The incidence and risk factors of secondary epilepsy after viral encephalitis in children: A 10-year single-center retrospective analysis.

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.

A case report of long-delayed diagnosis of pseudorabies virus encephalitis with endophthalmitis: lessons from metagenomic next generation sequencing.

BACKGROUND: Pseudorabies virus (PRV) was thought to only infect animals. Recent studies have shown that it can also infect human. CASE PRESENTATION: We report a case of pseudorabies virus encephalitis and endophthalmitis, diagnosed 89 days after onset, confirmed with intraocular fluid metagenomic next generation sequencing (mNGS) after the result of two cerebrospinal fluid (CSF) mNGS tests were negative. Although treatment with intravenous acyclovir, foscarnet sodium, and methylprednisolone improved the symptoms of encephalitis, significant diagnostic delay resulted in permanent visual loss. CONCLUSIONS: This case suggests that pseudorabies virus (PRV) DNA in the intraocular fluid may have a higher positivity than that in the CSF. PRV may persist in the intraocular fluid for an extended period and may thus require extended antiviral therapy. Patients with severe encephalitis and PRV should be examined with the focus on pupil reactivity and light reflex. A fundus examination should be performed in patients with a central nervous system infection, specifically, those in a comatose state, to help reduce eye disability.

Risk factors of epilepsy secondary to viral encephalitis: A meta-analysis.

OBJECTIVE: To systematically evaluate the risk factors of post-encephalitis epilepsy (PEE). METHODS: Systematic computerized searches of databases such as Cochrane Library, PubMed and EMBASE were performed. The meta-analysis of pooled odds ratios and 95% confidence intervals for PEE risk were calculated. RESULTS: Sixteen studies with 2504 patients were included for meta-analysis. The results showed that PEE was associated with coma, seizure, status epilepticus, cranial MRI abnormality, focal EEG abnormality, and positive herpes simplex virus (HSV) in cerebrospinal fluid (CSF). CONCLUSION: Coma, seizures or status epilepticus, abnormal MRI and focal EEG, and HSV in CSF were the risk factors of PEE.

Glasgow Coma Score Predicting the Poor Outcome of the Patients Presenting Fever with Altered Sensorium.

To assess the role of the Glasgow Comma Score (GCS) for predicting the outcome of the patient with fever and altered sensorium was the objective of the study. This prospective observational study was conducted for six months following ethical approval. Informed consent was obtained prior enrollment. A total of 50 patients with complaints of fever for <2 weeks duration with altered sensorium with or without seizure were included in the study. GCS was calculated for all patients just after admission and before starting interventions. All patients were investigated and managed according to the hospital protocol. The outcome of the patients (living or dead within the hospital) was evaluated against the admission GCS score. The study was performed in accordance with the current Declaration of Helsinki. Of all, 42.0% (n=21) of the patients had bacterial meningitis, followed by viral encephalitis, cerebral malaria and coma vigil. Complete recovery occurred in 60.0% of cases, while recovery with disability occurred in 28.0% of cases. Death occurred in 12.0% of cases (n=6) due to cerebral malaria, viral encephalitis and bacterial meningitis (n=2 each cause). A higher number of deaths occurred in the lower GCS group (n=5 in GCS group 3-5) and this difference was statistically significant (p<0.05). Moreover, considering death as an outcome, multivariate logistic regression showed that GCS (OR 70.598, 95% CI-1.243-4009.41; p=0.039) was an independent predictor of the outcome. GCS seemed to be a predictor of the short-term outcome of the patient presenting with fever and altered sensorium in our setting. However, further exploration in larger setting with appropriate study design is recommended.

Cerebrospinal fluid in Borna disease virus 1 (BoDV-1) encephalitis.

Borna disease virus 1 (BoDV-1) has been recognized as a rare cause of very severe encephalitis with rapid onset in central Europe. Data on cerebrospinal fluid (CSF) analysis have not yet been analyzed in detail. Here, we present the first study on CSF changes in BoDV-1 encephalitis. We retrospectively analyzed CSFs from 18 BoDV-1 encephalitis cases from Bavaria, Germany, an endemic region, from 1996 to 2021. Data were obtained through review of medical records and institutional databases. We found that white blood cell count (WBC) in CSF is elevated in 13 of our 18 patients at first examination (average 83.2 ± 142.3 leukocytes/µl) and cytology showed predominance of lymphocytes. Patients with typical symptoms of meningoencephalitis had higher WBC in first CSF analyzation (133.5 ± 163.1 vs 4.0 ± 3.2/µl; p = 0.065). BoDV-1 PCR of CSF is not always positive when tested (7 of 9 cases). Four of five patients tested showed a polyvalent reaction against multiple viruses in the CSF suggesting that BoDV-1 may trigger autoimmune mechanisms. CSF changes in BoDV-1 encephalitis seem similar to those of other viral encephalitis and at the beginning WBC can be normal in up to 28%, making the diagnosis even more challenging. All in all, BoDV-1 should be included in the diagnostic workup of patients with rapidly evolving and/or severe encephalitis and patients with severe neuropathy and secondary encephalopathy with and without CSF changes. Repeated CSF examinations as well as BoDV-1 serology and CSF PCR have to be considered in endemic areas.

