Prion Diseases Flashcards
Differential diagnosis of rapidly progressive dementia with abnormal movements
Creutzfeldt-Jakob disease: types
sporadic (sCJD) 85–90% of all CJD cases
familial or genetic (gCJD)
iatrogenic (iCJD)
and variant (vCJD)
sporadic CJD pathogenesis
Prions are infectious, protein-containing particles (PrPSc) that replicate by auto-catalytic templating, replacing normal prion proteins (PrPC) and leading to neurotoxicity.
In sporadic CJD (sCJD), the origins of the disease-causing form of the prion protein are not known, but are not thought to be acquired.
Genetic CJD pathogenesis and difference in phenotype from sporadic
It results from 1 of more than 20 recognized point mutations (most commonly E200K) or insertions in the PRNP gene.
In some cases, there may not be a family history, even though there is a genetic mutation.
The phenotypes of genetic prionopathies are often similar
to sCJD.
However, onset is commonly at an earlier age (eg, 30–50 years), and the disease course is in some cases more protracted (eg, 1–10 years).
Iatrogenic CJD pathogenesis
iCJD is a consequence of human-to-human transmission.
Cases have been reported from a variety of transplants
of nervous system–containing tissues, including
1) corneal grafts
2) dura mater grafts
3) reuse of contaminated intracerebral electrodes or neurosurgical equipment
4) human pituitary–derived growth hormone.
There are no known cases of CJD transmission through transfusion of blood products, although such transmission has been found in four cases for variant CJD.
Are health care proffesionals at higher risk for CJD?
Physical contact with patients with CJD entails no risk of transmission and special precautions are not required in their routine care.
However, special precautions should be employed in the handling of brain tissue
sCJD clinical findings
Rapidly progressive dementia, focal neurologic deficits, and myoclonus are the classic clinical manifestations of sCJD.
The earliest symptoms may be vague and constitutional
(insomnia, anorexia, or fatigue) or psychiatric (depression,
anxiety, emotional lability).
Cognitive impairment (memory, concentration, aphasias, perceptual disorders), focal neurologic deficits (hemianopia, focal weakness, ataxia), and psychiatric abnormalities (hallucination and delusions) ensue shortly thereafter.
Myoclonus, especially provoked by startle, is present in more than 80% of patients by the middle to late stages of the disease.
The neurologic status deteriorates to akinetic-mutism and then to death, typically within months of clinical onset.
Subtypes of sCJD
● MM1 and MV1 account for approximately 70 percent of cases and correlate with the “classic CJD” phenotype with mid- to late-life onset, a rapidly progressive dementia with early and prominent myoclonus and ataxia, and a short duration of illness (mean 3.9 months).
The MM1 phenotype is most commonly associated with periodic sharp wave complexes (PSWC) on EEG
●VV2 (ataxic variant) accounts for approximately 10 percent of sCJD cases and presents with ataxia at onset, often as an isolated feature; late dementia; and a slightly longer duration of illness (mean seven to nine months)
● MV2 (kuru plaque variant) accounts for another 10 percent of sCJD cases and presents with progressive dementia with prominent psychiatric features and longer duration (mean 17.1 months).
PSWC are not frequent on EEG in patients with this subtype
● MM2 can present as either a thalamic variant or a cortical variant. Some patients have a young age at onset, and the disease course is typically longer, with a median disease duration of 14 months in one study.
PSWC on EEG are more often absent in MM2 compared with other MM and MV subtypes.
The clinical features of MM2-type sCJD may resemble those of vCJD.
The thalamic MM2 variant (also referred to as sporadic fatal insomnia [sFI]) accounts for 2 percent of cases. The mean disease duration is 15.6 months.
Insomnia, psychomotor hyperactivity, ataxia, and cognitive impairment are the predominant manifestations, resembling fatal familial insomnia (FFI)
The cortical MM2 variant accounts for another 2 percent of cases, with a mean disease duration of 15.7 months. Dementia is the predominant manifestation, while cerebellar and visual signs are rarely described at presentation
● VV1 accounts for 1 percent of cases and is notable for progressive dementia, younger age at onset, and longer duration (mean 15.3 months). A case series of nine patients with this subtype confirmed the slower, more prolonged course (median 21 months).
None had PSWC on EEG, and cortical, rather than basal ganglia, abnormalities were more common on magnetic resonance imaging (MRI).
Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) is negative in most sCJD VV1 cases.
CJD: CSF findings
The CSF cell count and glucose level are typically normal, whereas the protein level may be mildly elevated.
Elevations of CSF 14-3-3, neuron-specific enolase, S100 protein, and tau protein, neuronal proteins whose level in the CSF can markedly increase following acute neuronal damage of various causes, may support the diagnosis of CJD if used in the proper clinical setting;
the most useful of these markers is tau protein, which is usually highly elevated in CJD.
However, their presence does not exclude other diagnoses, and their absence does not exclude the diagnosis of CJD.
CSF RT-QuIC is the most sensitive and specific CSF diagnostic test for sCJD.
CJD: MRI findings
abnormal hyperintense signal in the putamen and head of the caudate and in a cortical ribboning pattern of the cortex.
Sensitivity and specificity for typical MRI findings range between 83 to 92 percent and 87 to 95 percent, respectively
++ Pulvinar sign and hockey stick sign 90% of variant CJD
CJD does not enhance on T1+c!
sporadic CJD diagnostic criteria
Clinical and pathologic characteristics distinguishing variant CJD from classic sporadic CJD
variant CJD: pathogenesis
● The available evidence indicates that vCJD represents bovine-to-human transmission of bovine spongiform encephalopathy, with most patients acquiring the disorder through ingestion of infected meat products.
Genetic factors may influence susceptibility and/or the clinical manifestations of the disease.
● A few cases of transmission of vCJD via blood transfusion have been reported.
variant CJD clinical findings
● vCJD presents with prominent psychiatric features often accompanied by sensory symptoms; in many patients the presence of neurologic signs (dementia, ataxia, involuntary movements) does not appear for a few to several months.
vCJD presents at a younger age than sCJD and has a more protracted although still rapidly evolving course.
variant CJD imaging
In vCJD, brain MRI typically shows signal hyperintensity in the pulvinar (pulvinar sign) or in both pulvinar and dorsomedial thalamus (hockey stick sign)
variant CJD diagnostic criteria
++ Examination of tonsillar tissue for PrPSc is a highly useful test for vCJD.
Tissue demonstration of PrPSc requires limited protease digestion of tissue samples followed by Western blotting
