Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

BACKGROUND: The pathogenesis of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remains unknown. METHODS: Fourteen stroke-like episodes in six patients with MELAS were studied using clinical, neuroradiologic, and electrophysiologic approaches. In two patients postmortem examination was done. RESULTS: Headache and epileptic seizure were the most common presenting symptoms. In 13 of 14 episodes the cerebral cortex was primarily involved with variable subcortical edema particularly in the temporal, occipital, and parietal cortex. Repeated MRI performed in two episodes revealed progressive spread of the cortical lesion to the surrounding cortex for a few weeks after the onset of symptoms. In 6 of 11 episodes T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis was seen during subacute stage of the episode. Fat-suppression MRI confirmed intracortical gyral hemorrhage in one episode. Petechial gyral microhemorrhages were also pathologically confirmed in the autopsy of another patient. In 9 of 11 episodes focal epileptiform discharges on EEG were noted in the acute brain lesion. In seven of nine episodes focal cortical hyperperfusion was seen in SPECT studies. CONCLUSION: The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.     

Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms

The pathogenesis of stroke-like episodes in mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) is not fully understood although two main theories have been proposed; ischemic vascular hypothesis caused by "mitochondrial angiopathy" and generalized cytopathic hypothesis caused by "mitochondrial cytopathy". Crucial molecular mechanism includes the lack of taurine modification at the wobble uridine of mutant transfer RNAsLeu(UUR) resulting in defective translation of cognate codons due to a defect in codon-anticodon interaction. Whereas recent clinical studies have shed light on the neuronal hyperexcitability, which may potentially initiate a cascade of stroke-like events. Stroke-like episodes are characterized by neuronal hyperexcitability, neuronal vulnerability, increased capillary permeability, and focal hyperaemia. It is recognized that stroke-like lesions not only evolve in the area incongruent to a vascular territory, but also potentially spread into the surrounding cortex with concomitant vasogenic edema presumably provoked by prolonged epileptic activities. Based on the clinical observations, we speculate that stroke-like episodes appear to be non-ischemic neurovascular events; once neuronal hyperexcitability developed in a localized brain region as a result from either mitochondrial dysfunction in the capillary endothelial cells, or in neurons or astrocytes, epileptic activities may depolarize the adjacent neurons leading to propagation of epileptic activities in the surrounding cortex. Increased capillary permeability provoked by epileptic activities in the presence of mitochondrial capillary angiopathy may cause unique edematous brain lesions predominantly involving the cortex. As a consequence, susceptible neuronal population in the cortex may result in neuronal loss with a laminar or pseudo-laminar distribution.     

A case with late-onset MELAS with hallucination and delusion]

We report a 53-year-old male patient with late onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes(MELAS) with hallucination and delusion. The patient manifested various neurological symptoms including perceptive deafness, muscle weakness of limbs with loss of consciousness, sensory abnormalities in hands, feet and a face, abnormal sense of taste, tremor, palsy of upward eye movement and weak deep tendon reflexes prior to the psychotic episode. He was diagnosed as MELAS, because of high serum lactic acid and pyruvic acid, and the point mutation in the mitochondrial DNA 3243. SPECT imaging showed decreased perfusion in occipital cortex and thalamus. These SPECT changes improved after disappearing visual hallucination. Hallucination might be caused by delirium due to stroke-like episode. Dysfunction in the occipital cortex and thalamus might be involved with this perfusion change.     

Neuroimaging of stroke-like episodes in MELAS

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) shows sudden neurological deficits that are called ‘stroke-like episodes’. With regard to the pathophysiology of stroke-like episodes, so-called mitochondrial angiopathy and cytopathy theories have been proposed, but the subject is still controversial. To clarify this matter and to contribute to the development of a treatment for MELAS, we review here current neuroimaging research and consider the pathophysiology of stroke-like lesions. With regard to diffusion-weighted imaging findings, early reports often showed an elevated apparent diffusion coefficient (ADC) in stroke-like lesions; this was considered to be mainly vasogenic edema in the acute phase and is a different pattern than that in stroke. However, there has recently been an increase in the number of reports of a decrease in ADC; these cases are considered to be cytotoxic edema in the acute phase, which is compatible with stroke. With regard to ¹H-magnetic resonance spectroscopy findings in stroke-like lesions, a decrease in N-acetylaspartate and an increase in lactate have been reported. With regard to single photon emission computed tomography findings for stroke-like lesions in MELAS, an overall trend is hyperperfusion in the acute stage (within 1 month) of stroke-like episodes and hypoperfusion in the chronic stage (several months later). With regard to positron emission tomography, nearly all of these reports are consistent with the mitochondrial cytopathy theory. With regard to neuropathology in MELAS, the most common findings during the chronic stage of stroke-like episodes include foci of necrosis and peculiar vascular changes (abnormalities of mitochondria in small arteries). Concerning the pathology of the acute stage of stroke-like episodes, extensive petechial hemorrhage along the gyri of the cortex corresponding to acute stroke-like lesions has been reported. To clarify the true pathophysiology of stroke-like episodes, we offer three suggestions. First, we must define the precise onset of stroke-like episodes. Second, current studies are limited by the difficulty of imaging just before and just after (within a few minutes) the onset of stroke-like episodes. Third, we hope to establish an experimental animal model. We should conduct a simultaneous multimodal imaging and histological study just before and just after (within a few minutes) the onset of stroke-like episodes in an experimental animal model.     

