Cerebral vasodilation and lesion patterns in stroke-like episodes of MELAS: a quantitative angiographic investigation

Introduction

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is an inherited mitochondrial disorder characterized by encephalopathy, lactic acidosis, and recurrent stroke-like episodes, which typically present with seizures, headaches, and focal neurological deficits (1,2). The term “stroke-like episodes” refers to recurrent clinical events that mimic a stroke, although their underlying mechanisms remain incompletely understood (3). These episodes exhibit distinctive neuroimaging features: they do not conform to vascular territories, preferentially involve the cerebral cortex, spread to adjacent regions over weeks to months, and often demonstrate spontaneous reversibility, distinguishing them from typical ischemic strokes (4). Additionally, increased apparent diffusion coefficient (ADC) values and vasogenic edema have been reported (5,6).

Recent neuroimaging studies have identified distinct perfusion patterns during stroke-like episodes, including focal hyperperfusion both acutely and up to three months prior to symptom onset, accompanied by reversible vasodilation (7-10). These findings indicate that the pathophysiology of stroke-like episodes in MELAS fundamentally differs from that of ischemic stroke. However, the precise mechanisms remain unclear, with conflicting reports regarding large-vessel changes; some studies report vasodilation, while others indicate stenosis or normal caliber (11). Understanding these vascular and perfusion alterations is crucial for elucidating the underlying mechanisms. Therefore, in this study, we retrospectively analyzed MELAS patients experiencing stroke-like episodes, focusing on vasodilation, changes in vessel diameter, and perfusion status. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2735/rc).

Methods

Study design and population

We conducted a single-center retrospective observational study from January 2010 to December 2023. Patients diagnosed with MELAS who experienced stroke-like episodes during this period were included. The diagnosis of MELAS was established based on clinical manifestations, genetic testing, magnetic resonance imaging (MRI) findings, and biochemical examinations. Among these patients, we selected those who underwent magnetic resonance angiography (MRA).

Data collection and image analysis

We collected the following data: demographic characteristics (age and sex), pathogenic variants, clinical manifestations of stroke-like episodes, the time interval from symptom onset to neuroimaging, and neuroimaging findings. The imaging parameters of interest included lesion location, the presence and location of vasodilation, and perfusion status.

Stroke-like lesions were classified according to the affected cerebral lobes based on visual inspection of fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences. The classification included the frontal, temporal, parietal, and occipital lobes, with combinations noted when lesions crossed anatomical boundaries. Cytotoxic edema was defined as areas exhibiting hyperintensity on DWI with corresponding hypointensity on ADC maps, indicating restricted water diffusion. In contrast, vasogenic edema was identified as areas demonstrating hyperintensity on ADC maps, indicating increased water diffusion (12). The differentiation between cytotoxic and vasogenic edema was performed through visual assessment of signal intensity patterns on ADC maps, comparing them to the unaffected contralateral side at the corresponding anatomical location. For patients with bilateral lesions, the comparison was made with the corresponding gray or white matter of normally appearing parenchyma (5). Hyperperfusion was confirmed by increased cerebral blood flow (CBF) on perfusion MRI or computed tomography perfusion image in the affected regions compared to contralateral sides, based on visual inspection.

We performed comparative measurements of major vessel diameters between the affected and unaffected sides in all patients with available angiographic imaging. Major vessel diameters were manually measured on both the affected and contralateral sides. Measurements were taken at the midpoint of the M1 segment of the middle cerebral artery (MCA) and the P2 segment of the posterior cerebral artery (PCA) between the bilateral vessels (13). Each vessel was measured three times, and the results were averaged to minimize measurement variability. Two investigators (K.S. and M.K.Y.), who were blinded to the patients’ clinical information, independently evaluated the imaging results. A third investigator (B.J.K.) acted as an adjudicator when interpretations differed.

Statistical analysis

A comparative analysis of vessel diameters between the affected and unaffected sides was performed using the Wilcoxon signed-rank test. All statistical analyses were performed using SPSS version 27.0 (IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05.

Ethics consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the institutional review board of Asan Medical Center (No. 2024-0149). The requirement for informed consent was waived due to the retrospective nature of the study.

