# Neurological outcomes and disability predictors in paediatric herpes simplex virus encephalitis: a multicentre cohort from French tertiary hospitals

Caroline Rey, Laetitia Giorgi, Hélène Maurey, Anne-Lise Poulat, Daniel Amsallem, Anne Lepine, Stéphane Auvin, Renaldo Florence, Juliette Ropars, Emmanuel Cheuret, et al.

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## To cite this version:

Caroline Rey, Laetitia Giorgi, Hélène Maurey, Anne-Lise Poulat, Daniel Amsallem, et al. Neurological outcomes and disability predictors in paediatric herpes simplex virus encephalitis: a multicentre cohort from French tertiary hospitals. European Journal of Paediatric Neurology, 2025, 57, pp.7 - 14. 10.1016/j.ejpn.2025.05.001. hal-05288083

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Original article

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# Neurological outcomes and disability predictors in paediatric herpes simplex virus encephalitis: a multicentre cohort from French tertiary hospitals

Caroline Rey<sup>a,1</sup>, Laetitia Giorgi<sup>a,s,1</sup>, Hélène Maurey<sup>a,s</sup>, Anne-Lise Poulat<sup>b,s ID</sup>, Daniel Amsallem<sup>c,s</sup>, Anne Lepine<sup>d,s</sup>, Stéphane Auvin<sup>e,s ID</sup>, Renaldo Florence<sup>f</sup>, Juliette Ropars<sup>g</sup>, Emmanuel Cheuret<sup>h,s ID</sup>, Sarah Baer<sup>i ID</sup>, Jean-Marc Pinard<sup>j</sup>, Anne Rolland<sup>k</sup>, Pierre-Louis Leger<sup>l</sup>, Sylvie Nguyen<sup>m,s</sup>, Pierre Castelnau<sup>n,s</sup>, Pierre Meyer<sup>o,s ID</sup>, Sylvain Renolleau<sup>p</sup>, Diana Rodriguez<sup>f,s</sup>, Frederic Villega<sup>q,r,s ID</sup>, Kumaran Deiva<sup>a,s,t,u,* ID</sup>

## ABSTRACT

**Objective:** To identify factors associated with the neurological outcome of HSVE in children.

**Materials and methods:** In this retrospective multicentric observational study, clinical, paraclinical data at onset and neurological outcomes at last follow-up of children (≥28 days and <18 years old) with HSVE, were studied. Univariate and multivariate analyses were performed to identify factors associated with neurological outcome.

**Results:** 49 children (mean age of 4.9 ± 5.5 years) were included. At last follow-up of 5.9 ± 3,13 years, 2 children died (4 %) and 37 (76 %) children presented with poor neurological outcome with epilepsy (57 %), intellectual disability (51 %) and language disorders (47 %). Rehabilitation was necessary for 76 % and 59 % had abnormal academic performances. At onset, younger age and seizures were significantly associated to language disorders (p < 0.01), motor disabilities (p = 0.01), and intellectual disabilities (p = 0.01) in univariate analysis. Abnormal MRIs were more frequent in children with neurological sequelae (p = 0.01). Multivariate analyses identified that: (1) epilepsy occurred more frequently in females (p = 0.03), with insular lesions (p = 0.048); (2) language disorders were more common in children who had seizures at onset (p 0.02); (3) motor disorders were more frequent in younger children (p = 0.03) with thalamic lesions (p = 0.04).

<footnote><sup>a</sup> Pediatric Neurology Department, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre Hospital, Faculty of Medecine, Paris-Saclay University, Le Kremlin-Bicêtre, France</footnote>

<footnote><sup>b</sup> Pediatric Neurology Department, University Hospitals of Lyon (HCL), Lyon, France</footnote>

<footnote><sup>c</sup> Pediatric Neurology Department, Centre Hospitalier Universitaire Besançon, France</footnote>

<footnote><sup>d</sup> Pediatric Neurology Department, Assistance Publique des Hôpitaux de Marseille, Hôpital Universitaire Marseille, France</footnote>

<footnote><sup>e</sup> Department of Pediatric Neurology, Hôpital Debrè, Assistance publique-Hopitaux de Paris, France</footnote>

<footnote><sup>f</sup> Department of Pediatric Neurology, Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, France</footnote>

<footnote><sup>g</sup> Department of Neuropediatrics, Brest University Hospital, LaTIM INSERM UMR 1101, Brest, France</footnote>

<footnote><sup>h</sup> Department of Pediatric Neurology, Purpan University Hospital, Toulouse, France</footnote>

<footnote><sup>i</sup> Department of Neuropediatrics, ERN EpiCare, Hopitaux Universitaires de Strasbourg, Strasbourg, France</footnote>

<footnote><sup>j</sup> Pediatric Intensive Care Unit and pediatric Neurology Department, Hôpital Universitaire Raymond Poincare, Paris, France</footnote>

<footnote><sup>k</sup> Department of Pediatrics, Nantes University Hospital Center, Nantes, France</footnote>

<footnote><sup>l</sup> Pediatric and Neonatal Intensive Care Unit, Hôpital Trousseau, Sorbonne-University, Paris, France</footnote>

<footnote><sup>m</sup> Pediatric Neurology Department, University Children Hospital, Lille, France</footnote>

<footnote><sup>n</sup> Pediatric Department, University Children Hospital, Tours, France</footnote>

<footnote><sup>o</sup> Pediatric Neurology Department, INM, INSERM, CHU Montpellier, University of Montpellier, Montpellier, France</footnote>

<footnote><sup>p</sup> Pediatric Intensive Care Unit, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France</footnote>

<footnote><sup>q</sup> Pediatric Neurology Department, CIC 0005, University Children Hospital, Bordeaux, France</footnote>

<footnote><sup>r</sup> Interdisciplinary Institute for Neurosciences, CNRS UMR 5297, France</footnote>

<footnote><sup>s</sup> National Reference Center for Rare Inflammatory Brain and Spinal Diseases (MIRCEM), France</footnote>

<footnote><sup>t</sup> Institut Universitaire de France, Paris, France</footnote>

<footnote><sup>u</sup> Inserm UMR 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France, ERN-RITA</footnote>

<footnote>* Corresponding author. Department of Pediatric Neurology, National Reference Center for Rare Inflammatory Brain and Spinal Diseases (MIRCEM), Institut Universitaire de France and Inserm UMR 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France.</footnote>

<footnote>E-mail address: kumaran.deiva@aphp.fr (K. Deiva).</footnote>

<footnote n="1">¹ both authors contributed equally.</footnote>
**Conclusion:** Our findings indicate that despite decrease in mortality rates, neurological disabilities in children with HSVE still persist at high levels. This underscores the need to enhance HSVE management strategies. Moreover, the identified risk factors associated with poor neurological outcomes can aid in identifying high-risk children, facilitating the implementation of alternative treatment approaches such as immunotherapy or intensive rehabilitation.

