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Introduction: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is reported to be a secondary cause of chronic intestinal pseudo-obstruction (CIPO). Although few case reports have described CIPO in MELAS, effective treatment for CIPO has not been established. Here, we present a case report of amelioration of CIPO symptoms using acotiamide in a patient with MELAS. Case Presentation: A 51-year-old Japanese female with a mitochondrial disorder with m.3243A>G mutation and a history of anorexia for 2 years presented to our hospital with a left temporal headache and acute paraphasia. A stroke-like episode of MELAS was suspected and combined therapy with arginine, edaravone, and levetiracetam was initiated. Although her symptoms improved, she presented with nausea and vomiting and abdominal distension 6 days following admission. Abdominal contrast-enhanced computed tomography revealed dilatation from the stomach to the intestine, particularly marked the stomach, with neither obstruction nor impaired blood flow in the intestine. CIPO exacerbation with MELAS was suspected, and the patient’s symptoms gradually improved with acotiamide. Conclusion: Patients with MELAS could possibly experience stroke-like episodes during CIPO. Since acetylcholine possibly plays an important role in the pathophysiology of CIPO and acotiamide possesses prokinetic activity by inhibiting acetylcholinesterase, acotiamide could possibly improve CIPO symptoms. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders. Case presentation A 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level. Conclusion Genetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.

Epilepsy in Sturge-Weber syndrome (SWS) is common, but drug-refractory epilepsy (DRE) in SWS has rarely been studied in children. We investigated the characteristics of epilepsy and risk factors for DRE in children with SWS. A retrospective study was conducted to analyze the clinical characteristics of children with SWS with epilepsy in our hospital from January 2013 to October 2022. Univariate and multivariate logistic analyses were performed to investigate the factors influencing DRE in children with SWS. A total of 35 SWS children with epilepsy were included (51% male; mean age of presentation 3.6 ± 0.5 years), 71% of children with SWS had their first seizure within the first year of life, and the most common type of seizure was focal seizure (77%). Eleven (31%) patients developed DRE. The median age of onset for the first seizure was 1.0 years and all these cases were of SWS type I. Multivariate logistic analysis revealed that stroke-like episodes and seizure clusters were risk factors for DRE in SWS children. A poor neurological function group was observed in twenty-five children with SWS. Status epilepticus was a risk factor that affected the neurological function of SWS children with epilepsy. Conclusion: The study explored the epileptic features of children with SWS. The results revealed that stroke-like episodes and seizure clusters are risk factors for DRE in children with SWS. The occurrence of status epilepticus impacts the neurological function of SWS children with epilepsy. Thus, long-term follow-up is necessary to monitor outcomes. What is Known: • Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder, over 75% of children with SWS experience seizures, and 30–57% develop drug-refractory epilepsy (DRE), which leads to a poor outcome. • Drug-refractory epilepsy in SWS has been rarely studied in children, and the risk factors associated with DRE are unclear. What is New: • Clinical features of SWS children with drug-refractory epilepsy. • In SWS, stroke-like episodes and seizure clusters are risk factors of DRE, the occurrence of status epilepticus impacts the neurological function. [ABSTRACT FROM AUTHOR]

Key Clinical Message: MELAS is a disorder with clinical variability that also responsible for a significant portion of unexplained hereditary or childhood‐onset hearing loss. 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. It is crucial to consider MELAS as a potential cause of stroke‐like events if age at presentation and symptoms are atypical, especially among middle‐aged patients without vascular risk factors. MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes) is a rare genetic condition that most patients develop stroke‐like episodes before the age of 40. We report a 52‐year‐old female with a documented 40‐year history of progressive sensorineural hearing loss, developed a visual field deficit and stroke‐like events in her middle age who finally diagnosed was MELAS. The patient was started on vitamin E, l‐carnitine, l‐arginine, and coenzyme Q10 that gradually improved before dismissal from the hospital. This case highlights the importance of considering MELAS as a potential cause of stroke‐like events if imaging findings are atypical for cerebral infarction, especially among middle‐aged patients without vascular risk factors and an unusual cause of progressive sensorineural hearing loss. [ABSTRACT FROM AUTHOR]

The MT‐TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5‐year‐old child with heteroplasmy for this variant who developed neurological regression and stroke‐like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z‐scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke‐like episodes. The use of intravenous arginine during stroke‐like episodes and daily enteral L‐citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1‐methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N‐acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT‐TL2 m.12315G>A to include neurological regression and a MELAS‐like phenotype. Individuals with this variant should undergo in‐depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment. [ABSTRACT FROM AUTHOR]

