Refining the Neuroimaging Definition of the Dandy-Walker Phenotype

DISCUSSION

The literature is rife with confusing terminology regarding abnormalities of the posterior fossa. Imprecise definitions and inconsistent use of DWM and related terms (variant, continuum, spectrum), VH, inferior vermian hypoplasia, and partial caudal vermian agenesis have contributed to poor correlations between neuroimaging phenotypes and clinical outcome. Clarification would improve counseling for pregnancy planning, prognosis, and genetic work-up. In our cohort, we found evidence of this ongoing confusion and descriptive heterogeneity. If we used vermian structure, choroid plexus/tela choroidea location, and fastigial recess angles as primary diagnostic criteria, 96 of 407 (23.6%) posterior fossa malformations were originally misdiagnosed with a predominant bias of intraventricular hemorrhage and BPC (n = 29) and intraventricular hemorrhage (n = 17) instead of DWM.

Current diagnostic imaging criteria for DWM include VH with enlargement of the fourth ventricle and posterior fossa.¹ However, there is wide variability in the degree of vermian underdevelopment and posterior fossa enlargement, sometimes without correlation between the 2. Our results support this variability in that posterior fossa enlargement was not a significant differentiator between the DWM and non-DWM groups. Often, there are imaging features that approach but do not meet the full diagnostic criteria. While Dandy-Walker variant is an antiquated, poorly defined label, its intended use once served an important purpose: to indicate less pronounced phenotypes that appeared similar to a DWM proper. The problem with the term Dandy-Walker variant was not an intrinsic one; rather, it was that its misuse in the literature left it without a clear definition and even rendered it, at times, misleading. Abandonment was necessary, leaving a descriptive void.

We are reluctant to overly emphasize the imaging appearance of these malformations for fear of overstating the importance of the imaging phenotype for prognosis and management. Ultimately, clinical outcome is the most important factor for prognosis, so there is a need for long-term longitudinal clinical follow-up to determine to what extent an imaging subclassification scheme matters, if at all. In addition, myriad causative mechanisms (postmigrational insult, infection, germline genetic abnormality, somatic mutation) must be better elucidated and understood in the context of the mechanism of normal cerebellar development. Evidence of prior vascular injury was found in a minority of our cohort but did not differentiate the DWM from the non-DWM group. Nevertheless, MR imaging sensitivity for hemorrhage detection wanes with time, and prior injury may be indiscernible on fetal MR imaging, particularly with insufficient resolution or when motion artifacts are present.

To fully appreciate the developmental pathogenesis of any brain malformation, one must identify the approximate timing of the insult following which development goes awry. DWM is characterized by upward, under-rotation of a hypoplastic vermis vis-à-vis the brainstem. Extensive analysis points to the posterior vermis being disproportionately hypoplastic.^10,11 Our updated imaging criteria stem from an improved understanding of the mechanism of injury (disrupted growth of the posterior vermis) during a specific developmental epoch generally thought to result in the Dandy-Walker phenotype—that is, inferior vermian–predominant hypoplasia with an unpaired caudal lobule, an obtuse fastigial recess, a large TVA, and inferolateral displacement of the taenia–tela choroidea complex and choroid plexus, the latter due to failed resolution of the anterior membranous area.

Fourth ventricular size, posterior fossa size, and torcular location are poor imaging criteria for DWM because they are largely related to the degree of fourth ventricular outflow impedance and are not direct sequelae of the injury or malformation. Rather, imaging determination should hinge on the appearance of the vermis, choroid plexus, and tela choroidea in accordance with the time that the abnormality developed. Our receiver operating characteristic analysis quantitatively demonstrates the robust distinction between DWM and non-DWM cases with C-statistics of >0.9 when evaluating structures such as the fastigial recess or measuring the TVA. As objective measures of the more subjective DWM imaging features, these strongly predictive quantitative data may facilitate neuroimaging classification by those with less clinical expertise than our expert panel or by, yet developed, artificial intelligence tools. Although more complex linear models were more predictive (Online Supplemental Data), the strong predictive value of TVA alone suggests that such complexity may be unnecessary in most cases; however, it would be necessary to compare patients with posterior fossa abnormalities to a cohort of healthy control subjects to better determine the importance of predictive imaging variables for diagnosis.

