

Case Report: Electroencephalography in a neonate with isolated sulfite oxidase deficiency – a case report and literature review

Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessive neuro-metabolic disorder caused by a mutation in the sulfite oxidase (SUOX) gene situated on chromosome 12. Due to the deficiency of this mitochondrial enzyme (sulfite oxidase), the oxidative degradation of toxic sulfites is disrupted. The most common form of this disease has an early onset (classical ISOD) in the neonatal period, with hypotonia, poor feeding and intractable seizures, mimicking hypoxic-ischaemic encephalopathy. The evolution is rapidly progressive to severe developmental delay, microcephaly and early death. Unfortunately, there is no effective treatment and the prognosis is very poor. In this article, we described the evolution of early continuous electroencephalography (EEG) in a case of ISOD with neonatal onset, as severely encephalopathic background, with refractory seizures and distinct delta-beta complexes. The presence of the delta-beta complexes might be a diagnostic marker in ISOD. We also performed a literature review of published cases of neonatal ISOD that included EEG monitoring.

Successful Treatment of Severe Lamotrigine Intoxication with CytoSorb Hemoadsorption

Severe intoxication with the anti-epileptic drug, lamotrigine can cause cardiovascular collapse, neurotoxicity – expressed as intractable seizures, and even death. As there is currently no known specific antidote, extracorporeal removal therapies such as CytoSorb hemoadsorption might represent a promising therapeutic option. We report on a deeply comatosed 60-year-old woman who was treated in our intensive care unit with severe lamotrigine intoxication. To support removal from the blood, combined treatment with continuous veno-venous hemodialysis and CytoSorb hemoadsorption was started. Pre- and post-adsorber drug level measurements showed the rapid elimination of lamotrigine accompanied by an impressive clinical improvement in the patient. Two days after treatment discontinuation, there were no more clinical signs of intoxication and the patient could be extubated, followed by transfer to the stroke unit in a stable condition the following day. In the absence of a viable antidote, for the efficient short-term removal of lamotrigine, hemoadsorption with the CytoSorb device could represent a feasible treatment option for patients with severe lamotrigine intoxication.

P.103 Midline Spikes and Intractable Seizures in Pediatric Epilepsy

Background: Epileptic discharges localized to the midline vertex are rare. However, they have been associated with intractable seizures and severe long-term consequences in the developing brain. Our study aimed to understand the etiology of pediatric midline seizures and define post-surgical seizure outcomes. Methods: We reviewed charts, electroencephalography (EEG), and neuroimaging studies of ten pediatric patients with epileptic discharges localized to the midline vertex in the Comprehensive Epilepsy Program. The seizures were classified according to the International League Against Epilepsy criteria, patient age, sex, neuroimaging results, seizure etiology and outcomes were obtained. Results: Age of seizure onset was within the first 10 years of life in 90% of patients, with focal seizures being the most prevalent. Focal cortical dysplasia (FCD) was the most common etiology present in 50% of patients. These children had normal neuroimaging studies and intractable epilepsy. However, seizure freedom was achieved following surgical resection of the epileptogenic zone. Conclusions: We demonstrated that patients with midline epileptic discharges are associated with intractable focal seizures and early seizure onset. Despite normal neuroimaging reports, FCD was the most common pathology. Thus our study suggests early localization and resection of the epileptogenic zone may be beneficial for achieving seizure freedom in children with this electroclinical syndrome.

Expanding the Phenotype of Molybdenum Cofactor Deficiency in Neonates: Report of Two Cases

Molybdenum cofactor deficiency (MoCD) is a rare neurometabolic disorder characterized by intractable seizures, progressive microcephaly, tone abnormalities, facial dysmorphism, and feeding difficulties in the neonatal period. We present two different neonatal cases of MoCD with atypical presentations which could have been easily missed. One is a preterm baby admitted with features of sepsis, poor perfusion, and seizures who later developed tone abnormalities and feeding difficulty. The second is a term baby who presented with stridor, respiratory distress, and metabolic acidosis followed by intractable seizures and encephalopathy. Both babies had characteristic radiological and biochemical findings, and genome sequencing identified mutations in MOCS2 and MOCS1 genes, respectively. MoCD presenting as hypoxic-ischemic encephalopathy and cerebral palsy are well described, but its presentation in preterm with “sepsis-like features with drug-responsive seizures” in the early newborn period is not described, and can also cause unnecessary delay in the diagnosis. Its clinical presentation with “stridor, respiratory distress, and metabolic acidosis” is also described for the first time in literature.