INTRODUCTION — Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably to death once clinical symptoms appear. Three categories of human prion diseases are recognized:
●Sporadic – Sporadic Creutzfeldt-Jakob disease (sCJD), sporadic fatal insomnia, and variably protease-sensitive prionopathy
●Genetic – Genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker syndrome (GSS)
●Acquired – Kuru, iatrogenic Creutzfeldt-Jakob disease (iCJD), and variant Creutzfeldt-Jakob disease (vCJD)
sCJD is the most well-known and accounts for more than 90 percent of sporadic prion disease [1].
Human prion diseases share neuropathologic features including neuronal loss, proliferation of glial cells, absence of an inflammatory response, small vacuoles within the neuropil that produce a spongiform appearance, and the presence of protease-resistant prion protein.
The clinical manifestations and diagnosis of sCJD will be reviewed here. vCJD, kuru, GSS, FFI, the biology of prions, and the genetics of prion diseases are discussed separately.
●(See "Variant Creutzfeldt-Jakob disease".)
●(See "Diseases of the central nervous system caused by prions".)
EPIDEMIOLOGY — CJD is the most common of the human prion diseases, although it is still rare. Sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD), and variant (vCJD) are all recognized. The vast majority of CJD cases are sporadic (85 to 95 percent), while 5 to 15 percent are due to gCJD; iCJD and vCJD generally account for less than 1 percent [2,3]. Approximately one to two new cases of sCJD occur per 1,000,000 individuals across the entire population per year with a worldwide distribution [4].
The mean age for the onset of disease is approximately 62 years, although cases in young adults and those over 80 years of age have been described [3,5-8]. Patients with vCJD and iCJD tend to be much younger, which led to an early appreciation that the mode of transmission might be different. gCJD patients have only a slightly younger mean age of onset compared with sCJD [9].
There is no sex predilection for CJD.
In the United States, the incidence of CJD appears to be lower in African Americans and Native Americans including Alaska Natives compared with the White population; however, this observation may reflect ascertainment bias [10,11]. The incidence of CJD is increased 30- to 100-fold in certain geographic regions (including areas of North Africa, Israel, Italy, and Slovakia) due primarily to clusters of gCJD [9]. The intensity of national surveillance methods also influences the reported incidence of CJD, as well as other prion diseases [4].
Epidemiologic studies have found conflicting associations between sCJD and a history of surgical procedures that do not include procedures recognized to cause iCJD [12-15]. The details of these studies vary with regard to the type of surgery, receipt of blood products, number of surgeries, and latency between surgery and the infection. In general, these are low-quality, small studies that may be influenced by recall bias.
Other risk factors that have been variably identified for CJD include residence on a farm [12], a family history of CJD (adjusted odds ratio [OR] 19.1), and medical history of psychosis (OR 9.9) [16].
Although not pathogenic, genetic polymorphisms affect sCJD risk. The largest genetic risk factor for sCJD is the prion protein (PRNP) gene, particularly codons 129 and 219, which confer protection when heterozygous and increase risk when homozygous [17]. Single nucleotide polymorphisms outside of PRNP, including syntaxin 6 (STX6) and galactose-3-O-sulfotransferase 1 (GAL3ST1), may also increase risk of sCJD to a lesser degree [18].
PATHOGENESIS
Sporadic CJD — Prions are infectious, protein-containing particles (PrPSc) that replicate by auto-catalytic templating, replacing normal prion proteins (PrPC) and leading to neurotoxicity. This process is described separately. (See "Diseases of the central nervous system caused by prions", section on 'Pathogenesis of prion diseases'.)
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. Small clusters of sCJD cases have been reported [19-21]. A retrospective case-control study of all sCJD cases from 1990 to 1998 in the United Kingdom concluded that sCJD cases lived closer together than might be expected in the absence of a disease-clustering mechanism; the results suggested that some sCJD cases may result from exposure to a common external factor [22]. However, the significance of these possible clusters remains unclear. The results of one statistical analysis suggest that these apparent clusters may result from higher intensity of surveillance in localized geographic regions [23].
In addition to the prion strain reported to cause variant CJD (vCJD), other prion strains have been reported to cause spongiform encephalopathy in cattle [24-26]. One of these strains is associated with atypical amyloid deposition, a neuropathological feature not found in typical bovine spongiform encephalopathy (BSE) [26]. The pathologic prion protein (PrPSc) molecular signature of this amyloidotic form of BSE (called BASE) is similar to that of sCJD subtype MV2 (see 'Subtypes of sCJD' below). The significance of this PrPSc molecular similarity is unclear. One explanation is that some cases of sCJD with the PrPSc MV2 pattern might be the result of exposure to BASE. However, it is important to recognize that glycosylation and migration patterns of PrPSc may not be a reliable indicator of prion protein origin. Until further evidence accumulates, the role, if any, of BASE exposure as a source of sCJD is considered speculative [27].
Variant CJD — Variant CJD is a distinct, acquired prion disease. Available evidence suggests that a single bovine prion strain responsible for BSE has infected humans to cause vCJD.
vCJD is discussed separately. (See "Variant Creutzfeldt-Jakob disease".)
Genetic CJD — Mutations of the gene encoding prion protein have been identified and associated with forms of genetic CJD (gCJD). gCJD contributes to less than 15 percent of CJD cases.
gCJD is discussed in more detail separately. (See "Diseases of the central nervous system caused by prions", section on 'Genetic CJD'.)
Iatrogenic CJD — Iatrogenic CJD (iCJD) is believed to have been largely eradicated by current practices; new cases are likely to be those with very long incubation periods [28].
