Pediatric Moyamoya Disease Patients Research Articles

Abstract 2029: Augmenting Mitochondrial Respiration In Immature Smooth Muscle Cells Is A Therapeutic Target For Moyamoya-like Cerebrovascular Disease

Introduction: Moyamoya disease (MMD), characterized by occlusive lesions in the distal internal carotid arteries, is a malignant cause of pediatric stroke. Surgical revascularization is the mainstay treatment, but peri- and postoperative ischemic complications are common. Multiple identified genes account for only a small percentage of cases. Identifying a common pathway of disease pathogenesis would enhance care for MMD patients. Goal and Approach: We used cellular and animal models for a rare cause of MMD-like cerebrovascular disease, heterozygous ACTA2 p.R179 pathogenic variants, to define molecular mechanisms and assess therapeutic strategies. Our prior work showed that smooth muscle cells (SMCs) with ACTA2 p.R179 variants are incompletely differentiated. We hypothesized that these immature phenotypes could be rescued by manipulation of cellular metabolism. We validated our results with cellular models of other pediatric MMD-associated variants: loss-of-function variants in Pcnt (explanted from a mouse model) and a pathogenic variant in RNF213 (generated via Crispr/Cas9 in human iPSCs). Results: Acta2 SMC-R179C/+ SMCs have increased glycolysis and reduced oxidative respiration on Seahorse analyses. Molecular characterization showed that Acta2 SMC-R179C/+ SMCs have reduced mitochondrial mass and decreased complex I activity, which is rescued by nicotinamide riboside (NR) treatment. NR surprisingly also increases SMC differentiation and decreases migration. Acta2 SMC-R179C/+ mice and littermate controls were subjected to carotid artery ligation, and 33% of Acta2 SMC-R179C/+ mice died due to strokes while all control mice survived (Kaplan-Meier p<0.01). Surviving Acta2 SMC-R179C/+ mice have significant cerebrovascular remodeling and persistent occlusive carotid artery lesions. Treatment with NR reduces death (Kaplan-Meier p=0.08) and resolves persistent lesions (p<0.05) in Acta2 SMC-R179C/+ mice after carotid ligation. Pcnt and RNF213 mutant SMCs have a similar phenotype of incomplete differentiation and decreased mitochondrial respiration as ACTA2 p.R179 and are responsive to NR treatment. Conclusions: These data provide evidence for a common and therapeutically targetable pathway in pediatric MMD patients.

Abstract WP219: Diffusion Weighted Imaging Characteristics in Deep White and Gray Matter Structures in Pediatric Patients With Moyamoya Disease

Background: Moyamoya Disease (MMD) is a steno-occlusive arteriopathy associated with transient ischemic attacks, stroke, and cognitive impairments. In adult MMD, normal-appearing deep gray and white matter structures (NADWM) show diffusion changes that are associated with cognitive impairments. Apparent diffusion coefficient [ADC] measures the mean diffusion and is sensitive to these changes. The association of ADC changes in NADWM in pediatric MMD is not clear. Our objective is to determine whether ADC is elevated in NADWM in pediatric MMD patients. Hypothesis: ADC values in NADWM will be elevated in MMD patients compared to controls. Methods: Twenty-nine MMD patients and no stroke and 7 healthy controls (HC) were included in a single center, retrospective study. Diffusion and T1-weighted images were analyzed. We constructed a script implementing a convolutional neural network (CNN) based approach to segment and binarize cortical regions of interest (ROI) and allow extraction of ADC values (units =[x10 -6 mm 2 /s]). Segmented ROIs included: 1) all white matter (WM), and NADWM including: 2) thalamus, 3) caudate, 4) putamen, 5) globus pallidus, 6) hippocampus. Mean ADC values were compared for: 1) all ROIs between MMD and controls, and 2) all ROIs in the MMD affected and the contralateral hemispheres within the MMD group. Results: Patients were on average 7.7 + 5.4 years at MMD diagnosis. In all WM, MMD patients had significantly higher ADC values than controls in the left (mean= 865.7 + 101.6 versus 762.4 + 21.6, p=0.01) and right hemispheres (mean= 869.9 + 104.9 versus 761.0 + 21.3, p=.01), respectively. In NADGM, there were no significant differences found between the MMD and control groups in any of the NADGM ROIs. In the NADGM of MMD patients, higher ADC values were found in the putamen (mean= 778.2 + 46.0, p=0.041), hippocampus (mean=1009.5 + 58.6, p=0.005) and all NAWM (mean= 860.3 + 57.0, p<0.0001) in the MMD affected compared to the contra-lesional hemisphere. Conclusions: In pediatric patients with MMD, we found elevated ADC values in deep gray and white matter structures in the diseased hemisphere indicating alterations in the underlying microstructure. Our future analysis will integrate hemodynamic profiles and cognitive outcomes.

