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Purpose Magnetic resonance spectroscopy (MRS) is a diagnostic tool used to detect abnormal accumulation of lactate in the brain parenchyma in various metabolic diseases. This study evaluated the clinical roles of brain MRS in the initial assessment of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by impairment of the mitochondrial respiratory chain. Methods Twenty-five patients with the A3243G mutation among 34 MELAS patients referred to the pediatric neurology clinic of Gangnam Severance Hospital between January 2006 and December 2020 were included. In this retrospective study, demographic, clinical, laboratory (serum lactate and lactate-to-pyruvate ratio), magnetic resonance imaging (MRI), and initial MRS (presence of lactate peak and abnormal N-acetylaspartate [NAA]) data were reviewed. Results Brain MRI showed cortical lesions in 24 of 25 genetically confirmed A3243G MELAS patients with neurologic symptoms in this study. On MRS, 18 patients (72%) had increased lactate peaks, depicting anaerobic energy metabolism, and 17 patients (68%) had decreased NAA levels, indicating neuronal integrity. Ten patients underwent MRS in the acute stage (within 2 weeks of symptoms). Unlike patients who underwent MRS more than 2 weeks after symptom onset, a lactate peak on MRS was observed in all patients in the acute stage (P=0.011). Conclusion Elevated lactate peaks in acute cerebral infarctions are highly suggestive of mitochondrial encephalopathy. MRS alone is insufficient to diagnose MELAS, but it is valuable as a noninvasive supplemental diagnostic tool in combination with genetic testing.

Mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) is a multisystem mitochondrial disorder that is rarely observed in adulthood. We report a case of MELAS syndrome diagnosed in a 22-year-old man presented with status epilepticus (SE) without a preceding stroke-like episode. Genetic testing revealed a mutation of heteroplasmic m.3243A>G. MELAS should be suspected in patients with recurrent, uncontrolled SE with unexplained severe lactic acidosis.

BACKGROUND Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare maternally inherited genetic disease; however, little is known about its underlying brain basis. Furthermore, the dynamic functional connectivity (dFC) of brain networks in MELAS has not been explored. PURPOSE To investigate the abnormalities of dFC in patients with MELAS at the acute and chronic stages, and to determine the possible relations between dynamic connectivity alterations and volumes of stroke-like lesions (SLLs). STUDY TYPE Prospective. SUBJECTS Twenty-two MELAS patients at the acute stage, 23 MELAS patients at the chronic stage, and 22 healthy controls. FIELD STRENGTH/SEQUENCE Single-shot gradient-recalled echo planar imaging (EPI) sequence at 3T. ASSESSMENT Dynamic FC states were estimated using the sliding window approach and k-means clustering analyses. Combined with graph theory, the topological properties of the dFC network were also accessed. STATISTICAL TESTS Permutation test, Pearson correlation coefficient, and false discovery rate correction. RESULTS We identified four dFC states and found that MELAS patients (especially at the acute stage) spent more time in a state with weaker connectivity (state 1) and less time in states with stronger connectivity. In addition, volumes of acute SLLs were positively correlated with mean dwell time in state 1 (r = 0.539, P

Metabolic encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is characterized by encephalopathy mimicking acute stroke, which is rarely observed in adulthood. We present a case of a female who presented with several neurologic deficits and diagnosed with MELAS syndrome. Brain magnetic resonance imaging (MRI) showed acute lesions mimicking stroke, which were not compatible with specific vascular territories. Magnetic resonance spectroscopy showed lactate peaks in both symptomatic and asymptomatic area. Single proton emission computed tomography (SPECT) shows hyperperfusion in the same area. On follow-up image, MRI lesion nearly disappeared and hyperperfusion on SPECT changed into hypoperfusion. We discuss the clinical characteristics and image findings of our patient.

Objective: To investigate the clinical features and imaging characteristics of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).Methods: Seventeen patients wi...

Purpose of review We would like to inform clinicians that the systematic administration of oral and intravenous l-arginine is therapeutically beneficial and clinically useful for patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), when they maintain plasma arginine concentration at least 168 μmol/l. Recent findings MELAS is associated with endothelial dysfunction by decreased plasma l-arginine, nitric oxide (NO), and cyclic guanosine monophosphate. Endothelial dysfunction is also evident using flow-mediated vasodilation measurement by high-resolution Doppler echocardiography in the forearm artery in patients with MELAS. l-arginine is known to be an important precursor of NO to normalize the endothelial function in MELAS. In our clinical trial followed by 7 years follow-up study, the systematic administration of l-arginine to patients with MELAS significantly improved the survival curve of patients compared with natural history. Maintaining plasma arginine concentration at least 168 μmol/l may prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction. Summary Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. Therapeutic regimen of l-arginine on MELAS may be beneficial and clinically useful for patient care with MELAS.

