The unique characteristics and risk factors of enlarged perivascular spaces in pediatric moyamoya disease

Introduction

Moyamoya disease (MMD) is a progressive cerebrovascular disorder with features of chronic stenosis or occlusion at Willis circle and prominent collateral artery formation (1). The abnormal cerebrovascular morphology leads to chronic impairment of cerebral perfusion and abnormal cerebral hemodynamics, resulting in cerebral ischemia or intracranial hemorrhage (2), lacunes, white-matter hyperintensities, ivy sign, and brain atrophy in patients with MMD (3) on magnetic resonance imaging (MRI). The visible flow voids in the basal ganglia on MRI reflect the abnormal vascular networks of MMD (4). MMD is caused by multiple factors, including genetic, immune, and inflammatory factors. Accumulating molecular and clinical evidence has demonstrated that immune inflammation–associated responses could serve as a crucial triggering factor for MMD (5,6), second to genetic factors in significance (7). In the absence of evident infection, systemic immune-inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) derived from blood cell counts can more suitably reflect systemic inflammation and immune status than can neutrophil or lymphocyte measures alone. The systemic immune-inflammatory markers have been validated in numerous immune-inflammatory disorders (8,9), with MMD being among them. NLR, PLR, and SII are higher in adult patients with MMD than in healthy individuals (10), with these elevated systemic immune-inflammatory markers being associated with the risk of MMD and the progression of MMD in adult patients (11).

Perivascular spaces are fluid-filled cavities that surround penetrating arteries and venules, which serve as a drainage conduit for cerebral interstitial fluid and are recognized as the important constitute of glymphatic system (12). Enlarged perivascular spaces (EVPSs) are visible on T2-weighted MRI (13) and are associated with cerebral small-vessel disease, old age, hypertension, Alzheimer disease, and vascular dementia (14,15). The associations between EPVS and cognitive decline have also been observed after stroke and transient ischemic attack (TIA) (16), while a strong association between systemic immune-inflammatory markers and EPVSs has been observed in cerebral small-vessel disease (17).

An increased number of EPVSs have been reported in adult patients with MMD (18), and these elevated numbers have been associated with hypertension, female gender, and the presence of flow voids in the basal ganglia (18). In one study, EPVS burden was correlated with middle cerebral artery (MCA) stenosis (19). However, the characteristics of EPVS in pediatric patients with MMD have not been characterized. Compared with that for adult MMD, the research for pediatric MMD is scarce. It is widely recognized that MMD has two peak incidences: around the ages of 5 and 40 years (2). A hemorrhagic attack is extremely rare in pediatric patients, which is not the case with adult patients (2). Pediatric MMD typically manifests with cerebral ischemic symptoms, seizure, decreased mental function and intelligence, and brain atrophy (2). Moreover, distinctive linear hyperintensities on fluid-attenuated inversion recovery (FLAIR) imaging, extending into the deep white-matter’s perivascular spaces, have been noted in patients with pediatric MMD, a phenomenon known as “hyperintense medullary streaks on FLAIR” (HMSFs) (20); however, such findings are not typical of adult patients. HMSFs may represent the stagnation of the cerebral interstitial fluid of the perivascular spaces, which were similar to EPVSs (20). Considering of the difference between adult and pediatric MMD, we sought to identify the related characteristics and risk factors of EPVSs in pediatric MMD. We specifically focused on the unique radiological features and systemic immune-inflammatory markers in pediatric MMD that could differ from those of adult MMD. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2175/rc).

Methods

Participants

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University (approval No. 202412-052-1). The requirement for informed consent was waived due to the retrospective nature of the analysis.

