Neurodiagnostic Abnormalities and Immunotherapeutic Responses in Persons with Down Syndrome Regression Disorder

Background: Down syndrome regression disorder (DSRD) is a symptom cluster consisting of neuropsychiatric regression without cause. No studies evaluating a neurologic component to the disease have been performed. This study sought to evaluate the incidence of neurodiagnostic study abnormalities in individuals with DSRD and to determine if study abnormalities are indicative of responses to therapeutic intervention, specifically, immunotherapy. Methods: A retrospective, multi-center, case-control, study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living and/or a new movement disorder). The primary study outcomes were the presence of abnormalities on EEG, MRI, and cerebrospinal fluid (CSF). Secondary endpoints included therapeutic response to interventions with antidepressants, antipsychotics, benzodiazepines, electroconvulsive therapy, and immunotherapy. Findings: Individuals with DSRD were comparable to a cohort of individuals with only DS although had higher rates of autoimmune disease ( p = 0·02, 95%CI: 1·13-3·59). Neurodiagnostic abnormalities were found on EEG (n=13, 27%), neuroimaging (n=11, 23%) and CSF (n=8, 19%). Pleocytosis was appreciated in three cases, elevated total protein in eight cases, elevated IgG index in five cases, and oligoclonal bands in one case. Individuals tested within three years of onset of symptoms were more likely to have neurodiagnostic abnormalities ( p = 0·003, 95%CI: 2·29-61·40). In patients with neurodiagnostic abnormalities immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR: 3·8, 95%CI: 1·34-10·90). In those with normal neurodiagnostic studies (n=27), IVIg was effective in seven of eight (88%) patients as well although other immunotherapies were uniformly ineffective. Interpretation: This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with DSRD, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology. Funding Information: None to declare. Declaration of Interests: None to declare. Ethics Approval Statement: Patients were retrospectively identified following IRB approval through an institution-based audit of in-person evaluations and telemedicine-based consultations for persons with Down syndrome and neurocognitive regression from July 1 2019 to July 1 2021.