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Creutzfeldt-Jakob Disease (CJD)

(Subacute Spongiform Encephalopathy; Creutzfeldt-Jakob's Disease)

By Pierluigi Gambetti, MD, Professor and Director, National Prion Disease Pathology Surveillance Center, Institute of Pathology, Division of Neuropathology, Case Western Reserve University

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Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. It occurs worldwide and has several forms and subtypes. CJD symptoms include dementia, myoclonus, and other CNS deficits; death usually occurs between 4 mo and 2 yr after infection, depending on the CJD form and subtype. Treatment is supportive.

CJD has three forms (1):

  • Sporadic (sCJD)

  • Familial

  • Acquired

sCJD is the most common type, accounting for about 85% of cases. sCJD typically affects people > 40 yr (median, about 60 yr).

Familial CJD occurs in about 5 to 15% of cases. Inheritance is autosomal dominant; age at onset is usually earlier than that in sCJD, and disease duration is longer.

Acquired CJD probably accounts for < 1% of cases. It has occurred after the ingestion of beef contaminated by prions (in variant CJD [vCJD]). Iatrogenic CJD (iCJD) has been acquired via use of cadaveric corneal or dural transplants, stereotactic intracerebral electrodes, or growth hormone prepared from human pituitary glands (2). About half of iCJD cases involve changes similar to those of Alzheimer disease, suggesting that in iCJD, a disorder that resembles Alzheimer disease (in addition to CJD) can be acquired iatrogenically (3).

Variant CJD (vCJD)

vCJD is a rare acquired form of CJD. Most cases have occurred in the United Kingdom (UK), which had 178 cases as of November 2016, compared with 53 cases in all other European and non-European countries. vCJD occurs after ingestion of beef from cattle with bovine spongiform encephalopathy (BSE), also called mad cow disease.

In vCJD, symptoms develop at a younger average age (< 30 yr) than in sCJD. In recent cases, the incubation period (time between ingestion of contaminated beef and development of symptoms) has been 12 to > 20 yr.

In the early 1980s, because of relaxed regulations for processing animal by-products, contaminated tissue, probably from sheep infected with scrapie or cattle infected with BSE, introduced the scrapie prion protein (PrPSc) into cattle feed. Hundreds of thousands of cattle developed BSE. Despite widespread exposure, relatively few people who ate meat from affected cattle developed vCJD.

Because the incubation period in BSE is long, a connection between BSE and contaminated feed was not recognized in the UK until BSE had become an epidemic. The BSE epidemic came under control after a massive slaughter of cattle and after changes in the rendering procedures, which drastically reduced contamination of meat by nervous system tissue. In the UK, the annual number of new cases of vCJD, which peaked in 2000, has steadily declined, with only 2 cases after 2011.

Four cases of vCJD have been linked to blood transfusion; they occurred in people who received transfusions between 1996 and 1999. In the UK, about 1/2000 people may carry vCJD (based on examination of a large number of appendix tissue samples) but have no symptoms; these people may transmit the disease if they donate blood or have a surgical procedure. Whether there is a latent pool of people who have received contaminated blood transfusions and who are thus at risk of later development of vCJD is unclear. However, new blood donor referral criteria related to vCJD may further reduce the risk of vCJD transmission by blood transfusion, which is already very low outside of France and the UK.

Although no case of vCJD originating in North America has been reported, BSE has been reported in a few North American cattle (4 in the US and 19 in Canada).

General references

  • 1. Gambetti P, Kong Q, Zou W, et al: Sporadic and familial CJD: Classification and characterisation. Br Med Bull 66 (1): 213–239, 2003. doi: https://doi.org/10.1093/bmb/66.1.213.

  • 2. Ritchie DL, Barria MA, Peden, AH, et al: UK Iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches. Acta Neuropathol 2016. [Epub ahead of print]

  • 3. Jaunmuktane Z, Mead S, Ellis M, et al: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525:247–250, 2015 doi:10.1038/nature15369.

Symptoms and Signs

About 70% of patients with CJD present with memory loss and confusion, which eventually develop in all patients; 15 to 20% present with incoordination and ataxia, which often develop early in the disease. Myoclonus provoked by noise or other sensory stimuli (startle myoclonus) often develops in the middle to late stages of disease. People with vCJD present with psychiatric symptoms (eg, anxiety, depression), rather than memory loss. Later symptoms are similar in both forms.

Although dementia, ataxia, and myoclonus are most characteristic, other neurologic abnormalities (eg, hallucinations, seizures, neuropathy, various movement disorders) can occur.

