Evaluation of Intravenous Immunoglobulin in Pediatric Acute-Onset Neuropsychiatric Syndrome

Abstract

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinical diagnosis in children who have an acute manifestation of varied neuropsychiatric symptoms, including obsessive compulsive disorder, eating disorders, tics, anxiety, irritability, and problems with attention/concentration. PANS may develop as a result of a postinfectious syndrome and may represent a new form of postinfectious autoimmunity. To test the hypothesis that multiple, consecutive infusions of intravenous immunoglobulin (IVIG) for PANS can be efficacious, a multisite, open-label study was designed. Methods: The primary endpoint was evaluation of the efficacy of IVIG [Octagam 5%] in PANS over a period of 6 months (six infusions) based on mean changes in psychological evaluation scores using 6 different assessments, including the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Clinical Global Impression of Severity, and the Parent-Rated Pediatric Acute Neuropsychiatric Symptom Scale (PANS Scale). Results: The final cohort consisted of 21 subjects (7 per site) with moderate to severe PANS. The mean age was 10.86 years (range: 4-16 years). Results demonstrated statistically significant reductions in symptoms from baseline to end of treatment in all six assessments measured. CY-BOCS results demonstrated statistically significant reductions in obsessive compulsive symptoms (p < 0.0001), resulting in >50% improvement sustained for at least 8 weeks after the final infusion and up to 46 weeks in a subset of subjects. Conclusions: In PANS, which may be associated with an underlying immune dysregulation, sequential infusions of IVIG [Octagam 5%] successfully ameliorated psychological symptoms and dysfunction, with sustained benefits for at least 8 weeks, and up to 46 weeks in a subset of subjects. In addition, baseline immune and autoimmune profiles demonstrated significant elevations in a majority of subjects, which requires further evaluation, characterization, and study to clarify the potential immune dysfunction by which PANS manifests and progresses.

Trial registration: ClinicalTrials.gov NCT03348618.

Keywords: IVIG; Octagam; PANDAS; PANS.

Conflict of interest statement

I.M. has received honoraria and research support from Octapharma AG; he has also received honoraria and research support from the Pharming group. R.H.K. has received honoraria and research support from Octapharma AG, research support and honoraria from Takeda (previously Baxalta/Shire), research support from the Vietnam Respiratory Society, Hanoi Vietnam, research support from Vietnam National Children and Hospital Hanoi, Vietnam, and personal fees/honoraria from UCLA School of Medicine. M.O. has received honoraria and research support from Octapharma AG. A.L.K. has received honoraria, research support from Octapharma AG. All other authors have nothing to disclose other than their employment affiliations.

Figures

FIG. 1.

Unadjusted mean CY-BOCS total scores (*p < 0.05 was considered statistically significant). Note that in a subset of subjects (n = 12) who participated in a late follow-up visit (29–46 weeks following the final infusion), results continued to improve compared to baseline. The timing of evaluations is as follows: Visit 7 (19 weeks after baseline), Visit 8 (26 weeks after baseline), Visit 9 (29–46 weeks after Visit 8/final infusion and 55–72 weeks after baseline). CY-BOCS, Children's Yale-Brown Obsessive Compulsive Scale.

FIG. 2.

Unadjusted mean CGI-S scores (*p < 0.05 was considered statistically significant). Note that in a subset of subjects (n = 12) who participated in a late follow-up visit (29–46 weeks following the final infusion), results continued to improve compared to baseline. The timing of evaluations is as follows: Visit 7 (19 weeks after baseline), Visit 8 (26 weeks after baseline), Visit 9 (29–46 weeks after Visit 8/final infusion and 55–72 weeks after baseline). CGI-S, Clinical Global Impression of Severity.

FIG. 3.

Unadjusted mean YGTSS scores (*p < 0.05 was considered statistically significant). Note that in a subset of subjects (n = 12) who participated in a late follow-up visit (29–46 weeks following the final infusion), results indicate that tics returned, although they were still below baseline levels. The timing of evaluations is as follows: Visit 7 (19 weeks after baseline), Visit 8 (26 weeks after baseline), and Visit 9 (29–46 weeks after Visit 8/final infusion and 55–72 weeks after baseline). YGTSS, Yale Global Tic Severity Scale.

FIG. 4.

Unadjusted mean scores from infusion 1 to infusion 6 (infusions occurred every 3 weeks) of the PRPQ (Supplementary Appendix S2) (*p < 0.05 was considered statistically significant). This questionnaire takes 10–20 minutes to complete and contains 58 items selected as key symptoms of interest for data analysis per the most important PANS characteristics reported in the literature. The importance of this assessment, compared to the others conducted in this study, is that it demonstrates the efficacy of IVIG following each infusion. Statistically significant reductions in symptoms were noted by the third IVIG infusion. IVIG, intravenous immunoglobulin; PANS, pediatric acute-onset neuropsychiatric syndrome; PRPQ, Parent-Rated Pediatric Acute-Onset Neuropsychiatric Syndrome Questionnaire.

FIG. 5.

The subject was asked to draw a house. (A) Subject's drawing before treatment. (B) Subject's drawing following IVIG treatment. IVIG, intravenous immunoglobulin.

FIG. 6.

The subject was asked to draw, “self and others.” (A) Subject's drawing before treatment. (B) Subject's drawing following IVIG treatment. IVIG, intravenous immunoglobulin.