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August 25, 2020; 95 (8) Article

Diagnosis of prion diseases by RT-QuIC results in improved surveillance

Daniel D. Rhoads, Aleksandra Wrona, Aaron Foutz, Janis Blevins, Kathleen Glisic, Marissa Person, Ryan A. Maddox, View ORCID ProfileErmias D. Belay, Lawrence B. Schonberger, Curtis Tatsuoka, Mark L. Cohen, Brian S. Appleby
First published June 22, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010086
Daniel D. Rhoads
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Aleksandra Wrona
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Aaron Foutz
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Janis Blevins
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Kathleen Glisic
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Marissa Person
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Ryan A. Maddox
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Ermias D. Belay
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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  • ORCID record for Ermias D. Belay
Lawrence B. Schonberger
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Curtis Tatsuoka
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Mark L. Cohen
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Brian S. Appleby
From the National Prion Disease Pathology Surveillance Center (D.D.R., A.F., J.B., K.G., M.L.C., B.S.A.) and Department of Population and Quantitative Health Sciences (C.T.), Case Western Reserve University; Departments of Pathology (D.D.R., M.L.C., B.S.A.), Neurology (C.T., M.L.C., B.S.A.), and Psychiatry (B.S.A.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; School of Public Health (A.W.), Yale University, New Haven, CT; and Division of High-Consequence Pathogens and Pathology (M.P., R.A.M., E.D.B., L.B.S.), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
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Diagnosis of prion diseases by RT-QuIC results in improved surveillance
Daniel D. Rhoads, Aleksandra Wrona, Aaron Foutz, Janis Blevins, Kathleen Glisic, Marissa Person, Ryan A. Maddox, Ermias D. Belay, Lawrence B. Schonberger, Curtis Tatsuoka, Mark L. Cohen, Brian S. Appleby
Neurology Aug 2020, 95 (8) e1017-e1026; DOI: 10.1212/WNL.0000000000010086

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Abstract

Objective To present the National Prion Disease Pathology Surveillance Center's (NPDPSC’s) experience using CSF real-time quaking-induced conversion (RT-QuIC) as a diagnostic test, to examine factors associated with false-negative RT-QuIC results, and to investigate the impact of RT-QuICs on prion disease surveillance.

Methods Between May 2015 and April 2018, the NPDPSC received 10,498 CSF specimens that were included in the study. Sensitivity and specificity analyses were performed on 567 autopsy-verified cases. Prion disease type, demographic characteristics, specimen color, and time variables were examined for association with RT-QuIC results. The effect of including positive RT-QuIC cases in prion disease surveillance was examined.

Results The diagnostic sensitivity and specificity of RT-QuIC across all prion diseases were 90.3% and 98.5%, respectively. Diagnostic sensitivity was lower for fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, sporadic fatal insomnia, variably protease sensitive prionopathy, and the VV1 and MM2 subtypes of sporadic Creutzfeldt-Jakob disease. Individuals with prion disease and negative RT-QuIC results were younger and had lower tau levels and nonelevated 14-3-3 levels compared to RT-QuIC–positive cases. Sensitivity was high throughout the disease course. Some cases that initially tested RT-QuIC negative had a subsequent specimen test positive. Including positive RT-QuIC cases in surveillance statistics increased laboratory-based case ascertainment of prion disease by 90% over autopsy alone.

Conclusions RT-QuIC has high sensitivity and specificity for diagnosing prion diseases. Sensitivity limitations are associated with prion disease type, age, and related CSF diagnostic results. RT-QuIC greatly improves laboratory-based prion disease ascertainment for surveillance purposes.

Classification of evidence This study provides Class III evidence that second-generation RT-QuIC identifies prion disease with a sensitivity of 90.3% and specificity of 98.5% among patients being screened for these diseases due to concerning symptoms.

Glossary

CI=
confidence interval;
NPDPSC=
National Prion Disease Pathology Surveillance Center;
OR=
odds ratio;
RT-QuIC=
real-time quaking-induced conversion;
sCJD=
sporadic Creutzfeldt-Jakob disease

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Class of Evidence: NPub.org/coe

  • Podcast: NPub.org/q1pho3

  • Received September 30, 2019.
  • Accepted in final form February 18, 2020.
  • © 2020 American Academy of Neurology
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