Abstract
Secondary epilepsy is a common concomitant disease of viral encephalitis (VE) in children. However, the risk factors for secondary epilepsy after VE remain debated. The aim of this study was to perform a 10-year single-center retrospective analysis to investigate the incidence and risk factors of secondary epilepsy after VE in children. A total of 8691 patients suffered from VE in our hospital between December 2011 and February 2022 were included. The patients were divided into control group (Group C) and epilepsy group (Group E) according to whether they followed secondary epilepsy. Information about treatment process was collected from medical records to determine the incidence. Univariate analysis and multivariate logistic regression analysis were performed to identify the independent risk factors. In the current study, the occurrence of secondary epilepsy after VE in pediatric patients was 10.99% (385 of 3503). The results of univariate and multivariate analysis showed that unconsciousness, convulsions, times of epilepsy >2, epileptiform discharge of Electroencephalogram (EEG), and cortical and subcortical damage of magnetic resonance imaging/computer tomography were the significant risk factors for secondary epilepsy after VE. Nearly one tenth of pediatric patients suffered from secondary epilepsy after VE. Interventions for identified risk factors should be used to prevent the occurrence of secondary epilepsy.
Keywords: incidence, retrospective study, risk factors, secondary epilepsy, viral encephalitis
1. Introduction
Viral encephalitis (VE) is characterized as an acute inflammation of the brain caused by viral infection. Clinical investigations indicate that the causative virus is detected in only a range of 33% to 25% of cases, with enteroviruses being responsible for the majority (80%) of cases, followed by arboviruses and adenoviruses.[1,2] The manifestations of VE can vary depending on the virulence of the pathogen and the response of the host. If the lesion primarily affects the meninges, viral meningitis is the predominant clinical presentation, whereas VE becomes the prominent feature if when the lesion main brain is primarily affects the brain parenchyma.[3,4] From an anatomical standpoint, the meninges and brain parenchyma are in close proximity, thus when both are afflicted, the condition is referred to as viral meningoencephalitis. This particular ailment predominantly affects children aged 2 to 10, exhibiting a notable propensity for infecting the nervous system. Manifestations of this condition encompass fever, vomiting, convulsions and, in cases where the brain parenchyma sustains damage, coma.[5]
The severity and prognosis of VE exhibit considerable heterogeneity among pediatric patients. Mild cases generally demonstrate a favorable prognosis, whereas severe cases can result in various debilitating outcomes such as epilepsy, limb paralysis, hearing or visual impairment, altered consciousness, and even mortality.[6] Existing literature indicates that secondary epilepsy frequently manifests as a complication of VE.[7,8] Notably, children with VE are more susceptible to developing secondary epilepsy compared to adults. Following VE, approximately 8.9% of cases experience secondary epilepsy, with refractory epilepsy accounting for 24.12% of these instances. Patients with epilepsy may encounter motor dysfunction, mental impairments, or even fatality due to the ailment. Failure to timely control seizures can exacerbate the irreversible harm caused by the primary disease and inflict damage on multiple bodily systems. Consequently, there is an urgent requirement for interventions aimed at averting secondary epilepsy subsequent to VE.[9,10] Although certain studies have investigated the risk factors associated with VE complicated by secondary epilepsy, the sample size was limited, the duration of observation was brief, and the analysis lacked thoroughness.
Given that, the aim of this study was to analyze patients with VE at the Children’s Hospital of Hebei Province over the past decade and establish a theoretical foundation for the development of a more comprehensive treatment approach for children with VE by examining the incidence and risk factors of secondary epilepsy after VE in children. Additionally, the study sought to propose preventive measures and drug treatments based on the current clinical data of VE to mitigate the occurrence of secondary epilepsy.
2. Materials and methods
This retrospective study adhered to the principles outlined in the Declaration of Helsinki guidelines. Approval was obtained from the institutional review board of the Children’s Hospital of Hebei Province (Grant No. 202302), and all participants provided informed consent to participate in the study.
