Creutzfeldt-Jakob Disease is a rapidly progressive fatal neurodegenerative disease caused by prion accumulation causing spongiform brain appearance and is characterised by T2 changes in the basal ganglia, thalamus, and cortex.
Description
Creutzfeldt-Jakob Disease (CJD) is a rare, fatal neurodegenerative disorder caused by abnormal prion proteins. It leads to rapid brain damage and a characteristic spongiform appearance of the brain tissue. Patients classically present with rapid cognitive decline, ataxia, and myoclonus.
Pathogenesis
CJD is caused by the misfolding of a normal cellular protein (prion protein) into a pathogenic form which accumulates in and around neurons, leading to brain cell death. The prions can be created endogenously from misfolded normally host-encoded protein or can be infectious, or less commonly be acquired through contaminated food or medical procedures.
Subtypes
- Sporadic CJD (sCJD): Most common form (90%), occurring without known risk factors.
- Familial CJD: Second most common (10%). Caused by an inherited genetic mutation in the PRNP gene.
- Variant CJD (vCJD): Rare. Linked to consumption of beef infected with Bovine Spongiform Encephalopathy (Mad Cow Disease).
- Iatrogenic CJD: Resulting from medical procedures using contaminated instruments or tissues.
Epidemiology, Risk Factors & Associations
- Affects about 1-1.5 per million people worldwide annually.
- Most cases are sporadic with no identified risk factors.
- Familial CJD is associated with mutations in the PRNP gene.
Clinical Features
- Rapidly progressive dementia.
- Neurological symptoms including ataxia, myoclonus, and visual disturbances.
- Behavioral and personality changes.
- Muscle stiffness and weakness.
Complications
- Severe neurological impairment leading to bedridden state.
- Myoclonus and other involuntary movements.
- Mutism and loss of voluntary movement.
- Death, typically within a year of symptom onset.
Pathological Features
Histopathology
- Macroscopic: Brain atrophy in advanced stages.
- Microscopic: Spongiform changes, neuronal loss, and gliosis with prion protein deposits.
Radiological Features
General Features
- High signal abnormalities in the cortical and basal ganglia regions.
MRI
- T2/FLAIR: Hyperintense signal in the basal ganglia, thalamus and cortical ribbon (especially insula).
- Cortical ribboning – is seen in sCJD.
- Pulvinar sign – Symmetric T2 hyperintensity in the pulvinar nuclei/posterior region of thalmus, seen in vCJD
- Hockey-stick sign – Combination of pulvinar sign and increased signal in the dorsomedial thalamus
- T1: Usually unremarkable. No involvement of white matter.
- DWI/ADC: Restricted diffusion in affected cortical areas. DWI hyperintensity reduces over time.
- T1 Gad+: No significant enhancement typically.
CT
- Often normal in early disease; may show generalised brain atrophy in later stages.
PET FDG
- May show decreased cerebral metabolism in affected areas.
Grading and Staging
- Not formally graded or staged; progression is typically rapid and uniform.
Diagnosis
- Based on clinical presentation, EEG, MRI findings, and CSF analysis for 14-3-3 protein.
- Definitive diagnosis requires brain biopsy or post-mortem examination.
Differential Diagnosis
Clinical-based
- Alzheimer’s disease: More gradual cognitive decline and different MRI findings.
- Vascular dementia: Stepwise deterioration with history of strokes.
- Other rapidly progressive dementias like Lewy body dementia.
Imaging-based
More Common
- Acute Cerebral Ischemia-Infarction: Diffusion restriction in basal ganglia & thalamus due to occlusion of small perforators arising from circle of Willis, often unilateral. Bilateral paramedian thalamic &/or midbrain infarcts. Occlusion of artery of Percheron or tip of basilar artery
- Deep Venous Thrombosis: Thrombotic occlusion of internal cerebral veins, vein of Galen, straight sinus can cause T2/FLAIR hyperintense swelling of thalami & basal ganglia with diffusion restriction (seen early)
Less Common
- Drug abuse: Cocaine, amphetamines, MDMA (ecstasy), heroin, & opiates can cause restricted diffusion in the basal ganglia. Globus pallidi & occipital cortex are susceptible to MDMA-induced ischaemia.
- Osmotic Demyelination Syndrome: Occurs in alcoholic, hyponatremic patients with rapid correction of serum sodium. Typically affects pons. Extrapontine manifestations include T2/FLAIR hyperintensity in globus pallidus, putamen, thalamus and may show restricted diffusion (early).
- Status Epilepticus: Seizures persisting for more than 5 minutes. DWI restriction (acute-subacute phases) and T2 hyperintensity can be seen in gray matter, subcortical white matter and often the pulvinar nucleus of thalamus.
Management
- No cure; management is supportive and palliative.
- Symptomatic treatment for myoclonus, seizures, and psychiatric symptoms.
- Multidisciplinary care including neurology, psychiatry, and palliative care teams.