Age-related changes in the inflammatory responses to viral infections in the central nervous system during childhood.

BACKGROUND: The developmental stages and function of immune cells in the central nervous system during infancy and childhood are poorly understood. We analyzed whether cytokine and chemokine profiles in children and adolescents with viral central nervous system infections were different depending on age. METHODS: The acute phase cerebrospinal fluid of 80 children (mean age 98 months, range 1-206 months) were analyzed for protein levels of interleukin-1ß (IL-1ß), IL-1-RA, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, monocyte chemoattractant protein-1 (MCP-1), interferon (IFN) gamma-induced protein 10 (IP-10), IFN-γ, and macrophage migration inhibitory factor (MIF). RESULTS: We found an age-dependent increased expression of IL-4, IL-6, IL-13, MIF, IP-10, and IFN-γ and a decreased expression of MCP-1 and IL-15 in response to a viral infection of the central nervous system. In contrast, all other cytokines and chemokine were unaffected by the age of the patient. CONCLUSION: These findings demonstrate that the immunological response to a viral infection matures during childhood and adolescence. This may in turn be of importance for the outcome of a viral infection and the risk for subsequent sequela. It also demonstrates that age is a factor that needs to be considered when using cytokines and chemokines as biomarkers for infections in the central nervous system. IMPACT: The immunological response to a viral infection matures during childhood and adolescence. This may be of importance for the outcome of a viral infection and the risk for subsequent sequela. It also demonstrates that age is a factor that needs to be considered when using cytokines and chemokines as biomarkers for infections in the central nervous system.

Review of the aetiology, diagnostics and outcomes of childhood encephalitis from 1970 to 2009.

AIM: Encephalitis is a rare, serious condition, and antiviral therapies, increased knowledge of inflammatory pathways and improved diagnostics have increased the therapeutic possibilities. We describe 40 years of childhood encephalitis in Sweden, covering the diagnostics, aetiology and outcomes. METHODS: We reviewed the clinical data that were available for all children discharged from the Karolinska University Hospital in Stockholm following treatment for encephalitis from 1970 to 2009. The hospital treated all children in the region with the condition during the study period. RESULTS: There were 408 episodes of encephalitis from 1970 to 2009 and the incidence was similar over the whole period, ranging from 6.4 to 8.7 per 100 000 child years. Although mortality markedly decreased from 10% in the first decade to zero in the last decade, and aetiologies shifted, no clear long-term improvements in outcome were seen. The need for intensive care was unchanged (18-20%) for each of the study intervals, possibly indicating that the severity of cases remained unaltered. CONCLUSION: Understanding the pathophysiological mechanisms of encephalitis is vitally important for developing more efficient treatment regimens. As well as reporting the results of this 40-year study, this study considers possible explanations, addresses current therapeutic options and explores directions for central nervous system infection research.

Tick-borne encephalitis carries a high risk of incomplete recovery in children.

OBJECTIVE: To examine long-term outcome after tick-borne encephalitis (TBE) in children. STUDY DESIGN: In this population-based cohort, 55 children with TBE with central nervous system involvement infected during 2004-2008 were evaluated 2-7 years later using the Rivermead post-concussion symptoms questionnaire (n = 42) and the Behavior Rating Inventory of Executive Functioning for parents and teachers (n = 32, n = 22, respectively). General cognitive ability was investigated in a subgroup (n = 20) using the Wechsler Intelligence Scale for Children, 4th edition. RESULTS: At long-term follow-up, two-thirds of the children experienced residual problems, the main complaints being cognitive problems, headache, fatigue, and irritability. More than one-third of the children were reported by parents or teachers to have problems with executive functioning on the Behavior Rating Inventory of Executive Functioning, mainly in areas involving initiating and organizing activities and working memory. Children who underwent Wechsler Intelligence Scale for Children, 4th edition testing had a significantly lower working memory index compared with reference norms. CONCLUSION: A large proportion of children experience an incomplete recovery after TBE with central nervous system involvement. Cognitive problems in areas of executive function and working memory are the most prevalent. Even if mortality and severe sequelae are low in children after TBE, all children should be followed after TBE to detect cognitive deficits.

