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Edwin Trevathan

Publications and source records attributed to Edwin Trevathan.

13 recordsLinked to original sources
PubMed2026

ARX mutation-associated interneuron defects provide insights into mechanisms underlying developmental epilepsies.

Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures, whereas its loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and its relationship to seizure phenotype, Arx conditional mutant mouse lines were investigated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that ARX abrogation results in defects in cIN density and distribution, as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence to medial ganglionic eminence identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation and sequencing revealed that ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation and cIN migration. Investigation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates the number and distribution of cINs in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate that ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX, who was diagnosed with developmental epileptic encephalopathy. Together, our data provide novel insights into how ARX and its target genes regulate cIN development and migration and into the pathogenic mechanisms underlying a spectrum of neurodevelopmental disorders linked to loss of ARX.

Animals↗
PubMed2006

Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures.

CONTEXT AND OBJECTIVE: Primary generalized tonic-clonic seizures are relatively more common among children than among adults. Primary generalized tonic-clonic seizures are associated with increased risk of injury and death. Therefore, effective control of primary generalized tonic-clonic seizures is necessary to reduce epilepsy-related morbidity and mortality. Lamotrigine has demonstrated efficacy from published randomized clinical trials for childhood partial seizures, absence seizures, and for the generalized seizures associated with Lennox-Gastaut syndrome. A randomized, blinded, placebo-controlled study was conducted to assess the efficacy and tolerability of adjunctive therapy with lamotrigine in the treatment of primary generalized tonic-clonic seizures among patients > or = 2 years of age; we report the data from children and adolescents 2 to 20 years of age from this randomized clinical trial. This is the first published analysis of data from a randomized, double-blind, controlled clinical trial of primary generalized tonic-clonic seizures focusing on children and adolescents. PATIENTS AND METHODS: We randomly assigned (1:1) 117 patients, aged 2 to 55 years, with primary generalized tonic-clonic seizures inadequately controlled on 1 to 2 current antiepileptic drugs and with evidence of primary generalized tonic-clonic seizures on electroencephalogram and no historical or electroencephalogram evidence of partial seizures to either lamotrigine or placebo in a double-blind parallel group clinical trial from 2001 through 2004. We analyzed the subgroup of children and adolescents, aged 2 to 20 years (n = 45), from this randomized clinical trial. Patients having > or = 3 primary generalized tonic-clonic seizures over an 8-week baseline were randomly assigned (1:1) to receive either lamotrigine or placebo. The treatment period consisted of an escalation phase (12 weeks for patients 2-12 years; 7 weeks for patients > 12 years) and a maintenance phase (12 weeks). The study had 4 phases: screening phase, baseline phase, escalation phase, and maintenance phase. During the screening phase, baseline medical examinations and seizure type and seizure frequency assessments were performed. During the 8-week baseline phase, the number and dosages of concomitant antiepileptic drugs were maintained while seizure frequency was assessed. The assessment of primary generalized tonic-clonic seizure frequency was determined during the 8-week baseline phase. Patients eligible for random assignment experienced > or =3 primary generalized tonic-clonic seizures during the baseline phase and > or = 1 primary generalized tonic-clonic seizure in the 8 weeks before the baseline phase. Lamotrigine was introduced and titrated using a schedule based on the patients' age and concurrent antiepileptic drug regimen. During the escalation phase, the number and doses of concomitant antiepileptic drugs were not changed. The escalation phase was followed by a 12-week maintenance phase during which time the lamotrigine dose was maintained at a specific dose defined by the patients' age and concomitant antiepileptic drugs, whereas the doses of concurrent antiepileptic drugs were maintained at a constant dose. Concurrent antiepileptic drugs could not be discontinued or added during the maintenance phase. The primary efficacy end point measure was the median reduction in the frequency of primary generalized tonic-clonic seizures from baseline; seizure counts were recorded prospectively in standardized daily seizure diaries. Other efficacy end point data for analysis were as follows: the median seizure counts, the median percentage change from the baseline phase in average monthly seizure frequency for other generalized seizure types, and the percentage of patients with a reduction of > or = 25%, > or = 50%, > or = 75%, or 100% in frequencies of primary generalized tonic-clonic seizures and all generalized seizures during the escalation phase and/or maintenance phase relative to the baseline phase. Accurate counts of absence seizure frequency require electroencephalogram-video monitoring; absence seizure frequency was not an outcome measure for this analysis. RESULTS: Forty-five (21 lamotrigine and 24 placebo) patients 2 to 19 years of age were randomly assigned and received study drug. Eight patients (3 lamotrigine and 5 placebo) had a combination of clinical (myoclonus and/or absence seizures) and electroencephalogram findings that were consistent with juvenile myoclonic epilepsy. Among the 45 children randomly assigned, 74% had generalized spike, polyspike, and/or generalized spike and wave discharges on routine electroencephalogram recordings; the remaining 26% of children had no electroencephalogram findings suggestive of partial epilepsy and a clear history consistent with primary generalized tonic-clonic seizures. Electroencephalogram findings were not significantly different between the lamotrigine and the placebo treatment groups. The median percentage decrease from baseline in primary generalized tonic-clonic seizures during the entire treatment period was 77% in the lamotrigine group and 40% in the placebo group (P = .044). The median primary generalized tonic-clonic seizure counts per month were 0.7 in the lamotrigine group and 3.6 in the placebo group during escalation (P = .008), 0.3 in the lamotrigine group and 2.0 in the placebo group during maintenance (P = .005), and 0.4 in the lamotrigine group and 2.5 in the placebo group during the entire treatment period (P = .007). Trends were noted during escalation and maintenance with a median percentage decrease in primary generalized tonic-clonic seizures during escalation of 72% in the lamotrigine group and 30% in the placebo group (P = .059), and 83% in the lamotrigine group and 42% in the placebo group during maintenance (P = .058). During the maintenance phase, 48% of lamotrigine patients were seizure free compared with 17% treated with placebo (P = .051). One patient from each treatment group discontinued from the study because of an adverse event; 1 patient who received lamotrigine experienced "disorientation"; and 1 patient who received placebo had a convulsion with apnea. No rashes occurred among patients taking lamotrigine or placebo. No patient experienced worsening of the intensity or frequency of myoclonus. CONCLUSIONS: Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.