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

PURPOSE: To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. MATERIALS AND METHODS: Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. RESULTS: Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. CONCLUSION: These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Epidemiology and Disease Burden of Hospitalized Children With Viral Central Nervous System Infections in China, 2016 to 2020.

BACKGROUND: Viral central nervous system (CNS) infections seriously threaten the life and health of children, with a high mortality and severe sequelae in China and globally. Surveillance of viral CNS infections in children is important, especially in hospitalized children, to facilitate disease evaluation. METHODS: In this study, we collected the data on the discharged Face Sheet of Medical Records from database from 2016 to 2020 and analyzed the epidemiologic characteristics and disease burden of hospitalized children (≤18 years old) with viral CNS infections in China. We classified the discharge diagnosis of viral CNS infection as viral encephalitis (VE), viral meningitis (VM), viral meningoencephalitis (VME), viral encephalomyelitis (VEM), and viral meningomyelitis (VMM). RESULTS: A total of 42,641 cases of viral CNS infections were included in the database, consisting of 39,279 cases with VE (92.47%), 2011 cases with VM (4.73%), 1189 cases with VME (2.80%), 118 cases with VEM (0.28%), and 44 cases with VMM (0.10%). The number of hospitalized patients with viral CNS infections accounted for 0.74% (42,641 of 5,790,910) of all hospitalized cases. The onset of viral CNS infections presented seasonal characteristic, with peaks in June to July and December to January. Seizures are the most frequent complication of this disorder. Median length of stay and inpatient expenditures for patients with viral CNS infections were 9 days and 1144.36 USD. Causative viruses were identified in 4.33% (1848 of 42,641) of patients. CONCLUSIONS: This study will help understand the clinical epidemiology and disease burden of hospitalized children with viral CNS infections in China.

Early clinical features of new-onset refractory status epilepticus (NORSE) in adults.

BACKGROUND: The aim of this study was to identify early clinical features of patients with new-onset refractory status epilepticus (NORSE) that could direct the treatment in the first days of hospitalisation. METHODS: A retrospective cohort study of adult NORSE patients treated in the intensive care units of Helsinki University Hospital 2007-2018. RESULTS: We found 19 adult NORSE patients who divided into three subgroups on the basis of their clinical features: viral encephalitis (n = 5, 26%), febrile infection-related epilepsy syndrome (FIRES) (n = 6, 32%) and afebrile NORSE (n = 8, 42%). FIRES and afebrile NORSE patients remained without confirmed etiology, but retrospectively two paraneoplastic and two neurodegenerative causes were suspected in the afebrile NORSE group. Viral encephalitis patients were median 64 years old (IQR 55-64), and four (80%) had prodromal fever and abnormal findings in the first brain imaging. FIRES patients were median 21 years old (IQR 19-24), all febrile and had normal brain imaging at onset. In the afebrile NORSE group, median age was 67 (IQR 59-71) and 50% had prodromal cognitive or psychiatric symptoms. FIRES patients differed from other NORSE patients by younger age (p = 0.001), respiratory prodromal symptoms (p = 0.004), normal brain MRI (p = 0.044) and lack of comorbidities (p = 0.011). They needed more antiseizure medications (p = 0.001) and anesthetics (p = 0.002), had a longer hospital stay (p = 0.017) and more complications (p < 0.001). CONCLUSIONS: Among febrile NORSE patients, FIRES group was distinctive due to patients' young age, prodromal respiratory symptoms and normal first brain imaging. These features should be confirmed by subsequent studies as basis for selecting patients for early intensive immunotherapy.

Common infectious and parasitic diseases as a cause of seizures: geographic distribution and contribution to the burden of epilepsy

This educational review article aims to provide information on the central nervous system (CNS) infectious and parasitic diseases that frequently cause seizures and acquired epilepsy in the developing world. We explain the difficulties in defining acute symptomatic seizures, which are common in patients with meningitis, viral encephalitis, malaria, and neurocysticercosis, most of which are associated with increased mortality and morbidity, including subsequent epilepsy. Geographic location determines the common causes of infectious and parasitic diseases in a particular region. Management issues encompass prompt treatment of acute symptomatic seizures and the underlying CNS infection, correction of associated predisposing factors, and decisions regarding the appropriate choice and duration of antiseizure therapy. Although healthcare provider education, to recognize and diagnose seizures and epilepsy related to these diseases, is a feasible objective to save lives, prevention of CNS infections and infestations is the only definitive way forward to reduce the burden of epilepsy in developing countries.

