Background: There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking.
Objective: To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness.
Design: Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children.
Setting: Twenty-one NHS Hospitals in the UK.
Participants: Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis.
Intervention: Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment.
Main outcome measure: Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation.
Secondary outcomes: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data.
Results: We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period.
Conclusion: ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children.
Study limitations and future work: The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question.
Trial registration: This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925.
Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information.
Encephalitis (inflammation of the brain) is a serious but rare condition affecting approximately 5 in 100,000 children in England. Encephalitis can have a big impact on affected children and their families. Approximately 12 out of 100 affected children will die and half of those that survive experience varying difficulties in the long term; these might include problems with memory, physical disabilities, seizures and changes in how they think and behave.
There is some evidence that a treatment called intravenous immunoglobulin may benefit people affected by encephalitis. Intravenous immunoglobulin contains antibodies obtained from blood donations by different people, which is used to treat some types of inflammation. However, there have been no research studies investigating the effect of intravenous immunoglobulin when used in large numbers of children with all types of encephalitis. Furthermore, although intravenous immunoglobulin is sometimes used to treat children with encephalitis, it is often given after other treatments have been unsuccessful. Outcomes from encephalitis are determined largely by the amount of brain inflammation; it would therefore seem logical that giving a treatment early in the illness to limit the inflammation would be beneficial.
In the ImmunoglobuliN in the Treatment of Encephalitis study, we aimed to find out whether giving intravenous immunoglobulin to children with encephalitis early in the illness can help them get better more quickly and reduce the difficulties they experience later on. Half of the children in the trial received intravenous immunoglobulin and the other half received an inactive medicine, known as placebo, in addition to the normal care they would receive in a hospital. We aimed to compare the recovery and outcomes between children in these two groups.
This trial was stopped early due to withdrawal of funding, as fewer children than expected were enrolled into the study. Too few children were enrolled for us to be sure whether intravenous immunoglobulin benefits children with encephalitis. However, the trial findings highlight the impact of encephalitis on affected children, with around half of children demonstrating ongoing difficulties 1 year after the illness.
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