Adolescent↗
PubMed2006

Ellen R. Grass Lecture: Rapid EEG analysis for intensive care decisions in status epilepticus.

Nonconvulsive status epilepticus in intensive care units (ICUs) is common and increases the risk of death. Nonconvulsive status epilepticus treatment delays are associated with poor patient outcomes. Continuous EEG or EEG-video monitoring is used in ICU settings to diagnose subtle seizures and nonconvulsive status epilepticus among at-risk populations including patients with closed head injuries and altered consciousness, stroke, subarachnoid hemorrhage, neonates at-risk for sepsis or hypoxic-ischemic encephalopathy, and children who have undergone surgery for congenital heart disease. However expert EEG interpretation, currently required for accurate diagnosis, often lags behind the real-time recordings by hours or even longer. At most hospitals the numbers of at-risk patients in intensive care units far exceeds the capacity of the available EEG equipment and personnel to perform and interpret EEGs. Seizure-detection software, compressed EEG spectral arrays, and near real-time remote EEG interpretation have brought us closer to the goal of real-time analysis of EEG for intensive care decisions, but even at major tertiary referral centers the vast majority of at-risk ICU patients do not undergo EEG monitoring. Additional technological advances, innovative use of EEG technologists and ICU personnel, and clinical trials of new EEG monitoring technology and associated clinical outcomes are needed to achieve the goal of optimal use of EEG data for intensive care decisions.

Critical Care↗
PubMed2004

Seizures and epilepsy among children with language regression and autistic spectrum disorders.

Clinical and subclinical seizures occur frequently among children with autistic spectrum disorders. Electrographic status epilepticus in sleep, or continuous spike-wave in slow-wave sleep, is a typical feature of acquired epileptic aphasia and Landau-Kleffner syndrome. Seizures and epilepsy are more common among children with autistic spectrum disorder who experience language regression, especially those who experience language regression after the age of 2 years. Although the seizures associated with Landau-Kleffner syndrome and with acquired epileptic aphasia can be easily treated, improvement in language function often does not follow successful treatment of seizures. There are no published randomized clinical trials of treatments for Landau-Kleffner syndrome or for autistic language regression. Broad-spectrum antiepileptic drugs not associated with cognitive slowing are probably the treatment of choice for epilepsy among children with autistic spectrum disorder. Large multisite trials are needed to determine treatment efficacy among children with Landau-Kleffner syndrome and acquired epileptic aphasia and to establish whether there is a cause-effect relationship between electrographic status epilepticus in sleep or continuous spike-wave in slow-wave sleep and autistic language regression.

Anticonvulsants↗
PubMed2003

Antiepileptic drug development for "therapeutic orphans".

Epilepsy is the most common serious neurological disorder among children. Excluding the elderly, the incidence of epilepsy is highest among children. About half of children with epilepsy have epilepsy syndromes that have unique onset in childhood. Clinical drug trials of antiepileptic drugs (AEDs) among children have been primarily performed using drugs developed for the larger adult partial epilepsy market. The current AED drug development system essentially renders children with epilepsy "therapeutic orphans" who can only benefit from AED development if a drug developed for adult partial epilepsy happens to also be effective for a pediatric epilepsy syndrome. The rapid evolution of different seizure types and childhood epilepsy syndromes, and rapid changes in baseline neurological status, make distinguishing clinical changes due to study drugs in clinical trials and the natural history of the epilepsy syndrome difficult. Unique ethical issues (e.g., informed consent), practical and logistical issues (e.g., serum AED level monitoring with microassay methods), as well as major financial and regulatory disincentives for the pharmaceutical industry are additional barriers to need-based AED development for children. A government-funded pediatric epilepsy group or consortium to conduct clinical trials similar to the successful Children's Oncology Group (COG) and regulations plus financial incentives that encourage the pharmaceutical industry to develop AEDs specifically for children are needed.

Anticonvulsants↗
PubMed2002

Infantile spasms and Lennox-Gastaut syndrome.

Infantile spasms and Lennox-Gastaut syndrome are rare but are important to child neurologists because of the intractable nature of the seizures and the serious neurologic comorbidities. New antiepileptic drugs offer more alternatives for treating both infantile spasms and Lennox-Gastaut syndrome. Selected children with infantile spasms are candidates for epilepsy surgery. Vagus nerve stimulation, corpus callosotomy, and the ketogenic diet are all options for selected children with Lennox-Gastaut syndrome. The epidemiology, clinical manifestations of the seizures, electroencephalographic characteristics, prognosis, and treatment options are reviewed for infantile spasms and Lennox-Gastaut syndrome. Additional therapies are needed for both infantile spasms and Lennox-Gastaut syndrome as many children fail to achieve adequate seizure control in spite of newer treatments.

Anticonvulsants↗