Characteristics of stroke-like lesions on cerebral imaging.

Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial ence­pha­lopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome but occur in other mitochondrial and non-mitochondrial disorders as well. This mini-review aims at summarising and discussing recent findings to open up future perspectives how to manage this fleeting phenomenon.
Results – Typically, SLLs are dynamic lesions, which increase in size and intensity to regress after a nadir. SLLs are incongruent with a vascular territory, originate frequently from the cortex to spread subcortically, can be monofocal or multifocal, run through an acute (attack) and chronic (remission) stage, and may either completely disappear or end up as laminar cortical necrosis, white matter lesion, subcortical atrophy, cyst, or the toenail sign. On cerebral CT, SLLs are hypodense. SLLs can be best visualized on multimodal MRI showing up as hyperintensity on T2, FLAIR, DWI, and PWI, and as hypointensity on OEF-MRI. On MR-spectroscopy, SLLs typically present with a decreased N-acetyl-aspartate peak and an increased lactate peak. DTI in acute SLLs reveals reduced connectivity, increased global efficiency, and reduced focal efficiency. Tc-HMPAO SPECT of SLLs indicates hyperperfusion and L-iomazenil SPECT reduced tracer uptake. FDG-PET typically shows hypometabolism within a SLL.
Conclusion – SLLs present with typical findings on various imaging modalities but the combination of cerebral CT, multimodal MRI, MRS, and PET clearly delineate a SLL from other acute or chronic cerebral lesions. 

First Case of MELAS Syndrome Presenting with Local Brain Edema Requiring Decompressive Craniectomy.

Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes (MELAS) syndrome is a rare but one of the most common maternally inherited multisystem disorder. Although patients with MELAS present a variable clinical profile, strokelike lesions have been detected in 90% of cases, with stroke being the first presenting symptom in 25% of cases. However, cases of local brain edema requiring decompressive craniectomy has not been reported. A 12-year-old male patient was admitted to our pediatric intensive care unit with altered mental status, seizures, and vision loss. The patient was stuporous and presented neck stiffness. Complete blood count, serum electrolytes, biochemistry (including lactate level), acute phase reactants, and repeated blood gas analysis were unremarkable. Brain magnetic resonance imaging (MRI) revealed an edematous stroke-like lesion in the right occipital lobe accompanied by brain swelling. Intravenous ceftriaxone, acyclovir, intravenous immunoglobulin (IVIG), and pulse steroid therapy were started for possible diagnosis of viral/bacterial/autoimmune encephalitis; levetiracetam, phenytoin, and an infusion of sodium thiopental were started for refractory status epilepticus; and a 3% NaCl infusion was started for local brain edema. The results of serum autoimmune encephalitis panel were negative. Further investigations for rheumatic, vascular, and metabolic disorders were unremarkable. Despite these supportive treatments, the patient was clinically decompensated due to brain swelling that progressed to the left midline shift, and he underwent decompressive craniectomy. Histologic examination of brain biopsy specimen revealed non-specific encephalitis findings. A pathogenic variant of the MT-TL1 gene (m.3243A > T), responsible for MELAS, was detected. The patient?s condition dramatically improved after specific treatment for MELAS. If the diagnosis and treatment are delayed, MELAS syndrome can cause serious brain edema, which may ultimately require decompressive craniectomy.

Mitochondrial Strokes: Diagnostic Challenges and Chameleons.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) Syndrome: Frequency, Clinical Features, Imaging, Histopathologic, and Molecular Genetic Findings in a Third-level Health Care Center in Mexico.

INTRODUCTION: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, is a multisystemic entity of mitochondrial inheritance. To date, there is no epidemiological information on MELAS syndrome in Mexico. CASE SERIES: A retrospective, cross-sectional design was employed to collect and analyze the data. The clinical records of patients with mitochondrial cytopathies in the period ranging from January 2018 to March 2020 were reviewed. Patients who met definitive Yatsuga diagnostic criteria for MELAS syndrome were included to describe frequency, clinical, imaging, histopathologic, and molecular studies. Of 56 patients diagnosed with mitochondrial cytopathy, 6 patients met definitive Yatsuga criterion for MELAS (10.7%). The median age at diagnosis was 34 years (30 to 34 y), 2 females and the median time from onset of symptoms at diagnosis 3.5 years (1 to 10 y). The median of the number of stroke-like episodes before the diagnosis was 3 (range, 2 to 3). The main findings in computed tomography were basal ganglia calcifications (33%), whereas in magnetic resonance imaging were a lactate peak in the spectroscopy sequence in 2 patients. Five patients (84%) had red-ragged fibers and phantom fibers in the Cox stain in the muscle biopsy. Four patients (67%) had presence of 3243A>G mutation in the mitochondrial MT-TL1 gene. One patient died because of status epilepticus. CONCLUSIONS: MELAS syndrome represents a common diagnostic challenge for clinicians, often delaying definitive diagnosis. It should be suspected in young patients with stroke of undetermined etiology associated with other systemic and neurological features.

