Etiology of Nodding Syndrome: an Epileptic Disorder of East African Children

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PROJECT SUMMARY Nodding syndrome (NS) is an epileptic encephalopathy of unknown etiology that manifests in previously healthy children and adolescents in eastern Africa, with confirmed cases reported in Tanzania, South Sudan and Uganda. In 2014, after the NS epidemic in post-conflict northern Uganda had terminated, we carried out a case-control study that revealed significant NS case association with reported prior measles infection and family dependence on moldy food during their wartime residence in squalid internal displacement camps where infectious disease was rife and immunization erratic. Whether measles virus infection (MVI) was correctly diagnosed is uncertain because some Ugandans who meet the case definition for MVI have proven instead to have rubella virus infection (RVI or German measles). MVI and RVI are both potentially relevant to NS because infants who develop acute illness from either virus occasionally develop many years later brain diseases (SSPE, PRP) that overlap clinically with Nodding syndrome. MV-triggered SSPE (subacute sclerosing panencephalitis) and SSPE-like RVI-initiated progressive rubella panencephalitis (PRP) are, like NS, seizure-associated neurological disorders, with head nodding recorded in SSPE. We propose to create and equip a small biofluid screening laboratory and enhance the technical capacity of Ugandan Research Fellows from Makerere University College of Health Sciences (MCHS), who will test the hypothesis that NS is a slow virus disorder comparable to these (SSPE/PRP) delayed-onset brain diseases. They will screen existing serum samples from clinically defined Ugandan NS Cases (n=50) and Controls (n=50) for footprints of prior viral infection with MV, RV or other neurotropic viruses. They will also screen blood and cerebrospinal fluid (CSF) from subjects with NS and non-NS, hospital-based patients undergoing CSF analysis for other medical reasons. Coded serum and CSF specimens will be tested blind by enzyme-linked immunosorbent assay (ELISA) for IgG antibodies associated with slow viruses (MV, RV) and other neurotropic viruses (HSV, CMV, EBV and B19). The Reverse Transcriptase Polymerase Chain Reaction will be used to detect viral genomes and confirm ELISA results. Research Fellows from MCHS will receive individualized research training and laboratory-based analytical experience at Oregon Health & Science University (OHSU) that will allow them independently to conduct parallel analyses at OHSU and MCHS on the biological samples (serum and csf) obtained from NS Cases and Controls. Along with other interested health professionals, the Ugandan Research Fellows will participate in customized seminars and workshops that address Nodding syndrome and other brain diseases present in Uganda, attend relevant biomedical meeting(s) on the African continent, and participate in the annual meeting of grantees in the USA at NIH FIC. !