A diagram of the study’s workflow in Figure 1 provides a detailed depiction of the inclusion and exclusion process. A total of 36 patients with pediatric MMD were recruited from the Pediatric Neurology Department of Shandong Provincial Hospital Affiliated to Shandong First Medical University between January 2009 and January 2023. Their MMD diagnoses were confirmed by two experienced associate chief neuropediatricians (N.C. and J.G.) according to the diagnostic criteria for MMD (2009 and 2022) (4). The inclusion criteria for patients were as follows: (I) age under 18 years when first admitted to hospital and diagnosed as MMD; (II) treatment-naive; (III) no contraindications to magnetic resonance (MR) or magnetic resonance angiography (MRA) examination; (IV) exclusion of moyamoya syndrome (clinical manifestation and blood tests, such as anemia and autoimmune markers, and imaging, such as MRI, were used to rule out underlying etiologies of moyamoya syndrome); and (V) no history of atherosclerosis, meningitis, brain tumor, head trauma, Down syndrome, neurofibromatosis type 1, cerebrovascular lesions after head irradiation, autoimmune disease, or hyperthyroidism.

Figure 1 Workflow diagram depicting the inclusion and exclusion process for the study. MMD, moyamoya disease; MR, magnetic resonance; MRA, magnetic resonance angiography.

A total of 36 age-matched children were recruited from the Pediatric Neurology Department of Shandong Provincial Hospital Affiliated to Shandong First Medical University. The inclusion criteria for the control group were as follows: (I) age under 18 years when first admitted to hospital; (II) no TIA or previous stroke; (III) completion of MRI and MRA examinations; (IV) no structural diseases detected in the MRI and MRA series; and (V) no history of atherosclerosis, meningitis, brain tumor, head trauma, Down syndrome, neurofibromatosis type 1, cerebrovascular lesions after head irradiation, autoimmune disease, or hyperthyroidism.

Image acquisition

All patients underwent brain MRI on a 3.0-T MR system (MAGNETOM Prisma 3.0, Siemens Healthineers, Erlangen, Germany) with a standard eight-channel head coil. The following MRI sequences were included: T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), FLAIR, diffusion-weighted imaging (DWI), and time-of-flight MRA (TOF MRA). The T1WI parameters were as follows: time to repetition (TR) =1,775 ms, time to echo (TE) =21.6 ms, inversion time (TI) =650 ms, flip angle =111°, field of view (FOV) =240×168 mm, number of slices =40, slice thickness =4.0 mm, acquisition matrix =384×224, and echo train length (ETL) =8. The T2WI parameters were as follows: TR =5258 ms, TE =84 ms, flip angle =142°, FOV =220×220 mm, number of slices =36, slice thickness =4.0 mm, acquisition matrix =384×320, and ETL =20. The FLAIR sequence parameters were as follows: TR =12,000 ms, TE =122 ms, flip angle =160°, FOV =220×176 mm, number of slices =36, slice thickness =4.0 mm, acquisition matrix =320×224, and ETL =18. The DWI sequence parameters were as follow: TR =3,600 ms, TE =64 ms, flip angle =90°, FOV =220×220 mm, number of slices =36, slice thickness =4.0 mm acquisition matrix =128×128, and ETL =1. Three-dimensional TOF MRA sequence’s parameters were as follows: TR =16 ms, TE =2.1, flip angle =160°, FOV =220×220 mm, number of slices =288, slice thickness =1.2 mm, acquisition matrix =320×224, and ETL =1.

Assessment of EPVSs

Because patients with MMD exhibit abnormal vascular networks in the basal ganglia, the EPVSs in the basal ganglia cannot be precisely evaluated. The presence of EPVSs with a diameter >2 mm and <3 mm round or linear cerebrospinal fluid isointense lesions in centrum semiovale was visually assessed via T2WI (Figure 2) and T1WI/FLAIR images (13) by two neuroradiologists (F.X. and Hui Jiao, MD), blinded to one another’s ratings and to patients’ clinical information. Axial slices depicting the maximal area of the centrum semiovale were evaluated, and the slice exhibiting the highest number of EPVSs was selected to characterize the severity of the EPVSs. The number of EPVSs were graded as follows (21): grade 0 = none, grade 1 =1–10, grade 2 =11–20, grade 3 =21–40, and grade 4 ≥40 EPVSs. The EPVS grades were divided into two groups: a high-EPVS grade group (EPVS grade =4) and a low-EPVS grade group (EPVS grade =0–3). The interrater variability was then assessed, as documented in Table 1.

