Evidence of Neuroinflammation and Immunotherapy Responsiveness in Individuals with Down Syndrome Regression Disorder
Jonathan Santoro1, Rebecca Partridge2, Runi Tanna3, Dania Pagarkar4, Mellad Khoshnood5, Ryan Kammeyer6, Grace Gombolay7, Jane El-Dahr8, Alison Christy9, Lina Patel6, Melanie Manning10, Heather Van Mater11, Michael Rafii12, Eileen Quinn13
1Department of Neurology, Children's Hospital Los Angeles, 2Virginia Mason Health System, 3Childrens Hospital Oakland, 4University of Southern California, 5Children's Hospital Los Angeles, 6Childrens Hospital Colorado, 7Emory University, 8Tulane University, 9Providence Health & Services, Pediatric Specialty Clinic, 10Stanford School of Medicine, 11Duke University, 12USC Alzheimer'S Therapeutic Research Institute, 13University of Toledo
Objective:
This study sought to phenotype and characterize neurodiagnostic abnormalities in persons with Down syndrome regression disorder. In addition, we sought to assess therapeutic responses to a variety of different pharmacologic interventions.
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.
Design/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.