Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD): a scoring system for moyamoya severity based on multimodal hemodynamic imaging

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OBJECTIVE

Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya. The authors performed digital subtraction angiography and noninvasive structural and hemodynamic MRI, and they outline a new classification system for patients with moyamoya that they have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD).

METHODS

Healthy control volunteers (n = 11; age 46 ± 12 years [mean ± SD]) and patients (n = 25; 42 ± 13.5 years) with angiographically confirmed moyamoya provided informed consent and underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2*- and cerebral blood flow–weighted) 3-T MRI. Cerebrovascular reactivity (CVR) in the internal carotid artery territory was assessed using susceptibility-weighted MRI during a hypercapnic stimulus. Only hemispheres without prior revascularization were assessed. Each hemisphere was considered symptomatic if localizing signs were present on neurological examination and/or there was a history of transient ischemic attack with symptoms referable to that hemisphere. The PIRAMD factor weighting versus symptomatology was optimized using binary logistic regression and receiver operating characteristic curve analysis with bootstrapping. The PIRAMD finding was scored from 0 to 10. For each hemisphere, 1 point was assigned for prior infarct, 3 points for reduced CVR, 3 points for a modified Suzuki Score ≥ Grade II, and 3 points for flow impairment in ≥ 2 of 7 predefined vascular territories. Hemispheres were divided into 3 severity grades based on total PIRAMD score, as follows: Grade 1, 0–5 points; Grade 2, 6–9 points; and Grade 3, 10 points.

RESULTS

In 28 of 46 (60.9%) hemispheres the findings met clinical symptomatic criteria. With decreased CVR, the odds ratio of having a symptomatic hemisphere was 13 (95% CI 1.1–22.6, p = 0.002). The area under the curve for individual PIRAMD factors was 0.67–0.72, and for the PIRAMD grade it was 0.845. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.

CONCLUSIONS

A scoring system for total impairment is proposed that uses noninvasive MRI parameters. This scoring system correlates with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response.

ABBREVIATIONSASPECTS = Alberta Stroke Program Early CT Score; AUC = area under the curve; BOLD = blood oxygen level–dependent; CBF = cerebral blood flow; CBV = cerebral blood volume; CVR = cerebrovascular reactivity; DSA = digital subtraction angiography; ETCO2 = end-tidal CO2; ICA = internal carotid artery; MCA = middle cerebral artery; mSS = modified Suzuki score; PIRAMD = Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease; ROC = receiver operating characteristic; Xe-CT = xenon-enhanced CT.

OBJECTIVE

Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya. The authors performed digital subtraction angiography and noninvasive structural and hemodynamic MRI, and they outline a new classification system for patients with moyamoya that they have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD).

METHODS

Healthy control volunteers (n = 11; age 46 ± 12 years [mean ± SD]) and patients (n = 25; 42 ± 13.5 years) with angiographically confirmed moyamoya provided informed consent and underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2*- and cerebral blood flow–weighted) 3-T MRI. Cerebrovascular reactivity (CVR) in the internal carotid artery territory was assessed using susceptibility-weighted MRI during a hypercapnic stimulus. Only hemispheres without prior revascularization were assessed. Each hemisphere was considered symptomatic if localizing signs were present on neurological examination and/or there was a history of transient ischemic attack with symptoms referable to that hemisphere. The PIRAMD factor weighting versus symptomatology was optimized using binary logistic regression and receiver operating characteristic curve analysis with bootstrapping. The PIRAMD finding was scored from 0 to 10. For each hemisphere, 1 point was assigned for prior infarct, 3 points for reduced CVR, 3 points for a modified Suzuki Score ≥ Grade II, and 3 points for flow impairment in ≥ 2 of 7 predefined vascular territories. Hemispheres were divided into 3 severity grades based on total PIRAMD score, as follows: Grade 1, 0–5 points; Grade 2, 6–9 points; and Grade 3, 10 points.

RESULTS

In 28 of 46 (60.9%) hemispheres the findings met clinical symptomatic criteria. With decreased CVR, the odds ratio of having a symptomatic hemisphere was 13 (95% CI 1.1–22.6, p = 0.002). The area under the curve for individual PIRAMD factors was 0.67–0.72, and for the PIRAMD grade it was 0.845. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.

CONCLUSIONS

A scoring system for total impairment is proposed that uses noninvasive MRI parameters. This scoring system correlates with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response.

Moyamoya is a progressive stenoocclusive disease of the distal internal carotid arteries (ICAs) and their proximal terminal branches. Patients most frequently present with ischemic stroke or recurrent transient ischemic attacks. Quantification of the severity of vasculopathy and its impact on vascular morphology and parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response. Current management decisions use angiographic data combined with MRI evidence of infarct, along with perfusion studies based on PET or SPECT. Studies of hemodynamic reserves are probably a useful adjunct; however, current clinical methods require exogenous contrast administration and/or ionizing radiation. Although such tools have improved our understanding of moyamoya, these methods are suboptimal for longitudinal monitoring of patients or assessing revascularization response, because of dose restrictions.

