What is Creutzfeldt-Jakob disease (CJD)?

Creutzfeldt-Jakob Disease: A Fatal Prion Disorder

Creutzfeldt-Jakob disease (CJD) is a universally fatal neurodegenerative disease caused by misfolded prion proteins that accumulate in the brain, leading to rapid cognitive decline, movement disorders, and death within months, with no effective treatment available. 1, 2

What CJD Is and How It Develops

CJD belongs to a family of prion diseases characterized by the abnormal misfolding of a normal cellular protein called PrPc into a pathological form called PrPSc. 1 Once formed, these misfolded prions act as templates that convert additional normal prion proteins into the abnormal form, creating a self-propagating cascade. 1 This accumulation causes progressive neuronal death and characteristic spongiform (sponge-like) changes in brain tissue that are pathognomonic for the disease. 3, 1

The disease affects approximately 1-2 cases per million population per year, making it rare but consistently fatal. 3, 1

The Three Main Forms of CJD

Sporadic CJD (85% of cases)

• Occurs through spontaneous, posttranslational conversion of normal prion protein into the pathological form without any identifiable genetic or environmental trigger. 1
• Represents the most common form with an incidence of 1.5-2.0 per million person-years. 1
• The disease phenotype varies based on methionine/valine polymorphism at codon 129 of the PRNP gene and the molecular mass of PrPSc. 1

Familial/Genetic CJD (10-15% of cases)

• Results from autosomal dominant gain-of-function mutations in the prion protein gene (PRNP). 3, 1
• The E200K mutation is one of the most common pathogenic variants. 1
• A critical pitfall: phenotypic variability often obscures family history, so PRNP gene sequencing should be performed for all suspected CJD cases regardless of apparent family history. 1

Acquired/Iatrogenic CJD (rare today)

• Occurs through external transmission of prions via contaminated medical procedures or dietary exposure. 1, 4
• Historical iatrogenic routes include contaminated neurosurgical instruments, dura mater grafts, and pituitary-derived hormones. 1, 4
• Important caveat: standard sterilization does not reliably eliminate prion infectivity—approximately 10 successive decontamination cycles are required to reduce infectivity to negligible levels. 1, 4

Variant CJD (vCJD)

• Caused by transmission of bovine spongiform encephalopathy (BSE) from cattle to humans through dietary contamination with BSE-infected beef products. 1, 4
• Affects younger individuals (children and young adults) compared to sporadic CJD which typically affects ages 55-75. 4
• Critical distinction: vCJD prion protein extends to lymph nodes, appendix, and tonsils, making it potentially transmissible through medical and surgical interventions involving lymphoid tissue, whereas sporadic CJD prion protein is confined to brain, spinal cord, and posterior eye. 1, 4

Clinical Presentation

The hallmark presentation includes rapidly progressive dementia with personality changes and memory impairment evolving over weeks to months. 2 Common features include:

• Cognitive symptoms: rapidly progressive dementia, memory impairment, disorientation, and confusion progressing to akinetic mutism. 2
• Movement disorders: myoclonus (particularly when startled), resting tremors, and ataxia. 2
• Behavioral changes: personality changes, paranoid thoughts, and agitation. 5, 6
• Median survival: approximately 5 months from symptom onset, though some subtypes may have longer duration. 2, 5

Important pitfall: CJD can present with predominantly dysexecutive syndrome mimicking other dementias like Alzheimer's disease, which delays diagnosis. 6

Diagnostic Approach

Gold Standard Test

CSF RT-QuIC (real-time quaking-induced conversion) has emerged as the gold standard biomarker, with sensitivity of 94-96% and specificity of 99-100%. 2 RT-QuIC positivity alone is now sufficient for a diagnosis of probable CJD, even when other classical criteria are not fully met. 2

Critical caveat: RT-QuIC may have varied sensitivity across CJD subtypes, with rare false negatives reported in certain subtypes like VV1. 5

Supporting Diagnostic Tests

• MRI brain with DWI and FLAIR sequences: shows T2 hyperintensity and diffusion restriction in cortical regions, caudate, and putamen. 2
• EEG: may show periodic sharp wave complexes (PSWCs) with 1:1 relationship to myoclonic jerks, though these may be absent in atypical cases. 2, 5
• CSF biomarkers: 14-3-3 protein elevation and total tau elevation, though less specific than RT-QuIC. 2

Avoid this pitfall: brain biopsy, formerly used in diagnosis, is presently discouraged. 3

Treatment Reality

There is no effective treatment available for CJD; management is entirely supportive and palliative, focusing on symptom control and end-of-life care. 2 No disease-modifying therapies exist, and all cases are universally fatal regardless of intervention. 2

Critical warning: considering experimental therapies outside of formal research protocols offers false hope and diverts focus from quality end-of-life care. 2 The focus should be on appropriate palliative care and support for patients and families. 7

Emerging Developments

In the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals with genetic forms may be best positioned to benefit from future interventions. 3 Development of more sensitive diagnostic tests, including blood-based biomarkers, is being researched. 2