Response to Letter

We thank Savoldi Laura Maria Borges and colleagues for their comments on our study on the fetal MRI findings, etiology and outcomes in schizencephaly (George et al, 2025).
We read with interest the authors’ preclinical work on neonatal mice subject to a transcranial freeze lesion where hydrocortisone treatment was associated with replacement of schizencephaly with “microgyria” (Savoldi et al, 2025). Our study results support intrauterine injury/hemorrhage as the cause of majority of cases of schizencephaly (George et al, 2025). We agree our results likely underestimate the proportion of subjects with prior vascular injury as evidence of prior ischemia or hemorrhage can be hard to detect on fetal and even neonatal MRI. Prompt identification of fetal hemorrhage would be optimal, and current imaging is more sensitive and specific for the detection of fetal intracranial hemorrhage in its early stages. However, due to the lack of detectable clinical symptoms in fetuses, these injuries, when detected prenatally, are often identified incidentally on prenatal US. Furthermore, other than the timing of injury in relation to neuronal migration, it is unclear why some insults result in porencephalic cysts while others result in a spectrum of cortical malformations.
In our study on fetal schizencephaly, 4/7 subjects with postnatal follow-up (median age of 4 years at follow-up) had epilepsy. Epilepsy was not associated with open vs. closed cleft or cleft size on fetal MRI. Due to the small number with epilepsy, we could not examine how imaging features were associated with age of onset and medication refractoriness. As the authors point out, Kim et al recently demonstrated an association between cleft size and epilepsy but there are substantial differences in study design as Kim et al assessed MRIs in a case-control study design among 102 adults with schizencephaly (Kim et al, 2022). We and others have shown that cleft size changes from fetal to postnatal life (George et al, 2025) and larger studies are necessary to better understand the developmental implications of fetal cleft characteristics. Interestingly, we reported an association of cortical malformation remote from the schizencephaly with epilepsy, which is similar to Kim et al who report an association of cortical dysplasia with epilepsy. While epilepsy and neurodevelopmental impairments were common in the children with follow-up in our cohort, we disagree with characterizing these outcomes as “catastrophic.”
We applaud the authors on their work in identifying therapeutic targets toward preventing the development of schizencephaly while acknowledging the significant challenges in targeted application of such intervention to alter the course of fetal cortical development. A comprehensive understanding of the etiologies and natural history of fetal schizencephaly will be foundationally important for the translation of novel preventative or reparative therapies in utero. Multicenter collaboration is needed to address critical gaps in our understanding of the etiologies and outcomes of fetal schizencephaly, as well as other fetal malformations of cortical development (Russ et al, 2025).

References

1. George E, Vassar R, Yu Y, Norton ME, Gano D, Glenn OA. Fetal MRI Findings, Etiology, and Outcome in Prenatally Diagnosed Schizencephaly. AJNR Am J Neuroradiol 2025; 46(4): 800-7.
2. Savoldi LMB, Heringer LDS, Carneiro MB, Martinez AMB, Mendonca HR. Hydrocortisone Attenuates the Development of Malformations of the Polymicrogyria Spectrum. Int J Dev Neurosci 2025; 85(1): e10414.
3. Kim HJ, Koo YS, Yum MS, Ko TS, Lee SA. Cleft size and type are associated with development of epilepsy and poor seizure control in patients with schizencephaly. Seizure 2022; 98: 95-100.
4. Russ JB, Agarwal S, Venkatesan C, et al. Fetal malformations of cortical development: review and clinical guidance. Brain 2025; 148(6): 1888-903.