**Abbreviations**

CNIL: commission nationale de l'informatique et des libertés

CRP: C reactive protein

CSF: cerebrospinal fluid

DNA: deoxyribonucleic acid

EEG: electroencephalogram

HSV: herpes simplex virus

HSVE: HSV encephalitis

IG: intelligence coefficient

MRI: magnetic resonance imaging

mRS: mRankin score

NMDARE: anti-n-methyl-d-aspartate receptor encephalitis

PCR: Polymerase chain reaction

# 1. Introduction

Herpes Simplex virus (HSV), a double-stranded DNA viruses, is the primary cause of sporadic viral encephalitis in Western countries with an incidence ranging from 1 to 4 cases per million inhabitants per year [1–3].

The typical clinical presentation includes fever, alteration of consciousness, behavioral difficulties, focal neurological symptoms, or meningitis. However, the initial symptoms can be nonspecific, especially in children outside the neonatal period, which can lead to a delayed diagnosis [2]. Acyclovir is now the commonly accepted treatment to initiate upon suspicion of HSV encephalitis (HSVE) as early as possible [4].

HSVE, despite adequate treatment, frequently leads to poor neurological outcome. Complications at medium to long term follow-up are found in up to 63 % of these children [5]. Mortality has been drastically reduced since the systematic use of acyclovir, with prevalence ranging from 0 to 10 % according to studies [2,6]. Epilepsy emerges as the most common sequelae in most studies, followed by intellectual disabilities and motor impairments. Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) have been increasingly identified over the past decade [7–9]. The prevalence of secondary NMDARE in cohorts of children with HSVE varies from 17 to 38 % [8,10,11].

Therefore, our objective was to analyze the neurological outcomes of HSVE in children in France during these recent years. We focused on investigating the prevalence of each complication and tried to identify potential risk factors of poor neurologic outcomes that could later guide our therapeutic decisions to minimize these disabilities.

# 2. Materials and methods

## 2.1. Patients

Fourteen French tertiary pediatric neurology centers (University hospitals of Bicêtre, Robert Debré, Trousseau, Lyon, Amiens, Montpellier, Tours, Bordeaux, Brest, Marseille, Strasbourg, Nantes, and Lille) and intensive care units (University hospitals of Raymond Poincaré, Trousseau, and Necker) participated in this study. Children, aged between 28 days and 18 years at onset, hospitalized for herpes simplex virus (HSV) encephalitis with a positive HSV-1 PCR in the cerebrospinal

fluid (CSF), between 2009 and 2020, were included. Exclusion criteria were HSVE in children <28 days of age (as pathophysiology of HSVE is different in this group age), immunocompromised children and those with underlying neurological conditions.

Age, sex, symptoms at onset (fever, seizures, meningismus, altered consciousness, and the presence of herpetic gingivostomatitis in the preceding days), admission to the intensive care unit for initial management and year of diagnosis were noted for each patient. Paraclinical data included results of CSF (cells, proteins), serum (CRP, increased white blood cells, procalcitonin), EEG (slow background activity, periodic or focal spikes). On MRI assessments, localization of the lesion (frontal, temporal, insular, parietal or occipital, deep grey matter, thalamus), presence of white matter lesions was collected. Treatment data included the delay between clinical symptoms at onset and the start of the antiviral treatment, the dose used and the duration of the treatment, start of other immunosuppressive therapy. Neurological outcome was assessed during the follow-up (occurrence of epilepsy, NMDARE, HSVE relapse) and at last follow-up: mRankin score (mRS), persistence of epilepsy. Cognitive and behavioral outcomes—including academic performance (normal schooling, schooling with special needs assistant, class for children with special educational needs) and descriptions of behavioural disturbances—were collected retrospectively from parental and caregiver reports, along with information on rehabilitation needs physiotherapy, psychomotor therapy, psychotherapy, and speech therapy. Neurological sequelae, disabilities or poor neurological outcome is defined as the occurrence of any complications stated above during follow-up.

## 2.2. Statistics

Non-parametric tests were used for quantitative variables: Mann-Whitney test for single variables or Kruskal-Wallis test for variables with multiple groups. Additionally, in the case of statistically significant findings (p-value <0.05) for tests on multiple groups, pairwise comparison tests (“Post-hoc”) were considered using Tukey’s HSD method. A Chi-square test was used for categorical variables. The alpha error risk was set at 5 %.

For multivariate analysis, a multivariate logistic regression was performed to explore the impact of multiple associated symptoms.

## 2.3. Ethics

Children’s data were collected in compliance with the commission nationale de l’informatique et des libertés (CNIL) obligations. This study adheres to the French requirements of MR-004 reference methodology governing the processing of personal data for study, evaluation, or research not involving human subjects. This work was registered in the Assistance Publique-Hôpitaux de Paris general treatment registry on October 2, 2019.

## 2.4. Data statement

Any data not published within this article are available at Bicêtre Hospital. Patient-related data will be shared on request from any qualified investigator, maintaining anonymization of the individual patients.
# 3. Results

## 3.1. Patients

A total of 49 children met the inclusion criteria of our study (Supplemental Fig. 1). Patients clinical and paraclinical characteristics are summarized in Table 1. Thirty-eight patients (78 %) experienced partial or generalized seizure, thirty-five (71 %) presented with altered levels of consciousness and 46 children (94 %) had fever. Five children (10 %) had herpetic gingivostomatitis in the preceding days, and 32 patients (65 %) were admitted to intensive care due to the severity of their initial condition. One patient developed threatening intracranial hypertension at onset, requiring a decompressive hemicraniectomy.

All patients were positive for HSV-1 in the CSF. MRI findings were abnormal in 94 % of cases, with involvement of more than two regions in 35 % of cases. EEG was abnormal in 47 (96 %) of patient.