Results

Patient characteristics

We identified 17 patients [male, n=10 (58.8%)] with MELAS who experienced stroke-like episodes during the study period (Table 1). The median age of the patients was 38 years (range, 18–61 years). Sixteen patients (94.1%) carried the m.3243A>G pathogenic variant, while one patient had the m.13453C>T pathogenic variant in the mitochondrially encoded NADH dehydrogenase 5 (MT-ND5) gene. The most common presenting symptoms were confusion (n=9, 52.9%), seizure (n=5, 29.4%), headache (n=4, 23.5%), and aphasia (n=3, 17.6%). Other manifestations included focal neurological deficits. The median time from symptom onset to the initial MRI was 2 days (range, 0–10 days).

Neuroimaging findings

DWI analysis revealed distinct ADC signal patterns in stroke-like lesions. In 15 patients (88.2%), a characteristic pattern of cortical cytotoxic edema combined with subcortical vasogenic edema was observed, manifesting as dark signal intensity in cortical regions and corresponding bright signal in adjacent subcortical white matter on ADC maps (Figure 1A-1C). Among the remaining two patients, one presented with lesions that were insufficient in size for assessment, while the other exhibited isolated vasogenic edema without evidence of a cytotoxic component.

Figure 1 Reversible vasodilation and hyperperfusion during a stroke-like episode. Patient #7, a 25-year-old male, presented with a headache and confusion. (A-C) Diffusion-weighted imaging, apparent diffusion coefficient mapping, and fluid-attenuated inversion recovery imaging showed an acute stroke-like lesion in the right temporo-parieto-occipital lobe. Cortical cytotoxic edema, combined with subcortical vasogenic edema, was observed. (D) Increased CBF was noted in the stroke-like lesion area. (E) MRA showed dilation of the right MCA. (F) A follow-up MRA image taken 105 days after the onset showed resolution of the vasodilation. CBF, cerebral blood flow; MCA, middle cerebral artery; MRA, magnetic resonance angiography.

Stroke-like lesions predominantly affected the temporal (n=15, 88.2%), parietal (n=9, 52.9%), and occipital (n=7, 41.2%) regions. Initial perfusion-weighted MRI was performed in three patients, all of whom exhibited hyperperfusion in the territories corresponding to the stroke-like lesions. Angiographic analysis revealed vasodilation of major vessels in 10 out of 17 patients (58.8%) during acute stroke-like episodes. Among these, MCA dilation was the most common, observed in 8 patients, which corresponded to their cortical lesion territories (Table 1, Figure 1). PCA dilation was identified in 2 patients, also correlating with their respective occipital lesion distributions. The remaining 7 patients (41.2%) exhibited normal vessel caliber upon initial angiographic evaluation. A comparative analysis of major vessel diameters between the affected and contralateral sides revealed significant differences during stroke-like episodes, with the affected side showing a larger median diameter (1.92 mm, interquartile range, 1.76–2.42 mm) compared to the contralateral side (1.84 mm, interquartile range, 1.74–2.22 mm, Z=−2.250, P=0.024; Figure 2). This analysis included all 17 patients with available angiographic imaging.

Figure 2 Comparative analysis of major vessel diameters between affected and contralateral sides during stroke-like episodes.

Follow-up angiographic imaging was conducted in three patients who exhibited initial vessel dilation, performed at a median of 682 days (range, 105–718 days) after the initial scan. All three cases showed an improvement in the previously observed vasodilation.

Discussion

In this study, we observed significant vasodilation in the major cerebral arteries and hyperperfusion in the corresponding lesions during stroke-like episodes in MELAS. Quantitative analysis of vessel diameter revealed statistically significant differences between the affected and unaffected sides. The reversible nature of both parenchymal lesions and changes in vessel diameter distinguishes these episodes from conventional ischemic stroke. Despite the term “stroke-like”, these findings suggest distinct underlying pathophysiological mechanisms.

Current evidence supports several major pathogenic mechanisms in MELAS stroke-like episodes: mitochondrial angiopathy, mitochondrial cytopathy, and the neuronal hyperexcitability theory (4). The mitochondrial angiopathy theory posits that there is impaired blood perfusion in the microvasculature during stroke-like episodes (2). However, our findings of consistent vasodilation and hyperperfusion, rather than solely ischemia, suggest that the mitochondrial angiopathy hypothesis may not fully explain the underlying pathophysiology.