Figure 2 Magnetic resonance images of EPVSs in the centrum semiovale (A: grade 1; B: grade 4). (A) In the right hemisphere of a healthy control (a 9-year-old male), the mean count of EPVS was 9 and was categorized as grade 1. (B) In the right hemisphere of a 9-year-old male patient with MMD, the mean count of EPVSs was 80 and was categorized as grade 4. Dot-like EPVSs are indicated by the white arrow, and linear EPVSs are indicated by the black arrow. A, anterior; EPVS, enlarged perivascular space; L, left; MMD, moyamoya disease; P, posterior; R, right.

Assessment of other imaging features of MRI and MRA

Stroke lesions were categorized three types. They were lacunar stroke with a maximum diameter ≤1.5 cm, large ischemic stroke with a maximum diameter >1.5 cm, and hemorrhagic stroke. White-matter lesions in deep and periventricular white matter were classified in four grades (0–3) according to the Fazekas scale (16,22) (Figure 3A-3D). When two or more visible flow voids in the basal ganglia were present at least unilaterally on MRI, they were deemed to indicate abnormal vascular networks (2) (Figure 3E). A rating of “absent =0” or “present =1” was assigned for the flow voids in basal ganglia. The “ivy sign” was defined as continuous or discontinuous linear high signal intensities along the cortical sulci and subarachnoid space on FLAIR imaging (23) (Figure 3F), with a rating of “absent =0,” “equivocal =1,” or “present =2” being assigned (23). HMSFs were defined as unique linear hyperintensities on FLAIR imaging that extended into the perivascular space of the deep white matter (20) (Figure 3G,3H), with a rating of “absent =0”, “low <5”, or “high ≥5” being assigned. According to a previously published protocol (24), atrophy scores were assigned to each of the following: cerebellar hemisphere atrophy, corpus callosum atrophy, lobar (deep) white-matter atrophy, pons atrophy, lateral ventricle enlargement, subarachnoid space enlargement, and fourth ventricle enlargement. Atrophy or enlargement was graded as normal =0, slight =1, moderate =2, and severe =3. The total score was rated on a scale of 0 to 21. According to Houkin et al.’s classification (25), MRA scores were assigned depending on the severity of the steno-occlusive changes to each of the following: C1 portion of the internal carotid artery (ICA), M2 portion of the MCA, A1 portion of the anterior cerebral artery (ACA), and P2 portion of the posterior cerebral artery (PCA). The total score was rated on a scale of 0 to 10. To limit subjectivity in interpretation, all imaging features were determined in a blinded manner by two neuroradiologists (F.X. and Hui Jiao, MD). All scores were calculated for each hemisphere.

Figure 3 Magnified images of radiological characteristics of patients with pediatric MMD. (A,B) The white arrow indicates the white-matter lesion on (A) T1- and (B) T2-weighted MR images (grade 1). (C,D) The white arrow indicates the white-matter lesion on (C) T1- and (D) T2-weighted MR imaging (grade 3). (E) The white arrow indicates the flow voids on a T2-weighted MR image. (F) The white arrow indicates the ivy sign on the FLAIR MR image. (G,H) The white arrow indicates the HMSF on T2-weighted MR images (G) and on FLAIR images (H). A, anterior; FLAIR, fluid-attenuated inversion recovery imaging; HMSF, hyperintense medullary streaks on FLAIR; L, left; MMD, moyamoya disease; MR, magnetic resonance; P, posterior; R, right.