Can diffusion weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS?

The precise mechanism of neurological symptoms in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is still controversial. The diffusion weighted MR findings at the acute phase of a neurological event in MELAS are described and the pathophysiology of stroke-like lesion in the light of diffusion changes is discussed.Brain MRI was performed 2 days after the sudden onset of cortical blindness in a 25 year old patient with MELAS. Fluid attenuated inversion recovery (FLAIR) images showed multifocal cortical and subcortical hyperintensities located bilaterally in the frontobasal and the temporo-occipital lobes. Diffusion weighted images showed normal to increased apparent diffusion coefficient values in the acute left temporooccipital lesion and increased values in the older stroke-like lesions.These diffusion weighted findings support the metabolic rather than the ischaemic pathophysiological hypothesis for stroke-like episodes occurring in MELAS. Normal or increased apparent diffusion coefficient values within 48 hours of a neurological deficit of abrupt onset should raise the possibility of MELAS, especially if conventional MR images show infarct-like lesions.     

Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.     

Mitochondrial Encephalopathy With Lactic Acidosis and Stroke-like Episodes (MELAS) May Respond to Adjunctive Ketogenic Diet

BackgroundMitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome can present management challenges. Refractory seizures and stroke-like episodes leading to disability are common.PatientWe analyzed the clinical, electrophysiologic, and radiologic data of a 22-year-old woman with multiple episodes of generalized and focal status epilepticus and migratory cortical stroke-like lesions who underwent muscle biopsy for mitochondrial genome sequencing.ResultsAlthough initial mitochondrial genetic testing was negative, muscle biopsy demonstrated a mitochondrial DNA disease-causing mutation (m.3260A > G). New antiepileptic medications were added with each episode of focal status epilepticus with only temporary improvement, until a modified ketogenic diet and magnesium were introduced, leading to seizure freedom despite development of a new stroke-like lesion, and subsequent decrease in frequency of stroke-like episodes. We propose a metabolic model in which the ketogenic diet may lead to improvement of the function of respiratory chain complexes.ConclusionsThe ketogenic diet may lead to improvement of mitochondrial dysfunction in MELAS, which in turn may promote better seizure control and less frequent stroke-like episodes.     

MELAS型线粒体脑肌病1例临床病理

目的分析1例MELAS型线粒体脑肌病的临床病理特点。方法对该患者的临床、实验室、影像学及肌肉病理特点进行回顾性分析。结果血和脑脊液乳酸高,头颅CT、MRI显示病灶局限于颞顶枕部,肌肉活检证实患者的骨骼肌存在大量典型的不整边红纤维。结论对年轻患者反复表现为卒中样发作、局限性或全面性癫痫,病灶局限于颞顶枕部,应行肌肉活检,避免误诊。     

An autopsy case of generalized seizures, myoclonus, blindness and deafness

We have reported the clinical and autopsy findings in a case with generalized seizures, myoclonus, blindness and deafness which was accompanied by stroke-like episodes. This case was diagnosed as mitochondrial encephalomyopathy, lactic acidosis & stroke-like episodes (MELAS) from these findings. Solitary and continuous lesions of softening were distributed in both hemispheres, more severely in the frontal and occipital poles. These lesions did not correspond to a vascular supply. The pulvinar, lateral and medial geniculate body of the thalamus, cerebellar vermis and dentate nucleus had small lesions of softening. The cortical lesions occurred mainly in layer 4, and the most prominent lesions among them appeared cystic, involving the subcortical white matter, but nerve cells in layer 1 and 2 were preserved. Proliferation of small blood vessels was seen around the softening areas. Electron microscopy revealed increased mitochondria in endothelial cells of these vessels, abnormal dense bodies in skeletal muscle cells and tightly packed mitochondria in choroid plexus epithelial cells. Immunohistochemical study suggested that vimentin positive cells were seen around lesions and proliferated vessels are different from those seen in the intact tissues.     

