Different hypotheses have been proposed to explain these findings. According to the mitochondrial angiopathy hypothesis, lesions are ischemic in nature and are caused by cerebral small-vessel mitochondrial and vascular dysfunction.26 However, perfusion MRI, positron emission tomography, and single-photon emission computed tomography studies of patients with MELAS have shown evidence of hyperemia, and MRI studies usually do not show cytotoxic edema typically seen in brain ischemia.27 Alternatively, a mitochondrial-mediated cytopathic mechanism has been proposed. The transfer RNA of leucine mtDNA mutation decreases protein synthesis and causes oxidative phosphorylation failure, leading ultimately to adenosine triphosphate depletion and energy failure. Sano et al28 have provided support for this hypothesis by showing decreased cerebral metabolic rate for oxygen and decreased cerebral oxygen/glucose metabolic ratio. These results are consistent with preserved cerebral perfusion and failure of oxidative phosphorylation.28 In addition, combining the results obtained using MRI, MR spectroscopy, and MR perfusion imaging, Ito et al27 showed that strokelike episodes are related to vasogenic edema, hyperperfusion, and neuronal loss implicating cytopathic toxicity secondary to energy imbalance.