Cerebrovascular reactivity (CVR) is a well-documented and valuable surrogate marker of cerebrovascular reserve in patients with previously identified intravascular pathology.1,9–12 In healthy parenchyma, CVR primarily derives from a large increase in cerebral blood flow (CBF) and cerebral blood volume (CBV) in response to a vasostimulatory agent such as CO2 (i.e., hypercapnia). Significantly diminished or negative changes in CVR during hypercapnia have previously been shown to correlate with regions affected by prior infarct and symptomatology.1,26,29 However, due to the relative novelty of hypercapnic CVR mapping performed using MRI compared with more established clinical measures such as acetazolamide SPECT, interpretation of hypercapnic CVR maps has not been standardized.

In this study we outline an integrated, neuroimaging-based classification system for moyamoya severity that we have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD). This scoring system accounts for functional measurements of hemodynamic impairment in moyamoya by using blood oxygen level–dependent (BOLD) MRI-weighted CVR, and therefore may be a comprehensive approach toward stratification of moyamoya severity.

Methods

Patient Selection

All procedures were followed in accordance with the ethical standards of the Vanderbilt University Institutional Review Board. Patients presenting with angiographically confirmed moyamoya between January 2011 and May 2015 underwent hemodynamic 3-T MRI (Philips) performed using body coil transmission and 12-channel sensitivity-encoding (SENSE) array neurovascular coil for reception. Patients were included in the study if cerebral digital subtraction angiography (DSA) was performed within 90 days of MRI, without any surgical intervention in the interval. Only hemispheres without a prior revascularization procedure were considered.

Neurological Assessment

A neurologist (L.J.) retrospectively reviewed patient symptomatology derived from the electronic medical record. Symptomatic hemispheres were defined as those with either a history of recurrent localizable transient ischemic attacks or persistent neurological deficits (motor, sensory, and/or language) referable to the hemisphere. Psychological symptoms, deficits in concentration and memory, and/or headache were not included, given the potential ambiguity in localization.

Imaging Protocol

The BOLD imaging sequences consisted of a T2*-weighted single-shot gradient-recalled echo planar imaging acquisition (slice thickness 5 mm, TR/TE 2000/35 msec, field of view 240 × 240 mm, spatial resolution 3 × 3 × 5 mm) across the entire brain. The experimental paradigm consisted of 5 total blocks each of 3 minutes' duration, beginning and ending with the delivery of medical-grade (purified) room air and interleaved with hypercapnic gas (5% CO2/95% O2) administration. We have recently quantified relationships between such hypercapnic hyperoxic and hypercapnic normoxic stimuli in healthy adults and patients with intracranial stenosis,9 and have demonstrated the ability of this stimulus to be performed safely in a large volume of patients, to provide contrast consistent with symptomatology and lateralizing disease, and to correlate with perfusion reactivity on appropriate postprocessing. Gas delivery was performed using a custom-made nonrebreathing face mask, and core physiological parameters including end-tidal CO2 (ETCO2), heart rate, blood pressure, and arterial oxygen saturation were monitored throughout the experiment.

Radiological Evaluation

Prior Infarct

Each hemisphere under review was considered separately. Two board-certified neuroradiologists (M.K.S., L.T.D.) who were blinded to clinical history and hemodynamic findings reviewed FLAIR imaging acquired at the time of BOLD MRI to determine the presence of infarct. The T2-weighted imaging was also reviewed when available. For lacunar infarcts, a size criterion for hyperintense lesions of greatest axial diameter ≥ 4 mm on T2-weighted imaging was used to separate prior infarcts from white matter changes.16,22 The T1-weighted sequence was used to verify encephalomalacia when infarcts were suspected based on the FLAIR sequence.

Cerebrovascular Reactivity

Healthy control volunteers (n = 11; age 46 ± 12 years [mean ± SD]) and patients (n = 25; 42 ± 13.5 years) underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2*- and CBF-weighted) 3-T MRI (Fig. 1). The ICA territory was defined by a predetermined mask (Fig. 2). The ICA-territory CVR was assessed using susceptibility-weighted MRI during a hypercapnic (ΔETCO2 approximately 5 mm Hg; 2 repeats) stimulus and normalized to cerebellar CVR. For each patient hemisphere (anterior circulation), the number of standard deviations by which CVR differed from the control mean CVR (Z-statistic: mean = 0.69, SD = 0.19) was calculated.

FIG. 1.
FIG. 1.

Admission MRI studies obtained in a patient with a symptomatic left hemisphere. Corresponding atlas maps for hemodynamic sections (A) and orthogonal representations of reactivity maps (B), demonstrating impairment in CVR in the left hemisphere (yellow arrows). Right hemisphere (asymptomatic) PIRAMD score: 0 (Grade 1); left hemisphere (symptomatic) PIRAMD score: 10 (Grade 3). A = anterior; I = inferior; L = left; P = posterior; R = right; S = superior. Figure is available in color online only.

FIG. 2.
FIG. 2.

The ICA territory masks used to define right (red) and left (blue) regions of interest for assessment of CVR. Figure is available in color online only.

