CREUTZFELDT-JAKOB DISEASE

Creutzfeldt-Jakob disease (CJD) is a rare and fatal human neurodegenerative condition that occurs worldwide. It is classified as a transmissible spongiform encephalopathy (TSE) because of characteristic spongy degeneration of the brain and its ability to be transmitted to laboratory animals. TSEs also affect a range of animal species including sheep, goats, cows, mink and deer.

Bovine spongiform encephalopathy (BSE), a TSE affecting cattle, was first reported in the United Kingdom in 1986 and over 168 000 cases have been reported since then in that country alone (see WHO Fact Sheet number 113 for more details on this disease). Relatively small numbers of cases have also been reported in native cattle in France, the Republic of Ireland, the Netherlands, Portugal and Switzerland. Small numbers of cases have also been reported in Canada, Denmark, the Falkland Islands, Germany, Italy and Oman, but solely in animals imported from the United Kingdom.

The United Kingdom Government made BSE a notifiable disease in June 1988 and shortly afterwards a statutory ban on the feeding of protein derived from ruminants (e.g., cattle, sheep and goats) to any ruminant was introduced. The use in the food chain of those bovine offals considered to pose a potential risk to humans was banned in the United Kingdom in 1989 and subsequently in other European Union countries where BSE was identified.

The nature of the TSE agent is being investigated and is still a matter of debate. According to one theory the agent is composed largely, if not entirely, of a self-replicating protein (the prion theory) whilst, according to another, the agent is virus-like and possesses nucleic acids which carry genetic information. Although strong evidence has become available over the past decade supporting the prion theory, the ability of the TSE agent to form multiple strains is more easily explained by a virus-like agent.

Different forms of CJD Until recently 3 forms of CJD had been recognized:

• Sporadic CJD, the most common subtype (85% of cases), usually affects individuals between the age of 50 and 75, and is characterised by a rapidly progressive dementia. The cause of sporadic CJD remains unknown and there is no evidence of a causal link with animal TSEs.
• Familial CJD (10-15% of cases) is an inherited disease associated with a gene mutation.
• Iatrogenic CJD (<5% of cases) results from transmission of the causative agent via medical or surgical treatment using accidentally contaminated materials, e.g. surgical instruments.

New variant CJD (nvCJD) is a new disease which was first described in March 1996. It is most likely linked with exposure to the BSE agent. In contrast to typical cases of sporadic CJD, this variant form has affected young patients (average age 27 years vs. 65 years) with a relatively long duration of illness (median 14 months vs. 4.5 months). Pathologically, the new variant demonstrates a consistent but previously unseen pattern. Twenty-two cases had been identified prior to September 1997, 21 in the United Kingdom and a single case in France.

Clinical features of nvCJD

Patients usually experience psychiatric symptoms early in the illness, which most commonly take the form of depression or less often a schizophrenia-like psychosis. Painful and persistent sensory symptoms have been experienced by half of the cases early in the illness. Neurological signs, including ataxia (unsteadiness) and involuntary movements, develop as the illness progressed and, shortly before death, patients become completely immobile and mute.

Diagnosis

The brainwave pattern was abnormal in most of the nvCJD patients, but the wave forms characteristic of sporadic CJD, did not develop in any case. Most cranial magnetic resonance scans were reported as normal but four cases were noted to have abnormal areas in a region at the base of the brain; this may become a useful diagnostic sign. Yet, currently the diagnosis of nvCJD can only be confirmed following pathological examination of the brain. Characteristically, multiple microscopic and abnormal aggregates encircled by holes are seen, resulting in a daisy-like appearance and the descriptive term "florid plaques".

The influence of genetic factors is demonstrated by the identification of a particular genetic variant in all 20 cases tested to date. This gene type has been found to occur in about two-fifths of unaffected people tested. It is possible however that nvCJD cases with other genetic types may occur in the future.

Epidemiology

The earliest onset of symptoms in what turned out to be nvCJD occurred in January 1994. All the patients lived in the United Kingdom, apart from the single French case. Some of the patients had been long-standing residents in Wales, Scotland or Northern Ireland, and there was no preponderance of patients from any single part of the United Kingdom. Information on potential risk factors has been published for ten cases. There is no convincing evidence to indicate that, as a group, these cases had an increased exposure to the BSE agent due to their occupations, diet or medical histories. Dietary histories are available for nine cases, all were reported to have eaten beef or beef products since 1986, but none were reported to have eaten brain. One of the cases had been a strict vegetarian since 1991.

Evidence of a link between nvCJD and BSE

The hypothesis of a link between nvCJD and BSE was first raised because of the association of these two TSEs in place and time. More recent evidence supporting a link includes identification of pathological features similar to nvCJD in brains of macaque monkeys inoculated with BSE, and the demonstration that nvCJD is associated with a molecular marker that distinguishes it from other forms of CJD and which resembles that seen in BSE transmitted to a number of other species.

The most recent and powerful evidence comes from studies showing that the transmission characteristics of BSE and nvCJD in mice are almost identical, strongly indicating that they are due to the same causative agent. It is also noteworthy that transgenic mice (mice carrying a human gene) have now been shown to be susceptible to BSE. Furthermore, no other plausible hypothesis for the occurrence of nvCJD has been proposed and intensive CJD surveillance in five European countries, with a low potential exposure to the BSE agent, has failed to identify any additional cases. In conclusion, the most likely cause of nvCJD is exposure to the BSE agent, most plausibly due to dietary contamination by affected bovine central nervous system tissue and with an incubation period of five-ten years. Insufficient information is available at present to make any well-founded prediction about the future number of nvCJD cases.

WHO involvement

Since 1991, WHO has convened six scientific consultations on issues related to animal and human TSEs. These meetings have made wide ranging recommendations aimed at protecting human and animal health. The last consultation was held in March 1997 and addressed in particular the issue of the safety of medicinal products. The potential future public health implications of nvCJD were addressed by a WHO consultation in May 1996. As exposure to the BSE agent may extend to populations outside the United Kingdom and Western Europe, it was recommended that to ascertain the number and distribution of any future cases, global surveillance of CJD and its variants would be required. Surveillance has already been established in many European countries, North America, Canada and Australia. Throughout 1997 and 1998 WHO will be running a series of training courses worldwide, particularly in developing countries, with the intention of helping individual countries establish national surveillance of CJD and its variants. The first workshop for Western African countries was held in Dakar, Senegal in June 1997. Similar workshops will be held soon: on 6-8 October 1997 in Bangkok for countries of South East Asia and in China for countries of the Western Pacific early in 1998.