Review
Jeffrey N Stout, PhD, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, 02115, USA, jeffrey.stout@childrens.harvard.edu
Kristin P Guilliams, MD MSCI, Washington University School of Medicine, Depts of Neurology, Pediatrics, and Radiology, kristinguilliams@wustl.edu
Banu Ahtam, DPhil MSc, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, 02115, USA, banu.ahtam@childrens.harvard.edu
Laura Lehman, MD, MPH Boston Children’s Hospital. 300 Longwood Ave, Boston, MA 02115
Alfred P. See, MD, Boston Children’s Hospital, pokmeng.see@childrens.harvard.edu
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Introduction
Moyamoya arteriopathy (MMA) refers to the progressive narrowing of the intracranial internal carotid arteries and their proximal branches, with ensuing development of collateral circulation based on proliferation of tiny arterial perforators in an attempt to meet the brain’s metabolic demand (Figure 1A, 2A).1,2 MMA has no medical cure, so surgery is usually undertaken to reduce the risk of future ischemic brain injury (Figure 1A-C, 2B, 2D).2 Currently, low complication rates for revascularization surgery alongside associated improved symptomatology bias clinical care of pediatric MMA towards surgical intervention.3 However, some patients still suffer strokes, despite surgery. Variable response to surgery, as well as perisurgical complications, symptomatic regression without treatment in some cases,3,4 and otherwise asymptomatic patients, suggest that technology to quantify an individual’s cerebral hemodynamic state could contribute to personalized treatment plans and improved outcomes.
Qualitative neuroimaging has played a central role in the diagnosis and surgical planning in MMA, but quantitative approaches to improve accuracy and efficacy of treatment are entering the scene. Quantitative approaches may offer far more insight into physiological mechanisms of disease–the specific hemodynamic states where the brain is most vulnerable to injury–but must be developed in ways that give physicians confidence in their value. These new tests should be rigorously evaluated, and there are published frameworks for both the typical steps of test development and guidelines for reporting diagnostic accuracy studies.5,6 Researchers and funding bodies should be motivated to develop tests that can be deployed in randomized trials as these are foundational to a quantitative test’s continued use in the clinical setting.
There are several quantitative MRI-based neuroimaging techniques being developed as metrics to personalize the diagnosis and treatment of pediatric MMA. MRI-based approaches deserve special attention for use in pediatric populations where sensitivity to ionizing radiation exposure is more pronounced. MRI-based quantitative techniques include oxygenation, perfusion, cerebrovascular reactivity and diffusion-weighted imaging. All these techniques have been developed in adults, with some promising results already available in children, so work remains across all phases of test development to evaluate their utility in pediatric populations. This review aims to highlight work to develop these MRI-based techniques for pediatric MMA, and to identify next steps in the development of these quantitative biomarkers.
Perfusion
MMA’s most pronounced physiological feature, the restriction of cerebral blood flow, leads to its most pronounced diagnostic feature, the growth of many tiny arterial perforators that develop into a collateral circulation. Thus, ascertaining whether there is adequate cerebral perfusion–parenchymal blood flow delivering nutrients and oxygen–is a central diagnostic question. Furthermore, the ability to track perfusion changes with treatment may show the way to improved outcomes. However, MRI-based perfusion imaging is technically demanding and this has limited its widespread adoption.
Arterial spin labeling (ASL) uses arterial blood as an endogenous tracer by magnetically labeling it using radio frequency pulses. During a post-label delay this tracer is allowed to flow and diffuse into brain parenchyma, and then MR images are taken. The resulting signal modulation from the labeled blood can be modeled to estimate parenchymal perfusion in canonical units of ml/100g/min. The modeling depends on user controllable imaging parameters (e.g. labeling type, post-labeling delay, and readout specifications) and variables that are outside operator control (e.g. the longitudinal relaxation time (T1) of blood, and partition coefficient). Consensus parameters for adult imaging and quantification are available in “the ASL white paper,”[7] with pediatric guidance recently available in a follow up commentary.[8] Physiological aspects of pediatric MMA makes accurate perfusion quantification difficult.