Digital Subtraction Angiography

Moyamoya changes on DSA were scored with a modified Suzuki score (mSS), ranging from 0 to IV by 2 neuroradiologists (M.K.S., L.T.D., Table 1), with higher grades representing more severe disease.30 The mSS accounts for ICA, middle cerebral artery (MCA), and anterior cerebral artery disease, along with the presence or absence of lenticulostriate collaterals. Regional collateralization on DSA was assessed via modification of a previously reported technique.18,33 In brief, DSA was divided into 7 anatomical sites based on Alberta Stroke Program Early CT Score (ASPECTS)-defined regional vascular territories:28,33 M1–M6 and basal ganglia (Fig. 3). An interventional neurologist (M.T.F.) and a neuroradiologist (M.K.S.) working in tandem reviewed each territory on DSA for each patient and assessed whether or not regional CBF was impaired for the ASPECTS-defined regions. A territory was considered impaired if there were no visible collateral vessels supplying the ischemic site or if there were collaterals only to the periphery of the ischemic site. A territory was considered not to be impaired if collateral flow provided complete irrigation of the ischemic bed or if there was normal anterograde flow. Flow classification was made based on consensus. The total number of impaired territories (0–7) was counted for each hemisphere.

TABLE 1.

Modified Suzuki scoring*

ScoreDescription of Classification
0No evidence of disease
IMild-to-moderate stenosis around ICA bifurcation w/ absent or slightly developed ICA MMD
IISevere stenosis around the ICA bifurcation or occlusion of either proximal anterior or MCA branches w/ well-developed ICA MMD
IIIOcclusion of both anterior & MCA branches w/ well-developed ICA MMD (only a few of anterior or MCA branches or both are faintly opacified in antegrade fashion through meshwork of ICA MMD)
IVComplete occlusion of both anterior & MCA branches w/ absent or small amount of ICA MMD (w/o opacification of either anterior or MCA branches in antegrade fashion)

MMD = moyamoya disease.

Reprinted with permission from Strother MK, Anderson MD, Singer RJ, Du L, Moore RD, Shyr Y, et al: Cerebrovascular collaterals correlate with disease severity in adult North American patients with Moyamoya disease. AJNR Am J Neuroradiol 35:1318–1324, 2014.

FIG. 3.
FIG. 3.

Lateral projections (A, early-; B, mid-; and C, delayed-phase sequences) from left ICA injection on DSA. The 7 DSA territories measured are labeled in the lower row from the same left ICA injection (D, AP projection; E, lateral projection); impaired regions with delayed perfusion from collaterals are labeled in white (E). BG = basal ganglia; M1–M6 = ASPECTS territories.

Optimization of PIRAMD System and Analysis

Each component of PIRAMD was converted to a categorical variable and given a preliminary, simplified scoring system. The preliminary scoring system was optimized via simple logistic regression analysis and receiver operating characteristic (ROC) curve analysis by using symptomatology as the dependent variable to determine a clinically valid and statistically significant stratification system. Acceptability criteria were p < 0.05 for binary logistic regression analysis, and area under the curve (AUC) > 0.6 for ROC curve analysis. The PIRAMD component grading is summarized in Table 2.

TABLE 2.

The PIRAMD scoring system

VariableCharacteristicsPoints
MRIPrior infarct1
CVRDecreased3
mSS≥ Grade II3
Collaterals≥ 2 territories impaired3

Grading With the PIRAMD System

The relative weight for each factor in the PIRAMD score was determined by using the factor's odds ratio from simple logistic regression analysis. The lowest odds ratio was used as the baseline by which all other factors were scaled. The weighted scores for each component of PIRAMD were added together for a raw PIRAMD score. The PIRAMD score was divided into 3 grades: PIRAMD 1, PIRAMD 2, and PIRAMD 3. Grade stratification was determined through optimization by ROC curve analysis and simple binary logistic regression analysis, considering PIRAMD score as a discrete independent variable for those purposes. The ROC and binary logistic regression analyses were also repeated for PIRAMD grade. Acceptability criteria were p < 0.01 for binary logistic regression analysis, and AUC > 0.8 for ROC curve analysis.

Validation of the PIRAMD System

Additional internal validation was conducted on the data set via a bootstrap method. The 95% confidence interval estimates for the binary logistic regression analyses were generated in SPSS using a bootstrap sample size of 1000. Bootstrapped p values and confidence intervals were obtained and reported. The ROC bootstrapping also was performed in SPSS using an adapted public domain macro (available at http://gjyp.nl/marta/ [Accessed February 16, 2016]), with a bootstrap sample size of 1000. Bootstrapped AUC and 95% confidence intervals were obtained and reported.

Results

Participants in Study

There were 25 participants with moyamoya in the study, accounting for 46 hemispheres (Table 3). The mean age was 42 years, with an SD of 12 years. Most patients were female (20; 80%). There were 28 (60.9%) symptomatic hemispheres. The majority of patients had bilateral disease (22; 88%). Four of the 46 hemispheres analyzed (8.7%) had undergone a prior contralateral revascularization surgery, but none had a prior ipsilateral revascularization surgery. The mean interval between MRI scan and diagnostic angiography was 30 days, with an SD of 24.2 days.