Key Clinical Message MELAS is a disorder with clinical variability that also responsible for a significant portion of unexplained hereditary or childhood‐onset hearing loss. 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. It is crucial to consider MELAS as a potential cause of stroke‐like events if age at presentation and symptoms are atypical, especially among middle‐aged patients without vascular risk factors. Abstract MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes) is a rare genetic condition that most patients develop stroke‐like episodes before the age of 40. We report a 52‐year‐old female with a documented 40‐year history of progressive sensorineural hearing loss, developed a visual field deficit and stroke‐like events in her middle age who finally diagnosed was MELAS. The patient was started on vitamin E, l‐carnitine, l‐arginine, and coenzyme Q10 that gradually improved before dismissal from the hospital. This case highlights the importance of considering MELAS as a potential cause of stroke‐like events if imaging findings are atypical for cerebral infarction, especially among middle‐aged patients without vascular risk factors and an unusual cause of progressive sensorineural hearing loss.

Abstract Background Arterial spin-labeling (ASL) imaging is currently the most useful method for diagnosing mitochondrial encephalomyopathy, lactic acidosis, and stroke-like attack syndrome (MELAS). However, ASL is often an optional feature of standard MRI systems. Therefore, not all MRI systems can perform ASL imaging. In contrast, fluid-attenuated inversion recovery (FLAIR) imaging is one of the common sequences in brain MRI because FLAIR imaging can be performed regardless of the specifications of the equipment. This study aimed to compare the diagnostic performance of quantitative analysis of signal intensity obtained from fluid-attenuated inversion recovery (FLAIR) images with ASL images for MELAS with recurrent stroke-like episodes (SLEs). A total of 68 cases with normal magnetic resonance imaging findings and 25 cases diagnosed MELAS with recurrent SLEs were included. We evaluated the frontal lobe and cuneus as target areas and compared the regional cerebral blood flow (rCBF) values obtained from ASL images with the normalized signal intensity (nSI) obtained from FLAIR images. Results The sensitivity and specificity for diagnosing MELAS from linear discriminant analysis (LDA) obtained from the rCBF values were 0.84 and 0.941, respectively, and those of nSI were 0.8 and 0.897, respectively. The area under the ROC curves (AUC) calculated from the receiver operating characteristic (ROC) curve analysis using rCBF values and nSI were 0.889 and 0.804, respectively. Conclusion Quantitative analysis using the signal intensity of the FLAIR image could have a diagnostic performance equivalent to that of rCBF values obtained from ASL images.

Background: Arterial spin-labeling (ASL) imaging is currently the most useful method for diagnosing mitochondrial encephalomyopathy, lactic acidosis, and stroke-like attack syndrome (MELAS). However, ASL is often an optional feature of standard MRI systems. Therefore, not all MRI systems can perform ASL imaging. In contrast, fluid-attenuated inversion recovery (FLAIR) imaging is one of the common sequences in brain MRI because FLAIR imaging can be performed regardless of the specifications of the equipment. This study aimed to compare the diagnostic performance of quantitative analysis of signal intensity obtained from fluid-attenuated inversion recovery (FLAIR) images with ASL images for MELAS with recurrent stroke-like episodes (SLEs). A total of 68 cases with normal magnetic resonance imaging findings and 25 cases diagnosed MELAS with recurrent SLEs were included. We evaluated the frontal lobe and cuneus as target areas and compared the regional cerebral blood flow (rCBF) values obtained from ASL images with the normalized signal intensity (nSI) obtained from FLAIR images. Results: The sensitivity and specificity for diagnosing MELAS from linear discriminant analysis (LDA) obtained from the rCBF values were 0.84 and 0.941, respectively, and those of nSI were 0.8 and 0.897, respectively. The area under the ROC curves (AUC) calculated from the receiver operating characteristic (ROC) curve analysis using rCBF values and nSI were 0.889 and 0.804, respectively. Conclusion: Quantitative analysis using the signal intensity of the FLAIR image could have a diagnostic performance equivalent to that of rCBF values obtained from ASL images. [ABSTRACT FROM AUTHOR]

