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KEY FACTS

Terminology
- Creutzfeldt-Jakob disease (CJD): Rapidly progressing, fatal, potentially transmissible dementia caused by prion
Imaging
- Best imaging clue: Progressive DWI/FLAIR hyperintensity of basal ganglia (BG), thalamus, and cerebral cortex
- Predominantly gray matter (GM): Caudate and putamen > globus pallidus (GP) - Thalamus: Common in variant CJD (vCJD) - Cerebral cortex: Frontal, parietal, and temporal
- Heidenhain variant: Occipital lobe
- 2 signs seen in 90% of vCJD but can also occur in sporadic CJD (sCJD) - Pulvinar sign: Symmetric T2 hyperintensity of pulvinar of thalamus - Hockey stick sign: Symmetric pulvinar and dorsomedial thalamic nuclear hyperintensity
- Best imaging tool: MR with DWI
Top Differential Diagnoses
- Hypoxic-ischemic injury
- Osmotic demyelination syndrome
- Other causes of dementia - Alzheimer, frontotemporal, and multiinfarct dementia; dementia in motor neuron disease
- Leigh syndrome
- Corticobasal degeneration
Clinical Issues
- Definite CJD diagnosed by neuropathology
- Progressive dementia associated with myoclonic jerks and akinetic mutism; variable constellation of pyramidal, extrapyramidal, and cerebellar signs
- CSF protein biomarkers: 14-3-3 protein, total tau (t-tau), S100 and neuron-specific enolase (NSE)
- DWI MR has higher diagnostic accuracy, 97% more than any or all of these CSF biomarkers
- Incidence 1 per 1,000,000 (USA and internationally) - sCJD (85%), familial (15%), infectious/iatrogenic (< 1%) (includes vCJD)
- Death usually ensues within months of onset

TERMINOLOGY

Abbreviations
- Creutzfeldt-Jakob disease (CJD)
- Sporadic Creutzfeldt-Jakob disease (sCJD)
- Variant Creutzfeldt-Jakob disease (vCJD)
Definitions
- Rapidly progressing, fatal, neurodegenerative disorder caused by prion (proteinaceous infectious particle devoid of DNA and RNA) - Transmissible spongiform encephalopathy

IMAGING

General Features

Best diagnostic clue

- Progressive T2 hyperintensity of basal ganglia (BG), thalamus, and cerebral cortex

Location

- Predominantly gray matter (GM)
        - BG: Caudate and putamen > globus pallidus (GP)
        - Thalamus (common in vCJD)
        - Cerebral cortex (most commonly frontal, parietal, and temporal lobes)
                  - Cortical involvement often asymmetric
                  - Heidenhain variant: Occipital lobe
                  - Brownell-Oppenheimer: Cerebellum
- May involve only peripheral cortex
        - Cortical involvement often asymmetric
        - Primary sensorimotor cortex relatively spared
- White matter (WM) usually not involved

Size: Slight decrease (atrophy)
Morphology: Hyperintense T2 signal conforms to outline of BG and gyriform pattern in cortex

CT Findings
- NECT: Usually normal - May show rapidly progressive atrophy and ventricular dilatation on serial CT - Serial CT illustrates atrophy progression

MR Findings

T1WI

- Normal
- GP hyperintensity reported in sCJD

T2WI

- Hyperintense signal in BG, thalami, cortex
- Cerebral atrophy
- With time, hyperintense foci may develop in WM

FLAIR

- 2 signs seen in 90% of vCJD but can also occur in sCJD
        - **Pulvinar**sign: Bilateral symmetrical hyperintensity of **pulvinar** (posterior) nuclei of **thalamus**
        - **Hockey stick** sign: Symmetrical **pulvinar and dorsomedial thalamic** nuclear hyperintensity
- Periaqueductal GM hyperintensity
- Cortical hyperintensity (common in sCJD)

DWI

- Progressive hyperintensity in striatum and cortex
- Gyriform hyperintense areas in cerebral cortex (cortical ribbon sign*)*
        - Correspond to localization of periodic sharp wave complexes on EEG
- DWI hyperintensity may disappear late in disease

T1WI C+: No abnormal enhancement

Nuclear Medicine Findings
- F-18 FDG PET: Regional glucose hypometabolism correlates with sites of neuropathologic lesions
- SPECT with N-isopropyl-p-(I-123) iodoamphetamine (DaTSCAN) - ↓ uptake of tracer in BG reported - Sometimes in asymmetrical pattern
Imaging Recommendations
- Best imaging tool: MR with DWI and FLAIR

