Deciphering the link between spina bifida and the Chiari II malformation

Open spina bifida causes impaired motor and sensory function at and below the level of the spinal lesion. Up to 90% of affected individuals also have a Chiari II malformation, which is the herniation of the hindbrain into the vertebral column, often resulting in hydrocephaly. Around 20-25% of these children have neurocognitive deficits. The learning deficits are linked to heterotopia, the abnormal arrangement of neuronal cells within the neocortex, cranial nerve hypoplasia and partial formation of the corpus callosum – which contains axons that link the left and right cerebrum – and hippocampus, responsible for memory (Schneider et al., 2021). A long-term outstanding question in the field has been whether Chiari II malformation, with other associated brain alterations, and spina bifida occur together because of shared genetic and/or environmental factors or whether Chiari II malformation arises as a secondary consequence of spina bifida.Clark, Copp and colleagues address this important question using a Pax3 mutant spina bifida mouse model, Cdx2cre/+;Pax3f/f, in which Pax3 is specifically inactivated in the developing spinal cord and is not inactivated in the head. Therefore, any brain anomalies that arise must be secondary to defective spinal cord development. By micro-computed tomography and histological analyses, the authors conclusively show that key features of Chiari II malformation – including hindbrain herniation, reduced posterior cranium ossification, and misplacement of the pons and hypothalamus – occur in the Cdx2cre/+;Pax3f/f mouse model. Analysis of brains at embryonic day 18.5 revealed a thinner cortical plate, with expansion of the ventricular stem cell layer relative to the other cortical layers, and a decrease in the number of BRN2+ post-mitotic neurons, indicating delayed differentiation. There is also neocortical heterotopia, indicating altered neuronal migration. Additionally, the hippocampus is hypoplastic, with decreased neuronal differentiation, and the corpus callosum axonal tracts are underdeveloped.The spectrum of brain anomalies analysed in this mouse study recapitulate the changes observed in humans with open spina bifida. Therefore, the authors have convincingly demonstrated that Chiari II malformation and other brain anomalies can arise as secondary consequences of open spina bifida. The recent advance of in utero spina bifida surgical repair at 20-26 weeks’ gestational age significantly reduces the risk of the Chiari II malformation. However, there is no significant improvement in the risk of cognitive deficits (Houtrow et al., 2020) and higher-brain structural abnormalities (Bruzek et al., 2024; Calle et al., 2020). These clinical data indicate that the neurocognitive changes are not secondary to the hindbrain herniation, arising as independent events before week 26. During human development, the neural tube (spinal cord progenitor) closes by day 28 of gestation, and spina bifida is routinely detected at the 20-week anomaly ultrasound scan (Di Mascio et al., 2021). This new mouse model will be an invaluable tool to increase our understanding of exactly how Chiari II malformations arise, and will also help pinpoint when and how the intellectual deficits arise in an attempt to ultimately mitigate the cognitive impairment.