MELAS型线粒体脑肌病的脑部MRI表现(附三例报道)

目的 总结分析MELAs型线粒体脑肌病的脑部MRI表现.方法 回顾性分析3例MELAS型线粒体脑肌病患者的临床资料和MRI表现.结果 MRI显示MELAS型线粒体脑肌病表现为以颞叶、顶、枕叶为主的皮层及皮层下白质病变,病变多呈双侧非对称性分布,部分患者以累及基底节为主要表现,T2WI和液体衰减翻转恢复序列对病变的显示有独特的作用,DWI、ADC图及增强扫描能够诊断及鉴别诊断线粒体脑肌病及卒中,MRS对其诊断可以起到辅助作用.结论 MELAS型线粒体脑肌病在MRI图像上具有特征性,MRI影像表现结合临床资料对本病多能作出正确的诊断.     

Deep white matter pathologic features in watershed regions: a novel pattern of central nervous system involvement in MELAS

BACKGROUND: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome typically manifests in adults younger than 40 years with encephalopathy, stroke-like episodes, and lactic acidosis. Magnetic resonance imaging (MRI) abnormalities typically involve the cortical gray and the adjacent subcortical white matter. OBJECTIVE: To describe a 58-year-old woman diagnosed with MELAS who was initially seen with acute myopathy, cardiac ischemia, psychosis, and MRI changes in a watershed distribution. RESULTS: Initial MRI of the brain showed the characteristic parieto-occipital gray matter lesions involving the adjacent white matter. Follow-up MRI revealed striking deep white matter involvement in a watershed distribution. A cerebral angiogram and thorough hypercoagulable workup results were normal. Electromyography showed acute denervation and myopathy. A muscle biopsy specimen revealed ragged red and cytochrome-c oxidase-negative fibers. Mitochondrial DNA analysis revealed an A3243G mutation. CONCLUSIONS: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes should be considered in older patients with myopathy, cardiomyopathy, encephalopathy, and unaccountable MRI findings. Watershed pathologic features are a rare pattern of cerebral involvement in MELAS.     

MELAS with prominent white matter gliosis and atrophy of the cerebellar granular layer: a clinical, genetic, and pathological study

This report concerns an autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with unusual neuropathological findings. The patient was a Japanese woman who was 21 years old at the time of death. Her mother is a patient with genetically confirmed MELAS. Her clinical manifestations included convulsions and lactic acidosis in the latter half of the first decade of life, followed by deafness, dementia, muscle weakness in the lower extremities, slight ataxia in the upper and lower extremities, and diabetes mellitus. Muscle biopsy revealed ragged-red fibers, and genetic study showed a point mutation at nucleotide pair 3243 in mitochondrial DNA. She died of lactic acidosis. In the clinical course, she did not develop stroke-like episodes. The neuropathological examination revealed not only minute to small necrotic foci in the cerebral cortex, amygdala, hippocampus, and cerebellum, but also prominent white matter gliosis in the central nervous system and cerebellar cortical degeneration of granular cell type. Our neuropathological findings, including prominent white matter gliosis of the central nervous system and cerebellar cortical degeneration of granular cell type, may indicate morphologically widespread cellular dysfunction, not restricted to either neuronal or vascular derangement, in the brain pathology of MELAS. Received: 28 July 1998 / Revised, accepted: 27 October 1998     

MELAS综合征八例

目的探讨MELAS综合征(线粒体脑肌病伴乳酸血症和卒中样发作)的临床特征,为早期诊断和治疗提供参考。方法对8例确诊的MELAS综合征患者的临床表现、肌活检病理及影像学资料进行回顾性分析。结果头痛、抽搐、运动耐受差、智能障碍、脑卒中样发作、血乳酸水平升高为本组患者的主要临床表现。8例患者脑内病灶均表现为T1WI低信号、T2WI高信号,病变主要累及额、颞、顶、枕叶皮层、皮层下及基底节,伴有不同程度的脑萎缩,病灶多发且与血管分布区不一致。8例患者行肌肉活检可见破碎红纤维(RRF)、异常线粒体增多。结论 MELAS综合征临床表现复杂多样,确诊依赖于临床特征分析和肌肉活检。磁共振成像在线粒体脑肌病的诊断、鉴别诊断方面具有一定的价值。     