The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS). Their clinical symptoms have been estimated to occur with an increased mitochondrial DNA (mtDNA) heteroplasmy and reduced activity of oxidative phosphorylation (OXPHOS) complexes, but their trends in the central nervous system remain unknown. Six autopsied mutant cases and three disease control cases without the mutation were enrolled in this study. The mutant cases had a disease duration of 1–27 years. Five of six mutant cases were compatible with MELAS. In the mutant cases, cortical lesions including a laminar necrosis were frequently observed in the parietal, lateral temporal, and occipital lobes; less frequently in the frontal lobe including precentral gyrus; and not at all in the medial temporal lobe. The mtDNA heteroplasmy in brain tissue samples of the mutant cases was strikingly high, ranging from 53.8% to 85.2%. The medial temporal lobe was preserved despite an inhospitable environment having high levels of mtDNA heteroplasmy and lactic acid. OXPHOS complex I was widely decreased in the mutant cases. The swelling of smooth muscle cells in the vessels on the leptomeninges, with immunoreactivity (IR) against mitochondria antibody, and a decreased nuclear/cytoplasmic ratio of choroidal epithelial cells were observed in all mutant cases but in none without the mutation. Common neuropathological findings such as cortical laminar necrosis and basal ganglia calcification were not always observed in the mutant cases. A high level of mtDNA heteroplasmy was observed throughout the brain in spite of heterogeneous cortical lesions. A lack of medial temporal lesion, mitochondrial vasculopathy in vessels on the leptomeninges, and an increased cytoplasmic size of epithelial cells in the choroid plexus could be neuropathological hallmarks helpful in the diagnosis of mitochondrial diseases. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include stroke-like episodes, epilepsy, dementia, headache and myopathy. Among these, acute visual failure, usually in association with cortical blindness, can occur because of stroke-like episodes affecting the occipital cortex or the visual pathways. Vision loss due to optic neuropathy is otherwise considered a typical manifestation of other mitochondrial diseases such as Leber hereditary optic neuropathy (LHON). Case presentation: Here we describe a 55-year-old woman, sister of a previously described patient with MELAS harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms. Conclusions: Atypical clinical presentations must be always considered in mitochondrial disorders, even in well-described phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include stroke-like episodes, epilepsy, dementia, headache and myopathy. Among these, acute visual failure, usually in association with cortical blindness, can occur because of stroke-like episodes affecting the occipital cortex or the visual pathways. Vision loss due to optic neuropathy is otherwise considered a typical manifestation of other mitochondrial diseases such as Leber hereditary optic neuropathy (LHON). Case presentation Here we describe a 55-year-old woman, sister of a previously described patient with MELAS harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms. Conclusions Atypical clinical presentations must be always considered in mitochondrial disorders, even in well-described phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders.

Background and purpose: Stroke‐like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non‐congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology. Methods: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20‐year period. Inclusion criteria were compatible clinical symptoms and stroke‐like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion‐weighted imaging in a non‐vascular territory. Results: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48‐h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18). Conclusion: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE. [ABSTRACT FROM AUTHOR]

Objective: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common inherited mitochondrial disorders. Due to the high clinical and genetic heterogeneity of MELAS, it is still a major challenge for clinicians to accurately diagnose the disease at an early stage. Herein, we evaluated the neuroimaging findings of MELAS with an m.3243A>G mutation in MT-TL1 and analyzed the possible underlying pathogenesis of stroke-like episodes. Materials and methods: Fifty-nine imaging studies in 24 patients who had a confirmed genetic diagnosis of m.3243A>G (MT-TL1; tRNALeu) associated with MELAS were reviewed in our case series. The anatomic location, morphological features, signal/intensity characteristics and temporal evolution of lesions were analyzed on magnetic resonance imaging (MRI), and computed tomography (CT) images. The supplying vessels and metabolite content of the lesions were also evaluated by using MR angiography (MRA)/CT angiography (CTA), and MR spectroscopy (MRS), respectively. [ABSTRACT FROM AUTHOR]

Mitochondrial disorders are a group of metabolic disorders with variable presentation and usually affect organs with high energy requirements like the brain, eye, and heart. Seventeen-month-old girl child presented with right hemiparesis and regression of milestones following chicken pox. Investigations showed elevated lactate, white matter signal changes in both periventricular and subcortical white matter with frontal predominance in the MRI of the brain, cardiomyopathy in the echocardiography, with complex I deficiency in respiratory enzyme assay in the muscle biopsy. A homozygous missense variant c.304C>T (p. Arg102Cys) in exon 5 of NDUFS8 gene (chr11:67800682C>T; NM_002496.4) was detected on whole exome sequencing with positive parental Sanger for the same gene. The child was started on a mitochondrial cocktail, ramipril, and frusemide. Mitochondrial complex deficiency should be considered in cases with stroke-like episodes, and predominant white matter involvement on imaging mimicking classical genetic leukodystrophy like Alexander disease.

