Neurological and non-neurological complications in adult-onset “Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes” syndrome: a diagnostic challenge for internal medicine. A narrative review

Objective To analyze the dynamic evolution of brain MRI in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Methods A retrospective study was performed on 58 MELAS cases with pathologically and （or） molecularly confirmed diagnosis. MRI were repeated within 60 days after the onset of stroke-like episodes (SLE) and the evolution changes of cerebral lesions were accessed. Brain atrophy index (BAI) was calculated in the remission stage from 31 patients with MELAS, and the correlation between BAI, age and disease duration was analyzed. Results The proportion of lesions expansion, migration and shrink within 30 days after the onset of SLE was 64.1%(25/39), 10.2%(4/39), 17.9%(7/39), respectively, and 13%(3/23), 21.7%(5/23),56.5%(13/23), between 30—60 days after the onset of SLE respectively.In the recovery stage of SLE, the BAI in 31 patients with MELAS was 15.2%±2.8%. The correlation coefficient between BAI and the age, total disease course and duration of encephalopathy was 0.329(P=0.043)，0.405(P=0.012) and 0.649(P=0.000). Conclusions Brain atrophy in the studied MELAS patients gradually develops and stroke-like lesions shrink with progression of the disease. However, the migration of lesions is persistent. Key words: MELAS syndrome; Magnetic resonance imaging; Atrophy; Brain

Anesthetic considerations for renal transplant surgery in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome: a case report

A Follow-up Study in a Taiwanese Family with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like Episodes Syndrome

BackgroundMaternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are examples of mitochondrial diseases that are relatively common in the adult population. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are assumed to be associated with decreases in arginine and citrulline. Biomarkers, such as growth differentiation factor-15, were developed to assist in the diagnosis of mitochondrial diseases.Case presentationA 55-year-old Japanese man, an insulin user, presented after a loss of consciousness. A laboratory test showed diabetic ketoacidosis. He and his mother had severe hearing difficulty. Bilateral lesions on magnetic resonance imaging, the presence of seizure, and an elevated ratio of lactate to pyruvate, altogether suggested a diagnosis of mitochondrial disease. Mitochondrial DNA in our patient’s peripheral blood was positive with a 3243A>G mutation, which is the most frequent cause of maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. As a result, maternally inherited diabetes and deafness/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes was diagnosed. We measured growth differentiation factor-15 and multiple amino acids in his blood, longitudinally during and after the stroke-like episode. Growth differentiation factor-15 was increased to an immeasurably high level on the day of the stroke-like episode. Although his diabetes improved with an increased dose of insulin, the growth differentiation factor-15 level gradually increased, suggesting that his mitochondrial insufficiency did not improve. Multiple amino acid species, including arginine, citrulline, and taurine, showed a decreased level on the day of the episode and a sharp increase the next day. In contrast, the level of aspartic acid increased to an extremely high level on the day of the episode, and decreased gradually thereafter.ConclusionsGrowth differentiation factor-15 can be used not only for the diagnosis of mitochondrial disease, but as an indicator of its acute exacerbation. A stroke-like episode of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes reflects a drastic derangement of multiple amino acids. The involvement of aspartic acid in the episodes should be explored in future studies.

BackgroundMitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder which presents with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Mitochondrial diabetes is the cause in 1% of all diabetic patients. Here we present a case of a patient with insulin dependent diabetes mellitus (DM) who experienced sensorineural deafness and was diagnosed with MELAS.Case33-year-old female presented with stroke like symptoms in December 2018. Medical history was significant for Diabetes Mellitus (DM), bilateral deafness and end stage renal disease requiring peritoneal dialysis with subsequent kidney transplant. On presentation, she had left sided weakness, lab work revealed lactic acidosis. MRI brain showed large areas of restricted diffusion in right hemisphere and cerebral edema. CSF analysis was positive for lactate and pyruvate. Left lower extremity muscle biopsy and mitochondrial genome analysis were positive for m.3243A>G in the MT-TL1 with 80% heteroplasmy, confirming the diagnosis of MELAS. Patient was started on Arginine, CoQ10, Levetiracetam, phenytoin, IVIG and her symptoms improved. DM was diagnosed in 2013 when patient was on peritoneal dialysis. Family history significant for type 2 DM in maternal uncle.DiscussionMitochondrial diseases are rare, maternally inherited, heterogeneous conditions caused by mutations in mitochondrial DNA and present with a variety of clinical symptoms. Mitochondrial diabetes results from the 3243 A>G gene mutation, responsible for both MELAS and Mitochondrial inherited diabetes and deafness (MIDD). MELAS presents with encephalopathy, stroke like symptoms and lactic acidosis (1). MIDD presents with nerve deafness, which usually occurs at an early age (2). In our patient, she presented with neurological symptoms suggesting MELAS and bilateral deafness suggesting MIDD. Her presentation is unusual and constitutes an overlap between both disorders.ConclusionEarly recognition and diagnosis of mitochondrial diabetes is important. The diagnosis has important genetic implications for other family members. This case report highlights the presentation of MELAS and MIDD and importance of genetic studies in the confirmation of diagnosis1) D. M. Sproule and P. Kaufmann, "Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome," Annals of the New York Academy of Sciences, vol. 1142, pp. 133–158, 20082) Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabetic Medicine 2008. Apr;25(4): 383-99. doi: 10.1111/j.1464-5491.2008.02359.x.Epub 2008 Feb 18. PMID: 18294221.Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare congenital disorder of mitochondrial DNA. Patients with this syndrome may present acute onset of sensorineural hearing loss, which is genetic in origin. An impression of the MELAS syndrome is favored because hearing loss is part of the syndrome for some patients with epilepsy. We report a 20-year-old man who suffered from acute onset of bilateral hearing loss with epilepsy and two stroke-like events which recovered without any sequela. Epilepsy with complex partial seizures was controlled by antiepileptic drugs. Brain magnetic resonance images showed high signal lesions in bilateral temporal lobes. Serum levels of pyruvate and lactate were elevated. Muscle biopsy showed ragged-red fibers and molecular genetic study showed a point mutation of the mitochondrial A3243G gene. Mitochondrial disease with the MELAS syndrome was diagnosed and then he was treated with Co-enzyme Q10 and carnitine. The symptoms recovered gradually.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial genetic condition affecting the capacity of the cells to create energy. Tissues with high-energy demands, such as the brain tissue, are disproportionately affected by this disease and result in significant neurological sequela including seizures and stroke-like episodes. The cognitive and behavioral impact of these neurological insults is evident in neuropsychological impairments that are initially transient but eventually become permanent and ultimately lead to dementia and death. The age of onset for MELAS is between 5 and 15 years old and is preceded by a period of typical development. The disease course of MELAS in combination with its onset in childhood and adolescence poses a number of challenges to pediatric neuropsychologists, who are often charged with quantifying impairment over time and communicating to a broad audience the appropriate services and supports that the individual needs. This case study aims to provide pediatric neuropsychologists with an overview of MELAS and offers an approach to neuropsychological assessments among children and adolescents with disorders with a dementing disease course. The affected individual, a 19-year-old woman, presented for an initial neuropsychological evaluation following a protracted period of seizures; the etiology of which had only recently been identified as a symptom of MELAS. Considerations for tracking progress and decline longitudinally and recommendations addressing the mental health and educational needs of these individuals are addressed.

To show the multimodal imaging findings observed in a patient in whom the recognition of characteristic pigmentary retinopathy led to the diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Retrospective case report. A 47-year-old woman was referred for evaluation of macular changes detected on a routine ophthalmologic examination. Funduscopic examination showed bilateral findings of the focal areas of pigment hyperplasia in the paramacular region, forming a ringlike pattern in both eyes. Multimodal imaging was performed to further characterize the fundus changes. A review of systems revealed hearing difficulties and neurologic symptoms that further raised a suspicion for retinopathy associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome. Genetic testing showing the mitochondrial DNA A3243G point mutation confirmed the diagnosis. Multimodal imaging is a useful technique in diagnosing retinopathy associated with the mitochondrial DNA A3243G point mutation. Characteristic pigmentary retinopathy with suggestive systemic findings should prompt genetic testing for this mutation.

Adult-onset of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome Presenting as Acute Meningoencephalitis: A Case Report

Reversible focal brain edema in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome

The genetic metabolic disorder known as Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke- Like Episodes (MELAS) is characterised by mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes and is also associated with epilepsy. Pathogenesis is driven by a chronic state of energy failure, but is poorly understood with at least two hypotheses. The angiopathy (ischaemic) hypothesis suggests the presence of abnormal mitochondria in vascular endothelial cells, while the cytopathy hypothesis is thought to involve neuronal hyperexcitability, resulting in prolonged epileptic seizure activity and vasogenic oedema. We present an acute case of recurrent seizures and severe lactic acidosis precipitated by cocaine use in a patient with MELAS syndrome. The triad of lactic acidosis, seizures, and stroke-like episodes focus on the diagnosis. The neurological complications are probably precipitated by oxidative stress.