●Implicated procedures and incubation periods – Past cases of iCJD have followed administration of cadaveric human pituitary hormones (growth hormone and gonadotrophin) [29-31], dural graft transplants [32-35], use of dural mater [36], corneal transplants [37,38], use of contaminated neurosurgical instruments or stereotactic depth electrodes [39], and secondary infection with vCJD through transfusion of infected blood products. Dural graft transplants and use of cadaveric pituitary hormones account for the vast majority of iCJD cases [28].
The incubation period for iCJD is variable and depends upon the mode of transmission [40]. Studies have reported or estimated a mean time of 9 to 10 years for iCJD acquired after administration of human growth hormone and dural graft transplants [41,42]. However, incubation periods as short as five years and as long as 42 years have been reported in other patients [41,43,44].
Proven surgical routes for transmission have now been eliminated following changes in procedures used to prepare dural grafts [42] and use of recombinant-derived hormones. An international CJD surveillance team reported that, in 2000, all incident cases of iCJD were due to long incubation periods from infections acquired before 1985 [40]. An exception may be the use of Lyodura dural grafts; those manufactured before 1987 (before new procedures were instituted) were not recalled internationally, and continued to be used until 1993 [45]. Cases of iCJD related to these grafts continue to accrue, in some cases 25 years after surgery.
●Transfusion-related CJD – Available epidemiologic studies suggest that a history of preceding transfusion does not increase the risk of developing sCJD and no definite cases of primary transfusion-associated iCJD have been reported [46,47]. However, low levels of infectivity have been noted when whole blood, serum, or buffy coat derived from patients with sCJD is inoculated into animals. In one study of 436 individuals who received blood from 36 blood donors who subsequently developed CJD, no recipient developed CJD after 2096 person-years of follow-up [48]. There is one report of development of sCJD in a patient 8 to 10 months after albumin infusions during coronary artery bypass surgery [49]; however, this is likely to represent de novo sCJD.
Transfusion-associated vCJD has been reported. Donor deferral programs, leukocyte depletion, and other risk reduction measures introduced primarily to prevent vCJD will likely further lower any risk of transfusion-associated prion disease. (See "Variant Creutzfeldt-Jakob disease", section on 'Transfusion-related vCJD'.)
●Risk for health care workers – Case-control studies have not found that health care professionals are at increased risk for CJD [50-52]. 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; all materials and instruments used must be decontaminated according to established protocols [53-55]. (See "Infection prevention: Precautions for preventing transmission of infection".)
●Decontamination procedures – Prions are resistant to conventional physical decontamination methods, requiring procedures aimed at protein denaturation. It is important to keep instruments moist after use (either by immersion in water or a prionicidal detergent) because sterilization does not appear to be as effective on dried tissue. Prior to sterilization, instruments should be decontaminated in an automated dishwasher. Options for effective sterilization include [56]:
•Autoclaving at 134ºC for 18 minutes in a prevacuum sterilizer
•Autoclaving at 132ºC for 1 hour in a gravity displacement sterilizer
•Immersion in 1 N NaOH for 1 hour, followed by rinsing in water and autoclaving for 1 hour at 121ºC in a gravity displacement sterilizer or at 134ºC in a porous or prevacuum sterilizer
•Immersion in 1 N NaOH for 1 hour, followed by heating in a gravity displacement sterilizer at 121ºC for 30 minutes, cleaning, and routine sterilization
Instruments not fully accessible to the actions of the steam sterilant should be discarded. It should also be noted that the combination of NaOH and steam sterilization can be harmful to surgical instruments. However, flash sterilization or low-temperature methods for sterilization are ineffective.
CLINICAL FEATURES
Common symptoms and signs — Although CJD can be clinically heterogeneous, a common feature is rapid neuropsychiatric decline with death usually occurring within one year of symptom onset [57].
●Neuropsychiatric symptoms are uniformly seen and may manifest as dementia, behavioral abnormalities, and deficits involving higher cortical function including aphasia, apraxia, and frontal lobe syndromes [58].
Impaired concentration, memory, and judgment are frequent early signs [59]. Mood changes such as apathy and depression are common; euphoria, emotional lability, and anxiety occur less frequently [60]. Sleep disturbances, particularly hypersomnia, but also insomnia, are also common, and may be a presenting sign [61,62]. Some patients have psychotic features, especially visual hallucinations [63].
With disease progression, dementia becomes dominant in most patients and can advance rapidly.
●Myoclonus, especially provoked by startle, is present in more than 90 percent of patients at some point during the illness but may be absent at presentation, even when dementia is profound. Sporadic CJD (sCJD) should always be considered in a patient with the combination of a rapidly progressive dementia and myoclonus.
●Cerebellar manifestations, including nystagmus and ataxia, occur in approximately two-thirds of patients and are the presenting symptoms in 20 to 40 percent [59]. In particular, iatrogenic CJD (iCJD) related to human gonadotrophin and growth hormone treatment as well as to dura mater grafts has a propensity to manifest as a largely isolated cerebellar syndrome early in the disease course [31,64,65].
●Signs of corticospinal tract involvement develop in 40 to 80 percent of patients, including such findings as hyperreflexia, extensor plantar responses (Babinski sign), and spasticity.
●Extrapyramidal signs such as hypokinesia, bradykinesia, dystonia, and rigidity also occur.
Younger patients with sCJD have clinical features that differ somewhat from more typical older patients. In one case series of 52 patients younger than 50 years, psychiatric symptoms, in particular affective symptoms, were more prominent and the clinical course more prolonged than in older patients [66-68].
End-stage sCJD is generally characterized by akinetic mutism. Spasticity and myoclonus become more prevalent. Some patients develop seizures.