Mitochondrial disorders are a group of metabolic disorders with variable presentation and usually affect organs with high energy requirements like the brain, eye, and heart. Seventeen-month-old girl child presented with right hemiparesis and regression of milestones following chicken pox. Investigations showed elevated lactate, white matter signal changes in both periventricular and subcortical white matter with frontal predominance in the MRI of the brain, cardiomyopathy in the echocardiography, with complex I deficiency in respiratory enzyme assay in the muscle biopsy. A homozygous missense variant c.304C>T (p. Arg102Cys) in exon 5 of NDUFS8 gene (chr11:67800682C>T; NM_002496.4) was detected on whole exome sequencing with positive parental Sanger for the same gene. The child was started on a mitochondrial cocktail, ramipril, and frusemide. Mitochondrial complex deficiency should be considered in cases with stroke-like episodes, and predominant white matter involvement on imaging mimicking classical genetic leukodystrophy like Alexander disease. [ABSTRACT FROM AUTHOR]

Pediatric stroke can be either hemorrhagic or ischemic, with ∼5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 mo old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole-genome sequencing identified a novel variant in the F13A1 gene c.1352_1353delAT (p.His451ArgfsTer29).

Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common maternally inherited mitochondrial diseases which rarely affects elderly people. Case presentation: We reported the case of a 61-year-old male patient with MELAS. He was experiencing acute migraine-like headaches as the first symptoms. Laboratory data showed elevated lactate and creatine kinase levels. Brain magnetic resonance imaging (MRI) found a high signal intensity lesion in the left occipital-temporal-parietal lobe on diffusion-weighted imaging (DWI). Magnetic resonance angiography (MRA) revealed reversible vasoconstriction of the middle cerebral arteries and superficial temporal arteries. A muscle biopsy suggested minor muscle damage. A genetic study revealed a mitochondrial DNA A3243G mutation. Conclusion: Elderly onset of MELAS is rare and easily misdiagnosed as an ischemic stroke. MELAS with the onset of stroke-like episodes should be considered in adult or elderly patients with imaging findings that are atypical for cerebral infarction. The use of multimodal MRI in the clinical diagnosis of MELAS could be extremely beneficial. [ABSTRACT FROM AUTHOR]

Introduction: Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging (MRI). Main symptoms and/or important findings: A MELAS-patient had a rapid succession of 3 stroke-like episodes with dysphasia, visual field deficits and paresis of the right arm. MRI showed a lesion with corticosubcortical vasogenic edema without reduced diffusion, conforming to a stroke-like MELAS-lesion. Microhemorrhages within MELAS-lesions were detected on MRI. The main diagnoses, therapeutic interventions, and outcomes: Microhemorrhages are an atypical imaging finding in MELAS. The patient was treated with L-arginine. Conclusion: Microhemorrhages can present on MRI in (sub)acute MELAS lesions and may reflect mitochondrial microangiopathy.

Background: Mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome is one of the most well‐known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi‐systemic phenotype that predominantly features neurological manifestations––stroke‐like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses. Methods: A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed. Results: Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke‐like episodes. Heteroplasmy is higher in a tissue other than blood in most cases. Conclusion: The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered. [ABSTRACT FROM AUTHOR]

A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym “MELAS” (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.

Mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) is an important cause of stroke-mimicking diseases that predominantly affect patients before 40 years of age. MELAS results from gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) responsible for the wide spectrum of clinical symptoms and imaging findings. Neurological manifestations can present with stroke-like episodes (the cardinal features of MELAS), epilepsy, cognitive and mental disorders, or recurrent headaches. Magnetic resonance imaging (MRI) is an important tool for detecting stroke-like lesions, accurate recognition of imaging findings is important in guiding clinical decision making in MELAS patients. With the development of neuroimaging technologies, MRI plays an increasingly important role in course monitoring and efficacy assessment of the disease. In this article, we provide an overview of the neuroimaging features and the application of novel MRI techniques in MELAS syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging (MRI). Main symptoms and/or important findings: A MELAS-patient had a rapid succession of 3 stroke-like episodes with dysphasia, visual field deficits and paresis of the right arm. MRI showed a lesion with corticosubcortical vasogenic edema without reduced diffusion, conforming to a stroke-like MELAS-lesion. Microhemorrhages within MELAS-lesions were detected on MRI. The main diagnoses, therapeutic interventions, and outcomes: Microhemorrhages are an atypical imaging finding in MELAS. The patient was treated with L-arginine. Conclusion: Microhemorrhages can present on MRI in (sub)acute MELAS lesions and may reflect mitochondrial microangiopathy. [ABSTRACT FROM AUTHOR]