Dear Editor, We report a case study of mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome with presentation of headache and prolonged visual aura. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode syndrome is one of the most commonly recognized mitochondrial diseases. It is characterized by lactic acidosis, the occurrence of stroke-like episodes, and other secondary manifestations such as migraine-like headache, seizure, cognitive impairment, cardiac conduction defects, and short stature.1,2 These syndromic phenomena are most commonly caused by an m.3243A>G (adenine to guanine) mutation at position 3243 of the mitochondrial genome. The seizures are often associated with migraine-like headache and occur primarily in a group of patients who develop stroke-like episodes. Since stroke-like episodes have a predilection for the parieto-occipital and posterior temporal areas, the seizure semiology frequently demonstrates disturbance in these locations.1,3 We describe a MELAS syndrome patient who presented with recurrent headache and visual aura lasting for more than several days. The patient was a 23-year-old female who was referred to our outpatient clinic due to headache with visual aura lasting for 1 week. Her past medical history and family history were unremarkable, and with the exception of small stature (height, 147 cm; weight, 38 kg), a physical examination yielded normal results. During a neurological examination the patient was alert but complained of a continuous glittering light as well as visual loss in the left visual field. No abnormalities were found on motor, sensory, cerebellar, and reflex function testing. The results of laboratory studies, including blood lactic acid and CSF analyses, were normal. The diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI scans performed on the second day of hospitalization revealed a high signal intensity in the right parietal lobe (Fig. 1A, B, and C); the EEG exhibited rhythmic activities in the corresponding area. Fig. 1 A, B, and C: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI scans during the first episode showing a high signal intensity in the right parietal lobe. E, F, and G: DWI and FLAIR MRI scans during the second episode ... Under the presumptive diagnosis of partial status epilepticus, she was treated with levetiracetam (1,000 mg/day) after receiving an injection of intravenous lorazepam. The visual aura subsided completely after 3 days, and the follow-up MRI performed on day 7 of hospitalization revealed disappearance of the previously observed abnormality (Fig. 1D). The patient was maintained on low-dose levetiracetam (500 mg/day) for 2 years. Three years later the patient visited our outpatient clinic again for recurrence of visual aura lasting for 3 days, contralateral to the previous side. DWI and FLAIR MRI scans revealed a high signal intensity in the left occipital lobe (Fig. 1E, F, and G); a follow-up EEG showed rhythmic activities in the corresponding area. A genetic study revealed the presence of a mitochondrial mutation (m.3243A>G), indicating the presence of MELAS syndrome. Neurological problems are the most frequent clinical features of mitochondrial disorder, and recurrent strokes or transient-ischemic-attack-like episodes are the most common manifestations of MELAS syndrome. Stroke-like lesions usually appear as multifocal infarct-like areas with cortical involvement that has no matching vascular territory.4 The MRI abnormalities in MELAS syndrome often disappear on follow-up MRI, as in our case, as a result of the reversible pathogenesis due to mitochondrial cytopathy or angiopathy.4,5 However, other common and clinically nonserious symptoms of MELAS syndrome, including migraine-like headache, seizure, short stature, and even psychological problems such as depression and anxiety, can go unrecognized for up to 20 years before the onset of overt neurological impairment.6 The findings of the present study show that patients with MELAS syndrome can present with common neurological diseases, such as migraine with aura or occipital lobe epilepsy.1,2,3 Our experience suggests that clinical suspicion is important for an early diagnosis of this particular metabolic disease.

BackgroundMitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by cardiac depression, respiratory failure, myopathy, and anesthesia for affected patients is challenging. Although several anesthetics have been safely employed, there are no reports on remimazolam used in those patients.Case presentationA 47-year-old male with MELAS syndrome was diagnosed with mitral regurgitation and scheduled for transcatheter mitral valve repair under general anesthesia. Anesthesia was induced with remimazolam and remifentanil (0.3 µg/kg/min). Remimazolam was administered at 12 mg/kg/h until loss of consciousness for approximately 1 min. Anesthesia was maintained with 1.1–1.2 mg/kg/h of remimazolam and 0.1 µg/kg/min of remifentanil without circulatory collapse or severe metabolic acidosis. The tracheal tube was removed in the operating room.ConclusionRemimazolam may be a new option for anesthesia for MELAS syndrome patients with depressed heart function.

Objective To investigate the clinical, pathological and dynamic imaging characteristics of patients with mitochondrial myopathy,encephalopathy,lactic acidosis and stroke-like episodes (MELAS). Methods A retrospective analysis was performed on the clinical,pathological and dynamic imaging data of 10 patients with MELAS confirmed by muscle biopsy. Results The clinical manifestations included headache,seizures,nausea,vomiting,nystagrnus and visual disturbances.CT showed less lesions,and MRI could clearly show multiple lesions which mainly located in the temporal,parietal,occipital cortex and sub-cortex,having multifocal,asymmetric,migratory characterstics and not following the distribution of blood vessels.MRA showed no significant stenosis,and the lesion showed hyperperfusion and vasogenic edema,and Lae peak was visible.Muscle biopsy showed ragged red fiber optical microscope (RRF) and strongly SDH-reactive vessel (SSV),and electron microscope showed increased mitochondria number, and abnormal size and shape. Conclusion MELAS has certain clinical and imaging characteristics; by combining the muscle biopsy,we can diagnose the disease early and make differential diagnosis. Key words: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode; Imaging; Pathological feature

MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNAMet gene