What investigations should be performed in a patient suspected of having a prion disease?

In a patient suspected of having a prion disease, the initial investigations should include detailed clinical assessment and exclusion of other causes of rapidly progressive dementia. Definitive diagnosis relies on a combination of cerebrospinal fluid (CSF) analysis, neuroimaging, and electrophysiological studies.

CSF analysis is critical and should include testing for 14-3-3 protein and real-time quaking-induced conversion (RT-QuIC) assay, which have high sensitivity and specificity for prion diseases. Additional CSF biomarkers such as total tau protein and neurofilament light chain may support the diagnosis and help differentiate prion disease from other neurodegenerative conditions Satoh 2022 NICE NG97.

Magnetic resonance imaging (MRI) of the brain is essential, with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences being particularly useful to detect characteristic cortical ribboning and basal ganglia hyperintensities seen in prion disease NICE NG97.

Electroencephalography (EEG) can be performed to identify periodic sharp wave complexes, which are suggestive but not pathognomonic of prion disease NICE NG97.

Emerging evidence supports the use of positron emission tomography (PET) imaging to assess cerebral metabolism and may provide additional diagnostic information, although it is not yet standard practice in UK guidelines Mattoli et al. 2024 NICE NG97.

Overall, the diagnostic approach integrates clinical features with CSF biomarkers, MRI findings, and EEG results to establish a probable diagnosis of prion disease, with brain biopsy reserved for atypical or uncertain cases NICE NG97 Figgie MP Jr 2021.