<caption>**Table 1**</caption>

Clinical and paraclinical characteristics of children with HSVE with/without disabilities.

<table><thead><tr><th></th><th>All children<br>(n = 49)</th><th>Children with<br>neurological<br>disabilities (n<br>= 37)</th><th>Children<br>without<br>neurological<br>disabilities (n<br>= 12)</th><th>p-value</th></tr></thead><tbody><tr><td>Females (%)</td><td>21 (43 %)</td><td>17 (45,9 %)</td><td>4 (33,3 %)</td><td>1</td></tr><tr><td>Age at onset<br>(years, mean<br>(SD))</td><td>4,9 (5,5)</td><td>3,9 (4,7)</td><td>7,4 (6,5)</td><td>0,05</td></tr><tr><td>FU (years, mean,<br>SD)</td><td>5,9 (3,13)</td><td>6,5</td><td>3,4</td><td></td></tr><tr><td>Clinical symptoms at onset</td><td></td><td></td><td></td><td></td></tr><tr><td>- alteration of<br>consciousness</td><td>35 (71,4 %)</td><td>28 (75,7 %)</td><td>7 (58,3 %)</td><td>0,29</td></tr><tr><td>- Seizures</td><td>38 (77,6 %)</td><td>29 (78,4 %)</td><td>9 (75 %)</td><td>1</td></tr><tr><td>- fever</td><td>46 (93,9 %)</td><td>35 (94,6 %)</td><td>11 (91,6 %)</td><td>1</td></tr><tr><td>- meningismus</td><td>9 (18.4 %)</td><td>5 (10,2 %)</td><td>4 (33,3 %)</td><td>0,19</td></tr><tr><td>Need of ICU at<br>onset</td><td>32 (65.3 %)</td><td>23 (62,1 %)</td><td>9 (75 %)</td><td>0,55</td></tr><tr><td>Abnormal EEG</td><td>47 (96 %)</td><td>35 (95 %)</td><td>12 (100 %)</td><td>1</td></tr><tr><td>- Slow<br>background<br>activity</td><td>42 (85.7 %)</td><td>33 (89,2 %)</td><td>9 (75 %)</td><td>0,34</td></tr><tr><td>- Focal spikes</td><td>17 (34.7 %)</td><td>12 (32,4 %)</td><td>5 (41,7 %)</td><td>0,73</td></tr><tr><td>- Periodic spikes</td><td>7 (14.3 %)</td><td>4 (10,8 %)</td><td>3 (25 %)</td><td>0,34</td></tr><tr><td>Biological<br>inflammatory<br>syndrome</td><td>16 (32,7 %)</td><td>14 (37,8 %)</td><td>2 (16,7 %)</td><td>0,29</td></tr><tr><td>- Increased<br>leucocytosis</td><td>14 (28,6 %)</td><td>12 (32,4 %)</td><td>2 (16,7 %)</td><td>0,47</td></tr><tr><td>- Increased CRP</td><td>5 (10,2 %)</td><td>4 (10,8 %)</td><td>1 (8,3 %)</td><td>1</td></tr><tr><td>- Increased PCT</td><td>3 (6,1 %)</td><td>2 (5,4 %)</td><td>1 (8,3 %)</td><td>0,64</td></tr><tr><td>Abnormal MRI</td><td>46 (93,9 %)</td><td>37 (100 %)</td><td>9 (75 %)</td><td>0,01</td></tr><tr><td>- Temporal lesion</td><td>34 (69,4 %)</td><td>28 (75,7 %)</td><td>6 (50 %)</td><td>0,15</td></tr><tr><td>- Frontal lesion</td><td>20 (40.8 %)</td><td>18 (48,6 %)</td><td>2 (16,7 %)</td><td>0,09</td></tr><tr><td>- Parietal lesion</td><td>14 (28.6 %)</td><td>11 (29,7 %)</td><td>3 (25 %)</td><td>1</td></tr><tr><td>- Insular lesion</td><td>12 (24.5 %)</td><td>11 (29,7 %)</td><td>1 (8,3 %)</td><td>0,25</td></tr><tr><td>- Thalamic lesion</td><td>11 (22.4 %)</td><td>10 (27 %)</td><td>1 (8,3 %)</td><td>0,25</td></tr><tr><td>- Occipital lesion</td><td>5 (10.2 %)</td><td>3 (8,1 %)</td><td>2 (16,7 %)</td><td>0,58</td></tr><tr><td>- White matter<br>lesions</td><td>12 (24.5 %)</td><td>9 (24,3 %)</td><td>3 (25 %)</td><td>1</td></tr><tr><td>- Lesions ≥ 2<br>regions</td><td>17 (34,7 %)</td><td>15 (40,5 %)</td><td>2 (16,7 %)</td><td>0,17</td></tr><tr><td>CSF:</td><td></td><td></td><td></td><td></td></tr><tr><td>- Pleiocystosis<br>(&gt;5 wbc/mm³)</td><td>44 (89,8 %)</td><td>33 (89,2 %)</td><td>11 (91,7 %)</td><td>1</td></tr><tr><td>- Predominance of<br>PNN (&gt;50 %)</td><td>5 (10,2 %)</td><td>4 (10,8 %)</td><td>1 (8,3 %)</td><td>0,32</td></tr><tr><td>- Predominance of<br>lymphocytes<br>(&gt;50 %)</td><td>39 (79,6 %)</td><td>29 (78,4 %)</td><td>10 (83,3 %)</td><td>1</td></tr><tr><td>- Increased<br>protein level<br>(&gt;0,4 g/dL)</td><td>22 (44,9 %)</td><td>15 (40,5 %)</td><td>7 (58,3 %)</td><td>0,49</td></tr></tbody></table>

## 3.2. Treatment of HSVE

Acyclovir was consistently used as the treatment, with mean initiation time from symptom onset of 3.4 ± 2.6 days. The mean dosage was 20.4 mg/kg/8 h of acyclovir. The mean duration of treatment was 21 days, ranging from 14 to 40 days. Concomitant corticosteroid treatment was initiated in 4 (8 %) patients.

## 3.3. Outcome

The mean follow-up time was 5.9 ± 3.13 years and at the end of the follow-up, only 12 (24.5 %) were free of neurological disabilities at last follow-up. The mean age of onset of neurological sequelae was 85 ± 63 months, occurring 16 ± 24 months after disease onset (Table 2). Two children (4 %) died: the first patient died during the acute phase of management from intracranial hypertension with cerebral involvement. The second child was severely disabled with a mRS of 5 and died from pneumonia several years after onset of HSVE.