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a disease that should be considered as a differential diagnosis to acute ischemic stroke taking into account its onset pattern and neurological symptoms, which are similar to those of an ischemic stroke. Technological advancements in neuroimaging modalities have greatly facilitated differential diagnosis between stroke and MELAS on diagnostic imaging. Stroke-like episodes in MELAS have the following features: (1) symptoms are neurolocalized according to lesion site; (2) epileptic seizures are often present; (3) lesion distribution is inconsistent with vascular territory; (4) lesions are common in the posterior brain regions; (5) lesions continuously develop in adjacent sites over several weeks or months; (6) neurological symptoms and stroke-like lesions tend to be reversible, as presented on magnetic resonance imaging; (7) the rate of recurrence is high; and; (8) brain dysfunction and atrophy are slowly progressive. The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is most commonly associated with MELAS. Although the precise pathophysiology is still unclear, one possible hypothesis for these episodes is a neuronal hyperexcitability theory, including neuron–astrocyte uncoupling. Supplementation, such as with L-arginine or taurine, has been proposed as preventive treatments for stroke-like episodes. As this disease is still untreatable and devastating, numerous drugs are being tested, and new gene therapies hold great promise for the future. This article contributes to the understanding of MELAS and its implications for clinical practice, by deepening their insight into the latest pathophysiological hypotheses and therapeutic developments. [ABSTRACT FROM AUTHOR]

Abstract Background Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation. Case presentation A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000 mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum. Conclusions SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements.

This lecture with a description of clinical cases presents information on such a mitochondrial disease from the group of hereditary metabolic diseases, like MELAS syndrome (OMIM: 540000). The main manifestations of this progressive disease are stroke-like episodes and a specific form of encephalopathy, including epileptic seizures with the presence of a phenomenon of "ragged red fibers" and early dementia. Clinical cases, given in this lecture, supplement the piggy bank of genetically verified mitochondrial diseases leading to the development of polymorphic neurological disorders and characteristic neuroimaging picture, namely the appearance of polymorphic ischemic changes in the temporal, parietal or occipital regions of the brain, that do not correspond to the zones of the main vascular blood supply, as the basis for the formation of such focus is the phenomenon of mitochondrial angiopathy, and not thrombosis. The description of clinical cases reflects our own observations and the main steps in the diagnosis of this severe hereditary disease, taking into account of the latest neurogenetic representations. In addition to the data given in the clinical course of the disease, the results of the genetic interpretation of the MELAS syndrome are given; modern methods of diagnosis and therapy are considered.

Mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) is an important cause of stroke-mimicking diseases that predominantly affect patients before 40 years of age. MELAS results from gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) responsible for the wide spectrum of clinical symptoms and imaging findings. Neurological manifestations can present with stroke-like episodes (the cardinal features of MELAS), epilepsy, cognitive and mental disorders, or recurrent headaches. Magnetic resonance imaging (MRI) is an important tool for detecting stroke-like lesions, accurate recognition of imaging findings is important in guiding clinical decision making in MELAS patients. With the development of neuroimaging technologies, MRI plays an increasingly important role in course monitoring and efficacy assessment of the disease. In this article, we provide an overview of the neuroimaging features and the application of novel MRI techniques in MELAS syndrome.

Little is known about magnetic resonance imaging findings in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) with the m.3271 A > G mutation. A 31‐year‐old man presented with headache and left‐sided homonymous hemianopsia. Brain magnetic resonance imaging showed hyperintensities in the right occipital lobe on diffusion‐ and T2‐weighted imaging. MELAS was diagnosed, and the etiological mutation was identified as m.3271 T > C. Although his symptoms gradually resolved, magnetic resonance imaging revealed disseminated small cortical lesions in the left occipital lobe. We report a rare case of atypical stroke‐like lesions in a patient with MELAS with the m.3271 T > C mutation. [ABSTRACT FROM AUTHOR]