DIFFERENTIAL DIAGNOSIS

Hypoxic-Ischemic Injury
- BG and parasagittal cortical areas involved
- Hyperintense BG lesions on T1WI and T2WI
- DWI + symmetric GM involvement
Osmotic Demyelination Syndrome
- Extrapontine: T2-hyperintense putamen and caudate
- DWI positive acutely
Leigh Syndrome
- Primarily seen in pediatric patients
- T2 hyperintensity in putamen and GP
Other Causes of Dementia
Corticobasal Degeneration
- Neuronal loss in substantia nigra, frontoparietal cortex, and striatum (BG atrophy may be subtle)
- MR: Symmetric/asymmetric atrophy of pre- and postcentral gyri; prominent parasagittal involvement
- Subcortical gliosis: High intensity on T2WI
Wilson Disease
- WM and deep GM lesions (BG, dentate nucleus, brainstem); variably T2 hyperintense
- T1-hypointense (rarely hyperintense) lesions
Arteriolosclerosis
- BG involvement: Typically asymmetric and multifocal (rather than diffuse as in CJD)
- Focal hyperintensities in deep WM
- DWI negative, unless acute

PATHOLOGY

General Features

Etiology

- Prion protein is misfolded isoform (PrPSc) of normal host-encoded protein (PrPc)
        - PrPSc = conformationally isomer of PrPc
- PrPSc introduced into healthy cells → initiates self-perpetuating vicious cycle: PrPc → PrPSc → neurotoxicity
- sCJD: Spontaneous PrPc → PrPSc or somatic mutation
- Familial CJD (fCJD): Mutations in *PRNP*gene
- Iatrogenic CJD: Infection from prion-containing material
        - Surgical instruments, dura mater grafts, stereotactic electrodes
        - Cadaveric corneal transplants, human pituitary hormones (growth hormone and gonadotropins)
- vCJD: Bovine spongiform encephalopathy in cattle is transmitted to humans through infected beef
        - Primarily present in UK
        - a.k.a. new variant CJD (nvCJD)
- Risk for health care workers
        - Physical contact with patients is no risk for transmission
        - Special precautions in handling brain tissue
        - All used materials and instruments decontaminated as per established protocols

Genetics

- Can be inherited, sporadic, or acquired (infectious)
- 10-15% of human prion disease cases associated with dominant mutations in autosomal prion protein (PrPc) gene (*PRNP*) on chromosome 20
- PrPc is normal host protein on surface of many cells, particularly neurons

Associated abnormalities

- EEG: Periodic (high-voltage) sharp wave complexes (PSWCs) on background of low-voltage activity
        - 67-95% patients with sCJD show PSWCs at some point during course of illness
        - False-positive EEG findings in Alzheimer dementia and vascular dementia patients
        - PSWCs helpful in differentiating sCJD from other prion disease

Staging, Grading, & Classification
- Sporadic CJD - Definite - Characteristic neuropathology (biopsy or autopsy) - Protease-resistant PrPSc (PrPres) by Western blot - Probable - Neuropsychiatric disorder with positive RT-QuIC in CSF or other tissues - OR - Rapidly progressive dementia and at least 2 out of 4 clinical features listed in table 1 - AND positive result on at least 1 of 3 lab tests listed in table 1 - AND without routine investigations indicating alternative diagnosis - Possible - Progressive dementia and at least 2 out of 4 clinical features listed in table 1 - AND absence of positive lab tests that would classify case as "probable" - AND duration of illness < 2 years - AND without routine investigations indicating alternative diagnosis
- Iatrogenic CJD: Progressive cerebellar syndrome in recipient of human cadaveric-derived pituitary hormone; or sporadic CJD with recognized exposure risk, e.g., antecedent neurosurgery with dura mater implantation
- Familial CJD: Definite or probable CJD with definite or probable CJD in 1st-degree relative; &/or neuropsychiatric disorder with disease-specific PrP gene mutation
Gross Pathologic & Surgical Features
- Mild cortical atrophy - Diffuse or confined to affected structures
- Ventricular enlargement
Microscopic Features
- Spongiform encephalopathy: GM most affected - Marked neuronal loss with reactive astrocytosis - Replacement gliosis - Neuronal vacuolation with spongiform changes
- Spongiform panencephalopathy (very rare) - Primary extensive involvement of WM - Loss of myelin and axons associated with generalized spongiform change in WM - ± diffuse cerebral atrophy, loss of neurons, and proliferation of astrocytes in cerebral cortex
- 10% of patients with CJD have amyloid plaques in cerebellum or cerebral hemispheres - Apple-green birefringence using Congo red staining when viewed under polarized light
- Variable accumulation of PrPSc in brain tissue - PrPSc = abnormal, insoluble, protease-resistant amyloid form of PrPc - Diffuse (common in sCJD) or discrete plaques

