Teaching Video NeuroImages: Atypical childhood epilepsy with centrotemporal spikes: Seizures often discussed, rarely seen

A 7-year-old right-handed boy with poorly controlled epilepsy presented to the epilepsy monitoring unit for further clarification of his diagnosis. Seizure onset was at 3 years with focal motor seizures of left face and arm followed by confusion and aphasia. Prominent behavioral and school difficulties were also reported. Valproic acid monotherapy (23 mg/kg/d) was weaned by day 2 and a habitual event captured on day 5 (figure, video 1). Brain MRI and an epilepsy gene panel (including GRIN2A) were nonrevealing. The diagnosis was therefore consistent with atypical childhood epilepsy with centrotemporal spikes. This differs from benign rolandic epilepsy because of earlier seizure onset, increased seizure burden, EEG with background slowing (figure) with stereotyped discharges, seizure semiology, and more prominent comorbidities.1,

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Purpose This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients

Spectrum of KV2.1 Dysfunction in KCNB1‐Associated Neurodevelopmental Disorders

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152486/1/ana25607.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152486/2/ana25607_am.pd

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

PURPOSE: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. METHODS: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. RESULTS: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. CONCLUSION: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients

Gamma-radiation induced graft copolymerization of vinyl monomer onto rayon

107-110<span style="font-size:11.0pt;line-height:115%; font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-fareast-font-family:="" "times="" new="" roman";mso-fareast-theme-font:minor-fareast;mso-hansi-theme-font:="" minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:minor-latin;="" color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:="" ar-sa"="">Methyl acrylate (MA) has been graft copolymerized onto rayon in aqueous medium by using gamma-radiation as initiator in air by the mutual method. The graft yield has been determined as a function of different reaction parameters such as total dose, concentration of vinyl monomer and amount of water. The maximum grafting occurred at a total dose of 1.05 M rad using [MA] = 1.1 x 10-2 mol under optimum conditions. Grafting has also been studied in the presence of ferrous ammonium sulphate (FAS) as an additive. In presence of FAS, the maximum grafting occurred at a total dose of 0.35 M rad at [MA] = 1.1 x 10-2 mol using [FAS] = 1.9 x 10<span style="font-size:11.0pt;line-height: 115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;="" mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:minor-fareast;="" mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:="" minor-latin;color:#080808;mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">-<span style="font-size:11.0pt;line-height: 115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;="" mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:minor-fareast;="" mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:="" minor-latin;color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">4<span style="font-size:11.0pt; line-height:115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;="" mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:minor-fareast;="" mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:="" minor-latin;color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"=""> mol. The amount of water also influences the grafting and maximum grafting was obtained using 15 ml water in presence of FAS and 10 ml in absence of FAS<span style="font-size:11.0pt;line-height:115%; font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-fareast-font-family:="" "times="" new="" roman";mso-fareast-theme-font:minor-fareast;mso-hansi-theme-font:="" minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:minor-latin;="" color:#080808;mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:="" ar-sa"="">. <span style="font-size:11.0pt;line-height:115%;font-family: " calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-fareast-font-family:="" "times="" new="" roman";mso-fareast-theme-font:minor-fareast;mso-hansi-theme-font:="" minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:minor-latin;="" color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:="" ar-sa"="">The effect of methanol on grafting has also been studied. In all the experiments, 100 mg rayon was used<span style="font-size:11.0pt; line-height:115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;="" mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:minor-fareast;="" mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:="" minor-latin;color:#080808;mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">. <span style="font-size:11.0pt;line-height: 115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:minor-latin;="" mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:minor-fareast;="" mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;mso-bidi-theme-font:="" minor-latin;color:black;mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">Rayon-g-poly(methyl acrylate) has been characterized by IR spectroscopy and thermogravimetric analysis<span style="font-size: 11.0pt;line-height:115%;font-family:" calibri","sans-serif";mso-ascii-theme-font:="" minor-latin;mso-fareast-font-family:"times="" new="" roman";mso-fareast-theme-font:="" minor-fareast;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:calibri;="" mso-bidi-theme-font:minor-latin;color:#080808;mso-ansi-language:en-us;="" mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">.</span

Use of intranasal rescue therapy for seizure clusters in students with epilepsy: Nurses’ knowledge, perceptions, and practice

School nurses play a crucial role in the prompt, appropriate response to epilepsy-related seizure emergencies among students in the school setting. Two intranasal benzodiazepine rescue therapies are now approved and offer potential benefits of being easy to use and socially acceptable. In July 2021, a survey was sent to 49,314 US school nurses to assess knowledge, perceptions, and practice with seizure rescue therapy. Responses were received from 866 (1.8% response rate). Of respondents, 45.7% had used rectal diazepam gel; 9.3%, midazolam nasal spray; and 6.0%, diazepam nasal spray. The majority (58.7%) had not delegated authority to administer rescue therapy, with state/local regulations and lack of willingness of school personnel being the most common barriers to delegation (37.7% and 20.1%, respectively). Additional training of nurses and school staff and progress on delegation policies may help optimize appropriate use of intranasal rescue therapy for seizures and enhance care of students with epilepsy in schools

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder

The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others. A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development. Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder.

Analyses of patients who self-administered diazepam nasal spray for acute treatment of seizure clusters

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant.

Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay, and often have elevated risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, including KCNB1. The voltage-gated potassium channel KV2.1, encoded by KCNB1, is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons. In addition to its canonical role as a voltage-gated potassium conductance, KV2.1 also serves a highly conserved structural function organizing endoplasmic reticulum-plasma membrane junctions clustered in the soma and proximal dendrites of neurons. The de novo pathogenic variant KCNB1-p.G379R was identified in an infant with epileptic spasms, and atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected KV2.1 clustering at endoplasmic reticulum-plasma membrane junctions, KV2.1-G379R was expressed in HEK293T cells. KV2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and co-expression of KV2.1-G379R with KV2.1-wild-type lowered induction of these structures relative to KV2.1-WT alone, consistent with a dominant negative effect. To model this variant in vivo, we introduced Kcnb1G379R into mice using CRISPR/Cas9 genome editing. We characterized neuronal expression, neurological and neurobehavioral phenotypes of Kcnb1G379R/+ (Kcnb1R/+) and Kcnb1G379R/G379R (Kcnb1R/R) mice. Immunohistochemistry studies on brains from Kcnb1+/+, Kcnb1R/+ and Kcnb1R/R mice revealed genotype-dependent differences in the expression levels of KV2.1 protein, as well as associated KV2.2 and AMIGO-1 proteins. Kcnb1R/+ and Kcnb1R/R mice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. Spontaneous seizures were observed in Kcnb1R/R mice, as well as seizures induced by exposure to novel environments and/or handling. Both Kcnb1R/+ and Kcnb1R/R mutants were more susceptible to proconvulsant-induced seizures. In addition, both Kcnb1R/+ and Kcnb1R/R mice exhibited abnormal interictal EEG activity, including isolated spike and slow waves. Overall, the Kcnb1G379R mice recapitulate many features observed in individuals with DEE due to pathogenic variants in KCNB1. This new mouse model of KCNB1-associated DEE will be valuable for improving the understanding of the underlying pathophysiology and will provide a valuable tool for the development of therapies to treat this pharmacoresistant DEE