Arterial Spin-Labeling Perfusion for PHACE Syndrome

DISCUSSION

To our knowledge, this multicenter study of 41 patients represents the largest cohort to date of patients with PHACE syndrome scanned with ASL perfusion imaging. While nearly every patient (40/41) had an arteriopathy, only approximately one-quarter of patients (10/41) had decreased CBF signal in at least 1 major arterial territory. All patients with decreased CBF signal had involvement of the anterior circulation. None of the patients had acute or chronic infarction.

These findings suggest that ASL may serve a role in the imaging evaluation of patients with PHACE syndrome. The addition of ASL to the MR imaging/MRA protocol for PHACE can provide a potential physiologic assessment of stroke risk in future studies, as has been demonstrated in other intracranial arteriopathies.^10,11 Relying solely on the structural arterial anomalies may overestimate the risk of stroke because the CBF may still be normal, given the collateral supply (Fig 3). This physiologic metric can potentially aid with risk stratification.

The risk of stroke in PHACE syndrome is not based solely on the complex arteriopathies but is likely multifactorial. Stroke risk may be potentially related to beta blocker use. Propranolol is the widely accepted first-line pharmacologic treatment agent for complicated infantile hemangiomas.^16,17 Beta blockers could decrease cardiac output, reduce cerebral perfusion, and result in watershed infarcts, especially if there is a corresponding arteriopathy such as an absent vessel or severe stenosis.¹⁸ Increasing research related to propranolol therapy in PHACE syndrome has shown that the drug is well-tolerated with respect to stroke risk. A recent multicenter retrospective study of 76 patients treated with propranolol for infantile hemangioma in PHACE syndrome showed no serious adverse effect or stroke.¹⁸ Despite these reassuring data, stroke is still possible. One case report described an infant receiving propranolol at 11 months of age and developing a large right MCA infarct on MR imaging at 18 months of age. It is unclear whether the patient was still receiving propranolol at the time of the infarct, but the propranolol could have been a risk factor.⁵ ASL could be used as a helpful adjunct before propranolol therapy to help inform and potentially mitigate stroke risk.

In our practice, we have started to use the combination of ASL and MRA to provide a more complete picture of cerebrovascular hemodynamics in this group of patients before propranolol therapy. If there is a high risk of stroke based on CBF data and arterial anatomy, then propranolol is administered at the lowest possible dose and titrated judiciously in a monitored setting. Obviously, further research is needed to show the utility and efficacy of this practice. Hypoglycemia is another potential side effect of propranolol therapy for children with infantile hemangiomas. The mechanism is not fully understood but is possibly related to inhibition of β-adrenergic-mediated glycogenolysis, gluconeogenesis, and lipolysis, which impairs glucose homeostasis.¹⁹

The pathogenesis of arteriopathies in PHACE syndrome is poorly understood. In addition, the genetics of PHACE syndrome has not been well-elucidated but is hypothesized to be secondary to low-level postzygotic variants.²⁰ Despite a candidate potential locus identified on 7q33 in 2 individuals,²¹ more recent research suggests that the affected gene in PHACE syndrome has not been discovered because the variant allele frequency of the mosaic mutations is extremely low.²⁰ Further analysis with next-generation sequencing may provide causative mutations in PHACE syndrome.

ASL can provide additional assessment in PHACE beyond analysis of CBF. Hemangiomas are vascular tumors and show markedly hyperintense signal on ASL (Fig 2C).^12⇓-14 While hemangiomas are usually well seen on postcontrast T1 imaging, particularly with the use of fat suppression, ASL could increase lesion conspicuity for improved hemangioma detection, especially if fat suppression is not used or in locations that could be overlooked such as the internal auditory canals.²² Another advantage of ASL is its noncontrast technique. While we generally administer contrast to all patients with PHACE being scanned, ASL could also be performed to evaluate deep hemangiomas if contrast cannot be given or if refused by the patient or family. A sample MR imaging/MRA PHACE syndrome protocol is listed in the Table.

The utility and appearance of ASL imaging in cerebrovascular arteriopathies such as those seen in PHACE syndrome are dependent on a few factors that can potentially be a limitation if not properly recognized. Depending on the postlabel imaging time and severity of cerebrovascular stenosis, and hence arterial transit time, the appearance of ASL maps may be different. Typically, in single-delay ASL evaluations, the postlabel delay time is chosen so that by the time the brain is imaged, most of the label has ideally moved from the large arteries into the brain parenchyma, allowing more accurate parenchymal evaluation of CBF. In cases of arterial narrowing, slow flow, or flow through proximal collaterals, the label may still be mostly within the larger arteries and not yet transited into the parenchyma. There is also an additional confounder. The ASL label signal is T1-based and, therefore, has a very short time before inevitable longitudinal relaxation rapidly decreases the label brightness, which eventually loses signal very quickly and returns to normal. Therefore, in cases of more severe transit time delays, the low signal on ASL CBF maps may be due to the paucity of the remaining label in the assessed parenchyma rather than a true proportional decrease in CBF. In these cases of severe transit time delays, the parenchymal CBF map may be more transit time–weighted than being truly CBF-weighted.

This underestimation of parenchymal CBF should be recognized in these physiologic states. This phenomenon can lead to errors and bias in the quantitative measurement of CBF in patients with PHACE syndrome with severe stenoses. Multidelay ASL, which is less commonly used and not commercially available from all MR imaging vendors, can partially mitigate this problem, though in severe arterial transit delay, this problem of underestimated CBF remains a potential problem. Velocity-selective ASL has been shown to be less sensitive to arterial transit delay inaccuracies of CBF measurement and may also be useful.²³

Our study has limitations, including its retrospective nature. Different ASL techniques were used across our various institutions. Although these may be perceived as a limitation, use of different ASL techniques may potentially be a strength as well because it demonstrates the utility of the technique across a range of imaging schemes. On the other hand, differing parameters such as the labeling period and postlabel delay time could result in different CBF appearances in the same patient. In addition, these labeling periods and postlabel delays were not changed when scanning neonates versus children, the former having faster heart rates, possibly requiring a different postlabel delay.²⁴ Another limitation is that because CBF changes were evaluated qualitatively, there was a subjective component in the assessment. However, the neuroradiologists in this study were experienced in the use and limitations of ASL for cerebrovascular disease evaluation. Finally, the lack of propranolol data in our study is another limitation of the assessment on whether the decreased CBF signal in some of our patients was due to PHACE syndrome or propranolol or both. Further research is needed in this specific patient cohort.