Population-Based Epidemiology Study of Paraneoplastic Neurologic Syndromes

ObjectivesPopulation-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS.MethodsWe performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987–2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]).ResultsThere were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5–69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987–2002) to 0.8/100,000 person-years (2003–2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1–9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years.DiscussionPNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.

Distinct evolution of infection-enhancing and neutralizing epitopes in the spike protein of SARS-CoV-2 variants (from alpha to omicron) : a structural and molecular epidemiology study

Infection-enhancing antibodies may limit the efficiency of Covid-19 vaccines. We analyzed the evolution ofneutralizing and facilitating epitopes in 1,860,489 SARS-CoV-2 genomes stored in the Los Alamos databasefrom June to November 2021. The structural dynamics of these epitopes was determined by molecular modelingof the spike protein on a representative panel of SARS-CoV-2 variants. D614, which belongs to an antibody-dependent-enhancement (ADE) epitope common to SARS-CoV-1 and SARS-CoV-2, has mutated to D614G in2020, which could explain why ADE has not been detected following mass vaccination. A second epitopelocated in the N-terminal domain (NTD), specific of SARS-CoV-2, is highly conserved among most variants. Incontrast, the neutralizing epitope of the NTD showed extensive variations in SARS-CoV-2 variants. The balancebetween facilitating and neutralizing antibodies is in favor of neutralization for the Wuhan strain, alpha and betavariants, but not for gamma, delta, lambda, and mu. The recently emerging omicron variant is atypic as itsmutational profiles affects both neutralization and ADE epitopes. Overall, our data reveal that the evolution ofSARS-CoV-2 has dramatically affected the ADE/neutralization balance. Future vaccines should consider thesefindings to design new formulations adapted to SARS-CoV-2 variants and lacking ADE epitopes in the spikeprotein.