The most prevalent complication was epilepsy in 28 (57 %) with 18 (64 %) of these children being drug resistant. Ten patients presented a "relapse" of neurological symptoms: NMDARE was diagnosed in 7 (14 %) patients, which was distinct from true recurrences of HSVE observed in 3 (6 %) cases defined by positive HSV-1 PCR.

In 23 (47 %) children, behavioral disorders were observed. Motor sequelae such as hemi/monoparesis, hemi/monoplegia, dyskinesias, or dystonias were found in 22 (45 %) children. Furthermore, 2 (4 %) patients developed cerebral vasculitis diagnosed on MRI after onset of encephalitis. A total of 25 (51 %) children experienced intellectual disabilities (defined as an IQ < 70) and 23 (47 %) presented with language disorders, including 5 with complete aphasia, and the remaining 18 with varying degrees of dysphasia.

Regarding academic performances, 20 (41 %) children followed or had followed a normal schooling at last follow-up. Thirteen patients (27 %) required a special needs assistant, 14 (29 %) attended a class for children with special educational needs or a special education. Two (4 %) patients did not attend school due to the severity of herpes encephalitis disability.

Rehabilitation was provided for 37 (76 %) children, including 34 needing speech therapy, 19 requiring psychomotor therapy, 20 undergoing physiotherapy, and finally, 15 receiving psychological follow-ups.

Among the 4 patients who were treated with steroids after onset of the disease, one of them was part of the two deceased children and death occurred due to the severity of the disease. Two others were able to discontinue anti-epileptic treatment after the initial episode, but one

<caption>**Table 2**</caption>

Neurological outcomes at last follow-up.

<table><thead><tr><th></th><th>Neurological outcome n = 49</th></tr></thead><tbody><tr><td>Age at onset of disability, months (mean ± SD)</td><td>85 ± 63</td></tr><tr><td>Time to disability, months, (mean ± SD)</td><td>16 ± 24</td></tr><tr><td>Death</td><td>2 (4 %)</td></tr><tr><td>Children with neurological disabilities</td><td>37 (75,5 %)</td></tr><tr><td>- Seizures</td><td>28 (57,1 %)</td></tr><tr><td>- Intellectual disabilities</td><td>25 (51,0 %)</td></tr><tr><td>- Language disorders</td><td>23 (46,9 %)</td></tr><tr><td>- Behavioural disorders</td><td>23 (46,9 %)</td></tr><tr><td>- Motor disabilities</td><td>22 (44,9 %)</td></tr><tr><td>- Need of nasogastric tube/gastrostomy</td><td>7 (14,3 %)</td></tr><tr><td>NMDARE</td><td>7 (14.3 %)</td></tr><tr><td>HSVE relapse</td><td>3 (6,1 %)</td></tr><tr><td>Cerebral vasculitis</td><td>2 (4,1 %)</td></tr><tr><td>Need of rehabilitation</td><td>37 (75,5 %)</td></tr><tr><td>Academic performances</td><td></td></tr><tr><td>- Normal schooling</td><td>20 (40,8 %)</td></tr><tr><td>- Schooling with special needs assistant</td><td>13 (26.5 %)</td></tr><tr><td>- Class for children with special educational needs</td><td>14 (28 %)</td></tr><tr><td>- No schooling</td><td>2 (4,1 %)</td></tr><tr><td>mRS ≤2</td><td>38 (77,6 %)</td></tr></tbody></table>
<table><caption>**Table 3**
Specific neurological outcomes and age at onset.</caption><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="3">Age at onset (months)</th></tr><tr><th>median; mean (SD)</th><th>p</th></tr></thead><tbody><tr><td rowspan="2">Neurobehavioural disorders</td><td>No</td><td>20.00; 62.08 (66.82)</td><td rowspan="2">0,282</td></tr><tr><td>Yes</td><td>17.50; 49.96 (62.57)</td></tr><tr><td rowspan="2">Epilepsy</td><td>No</td><td>35.00; 74.33 (73.82)</td><td rowspan="2">0,084</td></tr><tr><td>Yes</td><td>13.00; 42.83 (55.64)</td></tr><tr><td rowspan="2">Language disorders</td><td>No</td><td>70.00; 82.22 (67.99)</td><td rowspan="2">0,002</td></tr><tr><td>Yes</td><td>8.00; 26.05 (45.63)</td></tr><tr><td rowspan="2">Motor disabilities</td><td>No</td><td>92.00; 88.75 (69.77)</td><td rowspan="2">&lt;0,01</td></tr><tr><td>Yes</td><td>9.50; 19.96 (30.44)</td></tr><tr><td rowspan="2">NMDARE</td><td>No</td><td>14.00; 51.91 (63.58)</td><td rowspan="2">0,069</td></tr><tr><td>Yes</td><td>40.00; 81.57 (73.77)</td></tr><tr><td rowspan="2">HSVE relapse</td><td>No</td><td>18.00; 57.07 (65.47)</td><td rowspan="2">0,39</td></tr><tr><td>Yes</td><td>25.00; 45.33 (55.37)</td></tr><tr><td rowspan="2">Rehabilitation</td><td>No</td><td>20.00; 53.36 (65.05)</td><td rowspan="2">0,463</td></tr><tr><td>Yes</td><td>16.00; 57.67 (65.94)</td></tr><tr><td rowspan="2">Intellectual disabilities</td><td>No</td><td>69.50; 83.08 (74.98)</td><td rowspan="2">0,009</td></tr><tr><td>Yes</td><td>11.00; 32.64 (42.22)</td></tr></tbody></table>

(NMDARE: N-methyl-D-Aspartate Receptor Encephalitis, Herpes Simplex Virus Encephalitis).

developed intellectual disability and behavioral difficulties. The fourth patient developed partial epilepsy. Anti-epileptic medication was continued upon discharge for 43 children (88%).

### 3.4. Factors associated with neurological disabilities

Comparing children with and without neurological disabilities, younger children seemed to be more prone to disabilities than the older one although it was not significant (Table 1). By looking it in detail, a younger age at onset of HSVE was significantly associated with the subsequent occurrence of language disorders, motor and intellectual disabilities (Table 3).

