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

Abstract

Background Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention. 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) and no other explanation for symptoms. Results Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04–1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64–37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88–9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective. Conclusions This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.

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

“…In addition, data from studies regarding co-morbid non-regression related causes of regression in persons with DS (e.g., autism spectrum disorders) were also reviewed in order to minimize overlapping diagnostic criteria and differentiate cases (17)(18)(19)(20)(21)(22)25). The moderator generated diagnostic criteria were evaluated against an existing DSRD data set prior to release to the panel (26). This was performed as a quality control measure to ensure that panelists would receive as high quality a proposal as possible.…”

“…Consensus diagnostic criteria were re-applied to the inception cohort that was originally used to generate the proposed diagnostic criteria referenced in the methods section (26). Application of the subsequent diagnostic criteria improved specificity to 100% for "possible" DSRD and 98% for "probable" DSRD.…”

Down syndrome regression disorder: updates and therapeutic advances

“…In 2022, an international multidisciplinary panel of experts in DSRD was convened and charged with the development of diagnostic recommendations [4 ▪▪ ]. The subsequent recommendations (Tables 1 and 2) were generated from a combination of existing, published evidence [8 ▪▪ ,9 ▪▪ ,11] and the desire to exclude common medical causes of encephalopathy, catatonia, and neuropsychiatric disease [4 ▪▪ ]. The work up entails a combination of blood work, EEG, neuroimaging and lumbar puncture, which can be performed in the outpatient setting.…”

“…Age of symptom onset is an important consideration in DSRD as prior to more broad recognition as a distinct condition, it was often alternatively diagnosed as ‘late onset’ ASD or ‘early onset’ Alzheimer's disease. The median age of onset is cited as between 14 and 17 years [8 ▪▪ ,9 ▪▪ ]. In general, consideration of DSRD should be primarily in individuals with neurocognitive regression between the ages of 10–30 years with serious consideration of major alternative diagnoses such as ASD and Alzheimer's disease when outside of these ranges.…”

“…As we will discuss below, therapeutic interventions with psychotropics, immunotherapy and ECT have been beneficial in this population in spite of their differences in mechanisms of action. Although there is some emerging evidence that neurodiagnostic abnormalities could indicate a higher likelihood of an inflammation or autoimmune component to the disease, this remains to be elucidated in large-scale studies [8 ▪▪ ].…”