Stenosis in the internal carotid arteries can greatly and variably lengthen the transit time from the labeling to imaging planes which makes the ideal post-labeling delay for a single post-label delay acquisition difficult to select. When the post-label delay is incorrect, artefactual hypoperfusion is observed,[9,10] which has cast doubt on the performance of ASL in pediatric MMA (Figure 1D, 1E). Two strategies can overcome this challenge, velocity-selective labeling or multi-delay sequences. Velocity selective ASL permits a blood label to be created in the arteries and arterioles in immediate spatial proximity to the capillary bed, which eliminates transit time effects (Figure 1G, 1H).[11,12] Indeed, velocity selective ASL has been shown to more accurately reflect intact perfusion in children with MMA.[9] However, it suffers from diffusion attenuation artifacts that have yet to be fully mitigated and can lead to overestimates of cerebral blood flow (CBF) near spaces filled with CSF.[13,14] Multi-delay ASL has been compared to positron emission tomography (PET) in adults with MMA finding that whereas the standard single delay approach overestimates areas of hypoperfusion, the multi-delay approach finds area of hypoperfusion that match PET (Figure 1). Impressively, the scan-rescan coefficient of variation for multi-delay ASL was lower than that for PET, which in addition to its much lower logistical burden, makes it it a good candidate for accurately determining areas of true hypoperfusion in patients with MMA.10
Dynamic susceptibility contrast (DSC) MR perfusion imaging can also provide quantitative parameters like cerebral blood volume (CBV), CBF, time to peak (TTP), and mean transit time (MTT).[15] However, interpreting DSC MRP in pediatric MMA has limitations. The presence of collateral vessels can lead to delayed arterial transit times, causing underestimation of CBF and overestimation of TTP and MTT.16 Additionally, the accuracy of DSC MRP depends on proper arterial input function (AIF) selection, which can be challenging in MMA patients with complex hemodynamics.[17] Despite these limitations, DSC imaging plays a crucial role in surgical decision-making. For example, if DSC MRP reveals critically reduced CBF and prolonged TTP in a specific brain region, it may indicate inadequate collateral flow and suggest the need for revascularization surgery to prevent further ischemic events.[18] However, DSC imaging may benefit from increased availability and familiarity for clinicians. It may also provide higher spatial resolution. Finally, it is able to provide direct quantitative CBV measurement that is more difficult to measure with ASL techniques.
There are promising indications that ASL can detect changes in perfusion after revascularization therapy,[19],[20] but the field must work to understand the relation of these changes to neurological outcomes. The authors are aware of only one group that is using multi-delay ASL to assess cerebral perfusion in pediatric MMA, and they detected significantly increased perfusion in affected hemispheres 6-months post bypass surgery.20 More studies of perfusion using standardized protocols in normal and MMA children are needed to progress toward useful perfusion-based biomarkers of disease state that may predict surgical or neurological outcomes.
Cerebrovascular Reactivity
Cerebrovascular reserve is the net hemodynamic balance between supply, demand and vascular tone. Cerebrovascular reactivity (CVR) is an indicator of reserve, and can be estimated by detecting cerebral blood flow increases resulting from a stimulus that induces vasodilation (breath hold, carbogen breathing, or acetazolamide administration).21 In the presence of an upstream occlusion, as in MMA, CVR may be blunted or even become negative as blood flows toward the lowest resistance territories.22 Negative CVR is often termed “steal” for this reason (Figure 1F, 2H).
Any neuroimaging method sensitive to cerebral blood flow can be used to measure CVR, but, MRI-based methods are of particular value in the pediatric population since they do not involve ionizing radiation or radiotracers and MRI scanners are widely available. ASL and gradient echo imaging are used in MRI-based CVR protocols due to their sensitivity to blood flow. ASL yields CVR estimates in absolute units of ml/100g/min per mmHg change in end-tidal CO2, but the longer acquisition time limits the choice of vasodilatory stimulus to acetazolamide. Gradient echo (GRE) imaging yields units of signal change per mmHg, but the vasodilatory stimulus can be non-pharmacological hypercapnia given the technique’s significantly higher temporal resolution. Patient comfort is a consideration, particularly for pediatric patients, for methods that involve hi-flow or rebreather masks to administer CO2 enriched air.
