Creutzfeldt-Jakob Disease (CJD)

Overview

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of progressive neurodegenerative disorders in humans and animals. The causative agents of TSEs are believed to be prions. Prion proteins are normal cellular proteins that are found most abundantly in the brain, and the function of these proteins are still not completely understood. The term “prions” refers to abnormal, pathogenic prion proteins that are transmissible and are able to induce abnormal folding of normal cellular prion proteins. As the amount of abnormal prion protein grows, it becomes hard to break down, causing brain degeneration and neurologic disease. Prion diseases are always fatal and have long incubation periods that are often measured in years. Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. Sporadic CJD makes up 85-95% of all CJD cases, followed by genetic or familial CJD with 5-15% of cases; <1% of cases are iatrogenic or variant CJD.

Organism/Etiologic Agent

Prion (infectious protein)

Transmission

• Sporadic CJD (sCJD) – No recognizable pattern of transmission or is unknown, but is not thought to be acquired
• Genetic CJD (gCJD) – Also called familial CJD (fCJD); is inherited and is due to a mutation in the prion protein gene
  • Gerstmann-Sträussler-Scheinker syndrome (GSS) – a rare genetic human prion disease
  • Fatal familial insomnia (FFI) – a rare genetic human prion disease
     
• Iatrogenic CJD (iCJD) - Iatrogenic CJD is associated with certain surgical or medical procedures, for example, neurosurgical procedures using contaminated instruments, corneal transplants, dura mater grafts, administration of contaminated cadaver derived human pituitary hormones, and stereotactic electroencephalogram (EEG) electrodes

  • Dural graft transplants and use of pituitary hormones from cadavers (particularly human growth hormone) account for the vast majority of iCJD cases. However, these iCJD cases have been largely eliminated due to changes in procedures used to prepare dural grafts or use of synthetic dural grafts and use of synthetic/recombinant human growth hormone.

  • Cases due to contaminated equipment occurred before the routine implementation of sterilization procedures currently used in healthcare facilities, and no cases have been reported since 1976. Refer to CDC’s website for CJD infection control and prevention recommendations.
     
• Variant CJD (vCJD) – Has been associated with consumption of beef products from cattle infected with bovine spongiform encephalopathy (BSE or “mad cow disease”); several iatrogenic cases of transfusion-related vCJD have been reported in the United Kingdom (donors developed vCJD or symptoms of vCJD after donation) and several laboratory-associated vCJD cases have been reported in France and Italy
  
  No vCJD cases have been linked to exposure in the United States.

Symptoms

• Sporadic CJD (sCJD) – Symptoms may include rapidly progressive dementia, myoclonus, ataxia, vision, and speech difficulties, as well as other symptoms. Sporadic CJD typically occurs in persons greater than 55 years of age, with a median age at death of 68 years of age. However, it has been reported in individuals younger than 55 years of age, but rarely younger than 30 years of age. Death usually occurs within one year of illness onset, and the median duration from illness onset to death is 4-5 months.
• Genetic CJD (gCJD) – Symptoms and duration of illness closely resemble sCJD but can vary within families and depend on the type of genetic mutation. Genetic CJD cases have a slightly younger mean age of onset compared with sCJD cases.
  • GSS – symptoms include progressive ataxia with cognitive and sensory abnormalities that typically begins in mid-life (30s-50s) and duration can be from 2-10+ years
  • FFI – symptoms include characteristic sleep disorders, autonomic disease, and gait disturbance that typically begins in mid-life and duration is several months to 5 years
• Iatrogenic CJD (iCJD) – Symptoms vary depending on the mode of transmission, but clinical and pathological features are often indistinguishable from sCJD. Human gonadotropin and human growth hormone treatment, as well as dura mater grafts, tend to begin as a cerebellar syndrome early in the disease course. However, infected dura mater grafts have also been noted to cause symptoms that relate to the anatomic placement of the graft. The age at onset depends on the age at exposure, and on the incubation period. Cases can be younger, however incubation periods can last decades. The reported or estimated mean time of occurrence is 9-10 years after administration of human growth hormone and dural graft transplants but can be from 5-40+ years. The mean incubation period after contaminated neurosurgical instrument exposure is 1.4 years. For additional information on iCJD, view the Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment article.
• Variant CJD (vCJD) – Symptoms may include early psychiatric/behavioral symptoms and sensory symptoms (ex. dysesthesia/paresthesia) progressing to ataxia, dementia, chorea/dystonia or myoclonus, and/or akinetic mutism. Variant CJD typically occurs in persons less than 55 years of age (median age at death in the United Kingdom is 28 years of age), and the mean duration of illness is 13-14 months.

Testing

Better diagnostic testing has improved CJD surveillance in Texas. In 2015, the National Prion Disease Pathology Surveillance Center (NPDPSC) introduced the 2nd Generation Real-Time Quaking Induced Conversion test or RT-QuIC, an ante-mortem cerebrospinal fluid (CSF or spinal fluid) test for the abnormal/pathogenic form of the prion protein. Though this test may aid physicians in the investigation of illness with rapidly progressive dementia, it is not a confirmatory test. Neuropathological analysis of autopsied whole brain tissue remains the only method for confirming or ruling-out prion disease.

Brain tissue is preferably obtained by autopsy rather than biopsy, as neuropathological analysis of biopsied brain tissue cannot rule out prion disease, and brain biopsies are generally not required unless a physician is trying to exclude an alternative treatable disease. Efforts continue to educate the public and medical providers of the importance of confirming a prion disease diagnosis and the services available to those interested in confirmatory testing. Please see the NPDPSC website for more information about the Autopsy Coordination Program, and other services offered.

