I mmuno g lobuli N i n the T reatment of E ncephalitis (IgNiTE): protocol for a multicentre randomised controlled trial

Abstract

IntroductionInfectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis.Methods and analysis308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is ‘good recovery’ (score of 2 or lower on the Glasgow Outcome Score Extended—paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4–6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed.Ethics and disseminationThis trial has been approved by the UK National Research Ethics committee (South Central—Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals.Trial registration numbersNCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.

Herpes simplex virus infection, Acyclovir and IVIG treatment all independently cause gut dysbiosis

“…We also explored the effects of IVIG treatment alone and in combination with ACV in HSV-infected and uninfected mice, because IVIG has been used to treat HSV encephalitis (HSE) and is also a frontline therapy for autoimmune encephalitis, which is triggered by HSE and other insults [ 58 – 60 ]. Moreover, IVIG is being evaluated in a randomized control trial for children with all-cause encephalitis to determine whether neurological outcomes are improved, compared to standard antiviral therapy alone, which is similar to our behavioral study that generated paradoxical results [ 15 , 61 ]. Reports that IVIG’s antigenic repertoire includes reactivities to a variety of gut commensal antigens and metabolites have increased recently [ 62 – 64 ], which is consistent with a report that gut commensals can somehow trigger systemic IgG responses under homeostatic conditions that protect against systemic infection [ 65 , 66 ].…”

Effectiveness of Intravenous Immunoglobulin Therapy for Pediatric Viral Encephalitis

“…Although IVIg has been used off-label for the treatment of encephalitis caused by enterovirus 71, Japanese encephalitis virus, and West Nile virus, there is a lack of clinical studies on the efficacy and safe-ty of IVIg for viral encephalitis [25][26][27]. Since 2015, the first randomized controlled trial, has been conducted to evaluate the effect of IVIg treatment in pediatric encephalitis of any cause [28]. This clinical trial included 308 children (6 months to 16 years) across 30 hospitals in the United Kingdom.…”

Functional Recovery in Autoimmune Encephalitis: A Prospective Observational Study

“…A small randomized trial has shown superiority of intravenous immunoglobulins (IVIG) to placebo in reducing seizure frequency in anti-leucine-rich, glioma-inactivated 1-antibody (anti-LGI1-Ab) and anti-contactin-associated protein-like 2antibody (anti-CASPR2-Ab) seropositive adult patients (7). Other randomized trials evaluating the efficacy of IVIG, rituximab and bortezomib are ongoing (8)(9)(10). We have set up a multicenter prospective observational study for a structured assessment of diagnostics and treatments applied in clinical routine in adult patients with autoimmune encephalitis.…”