Intellectual function and memory in children with moyamoya disease: relationship between Wechsler Intelligence Scale and Benton Visual Retention Test scores and regional cerebral blood flow.

Intellectual function declines in about 30% of children with moyamoya disease (MMD). Memory function underpins higher order brain function, but the relationship between intellectual function and memory in pediatric MMD patients has not been well studied. This study aimed to investigate correlations between scores on the Wechsler Intelligence Scale for Children (WISC) and the Benton Visual Retention Test (BVRT), a visual memory test that can be administered to children, in children with MMD. Relationships between intellectual function or memory and regional cerebral blood flow (rCBF) have also not been well clarified in pediatric MMD patients. The authors also investigated associations between WISC or BVRT scores and rCBF in various brain regions. WISC and BVRT scores and rCBF were assessed in 17 children with ischemic-onset MMD before revascularization. Single-photon emission CT with 123I-iodoamphetamine was used to measure rCBF. Relationships between WISC and BVRT scores were evaluated using Spearman's correlation coefficient and multivariate linear regression analysis. Cutoff values were identified for BVRT scores. Sensitivity and specificity were calculated to predict full-scale intelligence quotient (FSIQ) > 85 or ≤ 85. Associations between rCBF and WISC or BVRT scores were evaluated using linear regression analysis. BVRT scores were significantly correlated with FSIQ and scores on the Working Memory Index (WMI), Processing Speed Index, and Verbal Comprehension Index (VCI)/Verbal Intelligence Quotient (VIQ) of WISC. Multivariate linear regression revealed that number correct score and number of errors score of BVRT were associated with FSIQ. As cutoff values, a number correct score of 5 and a number of errors score of 8 offered the most reliable predictors of FSIQ > 85 and ≤ 85, respectively. FSIQ correlated positively with rCBF in the right and left hemispheres, right and left ganglia, right and left thalamus, right and left cerebellum, right middle cerebral artery (MCA) territory, pons, and vermis. WMI score was positively associated with rCBF in the right hemisphere, right anterior cerebral artery territory, right MCA territory, right basal ganglia, right and left thalamus, right and left cerebellum, pons, and vermis. BVRT score correlated well with WISC index scores, suggesting that BVRT may be helpful in screening for intellectual impairments in children with MMD. In the MCA territory, basal ganglia, thalamus, cerebellum, pons, and vermis, rCBF associated well with WISC index scores, suggesting that reduced rCBF in relevant brain regions may influence intellectual function.

Technical evolution of pediatric neurosurgery: moyamoya disease.

Moyamoya disease (MMD) is a rare steno-occlusive disease of the bilateral internal carotid arteries that predominantly occurs in East Asia. Since the first description of the MMD by Suzuki and Takaku in 1969, significant advances have been made in both basic and clinical understanding of the disease. The incidence and prevalence of pediatric MMD have increased, potentially due to improved detection rates. The advancement of neuroimaging techniques has enabled MRI-based diagnostics and detailed visualization of the vessel wall. Various methods of surgical treatments are successful in pediatric MMD patients, and recent studies emphasize the importance of reducing postoperative complications since the goal of MMD surgery is to prevent future cerebral infarction and hemorrhage. Long-term outcomes following appropriate surgical treatment in pediatric MMD patients have shown promising results, including favorable outcomes in very young patients. Further studies with a large patient cohort are needed to establish individualized risk group stratification for determining the optimal timing of surgical treatment and to conduct multidisciplinary outcome assessments.

Headache in Pediatric Moyamoya Disease after Revascularization Surgery

Introduction: Patients with moyamoya disease (MMD) often have headaches after successful revascularization surgery. We aimed to characterize headache in surgically treated MMD patients and elucidate its clinical meaning and pathophysiology. Methods: Headache and related symptoms were surveyed using structured questionnaires in pediatric MMD patients with follow-up for 6 months or longer after indirect revascularization surgery. Clinical information including initial presentation, surgical method, and outcome was collected from medical records. Surgical outcomes were assessed clinically and by perfusion imaging. We defined “headache associated with MMD” as the headache accompanied by a transient ischemic attack or provoked by hyperventilation. Other headaches were further classified based on the diagnostic criteria of the International Headache Society-3. We analyzed the characteristics of “headache associated with MMD” and newly developed headache after surgery. Results: Among 90 participants, 65 (72.2%) had headaches within the last year before survey, including 28 (43.1%) with “headaches associated with MMD,” 10 (15.3%) with probable migraines, 2 (3.1%) with infrequent episodic tension-type headaches, and 4 (6.2%) with probable tension-type headaches. Headache quality was pulsatile in 27 (41.5%) patients and pressing or tightening in 27 (41.5%) patients. Nausea or vomiting was accompanied in 30 (46.2%) patients. Headache upon awakening was reported in 37 (57.8%) patients. Headache disturbed daily life in 12 (18.5%) patients. Among the 32 (35.6%) patients who suffered headache during both the pre- and postoperative period, the headache quality was similar in 27 (84.4%) patients, and its severity decreased in 24 (75.0%) and did not change in 8 (25.0%) patients. Twelve (13.3%) patients experienced newly developed headaches after surgery. Among them, six (50.0%) were classified as having “headaches associated with MMD.” They were predominantly electric shock-like or stabbing in 5 (45.6%) patients and nondisturbing in all patients. All 90 patients achieved improvement of ischemic symptoms after surgery. Conclusion: Headaches often persist or newly develop after revascularization surgery in MMD patients. Accompanying nausea or vomiting and occurrence upon awakening are characteristic features. Postoperative headache does not necessarily imply insufficient disease control.