Features atypical for CJD — Some clinical findings, although compatible with CJD, should raise the suspicion of an alternative diagnosis, especially if they are among the more prominent features early in the illness. These include cranial nerve abnormalities and involvement of the peripheral nervous system. Disturbances of pupillary responses, trigeminal neuropathy, and vestibulocochlear dysfunction have all been reported in isolated cases but are not characteristic. Sensory signs and symptoms are a common clinical presentation in variant CJD (vCJD) but are less commonly a presenting symptom in sCJD.
Patients with iCJD from infected dura mater grafts have been noted to have a high frequency of clinical manifestations that relate to the anatomic placement of the graft [69].
Subtypes of sCJD — A number of clinical subtypes of disease have been defined based upon neurologic findings reflecting predominant involvement of individual brain regions. Examples of these include forms with mainly visual (Heidenhain variant), cerebellar (Oppenheimer-Brownell variant), thalamic, striatal, cognitive, and affective features [67,70].
At present, subtypes of sCJD are more usually classified postmortem according to the genotype of the PRNP gene at codon 129 and the molecular properties of the pathological prion protein (PrPSc). The PRNP genotype may be homozygous or heterozygous for methionine (M) or valine (V) at codon 129. The PrPSc type is determined by Western blot analysis and classified in the Parchi and Gambetti nomenclature as type 1 or type 2 depending on the size and electrophoretic mobility of the protease-resistant core fragment (PrPres) [71,72].
Using this molecular classification, six clinical phenotypes of sCJD have been described [72,73] based on a series of 300 cases in North America and Europe [72], and an additional 2451 patients were analyzed for diagnostic test characteristics [74]:
●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 electroencephalogram (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) [75].
●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) [76]. PSWC are infrequently seen on EEG in patients with this subtype [74,76-78].
●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 [79]. PSWC on EEG are more often absent in MM2 compared with other MM and MV subtypes [72,74,77-79]. The clinical features of MM2-type sCJD may resemble those of vCJD. (See "Variant Creutzfeldt-Jakob disease", section on 'Clinical and demographic features'.)
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) [80]. (See "Diseases of the central nervous system caused by prions", section on 'Fatal familial insomnia'.)
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 [81].
●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) [82]. 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 [83].
The classification for PrPSc is complicated by the existence of at least two nomenclatures, although the Parchi and Gambetti nomenclature for PrPSc [71,72] described above is the most widely used. The alternate Collinge nomenclature distinguishes four rather than two PrPSc subtypes [84-86]. The Collinge PrPSc types 1 and 2 are thought to correspond with Parchi and Gambetti PrPSc type 1, and Collinge types 3 and 4 with Parchi and Gambetti type 2 [87].
These molecular subtypes have also been associated with distinctive patterns of cerebral gene expression in CJD involving upregulation of genes involved in immune and stress responses and in cell death and downregulation of genes involved in synaptic function [88]. More than one molecular subtype may be present in 20 percent of individuals with sCJD, and PrPSc type may be influenced by both genetic and brain region-specific factors [89].
The ongoing identification of rare molecular subtypes of CJD not included in these classification schemes may require their subsequent modification [90]. As an example, it has been increasingly recognized that some patients with CJD have both type 1 and type 2 PrPSc, and that patients who have both types have a distinct clinical and pathologic phenotype [91]. In a series of 34 patients with the MM genotype, 20 individuals had both types (MM1+2) [92]. These patients had histopathologic features that were intermediate between patients with the MM1 and MM2 subtypes. A similar phenomenon has been demonstrated in VV1and VV2 cases [93].
EVALUATION — The evaluation of a patient with a rapidly progressive dementia includes neuroimaging, usually a brain MRI, EEG, and cerebrospinal fluid (CSF) evaluation.
Brain MRI — Of the available neuroimaging modalities, MRI is the most helpful in the diagnosis of CJD [94]. MRI examination excludes other potential causes of rapidly progressive dementia and also can suggest that CJD is the underlying etiology.
●Protocol – The recommended MRI protocol for assessment of patients with suspected CJD includes T1-weighted axial images, T2-weighted axial images, fluid-attenuated inversion recovery (FLAIR) axial and sagittal images at 3 mm slice thickness, and diffusion-weighted images (DWI) [95]. Administration of contrast is not necessary for the evaluation of suspected CJD, but it may be helpful to exclude other diagnoses.
●Findings – Hyperintense signal on DWI, FLAIR, and T2-weighted images involving the cerebral cortex and corpus striatum caudate head and putamen is the most common pattern on MRI in patients with sporadic CJD (sCJD) (image 1 and image 2) [95-99]. In particular, involvement of the superior frontal gyrus, superior parietal lobule, cingulate gyrus, and insular cortex is common; isolated limbic involvement is rare; and the perirolandic cortex is usually spared [100-106].
DWI is the most sensitive MRI sequence for the detection of CJD-related lesions, especially for cortical and striatal changes. In autopsy studies, reduced diffusivity (ie, decreased water diffusion manifesting as hyperintense signal on DWI) correlates with areas of spongiform change or vacuolization of the neuropil [107].
These findings are not entirely specific for CJD and may be confused with stroke, vasculitis, or reversible posterior leukoencephalopathy [108,109].
MRI abnormalities may vary with the clinical syndrome and molecular subtype. Patients with suspected sCJD and increased T2 signal in the caudate and putamen are more likely to have early dementia, shorter survival, and VV2, MV2, or MM1 codon 129 genotypes than those without high basal ganglia signal [61,110]. Thalamic hyperintensities occur most often in VV2 and MV2 subtypes, and wide cortical signal increase is most common in the VV1 and MV1 subtypes (image 3) [110]. Patients with the MM2 thalamic form of sCJD may have nearly normal brain by MRI and DWI, or show only late atrophy or white matter change [111]. sCJD molecular subtypes demonstrate fairly consistent lesion patterns on DWI that can be predicted with relative accuracy using an algorithm [112]. (See 'Subtypes of sCJD' above.)
