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  • Updated 04.23.2021
  • Released 10.27.1993
  • Expires For CME 04.23.2024

Creutzfeldt-Jakob disease

Introduction

Overview

The author reviews Creutzfeldt-Jakob disease, a member of the group of diseases known as prion diseases or the subacute spongiform encephalopathies. Creutzfeldt-Jakob disease has a subacute clinical course and distinctive gray matter pathology. This disease is transmissible and is induced by an abnormal form of the prion protein that is extremely resistant to physical and chemical inactivation. The unusual nature of the transmissible agent and the emergence of variant Creutzfeldt-Jakob disease (as a result of ingestion of contaminated beef) have had a significant impact on public health in addition to science and medicine. The most recent epidemiological information suggests there will not be an epidemic of variant Creutzfeldt-Jakob disease. New diagnostic tests, such as protein misfolding cyclic amplification and real time quaking-induced conversion (RT-QuIC), and new ideas about treatment of Creutzfeldt-Jakob disease are discussed.

Key points

• The transmissible subacute spongiform encephalopathies, also known as prion diseases, have a similar noninflammatory spongiform pathology and are caused by a similar transmissible agent -- an abnormal (“scrapie-like”) protease-resistant conformation of the prion protein (PrP), which is designated PrPSc

• Creutzfeldt-Jakob disease is a subacute fatal disease with a clinical triad of dementia, myoclonus, and EEG abnormalities that is usually associated with other neurologic signs, along with neuropathological evidence of neuronal loss, spongiform changes, and astrocytosis.

• A new test that makes use of protein misfolding cyclic amplification (real time quaking-induced conversion, RT-QuIC) has high sensitivity and specificity and is extremely valuable in making the diagnosis.

• Iatrogenic cases of Creutzfeldt-Jakob disease have been described related to corneal transplantation, implantation of intracerebral electrodes (inadequately sterilized with formaldehyde), growth hormone injection (from pooled pituitary glands), and dura mater implantation (from pooled dura mater).

• A variant form of Creutzfeldt-Jakob disease caused by bovine spongiform encephalopathy (mad cow disease) is distinctive because of the relatively young age of the patients, frequent behavioral abnormalities early in the disease, few EEG abnormalities, an MRI finding of increased signal in the pulvinar, and abundant “florid” plaques in the brain (similar to those seen with kuru).

• Prion diseases are transmissible after a prolonged incubation period by inoculating the infected CNS into nonhuman primates and some other species via multiple routes of inoculation; however, transmission is most efficient with an intracerebral inoculation into a species identical to the source of the infected CNS tissue.

Historical note and terminology

Jakob deserves credit for being one of the first to draw attention to a clinical and pathologic syndrome that we now refer to as Creutzfeldt-Jakob disease. Although Jakob believed that a previously published case by Creutzfeldt had the same clinical and pathological condition, this patient is now thought to have probably suffered from another disease process. In 1959, Klatzo and colleagues remarked on the similarity between the neuropathology of Creutzfeldt-Jakob disease and kuru, a noninflammatory ataxic spongiform encephalopathy found among the Fore tribesmen of the Eastern Highlands of Papua, New Guinea (30). In 1966 kuru was transmitted to nonhuman primates following intracerebral inoculation of CNS tissue (19); this prompted the inoculation of nonhuman primates with Creutzfeldt-Jakob disease-infected brain and its successful transmission (23).

Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, sporadic fatal insomnia, and a number of animal diseases (including scrapie, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk) are grouped as prion diseases, or transmissible subacute spongiform encephalopathies, because of their similar clinical and pathologic features and their transmissibility (19).

Table 1. Human Prion Diseases

Human prion diseases

Description

Etiology

Kuru

Cerebellar disease of New Guinea, now eradicated

Infection from endocannibalistic ritual

Creutzfeldt-Jakob disease

• Sporadic

Dementia, myoclonus, and other neurologic signs. Positive CSF RT-QuIC test. MRI DWI can show cortical ribboning. EEG can show periodic sharp wave complexes.

Unknown

• Familial

Autosomal dominant with clinical features similar to sporadic CJD

Mutation in PrP gene, PRNP

• Iatrogenic

Clinical features similar to sporadic CJD except frequent cerebellar signs

Infection from corneal transplants, intracerebral electrodes, dura mater grafts, growth hormone administration

• Variant

Early age of onset with psychiatric/behavioral symptoms. Declining incidence.

Infection from bovine spongiform encephalopathy tissue

Gerstmann-Sträussler-Scheinker disease

Autosomal dominant usually with cerebellar dysfunction and slower tempo than CJD.

Mutation in PrP gene, PRNP

Fatal insomnia (either sporadic or familial)

Insomnia, autonomic abnormalities

Sporadic – unknown
Familial – mutation in PrP gene, PRNP

The transmission of these diseases is of special interest because of the noninflammatory nature of the clinicopathologic syndrome, the long incubation period (ie, a “slow virus infection”), and the unusual nature of the transmissible agent, the prion (52; 54). The importance of these diseases was demonstrated by the award of the Nobel Prize to Gajdusek and Prusiner in 1976 and 1997, respectively. The prion diseases became more visible because of an epidemic of bovine spongiform encephalopathy (“mad cow” disease), found primarily in the United Kingdom, with the subsequent emergence of a variant of Creutzfeldt-Jakob disease. Variant Creutzfeldt-Jakob disease is thought to result from oral transmission of the bovine spongiform encephalopathy agent to humans. The recognition of chronic wasting disease as a prion disease of deer and elk in the United States has also focused attention on prion diseases.

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