Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis

Purpose Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. Methods We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA–), and effector memory (CCR7– CD45RA–) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. Results The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Conclusion Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Objective: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness. // Design: Phase 3b multicentre, double-blind, randomised placebo-controlled trial. // Setting: Twenty-one hospitals in the UK. // Participants: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308. // Intervention: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment. // Main outcome measure: The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended. // Secondary outcome measures: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data. // Results: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG. // Conclusions: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis. // Trial registration number: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925

Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT

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

Childhood encephalitis in the United Kingdom - epidemiology, trends in hospital admissions and the role of intravenous immunoglobulin

The burden from childhood encephalitis is significant, 30-60% of affected children develop long term disability despite treatment. Crucial to improving outcomes are a better understanding of the disease epidemiology, and the identification of alternative treatment strategies. To contribute to ongoing work currently addressing these issues globally, I conducted a 30-year review of childhood encephalitis hospital admissions in England, and also a 10- year review of paediatric intensive care unit (PICU) admissions in England and Wales (E&amp;W;). Through these projects, I defined the incidence of all-cause childhood encephalitis in England, and severe encephalitis in E&amp;W.; I described hospital admission trends for childhood encephalitis in England, and evaluated how these had varied with introduction of the combined measles, mumps, rubella vaccine. Furthermore, I estimated the potential cost burden from encephalitis PICU admissions, and identified factors associated with mortality and length of stay on PICU in children with severe encephalitis. This thesis provides high quality data from a Cochrane systematic review on the role of intravenous immunoglobulin (IVIG) treatment in childhood encephalitis, and describes the initiation of the first ever randomised controlled trial (RCT) of IVIG all-cause childhood encephalitis (IgNITE). The incidence for all-cause childhood encephalitis in England was between 2.91/100,000/year (95%CI 2.80-3.14) and 4.02/100,000/year (3.80-4.28), and the incidence of severe childhood encephalitis in E&amp;W; was 0.79/100,000/year (0.74-0.84). An increasing trend in encephalitis admissions was observed between 1999-2011, compared to the previous years. This increase was most marked in infants, and mostly seen in the ‘encephalitis of unknown aetiology’ group. Measles and mumps encephalitis admissions reduced by 30-fold after the two dose MMR vaccination schedule was introduced, compared with the pre MMR period. The PICU encephalitis bed cost was ~£414,000/year. The Cochrane review revealed paucity of RCTs of IVIG in encephalitis. Although the findings indicated some benefit from IVIG, the quality of the evidence was very low. Accordingly, I initiated the first ever RCT of IVIG treatment in all-cause childhood encephalitis, which had recruited 18 participants from 21 sites. Data from an interim analysis of this cohort showed that 60% were admitted to PICU, and 89% required invasive ventilation. Also, 80% of affected children had persisting symptoms at hospital discharge, 67% made poor recovery at 4-8 weeks after hospital discharge while 42% and 30% made poor recovery at 6 and 12 months follow up, respectively. The increasing trend in childhood encephalitis admissions in the context of the ongoing threat from emerging and reemerging pathogens, indicates the need for continued disease surveillance. The findings of the systematic review rationalise the need for the IgNiTE study. The results of the interim analysis of data from the IgNiTE trial indicate the need to identify strategies to improve outcomes in children with encephalitis. It is anticipated that the IgNiTE trial would yield results that could alter the way that children with encephalitis are managed.</p

Childhood encephalitis in the United Kingdom - epidemiology, trends in hospital admissions and the role of intravenous immunoglobulin

The burden from childhood encephalitis is significant, 30-60% of affected children develop long term disability despite treatment. Crucial to improving outcomes are a better understanding of the disease epidemiology, and the identification of alternative treatment strategies. To contribute to ongoing work currently addressing these issues globally, I conducted a 30-year review of childhood encephalitis hospital admissions in England, and also a 10- year review of paediatric intensive care unit (PICU) admissions in England and Wales (E&W). Through these projects, I defined the incidence of all-cause childhood encephalitis in England, and severe encephalitis in E&W. I described hospital admission trends for childhood encephalitis in England, and evaluated how these had varied with introduction of the combined measles, mumps, rubella vaccine. Furthermore, I estimated the potential cost burden from encephalitis PICU admissions, and identified factors associated with mortality and length of stay on PICU in children with severe encephalitis. This thesis provides high quality data from a Cochrane systematic review on the role of intravenous immunoglobulin (IVIG) treatment in childhood encephalitis, and describes the initiation of the first ever randomised controlled trial (RCT) of IVIG all-cause childhood encephalitis (IgNITE). The incidence for all-cause childhood encephalitis in England was between 2.91/100,000/year (95%CI 2.80-3.14) and 4.02/100,000/year (3.80-4.28), and the incidence of severe childhood encephalitis in E&W was 0.79/100,000/year (0.74-0.84). An increasing trend in encephalitis admissions was observed between 1999-2011, compared to the previous years. This increase was most marked in infants, and mostly seen in the âencephalitis of unknown aetiologyâ group. Measles and mumps encephalitis admissions reduced by 30-fold after the two dose MMR vaccination schedule was introduced, compared with the pre MMR period. The PICU encephalitis bed cost was ~£414,000/year. The Cochrane review revealed paucity of RCTs of IVIG in encephalitis. Although the findings indicated some benefit from IVIG, the quality of the evidence was very low. Accordingly, I initiated the first ever RCT of IVIG treatment in all-cause childhood encephalitis, which had recruited 18 participants from 21 sites. Data from an interim analysis of this cohort showed that 60% were admitted to PICU, and 89% required invasive ventilation. Also, 80% of affected children had persisting symptoms at hospital discharge, 67% made poor recovery at 4-8 weeks after hospital discharge while 42% and 30% made poor recovery at 6 and 12 months follow up, respectively. The increasing trend in childhood encephalitis admissions in the context of the ongoing threat from emerging and reemerging pathogens, indicates the need for continued disease surveillance. The findings of the systematic review rationalise the need for the IgNiTE study. The results of the interim analysis of data from the IgNiTE trial indicate the need to identify strategies to improve outcomes in children with encephalitis. It is anticipated that the IgNiTE trial would yield results that could alter the way that children with encephalitis are managed.</p