Atypical patterns on MRI are reported. Although DWI- and FLAIR-hyperintense signal in the cerebellum has been reported, cerebellar involvement on MRI is not typical despite the prevalence of cerebellar symptoms and neuropathological involvement in CJD. Cerebellar atrophy may be observed late in the disease [101,113,114]. Confluent hyperintense signal in the mesial and dorsal thalami on DWI, FLAIR, and T2-weighted MRI (the so-called "double hockey stick" or "pulvinar" sign) is the typical pattern for variant CJD (vCJD) but has been reported in rare cases of sCJD [115]. The MRI features of vCJD are described in detail separately. (See "Variant Creutzfeldt-Jakob disease".)
●Diagnostic utility – MRI may be the most sensitive test in the early stages of disease, showing abnormalities even before the onset of characteristic clinical findings such as myoclonus and periodic sharp wave complexes (PSWC) seen on EEG [100-102,116-118]. In studies that used patients with other causes of rapidly progressive dementia as controls, MRI with DWI had sensitivities that ranged between 83 and 94 percent, higher than for EEG abnormalities and similar to 14-3-3 protein in the CSF [100,101,119,120]. Specificities in these studies ranged from 72 to 95 percent, requiring some caution in MRI interpretation [121]. These test characteristics also vary depending on the criteria used to interpret the brain MRI [122].
Independent interpretation of MRI films in 193 patients with CJD by three radiologists was associated with 82 to 86 percent agreement as to whether findings were typical or atypical for CJD [123]. High degrees of interrater reliability have been found in other studies as well [101].
The sensitivity and specificity of MRI vary with the stage of the disease as discussed below. While an abnormal MRI supports the diagnosis in the correct clinical setting, a negative MRI does not exclude CJD when the clinical case is compelling and particularly if DWI is not performed.
●Evolution of MRI abnormalities – Case series document a characteristic progression of MRI signal change from early to late disease in sCJD and iatrogenic CJD (iCJD). Although the data are limited to small observational studies, the following MRI patterns have been reported [95,102,108,124]:
•Early CJD is characterized by increased DWI signal in cortex, corpus striatum (caudate and anterior putamen), or both. The abnormal signal may be unilateral or bilateral; focal, multifocal, or diffuse; and asymmetrical or symmetrical. The corresponding apparent diffusion coefficient (ADC) values are decreased, suggesting restricted diffusion from spongiform encephalopathy.
•Intermediate CJD is characterized on DWI by progression of unilateral/asymmetrical lesions to greater contralateral/symmetrical involvement and progression of caudate lesions to involve the putamen (image 1). FLAIR images are very likely to show high signal abnormalities, but with less prominence than DWI. Generalized atrophy and ventricular dilatation may be apparent on all sequences.
Although primarily a disease of gray matter, sCJD can cause secondary white matter abnormalities in early to intermediate stages as demonstrated on both MRI and neuropathologic studies [125,126].
•Late or terminal CJD is characterized by prominent generalized atrophy and ventricular dilatation [97,101,114]. Limited data suggest that loss of abnormal cortical and basal ganglionic DWI high signal may occur in some but not all cases.
In the early and intermediate stages of CJD, FLAIR appears to be more sensitive than T2 imaging [127], but sensitivity and conspicuity are best with DWI (image 1 and image 3). The relative sensitivities of these methods in late CJD are unclear.
Other neuroimaging studies — MRI is superior to computed tomography (CT) in detecting abnormalities in patients with sCJD [94,95]. A head CT scan is generally normal and serves mainly to exclude other diagnoses. However, serial CT scans performed over several months may show rapid ventricular enlargement and progressive cortical atrophy in some patients [128].
Abnormal 18-F fluorodeoxyglucose positron emission tomography (FDG-PET), single-photon emission computed tomography (SPECT), and MRI spectroscopy have also been described in patients with sCJD [129-131]. However, these tests have not been evaluated sufficiently to assess their clinical utility [94]. Although there is a correlation between FDG-PET findings and neuropathology in cortical areas, as well as with clinical symptoms, the diagnostic utility of these findings is likely nonspecific [111,132,133].
PET scans utilizing amyloid tracers (18F-florbetaben) may crossreact with prion proteins as found in one case [134]; however, tau tracers (eg, 18F-AV-1451) do not appear to demonstrate positive results in sCJD [135]. sCJD may also result in an abnormal 123I-FP-CIT SPECT (DaTscan) [136].
Electroencephalogram — A characteristic EEG pattern of periodic synchronous bi- or triphasic PSWC is observed in 67 to 95 percent of patients with sCJD at some time during the course of the illness. This finding provides supportive but not definitive evidence for CJD.
The PSWC typical of sCJD are characterized by the following features [137]:
●Strictly periodic cerebral potentials, the majority with a duration of 100 to 600 milliseconds and an intercomplex interval of 500 to 2000 milliseconds
●Generalized and/or lateralized complexes
●At least five repetitive intervals with a duration difference of <500 milliseconds required to exclude semiperiodic activity
PSWC with these characteristics have a very high specificity for the diagnosis of sCJD and low interobserver variability. Studies have found that objective EEG criteria for sCJD have a sensitivity and specificity of approximately 65 and 90 percent, respectively, and positive and negative predictive values of 95 and 49 percent, respectively [137,138]. False-positive EEG results have been reported in Alzheimer disease and vascular dementia.