Ocular disturbances (eg, visual field defects, diplopia, dimness or blurring of vision, visual agnosia) are common in sCJD.

Diagnosis

  • Diffusion-weighted MRI

  • CSF markers

  • Exclusion of other disorders

CJD should be considered in elderly patients with rapidly progressive dementia, especially if accompanied by myoclonus or ataxia. However, other disorders can mimic CJD and must be considered; they include

  • CNS vasculitis

  • Rapidly progressive Alzheimer disease

  • Hashimoto encephalopathy (an autoimmune encephalopathy that is characterized by high thyroid antibody levels and that responds to corticosteroids)

  • Intravascular lymphoma (a rare lymphoma)

  • Encephalitis that affects the limbic system, brain stem, and cerebellum

  • Intoxication with lithium or bismuth.

CJD is suspected in symptomatic younger patients when they have been exposed to prion-contaminated beef in the UK or other at-risk countries or who have a family history of CJD (familial CJD). Rarely, sCJD develops in young patients, but in such patients, other diseases must be excluded.

Diagnosis of CJD may be difficult.

The best noninvasive diagnostic test for CJD is

  • Diffusion-weighted MRI

It can detect evolving patchy areas of hyperintensity (bright areas) in the cortical ribbon, which strongly suggest CJD.

Proteins 14-3-3, brain-specific enolase, and tau are commonly increased in CSF but are not specific for CJD. A relatively new CSF test, called real-time quaking-induced conversion (RT-QuIC), amplifies and detects minimal amounts of prion activity in CSF; this test appears to be more accurate than previous CSF tests (1). A similar test can reliably detect evidence of vCJD by identifying prions in urine.

EEG is done. Results are positive in about 70% of patients with CJD; EEG shows characteristic periodic sharp waves, but this pattern typically occurs late in the disease and may be transient.

Brain biopsy is usually unnecessary.

Diagnosis reference

  • 1. Foutz A, Appleby BS, Hamlin C, et al: Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 81 (1):79–92, 2017. doi: 10.1002/ana.24833.

Prognosis

Death typically occurs after 6 to 12 mo, commonly due to pneumonia. Life expectancy in vCJD is longer (averaging 1.5 yr).

Treatment

  • Supportive care

There is no treatment for CJD. Treatment is supportive.

Prevention

Because there is no effective treatment, prevention of transmissible CJD is essential.

Workers handling fluids and tissues from patients suspected of having CJD must wear gloves and avoid mucous membrane exposure. Contaminated skin can be disinfected by applying 4% sodium hydroxide for 5 to 10 min, followed by extensive washing with water.

Steam autoclaving at 132° C for 1 h or immersion in sodium hydroxide 1 N (normal) or 10% sodium hypochlorite solution for 1 h is recommended for materials that come in contact with tissues of patients with suspected or confirmed CJD. Standard methods of sterilization (eg, exposure to formalin) are ineffective.

The US Department of Agriculture (USDA) currently carries out BSE surveillance for 2000 to 5000 cattle/mo. In 2004, a positive BSE case in the US caused testing to be expanded to an average of 1000 cattle/day, but testing was later reduced to 40,000/yr (0.1% of the cattle that are slaughtered).

Key Points

  • Creutzfeldt-Jakob disease (CJD) is the most common human prion disease; the sporadic form accounts for about 85% of cases.

  • Acquired CJD, which probably accounts for < 1% of CJD cases, can result from ingesting beef contaminated by prions (in variant CJD [vCJD]) or can be acquired iatrogenically.

  • Most cases of vCJD have occurred in the United Kingdom (178 cases as of November 2016, with only 2 since 2011); 53 cases have occurred in all other European and non-European countries.

  • About 70% of patients with CJD present with memory loss and confusion, which eventually develop in all patients; 15 to 20% present with incoordination and ataxia.

  • Consider CJD in elderly patients with rapidly progressive dementia, especially if they also have myoclonus or ataxia, and suspect it in symptomatic younger patients who have been exposed to prion-contaminated beef or who have a family history of CJD.

  • Do diffusion-weighted MRI to check for evolving patchy areas of hyperintensity in the cortical ribbon, which strongly suggest CJD; also consider doing an RT-QuIC test on CSF.

  • Death typically occurs after 6 to 12 mo, but life expectancy in vCJD is longer, averaging 1.5 yr.

  • Steam autoclaving or immersing contaminated materials in sodium hydroxide or sodium hypochlorite is recommended to prevent spread.

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