Elsevier

Brain and Development

Volume 33, Issue 4, April 2011, Pages 283-288
Brain and Development

Review article
Neuroimaging of stroke-like episodes in MELAS

https://doi.org/10.1016/j.braindev.2010.06.010Get rights and content

Abstract

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.

Introduction

Mitochondrial disorders are errors of metabolism caused by mutations in mitochondrial and nucleus genes that lead to impaired oxidative phosphorylation. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a type of mitochondrial disorder that was first described by Pavlakis et al. in 1984 [1]. It is characterized by nausea, vomiting, seizures, headaches, diabetes mellitus, short stature, muscle weakness, exercise intolerance, sensorineural hearing loss, myopathy, lactic acidosis, sudden neurological deficits, etc. Sudden neurological deficits are called ‘stroke-like episodes’ and are commonly present with hemiparesis, hemianopsia and/or cortical blindness [2]. To diagnose MELAS, we should demonstrate mitochondrial dysfunction and its characteristic clinical symptoms (stroke-like episodes, etc.). MELAS often shows elevated lactate and pyruvate concentrations on blood and spinal fluid examination. Approximately 80% of MELAS cases show mutation of mitochondrial DNA A3243G, and various other mutations have been reported. Muscle biopsy often shows the existence of ragged-red fiber and succinate dehydrogenase reactive vessels. With regard to the treatment of MELAS, there have been some reports on the efficacy of l-arginine on the acute stage of stroke-like episodes [3], [4], however, almost all other therapies (vitamin B, C, E, CoQ10, carnitine, etc.) are supportive. When a patient shows stroke-like episodes, magnetic resonance imaging (MRI) classically shows a signal change in both the grey and white matter, predominantly in the occipital and parietal lobes, which mimics infarction (stroke-like lesions). However, their distribution does not follow vascular territories and often shows a slowly progressive spread. Thus, it is different from the pattern in ischemic stroke, and their pathophysiology is still controversial. To clarify the true pathophysiology of stroke-like episodes 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.

Section snippets

Hypotheses regarding the pathophysiology of stroke-like episodes

Concerning the pathophysiology of stroke-like episodes, various hypotheses have been proposed: (1) ischemic vascular mechanism, (2) generalized cytopathic mechanism, and (3) non-ischemic neurovascular cellular mechanism [2]. Hypothesis (1) (ischemic vascular mechanism) refers to ischemic change due to hypoperfusion due to vascular abnormalities. This is the so-called mitochondrial angiopathy theory, and is supported by reports that describe abnormalities of mitochondria in small arteries [5],

Diffusion-weighted imaging findings in MELAS

There are many reports on the pathophysiology of stroke-like lesions in MELAS using diffusion-weighted imaging (DWI) [15], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Early reports often showed an elevated apparent diffusion coefficient (ADC) in stroke-like lesions [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]; this was considered to be mainly vasogenic edema in the acute phase and is a different pattern than that in stroke.

1H-MRS findings in MELAS

With regard to 1H-magnetic resonance spectroscopy (1H-MRS) findings of stroke-like lesions in MELAS, a decrease in N-acetylaspartate (NAA) and an increase in lactate have been reported [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]. NAA is thought to be an amino acid that is specific to neurons, and its decrease would reflect a loss or impairment of neurons. A lactate peak on 1H-MRS reflects anaerobic metabolism. A previous report showed a lactate peak on 1H-MRS even in

SPECT findings in MELAS

With regard to single photon emission computed tomography (SPECT) 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) [2], [14], [15], [16], [45], [46], [47], [48], [49], [50]. With regard to perfusion in stroke-like lesions on day 0 (hyperacute stage), Ito et al. showed hyperperfusion in perfusion imaging on MRI [24]. In contrast, Koga et al. found

