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Neuropediatrics
DOI: 10.1055/a-2792-0936
Short Communication

Hemiconvulsion–Hemiplegia–Epilepsy Syndrome Associated with SARS-CoV-2 Infection and a Heterozygous IRF3 Variant in a 10-month-old Girl: A Case Report

Authors

  • Catherine Wohlgemuth 

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland

  • Antonio Giulio Gennari 

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland
    2   MR-Research Centre, University Children's Hospital of Zurich, Zurich, Switzerland

  • Santo Pietro Lo Biundo 

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland

  • Eugen Boltshauser

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland

  • Seraina Prader 

    3   Department of Immunology, University Children's Hospital Zurich, Zurich, Switzerland

  • Katharina Steindl 

    4   University of Zurich, Zurich, Switzerland
    5   Institute of Medical Genetics, University Hospital of Zurich, Zurich, Switzerland

  • Andrea Rüegger 

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland

  • Georgia Ramantani 

    1   Department of Neuropediatrics, University Children's Hospital Zurich, Zurich, Switzerland
    4   University of Zurich, Zurich, Switzerland

Funding Information We thank the National Science Foundation (SNSF: 208184) (to G.R.) and the Anna Mueller Grocholski Foundation (to A.G.G.) for funding. The funders had no role in the study's design or analysis.
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Abstract

Hemiconvulsion–hemiplegia–epilepsy (HHE) syndrome is a rare pediatric epilepsy syndrome characterized by prolonged focal febrile seizures, postictal hemiparesis, and progressive unilateral brain injury, often followed by chronic epilepsy. We report a previously healthy 10-month-old girl who presented with a prolonged left-sided focal fever-associated seizure. She tested positive for SARS-CoV-2 but did not meet criteria for multisystem inflammatory syndrome in children. On admission, she had left-sided flaccid hemiparesis. Brain MRI showed mild diffusion restriction and marked hyperperfusion of the right hemispheric gray matter, most prominently in the frontal, temporo-occipital, and hippocampal regions. EEG showed high-amplitude slowing over the right hemisphere without epileptiform discharges. No further seizures occurred, and long-term antiseizure treatment was not required. At 9-month follow-up, the patient was seizure-free and developmentally age-appropriate, but the hemiparesis persisted. Serial MRI showed progressive right hemispheric cortical and subcortical atrophy and hippocampal sclerosis. Extensive diagnostic workup found no other structural, infectious, or metabolic cause. This case illustrates the classical biphasic course of HHE syndrome and highlights the diagnostic value of early MRI, EEG, and genetic testing. The patient carried a paternally inherited heterozygous IRF3 variant, a gene essential for innate antiviral immunity. Although causality cannot be established, the temporal association with SARS-CoV-2 infection and an IRF3 variant suggests a possible genetic predisposition to infection-triggered injury. Continued clinical vigilance and long-term follow-up are essential, as epilepsy develops in most children with HHE. Greater awareness of this syndrome may support earlier recognition and timely rehabilitation to optimize functional outcomes.


Keywords

hemiconvulsion–hemiplegia–epilepsy syndrome - febrile status epilepticus - SARS-CoV-2 - hippocampal sclerosis - infection-triggered encephalopathy - IRF3 - heterozygous IRF3 variant

Introduction

Hemiconvulsion–hemiplegia–epilepsy (HHE) syndrome is a rare but severe pediatric epilepsy syndrome, typically affecting children under 4 years of age.[1] [2] [3] It is now recognized within the spectrum of “infection-triggered encephalopathy syndromes” (ITES-related conditions).[4]

The acute phase follows a febrile illness and presents with prolonged unilateral convulsive status epilepticus, followed by flaccid hemiparesis contralateral to the seizure onset. Although partial or complete recovery can occur in up to 20% of children within 12 months, hemiparesis is often permanent.[4] [5] [6] [7] In the chronic phase, up to 85% develop relapsing focal epilepsy, most often focal motor or focal to bilateral tonic-clonic seizures, usually within 3 years. Seizures arise from temporal, extratemporal, or multifocal regions[7] [8] and are frequently drug-resistant, with cognitive and behavioral impairments as common long-term sequelae.[8]

Acute-phase MRI typically shows unilateral T2/FLAIR hyperintensities and diffusion restriction, especially in the subcortical white matter of the affected hemisphere, reflecting cytotoxic edema. These changes may produce mass effect with risk of herniation. Between days 8 and 15, edema typically subsides and progressive hemiatrophy becomes evident. By 4 weeks, chronic structural changes, including hemispheric atrophy and hippocampal sclerosis, are usually established.[5] [8] EEG in the acute phase shows hemispheric slowing, with later development of epileptic discharges.