Statistical analysis

Between the MMD and control group and between the high-EPVS grade and low-EPVS grade groups, the differences in continuous variables were determined via the Mann-Whitney in SPSS 18.0 software (IBM Corp., Armonk, NY, USA). The categorical variables were analyzed via Chi-squared tests. The threshold was set at a P value <0.05 (two-tailed). For tests that resulted in P<0.05, we used a simple logistic regression to perform univariate analyses of EPVS number in order to determine the relationships between EPVS number and potential risk factors. For continuous variables, patients were classified into a low-PLR group (≤120) and a high-PLR group (>120). Additionally, they were assigned to low (<5) and high (≥5) group according to the number of medullary streaks. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with these models. We selected the items via stepwise methods (model selection criterion: ɑ=0.10) and used multivariate analyses to determine the relationships between EPVSs and all factors found to be predictors in the univariate analysis.

Results

Demographic, clinical, and MRI features of the pediatric MMD and control groups

The demographic, clinical, and MRI features of the pediatric MMD and control groups are summarized in Table 1. The mean age of the pediatric MMD group was 7 years, and 21 (58.3%) patients were female. There were no significant differences in age or sex between the pediatric MMD and control groups (P>0.05). The proportion of participants with hypertension was significantly higher in the pediatric MMD group than in the control group (P=0.005). Of the 36 pediatric MMD patients, 23 had ischemic stroke, 1 had hemorrhagic attacks, 7 had TIA, 7 were epileptic, and 2 had headaches at their first admission to the hospital. Among the control group, 10 were emotional disturbance patients, 10 experienced nonepileptic events, 10 had headaches, 3 were epileptic, and 2 had benign paroxysmal vertigo. The PLR was higher in the pediatric MMD group than in the control group (P=0.03). The other systemic immune-inflammatory markers (NLR, SII, and LMR), white blood cell count, lymphocyte count, neutrophil count, monocyte, count, and platelet count were similar between the two groups. Compared with controls, the patients with pediatric MMD showed an increased number of EPVSs (P<0.001) (Figure 4A) and a higher median EPVS grade (P<0.001) (Table 1). The EPVS grades in pediatric MMD and control groups are shown in Figure 4B. The distribution of EPVS grade in the MMD group was as follows: grade 0 =0, grade 1 =5, grade 2 =11, grade 3 =21, and grade 4 =35; meanwhile, the distribution in the control group was as follows: grade 0 =3, grade 1 =34, grade 2 =18, grade 3 =12, and grade 4 =5. The pediatric MMD group had a higher number of patients with stroke lesions, with 45 of 72 (62.5%) hemispheres in the pediatric MMD group exhibiting stroke lesions, including 3 (6.7%) with lacunar stroke, 38 (84.4%) with large ischemic stroke, and 4 (8.9%) with hemorrhagic stroke. The prevalence of white-matter lesions was significantly higher in the pediatric MMD group (P<0.0001), with 68 of 72 (94.4%) hemispheres in the pediatric MMD group and 13 of 72 (18.1%) in the control group exhibiting white-matter lesions. The incidence of lacunar and hemorrhagic stroke was similar between the pediatric MMD and control groups. However, compared with the control group, the pediatric MMD group exhibited a greater incidence of HMSFs (P<0.0001), with 71 (98.6%) and 2 (2.8%) hemispheres exhibiting HMSFs in the pediatric MMD and control groups, respectively (Table 1).

Figure 4 The number of EPVSs and the distribution of EPVS grade in the pediatric MMD group and control group. (A) The number of EPVSs in the pediatric MMD and control groups. (B) The distribution of EPVS grade in the pediatric MMD and control groups. EPVSs, enlarged perivascular spaces; MMD, moyamoya disease.

