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 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

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

A population based observational study of childhood encephalitis in children admitted to pediatric intensive care units in England and Wales

BACKGROUND: Encephalitis is a serious neurologic condition which can result in admission to intensive care. Yet, there are no studies on pediatric intensive care unit (PICU) admission rates and usage of intensive care resources by children with encephalitis in England and Wales. The objectives of this study were to (i) define the PICU incidence and mortality rates for childhood encephalitis, (ii) describe usage of intensive care resources by children with encephalitis admitted to PICU, and (iii) explore the associated cost from PICU encephalitis admissions.METHODS: Retrospective analysis of anonymized data for 1031 children (0-17 years) with encephalitis admitted (January 2003 to December 2013) to PICU in England and Wales.RESULTS: The PICU encephalitis incidence was 0.79/100,000 population/year (95%CI 0.74-0.84), which gives an annual total of 214 bed days of intensive care occupancy for children admitted with encephalitis and an estimated annual PICU bed cost of £414,230 (IQR 198,111-882,495) for this cohort. PICU encephalitis admissions increased during the study period (annual percentage change = 4.5%, 95%CI 2.43%-6.50%, p=&lt;0.0001). In total, 808/1024 (78.9%) received invasive ventilation while 216/983 (22.0%) and 50/890 (5.6%) cases received vasoactive treatment and renal support, respectively. There were 87 deaths (8.4%), giving a PICU encephalitis mortality rate of 0.07 /100,000 population (0-17 years)/year (95%CI 0.05-0.08).CONCLUSIONS: These data suggest that encephalitis places a significant burden to the healthcare service. More work is needed to improve outcomes for children with encephalitis.</p

30-year trends in admission rates for encephalitis in children in England and effect of improved diagnostics and measles-mumps-rubella vaccination : a population-based observational study

Background: Encephalitis is a serious neurological disorder, yet data on admission rates for all-cause childhood encephalitis in England are lacking. We aimed to estimate admission rates for childhood encephalitis in England over 33 years, to describe trends in admission rates and to observe how these have varied with the introduction of vaccines and improved diagnostics. Methods: A retrospective analysis of hospital admission statistics for encephalitis for individuals aged 0-19 years was conducted using the English national Hospital Inpatient Enquiry (HIPE, 1979 -1985) and Hospital Episode Statistics (HES, 1990 -2011). Annual age-specific and age standardised admission rates in single calendar years and admission rate trends for specified aetiologies in relation to introduction of polymerase chain reaction (PCR) testing and measles-mumps-rubella (MMR) vaccination. Results: There were 16571 encephalitis hospital admissions (average hospital admission rate (AR): 5·97/100,000/year (95%CI 5·06-6·82)). Hospital ARs declined from 1979-1994 (annual percentage change, APC, 3·30%; 2·88%-3·66%; p<0·0001) and increased between 1995 and 2011 (APC=3·30%; 2·75%-3·85%; p<0·0001). Admissions for measles and mumps encephalitis decreased by 35- and 60-fold respectively following the introduction of the two-dose MMR vaccine. Hospital ARs for encephalitis of unknown aetiology have increased post-PCR. Interpretation: Hospital admission rates for all-cause childhood encephalitis in England are increasing. Admissions for measles and mumps encephalitis have decreased substantially. The numbers of encephalitis admissions without a specific diagnosis are increasing despite availability of PCR testing, indicating the need for strategies to improve aetiological diagnosis in children with encephalitis.Medicine, Faculty ofNon UBCPediatrics, Department ofReviewedFacultyGraduat

Mycotic aneurysm presenting as hip pain and severe anaemia

A 15-year-old boy with trisomy 21, moderate left atrioventricular (AV) valve regurgitation and a previously repaired AV septal defect developed Aerococcus urinae infective endocarditis. The infected left AV valve and surrounding tissue were surgically removed and replaced with a prosthetic mitral valve; this was followed by 6 weeks of intravenous antibiotics. Towards the end of his antibiotic course, his C reactive protein level began to rise, and he subsequently developed worsening hip pain and severe anaemia (Hb 3.7 g/dL). An ultrasound scan showed no hip joint effusion but incidentally identified an aortic aneurysm, confirmed by an abdominopelvic MRI scan. CT angiogram showed a large (14 cm) false distal aortic aneurysm with surrounding retroperitoneal haematoma (see figure 1A). Emergency repair of the aneurysm with an aorto-bi-iliac graft was performed. A day later, he developed an ischaemic right leg. CT angiogram showed an occluded right external iliac artery (EIA) (see figure 1B) with reconstitution of the right common femoral artery via collaterals with flow to the foot. Emergency vascular surgery revealed chronic dissection occluding the right EIA origin and an open patch plasty was performed. The patient recovered well

"European Society of Clinical Microbiology and infectious Diseases Guidelines on diagnosis and treatment of brain abscess in children and adults"

International audienc

Immunological effect of administration of sequential doses of Haemophilus influenzae type b and pneumococcal conjugate vaccines in the same versus alternating limbs in the routine infant immunisation schedule:an open-label randomised controlled trial

Background: the use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines.Methods: in this open-label, randomised, controlled study, eligible healthy infants 6–12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria–tetanus–acellular pertussis–inactived polio–Haemophilus influenzae type b combined vaccine (DTaP–IPV–Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP–IPV–Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib–MenC–TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518.Findings: between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 ?g/mL [95% CI 0·31–0·54] vs alternating limb 0·61 ?g/mL [0·45–0·82]; p=0·0268) and at 12 months (0·35 ?g/mL [0·28–0·43] vs 0·50 ?g/mL [0·40–0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40–1·90]) than in the alternating limb group (2·30 IU/mL [1·97–2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37–0·52] vs 0·61 IU/mL [0·51–0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups.Interpretation: use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further researc