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Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a distinct clinical syndrome caused by mutations in mitochondrial DNA. Crucial molecular mechanism includes a lack of taurine modification at the wobble uridine of the mutant tRNA(Leu(UUR)), causing UUG condon-specific translational defect and mitochondrial protein synthesis failure. However, the pathogenesis of stroke-like episodes remains unknown. We previously reported that stroke-like episodes were more likely non-ischemic events, characterized by increased capillary permeability, hyperperfusion, neuronal vulnerability and neuronal hyperexcitability, in which neuronal hyperexcitability plays an important role in initiation of the cascades of stroke-like events by increasing energy demand. We also emphasized a role of prolonged epileptic activities in progressive spread of stroke-like lesions, and then proposed a non-ischemic neurovascular cellular mechanism. Once neuronal hyperexcitability developed in a localized region as a result from either mitochondrial dysfunction in capillary endothelial cells, or in neurons or astrocytes, epileptic activities depolarize adjacent neurons, leading to propagation of epileptic activities in surrounding cortex. Increased capillary permeability in the presence of mitochondrial capillary angiopathy may cause unique edematous lesions predominantly involving the cortex. As a consequence, most susceptible layers of the cortex may result in neuronal loss. Therapeutic targets include each ongoing process of the disease.

We encountered an 11-year-old girl with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who developed occipital lobe epilepsy at the age of 7 years and 4 months. Thereafter she had repeated status epilepticus associated with stroke-like episodes. Status epilepticus consisted of repetitive complex partial seizures with or without secondarily generalized tonic clonic seizures. The seizures did not respond to conventional anticonvulsive drugs, including diazepam, midazolam, phenytoin, lidocaine, chloral hydrate, and thiamylal sodium, and lasted for several hours (mean 9.5 hours). At the age of 11 years, intravenous infusion of L-arginine (0.5 g/kg body weight) was first given five hours after the onset of status epilepticus. The seizures and electroencephalographic abnormalities improved dramatically. After the introduction of L-arginine, in addition to shortened duration of status epilepticus (mean 3 hours), clinical recovery from the status epilepticus was prompt, and the average hospitalization periods could be shortened. There were no obvious adverse effects, including vomiting, hypotension, and urticaria. Our experience suggests that early intravenous administration of L-arginine may be useful in the treatment of status epilepticus associated with stroke-like episode in patients with MELAS.

A 55-year-old woman, who had two episodes of difficulty in putting a key into a keyhole probably due to optic ataxia at age 52 and 54 years old, developed speaking errors and was admitted to our hospital. She was 152.5 cm in height and 52.5 kg in weight. Neurological examination revealed right homonymous hemianopsia and sensory aphasia. A CSF examination revealed lymphocytic pleocytosis of 88/microliter. Serum lactate and pyruvate were remarkably increased after an aerobic exercise test. A few ragged-red fibers were present in the biopsied brachial biceps muscle. Brain MRI by FLAIR method showed scattered high signal lesions in the left temporal lobe, bilateral parieto-occipital lobes, left insular cortex and left thalamus. The left superficial temporal lesion was enhanced by gadolinium-DTPA. The proton MRS demonstrated the lactic acid peak as well as the decrease of NAA/choline ratio (0.38) in the left parieto-occipital region. Thus, she was diagnosed as a case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and successfully treated with ubidecarenone (150 mg/day). Six months later, she again developed seizure, right hemiparesis and deterioration of aphasia and presented again CSF lymphocytic pleocytoses of 15/microliter. Brain MRI demonstrated new lesions in the left temporoparietal lobes, left insular cortex and left corona radiata. Therefore, CSF pleocytosis appeared to be associated with stroke-like episodes in this case. Although the mechanism of CSF pleocytosis remains to be elucidated, it may involve the breakdown of blood-brain barrier caused by mitochondrial dysfunction. Otherwise, an inflammatory process similar to that in cases of Leber disease, who developed multiple sclerosis-like additional lesions in the central nervous system, may also take place in MELAS.

A 39-year-old man with cardiomyopathy due to point mutation of mitochondrial DNA(3243) was admitted to our hospital because of exertional dyspnea accompanied by hearing disturbance and diabetes mellitus. Echocardiography revealed asymmetric hypertrophy of the anterolateral and posterior walls and systolic dysfunction of the left ventricle (fractional shortening = 18%). Pulsed Doppler mitral inflow velocity wave showed a pseudonormalized pattern. Iodine-123 betamethyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) myocardial scintigraphy showed decreased accumulation in the anterolateral, posterior, and apical walls. Left ventriculography showed moderately decreased ejection fraction (43%), and left ventricular end-diastolic pressure was mildly elevated (18 mmHg). Angiography showed normal coronary arteries, but coronary flow reserve measured by administering intravenous adenosine triphosphate was impaired in the left anterior descending and left circumflex arteries compared to the right coronary artery. Intracellular accumulations of abnormal mitochondria were detected by histologic examination of the cardiac and skeletal muscles. Evaluation of cardiac function showed that the area of myocardial hypertrophy was nearly consistent with the region of decrease in 123I-BMIPP accumulation and coronary flow reserve.

We report a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with prosopagnosia, topographical disorientation, and periodic lateralized epileptiform discharge (PLED) on electroencephalography (EEG) in a 23-year-old right-handed man. The first MELAS attack occurred on March 1, 1991, while the patient was drinking. Magnetic resonance imaging (MRI) revealed a lesion of abnormal intensity in the left occipital lobe. The second attack occurred on October 1, 1991. This time, the major symptoms were visual loss of acute onset, nausea, and vomiting. EEG examination showed transient PLED. MRI revealed a new area of abnormal intensity in the right occipital lobe, lingual gyrus, fusiform gyrus and the posterior part of the parahippocampal gyrus. During the clinical course of the patient, prosopagnosia and topographical disorientation appeared. There have been few reports of MELAS associated with prosopagnosia, topographical disorientation, and PLED. However, MELAS attacks tend to occur in the cortex of the occipital lobe. We therefore believe that these neuropsychological symptoms and PLED are likely to be associated with MELAS.

A 9-year-old girl was admitted to our hospital because of fever, headache, vomiting, and convulsive seizures. On admission, she was proved to have homonymous hemianopsia as well as elevated lactate and pyruvate levels in both serum and cerebrospinal fluid. Muscle biopsy study showed scattered ragged-red fibers and strongly succinatedehydrogenase-reactive blood vessels (SSV), suggesting systemic vascular involvement. She had a point mutation at nucleotide pair 3,243 in mitochondrial DNA extracted from muscle and blood samples. Brain CT and MRI showed a large abnormal area mimicking cerebral infarction in the region of the occipital cerebral artery. The cerebral lesion was assumed to be caused by vascular abnormality because of delayed and decreased cerebral blood flow together with vascular changes in her muscle biopsy.

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is one of the clinically-defined mitochondrial diseases, characterized by early onset and stroke-like symptoms. A point mutation at nucleotide pair 3243 within the tRNA-Leu (UUR) gene is found in 80% of MELAS patients and another mutation at nucleotide pair 3271 in 10%. In vitro and in vivo expression studies on 3243 mutant genome show that it affects both the transfer RNA and transcription termination functionally. By virtue of further analyses on relationship between the mutations and phenotypes, a new approach to deal with the disease could be obtainable.