Changes in the clinical spectrum of pediatric moyamoya disease over 40years.

To investigate the chronological changes in the clinical presentation and long-term prognosis of pediatric-onset moyamoya disease in our institute over 40years. We evaluated 282 pediatric-onset (≤ 15years old) moyamoya disease patients who visited our institute from 1981 to 2020 (divided into the former period, 1981-2000, and the latter period, 2001-2020). Differences in the clinical presentation and the long-term outcome were compared between the periods. Multivariate analysis was also performed to reveal the risk factors for poor long-term outcomes. Compared to the former period, the total number of patients, the onset age and both the number of patients with family history and relatively older patients without symptoms or with headache were greater in the latter period (p < 0.05). The number of patients with poor long-term outcomes was significantly lower in the latter period (24.9% vs. 6.7%, p < 0.01). Multivariate analysis revealed that stroke onset, late cerebrovascular events and postoperative complications were independent risk factors for poor long-term outcomes (odds ratio = 31.4, 40.8 and 5.4, respectively). Over the last 40years, the number of pediatric moyamoya disease patients has increased, especially in relatively older patients with mild presentation and favorable long-term outcomes. In clinical studies, these chronological changes and the inclusion period of the participants need to be accounted for. Whether the increased diagnostic rate in the recent era has led to a decrease in late cerebrovascular events and favorable outcomes throughout life remains unknown and should be evaluated in the future.

Surgical Approaches to Pediatric Moyamoya Disease

Moyamoya disease(MMD)is a chronic, occlusive cerebrovascular disease with unknown etiology, characterized by progressive stenosis of the internal carotid artery terminus and abnormal vascular network formation at the base of the brain. MMD has bimodal age distribution, with peaks in children and young adults, and surgical revascularization is a reasonable management choice for pediatric and adult patients with ischemic MMD. The superficial temporal artery-middle cerebral artery anastomosis with indirect pial synangiosis(combined revascularization)is a preferred surgical procedure for adult and pediatric MMD patients, providing early cerebral hemodynamic improvement and long-term favorable outcomes. Pediatric patients with MMD can present intrinsic postoperative hemodynamic complications, such as watershed shift ischemia and transient global hypoperfusion, even after successful revascularization. Therefore, perioperative management based on the early hemodynamic study is critical to avoid surgical complications, including perioperative cerebral infarction.

A novel method for improving the accuracy of MR-derived patient-specific vascular models using X-ray angiography

MR imaging, a noninvasive radiation-free imaging modality commonly used during clinical follow-up, has been widely utilized to reconstruct realistic 3D vascular models for patient-specific analysis. In recent work, we used patient-specific hemodynamic analysis of the circle of Willis to noninvasively assess stroke risk in pediatric Moyamoya disease (MMD)—a progressive steno-occlusive cerebrovascular disorder that leads to recurrent stroke. The objective was to identify vascular regions with critically high wall shear rate (WSR) that signifies elevated stroke risk. However, sources of error such as insufficient resolution of MR images can negatively impact vascular model accuracy, especially in areas of severe pathological narrowing, and thus diminish clinical relevance of simulation results, as local hemodynamics are sensitive to vessel geometry. To improve the accuracy of MR-derived vascular models, we have developed a novel method for adjusting model vessel geometry utilizing 2D X-ray angiography (XA), which is considered the gold standard for clinically assessing vessel caliber. In this workflow, “virtual angiographies” (VAs) of 3D MR-derived vascular models are conducted, producing 2D projections that are compared with corresponding XA images to guide the local adjustment of modeled vessels. This VA-comparison-adjustment loop is iterated until the two agree, as confirmed by an expert neuroradiologist. Using this method, we generated models of the circle of Willis of two patients with a history of unilateral stroke. Blood flow simulations were performed using a Navier–Stokes solver within an isogeometric analysis framework, and WSR distributions were quantified. Results for one patient show as much as 45% underestimation of local WSR in the stenotic left anterior cerebral artery (LACA), and up to a 56% underestimation in the right anterior cerebral artery when using the initial MR-derived model compared to the XA-adjusted model. To evaluate whether XA-based adjustment improves model accuracy, vessel cross-sectional areas of the pre- and post-adjustment models were compared to those seen in 3D CTA images of the same patient. CTA has superior resolution and signal-to-noise ratio compared to MR imaging but is not commonly used in the clinic due to radiation exposure concerns, especially in pediatric patients. While the vessels in the initial model had normalized root mean squared deviations (NRMSDs) ranging from 26 to 182 and 31 to 69% in two patients with respect to CTA, the adjusted vessel NRMSDs were comparatively smaller (32–53% and 11–42%). In the mildly stenotic LACA of patient 1, the NRMSDs for the pre- and post-adjusted models were 49% and 32%, respectively. These findings suggest that our XA-based adjustment method can considerably improve the accuracy of vascular models, and thus, stroke-risk prediction. An accurate, individualized assessment of stroke risk would be of substantial help in guiding the timing of preventive surgical interventions in pediatric MMD patients.