PSWC are helpful in the differentiation of sCJD from other prion disease [138].
●PSWC are occasionally found in patients with genetic CJD (gCJD), most commonly in patients who have the codon 200 mutation [139].
●PSWC are not found in patients with vCJD, kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), or fatal familial insomnia (FFI).
Other factors may contribute to the sensitivity of the PSWC finding:
●Disease duration – PSWC may not be recorded in the initial stages of the illness. The probability of recording PSWC corresponds to the amount of neuronal loss, and serial EEG recording may be useful in patients suspected of having sCJD when initial EEG recordings are negative [140]. PSWC typically disappear in later stages of sCJD, which are characterized by low voltage activity followed by electrocerebral inactivity [74,141].
●Molecular subtype – PSWC are less common in the thalamic variant of MM2 sCJD (ie, sporadic fatal insomnia [sFI]), as well as the MV2 and VV2 subtypes [74,76,142].
●Age – One analysis of 2083 patients with pathologically confirmed CJD found that the presence of PSWC steadily increased with age, from 22 percent in individuals <50 years old to 67 percent in those >70 years [74].
●Drugs such as barbiturates and benzodiazepines can mask PSWC.
●iCJD may also be less likely to be associated with PSWC [64].
The mechanism of PSWC is speculative, but attention has been called to the similarity of PSWC in sCJD to the EEG pattern seen in preterm newborns [138,140,143]; cortical degeneration due to sCJD may erode the normal physiologic sleep architecture, which is replaced by activity driven from an underlying midline pacemaker, possibly thalamic, and involved with the ascending reticulothalamocortical activating system [144].
Cerebrospinal fluid protein markers
Real-time quaking-induced conversion — Real-time quaking-induced conversion (RT-QuIC) is an assay in which disease-associated prion protein (PrPSc) initiates a conformational transition in recombinant prion protein (recPrP), resulting in the formation of amyloid that can be monitored in real time [145]. (See "Diseases of the central nervous system caused by prions", section on 'Detection of abnormal prion protein'.)
In one series with a validation cohort, the sensitivity and specificity of RT-QuIC were 87 to 91 percent and 98 to 100 percent, respectively [146]. In a United States sample, sensitivity and specificity of RT-QuIC were 92 to 95 percent and 98.5 to 100 percent, respectively [147]. Diagnostic sensitivity is higher in common sCJD molecular subtypes (eg, MM1 and MV1) and lower in less common subtypes (eg, VV1, MM2-C, and sFI) [83]. The National Prion Disease Pathology Surveillance Center based at Case Western Reserve University is the only clinical laboratory in the United States that performs RT-QuIC. CSF samples submitted to the Center also undergo 14-3-3 and tau analyses.
In one preliminary study that included 31 patients with CJD, RT-QuIC testing of olfactory epithelium obtained from nasal brushings was more sensitive (97 versus 77 percent) and similarly specific (100 percent) when compared with CSF testing; however, RT-QuIC on nasal brushings is not performed clinically in the United States [148,149].
14-3-3 protein — Detection of 14-3-3 protein in CSF should be considered an adjunctive rather than diagnostic test for the diagnosis of prion diseases as studies have reported mixed results regarding its sensitivity and specificity [74,150-154]. One systematic review reported an overall sensitivity of 92 percent and a specificity of 80 percent in diagnosing sCJD [155]. A specificity of 80 percent in a disease with a prevalence as low as that of CJD means that the vast majority of positive tests will represent false positives.
A negative test does not exclude the diagnosis, especially in cases of possible gCJD or nonclassical sCJD (eg, MM2 and MV2) in which the sensitivity of the test may be as low as 60 percent [74,76-78]. Other reports have found that the sensitivity may be lower in the very early stages and also the late stages of disease [74,78].
While positive results are frequent in nonprion diseases, a positive test slightly increases the probability of CJD when other clinical features are suggestive but not diagnostic [155]. False-positive elevations in CSF 14-3-3 have been noted in patients with a variety of neurologic diseases including herpes simplex encephalitis, hypoxic encephalopathy, cerebral metastases, paraneoplastic disease, and metabolic encephalopathies [78,151,156-158]. False-positive results are less likely, but have been described in neurodegenerative disease, including Alzheimer disease [78,158].
One investigation examined expression of this protein in cell cultures of neural and nonneural tissues and found the protein in all cell types, suggesting that the protein may be a marker of brain cell death rather than CJD [157]. Seven distinct isoforms of the 14-3-3 protein, with two phosphorylated subtypes, have been found in neurons. It has been suggested that CSF assays for one or more of the specific isoforms may have improved specificity for distinguishing sCJD from other dementias compared with the standard commercial 14-3-3 assay [159,160]. However, elevated CSF levels of most 14-3-3 isoforms are described in a variety of other conditions including Alzheimer disease, vascular dementia, metabolic and viral encephalopathies, and paraneoplastic syndromes, indicating that none of these assays will be diagnostic of prion disease.
Tau protein — An elevated tau level (>1150 picogram/mL) has superior accuracy and specificity when compared with 14-3-3 protein as a diagnostic test for CJD, although both tests produce significant numbers of false-negative and false-positive results [161-163].
In another study, patients with CJD were found to have elevated CSF tau levels, but not phosphorylated tau; an elevated ratio of total tau to phosphorylated tau levels had a very high specificity for CJD [160,164].
CSF total tau is also a prognostic marker for survival time in sCJD when used alone or with other variables (eg, age, codon 129, etc) [165,166].