10例误诊为线粒体脑肌病伴高乳酸血症及卒中样发作的青年卒中患者的临床分析

目的线粒体脑肌病伴高乳酸血症及卒中样发作(MELAS)是最常见的线粒体脑肌病类型之一,具有明显的临床和遗传异质性。MELAS最显著的核心症状是卒中样发作,容易与缺血性脑卒中混肴。方法通过分析10例曾误诊为MELAS的青年脑梗死患者的临床表现和辅助检查,并与MELAS患者相对比。同时结合文献复习,分析卒中发作与卒中样发作的相同与不同之处。结果所有10例患者均出现一次以上卒中发作,以偏侧肢体无力最常见,其次为偏侧肢体麻木、偏盲、失语等。其中8例患者存在一种以上血管病相关的危险因素。头部MRI发现皮质和皮质下白质病变,均累及多个脑叶,数月后复查可见软化灶形成。所有患者均同时存在基底节和/或深部白质病变。MRA均发现动脉闭塞或狭窄。结论本组患者卒中发作以偏瘫最常见。影像学上以皮质受累为主,同时常出现深部白质和/或基底节病变,后期可形成软化灶。     

线粒体脑肌病伴乳酸血症和卒中样发作综合征的临床、EEG、影像学及肌肉病理特点分析

目的 探讨线粒体脑肌病伴乳酸血症和卒中样发作(MELAS)综合征的临床症状、EEG、影像学及肌肉病理特点,以提高对其认识及诊断的正确率.方法 回顾性分析6例基因确诊的MELAS综合征患者的临床资料,分析其临床表现、EEG、影像学、肌肉病理特点.结果 6例患者中男性4例,女性2例,年龄最大者43岁,最小者4岁,平均起病年...     

Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS

Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke-like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime (^99mTc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased ^99mTc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of “hypoperfusion” on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs.     

MELAS综合征和Leigh病患者的影像学观察

目的观察线粒体脑肌病伴乳酸血症和卒中样发作(MELAS)综合征和Leigh病患者的影像学特点。方法对12例MELAS综合征、7例Leigh病和1例MELAS与Leigh病叠加患者的影像学特点进行系统分析。结果 12例MELAS综合征患者脑CT及MRI示病灶多位于枕、颞、顶叶皮质及皮质下,且病灶在左侧占优势;7例leigh病患者病变部位主要在双侧基底节、丘脑及脑干。4例MELAS综合征、4例Leigh病患者、1例叠加的核磁波谱检查示病变区乳酸水平明显增高。DWI仅显示新病灶,FLAIR可观察到所有新旧病灶,较T2像敏感。MELAS可见部分病变侧MRA血管增粗增多,且病情复发时病灶有迁徙,旧病变有萎缩的特点。结论 MELAS和Leigh的影像学特点有显著差异,前者以脑叶皮质及皮质下受累为主,病变范围较大,不符合大脑动脉供血区分布。Leigh患者主要病变部位在脑干、基底节,且病灶发展变化趋势有一定的规律性。FLAIR与DWI是不可缺少的扫描像位。MRS对线粒体脑病和线粒体脑肌病的诊断有重要价值,应作为本病常规扫描序列。     

Linear cortical cystic lesions: Characteristic MR findings in MELAS patients

BackgroundMitochondrial 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 methodsWe 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.ResultsThe 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.ConclusionA 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.     

线粒体基因G13513A突变导致的线粒体脑肌病六例临床表型分析

目的 报告6例mtDNA G13513A点突变引起的线粒体脑肌病患者的临床、影像学特点,总结mtDNA G13513A突变所致的线粒体病的临床表型.方法 对35例mtDNA常见突变(包括大片段缺失及A3243G、T3271C、A8344G、T8993G/C点突变)检查为阴性的线粒体脑肌病患者,用线粒体DNA全长测序和(或)聚合酶链反应-限制性片段长度多态法检测mtDNA G13513A点突变,分析阳性患者的临床特点,复习文献报道的mtDNA G13513A所致线粒体病的病例.结果 35例患者中有6例存在mtDNA G13513A突变.该6例患者均出现偏盲、轻偏瘫或偏身感觉障碍等卒中样发作表现,其中3例成人发病者以卒中样发作为主要症状,伴随癫痫、头痛、身材矮小、神经性耳聋等,头颅MRI显示以顶-枕-颢叶受累为主的大片病灶,符合成人型线粒体脑肌病伴高乳酸血症和卒中样发作(MELAS)的临床和影像学特点;3例青少年发病者除卒中样发作外,还有构音障碍、共济失调、眼外肌瘫痪等脑干受累的症状,MRI检查可见枕-颞叶大脑皮质非对称性病灶,以及双侧基底节和脑干的对称性病灶,符合青少年型MELAS-Leigh叠加综合征的临床和影像学特点.肌肉病理检查在5例患者发现不整红边纤维.经复习文献,发现mtDNA G13513A突变患者还存在婴幼儿型Leigh或Leigh样综合征表型.结论 mtDNA G13513A点突变是线粒体脑肌病较常见的致病性突变,主要导致Leigh综合征、MELAS-Leigh叠加综合征或MELAS综合征,其临床表型具有年龄依赖性.