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Rapidly progressive dementia associated with myoclonic jerks and akinetic mutism
- Variable constellation of pyramidal, extrapyramidal, and cerebellar signs

Clinical profile

- **sCJD**: Cerebellar dysfunction, rapidly progressive cognitive impairment, both
        - 6 molecular subtypes: MM1, MM2 (thalamic and cortical), MV1, MV2, VV1, and VV2
                  - Vary with respect to age at onset, disease duration, early symptoms, and neuropathology
- **vCJD**: Psychiatric and sensory symptoms
        - **Heidenhain variant** of CJD
                  - Isolated visual signs/symptoms (initially)
                  - Predominantly occipital lobe degeneration
                  - Normal conventional T1 and T2WI of brain
                  - DWI/FLAIR may detect early cortical abnormalities
        - **Brownell-Oppenheimer**: Cerebellar signs/symptoms
        - Extrapyramidal type of CJD
                  - May show ↑ signal intensity in BG
        - Pyramidal involvement with disease progression
        - BG dysfunction
        - Spinal cord involvement → muscle atrophy and fasciculations
- **CSF studies**
        - CSF protein biomarkers: 14-3-3 protein, total tau (t-tau), S100, neuron-specific enolase (NSE), and thymosin β4
                  - 14-3-3 protein detection is adjunctive rather than diagnostic for prior disease
                  - t-tau > 1,150 picogram/mL has superior accuracy and specificity than 14-3-3 protein for CJD
                  - Significant false-positives and negatives with 14-3-3 and t-tau protein test results
        - DWI MR has higher diagnostic accuracy than any or all CSF biomarkers
- Real-time quaking-induced conversion (RT-QUIC) testing of CSF to detected PrPsc
        - More sensitive using olfactory epithelium (nasal brushing) than CSF
        - Nasal brushing not performed in USA

Demographics

Age

- Younger in vCJD, older in sCJD (6th-7th decades)

Sex
```
- No sex preponderance
```

Ethnicity

- sCJD occurs throughout world, in all races
- In USA, CJD ↓ in Blacks, American Indians, and Alaskan natives than White population
- vCJD limited to Europe (nearly all cases in UK)

Epidemiology

- Incidence 1.0-1.5 per million in USA
- sCJD (85-95%), familial (5-15%), infectious/iatrogenic (< 1%)

Natural History & Prognosis
- Long incubation period but rapidly progressive once clinical symptoms begin
- Rapidly progressing dementia with death usually ensuing within months of onset - Median survival from time of onset of symptoms to death is 4.5 months - 90% live < 1 year
Treatment
- No effective treatment

DIAGNOSTIC CHECKLIST

Consider
- Heidenhain variant of CJD in patients with visual disorders of unclear origin and dementia
Image Interpretation Pearls
- Lack of BG findings does not rule out CJD

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References

Selected References

Tables

CDC Diagnostic Criteria for Creutzfeldt-Jakob Disease 2018

Clinical Features	Lab Tests
Myoclonus	Typical EEG (PSWCs)
Visual or cerebellar signs	14-3-3 CSF protein positive
Pyramidal/extrapyramidal signs	DWI/FLAIR ↑ signal in caudate/putamen or at least 2 cortical regions (temporal, parietal, occipital)
Akinetic mutism

Images

Selected Images

A 53-year-old man with rapidly progressing cognitive decline due to sporadic Creutzfeldt-Jakob disease (sCJD) is shown. Axial DWI MR demonstrates symmetric bilateral basal ganglia (BG) diffusion restriction and asymmetric cortical restricted diffusion (cortical ribbon sign) in bilateral (right > > left) hemispheres .

Axial FLAIR MR in the same patient demonstrates hyperintense signal in bilateral BG and cortex . CSF was positive for 14-3-3 protein indicating probable sCJD.