Intravenous immunoglobulin for the treatment of childhood encephalitis

Background: Encephalitis is a syndrome of neurological dysfunction due to inflammation of the brain parenchyma, caused by an infection or an exaggerated host immune response, or both. Attenuation of brain inflammation through modulation of the immune response could improve patient outcomes. Biological agents such as immunoglobulin that have both anti-inflammatory and immunomodulatory properties may therefore be useful as adjunctive therapies for people with encephalitis.Objectives: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) as add-on treatment for children with encephalitis.Search methods: The Cochrane Multiple Sclerosis and Rare Diseases of the CNS group's Information Specialist searched the following databases up to 30 September 2016: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and the WHO ICTRP Search Portal. In addition, two review authors searched Science Citation Index Expanded (SCI-EXPANDED) &amp; Conference Proceedings Citation Index - Science (CPCI-S) (Web of Science Core Collection, Thomson Reuters) (1945 to January 2016), Global Health Library (Virtual Health Library), and Database of Abstracts of Reviews of Effects (DARE).Selection criteria: Randomised controlled trials (RCTs) comparing IVIG in addition to standard care versus standard care alone or placebo.Data collection and analysis: Two review authors independently selected articles for inclusion, extracted relevant data, and assessed quality of trials. We resolved disagreements by discussion among the review authors. Where possible, we contacted authors of included studies for additional information. We presented results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI).Main results: The search identified three RCTs with 138 participants. All three trials included only children with viral encephalitis, one of these included only children with Japanese encephalitis, a specific form of viral encephalitis. Only the trial of Japanese encephalitis (22 children) contributed to the primary outcome of this review and follow-up in that study was for three to six months after hospital discharge. There was no follow-up of participants in the other two studies. We identified one ongoing trial.For the primary outcomes, the results showed no significant difference between IVIG and placebo when used in the treatment of children with Japanese encephalitis: significant disability (RR 0.75, 95% CI 0.22 to 2.60; P = 0.65) and serious adverse events (RR 1.00, 95% CI 0.07 to 14.05; P = 1.00).For the secondary outcomes, the study of Japanese encephalitis showed no significant difference between IVIG and placebo when assessing significant disability at hospital discharge (RR 1.00, 95% CI 0.60 to 1.67). There was no significant difference (P = 0.53) in Glasgow Coma Score at discharge between IVIG (median score 14; range 3 to 15) and placebo (median 14 score; range 7 to 15) in the Japanese encephalitis study. The median length of hospital stay in the Japanese encephalitis study was similar for IVIG-treated (median 13 days; range 9 to 21) and placebo-treated (median 12 days; range 6 to 18) children (P = 0.59).Pooled analysis of the results of the other two studies resulted in a significantly lower mean length of hospital stay (MD -4.54 days, 95% CI -7.47 to -1.61; P = 0.002), time to resolution of fever (MD -0.97 days, 95% CI -1.25 to -0.69; P &lt; 0.00001), time to stop spasms (MD -1.49 days, 95% CI -1.97 to -1.01; P &lt; 0.00001), time to regain consciousness (MD -1.10 days, 95% CI -1.48 to -0.72; P &lt; 0.00001), and time to resolution of neuropathic symptoms (MD -3.20 days, 95% CI -3.34 to -3.06; P &lt; 0.00001) in favour of IVIG when compared with standard care.None of the included studies reported other outcomes of interest in this review including need for invasive ventilation, duration of invasive ventilation, cognitive impairment, poor adaptive functioning, quality of life, number of seizures, and new diagnosis of epilepsy. The quality of evidence was very low for all outcomes of this review.Authors' conclusions: The findings suggest a clinical benefit of adjunctive IVIG treatment for children with viral encephalitis for some clinical measures (i.e. mean length of hospital stay, time (days) to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. For children with Japanese encephalitis, IVIG had a similar effect to placebo when assessing significant disability and serious adverse events.Despite these findings, the risk of bias in the included studies and quality of the evidence make it impossible to reach any firm conclusions on the efficacy and safety of IVIG as add-on treatment for children with encephalitis. Furthermore, the included studies involved only children with viral encephalitis, therefore findings of this review cannot be generalised to all forms of encephalitis. Future well-designed RCTs are needed to assess the efficacy and safety of IVIG in the management of children with all forms of encephalitis. There is a need for internationally agreed core outcome measures for clinical trials in childhood encephalitis.</p