Potential risk factors related to the severity of EPVS

We selected the factors from the above-mentioned tests that resulted in P values less than 0.05 in the univariate analysis to identify the risk factors related to the severity of EPVSs. We also performed multivariate analysis to assess selection bias (Table 2). In the univariate analysis, MMD patients were found to have a higher EPVS grade (OR 12.68; 95% CI: 4.57–35.13; P<0.001). High EPVS grade was associated with white-matter lesions (OR 14.39; 95% CI: 4.17–49.63; P<0.001), PLR (OR 2.71; 95% CI: 1.2–5.78; P=0.010), and HMSFs (OR 9.82; 95% CI: 3.76–25.46; P<0.001) (Table 2). The severity of EPVS was not significantly related to a higher prevalence of hypertension in children (P=0.361). Two items (MMD and HMSFs) were selected with stepwise methods. In the multivariate analysis, a high EPVS grade was associated with MMD (OR 7.86; 95% CI: 2.65–23.32; P<0.001) and HMSFs (OR 0.26; 95% CI: 0.09–0.72; P=0.01) (Table 2).

Demographic, clinical, and MRI features of patients with pediatric MMD in the high- and low-EPVS grade groups

The demographic, clinical, and MRI features of patients with pediatric MMD in the high- and low-EPVS grade groups are summarized in Table 3. The high-EPVS grade group comprised 35 hemispheres, while the low-EPVS grade group comprised 37 hemispheres. The median count of EPVSs in the high-EPVS grade group was 51.0 [interquartile range (IQR), 43.0–64.0], while that in the low-EPVS grade group was 23.0 (IQR, 15.0–30.5). The age, sex, prevalence of hypertension, MRA scores, prevalence of stroke (lacunar stroke, large ischemic stroke, and hemorrhagic stroke), the presence of white-matter lesions, flow voids in the basal ganglia, ivy sign, and brain atrophy score showed no differences between the high- and low-EPVS grade groups. However, the PLR was significantly higher (P=0.01) in the high-EVPS grade group (145.3±55.5) than that in the low-EVPS grade group (99.9±27.8). We used a simple logistic regression to determine the associations between EPVS and PLR in the pediatric MMD group. A high EPVS grade was associated with PLR (OR 4.45; 95% CI: 1.054–18.94; P=0.04). The median HMSF count was significantly higher (P=0.001) in the high-EPVS grade group (median 5; IQR, 2–7) than in the low-EPVS grade group (median 2; IQR, 1–3.5) (Table 3).

Discussion

The potential pathogenesis for an increased number of EPVSs in pediatric MMD

To the best of our knowledge, this is the first study to observe the characteristics and risk factors related to EPVSs in pediatric MMD. The study confirmed that pediatric patients with MMD had a higher number of EPVSs, similar to adult patients with MMD (18). We analyzed the EPVS-related risk factors in pediatric MMD. We found MMD to be a risk factor for EPVSs in the univariate and multivariate analyses. It is thought that damage to the blood-brain barrier, the inflammatory processes involving the blood-brain barrier, and impairment of waste clearance affecting the glymphatic system play a crucial role in the pathogenesis of EPVSs (26). According to our results and previous research, we speculate that there may be four reasons that can account for the increase in the number of EPVSs in pediatric MDD. First, large-vessel stenosis might result in EPVSs directly. There is a clear correlation between MCA stenosis and EPVS burden in adult MMD patients (19). We collected data from high-resolution vessel wall imaging to confirm this association exists in pediatric patients. Second, the vessels that form the collateral circulation in MMD are likely to have weaker arterial pulsations as compared to normal circulation, thereby inhibiting the glymphatic system and causing EPVSs, as reported previously (18). In our study, more than two flow voids in the basal ganglia were observed in 62 (86.1%) hemispheres in the pediatric MMD groups, suggesting that the presence of an abnormal vascular network and collateral circulation in patients with pediatric MMD may cause EPVSs. Third, damage to the blood-brain barrier might cause EPVSs, and blood-brain barrier impairment has been observed in patients with MMD (27). Fourth, environmental risk factors (e.g., infection, inflammation, and autoimmunity) play an important role in the development of MMD (2). The inflammatory processes in MMD might influence the blood-brain barrier and cause EPVSs. We explored the association between systemic immune-inflammatory markers and EPVSs in patients with pediatric MDD. Studies have meticulously examined systemic immune-inflammatory markers in MMD, but only among adult patients (10,11). To the best of our knowledge, ours is the first study to investigate systemic immune-inflammatory markers in pediatric MDD. We found PLR to be higher in patients with pediatric MDD than in controls, which is similar to the scenario with adult patients. It has been reported that PLTs are closely associated with vascular remodeling in MMD (11). Platelets secrete pro-inflammatory factors, including chemokines, and particularly, PLT-derived growth factor, which triggers the constriction and narrowing of the blood vessels and promotes collateral angiogenesis, thus contributing to the development of MMD (28). In our univariate analysis, PLR was associated with EPVS grade. However, it was not associated with EPVS in the multivariate analysis. In the pediatric MMD group, there was an association between EPVS and PLR. The results suggest that inflammatory processes, especially PLT-associated pathways, might participate in the pathology of EPVSs in pediatric MMD. The association between systemic immune-inflammatory markers and EPVSs in MMD need to be validated further, especially in adult patients.

