Despite clinical heterogeneity, postoperative PFS in childhood brain tumour patients is one of the better described neurobehavioural syndromes that can occur after infratentorial injury (Aguiar et al.
; Pollack et al.
; Gelabert-Gonzalez and Fernandez-Villa, 2001
; Wells et al.
). The diagnosis of PFS appears to be associated with worse neurological and cognitive outcomes (Doxey et al.
; Steinbok et al.
; Steinlin et al.
; Huber et al.
). One of the most intriguing aspects of this syndrome is that despite apparent presurgical similarities, only a subset of patients with posterior fossa tumours developed PFS after definitive resection. Surgical approach, tumour characteristics and various perioperative factors (concomitant hydrocephalus, infection, vasospasm and delayed ischaemia) have been posited as possible causative mechanisms (Pollack et al.
; Ersahin et al.
; Turgut, 1998
; Catsman-Berrevoets et al.
; Kotil et al.
; Frassanito et al.
). However, none of these factors has been conclusively accepted. Preventative or ameliorative interventions are lacking, in part, because of this incomplete understanding. Given its projection to the cerebral cortex, proximal dentatothalamocortical tract involvement in PFS is presumed, but this hypothesis has not been systematically examined (Crutchfield et al.
; Koh et al.
; Riva and Giorgi, 2000
; Robertson et al.
; Wells et al.
This study represents the first blinded review of magnetic resonance and diffusion weighted imaging obtained prospectively in a cohort of paediatric patients after recent resection of a posterior fossa embryonal tumour. Comparing patients who did and did not develop PFS, perturbation of the proximal dentatothalamocortical tract was identified to be a potentially important determinant of this debilitating disorder. On immediate postoperative evaluation, conventional imaging showed evidence of proximal dentatothalamocortical tract involvement in those patients diagnosed with PFS. Previous studies have suggested that injury to the dentate nuclei is critical to the development of PFS (Ersahin et al.
; Kusano et al.
; Puget et al.
). Our findings are generally supportive; however, neither unilateral nor bilateral damage to the dentate was required for development of PFS. Rather, patients with PFS were distinguished by bilateral, multi-focal postoperative injury (increased T2
signal suggestive of oedema) to structures within the posterior fossa. When examining the putative anatomical structures (pons, dentate nuclei, superior cerebellar peduncles and midbrain), the majority of patients with PFS (90%) were noted to have signal abnormalities within three or more of these structures. In contrast, none of the unaffected patients had ≥3 structures involved. Furthermore, bilaterality may be an important associative finding, as 80% of patients with PFS versus 15% of patients without PFS had evidence of bilateral injury within these structures. Thus, ‘multiple, bilateral hits’ within posterior fossa components of the cortico-cerebellar-cortical circuit may be required for PFS development. In a separate analysis utilizing the same cohort of patients, Miller et al.
) observed a positive association between PFS and bilateral damage to the dentatothalamocortical tracts as patients with bilateral damage were ~12 times more likely to develop PFS than those with unilateral injury only. These findings are consistent with Crutchfield's early hypothesis that bilateral interruption of the dentatothalamocortical pathways may be responsible for the development of PFS (Crutchfield et al.
To the best of our knowledge, the use of diffusion tensor imaging in PFS has not been previously reported. Consistent with our initial hypothesis, decreased integrity (as measured by decreased FA) among the white matter bundles comprising both superior cerebellar peduncles was also evident in patients with PFS. Interestingly, whereas bilateral involvement of the superior cerebellar peduncles is apparent on diffusion tensor imaging, on postoperative conventional imaging, unilateral signal abnormalities in these structures were typically observed. This discrepancy between conventional and diffusion tensor imaging suggests that a functional disturbance of the proximal efferent tract without a direct neuroanatomical correlate on conventional magnetic resonance imaging may be present. As supported by conventional imaging, the observed decreased anisotropy within bilateral superior cerebellar peduncles may not necessarily reflect direct, but rather additive effects of remote, injury (pons and/or dentate nuclei). Furthermore, as Pollock et al.
) have previously suggested, the delayed onset of symptoms in some patients indicates that the involved structures in PFS are not likely to be directly damaged in surgery (Pollack et al.
). In the future, it will be important to correlate the timing of PFS onset with the pattern of injury to determine if patients with direct injury to bilateral superior cerebellar peduncles exhibit symptoms sooner than patients with more remote, albeit salient injury. Irrespective of timing and pattern of injury, our findings support the suggestion that disruption of white matter tracts within the superior cerebellar peduncles (either through direct injury or remote perturbation) may represent the underlying pathophysiological substrate for PFS in patients undergoing posterior fossa surgery.
Based on a hypothesized link between proximal dentatothalamocortical tract injury and PFS, we also evaluated two novel preoperative measures (tumour above/below ratio and superior cerebellar peduncular splay) that were designed to predict development of PFS. Indeed, patients with tumours that resided higher in the fourth ventricle were statistically more likely to develop PFS. Tumour in this location may predispose to PFS because there is more preoperative stress, and increased vulnerability within the proximal dentatothalamocortical tract to operative injury. In this study, there was also a trend towards larger superior cerebellar peduncular splay in patients with PFS. In light of our findings noted above, a change in surgical approach based on these measures is not warranted. However, increased postoperative surveillance of patients with tumours that reside high in the 4th ventricle and/or widen the splay of the superior cerebellar peduncles should be given. A larger prospective study is required to determine the accuracy and thresholds of these measures for predicting PFS development.