2.1. Inclusion and exclusion criteria
From December 2011 to February 2022, a retrospective study was conducted at the Children’s Hospital of Hebei Province to recruit patients who had experienced VE. The recruitment process involved querying electronic medical records. The inclusion criteria encompassed the following aspects: The presence of infectious diseases, upper respiratory tract infections, or acute or subacute onset. Manifestation of symptoms indicative of brain parenchymal damage such as fever, convulsions, drowsiness, mental and emotional abnormalities, and even comas. Cerebrospinal fluid White blood cells were normal or slightly increased, lymphocytes dominated the classified count, and cerebrospinal fluid virus culture and specific antibodies appeared positive. Electroencephalogram (EEG) is characterized by diffuse or localized abnormal slow wave background activity. The clinical data of participants were complete. The exclusion criteria for this study included the following: A confirmed case of Japanese encephalitis. Family history of epilepsy, previous epilepsy, or other systemic progressive diseases causing epilepsy. Acute or post-discharge death due to other complications. Meningitis of the cerebrospinal fluid, caused by other immune-mediated diseases. History of taking psychotropic drugs. Other intracranial pathogenic infections, such as purulent meningitis, tuberculous meningitis, and cryptococcal meningitis. Reye syndrome. Not actively receiving treatment. Lost to follow-up for various reasons.
2.2. Diagnosis and grouping
According to the diagnostic criteria and historical records of secondary epilepsy, as well as EEG and head imaging examination, the participants of this study were categorized into 2 groups: control group (Group C) and epilepsy group (Group E) based on the presence or absence of secondary epilepsy.
2.3. Data collection
Two researchers (MSZ and GYZ) inquired patients’ electronic medical records and made telephone follow-up to record demographic information of each participant such as age, height, weight, gender, length of hospital stay, antiviral drugs in acute phase, clinical manifestations in acute phase, virology, cerebrospinal fluid, EEG monitoring, imaging examination, epilepsy control, and prognosis. Virological examination results include serum virus antibody examination, serum and throat swab virus nucleic acid examination were carefully recorded.
2.4. Statistical analysis
All statistical analysis was performed with the Statistical Package for Social Sciences software (version 23.0, SPSS Inc., Chicago, IL, USA). The continuous data were expressed as mean ± standard deviation (SD) or median (interquartile range). First, a univariate logistic analysis was performed to evaluate the relationship between each categorical variable and secondary epilepsy after VE. Whitney U test or t test was used to evaluate continuous variables, when appropriate depending on the data distribution (equal variance and normality or not). Multivariate logistic regression analysis was used to evaluate the risk of secondary epilepsy. P values lower than .05 were interpreted as statistically significant in all the statistical analysis model.
3. Results
3.1. Characteristics of secondary epilepsy after viral encephalitis
Four thousand one hundred ninety-three patients were assessed for study eligibility during this study. Six hundred ninety patients were excluded from the study, including 425 patients did not meet the inclusion criteria (Japanese encephalitis confirmed case: 48 patients, family history of epilepsy: 45 patients, died due to other complications in acute stage: 13 patients, died due to other complications in post-discharge: 12 patients, history of taking psychotropic drugs: 36 patients, history of tuberculous meningitis infection: 35 patients, history of suppurative meningitis infection:34 patients, history of cryptococcal meningitis infection: 33 patients, Reye syndrome: 19 patients, not actively receiving treatment: 52 patients, lost to follow-up for various reasons: 98 patients) and 265 patients declined to participate. Finally, a total of 3503 patients were enrolled in this study. As shown in Figure 1, there were 2097 males and 1406 females, with a mean age of 4.72 ± 2.13 years (range from 2 m–10 yrs). During the follow-up period, a total of 385 patients developed secondary epilepsy following VE and were subsequently assigned to the epilepsy group (Group E). Conversely, the control group (Group C) consisted of 3118 patients who did not experience secondary epilepsy after VE. Consequently, the incidence of secondary epilepsy after VE was determined to be 10.99%. Despite observations suggesting that patients in Group C exhibited higher age (4.83 vs 4.31), height (108.72 vs 106.58), and weight (16.64 vs 15.98) compared to those in Group E, no statistically significant differences in age, gender, weight, and height were found between the 2 groups.