We found that the other systemic immune-inflammatory markers such as NLR and SII were similar between the pediatric MDD and control groups, which is not the case with adult MDD. This might be explained by dynamic changes in the number of neutrophils and lymphocytes from birth to adolescence. Overlapping in the curve of the number of neutrophils and lymphocytes occurs in the fourth or fifth day after birth and at 4 or 5 years of age. The ages of the participants in our study ranged from 5 months to 17 years. The number of neutrophils and lymphocytes, NLR, and SII exhibit dynamic changes in pediatric participants. Thus, PLR might be a stable systemic immune-inflammatory marker for investigations into pediatric MMD based on our research findings.

In contrast to adult patients with MMD, hypertension was not associated with EPVSs in univariate analysis, although patients with pediatric MMD were more likely to have hypertension than were controls. The patients with a high EPVS grade did not show a greater incidence of hypertension than did those with a low EPVS grade. In our sample, there were only 8 (22.22%) patients with hypertension in the pediatric MMD group. The prevalence of hypertension varies, with a range of 5.9–29.0% in patients with pediatric MMD (29). We need to collect additional data to identify the relationship between hypertension and EPVSs in patients with pediatric MMD.

We also found that MRA scores, the presence of white-matter lesions, flow voids in the basal ganglia, ivy sign, and brain atrophy score were similar in the high- and low-EPVS grade groups of MMD, which were different from adult patients. MRA scores, flow voids in the basal ganglia, and ivy sign were all associated with disease stage (4,30,31). According to the MRA scores, we found that most of our patients were at stage III and IV and had unstable cerebral blood flow. In our study, all the data were collected when the patients were first admitted to hospital and diagnosed with MMD. Thus, we only included two stage I hemispheres and two stage V hemispheres. This explains why MRA score, the presence of stroke, the presence of white-matter lesions, flow voids in the basal ganglia, and ivy sign were similar between the high- and low-EPVS grade groups of MMD. This serves as a reminder that for pediatric MMD, those patients at stage I and II are typically not diagnosed until they experience ischemic stroke or attack and the disease progresses to stage III or IV. Ischemic stroke occurred in 23 (63.8%) of the patients in our cohort. We followed up our patients through the telephone and outpatient service and found that 21 (58.3%) patients underwent surgery (encephalo-duro-temporal-arterio synangiosis), and only 2 patients (9.5%) experienced ischemic stroke after surgery. The appropriate surgery in patients with pediatric MMD achieved favorable outcomes. Thus, the early diagnosis of young patients with MMD and early surgical intervention can achieve good long-term outcomes (32). However, recognizing pediatric MMD in the early stage and conducting follow-up to prevent first ischemic stroke remain significant challenges.

