Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis
Kulcsszavak
Absztrakt
Leírás
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).
Dátumok
| Utolsó ellenőrzés: | 06/30/2019 |
| Első benyújtás: | 07/23/2017 |
| Becsült beiratkozás benyújtva: | 09/03/2017 |
| Első közzététel: | 09/05/2017 |
| Utolsó frissítés beküldve: | 07/28/2019 |
| Utolsó frissítés közzétéve: | 07/30/2019 |
| A tanulmány tényleges kezdési dátuma: | 09/30/2019 |
| Becsült elsődleges befejezési dátum: | 09/30/2020 |
| A tanulmány becsült befejezési dátuma: | 03/31/2021 |
Állapot vagy betegség
Beavatkozás / kezelés
Drug: IA session
Drug: IA session
Fázis
Karcsoportok
| Kar | Beavatkozás / kezelés |
|---|---|
| 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. |
Jogosultsági kritériumok
| Tanulásra alkalmas nemek | All |
| Egészséges önkénteseket fogad | Igen |
| Kritériumok | 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). - 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: - 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 |
Eredmény
Elsődleges eredménymérők
1. Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS) [before and after the 10 IA sessions, 28 days maximum]
2. Change in Neurological status evaluated with the modified Rankin Scale (mRS) [before and after the 10 IA sessions, 28 days maximum]
Másodlagos eredménymérők
1. Need of hospitalization in ICU and pediatric neurology unit [28 days]
2. Duration of hospitalization in ICU and pediatric neurology unit [28 days]
3. Need for mechanical ventilation [28 days]
4. Need for vasopressive treatment [28 days]
5. Time of recovery of independent daily-life activities [28 days]
6. Name and duration of medication for behavioral disorders and sleep disorders [28 days]
7. Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy [28 days]
8. Biological evolution of NMDAR antibodies tested in serum [28 days]
9. Biological evolution of NMDAR antibodies tested in CSF [28 days]
10. Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session [28 days]
11. Duration of each immunoadsorption treatment [28 days]
12. Duration of use of medication for sedation by pharmaceutical class [28 days]
13. Occurrence of hypotension with need for vasopressive treatment [28 days]
14. Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea [28 days]
15. Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access) [28 days]
16. Total duration of the immunoadsorption therapy [28 days]
17. Total number of sessions [28 days]
18. Number of adsorbers used for each patient [28 days]
19. Adverse events of associated treatments [28 days]
20. PCPCS score [3 months]
21. mRS score [3 months]
22. PCPCS score [6 months]
23. mRS score [6 months]
24. PCPCS score [1 year]
25. PCPCS score [at 2 years]
26. mRS score [1 year]
27. mRS score [at 2 years]
28. Need of hospitalization in functional rehabilitation unit [2 years]
29. Duration of hospitalization in functional rehabilitation unit [2 years]
30. School attendance (special school or not) and rehabilitation attendance [2 years]
31. Neuropsychological assessment for cognitive and behavioral status with Wechsler scales [1 year]
32. Neuropsychological assessment for cognitive and behavioral status with Wechsler scales [at 2 years]
33. Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL) [1 year]
34. Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL) [at 2 years]
35. Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF) [1 year]
36. Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF) [at 2 years]
37. Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL) [1 year]
38. Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL) [at 2 years]
39. Visual attention evaluated with NEPSY scale [1 year]
40. Visual attention evaluated with NEPSY scale [at 2 years]
41. Rey's figure test to evaluate visuospatial abilities and memory [1 year]
42. Rey's figure test to evaluate visuospatial abilities and memory [2 years]
43. CMS to assess memory [1 year]
44. CMS to assess memory [2 years]
45. Digit span to assess memory [1 year]
46. Digit span to assess memory [2 years]
47. Movement disorders assessment with the Movement Disorder Childhood Scale [3 months]
48. Movement disorders assessment with video-taping [3 months]
49. Movement disorders assessment with the Movement Disorder Childhood Scale [6 months]
50. Movement disorders assessment with video taping [6 months]
51. Movement disorders assessment with the Movement Disorder Childhood Scale [1 year]
52. Movement disorders assessment with the Movement Disorder Childhood Scale [2 years]
53. Movement disorders assessment with video-taping [1 year]
54. Movement disorders assessment with video-taping [at 2 years]
55. Occurrence and date of relapses [2 years]
56. Presence of NMDAR antibodies in CSF [6 months]
57. Presence of NMDAR antibodies in CSF [1 year]
58. Presence of NMDAR antibodies in serum [3 months]
59. Presence of NMDAR antibodies in serum [6 months]
60. Presence of NMDAR antibodies in serum [1 year]
61. Proteinorachia [6 months]
62. Proteinorachia [1 year]
63. Presence of oligoclonal bands in serum [1 year]
64. Presence of oligoclonal bands in serum [3 months]
65. Presence of oligoclonal bands in serum [6 months]
66. Presence of oligoclonal bands in CSF [6 months]
67. Presence of oligoclonal bands in CSF [1 year]
68. Number of lymphocytes in serum [3 months]
69. Number of lymphocytes in serum [6 months]
70. Number of lymphocytes in serum [1 year]
71. Number of lymphocytes in CSF [6 months]
72. Number of lymphocytes in CSF [1 year]