Neurocognitive outcome in children and adolescents following infectious encephalitis.

Infectious encephalitis in children is fairly uncommon, but unfavorable outcomes are seen in many survivors. The aim of this study was to prospectively describe the long-term neurocognitive consequences following infectious encephalitis in childhood. Children admitted to a primary and tertiary hospital in Sweden between 2011 and 2016 were asked to participate. Fifty-nine children were assessed at a median time of 18 months (IQR 18-20) after hospitalization. Follow-up included measures of intellectual functioning, attention, working memory, and executive functions. Caregiver ratings of executive functioning and behavioral - emotional symptoms were assessed with standardized questionnaires. Neurocognitive outcome and measures of executive functions and behavioral-emotional symptoms varied greatly among participants. Basic auditory attention, working memory, and mental processing speed were affected and significantly lower compared to a standardized mean. Other domains identified as areas of vulnerability included executive functions, sustained attention, and the exert of self-control. Behavioral-emotional symptoms were less common; however, somatic complaints and behaviors related to conduct problems were seen in about one-third of individuals. This study highlights the importance of a comprehensive neurocognitive examination to identify children with unfavorable outcomes.

Post-encephalitic epilepsy in childhood: results from a prospective cohort study.

To investigate whether it is possible to predict outcome of post-encephalitic epilepsy based on findings during the acute phase of disease. Children (28 days to 17 years) diagnosed with acute encephalitis at Karolinska University Hospital between 2011 and 2016 were included in this study (n=89). They were examined clinically, with repeated electroencephalographic examinations and analysis of cerebrospinal fluid during the acute illness. Thereafter, patients were followed up to 24 months and evaluated for post-encephalitic epilepsy. Variables determined during the acute illness were used to predict the development of post-encephalitic epilepsy: electroencephalographic parameters, cerebrospinal fluid parameters, aetiology and clinical parameters. Fisher's exact test was used to estimate any predictors of epilepsy among the acutely measured parameters. The prevalence of post-encephalitic epilepsy was 9% (n=8) at 24 months. Of these, 3/8 responded to monotherapy with antiepileptic drugs and 5/8 required two or more and 3/8 were medically refractory at 24 months. Presence of acute seizures during admission, epileptic activity on electroencephalographic recordings and new-onset structural lesions demonstrated a significant association with development of post-encephalitic epilepsy (p<0.03) with an odds ratio greater than 5. Using the three above-mentioned parameters, we designed an algorithm to predict cohorts of patients with increased risk of developing post-encephalitic epilepsy. Moreover, patients who developed post-encephalitic epilepsy had a longer duration of hospital admission and longer care in intensive care units in comparison to those who did not. This study demonstrates that the risk of developing post-encephalitic epilepsy was mainly seen among patients with acute seizures, epileptic encephalographic activity in the acute setting or new-onset structural lesions. A simple algorithm could be used to predict the risk of post-encephalitic epilepsy.

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis.

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions.

The Cerebrospinal Fluid Interleukin-6/Interleukin-10 Ratio Differentiates Pediatric Tick-borne Infections.

