Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a maternally inherited disorder caused by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations in a diffuse multisystemic fashion. MELAS varies widely in the disease onset, symptoms, severity and prognosis. Its broad clinical presentation includes stroke-like episodes (SLEs), epilepsy, lactic acidemia, myopathy, hearing impairment, diabetes, cardiomyopathy and short stature (1, 2). The strong dependence of the central nervous system on oxidative metabolism predisposes to mitochondrial damage (3), and SLEs are the predominant features of MELAS (4). Typical neurological manifestations of SLEs are very similar to ischemic stroke in the acute phase. The diagnosis of MELAS is not difficult when the clinical and imaging findings are typical. However, due to the variability of the disease, diagnosis remains challenging and MELAS is easily misdiagnosed as cerebral infarction, viral encephalitis and other brain diseases, especially the first attack.

At present, with the wide application of new magnetic resonance imaging (MRI) techniques in the clinic, such as hydrogen proton magnetic resonance spectroscopy (1H-MRS), perfusion-weighted imaging (PWI) and arterial spin labeling (ASL), MRI has also become one of the effective methods for diagnosis of MELAS in addition to muscle biopsy and pathogenic gene testing. Clinicians have also gradually gained a deeper understanding of MELAS. In this paper, we review the conventional findings and the latest application of MRI in MELAS syndrome (Table 1).

MELAS is commonly associated with the m.3243A>G tRNALeu (UUR) mutation. Childhood and early adulthood are typically the age of onset with 65–76% of cases occurring at or before the age of 20, but disease onset can occur at any age (1, 4). Yatsuga et al. (5) found the juvenile of MELAS was associated with significantly higher mortality and a more rapid disease progression than the adult. Generally the earlier the clinical phenotypes appear, the severer the disease develops (6). SLEs, as one of the cardinal symptoms, classically present as acute hemianopia, hemiparesis, or cortical blindness. SLEs are usually recurrent and can lead to serious long-term consequences, such as neurodegeneration, cognitive impairment (7).

Energy deficiency can stimulate the proliferation of mitochondria of smooth muscle and small vascular endothelial cells at the same time. In MELAS, a variety of factors can lead to the lack of nitric oxide that can maintain the relaxation function of vascular smooth muscle. Both can cause microvascular blood perfusion damage, lead to stroke like attack and other complications (1). The basic neuropathological changes of MELAS were comprised of spongiform degeneration, neuronal cell loss, glial proliferation, and demyelination (8, 9).

At present, the diagnosis of MELAS is a comprehensive diagnostic criterion combining imaging findings, pathological examination, genetic testing, or muscle biopsy results with clinical manifestations. Among them, the discovery of pathogenic mutations in mtDNA or nDNA genes and typical pathological changes in mitochondrial myopathy by muscle biopsy is the “gold standard” for the diagnosis (10).

SLEs appear as stroke-like lesions (SLLs) on MRI. In acute SLEs, MRI findings include cortex swelling presenting with hyperintensity on T2WI and T2 FLAIR, named as “bright thickened cortical band” (Figures 1A,B). Part of cortical lesions show patchy or linear enhancement on T1-weighted postcontrast images (Figure 1C), due to local exudation or circulation disorders caused by the breakdown of the blood-brain barrier and increased regional cerebral blood flow in the affected areas (11). In the sub-acute phase, SLLs may develop gyriform hyperintensity on T1WI and hypointensity on T2WI/T2FLAIR (“black toenail sign”) because of cortical laminar necrosis. Whitehead et al. (12) found that the black toenail sign was a common imaging feature in MELAS, and the extent of gyral necrosis correlated with disease duration. A recent study observed that a cortical linear cystic lesion was a characteristic MR finding in MELAS patients (13), and it was defined as showing a linear or dotted cerebrospinal fluid signal in the deep layer of the affected cortex, and an iso-intensity line covered its surface. In the chronic stage, the affected areas gradually evolve into cerebral encephalomalacia, gliosis, and atrophy over time (Figure 1D).

