Pathophysiology of Stroke-Like Episodes in MELAS: A Possible Role of Neuron-Astrocyte Uncoupling in Cellular Damage during Synaptic Activation under Primary Oxidative Phosphorylation Defect (P01.033)

Abstract

Objective: To speculate the pathophysiological mechanism of stroke-like episodes (SEs) in MELAS based on clinical data and current concept of neuron-astrocyte communications. Background The pathogenesis of SEs remains unknown. We previously reported that SEs are non-ischemic neurovascular events presumably associated with neuronal hyperexcitability (Neurology 2002, Curr Neurovasc Res 2005, Future Neurology 2010), however, the basic molecular mechanism underlying neuronal hyperexcitability remains unknown. It has been demonstrated that astrocytic processes sense synaptic activity and transmit the signals to the arterioles. Astrocytes communicate with a number of neurons or astrocytes by releasing gliotransmitters. Thus, gliotransmitters are considered to control synaptic transmission, neuronal synchrony and neuronal excitability. During synaptic activation, neurons preferentially use lactate which is continuously supplied through astrocyte-neuron lactate shuttle. Design/Methods: Retrospective review of 30 consecutive SEs in 8 patients with MELAS (A3243G (n=7), G13513A (n=1)) who were admitted to our hospital since 1990. Results: Common presenting symptoms included headache, visual symptoms, altered levels of consciousness or seizure, and psychiatric symptoms. Seizure developed during the course of SEs (69%), suggesting sustained neuronal hyperexcitability. SEs were often accompanied by focal hyperperfusion, focal periodic epileptiform discharges, spreading cortical edema and cortical laminar necrosis. Focal lactate accumulation with leptomeningeal vasodilatation was seen at early stage. Calcitonin gene-related peptide (CGRP) was elevated in CSF. Conclusions: SEs are episodic events characterized by neuronal hyperexcitability, increased anaerobic glycolysis, vasogenic edema and vasodilatation. We speculate that 1) sustained astrocyte activation following synaptic activation contributes to focal periodic epileptiform discharges and hyperperfusion, 2) trigeminovascular activation causes headache, 3) limited availability of ATP impairs sodium-dependent glutamate transporter, resulting in decreased clearance of glutamate from the synaptic cleft, 4) low extracellular adenosine level due to decreased ATP production may cause disinhibition of synaptic activity, and 5) sustained release of lactate from activated astrocytes potentially abort glycolytic pathway. Neuron-astrocyte uncoupling may contribute to cellular damage during SEs. Disclosure: Dr. Iizuka has nothing to disclose. Dr. Hamada has nothing to disclose. Dr. Sakai has nothing to disclose.