Figure 1.
Flow diagram of study: Epilepsy group (Orange), control group (Blue). VE = viral encephalitis.
3.2. Univariate analysis of clinical manifestation and secondary epilepsy in patients with viral encephalitis
The study conducted a univariate analysis to determine the significant risk factors for secondary epilepsy following VE. Factors such as length of hospital stay, rate of antiviral drugs usage, convulsions, unconsciousness, headache, ataxia, positive meningeal irritation sign, diarrhea, positive Pan’s test and positive pyramidal tract sign and times of epilepsy >2 were found to be the significant risk factors. However, factors such as age, gender, peak body temperature, focal neurological dysfunction, weight, height, times of epilepsy <2 were not associated factors with secondary epilepsy after VE. For further details, please refer to Table 1.
Table 1.
Univariate analysis of factors associated with secondary epilepsy on demographic and clinical data of patients between 2 groups (χ ± s).
| Group C (n = 3118) | Group E (n = 385) | P value | |
|---|---|---|---|
| Age (yrs) | 4.83 ± 2.56 | 4.31 ± 2.07 | .389 |
| Height (cm) | 108.72 ± 8.81 | 106.58 ± 7.71 | .652 |
| Weight (kg) | 16.64 ± 4.67 | 15.98 ± 4.29 | .557 |
| Gender | .413 | ||
| Female (%) | 1247 (39.99%) | 159 (41.30%) | |
| Male (%) | 1871 (60.01%) | 226 (58.70%) | |
| Length of hospital stay (d) | 14.26 ± 2.79 | 19.57 ± 4.88 | .014 |
| Peak body temperature (°C) | 38.93 ± 0.44 | 39.02 ± 0.48 | .611 |
| Convulsions (case/[%]) | 280 (8.98%) | 220 (57.14%) | <.001 |
| Headache (case/[%]) | 524 (16.81%) | 155 (40.26%) | .009 |
| Ataxia (case/[%]) | 798 (25.59%) | 166 (43.12%) | .003 |
| Antiviral drugs usage (case/[%]) | 1247 (39.99%) | 327 (84.94%) | <.001 |
| Focal neurological dysfunction (case/[%]) | 498 (15.97%) | 76 (19.74%) | .534 |
| Unconsciousness (case/[%]) | 592 (18.99%) | 243 (63.12%) | <.001 |
| Positive meningeal irritation sign (case/[%]) | 1016 (32.58%) | 239 (62.08%) | .009 |
| Diarrhea (case/[%]) | 952 (30.53%) | 204 (52.99%) | .042 |
| Positive Pan’s test (case/[%]) | 119 (3.82%) | 141 (36.62%) | <.001 |
| Positive pyramidal tract sign (case/[%]) | 832 (26.68%) | 258 (67.01%) | .007 |
| Times of seizures | |||
| <2 | 2142 (68.70%) | 52 (13.51%) | .396 |
| >2 | 976 (31.30%) | 333 (86.49%) | <.001 |
3.3. Univariate analysis of auxiliary examination results and secondary epilepsy in patients with viral encephalitis
The significant risk factors for secondary epilepsy following VE were identified as cerebrospinal fluid herpes simplex virus infection, diffuse/extensive slow wave of EEG, epileptiform discharge of EEG, simple subcortical damage, cortical and cortical damage, and thalamic basal ganglia damage observed through magnetic resonance imaging (MRI)/computer tomography (CT), as indicated by the findings presented in Table 2. There was no significant association found between secondary epilepsy after VE and elevated intracranial pressure, White blood cell count, glucose levels, protein levels, monocyte count of cerebrospinal fluid, mycoplasma infection, rubella virus infection, cytomegalovirus infection, respiratory syncytial virus infection, enterovirus infection, coxsackievirus infection, rotavirus infection, chlamydia infection, adenovirus infection, Epstein-Barr virus infection in cerebrospinal fluid, or simple subcortical damage observed on MRI/CT scans.