Case report : A 30-year-old woman with a history of bilateral sensorineural deafness since the age of 14 years, a right occipital ischemic stroke with left hemianopia and epilepsy was admitted to the neurology department with speech disorders and a new epileptic insult. MRI revealed extensive cytotoxic edema of the left temporo–parieto–occipital cortex and mirrored right-sided sequelae (Fig. 1a, b). MR-angiography and MR-venography (not shown) were normal. [...]

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized by its genetic, biochemical and clinical complexity. The most common mutation associated with MELAS syndrome is the mtDNA A3243G mutation in the MT-TL1 gene encoding the mitochondrial tRNA-leu(UUR), which results in impaired mitochondrial translation and protein synthesis involving the mitochondrial electron transport chain complex subunits, leading to impaired mitochondrial energy production. Angiopathy, either alone or in combination with nitric oxide (NO) deficiency, further contributes to multi-organ involvement in MELAS syndrome. Management for MELAS syndrome is amostly symptomatic multidisciplinary approach. In this article, we review the clinical presentations, pathogenic mechanisms and options for management of MELAS syndrome.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a complicated maternally inherited disorder lacking of sensitive and specific biomarkers. The objective of this study was to investigate the serum neurofilament light chain (NfL) as a novel biomarker of neurological dysfunction in MELAS. Patients with different status of MELAS were enrolled in this study. The Mini-Mental State Examination (MMSE) was given to the participants to evaluate cognition status. Multiple functional MRI was performed on the participants. Blood samples were collected and the serum NfL concentrations were determined by the single-molecule array technology (Simoa). This study enrolled 23 patients with MELAS, 15 people in the acute attack phase of MELAS and 10 people in the remission phase, including 2 patients in both acute attack and remission phase. Sixteen healthy controls (HCs) were also enrolled. Serum NfL level increased significantly in patients with MELAS. Serum NfL level in the acute attack group (146.73 [120.91-411.31] pg/ml, median [IQR]) was higher than in the remission group (40.31 [19.54-151.05] pg/ml, median [IQR]) and HCs group (7.70 [6.13-9.78] pg/ml, median [IQR]) (p 0.05). The level of NfL in the remission phase group was higher than in HCs group (p 0.05). A negative correlation was found between the serum NfL level and MMSE (p = 0.006, r = -0.650). The NfL concentration correlated positively with stroke-like lesion volume in the brain (r = 0.740, p 0.001). Serum NfL may serve as a novel biomarker for the neurological dysfunction in MELAS patients.

Ein 16-jahriges bisher unauffalliges Madchen wird nach einer vermeintlichen erneuten Hyperventilationsepisode vorgestellt. Laborchemisch zeigen sich eine Laktacidose, Hepatopathie, Rhabdomyolyse und Kardiomyopathie. In der erweiterten Stoffwechseldiagnostik deutliche Hinweise auf eine Storung des Energiestoffwechsels. In der genetischen Diagnostik findet sich eine Mutation im mitochondrialen Genom (MT-TL1). Die Diagnose eines MELAS (Mitochondriale Enzephalomyopathie, Laktatazidose schlaganfallahnliche Episoden) wird gestellt. Entsprechend wird aus Mangel einer kausalen Behandlung eine supportive Therapie initiiert. Die weitere Prognose bleibt unklar.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a complicated maternally inherited disorder lacking of sensitive and specific biomarkers. The objective of this study was to investigate the serum neurofilament light chain (NfL) as a novel biomarker of neurological dysfunction in MELAS. Patients with different status of MELAS were enrolled in this study. The Mini-Mental State Examination (MMSE) was given to the participants to evaluate cognition status. Multiple functional MRI was performed on the participants. Blood samples were collected and the serum NfL concentrations were determined by the single-molecule array technology (Simoa). This study enrolled 23 patients with MELAS, 15 people in the acute attack phase of MELAS and 10 people in the remission phase, including 2 patients in both acute attack and remission phase. Sixteen healthy controls (HCs) were also enrolled. Serum NfL level increased significantly in patients with MELAS. Serum NfL level in the acute attack group (146.73 [120.91–411.31] pg/ml, median [IQR]) was higher than in the remission group (40.31 [19.54–151.05] pg/ml, median [IQR]) and HCs group (7.70 [6.13–9.78] pg/ml, median [IQR]) (p

Optical coherence tomography (OCT) is an imaging technique used to obtain three-dimensional information on the retina. In this article, we evaluated the structural neuro-retinal abnormalities, especially the thickness in the ganglion cell complex (GCC), in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The GCC thickness in MELAS patients was significantly thinner than that in normal controls even when they had no history of transient homonymous hemianopia. There was a negative correlation between GCC thickness and disease duration. In conclusion, OCT may be an effective tool to monitor and predict disease progression in MELAS patients.

