A new test algorithm for diagnosing Creutzfeldt-Jakob disease (CJD) — combining testing samples of cerebrospinal fluid (CSF) and nasal swabbing — has "virtually 100%" specificity and sensitivity and should lead to definitive diagnosis of this prion disease, researchers conclude in a new study.
The study, published online in JAMA Neurology on December 12, was conducted by a team led by Gianluigi Zanusso, MD, from the University of Verona, Italy.
They note that until now diagnosis of CJD — of which there are about 400 cases each year in the United States — has been problematic. Patients present with rapidly progressing dementia and cerebellar symptoms, which can often be confused with many other conditions.
With supportive investigations including CSF sampling, MRI, and electroencephalography analysis, these diagnostic criteria have still been associated with only an 83% sensitivity and a 71% specificity, leaving a high degree of uncertainty about the diagnosis and many patients with CJD not being identified.
The new test is known as a second-generation real-time quaking-induced conversion (RT-QuIC) assay, which can detect minute quantities (femtograms) of the CJD-specific abnormal prion protein from all subtypes of sporadic CJD in the CSF or nasal mucosa.
Dr Zanusso and colleagues note that the technology to conduct such a test is now available in most Western countries, so "inclusion of this procedure in clinical practice seems feasible." They add that in Italy, the mean cost ranges from the equivalent of US $100 to $200; results are available in about 3 days for CSF tests and in a single day for nasal mucosa tests.
"The combination of RT-QuIC and genetic testing would quickly confirm or dismiss the diagnosis of virtually all patients with clinically suspected human prion diseases," they write.
In an accompanying editorial, Paul Brown, MD, Laboratory of Central Nervous System Studies, National Institutes of Health, Bethesda, Maryland, states: "This practical, inexpensive, and accurate test has been a long time coming," but "[a]t last, we have a truly practical procedure for the diagnosis of sporadic CJD. Bravo to the authors for this impeccably conducted and convincing piece of work!"
In an interview with JAMA, Dr Brown noted: "It is important to be able to say with certainty if a patient has a specific diagnosis, and this has not been easy with CJD as it resembles a host of other neurodegenerative diseases.
"There have been a number of incidences when a CJD diagnosis has not been made as other diseases have been present and there have been several incidences when patients with unsuspected CJD have undergone surgery without precautions to prevent it from spreading. This test will prevent that from occurring."
"Hit the Jackpot"
"Any time we have a 100% specific and sensitive diagnostic test, we have hit the jackpot," Dr Brown added. "Results of this study should rather quickly become the standard for diagnosis of prion disease in humans."
He also suggests that this test could be included in the routine laboratory examination of all patients with mental and behavioral or cerebellar signs irrespective of the presumed diagnosis.
In the current case-control study, samples of CSF and nasal mucosa were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples.
The patients with suspected CJD were followed up until death (when definite diagnosis can be made with postmortem samples) or until an alternative diagnosis became available, when they were reclassified according to the internationally recognized diagnostic criteria. Final diagnosis among these patients yielded 69 patients with CJD; 17 patients were reclassified as having non-CJD.
The new tests correctly identified all 61 patients with sporadic CJD, with an overall diagnostic sensitivity of 100% (95% confidence interval [CI], 93% - 100%). All 71 patients with a final diagnosis of non–prion disease had negative findings, with the new algorithm giving 100% specificity (95% CI, 94% - 100%).
Of the 86 patients with potential CJD, 17 (20%) were promptly diverted to alternative diagnoses of non-CJD, and 5 of them received successful treatment.
The test was not so accurate at diagnosing genetic forms of the disease, however. Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Sträussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings, for a sensitivity of 75% (95% CI, 36% - 96%).
Dr Brown writes, "Given the near-100% positivity in patients with sporadic CJD, it is curious that only half of the 8 mutation-positive symptomatic individuals with genetic forms of prion disease had positive test results."
He notes that the number of genetic cases is still too small to permit any conclusions from this apparent disparity, but it suggests that some future cases of sporadic CJD will also have false-negative test results, or that the sporadic and genetic forms of disease may truly be different in terms of the timing and distribution of misfolded protein in CSF and nasal mucosa.
He adds that the test has not yet been optimized to detect misfolded protein in variant CJD, but this is "neither surprising nor worrisome" because this form of CJD has almost disappeared.
Dr Zanusso said the next step would be to develop a genetic test. "At present we may suspect CJD from clinical signs but we can't pick up patients before they develop symptoms. We need to find a test to identify patients who carry a prion disorder gene who might develop this disease in future. Then it may be possible to give a therapy very early to stop it from progressing."
Dr Brown agreed. Noting that animal studies have shown that the CJD misfolded protein is detectable very early in disease, well before symptoms begin, he suggests that asymptomatic members of families with prion disease undergo repeated testing, and nasal basal brushing will be especially useful as a patient-friendly procedure in this group.
This study was supported in part by a grant from Alliance Biosecure Foundation, joint projects OLFASSAY and support to individual investigators from Joint Programming Neurodegenerative Disease from the University of Verona, and the Intramural Research Program of the National Institute of Allergy and Infectious Disease. The authors and Dr Brown have disclosed no relevant financial relationships.
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Cite this: New Creutzfeldt-Jakob Diagnostic Test '100%' Accurate - Medscape - Jan 06, 2017.