Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis
- Registration Number
- NCT03274375
- Lead Sponsor
- Assistance Publique - H么pitaux de Paris
- Brief Summary
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.
- Detailed Description
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).
To assess the efficacy of IA-therapy at long term, patients will have a standardized follow-up during two years including neuropsychological evaluation at 1 year and at 2 years (see below for further details).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 20
- 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
-
Autoimmune encephalitis without NMDAR antibodies
-
PCPCS and mRS scores under 4 after first-line therapy
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description IA session IA session * 4 Rituximab injections * 10 IA sessions IA session Rituximab * 4 Rituximab injections * 10 IA sessions
- Primary Outcome Measures
Name Time Method Change in Neurological status evaluated with the modified Rankin Scale (mRS) 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) before and after the 10 IA sessions, 28 days maximum at least reduction of 1 point in PCPCS between the two evaluations is expected
- Secondary Outcome Measures
Name Time Method CMS to assess memory 2 years Number of adsorbers used for each patient 28 days To assess tolerance of IA therapy
Biological evolution of NMDAR antibodies tested in CSF 28 days at diagnosis and after IA sessions
Duration of hospitalization in ICU and pediatric neurology unit 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Movement disorders assessment with video taping 6 months To assess Immunoadsorption therapy at long term
Proteinorachia 1 year titration at 1 year
Need for mechanical ventilation 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Need of hospitalization in ICU and pediatric neurology unit 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Movement disorders assessment with the Movement Disorder Childhood Scale 2 years To assess Immunoadsorption therapy at long term
Occurrence of hypotension with need for vasopressive treatment 28 days To assess tolerance of IA therapy
Total number of sessions 28 days To assess tolerance of IA therapy
Duration of hospitalization in functional rehabilitation unit 2 years To assess Immunoadsorption therapy at long term
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 Need for vasopressive treatment 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time of recovery of independent daily-life activities 28 days independent ambulation, enteral feeding, responsiveness to simple instructions and verbal communication (first word)
Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session 28 days To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Duration of each immunoadsorption treatment 28 days To assess tolerance of IA therapy
Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access) 28 days To assess tolerance of IA therapy
Adverse events of associated treatments 28 days To assess tolerance of IA therapy
PCPCS score at 2 years To assess Immunoadsorption therapy at long term
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 To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Biological evolution of NMDAR antibodies tested in serum 28 days before and after IA sessions
Duration of use of medication for sedation by pharmaceutical class 28 days to assess need of sedation
Total duration of the immunoadsorption therapy 28 days To assess tolerance of IA therapy
School attendance (special school or not) and rehabilitation attendance 2 years To assess Immunoadsorption therapy at long term
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 To assess Immunoadsorption therapy at long term
Presence of NMDAR antibodies in CSF 1 year titration at 1 year
Presence of oligoclonal bands in serum 6 months checked at 6 months
Presence of oligoclonal bands in CSF 1 year checked at 1 year
Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea 28 days To assess tolerance of IA therapy
mRS score at 2 years To assess Immunoadsorption therapy at long term
Presence of NMDAR antibodies in serum 1 year titration at 1 year
Need of hospitalization in functional rehabilitation unit 2 years To assess Immunoadsorption therapy at long term
Occurrence and date of relapses 2 years Number of lymphocytes in serum 1 year checked at 1 year
Number of lymphocytes in CSF 1 year checked at 1 year
Trial Locations
- Locations (1)
H么pital Necker Enfants-Malades
馃嚝馃嚪Paris, France