Axial DWI MR in a patient with variant CJD (vCJD) demonstrates diffusion restriction in bilateral posteromedial aspect of thalami representing hockey stick sign.

Axial DWI MR in a different patient with vCJD shows diffusion restriction in bilateral posterior aspect of thalami in pulvinar region indicating pulvinar sign . These signs are more common in vCJD but can occur in sporadic cases.

Axial DWI MR in a patient with sCJD shows typical bilateral asymmetric (right > > left) cortical diffusion restriction with sparing of perirolandic cortex .

Axial DWI MR of a 59-year-old woman patient with rapidly progressive dementia and myoclonus demonstrates asymmetric patchy cortical restricted diffusion (cortical ribbon sign) in cingulate gyri and frontal lobe. EEG showed periodic sharp wave complexes.

Axial DWI MR in a patient with sCJD shows asymmetric diffusion restriction in right BG and cortex .

Axial DWI MR of a 61-year-old woman patient with sCJD 'Heidenhain clinical phenotype presenting with visual hallucination and optical distortion is shown. Image demonstrates cortical restricted diffusion in bilateral occipital lobes .

Axial DWI MR of a 58-year-old man with rapidly progressive dementia, myoclonus, and ataxia due to sCJD demonstrates diffusion restriction involving the left cerebellum .

Axial DWI MR through the vertex in the same patient shows involvement of perirolandic cortex on right . Typically the perirolandic cortex, cerebellum, and white matter are relatively spared in CJD.

Additional Images

Axial DWI MR in a different patient shows hyperintense signal consistent with restricted diffusion in right posterior temporal lobe and occipital lobe cortex.

Axial DWI MR shows hyperintense signal consistent with restricted diffusion within both amygdalae.

Axial DWI MR demonstrates bright signal of restricted diffusion in bodies of both caudate nuclei.

Axial FLAIR MR shows bilateral hyperintense signal in putamina and thalami from CJD.

Coronal FLAIR MR in the same patient with CJD demonstrates hyperintense signal in both thalami.

Coronal FLAIR MR shows hyperintense signal in caudate nuclei, lentiform nuclei, and within temporal lobe cortices and hippocampi.

Axial DWI MR shows bilateral restricted diffusion in the putamen and caudate nuclei with small foci in thalami.

Axial T2WI MR shows bilateral increased signal intensity in putamen and caudate nuclei in a patient with CJD.

Axial FLAIR MR shows symmetric hyperintensity in the caudate and putamen, characteristic of sCJD. sCJD is the most common type of CJD, representing 85% of cases.

Axial DWI MR shows asymmetric diffusion restriction in the caudate nuclei and putamen. Involvement of the anterior more than the posterior putamen is typical of CJD. There is also asymmetric hyperintensity in the frontal and temporal lobe cortical ribbons , typical of sCJD. (Courtesy N. Fischbein, MD.)

Axial DWI MR shows classic sCJD with diffusion restriction in the caudate and putamen as well as throughout the cortex. Frontal, temporal, and parietal cortical involvement is most common. Relative sparing of the pre- and postcentral gyri is typical of CJD.

Axial FLAIR MR shows bilateral, symmetric hyperintensities in the posterior thalami representing the "pulvinar" sign, which is characteristic of vCJD. Another "pulvinar" sign is the T1 shortening seen in Fabry disease.

Axial DWI MR shows symmetric hyperintensity in the BG and thalami bilaterally. The thalamic involvement shows the "hockey stick" sign, which is symmetric pulvinar and dorsomedial thalamus hyperintensity. This sign is most commonly seen in vCJD but may also be present in sCJD, as in this case.

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Clinical Issues

TERMINOLOGY

Abbreviations

Definitions

IMAGING

General Features

Best diagnostic clue

Location

CT Findings

MR Findings

T1WI

T2WI

FLAIR

DWI

Nuclear Medicine Findings

Imaging Recommendations

DIFFERENTIAL DIAGNOSIS

Leigh Syndrome

PATHOLOGY

General Features

Etiology

Genetics

Associated abnormalities

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Clinical profile

Demographics

Age

Sex

Ethnicity

Epidemiology

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Tables

CDC Diagnostic Criteria for Creutzfeldt-Jakob Disease 2018

Images

Selected Images

Additional Images

49 KiB

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