TABLE 3.

Characteristics of patients and hemispheres in study

CharacteristicValue
By patient (n = 25)
  Demographic data
     Age in yrs, mean ± SD42 ± 13.5
     Female sex20 (80%)
     Race
       Asian/Pacific islander3 (12%)
       Black/African American8 (32%)
       White/Caucasian, Hispanic/Latino1 (4%)
       White/Caucasian, non-Hispanic/Latino13 (52%)
  Clinical data
     Bilat moyamoya22 (88%)
     Days btwn MRI & DSA, mean ± SD30 ± 24.2
By hemisphere (n = 46)
  Clinical data
     Symptomatic28 (60.9%)
     Prior contralat revascularization4 (8.7%)
  Infarct
     No prior infarct16 (34.8%)
     Prior infarct30 (65.2%)
  CVR
     Normal/increased11 (23.9%)
     Decreased35 (76.1%)
  mSS
     03 (6.5%)
     I5 (10.9%)
     II20 (43.5%)
     III14 (30.4%)
     IV4 (8.7%)
  No. of collaterals impaired
     010 (21.7%)
     11 (2.2%)
     26 (13.0%)
     310 (21.7%)
     410 (21.7%)
     53 (6.5%)
     63 (6.5%)
     73 (6.5%)
  PIRAMD grade
    18 (17.4%)
    218 (39.1%)
     320 (43.5%)

Structural MRI Data

Thirty (65.2%) hemispheres had a prior infarct on T2-weighted FLAIR imaging. With a prior infarct, the odds of having a symptomatic hemisphere were 4.6 times greater than without a prior infarct; however, the bootstrapped confidence interval estimates crossed unity and were not statistically significant (95% CI 0.3–3.3, p = 0.016; Table 4). The AUC for prior infarct was 0.670 (95% CI 0.539–0.802).

TABLE 4.

Correlations with symptomatology

ComponentAUC95% CISubscoreOR95% CIp Value
Prior infarct0.6700.539–0.802Present4.60.3–3.30.016
CVR0.7160.585–0.844Decreased13.01.1–22.60.002
mSS0.6780.560–0.793≥ Grade II17.21.1–22.70.008
Collaterals0.7130.593–0.836≥ 2 territories13.01.1–22.70.006
PIRAMD Grade0.8450.735–0.9562

3
NA

NA
20.4–22.5

22.3–42.4
0.004

0.004

NA = not applicable.

Hemodynamic MRI Data

After normalizing ICA territory CVR by total cerebellar CVR, 35 (76.1%) hemispheres had reduced normalized CVR relative to the control cohort. With CVR lower than control CVR, the odds of having a symptomatic hemisphere were 13 times greater than when normal or increased CVR was present (95% CI 1.1–22.6, p = 0.002). The AUC for CVR was 0.716 (95% CI 0.585–0.844).

Angiographic Data

Thirty-eight hemispheres (82.6%) had an mSS of ≥ Grade II. With an mSS in this range, the odds of having a symptomatic hemisphere were 17.2 times greater than with Grade 0–I mSS (95% CI 1.1–22.7, p = 0.008). The AUC for mSS was 0.678 (95% CI 0.560–0.793).

With regard to collateral flow impairment, 35 (76.1%) hemispheres had 2–7 territories impaired. With ≥ 2 impaired territories, the odds of having a symptomatic hemisphere were 13 times greater than with 0–1 impaired territories (95% CI 1.1–22.7, p = 0.006). The AUC for collaterals was 0.713 (95% CI 0.593–0.836).

Development of PIRAMD Score

After the simple analysis of the individual PIRAMD factors, the relative weighting for each factor was determined by scaling the odds ratio for prior infarct (4.6), because this had the lowest odds ratio. The PIRAMD scoring system is summarized in Table 2. Scores were added to ascertain the hemisphere's PIRAMD score, and in this way, PIRAMD was scored from 0 to 10, with increasing score representing increasing impairment (Fig. 4).

FIG. 4.
FIG. 4.

Graph showing the PIRAMD grade versus proportion of patients who were symptomatic. Vertical dashed lines represent PIRAMD Grade 2 (≥ 6) and Grade 3 (10) demarcations, respectively. Figure is available in color online only.

The PIRAMD Grade

Hemispheres were divided into 3 severity grades based on total PIRAMD score: Grade 1, 0–5 points; Grade 2, 6–9 points; and Grade 3, 10 points. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively (Fig. 5). The AUC for the PIRAMD grade (Grade 1–3) was 0.845 (95% CI 0.735–0.956). The AUC for the PIRAMD score (i.e., 0–10) was 0.860 (95% CI 0.746–0.974).

FIG. 5.
FIG. 5.

Bar graph showing the PIRAMD grade versus symptomatology. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.

Discussion

The PIRAMD classification is a simple scoring system for impairment in moyamoya, which uses noninvasive functional MRI parameters in addition to angiographic data. The PIRAMD score was found to correlate well with symptomatology (AUC 0.860). There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.