Typical SLLs in MELAS mainly distribute in the cerebral cortex and subcortex white matter with a predilection to the posterior brain, although the deep gray matter such as the thalamus may also be affected probably reflecting its high metabolic demand (14). Lesions in the parietal and occipital lobe were twice as many as those in the temporal lobe and 4 times as many as those in the frontal lobe (15). Tschampa et al. (16) reported that deep gray matter changes presented in the majority of m.3243A>G mutation carriers lacking SLEs. Cortical lesions are typically multiple and asymmetrical; however, more and more symmetric cases have been recognized (17, 18), Bhatia et al. (18) thought highly specific cortical symmetry should also raise the possibility of MELAS. SLLs frequently spread to the cortex of adjacent gyri in a migratory fashion over time, resulting in large regions of cortical involvement that are not limited to vascular territories (4, 15, 19). The migratory, increasing and decreasing pattern of SLLs on imaging is the main feature of MELAS.

The diversity and complexity of clinical and radiological manifestations in patients with MELAS pose a challenge to the diagnosis. In imaging, the unilateral isolated cortical lesion is easily misdiagnosed as acute cerebral infarction, viral encephalitis, and low-grade glioma, etc., especially infarction. In acute SLLs, MRI differentiation of MELAS from other diseases mainly includes the following points: (1) lesions first involve the cortex and less deep white matter; (2) lesions commonly affect occipital and parietal lobes; (3) lesions are not limited to arterial territories and migrate over time; (4) a lactate peak appears in lesions, even in the normal-appearing region (brain parenchyma or cerebrospinal fluid area) on MRS, which is one of the indicators of diagnostic specificity; (5) lesions always present as hyperperfusion on PWI/ASL.

For acute ischemic stroke, patients are often accompanied by risk factors such as hypertension, diabetes, and hyperlipemia. The lesions of infarction are confined to the boundary of the vascular territories, and present hypoperfusion on PWI/ASL, effectively distinguishing it from MELAS. Chong et al. (54) discovered a new scoring criterion based on the vessel flow void sign and hyperintense vessel sign in T2FLAIR images was helpful to differentiate infarction from MELAS on conventional MRI, with sensitivity and specificity of 92.3 and 85.0%, respectively. Furthermore, cortical linear cystic lesions might help to distinguish the two diseases (13).

For viral encephalitis, patients may have a high fever, meningeal irritation with lymphocytic pleocytosis, and an elevated protein level on cerebrospinal fluid. On imaging, viral encephalitis usually involves the limbic system, such as the frontal orbital gyrus, hippocampus and temporal lobe, rather than the parietal, and temporal lobe. The diffusion restriction uninvolved the entire lesions might be an important differential diagnostic sign between them (55). Functional MRI techniques are also valuable for accurate diagnosis.

For low-grade glioma, patients often present with chronic onset. On imaging, the conventional MRI findings of low-grade glioma are sometimes similar to the single SLL, and MRS can help distinguish them. On MRS, low-grade glioma often presents with elevated choline peak and decreased N-acetylaspartate peak, but usually without an increased lactic acid peak, which is a characteristic of SLL.

In conclusion, MELAS is a rare progressive neurodegenerative disorder involving multi-organs. MELAS has obvious clinical heterogeneity as the clinical manifestations of different patients or the same patients vary in different phases, which makes the diagnosis a little arduous sometimes. However, neuroimaging of MRI demonstrates characteristic patterns of MELAS patients, including cortex swelling with a predilection for the posterior brain regions, not limited to arterial territories, hyperperfusion, and elevated lactate peak in both affected and non-affected regions, which may be found concurrently with encephalomalacia and atrophy. The recognition of these imaging features signs facilitates screening and early diagnosis of MELAS. Meanwhile, the novel MRI approaches have provided new dimensions in the evaluation of the disease. Multimodal MRI has shown great potential in risk stratification, course monitoring, progression, and efficacy evaluation of MELAS, and also provides a reference for understanding its neuropathological mechanism.

WC collected the data and wrote the manuscript. YZ and LH performed roles of the conception of this review and substantively revised it. All authors contributed to the article and approved the final manuscript.

This study was supported by grants from the joint Chongqing Health Commission and Chongqing Science and Technology Bureau Medical Research Project (No: 2020FYYX128) and Chongqing Science and Technology Bureau, Technology Foresight and System Innovation Project (No: cstc2021jsyj-yzysbAX0019).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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