BACKGROUND AND PURPOSE: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder affecting children and young adults. Stroke-like episodes are often associated with acute cortical lesions in the posterior cerebral cortex and are classically described as asymmetric and transient. In this study we assessed the anatomic distribution of acute cortical lesions, the incidence of symmetry, and the temporal evolution of lesions. MATERIALS AND METHODS: This was a retrospective cohort study of patients who had a confirmed genetic diagnosis of a pathogenic variant associated with MELAS and MR imaging performed at our center (2006–2018). Each MR imaging study was assessed for new lesions using T1, T2, FLAIR, DWI, ADC, and SWI. The anatomic location, symmetry, and temporal evolution of lesions were analyzed. RESULTS: Eight patients with the same pathogenic variant of MELAS (MT-TL1 m.3243A>G) with 31 MR imaging studies were included. Forty-one new lesions were identified in 17 of the studies (5 deep, 36 cortical). Cortical lesions most commonly affected the primary visual cortex, the middle-third of the primary somatosensory cortex, and the primary auditory cortex. Thirty of 36 cortical lesions had acute cortical diffusion restriction, of which 21 developed cortical laminar necrosis on subacute imaging. Six of 11 studies with multiple lesions showed symmetric cortical involvement. CONCLUSIONS: Acute cortical lesions in MELAS most commonly affect the primary visual, somatosensory, and auditory cortices, all regions of high neuronal density and metabolic demand. The most common pattern of temporal evolution is acute cortical diffusion restriction with subacute cortical laminar necrosis and chronic volume loss. Symmetric involvement is more common than previously described.

To compare the utility and limitation of magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL) in the differentiation between mitochondrial encephalomyopathy, lactic acidosis, plus stroke-like episodes (MELAS) and acute ischemic stroke (AIS), a retrospective review of 17 MELAS and 26 AIS patients were performed. In all patients both MRS and ASL scans were performed within 1 week after admission. Demographic, clinical, laboratory and MR imaging data were reviewed and compared between the two groups. Compared with AIS, MELAS patients had a younger age of onset, a longer disease duration, a higher occurrence of epilepsy attack, occipital and parietal lesions, and dilated cerebral arteries (P 0.05). In all MELAS patients lactate peak and hyperperfusion of the lesion was revealed. However in AIS lactate peak was observed in only 69.2% and hyperperfusion was observed in only 34.6% ischemic lesions (P 0.05). Choline/Creatine ratios and Lactate/Creatine ratios were higher in AIS, while in MELAS cerebral blood flow and lesion-normal perfusion ratio was much higher (P 0.05). No correlations was found between metabolite ratios and perfusion parameters in either group (P 0.05). Area under curve (AUC) of perfusion for the differentiation between MELAS and AIS was 0.958 (P 0.001). The cut-off value was 2.075, with a sensitivity of 88.2% and a specificity of 96.2%. AUC of Lactate/Creatine ratio was 0.469 (P = 0.737). Utility of MRS is limited in the differentiation between MELAS and AIS, while MR perfusion profiles are much more sensitive and specific.

Purposes The aims of the study were to analyze the conventional and diffusion-weighted MRI (DWI) of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and to investigate underlying mechanisms. Methods Features of 58 acute and 68 chronic stroke-like lesions as well as global brain abnormalities of 40 Chinese MELAS patients were analyzed. Results Gyriform DWI hyperintensity with decreased apparent diffusion coefficient (ADC) and patchy DWI hyperintensity with normal ADC were noted in 56 of 58 and 2 of 58 cortical regions of acute lesions, respectively. High ADC and mix of low and high ADC were observed in 51 of 58 and 5 of 58 affected subcortical white matters, respectively. Lacunar infarcts existed in 23 of 40 patients. Among 17 patients who have been followed, recurrence, progression, and progressive atrophy were noted in 8, 9, and 4 cases, respectively. Conclusions This study demonstrates the conventional and diffusional MRI features of MELAS, suggesting a model of acute stroke-like lesions in which the cortex manifest with cytotoxic edema and the subcortical area with vasogenic edema.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder that usually presents in childhood. Patients can have a wide array of neurological symptoms when presenting with stroke-like episodes, and imaging characteristics during the episodes can overlap with different neurological disorders.A 61-year-old woman presented with communication difficulties consistent with auditory agnosia and was found to have bitemporal abnormalities on imaging that first raised the concern for herpes simplex virus encephalitis. Further work-up, in conjunction with the patient's past medical and family history, suggested a mitochondrial disorder. Mitochondrial full genome analysis revealed m.3243AG variant in the MT-TL1 gene, with 6% heteroplasmy in blood leading to a diagnosis of MELAS.MELAS is a disorder with clinical variability. Neuroimaging studies during stroke-like episodes in MELAS can provide significant clues to the underlying disorder. Although patients typically present in childhood, the first stroke-like episode can occur later in life in some patients, potentially related to a lower heteroplasmy level.