Patients with moyamoya are heterogeneous with regard to their clinical presentations and outcomes; however, angiographic studies alone may not be sufficient to understand patient pathophysiology. Clinical severity does not follow a perfect correlation with angiography, because proximal occlusions may be completely compensated by robust pial and lenticulostriate autocollateralization. In contrast, uncompensated mild stenosis may portend a severe course.20,30 In some cases, angiography findings may not even correlate with hemodynamic impairment.4

Because surgical candidacy is weighted heavily by imaging appearance and symptomatology, efforts to stratify patients for intervention are critical. A contemporary issue in the management of patients with moyamoya is the selection of impaired individuals who are likely to benefit from surgical revascularization. Cerebrovascular reactivity may be predictive of outcome and may be useful in noninvasive monitoring of such patients.14,19,25,27 Han et al. have shown that postrevascularization CVR correlates with graft patency and clinical outcomes in moyamoya.14 In intracranial stenosis in general, Mandell et al. showed that patients with impaired CVR were more likely to have hemodynamic normalization after extracranial-intracranial revascularization.24

There has been a robust effort in the field to quantify and understand hemodynamic impairment in moyamoya. The CBF and CBV increase in the early stages of impairment, and oxygen extraction fraction increases when CBF cannot increase sufficiently to meet oxygen demands.21 The current methods available for assessing these impairments include PET, SPECT, xenon-enhanced CT (Xe-CT), dynamic perfusion CT, dynamic susceptibility contrast MRI, arterial spin labeling MRI, and Doppler ultrasound (see Table 1 in Lee et al.21). However, many of these methods (e.g., PET, SPECT, Xe-CT, and dynamic perfusion CT) require ionizing radiation exposure and/or administration of exogenous contrast (e.g., Gd, which causes renal failure in up to 2% of cases3). Diagnostic angiography carries risk, with a complication rate as high as 1.2% in the Asymptomatic Carotid Atherosclerosis Study (ACAS),32 in addition to potential dose-dependent radiation-induced skin injuries.31

Magnetic resonance imaging can use blood oxygenation level as an endogenous contrast agent and therefore does not require exogenous contrast or ionizing radiation. It can be acquired serially during routine structural MRI and therefore holds promise as a noninvasive, readily available, and valid adjunct to routine imaging of patients with moyamoya. Additionally, MR offers improved spatial (3-to 5-mm isotropic) and temporal (2- to 3-second) resolution, and may be more clinically available compared with PET and SPECT, especially in nonspecialized hospitals.

In patients with intracranial disease, compensation for secondary reductions in cerebral perfusion pressure may initially be achieved via an increase in CBV and CBF.2,7 To assess this autoregulatory capacity, a vasostimulus such as carbogen can be administered. Carbogen serves to increase the arterial partial pressure of O2 and CO2, CBF, and CBV, and in turn increases blood oxygenation. The resulting increase in the ratio of oxyhemoglobin compared with deoxyhemoglobin will lead to an increase in T2*-weighted MRI signal. The magnitude of this change in the BOLD signal, or CVR, reflects the ability of vessels to regulate CBF and CBV, indicating how close the parenchyma is to failing to meet the hemodynamic demand. This permits an endogenous signal to be measured, rather than having to rely on exogenous contrasts or acetazolamide. Carbogen is a safe substance for CVR measurement; in our experience with 92 consecutive patients, carbogen elicited no short-term neurological events, and longer-term (2-year) events fell within the expected range for patients with intracranial stenosis.9

Although the role of CVR in predicting long-term stroke risk is not yet completely known, numerous studies have established a strong correlation between CVR and intracranial vascular disease.9,15 In patients with moyamoya, strong inverse relationships between mean CVR and both the Suzuki score and the presence of collateral vessels have been identified.4,17 Patients with moyamoya that is refractory to medical management who undergo surgical revascularization have been shown to demonstrate postsurgical revascularization improvements in CVR in regions that were previously compromised.14,23,24

Using Xe-CT with acetazolamide challenge in 40 patients (80 hemispheres), Czabanka et al. created a similar scoring mechanism for moyamoya severity.6 Compromised cerebrovascular reserve capacity was defined with Xe-CT as a CBF decrease greater than 5% after acetazolamide challenge. Although for methodological reasons we were unable to compare PIRAMD to the Czabanka system directly, the AUC was similar between populations (0.80 for the Czabanka score vs 0.845 for the PIRAMD grade). Although that study has laid the foundation for using CVR in moyamoya severity stratification, the technical innovations that have occurred since then have led us to conclude that PIRAMD might be a more favorable scoring system for patients. This is particularly true in the US, where the use of xenon is not widespread due to concerns in the literature and from the FDA related to reports of respiratory side effects associated with xenon.5 Symptomatic classification was more conservative in our study. Whereas Czabanka et al. considered psychological or headache symptoms as bilaterally symptomatic, these were not counted in our study due to difficulty in localization. This may account for the apparent difference in the prevalence of symptomatic hemispheres between cohorts (60.9% in our study, 68% in the study by Czabanka et al.).

