In Reply: Brain Imaging Findings Show Efficacy of Fetal Endoscopic Third Ventriculostomy as Prenatal Treatment for Induced Congenital Hydrocephalus in Fetal Lambs

We thank Afshari1 for their interest in our article on the imaging evidence supporting fetal endoscopic third ventriculostomy (ETV) in an ovine model of congenital hydrocephalus.2,3 We fully agree that the goal of any prenatal neurosurgical intervention must be durable functional benefit for the child, and we welcome the opportunity to discuss our data in greater depth and to clarify the translational implications of our findings. Our experimental study comprised 50 lamb fetuses with hydrocephalus induced by fourth-ventricle obstruction. ETV was successfully completed in 64% of cases; when technically confounding polymer blockage was excluded, procedural success approached 80%.4 The principal causes of failure were limited intraventricular visibility for bioglue excessive migration, hemorrhage from the choroid plexus, and exceedingly narrow foramina of Monro, issues that inform future refinements in access trajectory and endoscope profile. In the cohort that underwent successful ETV, serial high-resolution MRI and postmortem analysis demonstrated a consistent reduction in lateral-ventricle volume and a visible re-expansion of the cortical mantle. Quantitatively, mean ventricular index decreased by >30% compared with untreated controls, while T2-weighted sequences showed improved parenchymal signal uniformity—findings that support true decompression rather than procedural artifact. These results substantiate the biological effect of fetal cerebrospinal fluid diversion on developing brain morphology. We agree with Afshari1 that radiological improvement cannot yet be equated with neurocognitive benefit. Nevertheless, our results provide mechanistic evidence that early ventricular decompression can restore more physiologic cerebral architecture during a critical period of neuronal proliferation and migration. This concept aligns with clinical observations that postnatal intervention, even when performed promptly after birth, often are too late to reverse prenatal cortical thinning.5 By shifting the timing of decompression upstream, fetal ETV could theoretically mitigate secondary white matter injury and optimize substrate for later neurodevelopment, that should be confirm after human translation in phase 2 trials with strict neurodevelopmental testing. First human fetal ETV cases performed in Brazil 20 years ago5 where anecdotical and not followed long term. The recent 10 cases reported by Peralta et al6 were performed using the preclinical data presented by our group in a more flexible regulatory environment and obviously will require long-term neurodevelopmental follow-up. At least, it showed to be safe and minimally invasive that allowed fetuses to deliver term or near-term. Our ongoing studies extend the follow-up of surviving lambs to late gestation and postnatal life. These protocols include diffusion-tensor imaging, myelination mapping, and behavioral testing to evaluate sensorimotor function. We are also comparing fetal ETV with novel prenatal shunting strategies such as ventriculo-subgaleal diversion, which may offer temporizing cerebrospinal fluid control until postnatal maturation allows for more definitive treatment.7 The fact that healing process in neonates and fetuses could obliterate the ostomy is a possibility that could require a redo surgery postnatally but at least can provide a temporary decompression of the fetal brain in a critical time of development that will help to improve the outcomes and that also can be reinforced postnatally. Until now, we left the brain deterioration to progress until birth, and now we have the possibility to arrest that deleterious process during the prenatal life. Regarding ethical considerations, we strongly agree that maternal-fetal safety must remain paramount. All current procedures are confined to preclinical models within accredited facilities and are conducted under institutional animal care oversight. We envision any future clinical translation only within the structure of multidisciplinary well-trained fetal-therapy programs, under prospective regulations, institutional review board approvals with explicit maternal consent, and long-term neurodevelopmental follow-up as the primary outcome. The discussion raised by Afshari1 underscores an important balance: Technical feasibility should not be mistaken for therapeutic readiness, yet feasibility data are indispensable to progress safely toward efficacy studies. Our work addresses this foundational step by confirming that fetal ETV can be executed reliably, achieves radiological decompression, and does not produce parenchymal injury in the immediate postprocedural period. The next phase must evaluate functional outcomes and refine the criteria that would define a candidate population, likely limited to fetuses with isolated, nongenetically related, aqueductal stenosis, and progressive ventriculomegaly. In conclusion, we are grateful for the constructive observations provided by Afshari1 and share their emphasis on long-term neurodevelopmental validation. We remain committed to systematic, collaborative investigation aimed at determining whether early correction of obstructive hydrocephalus can translate into measurable neurodevelopmental benefit. Constructive dialogue such as this will be critical to ensure that innovation proceeds with both scientific rigor and ethical responsibility.