Table 2.
Univariate analysis of factors associated with secondary epilepsy on auxiliary examination data of patients between 2 groups (χ ± s).
| Group C (n = 3118) | Group E (n = 385) | P value | |
|---|---|---|---|
| Elevated intracranial pressure (case/[%]) | 450 (14.43%) | 66 (17.14%) | .542 |
| Cerebrospinal fluid | |||
| WBC (×106/L) | 59.42 ± 8.81 | 62.74 ± 8.97 | .417 |
| Protein (mg/L) | 335.69 ± 34.76 | 298.64 ± 30.55 | .225 |
| Glucose (mmol/L) | 3.74 ± 0.59 | 3.58 ± 0.52 | .598 |
| Monocyte (×106/L) | 89.65 ± 14.28 | 93.76 ± 13.59 | .254 |
| Virological examination | |||
| Herpes simplex virus (case/[%]) | 135 (4.33%) | 88 (22.86%) | <.001 |
| Mycoplasma (case/[%]) | 63 (2.02%) | 8 (2.08%) | .199 |
| Rubella virus (case/[%]) | 125 (4.01%) | 19 (4.94%) | .206 |
| Cytomegalo virus (case/[%]) | 95 (3.05%) | 13 (3.38%) | .432 |
| Respiratory syncytial virus (case/[%]) | 33 (1.06%) | 5 (1.30%) | .297 |
| Enterovirus (case/[%]) | 34 (1.09%) | 6 (1.56%) | .334 |
| Coxsackievirus (case/[%]) | 156 (5.00%) | 20 (5.19%) | .541 |
| Rotavirus (case/[%]) | 38 (1.22%) | 5 (1.30%) | .295 |
| Chlamydia (case/[%]) | 94 (3.01%) | 11 (2.86%) | .335 |
| Adenovirus (case/[%]) | 17 (0.55%) | 2 (0.52%) | .717 |
| Epstein-Barrviru (case/[%]) | 30 (0.96%) | 4 (1.04%) | .394 |
| EEG | |||
| Diffuse/extensive slow wave (case/[%]) | 302 (9.69%) | 96 (24.94%) | .024 |
| Epileptiform discharge (case/[%]) | 124 (3.98%) | 58 (15.06%) | .002 |
| MRI/CT | |||
| Simple cortical damage (case/[%]) | 125 (4.01%) | 23 (5.97%) | .041 |
| Simple subcortical damage (case/[%]) | 571 (18.31%) | 55 (14.29%) | .201 |
| Cortical and subcortical damage (case/[%]) | 187 (6.00%) | 188 (48.83%) | <.001 |
| Thalamic basal ganglia damage (case/[%]) | 1091 (34.99%) | 208 (54.03%) | .015 |
CT = computer tomography, EEG = electroencephalogram, MRI = magnetic resonance imaging.
3.4. Multivariate logistic analysis of clinical data and secondary epilepsy in patients with viral encephalitis
In the multivariate model, several factors were found to be significant risk factors for secondary epilepsy after VE, including convulsions, unconsciousness, positive meningeal irritation sign, diarrhea, cerebrospinal fluid herpes simplex virus infection, times of epilepsy >2, epileptiform discharge of EEG and cortical and subcortical damage of MRI/CT. Following adjustment for confounding factors, unconsciousness, convulsions, times of epilepsy >2, epileptiform discharge of EEG and cortical and subcortical damage of MRI/CT were remained as independent risk factors associated with secondary epilepsy after VE (P = .005, <.001, .006, .014 and .003), and the adjusted odds ratio was 7.39 (4.12–16.83), 15.88 (11.26–29.74), 6.27 (3.89–10.11), 4.68 (3.06–6.29), and 9.97 (7.48–18.59) respectively. The detailed information is presented in Table 3.