We find it interesting that a milder correlation with symptomatology in our study was found with prior infarct. This is not to say that prior infarct is not important; it indicates that significant hemodynamic impairment has already occurred. In fact, we found post hoc that 22/28 (78.6%) of symptomatic hemispheres had an infarct. There was, however, a high rate of clinically silent infarcts (8/30 infarcts, 26.7%), particularly in the watershed distribution. There was considerable collinearity with other PIRAMD components; if a prior infarct was present, impairment in another PIRAMD component was also present in all but 2 cases (28/30; 93.3%). Unsurprisingly, with prior infarct the mean PIRAMD score was 8.5, versus 6.2 without (p = 0.013). However, for the hemispheres without infarct (especially the 21% of symptomatic hemispheres without infarct), the PIRAMD score adds more clarity to hemodynamic impairment than infarct assessment alone. Patients without infarct may have other impairments that increase the PIRAMD score, and this may weigh more heavily on the decision to revascularize.

Therefore, it is useful to complement this information with functional measures of impairment. The angiographic assessment of collateral perfusion is a strong contributor to the PIRAMD score, because it allows a functional, dynamic assessment of territory perfusion. However, it is invasive and requires radiation, which may limit its use in serial monitoring. Thus, we offer a functional complement of parenchymal impairment via BOLD MRI.8 The measurement of CVR using MRI provides a noninvasive method for assessing hemodynamic instability. We found that reduced CVR carried a 13-fold increase in the odds of the patient being symptomatic. When synthesizing angiographic and structural/hemodynamic MRI evidence of impairment via the PIRAMD score, the probability of being symptomatic can be calculated. We found that hemispheres were asymptomatic until the PIRAMD score reached 6, at which point a precipitous proportional rise in symptomatology occurred (Fig. 4).

The PIRAMD severity grades may be useful in counseling patients for further management. In particular, patients with PIRAMD Grade 3, if not already symptomatic, might have a high risk of becoming symptomatic, and surgery should be more strongly considered. In contrast, patients with PIRAMD Grade 1 might not become symptomatic, and conservative management with serial monitoring may be recommended. Of course, although reduced CVR may be associated with greater stroke risk,13 the long-term risks of PIRAMD grades have not yet been evaluated, and would need to be assessed in larger prospective studies. Nonetheless, the strong correlation between PIRAMD score and symptomatology suggests it may still have a role in patient stratification.

Limitations of the Study

This study is limited by its retrospective nature and small sample size, necessitating univariate analysis. Although we included patients if DSA was performed within 90 days, it would have been more ideal to have these studies obtained concurrently; the mean interval between angiography and MRI was 30 days. Although we performed a limited internal validation via bootstrapping, prospective external validation with a larger number of patients is needed. This study addresses historic symptom risk, and does not predict future symptoms or postoperative response, and therefore we are continuing to evaluate this prospectively.

Conclusions

A scoring system for total impairment in moyamoya is proposed in which noninvasive hemodynamic and structural MRI parameters are used, along with conventional angiography. This scoring system was found to correlate with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response.

Acknowledgments

This work was supported by the National Institutes of Health (5R01NS078828-02). Mr. Ladner received funding via the Medical Student Summer Research Fellowship from the AANS.

