Arterial Spin-Labeling Perfusion Metrics in Pediatric Posterior Fossa Tumor Surgery

Perfusion Metrics and Hydrocephalus

Seventy-to-ninety percent of children with posterior fossa tumors present with HCP.²⁷ However, the relation between ventricular size, compliance, and pressure is complex, and ventricular size can be equivocal with regard to underlying CSF mechanics.²⁸ In this series, the need for pre-resection CSF diversion was judged clinically by experienced pediatric neurosurgeons on the basis of features of raised ICP. It is to be expected that resection of a posterior fossa tumor alone will increase CBF due to the removal of an obstructing mass;⁵ however, we demonstrate that in patients with symptomatic HCP before tumor resection, the mean cortical CBF was lower and BAT was higher, with statistically significant differences in these parameters among groups.

The first study to evaluate the role of ASL in HCP compared 19 patients with HCP secondary to posterior fossa tumors with 16 healthy controls.⁷ The former group was found to have significantly lower CBF at baseline. CBF was significantly increased in this group after “alleviation of HCP,” ie, tumor resection (with additional CSF diversion in 6 patients). The present study replicates these findings, and by adding a temporal dimension in the form of multi-TI ASL, it is the first demonstration that reduction of CBF in symptomatic obstructive HCP occurs in conjunction with a prolonged arterial transit time. A regional analysis of perfusion metrics showed that CBF was lower in the HCP group for all brain regions other than the frontal and motor cortices. This finding is likely due to the raised ICP related to HCP causing reduced cerebral perfusion pressure. However, because the ICP was not directly measured in this study, we cannot provide any mechanistic evidence for this finding.

Changes in the BuxCBF in the HCP group were corresponding in direction, though only the comparison of the preoperative thalamic BuxCBF reached a level of statistical significance. BuxCBF values are inevitably higher than single-PLD CBF values because they capture blood flow in large arteries at earlier TIs. The concordance between these 2 metrics provides reassurance that the single-PLD CBF changes were not due to incomplete delivery of the labeled bolus at the PLD of 1.5 seconds.

The results of the linear multivariable mixed-effects modeling confirmed the effects of HCP on CBF seen by statistical hypothesis testing of the data. This confirmation indicated that HCP had a significant effect on CBF dependent on the time point, once age, sedation status, brain region, scanning time point, and CMS by time point were controlled for, reducing the mean CBF by 20.5 (SD, 6.27) mL/100g/min preoperatively (P < .01). Following tumor resection, children who had been treated with CSF diversion had significant increases in mean CBF at postoperative imaging (24.0 [SD, 5.13] mL/100g/min, P < .001) and at follow-up imaging (27.2 [SD, 5.18] mL/100g/min, P < .001).

One potential clinical implication of these results, when taken along with those of Yeom et al,⁷ is that in the presence of equivocal symptomatology of raised ICP, perfusion metrics from ASL may help in decisions regarding perioperative CSF diversion. To further investigate this possibility, dedicated studies using real-time ICP measurements, ventricular volumetry, and detailed clinical correlates are needed.

Perfusion Metrics and CMS

CMS is a common postoperative complication after posterior fossa tumor resection, occurring in around one-quarter of cases.⁶ The putative mechanism posits damage to the superior cerebellar peduncle at the operation as a key element causing a disturbance in cerebellocerebral circuitry. This, in turn, is thought to lead to diaschisis causing a loss of function in widespread supratentorial cortical areas, and the corollary hypoperfusion can be quantified with perfusion imaging. Thus, SPECT^11,12 and DSC-MRI¹³ studies have shown frontal hypoperfusion in patients with CMS. Similarly, ASL-derived CBF was found to be reduced in the frontal lobes in a patient with CMS, recovering to normal levels after resolution of the syndrome.¹⁵ This result was later confirmed in a small cohort study of children with posterior fossa tumors (11 patients with CMS compared with 10 without).¹⁴ A modest reduction in CBF in the right frontal lobe was observed postoperatively, with significant increases in CBF in both frontal lobes after clinical improvement. A systematic review of 5 studies concluded that cerebral perfusion is reduced in children with CMS postoperatively, though none of the included studies incorporated preoperative comparison imaging.²⁹

In this study, we were unable to replicate the findings of a statistically significant difference in postoperative CBF with respect to CMS status. However, we provide confirmatory evidence of increased CBF in children with CMS at the follow-up time point—after improvement of CMS symptoms in most—on single-PLD CBF (P = .0403). The multi-TI ASL results did not demonstrate any differences in BAT or BuxCBF among groups.