Perhaps unexpectedly, diffusion tensor imaging also identified three supratentorial tracts where FA was lower in patients with PFS than in the control group. Detection of these areas highlights the value of TBSS for efficient and unbiased group comparison of diffusion tensor imaging data. Although speculative, the observed disordered water diffusion within the fornices and white matter tracts proximate to the right angular gyrus and left superior frontal gyrus, areas known to process spatial and temporal information essential for normal cognitive, linguistic and motor behaviour, is provocative and may represent or suggest specific cortical regions relevant to the neurobehavioural manifestations of PFS. Indeed, with respect to language, comparable findings using single photon emission tomography (SPECT) in patients with cerebellar injury are reported (Marien et al.
, 2001). In these studies, expressive syntax disturbance, agrammatism and impaired prosody reminiscent of patients with acquired left frontal lesion were observed. Interestingly, a corresponding left frontal perfusion deficit was noted in these patients. To explain how a remote cerebellar injury may affect cortical functioning, a cerebello-cerebral diaschisis model has been proposed (Marien et al.
, 2001; Riva and Giorgi, 2000
). Using diffusion tensor imaging, our findings further support this model and are not dissimilar from other studies that have utilized SPECT in patients with PFS (Sagiuchi et al.
; Clerico et al.
; Ersahin et al.
). These latter studies, as well as our current data, may suggest critical cortical regions involved in additional aspects of PFS such as apraxia and behavioural lability. Further elaboration of the neural substrates of PFS, including grey matter and white matter, may help to clarify the role of the cerebellum in cognitive function (Glickstein, 2006
The fornices are not a classical component of the dentatothalamocortical pathway. Indeed, decreased FA in these structures may be confounded by increased hydrocephalus in the PFS patients (Evan's index = 0.43 versus 0.37 in non-PFS patients). Furthermore, to our knowledge, anterograde amnesia has not been reported in patients with PFS (although this would be very difficult to assess), as in other patients with bilateral fornical damage. However, several brainstem nuclei, most notably the ventral tegmental area within the midbrain, have reciprocal connections with limbic pathways that include the fornical columns (Morgane et al.
). Therefore, surgical or functional disruption of these nuclei, with subsequent alteration of limbic homeostasis, may underlie aspects of the behavioural–affective disorder commonly encountered in PFS. This suggested mechanism is speculative and needs to be further evaluated.
Several other limitations should be kept in mind when interpreting our data. First, despite well-established cardinal signs and symptoms, PFS is a heterogeneous syndrome that has thus far defied a strict diagnostic criterion. Although our patients with PFS were identified prospectively, onset, duration and level of impairments were not prospectively recorded. Thus, like other reports which characterize a PFS population, clinical heterogeneity within this cohort is expected and is not strictly accounted with respect to outcomes. Also, three patients (two non-PFS, one PFS) had multiple surgeries prior to definitive resection; baseline scan was arbitrarily assigned as the one prior to the initial surgical resection. Furthermore, because our institution serves as a national referral centre, onset of PFS could not always be accurately determined as some patients were referred after primary surgery and onset of symptoms. Related to this issue, the preoperative magnetic resonance images were often completed at other centres and thus were not of uniform technique or quality. This heterogeneity could have affected the interpretation of our predictive measures. In addition, preoperative FA data were not available for analysis. Systematic collection of such data would potentially enrich our understanding of the impact of preoperative stress upon the dentatothalamocortical tract. All patients with PFS in this study were male. We believe this to be a clinical anomaly rather than an important pathological finding. Nevertheless, gender differences could influence our findings. Finally, the diffusion tensor imaging findings in the supratentorium should be interpreted cautiously. Decreased FA observed proximate to the right angular gyrus (Tailerach coordinates 35, −71, 19) and left superior frontal gyrus (Tailerach coordinates −24, 57, 20) could potentially be the result of susceptibility artefacts related to ventricular blood present after surgery, air/tissue interfaces within the frontal sinuses and/or external ear canal, as well as metal devices (shunt, ommaya) secured on the surface of the skull.
Despite these limitations, our study adds significantly to the growing body of research that implicates the proximal dentatothalamocortical tracts in PFS. Using conventional magnetic resonance and diffusion tensor imaging, our findings suggest multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of PFS and that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of PFS. When postoperative injury is remote from the superior cerebellar peduncles, the cause or nature of this perturbation remains uncertain. With regard to clinical decision-making in patients with posterior fossa tumours, although measurements of splay and location were not robustly predictive, heightened concern should be given to those patients that harbour tumours high in the 4th ventricle. Prospective studies, including preoperative diffusion tensor imaging, intra-operative or postoperative conventional, functional and vascular imaging in conjunction with careful neurological and neurocognitive evaluations are needed to validate our findings and clarify further the neuroanatomical and functional substrates of this puzzling syndrome.