Histopathologically, DWM is thought to be underpinned by disruption in the structure of the rhombic lip (RL), a stem cell zone located in the posterior cerebellum that gives rise to ∼80% of all neurons in the human brain, including all glutamatergic neurons in the cerebellum.^10,11 During embryonic development, the human RL is trigonal but later expands into a tail-like structure trailing from the posterior cerebellum, with ventricular and subventricular compartments separated by a vascular bed. During this time, the fastigial recess remains flat. With an increase in size of the posterior cerebellum brought about by the outward growth of the nodulus beginning at 14 postconceptional weeks, the tail-like RL becomes integrated into the posterior-most lobule, causing the fastigial recess to sharpen (>14 postconceptional weeks).^10,11 In comparisons of DWM and VH, it is evident that in DWM, the fastigial angle remains flat or obtuse, while in VH, the angle becomes acute. This finding provides us with some clues to the potential timing of the insult and leads to the hypothesis that in DWM, RL disruption occurs before RL internalization, while in VH, aberrations in RL development and other processes occur following internalization. The delay in RL disruption leading to restricted hypoplasia of the posterior-most lobule suggests that the early RL likely contributes to the growth of the entire cerebellum, but postinternalization helps in the growth and maintenance of the posterior lobe only. Hence, the extent of hypoplasia would depend on the timing of the RL insult, with further work required to define this developmental stage.

The concomitant presence of brainstem dysmorphism in children with abnormalities of cerebellar development is unsurprising, given that the cerebellum is a dorsal derivative of the anterior hindbrain, rhombomere 1.^19,20 Developmentally, the neurons of the pontine nuclei arise from the both the cerebellar RL in rhombomere 1 and the RL of other more posterior hindbrain rhombomeres. These neurons migrate tangentially to their final position in rhombomeres 3 and 4.^19,20 Because both DWM and VH exhibit similar and statistically indifferentiable rates of pontine hypoplasia, this feature suggests that the pontine hypoplasia seen in these conditions is most likely due to a combination of deficient pontine nuclear neurogenesis/histogenesis and WM fiber reduction commensurate with the degree of cerebellar hypoplasia.

The growth and development of the posterior vermis are the most protracted of all regions, making it especially vulnerable to disruptive events.^10,11,21 The inferior vermis is the most common and most severely involved region in DWM and isolated vermian hypogenesis, ie, partial agenesis.¹¹ Nonetheless, inferior VH should be diagnosed only if it can be documented that the inferior vermis is small. Otherwise, the more general term “vermian hypoplasia” should be used.²¹ “Hypoplasia” should be reserved for a small but otherwise structurally normal-for-age vermis.²² The other less discussed and appreciated fact is that in some circumstances, one or more of these diagnoses may be present, further hampering interpretation (eg, VH and Blake pouch anomalies). Larger Blake pouch anomalies cause vermian measurement inaccuracies,⁶ thereby making vermian height in isolation an inadequate determinant for the Dandy-Walker phenotype, as seen in our prenatal cohort. Furthermore, the TVA is variable in both DWM and BPC. Although marked TVA enlargement strongly supports the diagnosis of DWM, the opposite is not true: Mild TVA elevation may be present in either DWM or BPC.

The retrospective nature of this cohort study and imaging review is a limitation and is subject to case-selection bias. Because the bulk of the cohort was accrued from imaging reports containing the terms “Dandy-Walker” and “vermian hypoplasia,” it lacks an unknown number of cases that were missed, misinterpreted, or mislabeled by the original interpreting radiologist. It also lacks a control group. This study, although the largest reported, is only the first step toward a more complete understanding of the Dandy-Walker phenotype and its (likely numerous) etiologies and diverse clinical presentations. Future work must involve more clinical outcome data, longitudinal clinical and imaging data, histopathologic and genomic analysis, healthy controls, and prenatal clinical history if we hope to bridge the divide between imaging appearance and clinical outcome. Ultimately, we aim to better understand the causes and contributing factors that result in the Dandy-Walker phenotype, and with that mechanistic understanding, we hope that we will one day be able to predict outcomes, heritability, and the likelihood of similar abnormalities in future pregnancies.