There have been considerations since the beginning of the Coronavirus pandemic that COVID-19 infection, like any other viral illness, can trigger neurological and metabolic decompensation in patients with mitochondrial diseases. At the time of writing, there were no published reports reviewing experiences and guidelines about management of COVID-19 infection in this patient population. We present a challenging case of an adult patient with a known diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS) complicated by COVID-19 infection. She initially presented with altered mental status and vomiting and went on to develop a stroke-like episode, pancreatitis, and pneumatosis intestinalis. We review salient features of her hospitalization, including initiation of thromboprophylaxis in relation to intravenous arginine therapy, caution regarding medications such as remdesivir, and the incidence of gastrointestinal complications. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial cytopathy caused by mutations in mitochondrial DNA. Clinical manifestation is typically before the age of 40. Case presentation We present the case of a 63-year-old female in whom the symptoms of MELAS were initially misdiagnosed as episodes of recurrent ischemic strokes. Brain imaging including MRI, clinical and laboratory findings that lent cues to the diagnosis of MELAS are discussed. In addition, MRI findings in MELAS in comparison to imaging mimics of MELAS are presented. Conclusions This case underscores the importance of considering MELAS as a potential cause of recurrent stroke-like events if imaging findings are untypical for cerebral infarction, even among middle-aged patients with vascular risk factors.

A stroke should be considered in cases of neurologic decompensation associated with inherited metabolic disorders. A resultant stroke could be a classical ischemic stroke (vascular stroke) or more commonly a “metabolic stroke.” A metabolic stroke begins with metabolic dysfunctions, usually caused by a stressor, and leads to the rapid onset of prolonged central neurological deficits in the absence of vessel occlusion or rupture. The cardinal features of a metabolic stroke are stroke-like episodes without the confirmation of ischemia in the typical vascular territories, such as that seen in classic thrombotic or embolic strokes. Identifying the underlying cause of a metabolic stroke is essential for prompt and appropriate treatment. This study reviews the major inherited metabolic disorders that predispose patients to pediatric stroke, with an emphasis on the underlying mechanisms, types, and management.

• The new scoring criterion based on FLAIR images differentiates MELAS from AIS. • The new scoring criterion differentiate MELAS from ALS. This study aimed to evaluate the sensitivity and specificity of the vessel signs, including the Vessel Flow Void Sign (VFVS) and the Hyperintense Vessel Sign (HVS) in Fluid Attenuated Inversion Recovery (FLAIR) images during the differentiation of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) in Acute Ischemic Stroke (AIS). Magnetic Resonance Imaging (MRI) scans of 13 MELAS and 20 AIS patients were obtained during the acute stage of the diseases (median time to scan <1 day from symptom onset). To evaluate VFVS and HVS on the FLAIR images, Logistic Regression was used to analyze their correlation with MELAS. Then, a new scale of scoring, involving two aspects (VFVS and HVS) on FLAIR images was established. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of the developed criterion. FLAIR images from 12 of the 13 MELAS patients exhibited VFVS while none exhibited HVS. Moreover, FLAIR images from 3 of the 20 AIS patients exhibited VFVS while 17 exhibited HVS. Logistic Regression showed that VFVS and the absence of HVS (NoHVS) were independent MELAS predictors. If there were VFVS, the patient scored 2 points, while there were NoHVS, the patient scored 1 point. Patients with >1.5 scores were prone to be MELAS, while patients with <1.5 scores were prone to be AIS. Sensitivity was found to be 92.3%, specificity was 85%, with an AUC of 0.94. We have established a new scoring criterion, with a high sensitivity and specificity, for differentiating between MELAS and AIS in patients during the acute stage. [ABSTRACT FROM AUTHOR]

A stroke should be considered in cases of neurologic decompensation associated with inherited metabolic disorders. A resultant stroke could be a classical ischemic stroke (vascular stroke) or more commonly a "metabolic stroke." A metabolic stroke begins with metabolic dysfunctions, usually caused by a stressor, and leads to the rapid onset of prolonged central neurological deficits in the absence of vessel occlusion or rupture. The cardinal features of a metabolic stroke are stroke-like episodes without the confirmation of ischemia in the typical vascular territories, such as that seen in classic thrombotic or embolic strokes. Identifying the underlying cause of a metabolic stroke is essential for prompt and appropriate treatment. This study reviews the major inherited metabolic disorders that predispose patients to pediatric stroke, with an emphasis on the underlying mechanisms, types, and management. [ABSTRACT FROM AUTHOR]

