Acute encephalitis in childhood : clinical characteristics and outcome with special reference to tick-borne encephalitis

Acute encephalitis is relatively uncommon but potentially devastating. The prognosis varies from complete recovery to severe sequelae or death. The diagnosis is difficult to establish and the etiology often remains unclear. Furthermore, the long-term prognosis of acute encephalitis in children is poorly described and prognostic markers in the acute phase are lacking. In this thesis, the aim was to characterize acute encephalitis in childhood in regard to etiology, clinical presentation and long-term outcome. Another aim was to study biomarkers in CSF of children with TBE and to identify markers predicting the long-term outcome.

Methods: We retrospectively studied the medical records of all children with acute encephalitis at Astrid Lindgren Children´s hospital in Stockholm during 2000–2004 (study I). This cohort was followed-up 3-8 years later using 2 questionnaires grading persisting symptoms and every day functioning. Seventy-one children were eligible for the follow-up (study II). In study III, 55 children with TBE in 2004-2008 were evaluated 2-7 years later. Two questionnaires were used grading persisting symptoms and executive functioning in everyday life. General cognitive ability was also investigated in a subgroup, using WISC-IV. In study IV, cytokines, chemokines and markers of neuronal damage were analyzed in CSF samples from 37 children with TBE in 2004-2010, using a multiplex assay.

Results: The etiology of childhood encephalitis was dominated by TBE, EV, VZV, influenza virus and RSV, but remained unknown in 52% of cases. Fever and encephalopathy were present in a majority of the children, seizures or focal neurological deficits were seen in 40%. EEG-examinations were pathological in 90%, and 55% of the children with acute encephalitis had pleocytosis. There were no mortalities, but 60% of the children had persisting symptoms at the time of discharge. In the long-term follow-up, persisting symptoms were reported by 54%, both in children with and without symptoms at discharge. Cognitive problems and personality changes were the dominating complaints. No other prognostic marker than the severity of the encephalitis leading to admission to the PICU was found. All children with encephalitis who made a full recovery did so within 6 to 12 months. In the acute phase of TBE, fever and headache were present in nearly all children, whereas seizures and focal neurological findings were less frequently seen. Nearly half of the children with TBE were classified as meningitis and the clinical picture were in these cases often unspecific and symptoms of CNS involvement vague. All children with TBE had pleocytosis. At follow-up, 69% experienced persistent problems; headache, fatigue and cognitive problems dominated. On more detailed tests of cognitive functions, problems with working memory and executive functioning were seen both in children with mild and with severe symptoms in the acute phase. In TBE, children with problems at follow-up had significantly higher levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF than children with a good outcome. Markers of neuronal damage did not discriminate between children with good or poor outcome.

Conclusion: We conclude that the etiology of encephalitis among Swedish children is at large the same as in other European countries endemic for TBE. EEG examination and analysis of CSF are essential for diagnosing CNS involvement, especially since CNS symptoms may be vague. Persisting symptoms were present in a substantial number of children at long-term follow-up, cognitive problems, headache, personality changes and fatigue dominated. The clinical picture in the acute phase cannot be used to predict outcome. In TBE, high levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF might indicate a risk of incomplete recovery. All children with acute encephalitis or TBE should be offered follow-up evaluations in order to detect long-term sequelae.

List of scientific papers

I. Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008; 12(6):484-490.
https://doi.org/10.1016/j.ejpn.2007.12.009

II. Fowler A, Stodberg T, Eriksson M, Wickstrom R. Long-term outcomes of acute encephalitis in childhood. Pediatrics. 2010; 126: e828-35.
https://doi.org/10.1542/peds.2009-3188

III. Fowler A, Forsman L, Eriksson M, Wickstrom R. Tick-borne encephalitis carries a high risk of incomplete recovery in children. J Pediatr. 2013; 163(2):555-60.
https://doi.org/10.1016/j.jpeds.2013.01.037

IV. Fowler A, Ygberg S, Bogdanovic G, Wickstrom R. Biomarkers in CSF in children with TBE – association with long-term outcome. [Manuscript]