mitochondrial myopathy , encephalopathy , lactic acidosis , and stroke - like episodes ( melas ) syndrome is a multi - system mitochondrial disorder characterized by stroke - like episodes with various combinations of additional symptoms . the diagnosis of melas is usually based on characteristic symptoms such as lactic acidosis , deafness , diabetes mellitus , short stature , myopathy , and cognitive decline , often with a family history showing maternal inheritance . we herein report an unusual case of melas - like encephalopathy with isolated recurrent stroke - like episodes in adulthood . the diagnosis in this case was supported by the detection of a mitochondrial mt - nd3 gene mutation . the patient was a 41-year - old man who had experienced generalized convulsions , insomnia , and depression since 20 years of age . he had been diagnosed with ischemic stroke at 33 years of age and epileptic seizure with epileptic encephalopathy at 37 years of age . he had no other systemic signs of mitochondrial disorder , such as short stature , diabetes mellitus , deafness or heart failure . he developed myoclonus in the distal extremities , gait disturbance , and dysarthria at 41 years of age . three months later , he was admitted to our hospital due to impaired consciousness and vomiting . a neurological examination showed gaze nystagmus , cerebellar ataxia , and myoclonic movement in his distal extremities . his mini - mental status examination score was 15/30 , and his frontal assessment battery score was 5/18 . a laboratory examination showed slightly increased serum pyruvic acid levels ( 1.2 mg / dl ) , but his serum lactate levels were normal ( 14.2 mg / dl ) . the cerebrospinal fluid lactate ( 34.8 mg / dl ) and pyruvic acid ( 1.6 mg / dl ) levels were elevated . brain magnetic resonance imaging ( mri ) showed bilateral cortical and subcortical high - intensity lesions on t2-weighted imaging ( t2wi ) and fluid attenuated inversion recovery ( flair ) , distributed bilaterally and almost symmetrically . bilateral red nuclei , mesencephalic tectum , vermis and cerebellar flocculus were also involved ( fig . some of the cortical and subcortical lesions gave a high signal on diffusion - weighted imaging ( dwi ) ( fig . these lesions appeared as high or iso signal intensity on the apparent diffusion coefficient ( adc ) map . ( a , c ) axial and coronal flair brain mri images showing cortical and subcortical high - intensity lesions distributed bilaterally and almost symmetrically . ( b ) some of the cortical and subcortical lesions gave a high signal on diffusion - weighted imaging . ( d ) a large lactate doublet ( arrow ) was identified on mrs centered in the lesion . ( e ) tc - ethylcysteinate dimer spect imaging revealed a bilateral multifocal increase in the perfusion of the cortical lesions . ( f ) a histopathological study of the biopsied muscle showed no myopathic changes or ragged red fibers on hematoxylin and eosin staining and gomori trichrome staining . a heteroplasmic substitution ( m.10158t > c ) was found in the mt - nd3 gene ( arrow ) . two weeks later , the high signal on dwi had diminished , and four weeks later , the high signal on t2wi and flair had diminished ( fig . h - mrs revealed elevated lactate concentrations in the lesions ( fig . 1d ) . tc - ethylcysteinate dimer single photon emission computed tomography ( spect ) imaging revealed bilateral multifocal increase of perfusion in the mri lesions ( fig . a histopathological study of the biopsied right biceps branchii muscle revealed mild variation in the fiber size , measuring from 30 to 90 microns in diameter , which was thought to be a non - specific change . no necrotic or regenerating fibers were seen . on modified gomori - trichrome stain , ragged red fibers ( rrfs ) were not observed . however , the complete sequencing of mitochondrial dna samples extracted from the biopsied muscle revealed a heteroplasmic m.10158t > c mutation , with a level of mutant heteroplasmy of 69.5% , in the mitochondrial complex i subunit gene , mt - nd3 ( fig . brain mri of dwi ( upper ) , adc map ( middle ) , and flair ( bottom ) images are shown . because his family had no clinical symptoms suggestive of mitochondrial diseases , we could not conduct a complete mtdna sequence analysis of his family . over a two - month period , he experienced two stroke - like episodes with simple partial seizure and vomiting . each time the stroke - like episodes ended within four days with drip infusion of edaravone and supportive care . to control epileptic seizure , we added levetiracetam ( 1,000 mg / day ) to zonisamide ( 400 mg / day ) and carbamazepine ( 400 mg / day ) . because he had not yet been diagnosed with melas - like encephalopathy at that time we herein report an unusual adult case of melas - like encephalopathy where the diagnosis was delayed because the adult - onset isolated stroke - like episodes were not accompanied with a family history showing either maternal inheritance or symptoms such as deafness , diabetes mellitus , heart failure , short stature , myopathy , or mental retardation . in addition , a histopathological study of the biopsied muscle revealed no myopathic features or rrfs . however , a sequence analysis of the mitochondrial genome extracted from the biopsied muscle revealed a heteroplasmic m.10158t > c mutation in the mitochondrial complex i subunit gene , mt - nd3 . stroke - like lesions may evolve subacutely over hours to days but have greater potential for reversibility than actual strokes . recent studies have demonstrated a beneficial effect of l - arginine in melas for the acute treatment and prevention of stroke - like episodes ( 1 ) . indeed , we previously reported a woman harboring a m.10158t > c mutation who was successfully treated with l - arginine and anti - epileptic agents ( 2 ) ( table ) . she developed right - side