PET findings in MELAS

There are several reports on the application of positron emission tomography (PET) in MELAS [12], [13], [44], [51], [52]. Nearly all of these reports are consistent with the mitochondrial cytopathy theory. Ikawa et al. performed double-PET functional imaging using [62Cu]-diacetyl bis (N4-methylthiosemicarbazone) (62Cu-ATSM) and [18F]-fluorodeoxyglucose (18FDG) in stroke-like lesions. Acute stroke-like lesions exhibited mild accumulations of 18FDG and 62Cu-ATSM in the early (reflects CBF) and

Neuropathology in MELAS

There have been many reports concerning the pathology of the chronic stage of stroke-like episodes in MELAS. The most common neuropathological findings during the chronic stage of stroke-like episodes include foci of necrosis and peculiar vascular changes. Solitary or multiple foci of necrosis, varying in size and stage, predominantly involving the cerebral cortex and to a lesser degree the cerebral white matter, basal ganglia, brainstem and cerebellum, have been described [2]. Betts et al.

Perspective for the future

While research on neuroimaging in MELAS has progressed, the results are controversial and it is difficult to accurately determine the pathophysiology of stroke-like episodes. To clarify the true pathophysiology of stroke-like episodes, we offer three suggestions. First, we must define the precise onset of stroke-like episodes. Generally, we equate the onset of stroke-like episodes with the onset of clinical symptoms, such as vomiting, hemiparesis, hemianopsia and cortical blindness. However, is

References (53)

  • J. Nishioka et al.

    Inappropriate intracranial hemodynamics in the natural course of MELAS

    Brain Dev

    (2008)
  • T. Fujii et al.

    123I-IMP SPECT findings in mitochondrial encephalomyopathies

    Brain Dev

    (1995)
  • S. Takahashi et al.

    Cerebral blood flow and oxygen metabolism before and after a stroke-like episode in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)

    J Neurol Sci

    (1998)
  • T. Gerriets et al.

    Middle cerebral artery occlusion during MR-imaging: investigation of the hyperacute phase of stroke using a new in-bore occlusion model in rats

    Brain Res Brain Res Protoc

    (2004)
  • S.G. Pavlakis et al.

    Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a distinctive clinical syndrome

    Ann Neurol

    (1984)
  • T. Iizuka et al.

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

    Curr Neurovasc Res

    (2005)
  • Y. Koga et al.

    l-Arginine improves the symptoms of strokelike episodes in MELAS

    Neurology

    (2005)
  • E. Ohama et al.

    Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy

    Acta Neuropathol (Berl)

    (1987)
  • R. Sakuta et al.

    Vascular involvement in mitochondrial myopathy

    Ann Neurol

    (1989)
  • K. Mizukami et al.

    Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study

    Acta Neuropathol (Berl)

    (1992)
  • J. Betts et al.

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

    Neuropathol Appl Neurobiol

    (2006)
  • Y. Koga et al.

    Endothelial dysfunction in MELAS improved by l-arginine supplementation

    Neurology

    (2006)
  • E. Wilichowski et al.

    Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS

    Neuropediatrics

    (1999)
  • M.J. Molnár et al.

    Cerebral blood flow and glucose metabolism in mitochondrial disorders

    Neurology

    (2000)
  • T. Nariai et al.

    Discordance between cerebral oxygen and glucose metabolism, and hemodynamics in a mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode patient

    J Neuroimaging

    (2001)
  • T. Iizuka et al.

    Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

    Neurology

    (2002)
  • Cited by (87)

    • Topological reorganization of brain functional networks in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes

      2020, NeuroImage: Clinical
      Citation Excerpt :

      In MELAS, recurrent SLEs followed by symptomatic remission may progressively damage the brain and cause neurological and neuropsychological deficits (Kaufmann et al., 2011). The most common neuropathological findings during the chronic stage of MELAS are foci of necrosis and peculiar vascular changes (Ito et al., 2011). Concerning the neuropathology of the acute stage of MELAS, autopsy specimen showed extensive petechial hemorrhage along the gyri of the cortex in the acute stroke-likes lesions (Iizuka et al., 2002).

    View all citing articles on Scopus
    View full text