Prospective Assessment of Efficacy of Immunoadsorption Therapy in Managing Childhood NMDA-Receptor (NMDAR) Antibodies Encephalitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Change in Neurological status evaluated with the modified Rankin Scale (mRS)
研究概览
简要总结
The purpose of the study is to assess the efficacy of immunoadsorption therapy (IA) on improving the neurological status of severe pediatric anti-NMDAR encephalitis patients.
详细描述
Anti-NMDA-Receptor (NMDAR) encephalitis, the most frequent autoimmune encephalitis after Acute Demyelinating encephalomyelitis (ADEM), affects children with predominant movement disorders, decline of consciousness, psychiatric symptoms, language dysfunction, seizures, dysautonomic symptoms. The cerebrospinal fluid (CSF) is most often abnormal with lymphocytic pleocytosis, CSF-specific oligoclonal bands with intrathecal synthesis of anti-NMDAR antibodies. Antibody titres in CSF and serum seem correlated with clinical outcome. Early start of immunotherapy has been reported to improve clinical outcome and associated with less relapses. In a recent large series (211 children/577), 77% of the patients were admitted to Intensive Care Unit (ICU) at the beginning. Within the group of children, first-line immunotherapy (95%) consisted of corticosteroids (89%), and/or intravenous immunoglobulins (IgIV) (83%), and/or plasma exchange (28%) with failure in 46%. The second-line immunotherapy consisting in rituximab (24%) and/or cyclophosphamide (16%) was proposed in 32%, and tended to be associated with good outcome (OR=3.35, CI: 0.86-12.98, p=0.081 for 53 children; statistical significance was achieved for the entire population including adults (OR: 2.69, CI: 1.24-5.80, p = 0.012) and less relapses.
In investigators' experience, the clinical benefit of rituximab is delayed over one month, while children go on worsening (50% admitted in ICU) thus claiming for faster removal of the antibodies. Plasma exchange is proposed in most of the series as alternative or combined treatment in the acute stage (first-line immunotherapy); recently, another plasmatherapy, immunoadsorption therapy (IA), has been reported as an efficient therapeutic approach in 11/13 patients. In this retrospective study, patients received a median of 6 IA sessions within a median period of 8 days with relevant clinical improvement. However these encouraging results and investigators' experience in few children need further prospective and standardized evaluation.
In IANMDAR study, each patient will receive 10 IA sessions during 28 days maximum. Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days):
- at least 1 day before each IA session
- the 4 injections should be done before V2 (Day 28 after the inclusion)
To assess the efficacy of IA-therapy at short term, the neurological status of patients will be evaluated before and after the 10 IA sessions using the Pediatric Cerebral Performance Category Scale (PCPCS) and the modified Rankin Scale (mRS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 0-18 years inclusive
- •Autoimmune encephalitis with positive anti-NMDAR antibodies in CSF (definite anti-NMDAR encephalitis according to Graus's criteria (Graus et al., 2016).
- •PCPCS and mRS at 4 or over at the inclusion after first line therapy (steroids and/or IgIV) when Rituximab therapy is warranted
- •Parents or legal guardians signed the Informed consent form
- •Social insurance affiliation
排除标准
- •Autoimmune encephalitis without NMDAR antibodies
- •PCPCS and mRS scores ≥ 3 before first symptoms
- •Contraindication to perform central vascular access
- •Pregnancy, breastfeeding or absence of effective contraception (including abstinence) in a pubertal patient.