In our study, cortical regions exhibiting cytotoxic edema were spatially correlated with areas of hyperperfusion, presenting a paradoxical phenomenon in which increased perfusion coexisted with restricted diffusion. This observation aligns with previous studies that reported a gradual progression of cytotoxic edema overlapped with hyperperfusion and vasogenic edema in serial MRI follow-ups of MELAS patients (5,14). Similar findings of cortical cytotoxic and subcortical vasogenic edema have been documented in MELAS patients, consistent with our observations (15). These temporal and spatial patterns collectively support the mitochondrial cytopathy hypothesis as the primary pathophysiological mechanism underlying stroke-like episodes. Given that cortical gray matter is particularly vulnerable to mitochondrial energy failure due to its high metabolic demands (16), mitochondrial energy failure initially triggers cortical regional hyperperfusion; as the metabolic derangement progresses, cortical cytotoxic edema develops, followed by vasodilation of major cerebral vessels and the development of subcortical vasogenic edema (Figure 3).

Figure 3 Sequential pathophysiology of lesion progression in stroke-like episodes.

Previous studies have reported diverse ADC characteristics during stroke-like episodes, with hyperperfusion present regardless of the ADC profile (5). Another study reported that the majority of cortical lesions exhibited cytotoxic edema, and subcortical lesions demonstrated increased ADC values suggesting vasogenic edema (15). Furthermore, preclinical regional hyperperfusion before the clinical onset of stroke-like episodes has been detected (8,17). Taken together with our findings, the pathogenesis of stroke-like episodes may involve a continuum of overlapping processes, including regional hyperperfusion driven by mitochondrial energy failure, cortical cytotoxic edema, subcortical vasogenic edema, and progressive major vessel vasodilation. This overlap of distinct pathophysiological processes at varying stages may account for the heterogeneous diffusion and perfusion characteristics reported across different studies and imaging time points.

Regarding major vessel involvement, prior research has documented vasodilation patterns that align with our findings (10). The characteristic features of stroke-like episodes, including preferential cortical involvement (2), progressive lesion spread, and frequent focal epileptic activity (18), suggest that cortical microvascular vasodilation occurs and may subsequently extend to involve major vessels. This hypothesized progression of vascular changes may explain the heterogeneous angiographic findings in our cohort, where major vessel vasodilation was observed in some patients while vessels remained normal in others.

The distribution of lesions and patterns of vasodilation observed in our study further support the proposed mechanism. The posterior predominance of lesion distribution in MELAS is well-established and has been attributed to the high metabolic demand and energy failure in these regions (19). Our patient cohort also exhibited predominant involvement of posterior brain regions, including the posterior temporal and occipital lobes. A consistent spatial relationship between lesion location and vascular involvement was noted. All patients with MCA dilation exhibited temporal lobe involvement, while all patients with PCA dilation demonstrated occipital lobe involvement. These spatial correlations between lesion location and vascular involvement are consistent with a process in which cortical metabolic stress propagates to the major vessels.

The primary strength of our study lies in the quantitative demonstration of vasodilation during stroke-like episodes, achieved through systematic measurements of vessel diameter. This objective methodology offers concrete evidence for vascular changes that have previously been described only qualitatively (9,10). However, several limitations must be acknowledged, including our relatively small sample size. Additionally, the retrospective nature of our imaging data limits the ability to establish the temporal sequence of pathophysiological events. Future prospective studies with standardized imaging protocols and larger patient cohorts are necessary to validate these findings and investigate targeted therapeutic strategies.

Conclusions

In conclusion, this study provides quantitative angiographic evidence of significant major vessel vasodilation during stroke-like episodes in MELAS, which was spatially correlated with hyperperfusion and characteristic lesion patterns of cortical cytotoxic edema and subcortical vasogenic edema. Our findings contribute to the pathophysiological understanding of MELAS based on mitochondrial energy failure. Future studies are needed to validate these findings and further elucidate the underlying mechanisms.

Acknowledgments

We are grateful to all patients and their families who contributed to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2735/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2735/dss

Funding: This research was supported by the Technology Innovation Program through the Korea Technology and Information Promotion Agency for SMEs (TIPA), funded by the Ministry of SMEs and Startups (MSS, Korea) (No. RS-2025-25457998).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2735/coif). B.J.K. reports the funding from the Technology Innovation Program through the Korea Technology and Information Promotion Agency for SMEs (TIPA), funded by the Ministry of SMEs and Startups (MSS, Korea) (No. RS-2025-25457998). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional review board of Asan Medical Center (No. 2024-0149), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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