Outcomes of Combined Revascularization Surgery for Moyamoya Disease without Preoperative Cerebral Angiography

Cerebral angiography is the gold standard for diagnosing moyamoya disease (MMD), whereas magnetic resonance (MR) imaging/angiography is becoming more popular in the field of cerebrovascular disease due to its low invasiveness. Although there are concerns about using only MR imaging/angiography for preoperative analysis of MMD, considering the underestimation of pre-existing transdural collateral circulations and dangerous collaterals related to the risk of hemorrhage, we retrospectively reviewed our 10-year experience of MR imaging-first diagnosis and analyzed the perioperative outcomes. We analyzed 160 consecutive direct/indirect combined revascularization procedures for MMD preoperatively assessed using MR imaging/angiography alone. Perioperative complications were assessed for up to 2weeks after surgery. Locations of the lesions responsible for complications were further classified into the surgical field, the ipsilateral hemisphere outside the surgical field, and the contralateral hemisphere. Sixty-four revascularization procedures were performed in 38 children, and 96 procedures were performed in 68 adults. There was no difference in the incidence of perioperative ischemic complications between adults (6.3%) and pediatric patients (4.7%), but hemorrhagic complications were more frequently observed in adults (7.3%) than in children (0%) (P < 0.05). There was no specific lesion deviation for ischemic complications; however, hemorrhagic complications predominantly occurred in the surgical field. Direct/indirect combined revascularization surgery based on our preoperative diagnostic protocol with the MR-first strategy resulted in favorable outcomes in pediatric MMD patients with relatively low complication rates. However, the validity of the MR-first diagnostic protocol should be further evaluated in adult patients with MMD.

Patient-Specific Modeling Could Predict Occurrence of Pediatric Stroke.

Moyamoya disease (MMD) is a progressive steno-occlusive cerebrovascular disease leading to recurrent stroke. There is a lack of reliable biomarkers to identify unilateral stroke MMD patients who are likely to progress to bilateral disease and experience subsequent contralateral stroke(s). We hypothesized that local hemodynamics are predictive of future stroke and set out to noninvasively assess this stroke risk in pediatric MMD patients. MR and X-ray angiography imaging were utilized to reconstruct patient-specific models of the circle of Willis of six pediatric MMD patients who had previous strokes, along with a control subject. Blood flow simulations were performed by using a Navier–Stokes solver within an isogeometric analysis framework. Vascular regions with a wall shear rate (WSR) above the coagulation limit (>5,000 s−1) were identified to have a higher probability of thrombus formation, potentially leading to ischemic stroke(s). Two metrics, namely, “critical WSR coverage” and “WSR score,” were derived to assess contralateral stroke risk and compared with clinical follow-up data. In two patients that suffered a contralateral stroke within 2 months of the primary stroke, critical WSR coverages exceeding 50% of vessel surface and WSR scores greater than 6× the control were present in multiple contralateral vessels. These metrics were not as clearly indicative of stroke in two additional patients with 3–5 year gaps between primary and contralateral strokes. However, a longitudinal study of one of these two cases, where a subsequent timepoint was analyzed, suggested disease stabilization on the primary stroke side and an elevated contralateral stroke risk, which was confirmed by patient outcome data. This indicates that post-stroke follow-up at regular intervals might be warranted for secondary stroke prevention. The findings of this study suggest that WSR-based metrics could be predictive of future stroke risk after an initial stroke in pediatric MMD patients. In addition, better predictions may be possible by performing patient-specific hemodynamic analysis at multiple timepoints during patient follow-up to monitor changes in the WSR-based metrics.

