Key Points
Disease summary:
Rare neurodegenerative diseases typically associated with rapidly progressive dementia and ataxia.
Disease subtypes—Sporadic (s) and familial (f) forms of Creutzfeldt-Jakob disease (sCJD and fCJD) and fatal insomnia (sFI and fFI). Gerstmann-Sträussler-Scheinker disease (GSS) is always genetic. Rarer forms caused by exposure to prions, include variant CJD (vCJD) and kuru. A new phenotype, labeled Variably Protease-Sensitive Prionopathy, has recently been recognized in a small number of patients.
Transmissible properties—Prions are misfolded isoforms of prion protein (PrP) that can interact with and convert normal prion protein (PrPC) to the misfolded pathogenic isoform (PrPSc). Nervous tissues from affected patients with any subtype of prion disease can potentially transfer disease to healthy individuals, if directly introduced.
Diagnostic tests—For sCJD, brain magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) sequences often show hyperintensity of the cortical ribbon or basal ganglia, and electroencephalography (EEG) may demonstrate periodic sharp waves complexes of approximately 1 per second. Cerebrospinal fluid (CSF) may show elevation of 14-3-3 and/or extremely elevated tau protein. In FI, positron emission tomography (PET) scan of brain shows a hypometabolic thalamus. Genetic testing assists with diagnosis of familial forms of prion disease.
Hereditary basis:
About 10% to 15% of all cases result from an autosomal dominant mutation of the PrP gene (PRNP). Homozygosity at the common polymorphic codon 129 of PRNP is more common in cases of sCJD and vCJD. Codon 129 genotype may influence the phenotype of some genetic prion diseases. No other genes are directly causal.
Differential diagnosis:
Other neurodegenerative conditions, including Alzheimer disease, Huntington disease, frontotemporal lobar dementias, spinocerebellar ataxia, and dementia with Lewy bodies, among others. CNS viral and bacterial infections, paraneoplastic syndromes, Hashimoto encephalopathy, and Whipple disease are important considerations in the workup.
Diagnostic Criteria and Clinical Characteristics
World Health Organization (WHO) criteria exists only for sporadic (s) CJD, which includes the following
Probable sCJDRapidly progressive dementia and at least two of the following
Myoclonus
Visual or cerebellar signs
Pyramidal or extrapyramidal signs
Akinetic mutism
And a positive result from at least one of the following
Periodic EEG
Positive CSF 14-3-3 (*or significantly elevated tau protein >1200 pg/mL) in patients with disease under 2 years duration
MRI of brain with high-signal abnormalities in basal ganglia (*or cortical ribbon) by DWI or fluid attenuated inversion recovery (FLAIR)
And the absence of
Routine investigations indicating an alternative diagnosis
(*indicate author’s modification of the WHO—levels may be greater than 3000 pg/mL)
Possible sCJD Progressive dementia and at least two of the following features
Myoclonus
Visual or cerebellar signs
Pyramidal or extrapyramidal signs
Akinetic mutism
And, the absence of a positive result [or unavailability of results] for any of the three tests described for probable CJD (a-c, earlier)
And, duration of illness less than 2 years
And, without routine investigations indicating an alternative diagnosis
Definite
Histopathologic presence of spongiform degeneration (vacuolation) and gliosis, and/or western blot presence of protease-resistant PrP. Note, this is the histopathology for CJD, not for other prion subtypes (see later).
Common core features include progressive dementia, ataxia, and myoclonus, although any neurologic or psychiatric feature can be seen, depending on the brain region affected by disease. There are four major subtypes of prion disease, outlined below. Kuru, a historic prion disease linked to cannibalistic rituals in New Guinea is not included. Although clinical features overlap considerably, the predominant presenting clinical feature is often used to distinguish between subtypes, although they are ultimately defined by their distinct histopathologies. Sporadic forms of disease generally present at a later age and progress faster than genetic forms. The four subtypes include
Onset of progressive dementia, followed by ataxia, and myoclonus. Age at onset typically greater than or equal to 55 years for sporadic (s) cases (average 68 years) and less than or equal to 55 for familial (f) cases, but exceptions exist. Death typically occurs within 4 to 6 months (~90% <1 year) from the onset of sCJD and 1 to 3 years from the onset of fCJD. MRI and EEG findings appear to be more common in sCJD than fCJD. Histopathology demonstrates spongiform degeneration diffusely distributed throughout the cortex and deep nuclei of the brain. Western blots reveal protease-resistant pathogenic prion protein (PrPSc).
Onset typically with psychiatric symptoms, especially apathy and depression, followed by painful sensations (dysesthesias) in the distal extremities, then dementia, ataxia, and myoclonus. Teens and young adults more commonly affected (average onset ~28 years). Progression to death is slightly greater than 1 year from disease onset. MRI (proton density weighting or DWI) often shows hyperintensities in the pulvinar region of the thalamus. EEG and CSF are often normal. Histopathology includes PrP amyloid plaques surrounded by a halo of spongiform degeneration, described as “florid” plaques. This disease occurs only from exposure to prions (contaminated beef) originating from bovine spongiform encephalopathy (BSE), or “mad cow disease.” Highest number of cases are from the United Kingdom. Occurrence has declined markedly since the first reports in 1995 to 1996. Three cases reported in the United States appear to have been exposed prior to emigration from the United Kingdom and Saudi Arabia.
Ataxia of gait is the most common presentation, but cognitive or behavioral symptoms predominate in some. Most cases also include abnormalities in muscle tone and strength. Onset is generally 30s to 50s, and progression is relatively slow (5-7 years). Imaging, CSF, and EEG studies are generally nondiagnostic. All reported cases of GSS have been linked to a genetic alteration in PRNP. Histopathology is distinct from other subtypes and demonstrates diffusely distributed PrP amyloid plaques, especially within the cerebellum, and minimal spongiform degeneration.
Classically presents with progressive insomnia, autonomic dysfunction (alteration in blood pressure, lacrimation, sweating, etc), followed by other typical features of prion disease, including ataxia and myoclonus. Insomnia may be mild or not apparent at onset. A sleep study demonstrates total reduction in sleep time. PET of the brain shows selective hypometabolism within the thalamus. Sporadic (SFI) and familial (FFI) forms of FI are known. The polymorphic codon 129 is a key determinant of the FI phenotype. FFI is caused by a single base-pair change (Asp178Asn) in allelic phase with Met coding of the polymorphic codon 129, while the same Asp178Asn mutation coupled with Val coding at codon 129 produces a more typical fCJD phenotype. Histopathology demonstrates neuronal loss and gliosis in brain stem and thalamic nuclei, with minimal spongiform change.
In this recently described subtype, common clinical features appear to include aphasia, ataxia, parkinsonian signs, or frontal lobe-like features, including impulsivity, euphoria, or apathy. Onset ranges from 48 to 81 years and duration is 2 to 6 years. It is distinguished from CJD primarily by the overall reduced protease-resistance of PrPSc isolated from the brain and the presence of punctate and target-like PrP amyloid deposits with moderate spongiform degeneration in histological sections. Diagnostic tests, such as EEG, MRI, and CSF studies are most often negative.