<table><caption>**Table 4**
Specific neurological outcomes and sex and symptoms at onset.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Female</th><th colspan="3">Fever</th><th colspan="3">Meningismus</th><th colspan="3">Seizures</th><th colspan="3">Alt. of consciousness</th><th colspan="3">Intensive care unit</th></tr><tr><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th></tr></thead><tbody><tr><td>Behavioral disorder</td><td>1,2</td><td>(0,4; 3,7)</td><td>0,71</td><td>0</td><td>(0; 0)</td><td>0,09</td><td>1,5</td><td>(0,4; 6,5)</td><td>0,57</td><td>0,7</td><td>(0,2; 2,6)</td><td>0,57</td><td>1,3</td><td>(0,4; 4,4)</td><td>0,72</td><td>0,5</td><td>(0,1; 1,6)</td><td>0,22</td></tr><tr><td>Death</td><td>1,3</td><td>(0,1; 22,6)</td><td>0,84</td><td>0</td><td>(0,0; 0,0)</td><td>0,8</td><td>0</td><td>(0,0; nan)</td><td>0,63</td><td>0</td><td>(0,0; nan)</td><td>0,06</td><td>0</td><td>(0,0; 0,0)</td><td>0,52</td><td>0</td><td>(0,0; 0,0)</td><td>0,46</td></tr><tr><td>Epilepsy</td><td>2,7</td><td>(0,8; 8,8)</td><td>0,1</td><td>0,7</td><td>(0,1; 7,7)</td><td>0,73</td><td>0,5</td><td>(0,1; 2,3)</td><td>0,39</td><td>1,8</td><td>(0,5; 7,1)</td><td>0,37</td><td>1,5</td><td>(0,4; 5,2)</td><td>0,52</td><td>1,9</td><td>(0,6; 6,2)</td><td>0,3</td></tr><tr><td>Language disorders</td><td>1,4</td><td>(0,5; 4,5)</td><td>0,54</td><td>0,5</td><td>(0,04; 5,7)</td><td>0,55</td><td>1,9</td><td>(0,4; 8,9)</td><td>0,44</td><td>14</td><td>(1,6; 124,1)</td><td><strong>&lt;0,01</strong></td><td>0,8</td><td>(0,2; 2,9)</td><td>0,74</td><td>2,2</td><td>(0,6; 7,6)</td><td>0,22</td></tr><tr><td>Motor disorders</td><td>1,7</td><td>(0,6; 5,2)</td><td>0,35</td><td>0,4</td><td>(0,03; 4,6)</td><td>0,43</td><td>0,6</td><td>(0,1; 2,5)</td><td>0,44</td><td>12</td><td>(1,4; 106,3)</td><td><strong>0,01</strong></td><td>0,5</td><td>(0,1; 1,8)</td><td>0,28</td><td>1,8</td><td>(0,6; 6,2)</td><td>0,33</td></tr><tr><td>NMDARE</td><td>11,2</td><td>(1,2; 101,9)</td><td><strong>0,01</strong></td><td>0</td><td>(0,0; 0,0)</td><td>0,47</td><td>2</td><td>(0,3; 12,5)</td><td>0,45</td><td>0,3</td><td>(0,1; 1,7)</td><td>0,16</td><td>2,7</td><td>(0,3; 24,7)</td><td>0,37</td><td>0,7</td><td>(0,1; 3,4)</td><td>0,62</td></tr><tr><td>mRankin score</td><td></td><td></td><td>0,71</td><td></td><td></td><td>0,07</td><td></td><td></td><td>0,32</td><td></td><td></td><td>0,22</td><td></td><td></td><td>0,9</td><td></td><td></td><td>0,29</td></tr><tr><td>HSVE relapse</td><td>2,8</td><td>(0,2; 33)</td><td>0,4</td><td>0,1</td><td>(0,01; 1,5)</td><td>0,04</td><td>0</td><td>(0,0; nan)</td><td>0,4</td><td>0</td><td>(0,0; 0,0)</td><td>0,34</td><td>0,8</td><td>(0,1; 9,5)</td><td>0,85</td><td>0</td><td>(0,0; 0,0)</td><td>0,19</td></tr><tr><td>Rehabilitation</td><td>1,4</td><td>(0,3; 5,4)</td><td>0,67</td><td>1,8</td><td>(0,1; 21,4)</td><td>0,66</td><td>1</td><td>(0,2; 6)</td><td>0,96</td><td>0,7</td><td>(0,1; 3,8)</td><td>0,67</td><td>1,5</td><td>(0,4; 6,4)</td><td>0,55</td><td>0,6</td><td>(0,1; 2,7)</td><td>0,52</td></tr><tr><td>Intellectual disabilities</td><td>1,1</td><td>(0,4; 3,4)</td><td>0,84</td><td>0,5</td><td>(0,04; 5,9)</td><td>0,58</td><td>0,7</td><td>(0,2; 3,1)</td><td>0,66</td><td>6,9</td><td>(1,3; 36,5)</td><td><strong>0,01</strong></td><td>1,6</td><td>(0,5; 5,5)</td><td>0,47</td><td>1,8</td><td>(0,6; 6,1)</td><td>0,32</td></tr><tr><td>Academic performances</td><td></td><td></td><td>0,69</td><td></td><td></td><td>0,35</td><td></td><td></td><td>0,72</td><td></td><td></td><td>0,1</td><td></td><td></td><td>0,53</td><td></td><td></td><td>0,44</td></tr></tbody></table>

(Alt: alteration; OR: odd ratio; IC: confidence interval; p-val: p-value, nan: not a number).

In terms of clinical symptoms at onset and the risk of neurological sequelae, female sex was significantly associated with the later development of NMDARE (Table 4). Seizures at onset were significantly linked to subsequent language disorders (p < 0.01), motor (p = 0.01), and intellectual disabilities (p = 0.009).

Furthermore, CSF analysis revealed that neutrophil predominance was associated with a higher risk of developing NMDARE (p = 0.03), whereas lymphocyte predominance correlated with a lower risk (p = 0.04) (Supplemental Table 1).