Transient Global Cerebral Hypoperfusion as a Characteristic Cerebral Hemodynamic Pattern in the Acute Stage after Combined Revascularization Surgery for Pediatric Moyamoya Disease: N-Isopropyl-P-[123I] Iodoamphetamine Single-Photon Emission Computed Tomography Study

Introduction: Surgical revascularization prevents cerebral ischemic attack by improving cerebral blood flow (CBF) in both adult and pediatric patients with moyamoya disease (MMD). Uneven hemodynamic changes, including local cerebral hyperperfusion and remote ischemia, can cause delayed intracerebral hemorrhage and perioperative infarctions in adult MMD patients, but the characteristic hemodynamic pattern among pediatric MMD patients after revascularization surgery is poorly understood. Methods: This study included 16 consecutive pediatric MMD patients (age, 6–16 years; mean age, 11.3) undergoing superficial temporal artery-middle cerebral artery anastomosis combined with encephalo-duro-myo-synangiosis on 21 affected hemispheres. Perioperative management was conducted by aspirin administration and strict blood pressure control (110–130 mm Hg). We prospectively performed N-isopropyl-p-[¹²³I] iodoamphetamine single-photon emission computed tomography on postoperative days (POD) 1 and 7 and analyzed the temporal changes in perioperative hemodynamics. Results: Four patients (19.0%, 4/21) exhibited immediate CBF improvement from POD 1, which was classified as “immediate redistribution pattern.” In contrast, 9 (42.9%, 9/21) demonstrated transient hemispheric global hypoperfusion at POD 1 and subsequent CBF improvement at POD 7, which was defined as “transient hypoperfusion pattern.” Although 8 patients, including 4 with “transient hypoperfusion pattern” (44.4, 4/9), developed mild transient neurological deterioration in the acute stage, it resolved in all 21 patients, and there were no permanent neurological deficits. Discussion/Conclusions: This study revealed that the “transient hypoperfusion pattern” after revascularization surgery is relatively common among pediatric MMD patients, and its outcome is favorable under strict perioperative management.

Image-based patient-specific flow simulations are consistent with stroke in pediatric cerebrovascular disease.

Moyamoya disease (MMD) is characterized by narrowing of the distal internal carotid artery and the circle of Willis (CoW) and leads to recurring ischemic and hemorrhagic stroke. A retrospective review of data from 50 pediatric MMD patients revealed that among the 24 who had a unilateral stroke and were surgically treated, 11 (45.8%) had a subsequent, contralateral stroke. There is no reliable way to predict these events. After a pilot study in Acta-/- mice that have features of MMD, we hypothesized that local hemodynamics are predictive of contralateral strokes and sought to develop a patient-specific analysis framework to noninvasively assess this stroke risk. A pediatric MMD patient with an occlusion in the right middle cerebral artery and a right-sided stroke, who was surgically treated and then had a contralateral stroke, was selected for analysis. By using an unsteady Navier-Stokes solver within an isogeometric analysis framework, blood flow was simulated in the CoW model reconstructed from the patient's postoperative imaging data, and the results were compared with those from an age- and sex-matched control subject. A wall shear rate (WSR) > 60,000s-1 (about 12 × higher than the coagulation threshold of 5000s-1 and 9 × higher than control) was measured in the terminal left supraclinoid artery; its location coincided with that of the subsequent postsurgical left-sided stroke. A parametric study of disease progression revealed a strong correlation between the degree of vascular morphology altered by MMD and local hemodynamic environment. The results suggest that an occlusion in the CoW could lead to excessive contralateral WSRs, resulting in thromboembolic ischemic events, and that WSR could be a predictor of future stroke.

Risk factors for postoperative ischemic complications in pediatric moyamoya disease

BackgroundIschemic events are the most common postoperative complication in bypass surgery for moyamoya disease (MMD), but the risk factors for pediatric MMD remain unclear. The goal of the study was to investigate the risk factors for postoperative ischemic complications in pediatric MMD patients.MethodsWe retrospectively reviewed a consecutive series of pediatric MMD cases at Beijing Tiantan Hospital, Capital Medical University from June 2010 through June 2019. Preoperative clinical variables and radiographic findings were recorded, and logistic regression analysis was carried out to identify the risk factors for postoperative ischemic events.ResultsA total of 533 operations in 336 patients were included in this study. Postoperative complications occurred after 51 operations (9.6%), including 40/447 indirect bypass procedures, 9/70 direct bypass procedures, and 2/16 combined bypass procedures. Postoperative ischemic events were the most common complication and occurred in 30 patients after 31 procedures (8.9% per patient; 5.8% per operation), including 26/447 indirect bypass procedures, 4/70 direct bypass procedures, and 1/16 combined bypass procedures, and the incidence of these events did not differ significantly between indirect and non-indirect bypass (5.8% vs 5.8%; p = 0.999). Multivariate logistic regression analyses revealed that older age at operation (OR 1.129, 95% CI 1.011–1.260, p = 0.032) and posterior cerebral artery involvement (OR 2.587, 95% CI 1.030–6.496, p = 0.043) were significantly associated with postoperative ischemic events.ConclusionWe speculate that older age at operation and posterior cerebral artery involvement are risk factors for postoperative ischemic events in pediatric MMD patients.