- •Contraindication to perform IA therapy :
- •Clinical conditions that prohibit transitory volume changes
- •Indications that prohibit anticoagulation using Heparin and/or ACD-A solutions
- •History of hypercoagulability
- •Generalized viral, bacterial and/or mycotic infections
- •Severe immune deficiencies (e.g. AIDS)
- •Suspected allergies against sheep antibodies or agarose
研究组 & 干预措施
IA session
- 4 Rituximab injections
- 10 IA sessions
干预措施: IA session (Drug)
IA session
- 4 Rituximab injections
- 10 IA sessions
干预措施: Rituximab (Drug)
结局指标
主要结局
Change in Neurological status evaluated with the modified Rankin Scale (mRS)
时间窗: before and after the 10 IA sessions, 28 days maximum
at least reduction of 1 point in mRS between the two evaluations is expected
Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)
时间窗: before and after the 10 IA sessions, 28 days maximum
at least reduction of 1 point in PCPCS between the two evaluations is expected
次要结局
- Biological evolution of NMDAR antibodies tested in CSF(28 days)
- Duration of hospitalization in ICU and pediatric neurology unit(28 days)
- Need for mechanical ventilation(28 days)
- Need of hospitalization in ICU and pediatric neurology unit(28 days)
- Occurrence of hypotension with need for vasopressive treatment(28 days)
- Total number of sessions(28 days)
- Number of adsorbers used for each patient(28 days)
- Duration of hospitalization in functional rehabilitation unit(2 years)
- Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)(at 2 years)
- Rey's figure test to evaluate visuospatial abilities and memory(2 years)
- Digit span to assess memory(2 years)
- Movement disorders assessment with the Movement Disorder Childhood Scale(2 years)
- Movement disorders assessment with video taping(6 months)
- Proteinorachia(1 year)
- Need for vasopressive treatment(28 days)
- Time of recovery of independent daily-life activities(28 days)
- Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy(28 days)
- Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session(28 days)
- Duration of each immunoadsorption treatment(28 days)
- Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)(28 days)
- Adverse events of associated treatments(28 days)
- PCPCS score(at 2 years)
- Neuropsychological assessment for cognitive and behavioral status with Wechsler scales(at 2 years)
- Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)(at 2 years)
- Visual attention evaluated with NEPSY scale(at 2 years)
- Name and duration of medication for behavioral disorders and sleep disorders(28 days)
- Biological evolution of NMDAR antibodies tested in serum(28 days)
- Duration of use of medication for sedation by pharmaceutical class(28 days)
- Total duration of the immunoadsorption therapy(28 days)
- School attendance (special school or not) and rehabilitation attendance(2 years)
- Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)(at 2 years)
- Movement disorders assessment with video-taping(at 2 years)
- Presence of NMDAR antibodies in CSF(1 year)
- Presence of oligoclonal bands in serum(6 months)
- Presence of oligoclonal bands in CSF(1 year)
- Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea(28 days)
- mRS score(at 2 years)
- CMS to assess memory(2 years)
- Presence of NMDAR antibodies in serum(1 year)
- Need of hospitalization in functional rehabilitation unit(2 years)
- Occurrence and date of relapses(2 years)
- Number of lymphocytes in serum(1 year)
- Number of lymphocytes in CSF(1 year)
- Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)(1 year)
- Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)(1 year)
- Visual attention evaluated with NEPSY scale(1 year)
- Rey's figure test to evaluate visuospatial abilities and memory(1 year)
- CMS to assess memory(1 year)
- Digit span to assess memory(1 year)
- Number of lymphocytes in serum(3 months)
- PCPCS score(3 months)
- mRS score(3 months)
- Number of lymphocytes in serum(6 months)
- PCPCS score(6 months)
- mRS score(6 months)
- PCPCS score(1 year)
- mRS score(1 year)
- Neuropsychological assessment for cognitive and behavioral status with Wechsler scales(1 year)
- Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)(1 year)
- Movement disorders assessment with the Movement Disorder Childhood Scale(3 months)
- Movement disorders assessment with video-taping(3 months)
- Movement disorders assessment with the Movement Disorder Childhood Scale(6 months)
- Movement disorders assessment with the Movement Disorder Childhood Scale(1 year)
- Movement disorders assessment with video-taping(1 year)
- Presence of NMDAR antibodies in CSF(6 months)
- Presence of NMDAR antibodies in serum(3 months)
- Presence of NMDAR antibodies in serum(6 months)
- Proteinorachia(6 months)
- Presence of oligoclonal bands in serum(1 year)
- Presence of oligoclonal bands in serum(3 months)
- Presence of oligoclonal bands in CSF(6 months)
- Number of lymphocytes in CSF(6 months)