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    • Export Citation
  • 7

    Derdeyn CPVideen TOYundt KDFritsch SMCarpenter DAGrubb RL: Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain 125:5956072002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Donahue MJAyad MMoore Rvan Osch MSinger RClemmons P: Relationships between hypercarbic reactivity, cerebral blood flow, and arterial circulation times in patients with moyamoya disease. J Magn Reson Imaging 38:112911392013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Donahue MJDethrage LMFaraco CCJordan LCClemmons PSinger R: Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis. Stroke 45:233523412014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Donahue MJStrother MKHendrikse J: Novel MRI approaches for assessing cerebral hemodynamics in ischemic cerebrovascular disease. Stroke 43:9039152012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Faraco CCStrother MKDethrage LMJordan LSinger RClemmons PF: Dual echo vessel-encoded ASL for simultaneous BOLD and CBF reactivity assessment in patients with ischemic cerebrovascular disease. Magn Reson Med 73:157915922015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Gao YZZhang JJLiu HWu GYXiong LShu M: Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spin-labeling magnetic resonance imaging. Curr Neurovasc Res 10:49532013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Gupta AChazen JLHartman MDelgado DAnumula NShao H: Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. Stroke 43:288428912012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Han JSAbou-Hamden AMandell DMPoublanc JCrawley APFisher JA: Impact of extracranial-intracranial bypass on cerebrovascular reactivity and clinical outcome in patients with symptomatic moyamoya vasculopathy. Stroke 42:304730542011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Han JSMikulis DJMardimae AKassner APoublanc JCrawley AP: Measurement of cerebrovascular reactivity in pediatric patients with cerebral vasculopathy using blood oxygen level–dependent MRI. Stroke 42:126112692011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Hassan AHunt BJO'Sullivan MParmar KBamford JMBriley D: Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 126:4244322003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Heyn CPoublanc JCrawley AMandell DHan JSTymianski M: Quantification of cerebrovascular reactivity by blood oxygen level-dependent MR imaging and correlation with conventional angiography in patients with Moyamoya disease. AJNR Am J Neuroradiol 31:8628672010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kim JJFischbein NJLu YPham DDillon WP: Regional angiographic grading system for collateral flow: correlation with cerebral infarction in patients with middle cerebral artery occlusion. Stroke 35:134013442004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kohno KOka YKohno SOhta SKumon YSakaki S: Cerebral blood flow measurement as an indicator for an indirect revascularization procedure for adult patients with moyamoya disease. Neurosurgery 42:7527581998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Kuroda SHashimoto NYoshimoto TIwasaki Y: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:143014352007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lee MZaharchuk GGuzman RAchrol ABell-Stephens TSteinberg GK: Quantitative hemodynamic studies in moyamoya disease: a review. Neurosurg Focus 26:4E52009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Longstreth WT JrBernick CManolio TABryan NJungreis CAPrice TR: Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 55:121712251998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Ma YLi MJiao LQZhang HQLing F: Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease. Neurosurg Rev 34:3473542011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Mandell DMHan JSPoublanc JCrawley APFierstra JTymianski M: Quantitative measurement of cerebrovascular reactivity by blood oxygen level-dependent MR imaging in patients with intracranial stenosis: preoperative cerebrovascular reactivity predicts the effect of extracranialintracranial bypass surgery. AJNR Am J Neuroradiol 32:7217272011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Mandell DMHan JSPoublanc JCrawley APStainsby JAFisher JA: Mapping cerebrovascular reactivity using blood oxygen level-dependent MRI in Patients with arterial stenoocclusive disease: comparison with arterial spin labeling MRI. Stroke 39:202120282008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Markus HCullinane M: Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 124:4574672001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Mikulis DJKrolczyk GDesal HLogan WDeveber GDirks P: Preoperative and postoperative mapping of cerebrovascular reactivity in moyamoya disease by using blood oxygen level-dependent magnetic resonance imaging. J Neurosurg 103:3473552005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Pexman JHWBarber PAHill MDSevick RJDemchuk AMHudon ME: Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol 22:153415422001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Siero JCWHartkamp NSDonahue MJHarteveld AACompter APetersen ET: Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with stenoocclusive artery disease. Neuroimage 105:2762852015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Strother MKAnderson MDSinger RJDu LMoore RDShyr Y: Cerebrovascular collaterals correlate with disease severity in adult North American patients with Moyamoya disease. AJNR Am J Neuroradiol 35:131813242014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Vano EFernandez JMSanchez RMMartinez DIbor LLGil A: Patient radiation dose management in the followup of potential skin injuries in neuroradiology. AJNR Am J Neuroradiol 34:2772822013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Walker MDMarler JRGoldstein MGrady PToole JBaker W: Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 273:142114281995

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Zaharchuk GDo HMMarks MPRosenberg JMoseley MESteinberg GK: Arterial spin-labeling MRI can identify the presence and intensity of collateral perfusion in patients with moyamoya disease. Stroke 42:248524912011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ladner, Donahue, Strother. Acquisition of data: Ladner, Donahue, Faraco, Roach, Davis, Jordan, Froehler, Strother. Analysis and interpretation of data: all authors. Drafting the article: Ladner. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ladner. Statistical analysis: Ladner, Faraco. Administrative/technical/material support: Donahue. Study supervision: Donahue, Strother.

Supplemental Information

Previous Presentations

A portion of the findings herein were presented as an oral abstract at the 2015 AANS/CNS Joint Cerebrovascular Section Annual Meeting on February 9, 2015, in Nashville, TN.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

INCLUDE WHEN CITING Published online March 11, 2016; DOI: 10.3171/2015.11.JNS15562.

Correspondence Travis R. Ladner, 1161 21st Ave. S, CCC-1108 MCN, Nashville, TN 37232-2380. email: travis.r.ladner@vanderbilt.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Admission MRI studies obtained in a patient with a symptomatic left hemisphere. Corresponding atlas maps for hemodynamic sections (A) and orthogonal representations of reactivity maps (B), demonstrating impairment in CVR in the left hemisphere (yellow arrows). Right hemisphere (asymptomatic) PIRAMD score: 0 (Grade 1); left hemisphere (symptomatic) PIRAMD score: 10 (Grade 3). A = anterior; I = inferior; L = left; P = posterior; R = right; S = superior. Figure is available in color online only.

  • View in gallery

    The ICA territory masks used to define right (red) and left (blue) regions of interest for assessment of CVR. Figure is available in color online only.

  • View in gallery

    Lateral projections (A, early-; B, mid-; and C, delayed-phase sequences) from left ICA injection on DSA. The 7 DSA territories measured are labeled in the lower row from the same left ICA injection (D, AP projection; E, lateral projection); impaired regions with delayed perfusion from collaterals are labeled in white (E). BG = basal ganglia; M1–M6 = ASPECTS territories.

  • View in gallery

    Graph showing the PIRAMD grade versus proportion of patients who were symptomatic. Vertical dashed lines represent PIRAMD Grade 2 (≥ 6) and Grade 3 (10) demarcations, respectively. Figure is available in color online only.