Other CSF findings and tests — The CSF contains no cells and usually has normal glucose. An elevated CSF protein occurs in approximately 40 percent of patients with CJD [121]. An elevated white blood cell count, the presence of oligoclonal bands, or immunoglobulin G (IgG) index should prompt other diagnostic considerations such as autoimmune encephalitis.
A variety of other CSF diagnostic tests have been reported in small series, including S100 protein [79], neuron-specific enolase [163,167], and thymosin β4 [168]. Studies are also examining the diagnostic utility of CSF test combinations in detecting CJD [78,154,169]. The presence of any of the following markers was associated with good sensitivity of CSF analysis for detecting CJD: 14-3-3, tau, S100, and neuron-specific enolase [78]. However, the sensitivity still remained low (50 to 85 percent) for the nonclassical MV2 subtype of CJD, and specificity was also low overall (57 to 88 percent).
Other laboratory findings — Routine laboratory studies are typically normal in CJD. In one case series, elevated plasma levels of several acute phase reactants were noted in patients with CJD [170].
Investigational studies — Establishing the diagnosis of prion diseases by detecting abnormal prions outside of the central nervous system (CNS) remains a research goal [171]. Investigators have examined a variety of techniques to make the diagnosis on samples from skin, nasal mucosa, and peripheral nerves as well as spleen and skeletal muscle [172-179]. As yet, none of these assays have sufficient evidence of diagnostic utility to be recommended for clinical practice.
Prion protein diagnostic assays performed on blood samples are in development [146,180].
DIFFERENTIAL DIAGNOSIS — CJD must be distinguished from other dementias. Occasionally Alzheimer disease, dementia with Lewy bodies, and corticobasal degeneration are associated with myoclonus and a more rapidly progressive course than is typical, and are therefore mistaken for CJD.
A limited number of conditions that are relatively uncommon produce a syndrome of rapidly progressive dementia that can be mistaken for CJD. While these are uncommon, some are treatable, and therefore the evaluation should be thorough. Among others, the differential diagnosis should include paraneoplastic syndromes and autoimmune encephalitis. Thus, neuroimaging and cerebrospinal fluid (CSF) analysis is essential.
Early in the disease course, a primary psychiatric disorder may be suspected, as behavior and personality changes may be prominent and obscure accompanying cognitive deficits [63]. However, as the disease progresses and neurologic signs become more prominent, evaluation for a dementia syndrome is generally undertaken.
DIAGNOSIS — CJD should be suspected in patients who present with rapidly progressive dementia syndrome, particularly if accompanied by myoclonus, ataxia, and/or visual disturbances. Other potentially treatable disorders must be excluded.
Pathological studies of brain material to detect protease-resistant PrPSc (PrPres) remain the gold standard for the diagnosis of prion diseases. Although neuropathologic examination can be achieved via brain biopsy, a probable diagnosis of sporadic CJD (sCJD) can be made with noninvasive testing and is generally sufficient.
Diagnostic criteria — Criteria for the diagnosis of sCJD have been proposed [2,181-183]. Appropriate clinical and laboratory features generally are sufficient for a "probable" diagnosis of sCJD, while a definitive diagnosis requires neuropathologic confirmation [171].
The Centers for Disease Control and Prevention (CDC) outline two criteria for probable sCJD [184]:
●Neuropsychiatric disorder with a positive real-time quaking-induced conversion (RT-QuIC) test, or
●Progressive dementia, and
•At least two out of the following four clinical features:
-Myoclonus
-Visual or cerebellar disturbance
-Pyramidal or extrapyramidal dysfunction
-Akinetic mutism
•Supportive findings on one or more of the following tests:
-A typical EEG (eg, periodic sharp wave complexes [PSWC]) during an illness of any duration
-Positive 14-3-3 cerebrospinal fluid (CSF) assay with a clinical duration to death less than two years
-MRI showing hyperintensity in caudate nucleus/putamen and/or in at least two cortical regions (temporal, parietal, and occipital) on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR)
•Routine investigations should not suggest an alternative diagnosis
Neuropathology — While neuropathology provides a definitive diagnosis of CJD, a brain biopsy is not required in most patients and should only be undertaken with the purpose of excluding an alternative treatable etiology rather than to provide definitive evidence of prion disease [185]. In particular, a brain biopsy is generally not necessary in the setting of a positive RT-QuIC result, given its high specificity for sCJD, unless an alternative diagnosis is being entertained.
However, autopsies are important to definitively diagnose prion disease and determine the precise phenotype. Autopsy is especially important for surveillance reasons to monitor the possibility of acquired cases and possible emerging prion diseases (eg, the potential transmission of chronic wasting disease from deer/elk to humans). Autopsies of suspected CJD cases can be arranged through a CDC-funded autopsy program at the National Prion Disease Pathology Surveillance Center.
A definitive diagnosis of sCJD requires the clinical and laboratory features described above and one or more of the following neuropathologic findings, combined with the absence of PRNP gene mutations:
●Loss of neurons, gliosis, spongiform degeneration, or plaques positive for PrPSc on histopathology of brain tissue
●Positive PrPSc staining following pretreatment of brain tissue with proteinase K to destroy PrPC (normal prion protein) reactivity
●Positive immunoblotting of brain tissue extracts for PrPSc after treatment with proteinase to destroy PrPC reactivity
●Transmission of characteristic neurodegenerative disease to experimental animals
Immunohistochemistry techniques such as enzyme-linked immunosorbent assay (ELISA) and conformation-dependent immunoassay (CDI) can detect the presence and levels of disease-causing PrPSc in human brain tissue at autopsy or in biopsy samples. The CDI method has a higher sensitivity for the diagnosis of sCJD disease compared with routine neuropathologic examination and immunohistochemistry [186], but its specificity remains to be established. (See "Diseases of the central nervous system caused by prions", section on 'Detection of abnormal prion protein'.)