In terms of imaging, abnormal MRI was significantly associated with poor outcome (Table 1). As shown in Table 5, temporal lobe lesions on MRI at onset were associated with intellectual disabilities and a higher risk of behavioral disorders (OR: 5,7 (IC:1,4–24,1), p = 0.04). Frontal (OR: 3,7 (IC:1,1–12,9), p = 0.04), insular (OR: 5,3 (IC:1,01–27,5), p = 0.04), and thalamic lesions (OR: 11 (IC:1,3–95,6), p = 0.01) on MRI were associated with a higher risk of epilepsy. Thalamic lesions were also significantly linked to motor disabilities (OR: 8,7 (IC:1,6–46,1), p = 0.01). Interestingly, occipital lesions were strongly associated with lower mRS scores.

Additionally, a longer time in the initiation of acyclovir (mean time of 4.26 days vs 2.58 days) was significantly associated with the later appearance of behavioral disorders (p = 0.019) (Supplemental Table 2).

In multivariate analyses, epilepsy occurred more frequently in females (OR: 3.5 (IC:1.52–12.4), p = 0.03), especially those who had insular lesions (OR: 8.1 (IC:1.43–54.1), p = 0.048). Furthermore, language disorders were more common in those who experienced seizures at onset (OR: 2.4 (IC: 1.32–10.1), p = 0.02). Motor disabilities occurred when there were thalamic lesions on the MRI (OR: 9 (IC:1.82–25.2), p = 0.04) and when age decreased (OR: 0.98 (IC: 0.97–0.99), p = 0.03). As for NMDARE, it was more prevalent in cases where children did not experience seizures at onset (OR: 0.23 (IC:0.05–0.98), p = 0.03) and did not have a predominance of lymphocytes in the lumbar puncture (OR: 0.09 (IC:0.01–0.69), p = 0.047).

### 4. Discussion

In this study of 49 French children with HSV encephalitis, we have shown that 37 (75.5 %) of these children had unfavorable neurological outcome with disabilities including epilepsy, language disorders, intellectual disabilities, behavioral disorders despite earlier acyclovir
<table><caption>**Table 5**
Specific neurological outcomes and localization of MRI lesions at onset.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Temporal</th><th colspan="3">Frontal</th><th colspan="3">Parietal</th><th colspan="3">Insular</th><th colspan="3">Occipital</th><th colspan="3">Thalamus</th><th colspan="3">White matter</th></tr><tr><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th><th>OR</th><th>CI</th><th>p-val</th></tr></thead><tbody><tr><td>Behavioral disorder</td><td>5,7</td><td>(1,4;<br/>24,1)</td><td><strong>0,01</strong></td><td>0,9</td><td>(0,3; 2,8)</td><td>0,82</td><td>1,2</td><td>(0,3; 4,1)</td><td>0,77</td><td>1,8</td><td>(0,5; 6,9)</td><td>0,36</td><td>0,7</td><td>(0,1; 4,8)</td><td>0,74</td><td>2,4</td><td>(0,6; 9,6)</td><td>0,21</td><td>1,8</td><td>(0,5; 6,9)</td><td>0,36</td></tr><tr><td>Death</td><td>0</td><td>(0,0; nan)</td><td>0,13</td><td>0</td><td>(0,0; 0,0)</td><td>0,22</td><td>0</td><td>(0,0; 0,0)</td><td>0,11</td><td>0</td><td>(0,0; nan)</td><td>0,57</td><td>0</td><td>(0,0; nan)</td><td>0,73</td><td>0</td><td>(0,0; nan)</td><td>0,59</td><td>0</td><td>(0,0; nan)</td><td>0,57</td></tr><tr><td>Epilepsy</td><td>1,9</td><td>(0,5; 6,3)</td><td>0,33</td><td>3,7</td><td>(1,1;<br/>12,9)</td><td><strong>0,04</strong></td><td>1,5</td><td>(0,4; 5,5)</td><td>0,52</td><td>5,3</td><td>(1,01;<br/>27,5)</td><td><strong>0,04</strong></td><td>0,5</td><td>(0,1; 3,1)</td><td>0,41</td><td>11</td><td>(1,3;<br/>95,6)</td><td><strong>0,01</strong></td><td>0,4</td><td>(0,1; 1,6)</td><td>0,21</td></tr><tr><td>Language disorders</td><td>2,3</td><td>(0,6; 8,5)</td><td>0,2</td><td>2,1</td><td>(0,6; 6,7)</td><td>0,23</td><td>1,2</td><td>(0,3; 4,5)</td><td>0,74</td><td>3,6</td><td>(0,8; 15,7)</td><td>0,08</td><td>1,6</td><td>(0,2; 10,4)</td><td>0,64</td><td>2,9</td><td>(0,7;<br/>13,1)</td><td>0,15</td><td>0,8</td><td>(0,2; 3,3)</td><td>0,71</td></tr><tr><td>Motor disorders</td><td>0,9</td><td>(0,3; 3,1)</td><td>0,87</td><td>2,9</td><td>(0,9; 9,3)</td><td>0,08</td><td>2</td><td>(0,6; 7)</td><td>0,28</td><td>3,3</td><td>(0,8; 13)</td><td>0,08</td><td>2</td><td>(0,3; 13)</td><td>0,47</td><td>8,7</td><td>(1,6;<br/>46,1)</td><td><strong>0,01</strong></td><td>1,3</td><td>(0,4; 4,8)</td><td>0,68</td></tr><tr><td>NMDARE</td><td>0</td><td>(0,0; 0,0)</td><td>0,06</td><td>0,5</td><td>(0,1; 3,1)</td><td>0,48</td><td>0</td><td>(0,0; nan)</td><td>0,07</td><td>0</td><td>(0,0; nan)</td><td>0,1</td><td>1,6</td><td>(0,2; 16,7)</td><td>0,7</td><td>0,5</td><td>(0,1; 5)</td><td>0,58</td><td>2,8</td><td>(0,5;<br/>14,6)</td><td>0,22</td></tr><tr><td>mRankin score</td><td></td><td></td><td>0,42</td><td></td><td></td><td>0,09</td><td></td><td></td><td>0,7</td><td></td><td></td><td>0,21</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0,32</td><td></td><td></td><td>0,71</td></tr><tr><td>3.0 * 1.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>6,6</td><td>(0,2; 181,7)</td><td>0,33</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>3.0 * 0.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>0,9</td><td>(0,1; 12,1)</td><td>0,96</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>3.0 * 2.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>3</td><td>(0,1; 86,1)</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>3.0 * 4.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>25</td><td>(0,1; 832,9)</td><td>0,07</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1.0 * 0.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>0,2</td><td>(0,01; 3,7)</td><td>0,23</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1.0 * 2.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>2,2</td><td>(0,04; 121,8)</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1.0 * 4.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>165</td><td>(2,6;<br/>10357,0)</td><td><strong>0,01</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.0 * 2.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>0,4</td><td>(0,02; 8,5)</td><td>1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0.0 * 4.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>27</td><td>(1; 748,9)</td><td>0,04</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>2.0 * 4.0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>75</td><td>(1,2; 4868,6)</td><td><strong>0,03</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HSVE relapse</td><td>0</td><td>(0,0; 0,0)</td><td>0,24</td><td>0</td><td>(0,0; 0,0)</td><td>0,03</td><td>5,7</td><td>(0,5;<br/>68,3)</td><td>0,13</td><td>0</td><td>(0,0; nan)</td><td>0,31</td><td>5,3</td><td>(0,4; 71,4)</td><td>0,17</td><td>1,8</td><td>(0,2;<br/>21,9)</td><td>0,64</td><td>0</td><td>(0,0; nan)</td><td>0,31</td></tr><tr><td>Rehabilitation</td><td>2,3</td><td>(0,6; 9,0)</td><td>0,25</td><td>4,3</td><td>(0,8;<br/>22,5)</td><td>0,07</td><td>2,2</td><td>(0,4;<br/>11,6)</td><td>0,36</td><td>4,2</td><td>(0,5; 37,2)</td><td>0,17</td><td>0,4</td><td>(0,1; 2,8)</td><td>0,34</td><td>0</td><td>(0,0; 0,0)</td><td><strong>0,04</strong></td><td>1,5</td><td>(0,3; 8)</td><td>0,67</td></tr><tr><td>Intellectual<br/>disabilities</td><td>4,4</td><td>(1,2;<br/>16,9)</td><td><strong>0,02</strong></td><td>1,9</td><td>(0,6; 5,9)</td><td>0,3</td><td>1,4</td><td>(0,4; 4,9)</td><td>0,59</td><td>2,4</td><td>(0,6; 9,2)</td><td>0,21</td><td>1,5</td><td>(0,2; 9,9)</td><td>0,67</td><td>3,3</td><td>(0,8;<br/>14,4)</td><td>0,1</td><td>1</td><td>(0,3; 3,5)</td><td>0,94</td></tr><tr><td>Academic<br/>performances</td><td></td><td></td><td>0,33</td><td></td><td></td><td>0,33</td><td></td><td></td><td>0,84</td><td></td><td></td><td>0,52</td><td></td><td></td><td>0,18</td><td></td><td></td><td></td><td>0,23</td><td></td><td></td><td>0,93</td></tr></tbody></table>