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 < 0.05) and negatively correlated with the number of transitions (r = −0.520, P < 0.05). Furthermore, MELAS patients at the acute stage exhibited significantly increased global efficiency (P < 0.01) and decreased local efficiency (P < 0.001) compared to the controls and the patients at the chronic stage. Patients at the chronic stage only showed significantly (P < 0.001) decreased local efficiency compared to the controls. Data Conclusion: Our findings suggest similar and distinct dFC alterations in MELAS patents at the acute and chronic stages, providing novel insights for understanding the neuropathological mechanisms of MELAS. Level of Evidence 2 Technical Efficacy Stage Stage 2 J. MAGN. RESON. IMAGING 2021;53:427–436. [ABSTRACT FROM AUTHOR]

• MELAS patients showed decreased brain activities beyond the distributions of SLLs. • The regions with decreased activities were much broader in patients at attack stage. • fALFF value in the left precuneus may be used for monitoring the status of MELAS. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) may cause whole-brain functional changes due to mitochondrial dysfunction. Our purpose is to comprehensively evaluate the alterations of spontaneous brain activity in MELAS patients at stroke-like episodes (SLE) attack and remission stages using resting-state functional magnetic resonance imaging. Forty MELAS patients at attack stage (n = 20) and remission stage (n = 20) and 22 healthy controls were enrolled in this study. We suggested that MELAS patients presented decreased spontaneous brain activities beyond the areas of stroke-like lesions (SLLs), with a downward trend from SLE attack stage to remission stage. In addition, the regional spontaneous activity of SLL, an inherent change in MELAS, was less than that in unaffected areas. Furthermore, the fractional amplitude of low frequency fluctuations value in left precuneus may be used as a promising neuroimaging biomarker for monitoring the disease status of MELAS. [ABSTRACT FROM AUTHOR]

Summary: Background: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. Results: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course. [ABSTRACT FROM AUTHOR]

Background: Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation.Case Presentation: A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000 mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum.Conclusions: SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements. [ABSTRACT FROM AUTHOR]

We described two patients (female, 47 years and male, 42 years)with mitochondrial encephalomyopathy, lactic acidosis andstroke-like episodes (MELAS). Diagnosis was confirmed bygenetic study (A3243G mitochondrial DNA mutation wasfound), muscle biopsy and elevated lactate level in the blood.Clinical picture of stroke-like episodes was presented by symptomsof mainly involvement of the posterior brain area (fluentand amnestic aphasia, hemianopia, paresis, ataxia), as well as byheadache and epileptic seizures. In the first patient stroke-likeepisodes recurred but their symptoms almost completelyregressed with time. The second patient had severe residualneurological deficit. Other clinical manifestations includedhearing loss, memory deterioration, cardiomyopathy, fatigueand type 1 diabetes mellitus. MRI in acute period of stroke-likeepisodes found cortical lesions mainly in the posterior parts ofthe brain. They completely disappeared in the first case, butpersisted in the second patient. The differential diagnosis ofstroke-like episodes and ischemic stroke and approaches totreatment are discussed.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that is most commonly caused by the m. 3243A>G mutation in the MT-TL1 mitochondrial DNA gene, resulting in impairment of mitochondrial energy metabolism. Although childhood is the typical age of onset, a small fraction (1–6%) of individuals manifest the disease after 40 years of age and usually have a less aggressive disease course. The clinical manifestations are variable and mainly depend on the degree of heteroplasmy in the patient's tissues and organs. They include muscle weakness, diabetes, lactic acidemia, gastrointestinal disturbances, and stroke-like episodes, which are the most commonly observed symptom. We describe the case of a 50-year-old male patient who presented with relapsing intestinal pseudo-obstruction (IPO) episodes, which led to a late diagnosis of MELAS. After diagnosis, he presented several stroke-like episodes in a short time period and developed a rapidly progressive cognitive decline, which unfortunately resulted in his death. We describe the variable clinical manifestations of MELAS syndrome in this atypical and relatively old patient, with a focus on paralytic ileus and stroke-like episodes; the first symptom may have driven the others, leading to a relentless decline. Moreover, we provide a brief revision of previous reports of IPO occurrence in MELAS patients with the m.3243A>G mutation, and we investigate its relationship with stroke-like episodes. Our findings underscore the importance of recognizing gastrointestinal disturbance to prevent neurological comorbidities.

