Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

Iizuka, Takahiro; Sakai, Fumihiko; Suzuki, Norihiro; Hata, Takashi; Tsukahara, Sonoko; Fukuda, Mai; Takiyama, Yoshihisa

doi:10.1212/wnl.59.6.816

Cited by 169 publications

(123 citation statements)

References 42 publications

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“…Energy failure is one plausible mechanism whereby neuronal dysfunction develops in mitochondrial disease,31 and it may be that localized perfusion deficits predispose to focal seizures. The extreme expression of this potential perfusion/activity mismatch is the stroke‐like episode 32, 33. In keeping with other accounts, we find that all of these events are associated with focal seizure activity.…”

Section: Discussionsupporting

confidence: 89%

Epilepsy in adults with mitochondrial disease: A cohort study

Whittaker

Devine

Gorman

et al. 2015

Annals of Neurology

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ObjectiveThe aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.MethodsWe prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death.ResultsOverall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).InterpretationEpilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957

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Section: Discussionsupporting

confidence: 89%

Epilepsy in adults with mitochondrial disease: A cohort study

Whittaker

Devine

Gorman

et al. 2015

Annals of Neurology

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“…The two main hypotheses being considered are: (1) ischemic, with suggestion of a "mitochondrial angiopathy" caused by mitochondrial dysfunction in smooth muscle cells of the small cerebral vessels leading to vascular occlusion with neuronal loss 7,8,9,10 ; and (2) metabolic, due to a "mitochondrial cytopathy", that trigger energy failure of brain tissue causing neuronal damage 11,12,13 . Currently, the mechanisms that trigger these episodes are correlated to a combination of these two hypotheses, in which both (neuronal and vascular dysfunction) are responsible for the pathogenesis of stroke-like episodes 14 .…”

Section: What Is the Pathogenesis?mentioning

confidence: 99%

“…The stroke-like episode may occur alone or in association with signs of the encephalopathy, such as seizures 5,6 . The clinical outcome of stroke-like episodes is more benign, with improvement of symptoms in a few months, but the symptoms related encephalopathy, such as dementia and seizures, may progressively worsen 6,12,14,27 . The presence of progressive dementia has also been found associated with changes in cerebral perfusion even in the absence of stroke-like episode, but with marked cortical atrophy in the chronic phase of the disease characterized neuronal loss, similar to what occurs in vascular dementia 27,28 .…”

Section: What Are the Clinical Features?mentioning

confidence: 99%

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

Lorenzoni

Werneck

Kay

et al. 2015

Arq. Neuro-Psiquiatr.

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Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

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“…Computed tomography scans are widely available and useful for showing focal or diffuse atrophy, calcifications, cysts or lacunas, ischemic lesions, hemorrhages, white matter lesions, demyelination, but have their limitations when trying to visualize other abnormalities, such as SLLs 57 , symmetric necrosis of the thalami, basal ganglia, diencephalon, or brainstem in patients with LS or LLS 45 . The CT may show diffuse atrophy or focal atrophy of the supratentorial cortex 22 or the cerebellum 58,59 , focal or diffuse demyelination, uni-or bilateral calcifications of the basal ganglia, frequently observed in MELAS 54,59 , dentate nuclei, or the cerebellum 59 , vasogenic edema 60,61 , bilateral striatal necrosis 59,62 , malformations 63 such as polymicrogyria 52 or tuberous sclerosis 53 , or macro-or microhemorrhages.…”

Section: Computed Tomography (Ct)mentioning

confidence: 99%

Central Nervous System Imaging in Mitochondrial Disorders

Finsterer

2009

Can. j. neurol. sci.

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Imaging of central-nervous-system (CNS) abnormalities is important in patients with mitochondrial disorders (MCDs) since the CNS is the organ second most frequently affected in MCDs and some of them are potentially treatable. Clinically relevant imaging techniques for visualization of CNS abnormalities in MCDs are computed tomography, magnetic resonance imaging, and MR-spectroscopy. The CNS abnormalities in MCDs visualized by imaging techniques include stroke-like lesions with cytotoxic or vasogenic edema, laminar cortical necrosis, basal ganglia necrosis, focal or diffuse white matter lesions, focal or diffuse atrophy, intra-cerebral calcifications, cysts, lacunas, hypometabolisation, lactacidosis, hemorrhages, cerebral hypo- or hyperperfusion, intra-cerebral artery stenoses, or moyamoya syndrome. The CNS lesions may proceed with or without clinical manifestations, why neuroimaging should be routinely carried out in all MCDs to assess the degree of CNS involvement. Some of these lesions may remain unchanged for years, some may show contiguous spread and progression, but some may even disappear, spontaneously or in response to medication. Dynamics of Stroke-like lesions may be positively influenced by L-arginine, dichloracetate, steroids, edavarone, or antiepileptics. Symptomatic treatment of CNS abnormalities in MCD patients may positively influence their outcome.

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Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

Cited by 169 publications

References 42 publications

Epilepsy in adults with mitochondrial disease: A cohort study

Epilepsy in adults with mitochondrial disease: A cohort study

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

Central Nervous System Imaging in Mitochondrial Disorders

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