Table 3.
Multivariate logistic regression analysis of factors associated with secondary epilepsy.
| Odds ratio | 95% CI | P value | |
|---|---|---|---|
| Unconsciousness | 7.39 | 4.12–16.83 | .005 |
| Convulsions | 15.88 | 11.26–29.74 | <.001 |
| Times of epilepsy >2 | 6.27 | 3.89–10.11 | .006 |
| Cortical and subcortical damage of MRI/CT (case/[%]) | 4.68 | 3.06–6.29 | .014 |
| Epileptiform discharge of EEG (case/[%]) | 9.97 | 7.48–18.59 | .003 |
CT = computer tomography, EEG = electroencephalogram, MRI = magnetic resonance imaging.
4. Discussion
VE, a prevalent childhood infection, exhibits a notable prevalence and fatality rate.[11] Consequently, children afflicted with this condition may experience neuronal impairment and neuropathy, leading to significant implications for their overall well-being, developmental trajectory, and physical growth. During the acute phase of VE, brain edema, nerve cell necrosis, and inflammatory infiltration in the frontal and temporal lobes are frequently observed.[12,13] The etiology of abnormal neuronal discharge in this context can be attributed to viral agents, autoimmune responses, toxic metabolites, and cerebral arteriovenous thrombosis. The prognosis and long-term impairment of brain function following VE complicated by epilepsy, a prevalent and serious complication, are unfavorable. Consequently, the objective of this study was to assist clinicians in assessing the risk factors associated with secondary epilepsy following VE in pediatric patients, in order to offer a more comprehensive approach to diagnosis and treatment. In this study, we conducted a 10-year retrospective study on children with VE in the Department of Neurology of Children’s Hospital of Hebei Province. Our investigation revealed that the incidence of secondary epilepsy after VE is 10.18%. Patients with unconsciousness, convulsions, times of epilepsy >2, epileptiform discharge of EEG, and cortical and subcortical damage of MRI/CT have a higher risk to secondary epilepsy after VE.
Childhood exerts a pivotal influence on the development of the brain, particularly with regards to intellectual growth. Infections targeting the central nervous system can significantly impede children’s development, potentially resulting in conditions such as epilepsy, attention deficit hyperactivity disorder, and learning disabilities, among others.[14] Notably, children afflicted with viral meningitis face a tenfold higher risk of developing secondary epilepsy compared to those unaffected by the condition.[9] This association is frequently observed within a 5-year timeframe following VE. In previous research, Wan et al investigated the risk factors associated with VE complicated by epilepsy. They identified the duration of acute epileptic seizures, herpes simplex virus infection, and changes in the focal nervous system as independent risk factors. However, it is important to note that the sample size in each study was limited and the duration of the research was relatively short.[15] Therefore, we intend to conduct a comprehensive assessment of the risk factors of secondary epilepsy after VE in children.