Objective: We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome.Methods: An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed.Results: Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials.Conclusion: We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy. [ABSTRACT FROM AUTHOR]

Objectives: To investigate a diversity of stroke-like episodes (SLEs) in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and report a disseminated form of SLEs (D-SLEs) attributed to a cluster of disseminated small cortical lesions. Methods: We retrospectively reviewed the clinical information of 27 MELAS patients seen at Kitasato University Hospital between January 1990 and April 2018. Among those, we selected 13 patients with m.3243A>G mutation [median age at onset, 35 years (11–68 years), two pediatric onset < 17 years] who had at least one SLE. SLEs were classified into classic or non-classic based on characteristic features of stroke-like lesions. Results: 44 SLEs were identified during a median observational period of 119 months (3–240 months). Among those, 29 (65.9%) were classic SLEs (C-SLEs) mainly attributed to a single continuous lobular lesion incongruent to vascular territory and occasionally accompanied by a gradual spread associated with hyperperfusion and persistent seizure activity. The remaining 15 were non-classic attributed to sparsely distributed (n = 10), disseminated (n = 4) or cerebellar lesions (n = 1). C-SLEs developed in all patients but non-classic SLEs in 5; D-SLEs developed in 4 patients accounting for 4 of 44 SLEs (9.1%). Non-classic SLEs developed more frequently in pediatric-onset than in adult-onset patients (12/15 vs. 3/29, p < 0.0001). SLEs began with acute onset of symptoms in 42 SLEs (95.5%), but D-SLEs of 2 adult-onset patients began with ill-defined subacute-onset fluctuating encephalopathy. Conclusions: This study showed a diversity of SLEs in patients with m.3243A>G mutation. Further studies are required to elucidate the pathophysiological mechanisms of non-classic SLEs including D-SLEs. [ABSTRACT FROM AUTHOR]

We present an autopsied case with A8344G‐mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes (MELAS) overlap syndrome accompanied by stroke‐like episodes localized to the precentral gyrus. A 16‐year‐old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho‐logically, multifocal laminar necrosis, which is responsible for stroke‐like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti‐mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)‐reactive blood vessels were also noted. Stroke‐like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke‐like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G‐mutated MERRF/MELAS overlap syndrome. [ABSTRACT FROM AUTHOR]

Abstract Inborn errors of metabolism are individually rare, but so many have now been described that the general paediatrician will encounter one from time to time. For many, early treatment is important. Unfortunately, most that present acutely do so with non-specific symptoms and signs. It is therefore necessary to identify and investigate those at high risk. The most common problems are neurological (including coma, seizures and stroke-like episodes), hypoglycaemia, disorders of acid-base regulation, acute liver disease, rhabdomyolysis, cardiomyopathy and sudden collapse. Treatment should be started as soon as an inborn error is suspected. This review is a short, practical introduction and cannot cover all situations. If in doubt, consult your local specialist metabolic centre. Free, detailed instructions on the acute management of individual inborn errors of metabolism can be found on the British Inherited Metabolic Disease Group (BIMDG) Website: http://www.bimdg.org.uk/ [ABSTRACT FROM AUTHOR]

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder that is most commonly caused by the m. 3243A>G mutation in the MT-TL1 mitochondrial DNA gene, resulting in impairment of mitochondrial energy metabolism. Although childhood is the typical age of onset, a small fraction (1–6%) of individuals manifest the disease after 40 years of age and usually have a less aggressive disease course. The clinical manifestations are variable and mainly depend on the degree of heteroplasmy in the patient's tissues and organs. They include muscle weakness, diabetes, lactic acidemia, gastrointestinal disturbances, and stroke-like episodes, which are the most commonly observed symptom. We describe the case of a 50-year-old male patient who presented with relapsing intestinal pseudo-obstruction (IPO) episodes, which led to a late diagnosis of MELAS. After diagnosis, he presented several stroke-like episodes in a short time period and developed a rapidly progressive cognitive decline, which unfortunately resulted in his death. We describe the variable clinical manifestations of MELAS syndrome in this atypical and relatively old patient, with a focus on paralytic ileus and stroke-like episodes; the first symptom may have driven the others, leading to a relentless decline. Moreover, we provide a brief revision of previous reports of IPO occurrence in MELAS patients with the m.3243A>G mutation, and we investigate its relationship with stroke-like episodes. Our findings underscore the importance of recognizing gastrointestinal disturbance to prevent neurological comorbidities. [ABSTRACT FROM AUTHOR]