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

Objective:  We present the National Prion Disease Pathology
Surveillance Center’s (NPDPSC) experience using cerebrospinal fluid (CSF)
real time quaking induced conversion (RT-QuIC) as a diagnostic test,
examine factors associated with false negative RT-QuIC results, and
investigate RT-QuIC’s impact on prion disease surveillance. 
  Methods:  Between May 2015-April 2018, the NPDPSC
received 10,498 CSF specimens that were included in the
study.   Sensitivity and specificity analyses were
performed using 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 was 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 sCJD.  Individuals with prion
disease and negative RT-QuIC results were younger, had elevated tau
levels, and non-elevated 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 2nd generation real time quaking-induced conversion
(RT-QuIC) identifies prion disease with sensitivity of 90.3% and
specificity of 98.5%, among patients being screened for these diseases due
to concerning symptoms.