Steroid responsive A3243G mutation MELAS: clinical and radiographic evidence for regional hyperperfusion leading to neuronal loss

Abstract

Introduction: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem disorder caused by systemic cellular metabolic derangement that is characterized predominantly by rapidly progressive deterioration of the central nervous system.

Case report: We describe a patient with an abrupt onset of rapidly recurring episodes of aphasia, hemianopsia, and parietal pseudocerebellar ataxia, leading to the diagnosis of A3243G mutation MELAS. These stroke-like episodes appeared to be initiated by metabolic derangement, as evidenced by lactic-acid elevation in the cerebral spinal fluid and lactate peaks observed on magnetic resonance spectroscopy. Magnetic resonance imaging further revealed that neuronal loss during the acute episodes occurred in regions of paradoxically increased cerebral blood flow. Diffusion-tensor and arterial-spin-labeled perfusion imaging showed that the volume of tissue loss after the stroke-like episodes greatly exceeded the limits of the cortical areas affected by the initial metabolic insult. The patient was consented to a trial of compassionate use, high-dose intravenous corticosteroids, resulting in marked and sustained clinical improvement.

Conclusions: The majority of neurons lost in an acute episode are injured not by a primary failure to meet metabolic demand, but by a poorly regulated compensatory hyperperfusion response. Regional hyperperfusion leads to apoptotic cell death through a progression from vasogenic to cytotoxic edema. The efficacy of corticosteroids in our study patient demonstrates that inflammatory mediators and blood-brain barrier dysfunction may play a role in the pathophysiological cascade that leads to the regional hyperperfusion in MELAS.