OR: odd ratio; IC: confidence interval; p-val: p-value; nan: not a number).
<table><caption>**Table 6**
Comparison with other studies.</caption><thead><tr><th></th><th>Our study n = 49<br>2009–2020</th><th>Elbers et al. [5] n = 16<br>1994–2005</th><th>Abel et al. [1]<br>n = 51<br>1985–2004</th><th>De Tiège et al. [12] n = 38<br>1990–1997</th><th>Lahat et al. [13]<br>n = 28<br>1984–1995</th></tr></thead><tbody><tr><td>Age at onset (mean, years)</td><td>4.9</td><td></td><td>1,35</td><td></td><td>7.16</td></tr><tr><td>Time to acyclovir treatment (days)</td><td>3.4</td><td>3</td><td>2</td><td>1,5</td><td></td></tr><tr><td>Follow-up (years)</td><td>5.9</td><td>4</td><td>7.8</td><td></td><td>5.5</td></tr><tr><td>Time to neurological disabilities occurrence (mean, months)</td><td>15.9</td><td></td><td></td><td></td><td>15</td></tr><tr><td>Female</td><td>43 %</td><td>50 %</td><td>55 %</td><td>44 %</td><td>21 %</td></tr><tr><td>Alteration of consciousness</td><td>71 %</td><td></td><td>60 %</td><td></td><td>68 %</td></tr><tr><td>Seizures</td><td>78 %</td><td>69 %</td><td>92 %</td><td></td><td>68 %</td></tr><tr><td>Fever</td><td>94 %</td><td>100 %</td><td>93 %</td><td></td><td>79 %</td></tr><tr><td>MRI</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Abnormal</td><td>94 %</td><td>88 %</td><td>100 %</td><td>84 %</td><td></td></tr><tr><td>• Limbic lesions</td><td>24 %</td><td>44 %</td><td></td><td></td><td></td></tr><tr><td>• Lesions >2 regions</td><td>35 %</td><td>31 %</td><td></td><td></td><td></td></tr><tr><td>CSF</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Meningitis</td><td>89 %</td><td>94 %</td><td>69 %</td><td></td><td>79 %</td></tr><tr><td>• Increases protein level</td><td>45 %</td><td>50 %</td><td>37 %</td><td>40 %</td><td>71 %</td></tr><tr><td>EEG</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Abnormal</td><td>98 %</td><td></td><td></td><td>100 %</td><td>86 %</td></tr><tr><td>• Slow background</td><td>86 %</td><td>81 %</td><td></td><td>31 %</td><td>61 %</td></tr><tr><td>• Focal spikes</td><td>35 %</td><td></td><td></td><td>69 %</td><td>28 %</td></tr><tr><td>• Periodic spikes</td><td>14 %</td><td>13 %</td><td></td><td>24 %</td><td></td></tr><tr><td>HSV-1</td><td>100 %</td><td>83 %</td><td></td><td></td><td></td></tr><tr><td>Neurological disabilities</td><td>76 %</td><td>63 %</td><td>75 %</td><td></td><td>36 %</td></tr><tr><td>Behavioural disabilities</td><td>47 %</td><td></td><td></td><td></td><td>14 %</td></tr><tr><td>Death</td><td>4 %</td><td>0 %</td><td></td><td></td><td>7 %</td></tr><tr><td>Epilepsy</td><td>57 %</td><td>44 %</td><td>56 %</td><td></td><td>14 %</td></tr><tr><td>Motor disabilities</td><td>45 %</td><td>13 %</td><td></td><td></td><td>18 %</td></tr><tr><td>HSV relapse</td><td>6 %</td><td></td><td>17 %</td><td></td><td>7 %</td></tr><tr><td>Intellectual disabilities</td><td>51 %</td><td>25 %</td><td>42 %</td><td></td><td>14 %</td></tr><tr><td>Poor academic performances</td><td>59 %</td><td></td><td>69 %</td><td></td><td></td></tr></tbody></table>

treatment. The multivariate analyses identified high risk children for specific disabilities: epilepsy in females with insular lesions; language disorders in children who had seizures at onset; motor disorders in younger children with thalamic lesions.

