Broadening the Differential of Autoimmune Encephalitis: Diagnostic and Therapeutic Considerations in Down Syndrome Disintegrative Disorder

Abstract

Objective To assess clinical features of Down Syndrome Disintegrative Disorder (DSDD) in trisomy 21 (T21) patients with a presumed diagnosis of autoimmune encephalitis (AE) and analyze immunotherapy regimens and timing. Background DSDD is characterized by acute to subacute developmental regression in social and functional skills with emergence of autistic behaviors in T21. In contrast to AE, brain imaging, cerebrospinal fluid (CSF) testing and AE antibody panels are often unremarkable in DSDD. However, anti-thyroid antibody seropositivity in the majority of DSDD patients as well as reported positive immunotherapy responses raise the question of an autoimmune etiology. Design/Methods Retrospective analysis of T21 patients with progressive social, cognitive, and/or functional decline referred to the University of Florida neuroimmunology clinic for establishment of care for suspected autoimmune encephalitis. Results Two female T21 patients were included with onset of autism, cognitive decline, insomnia, and psychosis at 12 (P1) and 16 (P2) years of age. Catatonia was present in one patient (P1). Diagnostic work-up was pertinent for anti-thyroid antibody-seropositivity in both cases (anti-microsomal and anti-thyroid peroxidase) and positive oligoclonal bands in one patient (P2). Otherwise, MRI, EEG, CSF and comprehensive serum/CSF AE antibody panels were negative. Both patients were treated with intravenous corticosteroids, intravenous immunoglobulins, and additional immunosuppressive agents (azathioprine [P2]; plasmapheresis, rituximab, cyclophosphamide [P1]). Earlier initiation of immunotherapy (9 months after symptom onset) was associated with partial sustained improvement (P2) while later initiation of immunotherapy (12 months after symptom onset) was associated with partial but non-sustained improvement (P1). Conclusions Both reported cases align with diagnostic features of DSDD and had partial response to immunotherapy. Sustained improvement was associated with earlier immunotherapy initiation. DSDD should be a diagnostic consideration in T21 patients with presumed AE diagnosis in setting of functional decline and developmental regression. Early initiation of immunotherapy should be considered for better chance of sustained recovery.