There are three types of Cerebrospinal Fluid (CSF) tests:
For many years, the only antemortem clinical laboratory test available for prion disease was limited to the detection of 14-3-3 and total Tau proteins in CSF. As rapid neurodegeneration is a hallmark of prion disease, these tests are used to gauge the probability of prion disease. However, as these are non-specific biomarkers of rapid neurodegeneration and prion specific tests, their specificity for prion disease is relatively low. CSF 14-3-3 and total Tau are proxy markers for the amount of neuronal injury present; though many conditions can cause these tests to be positive or elevated outside of prion disease (examples include Alzheimer's Disease, frontotemporal dementia, autoimmune encephalopathy, CNS infections, stroke, seizures, traumatic head injury, etc.).
In 2015, the NPDPSC introduced 2nd Generation Real-Time Quaking Induced Conversion test, or RT-QuIC, to aid in the diagnosis of prion disease from CSF samples. RT-QuIC is the only prion specific antemortem clinical laboratory test available for the diagnosis of prion disease aside from brain biopsy which is generally discouraged. 2nd Generation RT-QuIC has a sensitivity of 90.3% across all forms of prion disease and a specificity of 98.5% among patients being screened for prion disease based on concerning symptoms in an autopsy confirmed sample. However, it is important to note that some factors may contribute to a false-negative RT-QuIC result, such as atypical types of prion disease, discoloured CSF samples, age of the patient, and disease duration.1
A positive RT-QuIC test carries a >98% predictive value for prion disease, but RT-QuIC is not positive for all cases of prion disease. In case of a negative RT-QuIC result, the following should be considered:
- Re-examine the diagnosis
- Clinical phenomenology: do the symptoms mimic an atypical prion disease or other disease entity that requires further workup?
- Complete RPD work-up performed? Have all the appropriate prion disease mimickers been appropriately ruled out? 2
- Any positive findings addressed? If other diagnostic tests were abnormal, were the appropriate steps taken to address them?
- Are any other tests suggestive of prion disease?
- EEG: Are periodic sharp wave complexes (PSWC) present? PSWC's are fairly specific for prion disease, but some cases will not demonstrate PSWCs and they occur during specific times in the disease course.
- Brain MRI: Is the MRI suggestive of prion disease? Brain MRI's suggestive of prion disease typically demonstrate hyperintensity on DWI in the basal ganglia and/or at least two cortical areas (excluding frontal cortex). 3,4
- Any possibility of atypical prion disease?
- Sporadic or Familial Fatal Insomnia (FFI): Does the patient have sleep disturbance or dysautonomia? Further workup may include polysomnogram, brain FDG-PET or SPECT scans. Consider PRNP genetic history, especially in the presence of a family history of similar symptoms.5
- Gerstmann-Straussler-Scheinker (GSS) disease: Does the clinical phenotype have a prominence of early and isolated cerebellar or parkinsonian symptoms? Consider PRNP genetic testing, especially in the presence of family history or similar symptoms.
- Variant CJD: Are there early psychiatric/sensory symptoms? Has the patient resided in at-risk countries (e.g., European and Middle Eastern countries)? Is the brain MRI suggestive of variant CJD, which generally demonstrates the pulvinar sign of FLAIR sequences? 6,7
1. Rhoads D. D., Wrona A, Foutz A, Blevins J. E., Glisic K, Person M. K., et al. "Diagnosis of Prion Diseases by RT-QuIC Results in Improved Surveillance". Neurology 2020; In Press
2. Geschwind M. D., Haman A, Miller B. L. "Rapidly Progressive Dementia". Neurologic Clinics 2007; 25:783–807.
3. Bizzi A, Pascuzzo R, Blevins J. E., Grisoli M, Lodi R, Moscatelli M, et al. "New criterion for detecting prion
disease with diffusion magnetic resonance imaging: Diagnostic performance and comparison with
cerebrospinal fluid tests in a large autopsy cohort". JAMA Neurology 2020; In Press
4. Zerr I, Kallenberg K, Summers D. M., Romero C, Taratuto A, Heinemann U, et al. "Updated clinical diagnostic criteria for sporadic Creutzfeldt Jakob disease". Brain 2009; 132:2659–68.
5. Cracco L, Appleby B. S., Gambetti P. "Fatal familial insomnia and sporadic fatal insomnia". Handb Clin
Neurol 2018; 153:271–99.
6. Will R, Ironside J. "A new variant of Creutzfeldt-Jakob disease in the UK". Lancet 1996; 347:921.
7. Zeidler M, Sellar R. J., Collie D. A., Knight R, Stewart G, Macleod M. A., et al. "The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease". Lancet 2000; 355:1412–8.