ASL MRI has shown considerable promise in the quantitative assessment of CVR in pediatric MMA. One study utilized ASL to demonstrate post-surgical improvements in CVR, highlighting normalized responses to acetazolamide and improved blood flow in the ipsilateral middle cerebral artery (MCA) territory.23 The study also found a significant correlation between CVR values and Matsushima grades, emphasizing ASL’s sensitivity to physiological changes following surgery. A recent study observed short- and long-term hemodynamic changes in pediatric MMA patients post-revascularization surgery using single- and multi-delay PCASL, showing increased CBFand enhanced CVR over time.20 This improvement in hemodynamics can be indicative of successful surgical outcomes, although the study did not specifically tie these changes to neurodevelopmental outcomes. While ASL provides robust quantitative data, its practical application is limited by the need for patient stillness during long acquisition times and potential side effects from pharmacological agents used to elicit cerebrovascular responses.
GRE-based MRI studies leverage the high temporal resolution of this technique to assess CVR through non-pharmacological stimuli like CO2 inhalation. Dlamini et al. introduced the use of GRE-based BOLD MRI with a breath-hold hypercapnic challenge as a feasible method to assess cerebrovascular reactivity (CVR) in children with MMA, demonstrating good repeatability and substantial inter-rater reliability without the need for complex equipment.24 Expanding on this, subsequent research confirmed BOLD-CVR’s potential in predicting ischemic risk, finding significant associations between negative CVR responses and future ischemic events.25 Furthermore, it was linked to neurocognitive outcomes, showing that abnormal CVR correlated with slower processing speeds, thus extending the clinical implications of BOLD-CVR beyond vascular health to cognitive function.26 Addressing the method’s qualitative limitations, several groups have worked on enhancements to the breath hold protocol and modeling adjustments to estimate more accurate quantitative CVR.27–29 These studies collectively underscore the value of BOLD-CVR in evaluating and managing pediatric MMA, offering insights into both ischemic risk and broader neurovascular impacts with correlation to clinical outcomes
Oxygenation
While perfusion and CVR provide information about parenchymal blood flow, metabolic activity can be assessed using quantitative oxygenation imaging methods. There are two main groups of methods for MRI-based oxygenation imaging, whole brain and voxel-wise mapping.30 The most widely deployed whole-brain method is called T2-relaxation under spin tagging (TRUST).31 A voxel-wise method that has been used to observe OEF in sickle cell disease is called asymmetric spin echo (ASE).32,33 These methods have had only limited application to MMA34,35 and the authors are aware of no studies using MRI-based tools in pediatric MMA. One potential reason for this lacuna is continued uncertainty about the accuracy of these methods.
There have been different reports about whether oxygen extraction fraction (OEF) decreases or increases in sickle cell disease (SCD). The intuitive notion is that as oxygen carrying capacity in blood decreases OEF must increase. A recent report on cerebral oxygen extraction fraction (OEF) using the ASE technique in a comprehensive study involving 120 children, including healthy controls, anemic controls without sickle cell disease, and those with sickle cell anemia (SCA) found increased OEF in sickle cell anemia.33 This contrasts with decreased OEF reported in a study that used the TRUST method (Figure 3).36 This discrepancy might lead to confusion about the reliability of the methods. However, the difference in findings can be attributed to the distinct methodologies of OEF measurement: ASE quantifies spatial averages from microvascular tissue, whereas TRUST calculates flow averages from larger vessels like the superior sagittal sinus, each capturing different facets of oxygen physiology in the brain.37 There are also regional differences in OEF changes.38 Recognizing these methodological nuances is crucial for reconciling these observations and highlights the importance of both techniques in understanding cerebral oxygen dynamics in SCD.
