Diffusion-weighted MRI hyperintensity patterns

differentiate CJD from other rapid dementias – Vitali et al.

Neurology 76 May 17, 2011

CJD

• degenerative neurological disorder that is incurable and invariably fatal

• due to a type of infectious protein called a prion

• Prions are misfolded proteins which replicate by promotes refolding of native proteins into the diseased state

CJD Types

• sCJD: Spontaneous or somatic mutation

• Familial/genetic CJD (fCJD): Mutations in gene (PRNP) that codes for the prion protein (5–10% of all CJD cases)

• Iatrogenic CJD: Infection from prion contaminated material

• vCJD: BSE in cattle is transmitted to humans through infected beef

• Presents as a rapidly progressive dementia (RPD), but other (npRPD) disorders have similar presentation

• Many npRPD are treatable

• Important to diagnose CJD for infection control

• EEG & CSF biochem has limited utility in CJD dx

Aim

• Evaluate the sensitivity and specificity of FLAIR and DWI MRI for sCJD compared to a cohort of npRPD subjects

• Identify MRI features that differentiate CJD from other npRPD

Method - Subjects

• Retrospective case-control study

• Total of 90 included subjects (61 CJD : 29 npRPD)– in whom CJD was considered as a DDx– who had sufficient quality FLAIR and DWI

imaging performed at UCSF Memory & Aging Centre between Dec 2000 and Feb 2007

• 61 CJD– 48 sCJD (43/48 tested for PRNP

mutation ie fCJD – all negative)

• 41 path proven

• 7 non-pathology proven cases, met WHO criteria

– 6 fCJD– 7 GSS (Gerstmann–Sträussler–

Scheinker syndrome)

• 29 npRPD– 14/29 tested for PRNP: all

negative – 15/29 not pathologically

proven, but included• survival was outside the

range of sCJD subjects (> 3 years)

• definitive (e.g., serological or genetic) evidence of another disorder

• and/or they improved with (or without) treatment.

npRPD diagnostic groups Specific diagnosisTotal (N=29)

Path-proven

Serologically or genetic proven (N=5)

Neurodegenerative dementias Total 12 5

Corticobasal degeneration 3 1

Frontotemporal dementia 3 2

Alzheimer’s disease 2 2

Dementia with Lewy Bodies 2

Parkinson’s disease 1

Unknown dementia 1

Autoimmune or paraneoplastic encephalopathy Total 9 5 4

Antibody-mediated neuro-autoimmune disorder 4 3 4

Hashimoto’s encephalopathy 2

Sarcoidosis 1 1

metastatic non-CNS Hodgkin’s lymphoma 1 1

Multiple sclerosis 1

Vascular dementias Strokes 2

Tumors CNS lymphoma 2 2

Infectious Meningoencephalitis 2 2

Toxic- Metabolic Total 2 1

Alcoholic encephalopathy 1

MELAS 1 1

Exclusion criteria

• Some RPD subjects were initially excluded due to insufficient diagnostic confidence levels or diagnoses were not clear

• insufficient quality MRI*

Methods – MRI Acquisition

• 2 GE Signa 1.5T scanners

• FLAIR and DWI/DTI in axial planes; most had coronal planes

• Slice thickness varied from 3-5mm

Methods – Visual assessment• Multiplanar independent review by two neuroradiologists blinded to

clinical diagnosis– Reader 1: 4 years experience– Reader 2: 20 years experience

• Gray matter involvement on FLAIR and DWI reported according to 26 cortical and 5 cortical divisions per hemisphere

• Based on imaging findings, readers classified subjects as definitely, probably, probably not, or definitely not CJD according to prior MRI criteria

• Consensus review: if readers disagreed on diagnosis (?classification), MRI examined together to make a consensus diagnosis

Methods – Determining patterns of gray matter involement in sCJD

• Each of 31 hemispheric regions on DWI MRI was scored 0, 1, or 2, according to how many readers judged a region as hyperintense

• The percentage of subjects with sCJD with involvement of each brain region was determined by averaging the ratings of both readers

• Subjects with sCJD were categorized into 6 different patterns of gray matter involvement

Methods – Unblinded review and identifying differentiating features

• After consensus review, the readers re-examined the MRIs “unblinded” to identify crucial differentiating features.

• Modified sCJD MRI criteria based on the results of the analysis

Results - Sensitivity and specificityfor diagnosing sCJD

Sensitivity Specificity

Reader 1 92% 72%

Reader 2 94% 100%

Consensus reached in all but 3 cases(1 sCJD, 2 npRPD)

96% 93%

Pattern of FLAIR and DWI neocortical, limbic and subcortical hyperintensities in sCJD vs npRPD• 60/61 sCJD had

hyperintensities in neocortical, subcortical or limbic regions or in combination

• None had isolated limbic involvement

• Abnormalities more evident on DWI > FLAIR

Pattern of FLAIR and DWI neocortical, limbic and subcortical hyperintensities in sCJD vs npRPD• 9/29 npRPD had

abnormal gray matter hyperintensities

• All had limbic involvement (7 isolated; 2 cases with also subcortical involvement)

• Abnormalities more evident FLAIR > DWI

MRI features in genetic prion disease

• 5/6 fCJD had gray matter hyperintensities

• Overlapping pattern of MRI abnormality with sCJD

• 1/7 GSS read as positive• 2/7 GSS had isolated

limbic involvement• 4/7 GSS no abnormality

MRI unblinding

• False positives due to misinterpreting artifactual hyperintense signals on DWI as restricted diffusion (?without looking at ADC)

• False negatives due to failure to notice diffuse hyperintense cortical signals in subjects without subcortical abnormalities

Cases without MRI diagnosis at consensus review

• 1 sCJD

• 1 sarcoid

• 1 dementia with Lewy Bodies

Improving MRI criteria for sCJD

• MRI criteria for sCJD modified given the findings above

• Unblinded consensus review– 98% sensitivity– 100% specificity

Discussion

• In sCJD hyperintensity on DWI > FLAIR• In npRPD hyperintensity on FLAIR > DWI

• Subcortical DWI hyperintensity in sCJD always associated with ADC hypointensity ie. Diffusion restriction (which is thought to be due to vacuolation)

• *Diffusion restriction may decline in late stages of sCJD → therefore early MRI may yield better sensitivity than later MRI

Discussion

• Other npRPD conditions not included in the study cohort (eg. Extrapontine myelinolysis, Wilson’s

disease, Wernicke encephalopathy and Bartonella infection) may have MRI features that mimic sCJD

Discussion

• Isolated limbic involvement only seen in npRPD (and GSS)

• If isolated limbic involvement is seen FLAIR > DWI → “probably not CJD”

• If isolated limbic involvement is seen DWI > FLAIR, particularly with diffusion restriction → consider encephalitis and seizures

• fCJD MRI pattern closely resembles sCJD

• This MRI pattern not found in GSS

• Reader variability

Conclusion

• Patterns of FLAIR and DWI abnormalities can differentiate sCJD from npRPD

• Only some fCJD/GSS cases have overlapping features with sCJD

• MRI with DWI and ADC would be included in sCJD diagnostic criteria

Limitations

• ADC maps only examined only in cases with DWI hyperintensity

• Retrospective review after the study showed ADC hypointensities without DWI hyperintensity in some cases

• This may be due to “T2 blackout” effect caused by age related iron deposition in the GP and precental gyrus which cases hypointense signal and masks the hyperintense signal from prion disease