Epstein-Barr virus encephalitis with excessive daytime sleepiness as the main manifestation: Two case reports.

RATIONALE: Excessive daytime sleepiness (EDS) is a clinical manifestation of various disorders. Here, we report 2 cases of EDS related to Epstein-Barr virus (EBV) encephalitis. PATIENT CONCERNS: Both the patients were elderly men. Case 1 presented with EDS with headache and fever. Case 2 was presented with EDS only. The 2 patients slept normally at night without taking sleeping pill. They were able to get up and go to the toilet and eat by themselves during the day, but they almost slept at other times. DIAGNOSIS: After admission, a lumbar puncture was performed to collect the cerebrospinal fluid, and next-generation sequencing showed that EBV infection was detected. Combined with the patient's head magnetic resonance imaging and clinical features, a diagnosis of EBV encephalitis was made. INTERVENTIONS: Both patients received antiviral therapy. OUTCOMES: Case 1 had a rapid improvement in headache and fever and was discharged from the hospital after the symptoms of EDS gradually improved. In case 2, EDS symptoms gradually improved. Two patients were followed up for 3 months after discharge, and the outcome was good. LESSONS: EDS can also be the main clinical manifestation of viral encephalitis, and we should diagnose and identify it early and treat it promptly.

Clinical Characteristics of Children With Anti-N-Methyl-d-Aspartate Receptor Encephalitis After Japanese Encephalitis.

BACKGROUND: Viral encephalitis is an important trigger for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. We analyzed the clinical characteristics of anti-NMDAR encephalitis after Japanese encephalitis (JE) in children. METHODS: Clinical data of 185 children with anti-NMDAR encephalitis were retrospectively reviewed. Patients with a history of viral encephalitis other than JE or who were identified with other autoantibodies were excluded. RESULTS: Twenty children with anti-NMDAR encephalitis after JE were enrolled with a median age of 6 years and 10 months (interquartile range [IQR]: 3 years to 11 years and 5 months). The median time from JE to anti-NMDAR encephalitis was 29 (IQR: 25 to 32) days. At 12 months, most patients (17 of 18) recovered to at least their baseline modified Rankin scale (mRS) scores caused by JE. One hundred forty two children with classical anti-NMDAR encephalitis were enrolled. Compared with classical anti-NMDAR encephalitis, patients after JE had significantly more decreased level of consciousness (50% vs 18.3%, P = 0.003), more autonomic dysfunction (30.0% vs 9.9%, P = 0.021), fewer psychiatric or behavioral symptoms (70.0% vs 90.8%, P = 0.016), fewer seizures (25.0% vs 68.3%, P < 0.001), lesser improvement 4 weeks after immunotherapy (35.0% vs 73.2%, P = 0.001), and worse outcomes at 12 months (median mRS: 1 vs 0, P < 0.001). CONCLUSIONS: Anti-NMDAR encephalitis after JE in children mainly occurred within two months. Their clinical manifestation may differ from classical anti-NMDAR encephalitis. The prognosis of children with anti-NMDAR encephalitis after JE probably depends on the neurological sequelae after JE.

Viral Parkinsonism: An underdiagnosed neurological complication of Dengue virus infection.

Dengue virus (DENV) is a flavivirus that is a significant cause of human disease costing billions of dollars per year in medical and mosquito control costs. It is estimated that up to 20% of DENV infections affect the brain. Incidence of DENV infections is increasing, which suggests more people are at risk of developing neurological complications. The most common neurological manifestations of DENV are encephalitis and encephalopathy, and movement disorders such as parkinsonism have been observed. Parkinsonism describes syndromes similar to Parkinson's Disease where tremors, stiffness, and slow movements are observed. Parkinsonism caused by viral infection is characterized by patients exhibiting at least two of the following symptoms: tremor, bradykinesia, rigidity, and postural instability. To investigate DENV-associated parkinsonism, case studies and reports of DENV-associated parkinsonism were obtained from peer-reviewed manuscripts and gray literature. Seven reports of clinically diagnosed DENV-associated parkinsonism and 15 cases of DENV encephalitis, where the patient met the case criteria for a diagnosis of viral parkinsonism were found. Clinically diagnosed DENV-associated parkinsonism patients were more likely to be male and exhibit expressionless face, speech problems, and lymphocytosis. Suspected patients were more likely to exhibit tremor, have thrombocytopenia and low hemoglobin. Viral parkinsonism can cause a permanent reduction in neurons with consequential cognitive and behavior changes, or it can leave a latent imprint in the brain that can cause neurological dysfunction decades after recovery. DENV-associated parkinsonism is underdiagnosed and better adherence to the case definition of viral parkinsonism is needed for proper management of potential sequalae especially if the patient has an ongoing or potential to develop a neurodegenerative disease.