The presence of an unbalanced age distribution among groups may help explain the results from statistical hypothesis testing of the data. Age is known to be broadly negatively correlated with CBF in children²⁰ (confirmed by its significance in the final mixed-effects model with a model coefficient of −1.34), so the CMS group having a much younger mean age may have increased the CBF at all time points for this group. Other reasons for the lack of distinction in postoperative CBF include a small sample size in the CMS group, which will have hindered comparative statistical testing. Furthermore, the repeated-measures data are unbalanced due to the substantial logistic challenges in obtaining preoperative scans in many patients.

The linear mixed-effects models described above are able to circumvent this drawback to give meaningful insight into the effects of the age parameter in the cohort. The full model, which included both HCP and CMS with their time point interactions as terms, confirmed a significant increase in CBF in the CMS group at follow-up, and coefficients for the other time points almost reached the threshold for statistical significance. The results presented here indicate that future studies investigating perfusion in CMS must take clinical features such as HCP and tumor location (and therefore surgical approach) into account.

Limitations

The lack of a clear, objective determination of CMS status is a perennial issue in studies reporting neuroimaging correlates of the syndrome, and this criticism applies to this study as much as all others in the field. To mitigate this issue, the definition of CMS applied in this study was pragmatic, based on the key criterion of mutism or reduced speech output, applied contemporaneously by an experienced neurosurgical multidisciplinary team. Because the key clinical correlate in this study was a speech deficit in CMS, it is not known from the data presented here whether CBF alterations exist postoperatively in the setting of CMS symptoms other than a speech deficit. The development of a validated scoring system for CMS is essential to objectively classify CMS phenotypes and their imaging correlates.

The regional ASL analysis did not take into account laterality because the assumption was made that symmetric vasculature leads to symmetric blood delivery. This assumption is perfectly valid in healthy brains, yet it may not be entirely true in a postoperative cohort with data acquisition shortly after surgery. For instance, unilateral manipulation of major infratentorial arteries, such as the PICA, a necessary step during midline tumor approach in dissection of the posterior fossa, may have conceivably caused a degree of arterial spasm leading to a variation in CBF by laterality.

The parcellation of the brain into regions of cortical lobes in this analysis was a pragmatic one because we are ultimately interested in behavioral effects of CBF changes in this cohort. However, we recognize that the cerebral lobes are functional-not-vascular units, and interrogating perfusion on a truly vascular basis would require territorial ASL,³⁰ which is technically challenging, even more so in unwell perioperative pediatric patients. The multi-TI ASL acquisition was a research sequence that is not widely available, limiting the generalizability of the results.

With regard to the insights shown on CBF in symptomatic HCP in the setting of pediatric posterior fossa tumors, these findings may not be entirely generalizable to more chronic or complex HCP syndromes seen in the wider neurosurgical population, such as low-pressure hydrocephalic states,³¹ or those with an altered CSF constitution, such as following subarachnoid or intraventricular hemorrhage or CNS infection. In the adult literature, there is cautionary evidence that in normal-pressure HCP, CBF measured using ASL is reduced in deep-seated brain regions³² but that changes in CBF do not correlate with clinical improvement following shunting.³³

Radiation therapy has been shown to affect ASL CBF in children with posterior fossa tumors,³⁴ and this variable, in dichotomized form due to the lack of variation in the total dose, was included in the modeling analysis. It is possible that some of the increase in CBF and BuxCBF seen at the follow-up time point will have been accounted for by this effect, though radiation therapy was a nonsignificant feature of the model and diminished model performance; therefore, it was discarded.