Unexpected pain with electrocortical stimulation in a teenager with temporal encephalocele.

Temporal lobe encephalocele has emerged as a potentially unrecognized cause of drug-resistant temporal lobe epilepsy (TLE) that can be effectively treated with epilepsy surgery. Here we present a case in which a 17-year-old male with drug-resistant epilepsy and left temporal encephalocele underwent workup for epilepsy surgery, and experienced unexpected pain with electrocortical stimulation. Stimulation of stereo-EEG electrodes in the left temporal pole resulted in severe, unilateral left-sided facial pain due to inadvertent stimulation of the trigeminal nerve. Stereo-EEG showed seizure onset adjacent to encephalocele with no involvement of mesial temporal structures. A temporal pole resection sparing the mesial temporal structures and repair of the sphenoid bone defect was performed. The patient experienced post-operative seizure freedom, with no loss of language function or sensory deficits in the distribution of the trigeminal nerve. This case highlights temporal encephalocele as a potentially overlooked cause of TLE and underscores the anatomical proximity of the trigeminal nerve to the temporal pole, an important consideration for surgical planning.

Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder.

At neuronal synapses, synaptotagmin-1 (syt1) acts as a Ca2+ sensor that synchronizes neurotransmitter release with Ca2+ influx during action potential firing. Heterozygous missense mutations in syt1 have recently been associated with a severe but heterogeneous developmental syndrome, termed syt1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, we report the clinical, physiological, and biophysical characterization of three syt1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca2+-sensing domains of syt1. These mechanistic studies led to the discovery that a clinically approved K+ channel antagonist is able to rescue the dominant-negative heterozygous phenotype. Our results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for syt1-associated neurodevelopmental disorder.

Modeling pathogenesis and treatment response in childhood absence epilepsy.

OBJECTIVE: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. METHODS: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. RESULTS: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. SIGNIFICANCE: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.