Reduced oxygenation and elevated OEF found in adult studies of patients with MMA suggests that pediatric patients may have abnormal cerebral oxygen metabolism as well.34,35 Being mindful of the intrinsic methodological differences in the various MRI-based oxygenation imaging, greater physiological insight may result from studying pediatric MMA patients with these techniques.
Diffusion-Weighted Imaging
Diffusion MRI (dMRI) is an imaging method that allows us to reconstruct the brain’s white matter pathways and calculate the structural connectivity of the brain (Figure 1I).39 dMRI enables us to measure the white matter microstructure and monitor white matter injury. Microstructural measures derived from the diffusion tensor imaging (DTI) model include fractional anisotropy (FA), apparent diffusion coefficient (ADC), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Advanced measures include Diffusion Kurtosis Imaging,40 Free Water modeling,41,42 Neurite Orientation Dispersion and Density Imaging,43 Spherical Mean Technique,44 and Apparent Fiber Density.45
DTI has identified microstructural changes in the brains of MMA patients, through metrics such FA and MD, which help delineate the extent of white matter integrity.46 These metrics are closely tied to cognitive functions and disease progression. Increased ADC in frontal cortex normal appearing white matter was associated with reduced executive dysfunction in adults with MMA.47,48 Lower FA, increased MD, AD, and RD in adults with MMA was found in major white matter pathways such as inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus (UF), which were also correlated with cognitive impairments.49 Furthermore, adult MMA patients with cerebral infarction had lower FA and higher MD for the whole brain white matter compared to patients without infarction and controls.50 In adults with MMA, advanced stages of left hemispheric arterial occlusion was associated with lower FA in the cingulum, IFOF, and forceps major.51 Preoperative elevated ADC in normal appearing white matter in MMA adult patients has been shown to be predictive of postoperative transient neurological deficits.52 In adults with MMA, post-operative frontal normal appearing white matter ADC has been shown to decrease and normalize, which was correlated with an improvement of executive functions.53 Another study showed that FA increased in the white matter including in the superior longitudinal fasciculus (SLF), after surgery in adults with MMA.54 Regions of steal phenomenon were reported to be associated with increased ADC in adults with MMA.55 To date, only a handful of studies reported white matter abnormalities in children with MMA. Normal appearing white matter of children with MMA was reported to have lower FA and increased ADC.56 Children with MMA without an ischemic stroke (mean age 12.9 years) had higher ADC values in the white matter before surgery.57 In our previous work, we have shown lower FA and higher MD and RD in the tracks passing through the watershed regions in children with moyamoya without stroke or silent infarct prior to revascularization surgery which is concerning for unrecognized white matter injury. Further, this also raises the concern that these children may be chronically hypoperfused.58 These differences are critical for understanding the disease’s long term impact on the developing brain and may guide therapeutic strategies aimed at preventing cognitive deterioration.
Conclusion
The development and application of MRI-based quantitative biomarkers offer a promising avenue for advancing the diagnosis and treatment of pediatric MMA. These techniques, particularly perfusion imaging and cerebrovascular reactivity assessments, provide insights into the hemodynamic changes associated with MMA and have the potential to personalize therapeutic interventions, thus potentially improving surgical outcomes and neurological prognosis. As illustrated by MRI-based oxygenation imaging, significant challenges remain in standardizing these methods and validating their efficacy across diverse pediatric populations. Diffusion MRI metrics provide insight into the effects of chronically disrupted perfusion and oxygenation, even when no overt infarcts are observed. Future research should focus on including these quantitative biomarkers into clinical trials to establish their role in clinical practice. These methods could significantly enhance our understanding of MMA and lead to more effective, targeted therapies that minimize the risk of adverse outcomes and maximize recovery and quality of life for affected children.
