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We read with great interest the article published by George et al. (George et al., 2025), which retrospectively investigated a cohort of 22 patients prenatally diagnosed with schizencephaly by magnetic resonance imaging between 1996 and 2022. The authors interpreted 64% of the cases as secondary to lesions of vascular, infectious, placental or genetic origin, with intracerebral hemorrhage identified in half of the patients. Interestingly, genetic causes were found in only two cases, leaving six patients without an apparent reason for the development of the malformation. Considering that intracranial hemorrhages can be difficult to detect after the resolution of the hemorrhagic episode, it is possible that some cases of schizencephaly without an identified cause are also secondary to lesions. As typically occurs in schizencephaly, the neurological outcomes observed were catastrophic, with epilepsy being the most common, along with cerebral palsy, speech difficulties and intellectual decline.
Our research group has been dedicated to understanding the pathophysiological events that lead to the development of schizencephaly in a murine model, identifying key stages that could become therapeutic targets. We recently demonstrated that hemorrhage, neuroinflammation, hypoxia, and oxidative stress are present as early as 3–4 hours after injury, preceding the development of the malformation, when induced by transcranial freezing injury in neonatal mice (Savoldi et al., 2025; VK Rios, unpublished data, 2025). Interestingly, we demonstrated that treatment within this early time window – four days from the time of injury – results in a less severe malformation, leading to the development of microgyria rather than schizencephaly. In particular, hydrocortisone treatment modulated inflammation from a more pro-inflammatory to a reparative profile and led to reduced susceptibility to hyperthermia-induced seizures during infancy (Savoldi et al., 2025).
Although the authors claim that cleft volume is irrelevant for the development of epilepsy, this has recently been challenged by Kim et al. (Kim et al., 2022), who showed that both larger cleft volumes and open lip types are correlated with earlier onset of epilepsy in children. Similarly, in our experimental model, we found more severe pentylenetetrazol-induced seizures and altered neocortical circuitry in mice with schizencephaly when compared to those with microgyria (dos Santos Heringer et al., 2022). Therefore, identifying intracerebral hemorrhage as early as possible through fetal MRI may be a crucial tool for initiating treatments aimed at reducing brain damage secondary to hemorrhage: an event that George's work has shown to be responsible for the majority of cases of schizencephaly (George et al., 2025). Strategies such as iron chelation therapy with deferoxamine or reducing oxidative stress with antioxidant molecules—alone or in combination with anti-inflammatory agents—may be promising experimental treatments in preclinical models. If proven effective, such approaches could significantly help alleviate the devastating symptoms faced by patients with schizencephaly in the future.
References
George E, Vassar R, Yu Y, et al. Fetal MRI Findings, Etiology, and Outcome in Prenatally Diagnosed Schizencephaly. AJNR. AJNR Am J Neuroradiol 2025; 46: 800–807. DOI: https://doi.org/10.3174/ajnr.A8523
Savoldi LMB, Heringer LDS, Carneiro MB, et al. Hydrocortisone Attenuates the Development of Malformations of the Polymicrogyria Spectrum. Int J Dev Neurosci 2025; 85: e10414. Doi: https://doi.org/10.1002/jdn.10414
Kim HJ, Koo YS, Yum MS, et al. Cleft size and type are associated with development of epilepsy and poor seizure control in patients with schizencephaly. Seizure 2022; 98: 95–100. Doi: https://doi.org/10.1016/j.seizure.2022.04.002
Dos Santos Heringer L, Rios Carvalho J, Teixeira Oliveira J, et al. Altered excitatory and inhibitory neocortical circuitry leads to increased convulsive severity after pentylenetetrazol injection in an animal model of schizencephaly, but not of microgyria. Epilepsia open 2022; 7: 462–473. Doi: https://doi.org/10.1002/epi4.12625