The demographic data in our study aligned with previously published findings (Table 6, [1,5,12,13]). We observed a slight predominance of boys, though the age at onset was younger in our cohort (4.9 years versus 7.16 years) [13]. Consistent with prior research [14–17], we reaffirmed that younger age at herpes encephalitis onset is a risk factor for poorer neurological outcomes. Notably, periodic complexes were rare in initial EEGs (14 %), supporting previous observations that this finding is uncommon in children but present in nearly half of adult patients [5,6].

CSF assessments suggest that neutrophil predominance increases NMDARE risk, while lymphocyte predominance lowers it. Neutrophils indicate a nonspecific immune response, implying poor HSV control, which may increase the risk of autoimmune disease. In contrast, lymphocytes suggest an effective response. However, definitive conclusions are limited by wide confidence intervals and variability in lumbar puncture timing.

In pediatric patients, MRI often shows limbic system lesions, including the mesial temporal lobe, insula, and frontal lobes, similar to adults [18]. However, extra-temporal and bilateral lesions, especially in the parietal, occipital and thalamic regions, are more common in children (40 % in young children compared to 9–15 % in adults), suggesting hematogenous HSV spread rather than trigeminal transmission [2,15]. In our study, the initial MRI lesion distribution showed a significant correlation with behavioral disorders, epilepsy, and motor impairments. Interestingly, occipital lesions were associated with better mRS scores, contrasting previous studies that linked occipital involvement to greater disability at discharge [19]. This discrepancy may reflect differences in the age composition of study population.

Our study found that the time for starting acyclovir was longer compared to earlier studies (3 days versus 1.5 days in previous studies

[1,5,12]. This was surprising given that our study is more recent. The difference is likely to be related to how we measure the delay. For us, it is the time between the first symptoms and starting acyclovir, whereas in other studies, it was the time between hospital admission and treatment initiation. However, it is crucial to highlight that starting treatment earlier leads to better neurological outcomes [6,20–22].

In our cohort, children had more neurological disabilities compared to studies from Canada and Israel (63 % and 36 % respectively) [5,13]. However, this frequency was similar to a prior French study where neurological disabilities were present in 76 % [1]. This indicates that despite the time gap of more than 10 years, the number of complications has not decreased; it remains consistently high although mortality rate seems lower than previously reported (4 % vs 7 %) [13] which may suggest that either the diagnosis are not done early enough or acyclovir alone might not be sufficient to prevent neurological sequelae. Immunomodulatory therapies offer a promising approach to managing herpes encephalitis [23,24]. While steroids are frequently used, studies in both adults and children remain limited by small sample sizes and inconsistent results, necessitating further research [25–27]. Interferons, in combination with acyclovir, are also under investigation, as individuals with interferon pathway deficiencies may be more susceptible to the disease [28,29]. Preclinical studies suggest that recombinant interferon could reduce mortality and improve outcomes [30]. Early co-administration with acyclovir may represent a promising therapeutic strategy.

The prevalence of NMDARE in our study was lower than the reported 17–30 % in the literature [8,9,31] with higher susceptibility observed in females, consistent with the well-documented female predisposition to autoimmune diseases, often triggered by infections. NMDARE was clearly distinguishable from CNS relapses due to herpes virus reactivation, with a prevalence similar to the Israeli study (7 %) but lower than earlier reports (14–26 %)$^{11,28}$. This discrepancy may be attributed to improved diagnostic accuracy, differences in study populations, or the unavailability of anti-NMDAR antibody testing in past studies.
Like many studies on HSVE in children, limitations are due to a small number of patients, affecting the study's statistical power. Furthermore, our analysis was retrospective, which added to its limitations. There were differences in patient follow-up duration, although it was longer in our study compared to other published pediatric cohorts. Our data were specifically gathered from children admitted to university hospitals, introducing a selection bias, as these centers typically manage the most severe cases that might not be handled in non-university hospitals.

However, following Abel et al.'s study [1] that collected data of French children from 1985 to 2004, ours is currently the most extensive pediatric cohort of herpes encephalitis studied. Our data collection spanned from 2009 to 2020, well after the adoption of acyclovir as the preferred treatment for HSV encephalitis.

Another important aspect highlighted in our study is the need for rehabilitation and academic difficulties observed at the last follow-up, which have been rarely described in these children: despite a lower mRS (≤2) in 38 (78%) of the children, 37 (76%) experienced neurological disability, with a similar number needing rehabilitation, and 29 (59%) facing schooling difficulties. Because these outcomes were collected retrospectively, they are susceptible to recall and reporting bias. Future prospective studies should therefore incorporate harmonised neuropsychological test batteries (e.g., WISC-V, NEPSY-III) and validated behavioural rating scales (e.g., CBCL, BRIEF) at pre-defined intervals to better characterise and quantify these difficulties.

## 5. Conclusion

Neurological disabilities are still high and remains a major concern for the long-term outcome. This study underscores the necessity for a better management of these children. The identification of factors associated with specific neurological sequelae may help to define a more aggressive therapy in these specific children using other novel therapeutic options such as immunotherapy or intensive rehabilitation.

## Contributors statement page

Dr Caroline Rey and Laetitia Giorgi conceptualized, designed the study, supervised data collection, drafted the initial manuscript, and critically reviewed and revised the manuscript. Drs Hélène Maurey, Anne-Lise Poulat, Daniel Amsallem, Anne Lepine, Stéphane Auvin, Renaldo Florence, Juliette Ropars, Sarah Baer, Jean-Marc Pinard, Anne Rolland, Pierre-Louis Leger, Sylvie Nguyen The Tich, Pierre Castelnau, Pierre Meyer, Sylvain Renolleau, Diana Rodriguez and Frederic Villega critically reviewed and revised the manuscript. Dr Kumaran Deiva conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

## Funding of support

No funding was secured for this study.

## Declaration of competing interest

All authors have no conflict of interest to disclose regarding this article.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejpn.2025.05.001.

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