BACKGROUND: Borrelia burgdorferi and tick-borne encephalitis (TBE) virus are 2 types of tick-borne pathogens that can cause central nervous system infection. Routine diagnostics have so far included analysis of cerebrospinal fluid (CSF) cell numbers, CSF serology for Borrelia burgdorferi and serum serology for TBE virus. However, early diagnosis may be difficult based on antibody detection which takes time to analyze, and with the possibility of false negative results, thus delaying treatment. Cytokine analyses are becoming increasingly available in clinical routine care and may offer important information. METHODS: Fifteen cytokines and chemokines were measured in the CSF from the diagnostic lumbar puncture of 37 children with TBE, 34 children with neuroborreliosis and 19 children without evidence of central nervous system infection, using Luminex technology. RESULTS: Significantly higher levels of proinflammatory interleukin-6 were detected in the samples from TBE-infected children, when compared with neuroborreliosis or controls. In comparison, children with neuroborreliosis had significantly higher levels of interleukin-7, interleukin-8, interleukin-10, and interleukin-13 when compared with TBE infected or controls. Furthermore, the ratio between interleukin-6 and interleukin-10 was significantly different between the 2 types of tick-borne infections. CONCLUSIONS: The interleukin-6/interleukin-10 ratio can be used as a rapid diagnostic cue upon suspected tick-borne infection, enabling fast and correct treatment. Also, in serology-negative results, such information may strengthen a clinical suspicion.

Prospective Evaluation of Childhood Encephalitis: Predisposing Factors, Prevention and Outcome.

BACKGROUND: Acute encephalitis in childhood is a serious condition. The severity varies between studies, partly reflecting differences in study design where only severe cases from referral centers often are reported. The aim of this study was to prospectively study the clinical picture and etiology of acute encephalitis in childhood at a primary and tertiary pediatric hospital in Sweden. METHODS: All children with acute encephalitis were prospectively included from 2011 to 2016. Laboratory tests, investigations and follow-up were performed according to standardized study protocols. RESULTS: Eighty-nine children were included (46 female and 43 male) with a median age of 53 months. An etiology was established in 61/89. Tick-borne encephalitis virus, enterovirus and rotavirus dominated and 34% were caused by a virus preventable by vaccination. Immune-mediated encephalitis was seen in 7 children. An abnormal electroencephalography picture was seen in 77/86, pathologic findings on neuroimaging in 13/49, and 38/89 children had seizures. Sequelae were reported by 49%. A high prevalence of previous contact with child and adolescent psychiatry was seen and, although not statistically significant, the need for extra support at school before encephalitis and the presence of central nervous system disease in the family seemed to predispose for a longer hospital stay. CONCLUSION: Encephalitis is a condition with long-term consequences. Most children need admission to hospital, and many need surveillance in the intensive care unit. The etiology can be determined in a majority of cases, and 1/3 could have been prevented by vaccination. This study corroborates electroencephalography as a cornerstone in diagnosis.

Ophthalmological findings in children with encephalitis.

PURPOSE: To evaluate ophthalmological abnormalities in children with acute encephalitis. METHODS: Thirty-six children included in a hospital-based prospectively and consecutively collected cohort of children with acute encephalitis were investigated for ophthalmological abnormalities. The investigation included clinical ophthalmological examination, fundus photography, neuro-ophthalmological examinations as well as visual and stereo acuity. Results on laboratory examinations, clinical findings, neuroimaging and electroencephalography registrations were recorded for all children. RESULTS: The median age was 4.0 years (Interquartile Range 1.9-9.8). The aetiology was identified in 74% of cases. Three of 36 patients were found to have abnormal ophthalmological findings related to the encephalitis. Transient sixth nerve palsy was seen in a 15-year-old child and transient visual impairment was seen in a 3.5-year-old child. Bilateral miosis and ptosis, i.e. autonomic nerve system symptoms, were seen in an 11-month-old child, with herpes simplex 1 and N-methyl-d-aspartate receptor antibody encephalitis. All three children recovered and improved their ophthalmological function with time. CONCLUSION: Only 3 of 36 children were found to have ophthalmological abnormalities due to encephalitis and they all improved with time. Thus, ophthalmological consultation does not seem to fit in a screening programme for childhood encephalitis but should be considered in selected cases.

Cytokine and Chemokine Expression in CSF May Differentiate Viral and Autoimmune NMDAR Encephalitis in Children.