Human Herpes Virus 6 Encephalitis Presenting as Fatal Refractory Status Epilepticus: a Case Report and Systematic Review.

PURPOSE: Encephalitis secondary to human herpesvirus 6 (HHV-6) infection is frequently encountered in immunocompromised patients; in contrast, HHV-6 encephalitis in immunocompetent patients is rare. There are only 3 reports of status epilepticus due to HHV-6 encephalitis in immunocompetent adults. In the present study, a case of refractory status epilepticus secondary to HHV-6 encephalitis was reported in an immunocompetent female. CASE REPORT: We report a case of a previously healthy 46-year-old female who presented with a one-week history of back pain, fever and generalized tonic-clonic seizures that progressed to status epilepticus. The video electroencephalography showed epileptiform discharges on both frontotemporal regions. Neuroimaging showed hyperintensities on the bilateral insula and temporal lobes. The cerebrospinal fluid showed elevated pressure and was positive for HHV-6. She was given ganciclovir and a total of eleven antiepileptic drugs. Despite these medications, she developed refractory status epilepticus and eventually succumbed due to multiple medical complications. CONCLUSION: This case highlights HHV-6 encephalitis as an important diagnostic consideration in patients presenting with refractory status epilepticus, regardless of immune status.

Clinical Features and Outcomes of Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Infants and Toddlers.

OBJECTIVE: We describe the clinical features and outcomes of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in infants and toddlers. METHODS: This was a single-center retrospective study. Infants and toddlers who met the diagnostic criteria for anti-NMDAR encephalitis were recruited for the study. Data on clinical features, treatment, and long-term outcomes were collected retrospectively. RESULTS: A total of 41 patients (age range: six to 34 months; median age: 23 months; female: 19) were enrolled in this study. Nineteen (46%) patients exhibited classical anti-NMDAR encephalitis, whereas 22 (54%) patients exhibited anti-NMDAR encephalitis after viral encephalitis. There was a high presentation of movement disorders (100%), developmental regression (90%), abnormal behaviors (90%). All patients were administered first-line therapy, with only 17% of them being administered second-line immunotherapy. Two patients succumbed to the disease, whereas none of them relapsed. At the long-term follow-up (more than one year), 20 of 35 (57%) exhibited satisfactory outcomes (modified Rankin Scale ≤2). Compared with patients with classical anti-NMDAR encephalitis (n = 18), patients after viral encephalitis (n = 17) were more likely to have worse clinical outcomes. They exhibited a higher modified Rankin Scale/Pediatric Cerebral Performance Category score and more frequent seizures. A predictor of poor outcome was presentation after viral encephalitis (odds ratio 35.7, 95% confidence interval 4.64 to 275.03, P = 0.001). CONCLUSION: Anti-NMDAR encephalitis in infants and toddlers clinically presents with movement disorders, developmental regression, and abnormal behaviors. Interestingly, this group had a higher proportion of patients after viral encephalitis, which is regarded as the only risk factor for poor outcomes.

Acute Necrotizing Encephalopathy as a Complication of Chikungunya Infection.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy seen commonly in children triggered by various prodromal viral infections, most common being influenza virus and Human herpes virus-6. OBJECTIVE: We report two rare cases of ANE preceded by Chikungunya infection. CASES: A 13-year old girl presented with a three-day history of headache, fever, seizures, and altered sensorium. Another 42-year old man presented with two days history of fever and altered sensorium. Both were suspected to have viral encephalitis. Evaluation revealed serum positivity for Chikungunya virus. In both cases, diagnosis was clinched by characteristic bilateral symmetrical thalamic lesions with central necrosis and hemorrhage along with lesions in cerebral white matter, brainstem, and cerebellum. CONCLUSIONS: ANE is reported to have high morbidity and mortality. To the best of our knowledge, this is the first report of ANE post-Chikungunya infection. Apart from being rare etiologically, the patients had excellent response to steroids.

Case Report: Epstein-Barr Virus Encephalitis Complicated With Brain Stem Hemorrhage in an Immune-Competent Adult.

Encephalitis caused by Epstein-Barr virus infection is uncommon, but most patients have a good outcome after symptomatic treatment. The infiltration of mononuclear cells in blood vessels and necrosis resulting from the immune response to Epstein-Barr virus infection in a very small number of patients seem to be the main cause of death. We describe a fatal case of Epstein-Barr virus encephalitis diagnosed by next-generation sequencing in an immune-competent adult but progressed to brainstem hemorrhage.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.