The association with brain atrophy scores and EPVS grades has been inconsistently reported across MMD research (18,19). Our results were similar to those reported previously (19). Pediatric patients with high EPVS grades showed the similar atrophy scores as did those with low grades. Only 6 (16.7%) patients did not show brain atrophy, which supports the necessity of early recognition of pediatric MMD.

Medullary streaks were initially described by Harada et al. in 2001 and were defined as linear structures that could be observed crossing the frontal aspect of the semioval center on axial images (33). Medullary streaks appear as hypersignals on T2WI. The EPVS are defined as round or linear cerebrospinal fluid isointense lesions in the centrum semiovale visually assessed from the T2 and T1/FLAIR images with a diameter >2 and <3 mm (13). Considering these definitions of medullary streaks and EPVSs, we hypothesized that medullary streaks might represent linear forms of EPVSs. EPVS appear hypointense on FLAIR imaging; however, in pediatric MMD, some medullary streaks appear as hypersignals on FLAIR imaging (HMSFs). Notably, HMSFs have been reported exclusively in pediatric cases (23,31,34,35) and has not been observed in adult patients. HMSFs do not fully correspond to the vasculature. Instead, they coincide with the hyperintense medullary streaks seen on T2WI (20), which are possibly associated with the stagnated cerebrospinal fluid of the perivascular space (20). In our study, we found nearly all the hemispheres (98.6%) exhibited these streaks, the high-EPVS grade group exhibited a greater number of streaks, and there was an association between HMSFs and EPVS. Based on the previous report and our results, we believe that HMSFs may share certain similarities with EPVSs, but why HMSFs appear hyperintense on FLAIR imaging and the differences between EPVS and HMSF still need to be clarified.

Study limitations and future research

This study involved several limitations that should be addressed. First, we employed a retrospective, case-control design, and the dynamic changes in EPVSs of the examined hemispheres were not examined in the long term. EPVSs are considered to be neuroimaging markers of cerebral small-vessel disease and a potential biomarker of Alzheimer’s disease (14,15). In the pediatric population, the presence of EPVSs has also been associated with severe forms of autism, particularly in males (36). Higher EPVS burden has been associated with cognitive impairment, dementia, sleep disorder, and depression (26). Pediatric patients with MMD exhibit cognitive impairment (28). In the future, we will enroll these patients and complete the same MRI examination, cognitive assessment, and psychological tests and determine their association in order to understand the pathological significance of EPVSs in pediatric MMD. Second, the controls were not subjected to sufficiently rigid selection criteria in this study. It was highly challenging to enroll only healthy pediatric volunteers for MRI and MRA examination in this study because of the long acquisition time and the incompatibility with children. We enrolled patients with no organic abnormalities for the MRI and MRA series and excluded these with history of atherosclerosis, meningitis, encephaloma, head trauma, Down syndrome, neurofibromatosis type 1, cerebrovascular lesions after head irradiation, autoimmune disease, or hyperthyroidism. We included some patients with headache, epilepsy, and limb weakness due to childhood emotional disorder, the symptoms of which are similar to those of patients with MMD. Finally, the sample size was relatively small because pediatric MMD is rare. We aim to recruit a greater number of patients in future to confirm our observations.

Conclusions

Pediatric MMD patients exhibited an increased number of EPVS, HMSF, and higher PLR as compared to the controls. MMD is an independent risk factors for EPVSs in children, and EPVSs were independently associated with the pediatric radiological feature HMSF. The systemic immune-inflammatory marker PLR was associated with EPVS grade in pediatric patients with MMD. Our research can help form the foundation for further in-depth investigations into EPVSs among patients with pediatric MMD.

Acknowledgments

We would like to thank Hui Jiao from the Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, for helping to determine the EPVSs and all imaging features of participants.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2175/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2175/dss

Funding: This work was supported by Natural Science Foundation for Young Scholars of Shandong province (grant number ZR2023QH176).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2175/coif). The 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 the ethics committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University (No. 202412-052-1) 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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