Creutzfeldt-Jakob disease

Last revised by Assoc Prof Frank Gaillard on 23 Sep 2021

Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy that results in rapidly progressive dementia and death usually within a year from onset. The vast majority are sporadic, but familial and acquired forms are occasionally encountered.

On imaging, it classically manifests as hyperintense signal on DWI (and usually FLAIR) in regions of the cerebral grey matter (cortex, followed by the striatum, followed by thalamus).

Four types of Creutzfeldt-Jakob disease have been described 2,6:

  • sporadic (sCJD)
    • accounts for 85-90% of cases
    • further divided into numerous subtypes according to molecular markers (see pathology section below)
  • variant (vCJD)
    • bovine-to-human transmission of bovine spongiform encephalopathy (a.k.a. "mad cow disease"): considered zoonotic by some
    • especially if in the UK between 1981-1996
    • subsequent human-to-human transmission (e.g. transfusion) of vCJD
  • familial (fCJD)
    • 10% of cases
    • these individuals carry a PRPc mutation
  • iatrogenic (iCJD)
    • following administration of cadaveric human pituitary hormones (pre-1985)
    • various transplants

Sporadic Creutzfeldt-Jakob disease is characterized by rapidly progressive dementia and other features of neuropsychiatric decline resulting in death within a year of onset. Other common features include myoclonus, visual hallucinations, cerebellar dysfunction (such as ataxia and nystagmus), pyramidal or extrapyramidal signs (such as spasticity, rigidity, dystonia, or bradykinesia), and eventually akinetic mutism 22.

The Heidenhain variant presents as isolated visual symptoms such as impaired visual acuity, distortions of shapes and colors, and visual hallucinations.

The Brownell-Oppenheimer variant presents as isolated cerebellar ataxia.

Variant Creutzfeldt-Jakob disease presents mostly with psychiatric symptoms (such as depression) and sensory symptoms (dysesthesias or paresthesias).

  • characteristic results on electroencephalography (EEG)
  • S100
  • CSF 14-3-3 protein: positive result in a patient suspected clinically of having sCJD
  • CSF and/or olfactory mucosa real-time quaking-induced conversion (RT-QuIC) seeding assays: detects minute amounts of the disease-specific pathologic prion protein 12,13
    • found to be more sensitive than CSF 14-3-3 protein titers 12

A definitive diagnosis requires a brain biopsy, although in many institutions the difficulty involved in sterilizing equipment renders a biopsy undesirable. 

CJD is mediated via prions, a type of protein, which manifests in sheep as the disease scrapie, and in cows as bovine spongiform encephalopathy. Prions are considered infectious in the sense that they can alter the structure of neighboring proteins. 

CJD leads to spongiform degeneration of the brain, which is thought to be caused by the conversion of normal prion protein to proteinaceous infectious particles that accumulate in and around neurons and lead to cell death.

A number of subtypes of sporadic CJD are recognized based on molecular markers, and these have distinct clinical and pathological features. The classification is based on 16,17:

  • codon 129 in the prion protein gene
    • methionine (M) or valine (V) 
  • size of the protease-resistant core of the abnormal prion protein
    • PrPSc type 1 (21 kDa) or type 2 (19 kDa) 

Each variant of sporadic CJD results from the combination of codon 129 genotype (M or V) and PrPSc type (1, 2 or 1 + 2) 16,17

Additionally, the MM2 subtype has been noted to have distinctive histopathological features affecting the cerebral cortex or the thalamus and have therefore been separated into MM2 cortical (MM2C) and MM2 thalamic (MM2T).

Mixed types are also encountered. The result is that there is significant variation in the literature in regards to how many subtypes there are and if and how they should be grouped together 17.

Clinical patterns have been linked to various molecular subtypes (e.g. Heidenhain variant linked to MM1 and MM2C 18, and Brownell-Oppenheimer variant linked to VV2 19,20).

Specific sites of imaging abnormality are typical of sporadic Creutzfeldt-Jakob disease 22:

Involvement is usually bilateral but may be asymmetric or symmetric 5. The extent of abnormality increases as the disease progresses.

The Heidenhain variant predominantly involves the parieto-occipital cortex.

The Brownell-Oppenheimer variant involves the cerebellum and sometimes basal ganglia, and may not be visible until atrophy develops 22-23

Variant Creutzfeldt-Jakob disease characteristically shows the hockey stick sign and/or pulvinar sign of thalamic involvement. However, thalamic involvement is not pathognomonic of variant disease and is more commonly seen with sporadic Creutzfeldt-Jakob disease due to the overall greater prevalence of the sporadic CJD 22.

MRI is the modality of choice to assessing patients with suspected CJD.

The most sensitive sequence to identify characteristic changes is diffusion-weighted imaging (e.g. b=1000) which demonstrates increased signal, that is more conspicuous than either T2/FLAIR changes and ADC abnormalities 8,22-24

Signal abnormalities may be subtle initially but become more pronounced as the disease progresses. Review of sequential studies also typically demonstrates rapidly progressive cerebral atrophy.

  • DWI: hyperintensity (most sensitive) and more pronounced than T2/FLAIR changes due to a combination of true diffusion restriction and so-called T2 shine through.
  • ADC: variable, depends on timing
    • early: low values - these may be seen prior to marked changes on DWI or visible FLAIR changes
    • late: pseudonormalised or facilitated and associated with atrophy 22-24
  • T2-FLAIR: hyperintensity is more subtle than DWI changes and may be absent early in the course of the disease
  • T1: may show high signal in globus pallidus (uncommon) 25
  • T1 C+: no abnormal enhancement

Fluorine-18-FDG PET shows hypometabolism in the affected regions.

There is currently no curative treatment and the disease is invariably fatal with a mean survival of only seven months.

Creutzfeldt-Jakob disease is a notifiable disease in most countries, including European Union countries, Australia, United Kingdom, USA, and Canada.

It was named after Hans Gerhard Creutzfeldt (1885-1964), a German neurologist who first described the condition in 1920, and Alfons Maria Jakob (1884-1931), a German neurologist who also described the condition in a separate study in 1921 14,15

MRI imaging features overlap with many other conditions but the presentation will be different 8,10,11,21:

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