Creutzfeldt-Jakob Disease
Clinical Presentation
- Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, invariably fatal spongiform encephalopathy that causes progressive dementia and movement disorders with death typically in < 1 year.
Early Changes
- Psychiatric manifestations: personality changes
- Motor impairment
- Cognitive dysfunction (impaired judgment)
Later Changes
- Dementia
- Myoclonus
- Visual Blindness
Pathology
Prion-related protein (PrP) scrapie (Sc)
- Indicate that CJD is a prion disease. Prion stands for "proteinaceous infectious particle".
Two prion-related proteins (PrP):
PrPC
- PrPC is the non-pathogenic, cellular (C) form.
- PrPC has an alpha-helix-rich secondary protein structure.
PrPSc
- PrPSc is the pathogenic scrapie (Sc) form.
- PrPSc has a beta-pleated sheet-rich structure.
Note that the conformational difference in these prions is based in the difference of their secondary protein structures (their primary protein structures are the same).
Basic Pathophysiology
- PrPSc captures PrPC and then refolds it into the PrPSc conformation (the alpha-helices are converted to beta-sheets).
- Models exist to explain the exponential dissemination of PrPSc (they are beyond the scope of this tutorial).
Pathologic finding of Spongiform encephalopathy
- The term spongiform encephalopathy is used to describe the sponge-like vacuolation of the cerebral gray matter that is consistently observed in prion disease.
- We show a nucleus in neuropil with adjacent, clear vacuoles.
Diagnostic Evaluation
MRI Findings in Variant CJD (eg, Mad Cow Disease)
- Cortical ribboning may be the earliest presenting sign.
- Pulvinar Sign
- Bilateral FLAIR hyperintensities bilateral pulvinar
- Not exclusive to CJD (also seen in Fabry's disease, ADEM, bilateral thalamic infarcts secondary to occlusion of the artery of Percheron)
- Hockey Stick Sign
- Bilateral FLAIR hyperintensities bilateral pulvinar and dorsomedial thalamic nuclei bilaterally.
- We show the DWI (diffusion-weighted imaging) MRI sequence, which is the most sensitive indicator (it shows restricted diffusion).
- DWI is the most sensitive and specific test in CJD (~ 90% sensitive, ~ 95% specific).
CSF 14-3-3
- Elevated CSF 14-3-3 protein finding is indicative of CJD but its utility is argued because of its poor sensitivity and specificity and probably shouldn't be used in the extremes of pretest probability (less than 20% or greater than 90%), meaning when the clinician is most confident the patient has CJD or has little suspicion of CJD.
Periodic sharp-triphasic waves on EEG
- The characteristic pathologic EEG finding is periodic sharp-triphasic waves at ~ 1Hz frequency (0.5 to 2 Hz), which also has poor sensitivity (~ 65%) and specificity (~ 75%).
- They consist of sharp, biphasic or triphasic periodic waves.
- They have mixed spikes with a maximal amplitude in the fronto-precentral region.
Four Types of CJD
Sporadic CJD
- Vast majority of cases (> 85% of cases)
Iatrogenic (aka Acquired) CJD
- Especially, cadaveric human pituitary hormones
- Other forms of transplantation
Hereditary (aka Familial) CJD
- Familial Fatal Insomnia
- Gerstmann-Straussler-Scheinker Disease
Variant CJD
- From the consumption of Infected Tissue
- Mad Cow Disease: bovine spongiform encephalopathy, which ultimately transmitted to humans through consumption.
- Kuru: Tribe in Papua New Guinea that practiced ritualistic consumption of dead relatives.
CDC's Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD), 2010
1. Sporadic CJD
Definite:
- Diagnosed by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-resistant PrP; and /or presence of scrapie-associated fibrils.
Probable:
- 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:
- a typical EEG (periodic sharp wave complexes) during an illness of any duration; and/or
- a positive 14-3-3 cerebrospinal fluid (CSF) assay in patients with a disease duration of less than 2 years
- Magnetic resonance imaging (MRI) high signal abnormalities in caudate nucleus and/or putamen on diffusion-weighted imaging (DWI) or fluid attenuated inversion recovery (FLAIR)
- AND without routine investigations indicating an alternative diagnosis.
Possible:
- Progressive dementia; and at least two out of the following four clinical features:
- Myoclonus
- Visual or cerebellar signs
- Pyramidal/extrapyramidal signs
- Akinetic mutism
- AND the absence of a positive result for any of the three laboratory tests that would classify a case as “probable” (see tests a-c above)
- AND duration of illness less than two years
- AND without routine investigations indicating an alternative diagnosis.
2. Iatrogenic CJD
Progressive cerebellar syndrome in a recipient of human cadaveric-derived pituitary hormone; or sporadic CJD with a recognized exposure risk, e.g., antecedent neurosurgery with dura mater implantation.
3. Familial CJD
Definite or probable CJD plus definite or probable CJD in a first degree relative; and/or Neuropsychiatric disorder plus disease-specific PrP gene mutation.
- CDC's Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD), 2010. Adapted from: a) Global Surveillance, diagnosis, and Therapy of Human Transmissible spongiform Encephalopathies: Report of WHO consultation, February 9-11, 1998, Geneva, Switzerland; and b) Zerr, I, Kallenberg K, Summers DM, et al. Brain 2009, 132; 2659-2668.
References