Renovascular hypertension and RNF213 p.R4810K variant in Korean children with Moyamoya disease.

Moyamoya disease (MMD) is the most common underlying disease in Korean pediatric renovascular hypertension (RVH). The ring finger protein 213 (RNF213) p.R4810K variant is reported to be a pathologic variant in East Asian MMD. The purpose of this study was to evaluate hypertension (HTN) prevalence and clinical manifestations as well as RNF213 p.R4810K variant prevalence in Korean pediatric MMD patients. The medical records of pediatric MMD patients from January 2000 to June 2018 were retrospectively reviewed. RVH was confirmed by computer tomography angiography or renal Doppler ultrasonography. The American Academy of Pediatrics 2017 guideline for sex-, age-, and height-related blood pressure standards was used to define HTN. Of 706 patients with MMD, 40 (5.7%) had HTN. Among these patients, 22 had RVH and 12 had HTN with no evidence of renal artery stenosis (non-RVH). Patients with MMD and RVH had an MMD onset at a younger age and lower body mass index compared to those with MMD and non-RVH. Among the patients with MMD and HTN, 4 presented with HTN before developing MMD. Genetic testing for the RNF213 p.R4810K variant was performed in 32 patients with MMD and HTN. When the patient had a homozygous RNF213 p.R4810K variant, the odds ratio of RVH to non-RVH was 8.3. Our study suggests that RVH is more prevalent than non-RVH in pediatric MMD patients. Furthermore, RNF213 p.R4810K may be the cause of RVH in Korean children with MMD.

Time to peak and full width at half maximum in MR perfusion: valuable indicators for monitoring moyamoya patients after revascularization

Moyamoya disease (MMD) is a chronic, steno-occlusive cerebrovascular disorder of unknown etiology. Surgical treatment is the only known effective method to restore blood flow to affected areas of the brain. However, there are lack of generally accepted noninvasive tools for therapeutic outcome monitoring. As dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) is the standard MR perfusion imaging technique in the clinical setting, we investigated a dataset of nineteen pediatric MMD patients with one preoperational and multiple periodic DSC MRI examinations for four to thirty-eight months after indirect revascularization. A rigid gamma variate model was used to derive two nondeconvolution-based perfusion parameters: time to peak (TTP) and full width at half maximum (FWHM) for monitoring transitional bolus delay and dispersion changes respectively. TTP and FWHM values were normalized to the cerebellum. Here, we report that 74% (14/19) of patients improve in both TTP and FWHM measurements, and whereof 57% (8/14) improve more noticeably on FWHM. TTP is in good agreement with Tmax in estimating bolus delay. Our study data also suggest bolus dispersion estimated by FWHM is an additional, informative indicator in pediatric MMD monitoring.

Letter: Early Diffusion Magnetic Resonance Imaging Changes in Normal-Appearing Brain in Pediatric Moyamoya Disease.

