Clinical Pearls & Morning Reports
Published April 6, 2022
The major process underlying the pathogenesis of prion diseases is conformational change of the normal neuronal host prion protein (PrPC [C denotes cellular]) to its pathologic form (PrPSc [Sc denotes scrapie]). Read the NEJM Review Article here.
Q: What electroencephalographic (EEG) findings are characteristic of Creutzfeldt–Jakob disease (CJD)?
A: EEG findings of generalized, synchronous, sharp-and-slow-wave complexes of almost periodic recurrence, usually at 3 to 4 Hz, are characteristic of CJD, but they are also observed with lithium toxicity, toxic-metabolic disorders, and certain seizure disorders.
Q: Do the MRI findings associated with CJD appear early or late in the course of disease?
A: MRI is a sensitive technique for the diagnosis of prion diseases. Typical changes are high signal on diffusion-weighted imaging and on fluid-attenuated inversion recovery sequences in portions of the cerebral cortex (“cortical ribboning”), basal ganglia, or thalami. A few other disorders are characterized by imaging changes in the cortex that are similar to those in prion diseases. One value of these various MRI changes is their presence at very early stages of disease, when clinical diagnosis is difficult, and in rare cases, even before the onset of disease.
A: Increased CSF levels of 14-3-3 and tau proteins are found in up to 90% of patients with prion diseases. Neither protein is directly involved in the pathogenic processes in prion diseases; however, rapid damage to brain tissue leads to their release into the CSF. Specificity is approximately 95% if the clinical syndrome is consistent with CJD but is approximately 70% in unselected samples from patients with neurologic diseases, because increased levels are found in acute ischemia, after seizures, and in inflammatory brain diseases. Blood biomarkers, which are currently under investigation for the diagnosis of prion disease, could obviate the need for CSF sampling. The neuronal damage in CJD is reflected by increased plasma levels of biomarkers such as neurofilament light chain (NfL) and tau, and elevated plasma tau levels appear to correlate with disease progression. The sensitivity of these tests ranges from 70 to 100%, depending on the population studied, but the specificity is low because of overlap with other neurodegenerative diseases.
A: The goal of efforts to establish a definitive diagnosis of CJD is the detection of abnormally folded PrPSc in various tissues outside the brain. The development of seeding assays such as protein-misfolding conformation assays, which was followed by the development of the RT-QuIC assay, represents such an advance. These assays make use of the fact that conformationally altered proteins in their pathologic shape act as seeds for the propagation of more, similarly misfolded proteins from normal or recombinant protein and thus serially build aggregates of pathologic proteins. Repeated cycles of aggregate sonication (protein-misfolding conformation assays) or high-frequency shaking (RT-QuIC) amplify the formation of new seeds. The concentration of small amounts of the pathologically folded proteins is accelerated by alternating cycles of shaking and rest, and the result is visualized by measuring thioflavine T emission in a fluorescence plate reader. The technique currently used is the RT-QuIC assay in samples of CSF. In confirmed cases of CJD, the detection of misfolded PrP is close to 100%, and the specificity in most series has been 100%. The test has been recommended by an expert committee as an essential part of the diagnostic evaluation in suspected cases of CJD.