Linear cortical cystic lesions: Characteristic MR findings in MELAS patients.

BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a progressive neurodegenerative disorder with stroke-like lesions. The common MRI findings are gyral swelling and high signal intensity on T2WI/FLAIR images crossing the vascular territories. We have observed a linear cystic lesion and a laminar necrosis in the affected cortices of MELAS patients. Herein, we evaluated these cortical MRI findings in each subtype of mitochondrial disease. PATIENTS AND METHODS: We retrospectively reviewed the MRI findings of 71 consecutive patients with clinically and genetically confirmed mitochondrial diseases. The cortical cystic lesions and laminar necrotic lesions were evaluated on T1, T2, and FLAIR images in each subtype of mitochondrial disease, as were their clinical and other imaging characteristics. RESULTS: The cortical cystic lesion was observed in 21 of the 71 patients (29.6%) with mitochondrial diseases. Laminar necrosis was detected in only three patients (4.2%). MELAS was the most frequent subtype with cortical cystic lesions, accounting for 81.0%, and all showed the linear pattern except for one patient whose pattern was beaded-like. CONCLUSION: A cortical linear cystic lesion was a common MRI finding in our series of patients with mitochondrial disease, especially in those with MELAS, but laminar necrosis was not. These findings can help differentiate MELAS from infarction.

[Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes(MELAS)].

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes(MELAS)is the most dominant form of mitochondrial diseases, presenting with headaches, seizures, and stroke-like episodes. Stroke-like episodes is a distinguishing feature of MELAS. Symptoms appear before the age of 20 years in 65-76% of patients. For the clinical diagnosis of MELAS, evidence of lactate accumulation in the central nervous system is important. The radiographic features of MELAS are stroke-like lesions in the affected brain areas, primarily the occipito-parietal or posterior temporal lobe. MRI shows high signal intensities on T2-weighted or FLAIR images. The cerebral blood flow in lesions can be increased in the acute phase. MR spectroscopy(MRS)shows a lactate peak in the brain lesions, which is important evidence of lactate accumulation. In pediatric or young adult patients with occipito-parietal stroke-like lesions, a prominent lactate peak in MRS is the key radiographic sign that supports the diagnosis of MELAS.

Therapeutic management of stroke-like episodes varies from that of encephalitis.

INTRODUCTION: Stroke-like episodes (SLEs) are typical cerebral manifestations of certain mitochondrial disorders (MIDs). They are characterised by a vasogenic edema in a non-vascular distribution. PATIENTS CONCERNS:: none DIAGNOSIS:: SLEs show up on cerebral MRI as stroke-like lesions (SLLs), characterised by vasogenic edema in a non-vascular distribution. SLLs expand in the acute stage and regress during the chronic stage. They show hyperperfusion in the acute stage and hypoperfusion in the chronic stage. INTERVENTIONS: SLLs respond favorably to antiseizure drugs, to No-precursors, steroids, the ketogenic diet, and antioxidants. OUTCOME: SLLs end up as normal tissue, white matter lesion, grey matter lesion, cyst, laminar cortical necrosis, or the toenail sign. CONCLUSIONS: SLLs are a frequent manifestation of MIDs. They undergo dynamic changes in the acute and chronic stage. They need to be differentiated from ischemic stroke as they are differentially treated.

Mitochondrial metabolic stroke: Phenotype and genetics of stroke-like episodes.