We report a case of an asymptomatic 40-year-old African American male who was referred to our clinic for evaluation of bilateral macular drusen. Medical history was remarkable only for diabetes mellitus type 1. Fundoscopy revealed a peculiar, bilateral pigmentary maculopathy. Further imaging included autofluorescence imaging that showed an irregular hypo- and hyperautofluorescent pattern consistent with severe retinal pigment epithelial (RPE) dysfunction. Optical coherence tomography supported outer retinal layer loss and RPE atrophy. Fluorescein angiography and electroretinography were also performed. Further discussion with the patient yielded a family history where 4 older siblings died in their teenage years from strokes and seizures. The patient was referred to a geneticist who ultimately diagnosed him with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and genetic testing of his mitochondrial deoxyribonucleic acid identified an A3234G point mutation in the MT-TL1 gene.

•The pathophysiology of the stroke-like episodes of MELAS has not completely been elucidated.•Here we report a case of stroke-like episodes, successfully treated with levetiracetam.•Neuronal hyperexcitability can be the underlying mechanism of stroke-like episodes in MELAS.

The paper describes a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). The features of the course and therapy of epilepsy in MELAS are discussed. The disease is known for its late diagnosis when years elapse from the onset of the clinical manifestations to diagnosis. The paper presents clinical criteria for the diagnosis of MELAS and the specific features of brain neuroimaging changes that allow identification of the disease at an early stage.

Purpose Stroke-like episodes (SLEs) are a hallmark of various mitochondrial disorders, in particular MELAS syndrome. SLEs manifest with vasogenic oedema (DWI and ADC hyperintensity) or partial cytotoxic oedema (DWI hyperintensity, ADC hypointensity) in the acute and subacute stage, and with gyriform T1-hyperintensity (cortical necrosis) in the chronic stage. Principal results SLEs must be clearly distinguished from ischaemic stroke, since management of these two entities is different. SLEs may go along with or without seizures or epileptiform discharges on EEG. However, in MELAS syndrome seizures may also occur in the absence of SLEs. Focal and generalised seizures have been reported but it is currently unknown if the one or the other prevail. SLEs with and without seizures may respond to NO-precursors l-arginine, succinate, or citrulline. As a supportive measure a ketogenic diet should be initiated. Seizures prior to or during a SLE or paroxysmal EEG-activity during a SLE should be initially treated with antiepileptic drugs (AEDs) with low mitochondrion-toxicity. Only in case these AEDs are ineffective, AEDs with higher mitochondrion-toxicity should be added. Major conclusions All patients with SLEs need to have an EEG recorded irrespective if they have manifesting seizures or not. There are no mtDNA or nDNA mutations which predispose for SLEs with seizures.

Mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) is a multisystem mitochondrial disorder that typically presents in childhood. We describe the follow-up of a patient who was diagnosed with late-onset MELAS at the age of 49. Her clinical course includes sensorineural hearing loss, seizures, and multiple episodes of stroke-like metabolic crises. Molecular genetic testing on whole blood revealed 31% heteroplasmy of a m.3243A > G variant in the mtDNA, the causative variant in approximately 80% of MELAS cases. The original diagnostic criteria for MELAS required the onset of stroke-like episodes prior to 40 years of age but this case and others demonstrate that onset may be delayed in certain individuals. Therefore, MELAS should be included in the differential diagnosis of stroke-like episodes in patients of any age.

Heteroplasmy in patients affected with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) offers a chance to harvest specific cells which might have a very low or no mutation load of the mitochondrial DNA. Here we demonstrate establishment of induced pluripotent stem cells (iPSC) cell lines (with normal mitochondrial DNA copies), from unaffected tissues of a male patient with MELAS harbouring m.3243A > G mutations. This platform allowed us to compare specific pathway differences between the cells of the affected tissues of the patients and their isogenic counterparts derived from iPSCs, which do not harbour the mutations.

International audience; Letter to the Editor

Pathogenesis and management of stroke-like episodes in mitochondrial disorders is under debate and no consensus has been reached thus far how this phenomenon should be managed. Frequently applied are nitric oxide (NO) precursors but a well-designed study confirming the effectiveness of such an approach is lacking. Administration of antiepileptic drugs can be meaningful if there is paroxysmal activity on EEG or if a patient presents with seizures. The case reported by Sakai et al. suggests that administration of antiepileptic drugs for a stroke-like episode may be beneficial even in the absence of seizures or paroxysmal EEG activity. Keywords: Epilepsy, Seizures, Antiepileptic drugs, Stroke-like episode, Stroke-like lesion, Nitric-oxide precursors, Mitochondrial depletion, Gene, Encephalomyopathy, Deafness, M disorder