  • View in gallery

    Bar graph showing the PIRAMD grade versus symptomatology. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively.

References

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    • PubMed
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    Derdeyn CPVideen TOYundt KDFritsch SMCarpenter DAGrubb RL: Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain 125:5956072002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Donahue MJAyad MMoore Rvan Osch MSinger RClemmons P: Relationships between hypercarbic reactivity, cerebral blood flow, and arterial circulation times in patients with moyamoya disease. J Magn Reson Imaging 38:112911392013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Donahue MJDethrage LMFaraco CCJordan LCClemmons PSinger R: Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis. Stroke 45:233523412014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Donahue MJStrother MKHendrikse J: Novel MRI approaches for assessing cerebral hemodynamics in ischemic cerebrovascular disease. Stroke 43:9039152012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Faraco CCStrother MKDethrage LMJordan LSinger RClemmons PF: Dual echo vessel-encoded ASL for simultaneous BOLD and CBF reactivity assessment in patients with ischemic cerebrovascular disease. Magn Reson Med 73:157915922015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Gao YZZhang JJLiu HWu GYXiong LShu M: Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spin-labeling magnetic resonance imaging. Curr Neurovasc Res 10:49532013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Gupta AChazen JLHartman MDelgado DAnumula NShao H: Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. Stroke 43:288428912012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Han JSAbou-Hamden AMandell DMPoublanc JCrawley APFisher JA: Impact of extracranial-intracranial bypass on cerebrovascular reactivity and clinical outcome in patients with symptomatic moyamoya vasculopathy. Stroke 42:304730542011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Han JSMikulis DJMardimae AKassner APoublanc JCrawley AP: Measurement of cerebrovascular reactivity in pediatric patients with cerebral vasculopathy using blood oxygen level–dependent MRI. Stroke 42:126112692011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Hassan AHunt BJO'Sullivan MParmar KBamford JMBriley D: Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 126:4244322003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Heyn CPoublanc JCrawley AMandell DHan JSTymianski M: Quantification of cerebrovascular reactivity by blood oxygen level-dependent MR imaging and correlation with conventional angiography in patients with Moyamoya disease. AJNR Am J Neuroradiol 31:8628672010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Kim JJFischbein NJLu YPham DDillon WP: Regional angiographic grading system for collateral flow: correlation with cerebral infarction in patients with middle cerebral artery occlusion. Stroke 35:134013442004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kohno KOka YKohno SOhta SKumon YSakaki S: Cerebral blood flow measurement as an indicator for an indirect revascularization procedure for adult patients with moyamoya disease. Neurosurgery 42:7527581998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Kuroda SHashimoto NYoshimoto TIwasaki Y: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:143014352007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lee MZaharchuk GGuzman RAchrol ABell-Stephens TSteinberg GK: Quantitative hemodynamic studies in moyamoya disease: a review. Neurosurg Focus 26:4E52009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Longstreth WT JrBernick CManolio TABryan NJungreis CAPrice TR: Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 55:121712251998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Ma YLi MJiao LQZhang HQLing F: Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease. Neurosurg Rev 34:3473542011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Mandell DMHan JSPoublanc JCrawley APFierstra JTymianski M: Quantitative measurement of cerebrovascular reactivity by blood oxygen level-dependent MR imaging in patients with intracranial stenosis: preoperative cerebrovascular reactivity predicts the effect of extracranialintracranial bypass surgery. AJNR Am J Neuroradiol 32:7217272011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Mandell DMHan JSPoublanc JCrawley APStainsby JAFisher JA: Mapping cerebrovascular reactivity using blood oxygen level-dependent MRI in Patients with arterial stenoocclusive disease: comparison with arterial spin labeling MRI. Stroke 39:202120282008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Markus HCullinane M: Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 124:4574672001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Mikulis DJKrolczyk GDesal HLogan WDeveber GDirks P: Preoperative and postoperative mapping of cerebrovascular reactivity in moyamoya disease by using blood oxygen level-dependent magnetic resonance imaging. J Neurosurg 103:3473552005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Pexman JHWBarber PAHill MDSevick RJDemchuk AMHudon ME: Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol 22:153415422001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Siero JCWHartkamp NSDonahue MJHarteveld AACompter APetersen ET: Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with stenoocclusive artery disease. Neuroimage 105:2762852015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Strother MKAnderson MDSinger RJDu LMoore RDShyr Y: Cerebrovascular collaterals correlate with disease severity in adult North American patients with Moyamoya disease. AJNR Am J Neuroradiol 35:131813242014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Vano EFernandez JMSanchez RMMartinez DIbor LLGil A: Patient radiation dose management in the followup of potential skin injuries in neuroradiology. AJNR Am J Neuroradiol 34:2772822013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Walker MDMarler JRGoldstein MGrady PToole JBaker W: Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 273:142114281995

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Zaharchuk GDo HMMarks MPRosenberg JMoseley MESteinberg GK: Arterial spin-labeling MRI can identify the presence and intensity of collateral perfusion in patients with moyamoya disease. Stroke 42:248524912011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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