Congenital Zika Syndrome Presenting With Late-Onset Seizures: A New Phenotypic Variant

To the Editors: Congenital Zika virus (CZS) classically presents with severe microcephaly with a partially collapsed skull, subcortical calcifications, macular scarring, and focal pigmentary retinal mottling with congenital contractures and marked early hypertonia.1 However, as the first generation of children with CZS ages, a new clinical challenge is emerging: late-onset seizures (occurring after 1–2 years of age). We propose that this category represents a distinct, late-onset phenotypic variant of CZS with significant implications for long-term follow-up. The long-term burden of CZS is profound, with recent studies showing most children exhibit severe functional impairments across multiple domains 8 years after the initial epidemic.2 While early infantile seizures are well documented in the infantile period,3 ranging from 9% to 67%. We now observe children who pass the first year of life without seizures, only to develop epilepsy in their second or third year. This delayed presentation underscores a progressive encephalopathy and mandates lifelong neurological surveillance. The finding that epilepsy affects 90% of an older pediatric CZS cohort4 underscores the persistent hyperexcitability of the central nervous system following prenatal Zika virus injury. This provides a pathophysiological basis for our observation of late-onset seizures, suggesting the epileptogenic focus remains active for years. Neuroimaging techniques detect characteristic magnetic resonance imaging lesions that correspond to an enduring epileptogenic focus. Electroencephalography often reveals background disorganization and epileptiform discharges, even in pre-symptomatic children, highlighting an underlying cortical irritability that can manifest as late-onset seizures. Given the expanding phenotypic spectrum, it is important to recognize the emerging variant characterized by normal head circumference at birth, postnatal microcephaly and late-onset seizures. This warrants long-term neurologic surveillance to avoid missed diagnoses. The management of late-onset seizures in CZS presents unique challenges, as there are no evidence-based guidelines, and it relies mostly on an empirical approach. These children often have complex polypharmacy for other conditions. Anecdotal experience suggests some respond to standard antiseizure medications like levetiracetam and valproate,2 but robust clinical trials are entirely lacking. In the absence of clinical trials, therapeutic decisions are extrapolated from strategies used in other forms of symptomatic epilepsy arising from similar structural brain lesions, such as those seen in cerebral palsy or other congenital brain malformations. In summary, the need for indefinite long-term neurologic follow-up is crucial, as the absence of seizures in CZS is nonreassuring. A child presenting with late-onset seizures and with a maternal infection exposure mandates the neurologic workup of CZS. Emphasis should be placed on incorporating electroencephalography and magnetic resonance imaging for seizure evaluation, as they can aid detection. We must therefore reframe our clinical approach to CZS from a neonatal diagnosis to a mandate for lifelong, multidisciplinary care and research. Addressing these challenges with careful evaluation and targeted management will be key to improving outcomes in children affected by this disorder.