Figure 1. A 9-year-old had a stroke and diagnosis of moyamoya arteriopathy at a year-and-a-half of age managed with bilateral revascularization surgery. During follow-up imaging she had progression of ACA and basilar stenosis on MRA. A) Reconstruction of time-of-flight MRA shows the longstanding bilateral intracranial ICA stenosis and new basilar stenosis (black arrows) and the site of extra-cranial to intra-cranial revascularization surgery with superficial temporal artery supply to the brain parenchyma (white arrows). B and C) lateral projection of the left external carotid artery (ECA) injection during catheter angiography shows the early and late arterial phase demonstrating adequate ECA collateral supply to the left hemisphere with slight variability in transit time (black dashed outline earlier than white dashed outline). D) color map of the pulsed arterial spin label (pASL) indicated a calculated cerebral blood flow CBF deficit in the left hemisphere (white dashed outline) and normal calculated CBF in the area of the STA revascularization (black dashed outline). This is also seen on E) the grayscale montage of the pASL CBF calculations. F) Shows the cerebrovascular reserve map based on a cerebellar normalizing regressor. The color map indicates negative reserve in blue and positive reserve in red, overlayed on T1 anatomic imaging. The CVR suggests a small area of reduced reserve capacity. G) grayscale map of the calculated CBF based on velocity selective ASL (vsASL) indicates symmetric and appropriate grey matter and white matter distribution of CBF when the labeling occurs within the tissue parenchyma based on velocity-selective labeling. This is also seen on the H) grayscale montage of the vsASL CBF calculations. This contrasts with the pASL CBF that is subject to artifacts from transit delay due to collateral supply and an assumed arterial input function curve. I) shows the color diffusion map (blue represents superior-inferior tracts, green represents anterior-posterior, and red represents medial-lateral). On the left hemisphere that is more severely affected by moyamoya arteriopathy, there is visible decrease in the volume of the watershed region white matter tracts. The white arrow shows diminished anterior-posterior tracts correlating with the superior longitudinal fasciculus compared to the right hemisphere (black arrow with white outline). There is also more subtle diminished superior-inferior tract volume correlating with the corticospinal tract. This patient had overall equivocal imaging (with reassuring angiography including aggregate data from additional runs of the bilateral ECA, bilateral ICA, and vertebrobasilar supply, marginal area of compromised CVR and lack of tissue perfusion deficit on vsASL CBF) and was managed with further short-interval clinical and imaging follow-up. She has not suffered further stroke or required further surgery to date in 24-month follow-up.
Figure 2. A 12-year-old has a history of neurofibromatosis type I, renal artery stenosis and secondary hypertension treated with a renal artery stent at 5 years of age, and syndromic moyamoya arteriopathy presenting with TIA episodes treated with right side pial synangiosis at age 10. During follow-up she had right hemibody paresthesias and on imaging she had progressive stenosis of the territory supplied by the left ICA. A) shows prior reconstruction of TOF MRA with right A2 (black arrow) supply dependent on left ICA, left A1, and anterior communicating artery. B) shows interval TOF MRA reconstruction with diminished filling of the right A2 (black arrow) and distal right ACA territory as well as the prior right pial synangiosis revascularization (white arrow). C) AP-projection right ICA catheter angiography shows the right ICA filling the right posterior communicating artery (white arrow) to the PCA and no supply to the MCA or ACA territories. D) AP-projection right ECA catheter angiography shows the pial synangiosis transcranial supply to the right MCA territory (white dashed outline). E) AP-projection left ICA catheter angiography shows severe stenosis of the left ICA (white arrow) correlating with the MRA finding. There is faint opacification of the left MCA territory (white dashed outline) and no filling of the right or left ACA territories. F) AP-projection left vertebral artery catheter angiography shows that the left MCA and bilateral ACA territories are dependent on filling through the posterior communicating artery. The right A2 location is indicated with a black arrow as in panels A and B. These structural changes are correlated with G) vsASL diminished tissue perfusion in the bilateral ACA territories (white arrows) relative to other cortical territories, and H) diminished CVR manifesting as steal phenomenon in the right ACA territory (white arrows) and near zero CVR in the left ACA territory. She was managed with bilateral anterior cerebral revascularization with pial pericranial synangiosis. In 18-month follow-up she has not had further TIA although she has persistent headaches.
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Headache in SCD: Scoping Review