Stroke-like episodes (SLEs) are the hallmark of mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome but rarely occur also in other specific or nonspecific mitochondrial disorders. Pathophysiologically, SLLs are most likely due to a regional disruption of the blood-brain barrier triggered by the underlying metabolic defect, epileptic activity, drugs, or other factors. SLEs manifest clinically with a plethora of cerebral manifestations, which not only include features typically seen in ischemic stroke, but also headache, epilepsy, ataxia, visual impairment, vomiting, and psychiatric abnormalities. The morphological correlate of a SLE is the stroke-like lesion (SLL), best visualised on multimodal MRI. In the acute stages, a SLL presents as vasogenic edema but may be mixed up with cytotoxic components. Additionally, SLLs are characterized by hyperperfusion on perfusion studies. In the chronic stage, SLLs present with a colorful picture before they completely disappear, or end up as white matter lesion, cyst, laminar cortical necrosis, focal atrophy, or as toenail sign. Treatment of SLLs is symptomatic and relies on recommendations by experts. Beneficial effects have been reported with nitric-oxide precursors, antiepileptic drugs, antioxidants, the ketogenic diet, and steroids. Lot of research is still needed to uncover the enigma SLE/SLL.

Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy.

AIMS: Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. METHODS: In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. RESULTS: Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. CONCLUSIONS: Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.

Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less ρ0 cells and cybrids carrying MELAS mitochondrial DNA mutation.

OBJECTIVES: Radiolabeled Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) (*Cu-ATSM), including (60/62/64)Cu-ATSM, is a potential imaging agent of hypoxic tumors for positron emission tomography (PET). We have reported that *Cu-ATSM is trapped in tumor cells under intracellular overreduced states, e.g., hypoxia. Here we evaluated *Cu-ATSM as an indicator of intracellular overreduced states in mitochondrial disorders using cell lines with mitochondrial dysfunction. METHODS: Mitochondrial DNA-less ρ(0)206 cells; the parental 143B human osteosarcoma cells; the cybrids carrying mutated mitochondria from a patient of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (2SD); and that carrying wild-type one (2SA) were used. Cells were treated under normoxia or hypoxia, and (64)Cu-ATSM uptake was examined to compare it with levels of biological reductant NADH and NADPH. RESULTS: ρ(0)206 cells showed higher (64)Cu-ATSM uptake than control 143B cells under normoxia, whereas (64)Cu-ATSM uptake was not significantly increased under hypoxia in ρ(0)206 cells. Additionally, (64)Cu-ATSM uptake showed correlate change to the NADH and NADPH levels, but not oxygenic conditions. 2SD cells showed increased (64)Cu-ATSM uptake under normoxia as compared with the control 2SA, and (64)Cu-ATSM uptake followed NADH and NADPH levels, but not oxygenic conditions. CONCLUSIONS: (64)Cu-ATSM accumulated in cells with overreduced states due to mitochondrial dysfunction, even under normoxia. We recently reported that (62)Cu-ATSM-PET can visualize stroke-like episodes maintaining oxygen supply in MELAS patients. Taken together, our data indicate that *Cu-ATSM uptake reflects overreduced intracellular states, despite oxygenic conditions; thus, *Cu-ATSM would be a promising marker of intracellular overreduced states for disorders with mitochondrial dysfunction, such as MELAS, Parkinson's disease and Alzheimer's disease.

Cochlear implantation in a patient with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome.

OBJECTIVE: The aim of this study was to investigate the usefulness of a Nucleus C124M cochlear implant in a patient with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. MATERIAL AND METHODS: A 29-year-old woman with MELAS syndrome presented with sensorineural hearing loss and diabetes mellitus and underwent multichannel cochlear implantation. The follow-up period was 10 months. The case history, assessment of mitochondrial disease, indications for the cochlear implant and the benefits of cochlear implantation were evaluated. RESULTS: Nine months after the surgery the patient could use the telephone and was quite satisfied with the improvement in communication due to the cochlear implant. CONCLUSION: Cochlear implantation can be recommended for patients with MELAS syndrome if they have residual retrocochlear function. Single photon emission computerized tomography was found to be very useful for evaluating retrocochlear function.

[Mitochondrial encephalomyelitis, lactic acidosis and cerebrovascular accidents (MELAS) in pediatric age with the A3243G mutation in the tRNALeu(UUR) gene of mitochondrial DNA]. / Encefalomiopatía mitocondrial, acidosis láctica y accidentes cerebrovasculares (MELAS) en edad pediátrica con la mutación A3243G en el gen del ARNtLeu(UUR) del ADN mitocondrial.

