Fetal MRI Findings, Etiology, and Outcome in Prenatally Diagnosed Schizencephaly

Elizabeth George; Rachel Vassar; Yolanda Yu; Mary E. Norton; Dawn Gano; Orit A. Glenn

doi:10.3174/ajnr.A8523

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Response to Letter
Elizabeth George, Rachel Vassar, Yolanda Yu, Mary E Norton, Dawn Gano and Orit E Glenn

Published on: 17 June 2025
Finding intracerebral hemorrhages on fetal MRI may provide an opportunity to treat and attenuate the severity of schizencephaly
Savoldi Laura Maria Borges, Vanessa Kiill Rios, Stefanny Calixto da Silva, Luiza dos Santos Heringer and Henrique Rocha Mendonça

Published on: 12 May 2025

Published on: (17 June 2025)
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Response to Letter
Elizabeth George, Radiologist, University of California San Francisco
Other Contributors:
Rachel Vassar, Neurologist

Yolanda Yu, Medical Student

Mary E Norton, Obstetrician/Gynecologist

Dawn Gano, Pediatric Neurologist

Orit E Glenn, Radiologist
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. D...
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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.
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Competing Interests: None declared.
Published on: (12 May 2025)
Page navigation anchor for Finding intracerebral hemorrhages on fetal MRI may provide an opportunity to treat and attenuate the severity of schizencephaly
Finding intracerebral hemorrhages on fetal MRI may provide an opportunity to treat and attenuate the severity of schizencephaly
Savoldi Laura Maria Borges, Master Student, Universidade Federal do Rio de Janeiro
Other Contributors:
Vanessa Kiill Rios, Master Student

Stefanny Calixto da Silva, Master Student

Luiza dos Santos Heringer, PhD Student

Henrique Rocha Mendonça, Professor
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;...
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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
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Competing Interests: None declared.