On gross examination, most cases show no more than expected age-associated brain atrophy, although marked atrophic changes may be seen in patients with long survivals.
The main histologic features of prion disease are (picture 1):
●Spongiform change – The vacuoles that create the spongiform change in CJD are round and between 20 to 50 microns in diameter (picture 2). Electron microscopy has revealed that the vacuolization is an intraneuronal process, and that synaptic loss is common.
Neurodegenerative and cerebrovascular diseases associated with severe neuronal loss can also produce status spongiosus as a common feature in end stages. This is a coarse microvacuolization with obvious severe neuronal loss and reactive astrocytosis. The vacuoles are larger and more irregular than those seen in CJD. Spongiform change in frontotemporal dementias is usually restricted to the upper cortical layers and to the frontal and temporal lobes, while full thickness spongiosis in dementia with Lewy bodies is usually restricted to the medial temporal lobes. Acute hypoxic-ischemic and other metabolic encephalopathies can also give this microscopic appearance, although with ischemia, eosinophilic neuronal degeneration parallels the severity of the edematous changes. Finally, inadequate tissue fixation or poor processing can cause artefactual changes that resemble prion vacuoles, but are characteristically much more obvious surrounding cell bodies and blood vessels.
●Reactive gliosis – Reactive gliosis without inflammation.
●Accumulation of the abnormal prion protein – Accumulation of the prion protein is detected by immunohistochemical techniques (picture 3). The prion protein can be distributed in several patterns: synaptic, perineuronal, perivacuolar, and plaque-like.
Certain prion protein diseases, including sCJD-MV2, kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and variant CJD (vCJD), are characterized by prion plaques visible on routine hematoxylin and eosin stain. (See "Variant Creutzfeldt-Jakob disease" and "Diseases of the central nervous system caused by prions", section on 'Neuropathology'.)
The pattern and distribution of prion protein deposition may be specific to the subtype of sCJD (see 'Subtypes of sCJD' above). As examples, MM1 and MV1 subtypes have been associated with the synaptic pattern of prion protein immunostaining; MV2 and VV2 with plaque-like and perineuronal immunoreactivity, especially prominent in the deep cortical layers, basal ganglia, and cerebellum; and MM2 with perivacuolar and coarse plaque-like formations [187]. Iatrogenic CJD (iCJD) related to dura mater grafts has also been associated with plaque formation [64].
TREATMENT AND PROGNOSIS — There is no effective treatment for CJD, which is uniformly fatal. Death usually occurs within one year of symptom onset, with a median disease duration of six months [57,188,189].
Supportive and symptomatic treatment — No effective treatment has been identified for human prion diseases, which are universally fatal [190]. Care for patients with prion disease is supportive and includes [185]:
●Early and effective communication with family. Provision of vetted educational materials may be particularly helpful in the case of sporadic CJD (sCJD), as the diagnosis may be unfamiliar to patients and their families or other caregivers. The CJD Foundation is a resource. (See 'Information for patients' below.)
●Social services referral to coordinate care needs, arrange for hospice evaluation, and counsel families or other caregivers on end-of-life and financial matters. Referral is appropriate at the time of diagnosis.
Many patients with CJD are working at the time of disease onset and may be eligible for disability payments. In the United States, CJD is one of the diseases that allows "fast track" eligibility for benefits. Further information is available at the Social Security Administration website.
●Capacity and competence assessment as relates to health care and financial decisions. (See "Assessment of decision-making capacity in adults".)
Symptomatic treatment is often appropriate for management of distressing or disabling neuropsychiatric symptoms. Nonpharmacologic as well as pharmacologic options are described in detail separately. (See "Management of neuropsychiatric symptoms of dementia".)
Myoclonus may respond to benzodiazepines (eg, clonazepam) as well as to certain antiseizure medications such as levetiracetam and valproate. Dosing and administration of these agents are described separately. (See "Treatment of myoclonus".)
Treatment with cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists are not expected to be useful in sCJD and are not administered, though cholinesterase inhibitors reportedly help alleviate psychotic symptoms in some cases [63].
Other aspects of the care of patients with advanced dementia are discussed separately. (See "Care of patients with advanced dementia".)
Investigational treatments — A number of potential therapies have been investigated in sCJD. While hampered by study limitations including heterogenous patient populations and small trial sizes, these studies have not demonstrated a treatment effect including symptom improvement or longer survival. Investigated therapies have included:
●Flupirtine – Flupirtine maleate is a centrally acting, nonopioid analgesic that has displayed cytoprotective activity in vitro in neurons inoculated with a prion protein fragment [191]. The mechanism of neuroprotective action is unknown, but it may involve upregulation of the antiapoptotic protein Bcl-2 [191,192]. Alternatively, its NMDA antagonist properties might limit glutamate-mediated neurotoxicity [193].
In a European study, 28 patients with CJD were randomly assigned to treatment with flupirtine or placebo [194]. Flupirtine treatment was initiated at 100 mg per day, and increased over three days to a maintenance dose of 300 to 400 mg per day, which was continued for a median treatment duration of 29 days. There was no significant effect of flupirtine treatment on survival time compared with placebo. However, the patients treated with flupirtine performed significantly better on the cognitive part of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Flupirtine-treated patients also did better on the Mini-Mental State Examination, but the difference did not reach statistical significance. Caregiver's impressions were also significantly better in the flupirtine-treated group.