Childhood encephalitis is a potentially devastating condition with significant morbidity and mortality. Researchers currently lack biomarkers for differentiating infectious encephalitis from those with autoimmune causes which may delay adequate treatment. The authors studied the possibility of using cerebrospinal fluid cytokine and chemokine levels for this purpose. Children admitted to hospital care fulfilling criteria for encephalitis were prospectively included. Children who underwent lumbar puncture but were not classified as central nervous system infections served as controls. Cytokine and chemokine levels in the cerebrospinal fluid obtained upon initial presentation were analyzed using Luminex technology. In children with infectious encephalitis (n = 13), the cerebrospinal fluid displayed markedly elevated mean levels of IL6, IL7, and IL13 as compared to N-methyl-D-aspartate receptor (NMDAR) encephalitis (n = 4) and controls (n = 13). The expression of IL6 appeared to precede that of IL13. Analysis of selected cerebrospinal fluid cytokines may thus allow differential diagnosis of infectious and NMDAR encephalitis already at the initial lumbar puncture and enable immediate therapy.

Biomarkers in Cerebrospinal Fluid of Children With Tick-borne Encephalitis: Association With Long-term Outcome.

BACKGROUND: Tick-borne encephalitis (TBE) is a major cause of meningoencephalitis in children in endemic areas, and long-term residual problems are not uncommon. Currently, no predictive markers in the acute phase are available that identify children at risk of incomplete recovery. We measured cytokines, chemokines and markers of neuronal damage in cerebrospinal fluid (CSF) in children with TBE and central nervous system (CNS) involvement. METHODS: CSF from 37 children with TBE with CNS involvement was analyzed. Concentrations of 16 cytokines, chemokines and 5 markers of neuronal damage were assessed in CSF, using a multiplex assay, and correlated with clinical findings in the acute phase (n = 37), and with long-term outcome (n=22). RESULTS: Significantly higher levels of CSF interferon (IFN)-γ, interleukin (IL)-4, IL-6 and IL-8 were detected in the acute phase from children who later developed sequelae. Although most of the studied markers of neuronal damage displayed no significant differences between children with sequelae and those with good outcome, neuron-specific enolase correlated inversely. The grade of CSF pleocytosis correlated positively with the levels of IFN-γ, IL-4 and IL-6; however, pleocytosis alone did not predict sequelae. Increasing age correlated positively with IL-4, IL-6 and IL-8 values. CONCLUSIONS: The mechanism underlying the CNS pathology causing sequelae in TBE appears related to the grade of inflammation in CNS, rather than to direct neuronal destruction. High concentration of IFN-γ, IL-4, IL-6 and IL-8 in CSF might indicate a risk for incomplete recovery in childhood TBE.

Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse.

Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15-20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.

Long-term outcomes of acute encephalitis in childhood.

OBJECTIVES: The aims of this study were to investigate the long-term outcomes of childhood encephalitis and to examine possible prognostic factors. METHODS: Of 93 children who were treated for acute encephalitis in 2000-2004, 71 were eligible for follow-up evaluations. A structured interview, using 2 questionnaires, was conducted with the parents. Fifteen of the children with the most-severe symptoms at the time of discharge also underwent electroencephalographic recording and tests of reaction times and working memory. RESULTS: Persisting symptoms were reported by 54% of children. The predominant symptoms were personality changes and cognitive problems. Children who made a complete recovery did so within 6 to 12 months. The only significant risk factor for sequelae was disease severity leading to admission to the ICU. The risk of subsequent epilepsy was increased for children with seizures at presentation. Most follow-up electroencephalograms showed improvement, but results had not normalized for 9 of 15 children. Children with encephalitis had slower reaction times, compared with control subjects, but no difference in working memory could be seen. CONCLUSION: Persisting symptoms after childhood encephalitis were present for a substantial number of children. Seizures increased the risk of subsequent epilepsy; the only other prognostic marker was admission to the ICU. Even children who were considered fully recovered at discharge reported persisting symptoms at follow-up evaluations. Children who made a full recovery did so within 6 to 12 months, which suggests that all children with encephalitis should be monitored for 1 year after the acute illness.