What are the different variants of Creutzfeldt-Jakob Disease (CJD) and how are they diagnosed?

From the Guidelines

The diagnosis of Creutzfeldt-Jakob disease (CJD) should be approached with a combination of clinical evaluation, MRI brain scans, EEG, cerebrospinal fluid testing for 14-3-3 protein, tau protein, and RT-QuIC assay, as well as genetic testing for familial forms, with the RT-QuIC test being particularly valuable due to its high sensitivity and specificity 1.

Variants of CJD

CJD has four main variants:

• Sporadic CJD, which is the most common form (85-90% of cases), occurring randomly without known cause
• Familial CJD (10-15% of cases), which is inherited through mutations in the prion protein gene
• Iatrogenic CJD, resulting from accidental transmission during medical procedures
• Variant CJD, linked to consumption of beef contaminated with bovine spongiform encephalopathy

Diagnostic Approaches

Diagnosis involves a combination of approaches, including:

• Clinical evaluation for rapidly progressive dementia, myoclonus, and other neurological symptoms
• MRI brain scans, which may show characteristic signal abnormalities, particularly in the cortex and basal ganglia
• EEG, which often reveals periodic sharp wave complexes in sporadic CJD
• Cerebrospinal fluid testing for 14-3-3 protein, tau protein, and RT-QuIC (real-time quaking-induced conversion) assay for prion proteins, which provides supportive evidence
• Genetic testing, which can identify familial forms
• Brain biopsy, which shows spongiform changes and abnormal prion proteins, but is rarely performed due to infection control concerns

Importance of RT-QuIC Test

The RT-QuIC test is particularly valuable due to its high sensitivity and specificity, as noted in a study published in The Lancet Neurology in 2021 1. This test has constituted a major breakthrough for the confident pre-mortem diagnosis of sCJD, and its inclusion in updated diagnostic criteria will improve early clinical confirmation, surveillance, and trial monitoring.

Prognosis and Treatment

Unfortunately, there is no effective treatment for CJD, and it is invariably fatal, typically within one year of symptom onset. However, accurate diagnosis is crucial for providing appropriate care and support to patients and their families, as well as for preventing further transmission of the disease. As noted in a study published in the Journal of the American College of Radiology in 2020, the diagnostic breakdown of rapidly progressive dementias (RPDs) is robust, and a significant proportion of patients may have potentially treatable etiologies 1.

From the Research

Variants of Creutzfeldt-Jakob Disease

• There are four types of Creutzfeldt-Jakob disease (CJD): Sporadic (sCJD), familial or genetic (gCJD), iatrogenic (iCJD), and variant CJD (vCJD) 2
• sCJD can be classified into 6 types based on the combination of PrP(Sc) peptide and the status of the codon 129 of the PRNP gene: MM1, MV1, VV2, MV2, MM2, and VV1 2
• Genetic CJD is caused by diverse mutations in the PRNP gene 2

Diagnosis of Creutzfeldt-Jakob Disease

• Definitive diagnosis of CJD requires detection of the abnormally folded, CJD-specific form of protease-resistant prion protein (PrP(CJD)) in brain tissue obtained postmortem or via biopsy 3
• Supporting investigations, including MRI, EEG, and conventional analyses of cerebrospinal fluid (CSF) biomarkers, are helpful in the diagnostic work-up, but do not allow definitive diagnosis 3
• Novel ultrasensitive seeding assays, such as real-time quaking-induced conversion (RT-QuIC), have improved the diagnostic process and can be used for in vivo diagnosis of CJD 3
• RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD 3
• MRI is a useful tool in the diagnosis of CJD, with typical changes including increased signal intensity in the caudate nucleus and putamen 4
• Diffusion-weighted sequences are the most sensitive MRI sequences for detecting pathologic changes in CJD 4
• The current diagnostic criteria for CJD are limited, and test sensitivity and specificity vary with the genetics of the disease as well as the clinical stage 5
• A diagnostic pathway for the patient presenting with rapidly progressive dementia, including imaging studies, electroencephalography, and biomarkers, can help make the diagnosis of CJD without brain tissue samples 5