To the Editor: Recently, we read with great interest the article by Quon et al1 regarding the early diffusion magnetic resonance imaging (MRI) changes in normal-appearing brain in pediatric moyamoya disease (MMD). The authors found the significantly elevated apparent diffusion coefficient (ADC) values for MMD children in the representative brain regions could reflect microstructural changes stemming from exhaustion of cerebrovascular reserve (CVR). We really appreciate the interesting observation for their conclusion. Meanwhile, we would like to highlight 3 important questions that it raises. First, in recent years, the researchers of MMD have gradually formed a consensus: prior to the obvious ischemic changes on MRI, the microstructural impairments caused by reduced blood supply had appeared in the brain of MMD patients.2,3 Hypoperfusion and cytotoxic edema have been considered as the major cause of microstructural impairments.4,5 There are 2 different types of cerebral ischemic edema: the early cytotoxic type and the later vasogenic type. When the stimulation of anaerobic metabolism leads to the increase of osmotic pressure of brain tissue, which leads to the swelling of permeable cells, cytotoxic edema occurrs.6 With the development of tissue necrosis and the degradation of basement membrane, the blood-brain barrier is destroyed, and serum protein begins to leak into the brain from the blood, thus further improving the water content of the tissue and a later vasogenic type occurrs.7 However, due to the insensitivity of conventional MRI to the cytotoxic edema, most MMD patients had already suffered serious brain parenchymal damage by the time they receive treatment. In the present study,1 via the high sensitivity of diffusion-weighted imaging in distinguishing cytotoxic and vasogenic edema,8 the authors found the ADC value could precisely differentiate pediatric MMD patients from normal controls in the absence of imaging evidence of ischemic stroke. This observation indicated that it is possible to detect the serious imbalance of energy supplies and demands via the ADC value before the occurrence of irreversible lesions in brain parenchyma in MMD patients, so as to timely implement the intervention measures to obtain the maximum clinical effect. Second, revascularization surgery is considered to be the most effective way to treat MMD. Previous studies have confirmed that the preoperative clinical and hemodynamic changes could indicate the outcomes and complications from revascularization surgery for MMD patients.9,10 However, which severity of the preoperative changes in MMD patients can maximize the benefits from bypass surgery has always puzzled neurosurgeons. Recently, many non-invasive examination methods and indicators, such as CVR,11 ivy sign,12 and cortical hyperintensity belt sign,13 were proposed to reflect the clinical severity of MMD before obvious (usually means serious) changes appear on conventional MRI. The same is true for the ADC value in present study. Third, the authors in present study1 tried to explain a possible relation between the elevated ADC value and the impaired CVR. Although previous studies have observed simultaneous appearance of reduced CVR and elevated ADC in MMD patients, the mechanism remains to be clarified.14 In our opinion, CVR reflects the compensatory ability of cerebral arteries to compensate for the hypoperfusion, and its mechanism may partially due to the vasodilatory stimulation of metabolites like lactate to arteries. Meanwhile, the early cytotoxic edema in MMD patients may also due to the change of metabolism in brain cells during hypoperfusion.6 Therefore, there may not be a direct causal relationship between impaired CVR and elevated ADC, they may be 2 simultaneous results of the same change (hypoperfusion). Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Postoperative Symptomatic Cerebral Infarction in Pediatric Moyamoya Disease: Risk Factors and Clinical Outcome

Indirect bypass surgery is used to improve the hemodynamic status of pediatric patients with moyamoya disease (MMD). Symptomatic cerebral infarction during the early postoperative period may be the most frustrating complication. This study was conducted to investigate the factors associated with early postoperative symptomatic cerebral infarction. Between January 2000 and February 2014, we performed 1241 indirect bypass surgeries in 659 pediatric MMD patients. Symptomatic infarction during the early postoperative period was diagnosed in 63 operations in 61 patients. The overall incidence of symptomatic cerebral infarction after indirect bypass surgery was 5.1%. The median age of the patients with postoperative infarction was 6 years (mean, 6.4 years; range, 1-15 years). The performance of 2 craniotomies in single operation was associated with a higher rate of cerebral infarction. Moreover, the incidence was higher in young patients (age<6 years) compared with older patients. In a matched analysis, an immediate postoperative hemoglobin level >13g/dL was associated with decreased risk of infarction (odds ratio, 0.144; P= 0.003). Mutation of the methylenetetrahydrofolate reductase (MTHFR) gene occurred in a relatively high proportion of our infarction cohort. Postoperative symptomatic infarctions can occur despite a unified surgical method and formulaic perioperative management protocol. Patient-centered factors, such as young age, genetic background of MTHFR, and certain medical conditions, including hyperthyroidism, renovascular hypertension, and hemolytic uremic syndrome, as well as management-related factors, including 2craniotomies and low immediate postoperative hemoglobin level, could be risk factors for early postoperative symptomatic cerebral infarction.

Cognitive Performance Profile in Pediatric Moyamoya Disease Patients and Its Relationship With Regional Cerebral Blood Perfusion.

Object: Moyamoya disease affects the cognitive function of pediatric patients, and compromised cerebral blood flow might be the potential cause. We aimed to explore the specific correlation between cognitive impairment and regional perfusion status in pediatric moyamoya disease patients.Methods: We prospectively enrolled consecutive pediatric moyamoya disease patients admitted to Beijing Tiantan Hospital from July 2017 to March 2019. Arterial spin-labeling magnetic resonance and the Wechsler Intelligence Scale for Children (the 4th edition) were performed on all participants. The cognitive performance of patients was analyzed, and its correlation to cerebral perfusion status was also investigated in the region of interest-based analysis.Results: A total of 21 patients met the inclusion criteria (mean aged 11.14 ± 2.82, male: female = 11:10). Six patients (28.6%) showed no cognitive deficits in any index score, while 15 (71.4%) showed cognitive deficits with differing severity. Nine (42.9%) patients showed overall cognitive impairment, and all cognitive index scores except for Verbal Comprehension Index were significantly lower than the mean scores of normative data with corresponding age. Perceptual Reasoning Index (p = 0.019) were statistically lower in patients with radiologically confirmed cerebral infarction. Suzuki stage of the left hemisphere negatively correlated to Full-scale Intelligence Quotient (r = −0.452, p = 0.039). Region of Interest analysis showed that cerebral blood flow of the left temporal lobe independently associated with the Processing Speed Index (β = 0.535, p = 0.041).Conclusion: Pediatric moyamoya disease patients exhibited different levels of cognitive impairment. Cerebral infarction is related to poorer perceptual reasoning ability. Cerebral blood flow in the left temporal lobe positively correlates with processing speed.