Abstract：

Objective To report 6 Chinese patients with mitochondrial encephalomyopathy caused by mitochondrial DNA(mtDNA)G13513A mutation and discuss the mitochondrial phenotype associated with this mutation based on the data of our patient series as well as the reports by others.Methods Direct sequencing of polymerase chain reaction(PCR)products or PCR-RFLP analysis Was performed to screen mtDNA G13513A mutation in 35 cases with mitoehondrial encephalomyopathy.who carried no mtDNA common mutations(1arge 8eale deletion,A3243G,T3271 C,A8344G,or T8993G/C).The clinical features,MRI changes were retrospectively collected and analyzed.Published studies of all patients with mtDNA G13513A mutation were also reviewed.Results Six patients were identified carrying mtDNA G13513A mutation.All patients presented stroke-like episodes with hemianopsia.hemiparesis or hemiparesthesia.Three adult patients presented clinical and radiological features of adult-onset mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),including stroke-like episodes,epilepsy,headache,short stature,sensorineural deafness,multifocal lesions on parietal,occipital and temporal lobes on cranial MRI scans.Three iuvenile.onset patients presented the clinical and brain MRI features of MELAS-Leigh syndrome(LS)overlap syndrome.In addition to the stroke-like episodes,they also showed brain stem lesions with dysarthria,ataxia,and ophthalmopJegia. Brain MRI revealed asymmetrical lesions in the cortex of the oecipital and temporal lobes,as well as symmetrical lesions in the bilateral basal ganglia and brainstem.Muslce biopsy showed ragged redfibem in 5 patients.The infant-onset LS or Leigh-like syndrome with mtDNA G135 13A was described in the English literature.Conclusions mtDNA G13513A mutation is a common pathogenic mutmion for mitochondrial encephalomyopathy,which can result in Leigh syndrome,MELAS-LS overlap syndrome and adult MELAS.The onset of various phenotypes is relatively age-dependent.     

Serial brain imaging analysis of stroke-like episodes in MELAS

We report 2 patients of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and consider the pathophysiology of stroke-like lesions, using magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) on MRI, perfusion imaging on MRI, and 1H magnetic resonance spectroscopy (1H-MRS). In Patient 1, T2-weighted imaging (T2-WI) on MRI at onset and even at 44 days after onset of the stroke-like episode showed high intensity in left parietal, temporal, and occipital lobe lesions. In the temporal lobe lesion, the apparent diffusion coefficient (ADC) at 44 days after onset was higher (average: 1.219x10(-3)mm2/s) than that in a normal region (average: 0.796x10(-3)mm2/s). (1)H-MRS of the left parietal lobe lesion at the same day showed a decrease in N-acetylaspartate/(creatine+phosphocreatine) (NAA/Cr) (0.43) and a peak in lactate. 1H-MRS of the contralateral side at the same day showed NAA/Cr (1.57) and no peak in lactate. Thereafter, ADC gradually decreased and NAA/Cr gradually increased, and the peak in lactate disappeared in the lesion. In Patient 2, T2-WI at onset showed high intensity in bilateral occipital lobe lesions. In the left occipital lobe lesion, ADC at the same day was higher (1.082x10(-3)mm2/s) than that in a normal region (average: 0.841x10(-3)mm2/s). (1)H-MRS of the left occipital lobe lesion at the same day showed a decrease of NAA (3.0mM) and a peak in lactate (13.1mM) (measured by LCModel). In 1H-MRS of the normal left parietooccipital lobe at 4 months before onset, NAA was 7.6mM and there was no peak in lactate (0mM). Perfusion imaging at onset showed high intensity in bilateral occipital lobes, which indicated hyperperfusion in stroke-like lesions. Thereafter, ADC gradually decreased and the peak in lactate partially decreased, and the low concentration of NAA persisted (regardless of the partial recovery) in the lesion. These results suggest that the stroke-like episodes is related to vasogenic edema, hyperperfusion, and neuronal damage. Acute oxidative phosphorylation defect may have a crucial role in the pathophysiology of stroke-like episodes.