Immunotherapy Responsiveness and Risk of Relapse in Down Syndrome Regression Disorder

Abstract

Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean off therapy after 9–12 months of treatment. Baseline, on therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, p = 0.001), abnormal MRI (χ2 = 7.78, p = 0.005), and abnormal LP (χ2 = 5.45, p = 0.02), and a personal history of autoimmunity (OR: 6.11, p < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

Safety and tolerability of intravenous immunoglobulin infusion in Down syndrome regression disorder

“…Studies evaluating the long‐term use of IVIg in persons with DSRD has identified that many patients can be weaned off therapy after 12 months of infusions (Santoro, Spinazzi, et al, 2023). Although the exact mechanisms by which this is possible are being explored, the absence of abnormal neuroimaging and abnormal cerebrospinal fluid profiles are often predictive of the ability to wean off over time.…”

“…While these therapeutics were beneficial in individuals with DSRD, they did not treat the underlying cause of DSRD and thus required long‐term use while providing sub‐optimal efficacy. With advancements in the understanding of abnormal neurodiagnostics indicating neuroinflammation in some individuals with this condition, three large multi‐center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of DSRD (Santoro, Baumer, et al, 2022; Santoro, Partridge, et al, 2022; Santoro, Spinazzi, et al, 2023). Importantly, IVIg has been reported to have efficacy rates of 70–90% in individuals with DSRD and is most effective when neurodiagnostic biomarkers such as abnormal neuroimaging and/or abnormal cerebrospinal fluid analysis are present (Santoro, Baumer, et al, 2022; Santoro, Partridge, et al, 2022; Santoro, Spinazzi, et al, 2023).…”

“…With advancements in the understanding of abnormal neurodiagnostics indicating neuroinflammation in some individuals with this condition, three large multi‐center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of DSRD (Santoro, Baumer, et al, 2022; Santoro, Partridge, et al, 2022; Santoro, Spinazzi, et al, 2023). Importantly, IVIg has been reported to have efficacy rates of 70–90% in individuals with DSRD and is most effective when neurodiagnostic biomarkers such as abnormal neuroimaging and/or abnormal cerebrospinal fluid analysis are present (Santoro, Baumer, et al, 2022; Santoro, Partridge, et al, 2022; Santoro, Spinazzi, et al, 2023). Yet the tolerability of infusions in individuals with DS and the safety of the therapeutic product (IVIg) remains unknown in this pediatric and young adult populations.…”

RANZCP 2024 CONGRESS: Book of Abstracts

“…The diagnosis is often missed in mainstream mental health settings, causing significant delays and potentially poorer outcomes for individuals and their families. Effective treatments include treating the catatonia with lorazepam or electroconvulsive therapy, and use of immune-based therapies including intravenous immunoglobulin (Santoro et al, 2023).…”

Down Syndrome and Autoimmune Disease

“…Therapeutic interventions for this condition are broad and have ranged from antipsychotics to immunotherapy [99]. A minority of individuals with DSRD may have a neuroinflammatory etiology to the disease, confirmed by the presence of abnormal neurodiagnostic studies and dramatic immunotherapy responsiveness in some patients [93,95,100,101]. While immunotherapy provides a tool to rapidly reverse this clinical syndrome, guidance on dosing and duration of therapy remains unclear.…”