Additional ante-mortem tests that may assist with diagnosis include 14-3-3 protein and total Tau protein in CSF, brain magnetic resonance imaging (MRI), and electroencephalogram (EEG). Blood testing, or other specimen types, can be utilized for genetic testing if a genetic form of CJD is being considered.

Treatment & Prevention

There is no known prevention or treatment that will stop progression of these fatal diseases, but there is ongoing research for therapies.

Recent Texas Trends

Prion disease surveillance monitors the occurrence of prion diseases in the United States, but it also monitors for the emergence of vCJD and other potentially preventable new prion diseases, as well as for rare classic forms of prion diseases that are attributable to medical procedures. Prion disease surveillance also helps assess the efficacy of ongoing U.S. prevention measures.

CJD has been a NOTIFIABLE CONDITION in Texas since 1998, and it was likely under-reported and misdiagnosed for many years. For 15 years now, Texas has carried out enhanced surveillance (passive and active surveillance) for CJD, including sporadic, familial/genetic, and acquired (iatrogenic and variant) CJD. The success of this program is demonstrated by the identification and confirmation of sporadic (sCJD), familial (fCJD) and variant CJD (vCJD), as well as cases of Variably Protease Sensitive Prionopathy (VPSPr), Fatal Familial Insomnia (FFI), sporadic Fatal Insomnia (sFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. From 2012-2021 Texas reported 309 confirmed, probable and possible cases, of which there were 282 sCJD, 19 fCJD, 1 vCJD, 1 FFI, 1 sFI, and 5 VPSPr cases. Texas also investigates higher priority suspect cases, such as suspect cases in persons <55 years old, as vCJD is rarely found in individuals >55 years old, reported suspected clusters, suspected iatrogenic cases, and suspected cases and cases with risk factors that could expose them to other prion diseases, such as chronic wasting disease of deer, elk, moose, and other cervids.

In 2014, Texas had the 4^th US variant CJD case; the person was likely exposed to the infectious agent before moving to the United States. A full description of the case can be found at: https://stacks.cdc.gov/view/cdc/30921 or https://www.cdc.gov/eid/article/21/5/pdfs/14-2017.pdf.

Maheshwari A, Fischer M, Gambetti P, Parker A, Ram A, Soto C, Concha-Marambio L, Cohen Y, Belay ED, Maddox RA, Mead S, Goodman C, Kass JS, Schonberger LB,Hussein HM. Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications. Emerg Infect Dis. 2015 May;21(5):750-9. doi:10.3201/eid2105.142017. PubMed PMID: 25897712; PubMed Central PMCID: PMC4412247.

The Centers for Disease Control and Prevention (CDC) reports a worldwide (including the United States) CJD incidence rate of approximately 1-2 cases per million population per year, and from 2016-2020 the average annual rate in the United States was approximately 5 cases per million population per year in persons 55 years of age or older.

In Texas, the average rate of deaths per million population due to CJD over the past 10 years (2012-2021) is 1.1 cases per million population per year. The average rate over two consecutive 5-year periods, 2012-2016 & 2017-2021, are 0.85 & 1.31 (cases per million population per year), respectively. There has been an increase in CJD cases over the last several years, and this can be attributed to several factors. The population of Texas is increasing but also aging, the availability of a new more sensitive test, the RT-QuIC test, in 2015, as well as increased awareness of this testing and confirmatory testing available at the NPDPSC, has increased the surveillance capacity for human prion diseases in Texas (increased reporting and antemortem diagnosis of CJD). The intensity of surveillance methods can also influence the reported incidence of CJD, and other prion diseases. CDC also updated their criteria for classifying a CJD case, and this was implemented in Texas in 2019. The combination of a positive RT-QuIC CSF result with neuropsychiatric symptoms allows for decreased reliance on the presence of specific neurologic symptoms to classify a case of CJD. This has permitted the classification of CJD cases that previously may not have been counted. The change in the CJD criteria is evidence of the incorporation of scientific data into surveillance system approaches to count cases more accurately. In 2019, the number of CJD cases and the overall rate of CJD increased, however, in the majority of cases brain tissue was examined and there were no unusual findings. Also, only four of the 2019 cases were <55 years of age, all of whom had autopsies, and the brain tissue analysis did not reveal any unusual neuropathology. In 2020, the number of CJD cases and the overall rate of CJD decreased from 2019. This may be an influence from the COVID-19 pandemic and decreased seeking of healthcare; however, the rate did not significantly decrease like some other infectious diseases reported to public health. The number of cases that had brain tissue examined also decreased in 2020, and there was a higher number of cases in individuals <55 years of age. In 2020, nine cases were <55 years of age, of which three cases had brain tissue examined and there were no unusual findings, and six cases did not have brain tissue examined. In 2021, the number of CJD cases and overall rate of CJD increased but did not surpass the 2019 case count. The number of cases that had brain tissue examined increased from 2020 from 14 to 20 cases, and none of the cases were <55 years of age. There was only one case in 2021 that was <55 years of age, and brain tissue was not examined. Decreased brain tissue analysis in the last several years could be an influence of the COVID-19 pandemic and response, increased trust by physicians in RT-QuIC CSF results and less reliance on autopsy results, decreased consent to autopsy by the patient or family, or other factors. However, fluctuations in the rates of rare diseases, data obtained via CJD surveillance systems, and demographics of cases is expected from year to year. The rate of CJD decreased from 2019 to 2020 and then increased from 2020 to 2021, however small changes in case counts can lead to larger changes in rates, and with increased surveillance in Texas, a rate closer to 1.5 cases per million population per year may be more representative of CJD cases in Texas. There have also been efforts to increase autopsy rates, and the rate of cases that have brain tissue analysis will be monitored over time. All other CJD data will continue to be evaluated on an ongoing basis.