Convulsion refers to a single, multiple or persistent state of convulsion in the acute phase. Studies have shown that the risk of secondary epilepsy is the highest within 3 to 5 years after VE.[16] 22% of patients with convulsions in the acute phase of VE can have secondary epilepsy. The risk of secondary epilepsy is 10 times that of the general population, while the incidence of secondary epilepsy in patients without convulsions in the acute phase is 10%.[17] In the study of this project, the incidence rate of convulsions accounted for 10.18% of all patients with secondary epilepsy, which was consistent with the research results of Prof Misra UK.[9] Since children can not clearly express their feelings, the observation of the condition is very important. The assessment of consciousness and mental state in children can be determined through dialogue, calling, and pain stimulation in a clinical setting. Unconsciousness following VE is attributed to prolonged high fever and infectious agents associated with the condition, leading to neural damage in the brain. Our findings indicate that convulsions and unconsciousness are autonomous risk factors for the development of secondary epilepsy in children following VE, aligning with the conclusions drawn in Stafstrom CE’s research.[18]
The necrosis of brain cells and the infiltration of inflammatory cells in the acute stage of VE can affect the stability of nerve cell membrane and lead to acute seizures. After the acute phase, the necrosis, deletion, structural disorder and even abnormal proliferation of neurons in the lesion, potassium outflow and calcium influx caused by the imbalance of proton pump in cell membrane, abnormal biochemical metabolism, and the decrease of γ-aminobutyric acid can lead to the formation of permanent epileptic lesions.[19] Recurrent epileptic seizures during the acute phase of encephalitis have the potential to result in ongoing discharge of brain cells, resulting in damage to these cells. This damage can subsequently lead to the formation of new epileptic lesions, the onset of epilepsy, and the eventual development of postencephalitis epilepsy without any external triggers.[20] Consequently, it is crucial to actively manage epileptic seizures during the acute phase of encephalitis. Our study identified that experiencing epilepsy more than twice is an independent risk factor for the development of secondary epilepsy following VE in children.
EEG serves as a crucial diagnostic tool in the assessment of VE disorders, enabling the evaluation of brain function impairment and aiding in the identification of symptomatic epilepsy. The extent of brain function damage is directly associated with the abnormality level observed in EEG recordings. Epileptiform discharge denotes the anomalous EEG patterns exhibited by individuals with epilepsy, commonly characterized spike wave, sharp wave, spike slow complex wave or sharp slow complex wave.
There are several limitations inherent in this study that warrant Acknowledgments. Firstly, the retrospective nature of the study introduces a certain degree of bias, potentially impacting the accuracy of the obtained results. Secondly, the inclusion of data solely from a single hospital restricts the generalizability of the findings, thus rendering a large sample multicenter research design more desirable for enhancing the persuasiveness of the research outcomes. Lastly, the substantial number of patients lost to follow-up (130) and those who declined to participate (177) may introduce interference that could potentially affect the final results of this study.
5. Conclusion
In summary, our data suggest nearly one tenth of pediatric patients suffered from secondary epilepsy after VE. VE patients with unconsciousness, convulsions, times of epilepsy >2, epileptiform discharge of EEG, and cortical and subcortical damage of MRI/CT have a higher risk to develop secondary epilepsy. Therefore, deliberate treatment plan and close follow-up are necessary for cases with these risk factors.
Acknowledgments
We especially thank Professor Chao Zhang, School of Mathematical Sciences (Tian Jiabing Education College) of Hebei Normal University for his help in the statistical processing of data in this study. We would like to express our gratitude to the Researchers’ Home for their efforts in polishing and correcting grammar errors in the manuscript language.
Author contributions
Conceptualization: Yang Hu.
Data curation: Bo Huang, Mengsha Zhu, Guiying Zhang.
Formal analysis: Bo Huang, Mengsha Zhu.
Investigation: Suzhen Sun, Guiying Zhang.
Methodology: Suzhen Sun, Guiying Zhang.
Resources: Suzhen Sun.
Writing – original draft: Yang Hu.
Writing – review & editing: Yang Hu.
Abbreviations:
- EEG
- electroencephalogram
- SD
- Standard deviation
- VE
- Viral encephalitis
This study was supported by Hebei Medical Science Research Project (No. 20190816).
This study was approved by the institutional review board of the Children’s Hospital of Hebei Province (Grant No. 202302) in compliance with the Helsinki and declaration and consent were waived for its retrospective nature.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
How to cite this article: Hu Y, Huang B, Zhu M, Sun S, Zhang G. The incidence and risk factors of secondary epilepsy after viral encephalitis in children: A 10-year single-center retrospective analysis. Medicine 2024;103:11(e37544).
Contributor Information
Bo Huang, Email: huangbo@163.com.
Mengsha Zhu, Email: 18833219656@126.com.
Suzhen Sun, Email: SYZNeurology@163.com.
Guiying Zhang, Email: 636841255@qq.com.
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