Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease of unknown cause. Patients are usually aged between 50 and 75 and typical clinical features include a rapidly progressive dementia associated, myoclonus and a characteristic electroencephalographic pattern. Neuropathological examination reveals cortical spongiform change, hence the term `spongiform encephalopathy'.
H.G. Creutzfeldt is credited with the first description of the disorder in 1920, although by current diagnostic criteria his case would be highly atypical. A year later another German neurologist, A. Jakob, described four cases, at least two of whom had clinical features suggestive of the entity we recognise as CJD.
Although CJD appears to occur as a predominantly sporadic disorder it can also occur as a dominantly inherited or infective condition. The latter mode of transmission was first elucidated during the study of kuru in the 1950's. This neurodegenerative condition occurs only in the people of the Fore region of Papua New Guinea and is thought to have resulted from the consumption of brains during endocannabalistic funeral rituals. The similarities between kuru and scrapie, the transmissible spongiform encephalopathy of sheep, prompted a veterinary neuropathologist, Hadlow, to suggest that transmission studies of kuru be performed. The success of those studies and the recognition that the neuropathological changes in kuru were similar to those of CJD, was followed by the transmission of CJD to the chimpanzee by intracerebral inoculation of brain tissue. In 1974 a case of iatrogenic CJD due to corneal transplantation occurred and subsequently contaminated neuro-surgical instruments, dural grafts, and brain depth electrodes have all been recognised as transmitting the disease. In 1985 the first case was reported in a recipient of contaminated human derived growth hormone and subsequently over 60 similar cases have arisen world-wide in addition to 4 cases associated with human derived gonadotrophin. The familial occurrence of CJD has been recognised for many years but was unexplained. The discovery of linkage to a region on the short arm of chromosome 20 has led recently to the elucidation of various dominantly inherited mutations.
Aetiology
The nature of the transmissible agent is the matter of some controversy. Previously considered a `slow virus' no viral agent has ever been convincingly demonstrated and no evidence of an immunological response seen. Additionally the infectious pathogen shows a remarkable resistance to treatments that would normally be expected to inactivate viruses. The viral hypothesis has been elegantly challenged by the prion (`proteinaceous infectious particle') theory which states that the infectious agent is derived from a protease-sensitive protein (designated PrPc) which is a constituent of the normal cell membrane. It is postulated that the normal protein undergoes a post-translational conformational change forming the insoluble pathogenic form of the prion protein (PrPsc). This in turn induces more of the normal PrPc to form PrPsc - hence a chain reaction is set in motion with the exponential production of the insoluble prion protein being formed. The initial abnormal prion protein needed to seed this process may occur spontaneously as a rare event (which would account for the low incidence of sporadic CJD), following inoculation (accounting for observed transmission phenomena) or when initiated by a genetic abnormality of the PrP gene. The mechanism by which PrPsc induces the pathological changes in CJD - spongiform change, gliosis, neuronal loss and (infrequently) plaques remains unclear. Although the prion hyopthesis neatly explains many of the observed phenomena of transmissible spongiform encephalopathies (TSEs) it has one particular weakness. Scrapie is known to exhibit various `strains' characteristed by different incubation periods, clinical features and pathology when transmitted. This is much more in keeping with a virus-like agent and strain variation, independent of the host genome, is difficult to reconcile with the prion theory.
Epidemiology
The majority of cases are sporadic (85%), between 10-15% are familial and the remainder are iatrogenic.
CJD occurs worldwide with a roughly even incidence of between 0.5-1.0 cases per million per year. Higher rates (upto 100-fold) have reported in Slovakia and Libyan-born Israelis but this is explained by the high incidence of a certain mutation of the PrP gene in these groups. The geographical distribution of CJD in the United Kingdom over the past 25 years demonstrates no overall evidence of spatio-temporal aggregation of cases, despite the occurrence of local areas of relatively high incidence over short periods. There is no evidence of case to case transmission and spouses of sporadic cases do not have an increased incidence of the disease.
TSEs are known to affect various animal species including sheep, goats, mink, mule deer, cows and recently cats. Scrapie, a disorder of sheep and goats, has been known for over 300 years and is endemic in the British Isles. In 1938 experimental transfer of scrapie from one sheep to another by inoculation provided evidence of an infective aetiology. However there is no evidence of transmission of scrapie from sheep to man and there is no increased incidence of CJD in countries with scrapie compared to those without (e.g. UK and Australia).