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.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
10 IA sessions performed in 28 days maximum, using TherasorbTM adsorbers which contain sheep derived polyvalent antihuman-immunoglobulin coupled to SepharoseTM CL-4B.
Concomitantly, Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days): * at least 1 day before each IA session * the last injection will occur after the last session IA (minimum one day after)
Hôpital Necker Enfants-Malades
Paris, France
RECRUITINGChange in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)
at least reduction of 1 point in PCPCS between the two evaluations is expected
Time frame: before and after the 10 IA sessions, 28 days maximum
Change in Neurological status evaluated with the modified Rankin Scale (mRS)
at least reduction of 1 point in mRS between the two evaluations is expected
Time frame: before and after the 10 IA sessions, 28 days maximum
Need of hospitalization in ICU and pediatric neurology unit
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Duration of hospitalization in ICU and pediatric neurology unit
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Need for mechanical ventilation
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Need for vasopressive treatment
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Time of recovery of independent daily-life activities
independent ambulation, enteral feeding, responsiveness to simple instructions and verbal communication (first word)
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Time frame: 28 days
Name and duration of medication for behavioral disorders and sleep disorders
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Biological evolution of NMDAR antibodies tested in serum
before and after IA sessions
Time frame: 28 days
Biological evolution of NMDAR antibodies tested in CSF
at diagnosis and after IA sessions
Time frame: 28 days
Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
Time frame: 28 days
Duration of each immunoadsorption treatment
To assess tolerance of IA therapy
Time frame: 28 days
Duration of use of medication for sedation by pharmaceutical class
to assess need of sedation
Time frame: 28 days
Occurrence of hypotension with need for vasopressive treatment
To assess tolerance of IA therapy
Time frame: 28 days
Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea
To assess tolerance of IA therapy
Time frame: 28 days
Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)
To assess tolerance of IA therapy
Time frame: 28 days
Total duration of the immunoadsorption therapy
To assess tolerance of IA therapy
Time frame: 28 days
Total number of sessions
To assess tolerance of IA therapy
Time frame: 28 days
Number of adsorbers used for each patient
To assess tolerance of IA therapy
Time frame: 28 days
Adverse events of associated treatments
To assess tolerance of IA therapy
Time frame: 28 days
PCPCS score
To assess Immunoadsorption therapy at long term
Time frame: 3 months
mRS score
To assess Immunoadsorption therapy at long term
Time frame: 3 months
PCPCS score
To assess Immunoadsorption therapy at long term
Time frame: 6 months
mRS score
To assess Immunoadsorption therapy at long term
Time frame: 6 months
PCPCS score
To assess Immunoadsorption therapy at long term
Time frame: 1 year
PCPCS score
To assess Immunoadsorption therapy at long term
Time frame: at 2 years
mRS score
To assess Immunoadsorption therapy at long term
Time frame: 1 year
mRS score
To assess Immunoadsorption therapy at long term
Time frame: at 2 years
Need of hospitalization in functional rehabilitation unit
To assess Immunoadsorption therapy at long term
Time frame: 2 years
Duration of hospitalization in functional rehabilitation unit
To assess Immunoadsorption therapy at long term
Time frame: 2 years
School attendance (special school or not) and rehabilitation attendance
To assess Immunoadsorption therapy at long term
Time frame: 2 years
Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
Time frame: 1 year
Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
Time frame: at 2 years
Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
Time frame: 1 year
Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
Time frame: at 2 years
Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
Time frame: 1 year
Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
Time frame: at 2 years
Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
Time frame: 1 year
Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
Time frame: at 2 years
Visual attention evaluated with NEPSY scale
Time frame: 1 year
Visual attention evaluated with NEPSY scale
Time frame: at 2 years
Rey's figure test to evaluate visuospatial abilities and memory
Time frame: 1 year
Rey's figure test to evaluate visuospatial abilities and memory
Time frame: 2 years
CMS to assess memory
Time frame: 1 year
CMS to assess memory
Time frame: 2 years
Digit span to assess memory
Time frame: 1 year
Digit span to assess memory
Time frame: 2 years
Movement disorders assessment with the Movement Disorder Childhood Scale
To assess Immunoadsorption therapy at long term
Time frame: 3 months
Movement disorders assessment with video-taping
To assess Immunoadsorption therapy at long term
Time frame: 3 months
Movement disorders assessment with the Movement Disorder Childhood Scale
To assess Immunoadsorption therapy at long term
Time frame: 6 months
Movement disorders assessment with video taping
To assess Immunoadsorption therapy at long term
Time frame: 6 months
Movement disorders assessment with the Movement Disorder Childhood Scale
To assess Immunoadsorption therapy at long term
Time frame: 1 year
Movement disorders assessment with the Movement Disorder Childhood Scale
To assess Immunoadsorption therapy at long term
Time frame: 2 years
Movement disorders assessment with video-taping
To assess Immunoadsorption therapy at long term
Time frame: 1 year
Movement disorders assessment with video-taping
To assess Immunoadsorption therapy at long term
Time frame: at 2 years
Occurrence and date of relapses
Time frame: 2 years
Presence of NMDAR antibodies in CSF
titration at 6 months
Time frame: 6 months
Presence of NMDAR antibodies in CSF
titration at 1 year
Time frame: 1 year
Presence of NMDAR antibodies in serum
titration at 3 months
Time frame: 3 months
Presence of NMDAR antibodies in serum
titration at 6 months
Time frame: 6 months
Presence of NMDAR antibodies in serum
titration at 1 year
Time frame: 1 year
Proteinorachia
titration at 6 months
Time frame: 6 months
Proteinorachia
titration at 1 year
Time frame: 1 year
Presence of oligoclonal bands in serum
checked at 1 year
Time frame: 1 year
Presence of oligoclonal bands in serum
checked at 3 months
Time frame: 3 months
Presence of oligoclonal bands in serum
checked at 6 months
Time frame: 6 months
Presence of oligoclonal bands in CSF
checked at 6 months
Time frame: 6 months
Presence of oligoclonal bands in CSF
checked at 1 year
Time frame: 1 year
Number of lymphocytes in serum
checked at 3 months
Time frame: 3 months
Number of lymphocytes in serum
checked at 6 months
Time frame: 6 months
Number of lymphocytes in serum
checked at 1 year
Time frame: 1 year
Number of lymphocytes in CSF
checked at 6 months
Time frame: 6 months
Number of lymphocytes in CSF
checked at 1 year
Time frame: 1 year