hemianopia and motor aphasia at 63 years of age , which was her first stroke - like episode . her aphasia worsened with each episode but completely recovered to baseline with radiological improvement following treatment with high - dose l - arginine in each acute phase . at the three - year follow - up , she had no neurological deficit except for minimal word - finding difficulties and appeared otherwise healthy . these features are clearly different from the progressive nature of melas and may be due to the lack of multi - systemic features in melas . dwi : diffusion weighted image , adc : apparent diffusion coefficient , flair : fluid - attenuated inversion recovery , t2wi : t2 weighted image , rrf : ragged - red fibers , ssv : sdh - reactive blood vessels , cbz : carbamazepine , zns : zonisamide , lev : levetiracetam , pht : phenytoin , clb : clobazam , vit : vitamin this lack of multi - systemic features in melas and the atypical brain mri findings in the present case resulted in a delayed diagnosis . he was not developmentally disabled and had been healthy until he developed insomnia and depression at 20 years of age . when he was admitted to our hospital at 41 years of age , he was suffering from higher brain dysfunction . his higher brain functions and neurological manifestations worsened with each stroke - like episode , resulting in serious physical and cognitive sequelae . on comparing these two adult - onset cases harboring m.10158t > c , the early diagnosis and treatment for  mitochondrial stroke - like episodes , especially l - arginine therapy , may help prevent further deterioration , particularly of the higher brain function . the m.10158t > c mutation , which is known to cause lethal infant - onset leigh syndrome , is located within the coding region of the loop domain of the nd3 subunit protein . the m.10158t > c mutation has been reported to decrease complex i activity to 8 - 23% of that of controls ( 3,4 ) . the common clinical features related to the m.10158t > c mutation in a total of 10 patients , including our 2 adult - onset cases as well as previously described infant and pediatric patients , are a relatively high rate of sporadic occurrence , selective vulnerability of the central nervous system ( cns ) , no myopathic findings , and no rrfs or cytochrome c oxidase ( cox)-defective fibers , even in patients with relatively high mutation loads ( 2 - 7 ) . the mutation load has been reported to vary among patients and specimens : muscle , blood , hair and fibroblasts . all of the patients showed a higher mutation load in the muscles ( 73 - 100% ) and a lower load in the blood ( 0 - 48% ) ( 3 - 7 ) . therefore , to detect diagnostic pathogenic mutations , not only blood but also biopsied muscle should be analyzed . such heteroplasmy may account for the differences in the phenotypical expression , as patients harboring m.10158t > c mutation appear not to have non - neurological symptoms or relevant family history . despite the high mutation loads ( from 70% to more than 98% ) , a histological analysis of the biopsied muscle revealed no specific findings in the present or previous adult cases or in the previously reported infant harboring the m.10158t > c mutation ( 3 - 7 ) . rrfs have been found in up to 90% of melas patients , which is thought to be the histological hallmark of melas ( 8) . a higher proportion of heteroplasmic mitochondrial dna mutation was reported to be associated with rrfs , based on an analysis of patients with different large mitochondrial dna deletions and melas patients with the m.3243a > g point mutation ( 9 ) . in addition to the m.10158t > c mutation , the m.10191t > c as well as m.10197g > a mutations are located in the matrix - loop domain of the nd3 subunit protein and are known to cause leigh syndrome or leigh - like syndrome with dystonia , respectively ( 6,10 - 12 ) . patients aged 16 , 25 , and 52 years harboring 73% , 70% , and 77% m.10191t > c mutation in muscle ( 6,10,11 ) and 9-month - old and 37-year - old patients harboring 100% and 97% m.10197g > a mutation ( 12 ) were found to have no rrfs , although all of these patients who underwent an analysis of mitochondrial respiratory chain activities in muscle showed a specific defect in the activity of complex i. it seems to be unlikely that the pathological analysis of the muscle was conducted too early to show any pathological changes . thus , the absence of any pathological changes in the biopsied muscles despite a high mutation load and the predominance of cns manifestations might be common among patients harboring pathogenic mutations in the nd3 gene . although l - arginine has emerged as an effective treatment of stroke - like episodes in melas , the unique manifestation of adult - onset , isolated mitochondrial stroke - like episodes in our patients could be easily misdiagnosed , resulting in serious sequelae . mitochondrial dna analyses using biopsied muscle should be considered in patients with suspected stroke - like episodes , even if the muscle pathology shows a normal appearance .
the clinical features of mitochondrial myopathy , encephalopathy , lactic acidosis , and stroke - like episodes ( melas ) are not uniform . 
 we herein report a male patient with unusual melas - like encephalopathy who had been experiencing isolated recurrent stroke - like episodes since he was 33 years old without any particular family history . despite an extensive investigation , he had no other signs suggestive of melas . 
 although the muscle pathology showed a normal appearance , a mitochondrial genome sequence analysis of the biopsied muscle revealed a heteroplasmic m.10158t > c mutation in the mitochondrial complex i subunit gene , mt - nd3 . 
 to prevented further deterioration of the higher brain function , the early diagnosis and treatment of mitochondrial stroke - like episodes is important .