Case Study

A previously healthy 10-month-old girl, born at term after an uncomplicated pregnancy and delivery, was found by her mother with rhythmic clonic movements of the left leg, rightward head deviation, and unresponsiveness. The seizure lasted approximately 20 minutes. At the referring hospital, she was febrile (38°C) with a left-sided flaccid hemiparesis. Her prior development had been age-appropriate, with no relevant medical or family history. Two weeks earlier, she had experienced an upper respiratory tract infection.

On admission to our hospital, the hemiparesis persisted. Laboratory tests showed mildly elevated inflammatory markers. Nasopharyngeal PCR was positive for SARS-CoV-2. Cerebrospinal fluid analysis showed normal cell count, glucose, protein, and lactate. Additional viral tests in nasopharyngeal swabs and stool samples and bacterial cultures were negative. Metabolic screening was unremarkable. No further seizures occurred during hospitalization, and long-term antiseizure medication was not initiated. She was discharged with persistent left-sided hemiparesis. Follow-up evaluations were conducted at 4 weeks, 8 weeks, and 9 months.

Brain MRI and EEG findings at admission and at 9 months are presented in [Fig. 1A, B].

Zoom
Fig. 1 MRI and EEG findings throughout the disease course. (A) MRI on admission shows gyral swelling and sulcal effacement on T2-weighted images (void arrowheads), mild cortical diffusion restriction, and marked hyperperfusion on arterial spin labeling in the right frontal, temporal, and occipital lobes. The ipsilateral basal ganglia, thalamus (magnified box), and hippocampus were also involved. The hippocampus showed pronounced diffusion restriction and corresponding signal reduction on apparent diffusion coefficient (ADC) maps, consistent with cytotoxic edema (solid arrowheads). MR angiography (not shown) was unremarkable. At the 9-month follow-up, marked cortical and subcortical atrophy of the right hemisphere had developed (thin orange arrows), with additional features of hippocampal sclerosis (inset). (B) EEG on admission revealed high-amplitude slowing and mild asymmetry over the right hemisphere, without epileptiform discharges, with improvement noted at the 9-month follow-up.

Throughout follow-up, the patient remained seizure-free and continued to meet developmental milestones, as assessed by the Griffiths Scales of Child Development (Griffiths III), although the hemiparesis persisted. Repeat EEG showed improvement compared to the acute phase, with mild background asymmetry over the right hemisphere and no epileptiform discharges.

Extensive laboratory investigations, including metabolic, infectious, immunologic, and coagulation studies, were performed. Immunology showed mild hypogammaglobulinemia with normal vaccination responses to tetanus, Haemophilus, and pneumococci. Hypogammaglobulinemia persisted until the age of 2 years. Lymphocyte proliferation assays demonstrated a weak response to PHA and CD3, with normal LPS responses, suggesting mildly reduced T-cell proliferative responses with preserved B-cell/monocyte responses. During the first 10 months of life, the patient had an uneventful infection history. Overall, the pattern suggested mild immunological immaturity rather than a primary immunodeficiency, consistent with the absence of severe or recurrent infections. No alternative etiology was identified.

The clinical course, EEG findings, and serial neuroimaging[9] were consistent with an emerging HHE syndrome.

Genetic testing revealed a paternally inherited heterozygous IRF3 variant of uncertain significance (VUS, c.165 + 86_165 + 100del p.).