●Pentosan polysulfate – Pentosan polysulfate (PPS) is a heparin mimetic thought to interfere with the conversion of PrPC to PrPSc. Because it does not cross the blood-brain barrier, it must be given intraventricularly. A United Kingdom observational study examining the use of PPS in several prion diseases demonstrated longer than expected survival times on some patients [195]. Similarly, a study conducted in Japan demonstrated a possible increase in survival time in some cases [196]. However, no improvement in clinical features was noted in either study, and treatment was complicated by frequent subdural effusions. This treatment is not generally considered at present.
●Quinacrine – Quinacrine and chlorpromazine, specific derivatives of acridine and phenothiazine, were found to inhibit PrPSc formation in a cultured neuroblastoma cell line (ScN2a) chronically infected with prions [197]. Quinacrine was approximately 10 times more potent than chlorpromazine in inhibiting scrapie formation in culture.
Observational studies and two randomized trials did not find an overall survival benefit for quinacrine for either sCJD or variant CJD (vCJD) [198-200]. However, one trial in 54 patients with sCJD did demonstrate slower decline in the first two months of treatment on two of three cognitive variables in sCJD [200].
●Doxycycline – The tetracyclines minocycline and doxycycline have demonstrated efficacy in in vitro and animal models of prion disease by presumably preventing protein misfolding of the pathologic form of the prion protein [201].
In one trial of 121 patients with CJD, no survival benefit was observed for treatment with doxycycline [202]. In a subsequent meta-analysis that included largely observational data, a slight increase in survival time in the doxycycline treatment group was observed (hazard ratio [HR] 0.63, 95% CI 0.402-0.999), particularly if given early in the disease course in some subjects [203]. Given the unclear clinically meaningful benefit of this study, doxycycline is generally not routinely prescribed. A clinical trial examining the possibility of using doxycycline as a prophylactic treatment for asymptomatic mutation carriers of the fatal familial insomnia (FFI) mutation is currently in progress [204].
●Genetic therapies/engineering – Given the importance of the PrPC to prion disease, some future treatments are focusing on genetic therapies/genetic engineering designed to lower the expression of PrPC (eg, antisense oligonucleotides). Theoretically, this treatment approach would be effective in sCJD and genetic CJD (gCJD) [205,206].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Creutzfeldt-Jakob disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Creutzfeldt-Jakob disease (CJD) is the most frequent of the human prion diseases, although it is still rare. Approximately one new case of sporadic CJD (sCJD) occurs per 1,000,000 population per year. The mean age of onset is approximately 62 years. (See 'Epidemiology' above.)
●Pathogenesis – sCJD is the most common prion disease; the prion protein in sCJD is thought to be generated endogenously rather than acquired. Iatrogenic CJD (iCJD) has followed administration of cadaveric human pituitary hormones, dural graft transplants, and other procedures and is rare now that these vectors have been removed from the health care system. (See 'Pathogenesis' above.)
●Clinical features – Rapidly progressive mental deterioration, often with behavioral abnormalities, and myoclonus are cardinal clinical manifestations of sCJD. Extrapyramidal signs such as hypokinesia and cerebellar manifestations are also common. (See 'Common symptoms and signs' above.)
Clinical phenotypes of sCJD have been associated with molecular subtypes determined by the prion protein (PRNP) gene codon 129 genotype and the pathologic prion protein (PrPSc) type. (See 'Subtypes of sCJD' above.)
●Differential diagnosis – CJD is distinguished from more common causes of dementia by its rapidly progressive course with prominent myoclonus and gait disturbance. Other autoimmune, infectious, malignant, and toxic-metabolic etiologies should be excluded before settling on a diagnosis of CJD.
●Evaluation and diagnosis – A classic clinical presentation, exclusion of other causes, and corroborating findings on brain MRI, EEG, and cerebrospinal fluid (CSF) are sufficient in most cases to establish CJD as the probable diagnosis. (See 'Diagnosis' above.)
•MRI should be performed according to a suggested protocol and typically shows 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. (See 'Brain MRI' above.)
•A finding of periodic sharp wave complexes (PSWC) on EEG has a high specificity for the diagnosis of CJD, but a low sensitivity. (See 'Electroencephalogram' above.)
•Tests on CSF samples that are sent to the National Prion Disease Pathology Surveillance Center (tau, real-time quaking-induced conversion [RT-QuIC], and 14-3-3 protein) can support the diagnosis of CJD. CSF RT-QuIC is the most sensitive and specific CSF diagnostic test for sCJD. The 14-3-3 protein test in CSF is a nonspecific test finding for CJD. (See 'Cerebrospinal fluid protein markers' above.)
●Neuropathology – While neuropathologic examination is the gold-standard test, brain biopsies are often unnecessary. However, autopsies are important to definitively diagnose prion disease and determine its specific phenotype. This is especially important for surveillance and can be arranged through a Centers for Disease Control and Prevention (CDC)-funded autopsy program at the National Prion Disease Pathology Surveillance Center. (See 'Neuropathology' above.)
The main histologic features of prion disease are spongiform change, reactive gliosis without inflammation, and accumulation of the abnormal prion protein detected by immunohistochemical techniques. (See 'Neuropathology' above.)
●Treatment and prognosis – There is no effective treatment for CJD, which is uniformly fatal. Death usually occurs within one year of symptom onset. Supportive and symptomatic treatments are advised. (See 'Treatment and prognosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Henry G Brown, MD, PhD, and John M Lee, MD, PhD, who contributed to earlier versions of this topic review.
3 : Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada.
30 : The not-so-good old days: working with pituitary growth hormone in North America, 1956 to 1985.
81 : The MM2-cortical form of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance.
163 : Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.
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