Creutzfeldt-Jakob disease

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).

Epidemiology

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

Diagnosis

The United State of America's Centres for Disease Control and Prevention (CDC) defines the following diagnostic criteria ²⁷:

• sporadic CJDCreutzfeldt-Jakob disease (sCJD)

  • definite: diagnosed by standard neuropathological and/or immunocytochemically and/or Western blot confirmed protease-resistant PrP and/or presence of scrapie-associated fibrils

  • probable

    • neuropsychiatric disorder plus positive RT-QuIC in CSF or other tissuesor

    • rapidly progressive dementia; and at least two out of the following four clinical features: myoclonus; visual or cerebellar signs; pyramidal/extrapyramidal signs; akinetic mutism AND a positive result on at least one of the following laboratory tests: typical EEG; positive 14-3-3 CSF assay with disease duration <2 years; DWI or FLAIR high signal in the caudate/putamen or at least cortical regions (temporal, parietal, occipital) AND without routine investigations indicating an alternative diagnosis

  • possible: progressive dementia; and at least two out of the four clinical features above AND the absence of a positive result for any of the four tests above AND duration of illness <2 yearsAND without routine investigations indicating an alternative diagnosis

• iatrogenic CJDCreutzfeldt-Jakob disease (iCJD): progressive cerebellar syndrome in a recipient of human cadaveric-derived pituitary hormone; or sporadic CJDCreutzfeldt-Jakob disease with a recognised exposure risk, e.g., antecedent neurosurgery with dura mater implantation

• familial CJDCreutzfeldt-Jakob disease (fCJD): definite or probable CJDCreutzfeldt-Jakob disease plus definite or probable CJDCreutzfeldt-Jakob disease in a first degree relative; and/or neuropsychiatric disorder plus disease-specific PrP gene mutation

Clinical presentation

Sporadic Creutzfeldt-Jakob disease is characterised 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 Phenotypic variants ^{22, 28}:

• amyotrophic variant: initial amyotrophic lateral sclerosis-like presentation

• Brownell-Oppenheimer variant: initial cerebellar ataxia

• Heidenhain variant presents as isolated visual: initial visual symptoms such as impaired visual acuity, distortions of shapes and colours, and visual hallucinations.

• Stern-Garcin variant: initial extrapyramidal features

Variant Creutzfeldt-Jakob disease

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

Diagnostic markers

• characteristic results on electroencephalography (EEG)

• S100

• CSF 14-3-3 protein: positive result in a patient suspected clinically of having sCJDsporadic Creutzfeldt-Jakob disease

• 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 titres ¹²

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

Pathology

CJDCreutzfeldt-Jakob disease 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 neighbouring proteins. 

CJDCreutzfeldt-Jakob disease 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 neurones and lead to cell death.

Classification

A number of subtypes of sporadic CJDCreutzfeldt-Jakob disease are recognised 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 CJDCreutzfeldt-Jakob disease 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).

Radiographic features

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

• cerebral cortex (most common) ⁵:

  • most common: insula, cingulate gyrus, superior frontal gyrus

  • common: precuneus, cuneus, paracentral lobule, medial frontal gyrus, occipital gyri, angular/supramarginal gyrus, superior parietal lobule, inferior frontal gyrus

  • less common: postcentral gyrus, precentral gyrus, medial and superior temporal gyri

• deep grey matter

  • most common: striatum (caudate and putamen)

  • common: thalamus

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.Phenotypic variants of sporadic Creutzfeldt-Jakob disease also have characteristic initial radiographic features ^22,23:

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

• Heidenhain variant: initially involves the parieto-occipital cortex

• Stern-Garcin variant: initially involves the basal ganglia and thalamus

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 CJDCreutzfeldt-Jakob disease ²².

MRI

MRI is the modality of choice to assessing patients with suspected CJDCreutzfeldt-Jakob disease.

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

Nuclear medicine 

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

Treatment and prognosis

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.

History and etymology

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. 

Differential diagnosis

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

• autoimmune encephalitis

  • particularly anti-D2 dopamine antibodies

  • T2 signal change is dominant, with only minor, if any, diffusion change

• hypoxic/anoxic brain injury

• osmotic demyelination

• encephalitis

• hepatic encephalopathy

• hypoglycaemic encephalopathy

• mitochondrial disease