Discussion

This case illustrates the typical clinical and radiological features of HHE syndrome, with two notable aspects: (1) the temporal association with SARS-CoV-2 infection, and (2) the identification of a paternally inherited heterozygous IRF3 VUS. These findings highlight the diagnostic value of early MRI and EEG and raise the possibility that infection- and immunity-related mechanisms may contribute to HHE onset in genetically predisposed children. Despite the full acute and chronic radiological evolution of HHE—including early cytotoxic edema, hyperperfusion, progressive hemispheric atrophy, and hippocampal sclerosis, consistent with an emerging HHE[8]—the patient remained seizure-free and developmentally age-appropriate during the first 9 months of follow-up. This favorable course contrasts with the typical trajectory and underscores the variability of outcomes, even in the presence of severe imaging abnormalities.

Differential diagnoses included febrile seizures with Todd's paresis, ischemic stroke, and age-relevant causes of acute focal neurological deficits, such as early-onset genetic, developmental, and epileptic encephalopathies or metabolic disorders.[8]

The diagnosis of HHE is primarily clinical and supported by MRI and EEG findings, whereas extensive metabolic, immunological, or genetic investigations may be reserved for select cases.[8]

Given the child's age-appropriate development, normal cerebrospinal fluid, unremarkable MR angiography, and negative infectious and metabolic workup, these alternatives were unlikely. The prolonged unilateral seizure, postictal hemiparesis, hemispheric diffusion restriction in a non-vascular distribution, and evolving hemiatrophy supported an HHE diagnosis.

Although epilepsy develops in most children with HHE, its absence during early follow-up does not exclude later onset. According to the ILAE classification, children who fulfill criteria for the acute stage of HHE but have not yet progressed to the chronic epileptic phase are considered to have an emerging HHE syndrome.[8] No reliable acute-phase predictors currently allow confident prognostication regarding epilepsy development, beyond seizure duration and extent of hemispheric injury, which have shown inconsistent associations with outcome.

Although the observed seizure duration was approximately 20 minutes, the true duration was likely longer, as the event had already begun when discovered. This highlights a common HHE feature, where seizures often occur during sleep, leading to delayed recognition and prolonged ictal activity.

The acute-phase EEG showed high-amplitude slowing over the right hemisphere without epileptiform discharges, reflecting diffuse cortical dysfunction rather than ongoing seizures—an EEG pattern frequently reported in HHE. Together with neuroimaging findings, this is consistent with the proposed pathophysiological cascade of excitotoxic injury, metabolic failure, and secondary inflammation, ultimately resulting in hemispheric atrophy and hippocampal sclerosis.[8] [9] Mildly elevated inflammatory markers and SARS-CoV-2 positivity suggest that systemic or neuroinflammatory responses may have contributed to seizure generation.

Although HHE syndrome was first described by Gastaut in the 1960s,[1] [2] its pathophysiology remains incompletely understood.[5] Suggested contributors[4] [8] [10] include: (1) excitotoxic neuronal injury from prolonged febrile seizures, (2) inflammatory processes causing blood–brain barrier disruption, (3) infectious triggers such as human herpesvirus 6 or 7, (4) vascular factors such as hypercoagulability or vasospasm, (5) genetic susceptibility, including CACNA1A mutations.

HHE is considered an ITES-related disorder, distinct from acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and acute necrotizing encephalopathy (ANE). Unlike these entities, HHE typically presents with a single prolonged focal seizure, followed by unilateral hemispheric injury and persistent hemiparesis, usually without prolonged encephalopathy.

The association between HHE and febrile illness is well established,[4] [8] and a triggering infection was suspected in our case. Although the child did not meet criteria for multisystem inflammatory syndrome in children (MIS-C), the concurrent SARS-CoV-2 infection is noteworthy. Gong et al described a similar HHE presentation in the context of COVID-19 and MIS-C.[10] Although causality cannot be established, our case adds to evidence that SARS-CoV-2 may act as a febrile or inflammatory trigger in susceptible children.[10] [11]

Genetic testing revealed a paternally inherited heterozygous IRF3 VUS (c.165 + 86_165 + 100del p.). IRF3 encodes interferon regulatory factor 3, a transcription factor essential to innate antiviral responses, including those against coronaviruses. Although its role in acute encephalopathy is not fully understood,[12] IRF3 is considered a candidate gene for infection-induced encephalopathy, typically with autosomal dominant inheritance. The father, who carries the same variant, had no history of severe viral infections, suggesting variable penetrance. Disease manifestation in infancy may reflect immune immaturity. There is no evidence that the IRF3 variant explains the hypogammaglobulinemia, which more likely reflects age-related immune maturation. This underscores the importance of immunological follow-up and genetic counseling.

