IANMDAR: Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 last injection will occur after the last session IA (minimum one day after) 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: IA session 4 Rituximab injections 10 IA sessions |
Drug: IA session
10 IA sessions performed in 28 days maximum, using TherasorbTM adsorbers which contain sheep derived polyvalent antihuman-immunoglobulin coupled to SepharoseTM CL-4B.
Drug: Rituximab
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)
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
Secondary Outcome Measures
- 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
- 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
- Need for mechanical ventilation [28 days]
To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients
- 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)
- 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
- 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
- Biological evolution of NMDAR antibodies tested in serum [28 days]
before and after IA sessions
- Biological evolution of NMDAR antibodies tested in CSF [28 days]
at diagnosis and after IA sessions
- 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
- Duration of use of medication for sedation by pharmaceutical class [28 days]
to assess need of sedation
- Occurrence of hypotension with need for vasopressive treatment [28 days]
To assess tolerance of IA therapy
- Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea [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
- Total duration of the immunoadsorption therapy [28 days]
To assess tolerance of IA therapy
- Total number of sessions [28 days]
To assess tolerance of IA therapy
- Number of adsorbers used for each patient [28 days]
To assess tolerance of IA therapy
- Adverse events of associated treatments [28 days]
To assess tolerance of IA therapy
- PCPCS score [3 months]
To assess Immunoadsorption therapy at long term
- mRS score [3 months]
To assess Immunoadsorption therapy at long term
- PCPCS score [6 months]
To assess Immunoadsorption therapy at long term
- mRS score [6 months]
To assess Immunoadsorption therapy at long term
- PCPCS score [1 year]
To assess Immunoadsorption therapy at long term
- PCPCS score [at 2 years]
To assess Immunoadsorption therapy at long term
- mRS score [1 year]
To assess Immunoadsorption therapy at long term
- mRS score [at 2 years]
To assess Immunoadsorption therapy at long term
- Need of hospitalization in functional rehabilitation unit [2 years]
To assess Immunoadsorption therapy at long term
- Duration of hospitalization in functional rehabilitation unit [2 years]
To assess Immunoadsorption therapy at long term
- 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 Wechsler scales [1 year]
- 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) [1 year]
- Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL) [at 2 years]
- Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF) [1 year]
- Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF) [at 2 years]
- Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL) [1 year]
- Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL) [at 2 years]
- Visual attention evaluated with NEPSY scale [1 year]
- Visual attention evaluated with NEPSY scale [at 2 years]
- Rey's figure test to evaluate visuospatial abilities and memory [1 year]
- Rey's figure test to evaluate visuospatial abilities and memory [2 years]
- CMS to assess memory [1 year]
- CMS to assess memory [2 years]
- Digit span to assess memory [1 year]
- Digit span to assess memory [2 years]
- Movement disorders assessment with the Movement Disorder Childhood Scale [3 months]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with video-taping [3 months]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with the Movement Disorder Childhood Scale [6 months]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with video taping [6 months]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with the Movement Disorder Childhood Scale [1 year]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with the Movement Disorder Childhood Scale [2 years]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with video-taping [1 year]
To assess Immunoadsorption therapy at long term
- Movement disorders assessment with video-taping [at 2 years]
To assess Immunoadsorption therapy at long term
- Occurrence and date of relapses [2 years]
- Presence of NMDAR antibodies in CSF [6 months]
titration at 6 months
- Presence of NMDAR antibodies in CSF [1 year]
titration at 1 year
- Presence of NMDAR antibodies in serum [3 months]
titration at 3 months
- Presence of NMDAR antibodies in serum [6 months]
titration at 6 months
- Presence of NMDAR antibodies in serum [1 year]
titration at 1 year
- Proteinorachia [6 months]
titration at 6 months
- Proteinorachia [1 year]
titration at 1 year
- Presence of oligoclonal bands in serum [1 year]
checked at 1 year
- Presence of oligoclonal bands in serum [3 months]
checked at 3 months
- Presence of oligoclonal bands in serum [6 months]
checked at 6 months
- Presence of oligoclonal bands in CSF [6 months]
checked at 6 months
- Presence of oligoclonal bands in CSF [1 year]
checked at 1 year
- Number of lymphocytes in serum [3 months]
checked at 3 months
- Number of lymphocytes in serum [6 months]
checked at 6 months
- Number of lymphocytes in serum [1 year]
checked at 1 year
- Number of lymphocytes in CSF [6 months]
checked at 6 months
- Number of lymphocytes in CSF [1 year]
checked at 1 year
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age: 0-16 years inclusive
-
Autoimmune encephalitis with positive anti-NMDAR antibodies in CSF (definite anti-NMDAR encephalitis according to Graus's criteria (Graus et al., 2016).
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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
Exclusion Criteria:
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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 :
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Clinical conditions that prohibit transitory volume changes
-
Indications that prohibit anticoagulation using Heparin and/or ACD-A solutions
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History of hypercoagulability
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Generalized viral, bacterial and/or mycotic infections
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Severe immune deficiencies (e.g. AIDS)
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Suspected allergies against sheep antibodies or agarose
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hôpital Necker Enfants-Malades | Paris | France | 75015 |
Sponsors and Collaborators
- Assistance Publique - Hôpitaux de Paris
Investigators
- Study Chair: Rémi SALOMON, Md, PhD, Assistance Publique - Hôpitaux de Paris
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- P150919
- 2016-A00259-42