High prevalence of systemic hypertension in pediatric patients with moyamoya disease years after surgical treatment.

Although an association between moyamoya disease (MMD) and renovascular hypertension has been acknowledged, the literature on systemic hypertension without renal artery stenosis among patients with MMD is scarce. The authors aimed to evaluate the prevalence and risk factors of hypertension using data from MMD patients who visited an outpatient clinic of a pediatric neurosurgical department in 2016. The authors evaluated the blood pressure (BP) of pediatric MMD patients at their postsurgical appointment following the American Academy of Pediatrics clinical practice guideline on high BP, in which hypertension was defined as BP measurements higher than the value of age-, sex-, and height-specific 95th percentile of the general population from at least 3 separate visits. Growth of patients was determined using 2017 Korean National Growth Charts for children and adolescents. The cutoff value of the 95th percentile of BP was determined by referring to normative BP tables of Korean children and adolescents. A logistic regression model was used to assess the associations between patients' clinical characteristics and prevalent hypertension. In total, 131 surgically treated pediatric MMD patients were included, of whom 38.9% were male and the median age at diagnosis was 8.0 years (range 1.2-15.0 years). The definition of hypertension was met in 38 patients, with a prevalence of 29.0% (95% CI 21.2%-36.8%). A tendency was observed for a higher prevalence of hypertension in male patients (31.4%), in patients with posterior cerebral artery (PCA) involvement (47.8%), and in cases in which infarction was shown on initial MRI (37.3%). Age at diagnosis (adjusted OR [aOR] 0.82, 95% CI 0.70-0.97), PCA involvement (aOR 3.81, 95% CI 1.29-11.23), body mass index (aOR 1.30, 95% CI 1.13-1.51), and years of follow-up since surgery (aOR 0.80, 95% CI 0.68-0.94) were related to systemic hypertension. A high prevalence of hypertension was demonstrated in pediatric MMD patients. Therefore, adequate attention should be paid to reduce BP and prevent subsequent events.

Erratum. Results of more than 20 years of follow-up in pediatric patients with moyamoya disease undergoing pial synangiosis.

OBJECTIVEThere are limited data on the long-term outcomes for children undergoing surgical revascularization for moyamoya disease (MMD) in North America. The authors present a series of pediatric MMD patients who underwent a standard revascularization procedure, pial synangiosis, more than 20 years previously at a single institution by a single surgical team.METHODSThis study is a retrospective review of all patients aged 21 years or younger treated for MMD at Boston Children's Hospital who were operated on more than 20 years previously by the senior author (R.M.S.). Radiographic and operative reports, outpatient clinical records, and communications with patients and families were reviewed to document current clinical status, ability to perform daily activities, and concurrent or new medical conditions.RESULTSA total of 59 patients (38 female [64.4%], 21 male [35.6%]; median age at surgery 6.2 years [IQR 0.5-21 years]) were identified who were diagnosed with MMD and underwent surgical revascularization procedures more than 20 years previously. Clinically, all but 2 patients (96.6%) presented with the following symptoms alone or in combination: 43 (73%) presented with stroke, 22 (37%) with transient ischemic attack, 12 (20%) with seizures, 7 (12%) with headache, 3 (5%) with choreiform movements, and 2 (3%) with hemorrhage; MMD was incidentally detected in 2 patients (3%). Five patients had unilateral MMD at presentation, but 3 of these ultimately progressed to develop bilateral MMD after an average of 16 months; therefore, pial synangiosis was ultimately performed in a total of 116 hemispheres during the study period. Clinical follow-up was available at a median interval of 20.6 years (IQR 16.1-23.2 years). Modified Rankin Scale scores were stable or improved in 43 of 50 patients with evaluable data; 45 of 55 are currently independent. There were 6 patient deaths (10.2%; 3 due to intracranial hemorrhage, 2 due to tumor-related complications, and 1 due to pulmonary artery stenosis), 4 of whom had a history of previous cranial radiation. One patient (1.7%) experienced a late stroke. Synangiosis vessels remained patent on all available late MRI and MRA studies. Four patients reported uneventful pregnancies and vaginal deliveries years following their revascularization procedures.CONCLUSIONSRevascularization for MMD by pial synangiosis appears to confer protection from stroke for pediatric patients over long-term follow-up. A history of cranial radiation was present in 4 of the 5 patients who died and in the lone patient with late stroke. Most patients can expect productive, independent lives following revascularization surgery in the absence of significant preoperative neurological deficits and comorbidities.