Although the variant is not de novo and remains classified as a VUS, IRF3 plays a central role in type I interferon signaling and has been implicated in infection-induced encephalopathies. Even partial pathway disruption may predispose to exaggerated neuroinflammatory responses during systemic infections. Variable penetrance and age-related vulnerability may explain the father's lack of symptoms. The specific variant (c.165 + 86_165 + 100del p.) is not listed in gnomAD or other databases; its location within an intronic regulatory region raises the possibility of splicing or regulatory effects, although functional data are lacking. Ongoing evaluation may clarify its significance, identify potential immune vulnerabilities, and guide counseling, prophylactic measures (e.g., influenza vaccination), and early intervention if additional features emerge. This case highlights the value of multidisciplinary collaboration, including genetics, infectious disease, and immunology, in evaluating variants in innate immunity genes in children with ITES.

Although our patient showed no epilepsy or developmental delay during the first 9 months, long-term follow-up remains crucial. Up to 85% of children with HHE develop focal epilepsy, often within the first 3 years, and persistent hemiparesis is common. The identification of a genetic variant further supports comprehensive follow-up beyond standard epileptological and neuropediatric assessment, including continued immunological monitoring. Genetic analysis may help guide management and clarify individual susceptibility.

In summary, HHE diagnosis relies on recognizing its characteristic clinical features—febrile illness, prolonged unilateral seizures, and hemiplegia—supported by neuroimaging and EEG, and on excluding alternative causes. Genetic testing should be considered as part of the diagnostic workup, given the expanding genomic knowledge and increasing accessibility. Greater awareness of HHE may facilitate earlier diagnosis and targeted intervention, including prompt treatment of prolonged seizures, early rehabilitation, and surveillance for epilepsy, ultimately improving long-term outcomes.



Contributors' Statement

C.A.W.: conceptualization, investigation, writing—original draft; A.G.G.: resources, visualization, writing—review and editing; S.P.L.B.: visualization; E.B.: supervision, writing—review and editing; S.P.: supervision, writing—review and editing; K.S.: supervision, writing—review and editing; A.R.: supervision, writing—review and editing; G.R.: conceptualization, supervision, visualization, writing—review and editing.

Conflict of Interest

The authors declare that they have no conflict of interest.

Informed Consent

This work involved human subjects. Written informed consent for publication of the clinical details and any accompanying images was obtained from the patient's legal guardian.



Correspondence

Georgia Ramantani, MD, PhD
Department of Neuropediatrics, University Children's Hospital Zurich
Lenggstrasse 30, 8008 Zurich
Switzerland   

Publication History

Received: 04 December 2025

Accepted: 19 January 2026

Accepted Manuscript online:
20 January 2026

Article published online:
02 February 2026

© 2026. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany


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Zoom
Fig. 1 MRI and EEG findings throughout the disease course. (A) MRI on admission shows gyral swelling and sulcal effacement on T2-weighted images (void arrowheads), mild cortical diffusion restriction, and marked hyperperfusion on arterial spin labeling in the right frontal, temporal, and occipital lobes. The ipsilateral basal ganglia, thalamus (magnified box), and hippocampus were also involved. The hippocampus showed pronounced diffusion restriction and corresponding signal reduction on apparent diffusion coefficient (ADC) maps, consistent with cytotoxic edema (solid arrowheads). MR angiography (not shown) was unremarkable. At the 9-month follow-up, marked cortical and subcortical atrophy of the right hemisphere had developed (thin orange arrows), with additional features of hippocampal sclerosis (inset). (B) EEG on admission revealed high-amplitude slowing and mild asymmetry over the right hemisphere, without epileptiform discharges, with improvement noted at the 9-month follow-up.