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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

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Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias – Vitali et al.

Neurology 76 May 17, 2011


CJD CJD from other rapid dementias – Vitali et al.

  • 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
CJD Types CJD from other rapid dementias – Vitali et al.

  • 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



Aim (npRPD) disorders have similar presentation

  • 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
Method - Subjects (npRPD) disorders have similar presentation

  • 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 (npRPD) disorders have similar presentation

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.


Exclusion criteria
Exclusion criteria (npRPD) disorders have similar presentation

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

  • insufficient quality MRI*


Methods mri acquisition
Methods – MRI Acquisition (npRPD) disorders have similar presentation

  • 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
Methods – Visual assessment (npRPD) disorders have similar presentation

  • 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
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
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 specificity for diagnosing scjd
Results - Sensitivity and specificity featuresfor diagnosing sCJD


Pattern of flair and dwi neocortical limbic and subcortical hyperintensities in scjd vs nprpd
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 nprpd1
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
MRI features in genetic prion disease hyperintensities in sCJD vs npRPD

  • 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
MRI unblinding hyperintensities in sCJD vs npRPD

  • 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
Cases without MRI diagnosis at consensus review hyperintensities in sCJD vs npRPD

  • 1 sCJD

  • 1 sarcoid

  • 1 dementia with Lewy Bodies


Improving mri criteria for scjd
Improving MRI criteria for sCJD hyperintensities in sCJD vs npRPD

  • MRI criteria for sCJD modified given the findings above

  • Unblinded consensus review

    • 98% sensitivity

    • 100% specificity


Discussion
Discussion hyperintensities in sCJD vs npRPD

  • 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


Discussion1
Discussion hyperintensities in sCJD vs npRPD

  • 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


Discussion2
Discussion hyperintensities in sCJD vs npRPD

  • 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




Conclusion
Conclusion hyperintensities in sCJD vs npRPD

  • 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
Limitations hyperintensities in sCJD vs npRPD

  • 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


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