Case Report: Improvement Following Immunotherapy in an Individual With Seronegative Down Syndrome Disintegrative Disorder

Abstract

Down syndrome disintegrative disorder (DSDD) is a condition of unknown etiology characterized by acute cognitive decline, catatonia, insomnia, and autistic features in individuals with Down syndrome. A prior report of four patients with DSDD suggested a potential autoimmune etiology based on the presence of autoantibodies and on successful treatment with immunotherapy that included intravenous immunoglobulin (IVIG). Herein, we present the case of an 8-year old girl who developed acute cognitive decline to a dementia-like state, insomnia, catatonia, and autistic features. In contrast to the four patients with DSDD above, she had no evidence of autoimmunity and presented at a younger age. Given the gravity of her acute deterioration and the exclusion of other etiologies, she was treated with immunotherapy presumptively. She responded with near complete resolution of symptoms, but demonstrated a pattern of mild decline as she approached each monthly dosing of IVIG and steroids, reversed by treatment. Mycophenolate mofetil (MMF) was therefore added, with stability throughout the month and the ability to taper off IVIG. After stopping IVIG, she had a mild recurrence of symptoms that again resolved with repeat IVIG followed by tapering off. Outcome was assessed at 2.5 years after presentation, at which time she was back to her premorbid condition, except for persistent tics off immunotherapy. This case supports the contention that patients with a rapid onset of severe symptoms consistent with DSDD, who have a thorough evaluation with the exclusion of other etiologies, may warrant a trial of immunotherapy with steroids, IVIG and/or other agents like MMF even in the absence of evidence of autoimmunity on standard evaluation.

Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder

“…Thus, it could be argued that the obtainment of neurodiagnostic studies could be more beneficial for guiding second-line immunotherapy than for the initiation of primary immunotherapeutics such as steroids and IVIg, which carry a low side effect profile and marked efficacy in both sub-groups. However, the data builds upon prior reports [ 15 , 32 ] of the use of immunotherapy in individuals with DSRD regardless of neurodiagnostic study results. While the therapeutic response in both sub-populations is exciting, the interpretation of this data must be tempered by the non-randomized, non-controlled nature of the study.…”

“…This observation is particularly striking in that the observed therapeutic response validates the clinical significance of the neurodiagnostic abnormalities observed. The therapeutic response reported builds on prior reports of immunotherapy-responsive DSRD in individuals with neurodiagnostic study abnormalties [ 15 , 32 ]. Although steroids are well established as first-line therapy in a variety of neuro-immunologic disorders [ 33 – 37 ], efficacy was lower with regard to clinical improvement.…”

Assessment and Diagnosis of Down Syndrome Regression Disorder: International Expert Consensus

“…Down syndrome (DS) is the most common cause of genetic intellectual disability worldwide and occurs in 1 in 800-1,000 live births, with more than 214,000 people with DS living in the United States and 417,000 in Europe (1,2). Neurologic and psychiatric conditions in this population are well established although an increasing number of reports of a subacute neurocognitive regression of unclear etiology have been published over the last decade (3)(4)(5)(6)(7). This condition has been referred to as Down syndrome disintegrative disorder (DSDD), Down syndrome regression disorder (DSRD) and unexplained regression in Down syndrome (URDS) (6)(7)(8).…”

“…Symptoms of this condition include subacute loss or deterioration of previously acquired developmental skills in the domains of language, communication, cognition, executive function, behavioral, and adaptive skills (1,(5)(6)(7)(9)(10)(11)(12). Neuropsychiatric symptoms including catatonia, agitation, hallucination, and depersonalization have also been reported (3)(4)(5)(6)(7)(8). This condition is frequently severe and impacts the quality of life of both persons with DS and their caregivers, highlighting the need for expedited research in this area (6)(7)(8)(9).…”

Regression bei jungen Erwachsenen mit einem Down-Syndrom: Eine Fallserie

“…Ein Teil scheint jedoch durch autoimmunologische Phänomene im Sinne von (Begleit-) Encephalitiden bedingt zu sein: Insbesondere bei Nachweis z. B. einer Hashimoto-Thyreoiditis zeigte sich eine Behandlung mit intravenösen Immunglobulinen in vielen Fällen wirksam [11,12]. Darüber hinaus werden hormonelle Imbalancen sowie Veränderungen des serotonergen und cholinergen Systems diskutiert [7].…”