OBJECTIVES: To evaluate three patients with the mitochondrial encephalopathy, lactic acidosis and cerebrovascular accident syndrome (MELAS) diagnosed in childhood, with particular reference to the initial symptoms and clinical evolution during the first stage at a pediatric age, and to compare them with other studies on the subject. PATIENTS AND METHODS: Two boys and a girl of 10, 11 and 13 years had tests on lactate, pyruvate and aminoacids in biological fluids under basal conditions and also functional tests and enzyme activity assay of the mitochondrial respiratory chain of a muscle biopsy. We also analysed the particular DNA mutations related to MELAS in different tissues from these patients and in lymphocytes from members of the mothers' families who could be tested. RESULTS: The patients fulfilled the clinical criteria for the MELAS syndrome. Neuroimaging showed cerebrovascular accidents. Neurophysiological studies showed myopathy in one patient and neuroaxonal neuropathy in another. In two cases ophthalmological study showed retinitis pigmentaria and during cerebrovascular accidents transient phenomena of homonymous hemianopsia and cortical blindness were seen. In all patients muscle biopsy showed ragged red fibres and the biochemical study showed an enzyme deficit in the respiratory mitochondrial chain. On molecular genetic study of the mitochondrial DNA (mtDNA) there was a particular mutation A3243G on the tRNA(Leu) in all patients and some members of the mothers' families. CONCLUSIONS: In children with frequent episodes of migraine headaches, vomiting, refractory epilepsy and fatigue the presence of a mitochondrial disease should be suspected. On detection of mtDNA mutations MELAS may be diagnosed even without all the clinical criteria which characterise this syndrome.

Neuroradiological features of six kindreds with MELAS tRNA(Leu) A2343G point mutation: implications for pathogenesis.

OBJECTIVE: To determine the neuroradiological abnormalities associated with subjects carrying the mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) tRNA(Leu)(UUR) A3243G point mutation METHODS: Mitochondrial genetic analysis was performed on 24 subjects from six kindreds with the MELAS tRNA(Leu)(UUR) A3243G point mutation. Cerebral CT and MRI were performed on 24 patients and 15 patients respectively. Previous neuroradiological investigations including cerebral CT from four deceased members of the families were also reviewed. Histological examination of postmortem specimens of two patients within the kindreds was performed. RESULTS: The commonest radiological finding was basal ganglia calcification. Other abnormalities included focal lesions and cerebellar and cerebral atrophy. Basal ganglia calcification was progressive, symmetric, and asymptomatic. Histologically, basal ganglia calcification in one patient was found to be in the pericapillary regions of the globus pallidus, with no neuronal involvement. Focal lesions most commonly involved the grey matter of the parietal and occipital lobes and cerebellum. Histopathological examination suggested that these were due to cellular rather than vascular dysfunction. Enlargement of the fourth ventricle was the first sign of cerebellar atrophy. Cerebral and cerebellar atrophy were only present with severe disease. CONCLUSIONS: These radiological findings, when considered in the context of the clinical and pathological findings, seem to reflect two major disease processes: an intermittent abrupt loss of function associated with cell injury from which there is at least partial recovery and a slowly progressive degenerative process causing basal ganglia calcification, and cerebral and cerebellar atrophy. The clinical and radiological features resulting from these processes are distinctive and provide insight into the consequences of mitochondrial dysfunction on the brain.

[Evaluation of cardiac function by various cardiac imaging techniques in mitochondrial cardiomyopathy: a case report].

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

[Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with delayed and decreased cerebral blood flow on cerebral angiography--a case report].

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

Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations.

We reviewed 10 patients (5 males, 5 females) with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The age of symptom onset ranged from 3 months to 12 years. All had lactic acidosis, multiple stroke-like events with secondary neurological deficits, radiological changes of progressive brain infarction, and muscle biopsy showing ragged-red fibers. In patients with earlier onset of symptoms (< 2 yr), involvement tended to be more diffuse, with failure to thrive and early onset of delayed development. Patients whose symptoms appeared later tended to have focal neurological deficits with migraine-like headache, and a rate of cognitive regression reflecting the rapidity of disease progression. Radiological changes included multiple areas of infarction with initial predilection for parietal occipital areas, progressing to generalized atrophy. Pathological findings in muscle biopsies included type 1 fiber predominance, ragged-red fibers, increased intermyofibrillar lipid deposition, and abnormal mitochondria. Four patients showed mitochondrial DNA tRNA mutation at position 3,243. No difference was noted in clinical, radiological, or pathological findings in patients with and without this mutation, suggesting that multiple sites of point mutation may give rise to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.