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We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We conducted a case\u2010control study of 154 children (8\u00a0years or older) with long\u2010standing nodding syndrome and 154 healthy age\u2010matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow\u2010up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. <jats:italic>O<\/jats:italic>\u00a0<jats:italic>volvulus<\/jats:italic> infection was assessed by serology for anti\u2013OV\u201016 IgG levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mean (SD) age of the population was 15.1 (SD: 1.9) years, and the mean duration of nodding syndrome from diagnosis to enrollment was 8.3 (SD: 2.7) years. The majority with nodding syndrome had been exposed to <jats:italic>O<\/jats:italic>\u00a0<jats:italic>volvulus<\/jats:italic> (147\/154 (95.4%)) compared with community children (86\/154 (55.8%)), with an OR of 17.04 (95% CI: 7.33, 45.58), <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001. C5a was elevated in CSF of children with nodding syndrome compared to controls (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL\u201010, APRIL, CCL5 (RANTES), CCL2, CXCL13, and MMP\u20109 compared with community controls (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Nodding syndrome is associated with exposure to <jats:italic>O.\u00a0volvulus<\/jats:italic>. Compared to controls, children with long\u2010standing symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12463","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T22:11:03Z","timestamp":1609366263000},"page":"297-309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Systemic and cerebrospinal fluid immune and complement activation in Ugandan children and adolescents with long\u2010standing nodding syndrome: A case\u2010control study"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-7956","authenticated-orcid":false,"given":"Rodney","family":"Ogwang","sequence":"first","affiliation":[{"name":"Makerere University College of Health Sciences Kampala Uganda"},{"name":"Centre of Tropical Neuroscience (CTN) Kitgum Site Uganda"},{"name":"KEMRI\u2010Wellcome Trust Research Programme Centre for Geographic Medicine Coast Kilifi Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-8530","authenticated-orcid":false,"given":"Dennis","family":"Muhanguzi","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Animal Resources and Biosecurity Makerere University Kampala Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4252-0744","authenticated-orcid":false,"given":"Kioko","family":"Mwikali","sequence":"additional","affiliation":[{"name":"KEMRI\u2010Wellcome Trust Research Programme Centre for Geographic Medicine Coast Kilifi Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7924-7182","authenticated-orcid":false,"given":"Ronald","family":"Anguzu","sequence":"additional","affiliation":[{"name":"Centre of Tropical Neuroscience (CTN) Kitgum Site Uganda"},{"name":"Division of Epidemiology Institute of Health and Equity Medical College of Wisconsin Wisconsin WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Kubofcik","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases Bethesda MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas B.","family":"Nutman","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases Bethesda MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Taylor","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6999-5507","authenticated-orcid":false,"given":"Charles R.","family":"Newton","sequence":"additional","affiliation":[{"name":"KEMRI\u2010Wellcome Trust Research Programme Centre for Geographic Medicine Coast Kilifi Kenya"},{"name":"Department of Psychiatry University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Vincent","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5328-6511","authenticated-orcid":false,"given":"Andrea L.","family":"Conroy","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine Ryan White Center for Pediatric Infectious Disease &amp; 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