8 World Health • SlstYeor, No. 4, July-August 1998
New-variant Creutzfeldt·Jakob disease
Martin Zeidler & Daniel Hahn
A
group of diseases afffecting the central nervous system occur in several animal species, including humans. These conditions are called transmissible spongiform encephalopathies (TSE).They can be passed from animal to animal in the laboratory and are characterized by spongy degenera- tion of the brain. The one that oc- curs most commonly in humans is called Creutzfeldt-Jakob disease (CJD). Until recently, TSEs in humans were thought to exist inde- pendently of those in other animals, but now the agent which causes them appears to have crossed the species barrier. At present there is no reliable pre-symptomatic test for TSE and no effective treatment has yet been found that can stop the underlying disease process.
A TSE affecting cattle - bovine spongiform encephalopathy (BSE) - was first reported in the United Kingdom in 1986, and since then about 170 OOO cases have occurred in that country alone. Small num- bers of BSE cases have also been reported in native cattle in Belgium, France, Ireland, Luxembourg, the Netherlands, Portugal and
Switzerland. Cases have also been found in Canada, Denmark, the Falkland Islands (Malvinas), Germany, Italy, and Oman in ani- mals imported from the United Kingdom.
Food ban
It is thought that BSE was caused by animals being given feed supple- ments made from the remains of sheep contaminated with scrapie - a TSE that affects sheep. A reduction in the use of solvents and heat in the manufacturing process in the United Kingdom around 1980, combined
Seen under the microscope, a specimen from the bro in of a victim of the new variant of Creutzfeldt·
Jakob disease demonstrates a consistent and previously unseen pattern of multiple florid plaques, which con be distinguished on the left of the photo. Photo WHO, by courtesy of Dr). Ironside
with other factors, may have been the cause of the transmissible agent remaining active. In 1989 brain, spinal cord and certain other organs from cattle - the specified bovine offals (SBO) considered to pose a potential risk to humans - were banned from foodstuffs in the United Kingdom. Other European Union countries that had identified cases of BSE later established thier own SBO list also banned their use in food.
Opinions differ as to the nature of the TSE agent. According to one theory (the prion theory) it is com- posed largely, if not entirely, of a self-replicating protein. A second theory is that the agent is similar to a virus and possesses nucleic acids which carry genetic information.
Evidence gathered over the past 10 years supports the prion theory, but the TSE agent is able to form multi- ple strains, and this is more like the behaviour of a virus.
Four different forms of CJD have been identified: sporadic, familial, iatrogenic, and new variant.
• Sporadic CJD, which accounts for about 85% of cases, usually affects individuals between the
ages of 50 and 75, and is charac- terized by a rapidly progressive dementia, jerking movements of the limbs, and a specific abnor- mal brain wave pattern. The cause of sporadic CJD remains unknown and there is no evi- dence of a causal link with any animal TSE.
• Familial CJD accounts for 10-15% of cases and is an inher- ited disease associated with a gene mutation.
• Iatrogenic CJD, accounting for less than 5% of cases, results from the accidental transmission of the causative agent from contaminated materials - such as neurosurgical instruments - during medical or surgical treat- ment.
• New variant CJD (nvCJD) is a new disease which was first reported in March 1996 and which is probably linked with exposure to the BSE agent.
Unlike most cases of CJD this variant form has affected young people. The average age of patients with nvCJD is 27 years compared with 65 years for other
World Health • SlstYear, No. 4, July-August 1998
forms of CJD; and the illness generally lasts longer - 14 months on average compared with 4-5 months. When viewed under a microscope, the brain of patients with the new variant demonstrates a consistent but previously unseen pattern.
Clinical features
Patients with nvCJD usually experi- ence psychiatric symptoms early in the illness which most commonly take the form of depression, or less often a schizophrenia-like psychosis.
Persistent and unpleasant sensory symptoms, such as tingling or burn- ing feelings, have been experienced by half of the cases early in the illness. Neurological signs, includ- ing unsteadiness and involuntary jerking or fidgeting, develop as the illness progresses, and just before death patients are unable to move or to talk. It is important to note that depression and sensory symptoms are common in the general popula- tion and are usually not due to any serious underlying disease.
The first patient with nvCJD became ill in January 1994. By the end of June 1998, 28 cases had been identified - 27 in the United Kingdom and one in France. There was no concentration of cases in any particular area of the United
Kingdom. Moreover, the occupa- tions, diets and medical histories of the cases do not provide convincing evidence that, as a group, they might have had a greater exposure to the BSE agent than the rest of the popu- lation. Information on the potential risk factors has been published for 10 cases; nine cases were reported to have eaten beef or beef products since 1986, but none was reported to have eaten brain. One of the cases had been a strict vegetarian since 1991.
Diagnosing new variant CJD
Patients with the new variant CJD do not have the characteristic brain wave pattern of sporadic CJD. Blood and spinal fluid tests are normal or
Processing beef in the United Kingdom.
The ports which are considered to pose a potential risk to human health are discarded and destroyed Photo WHO, by courtesy of Or B. Hornlimann
unhelpful. Four cases were reported to have a specific abnormality re- vealed by magnetic resonance brain scanning and this may in future be a useful diagnostic sign. At present, the diagnosis of nvCJD can only be confirmed following examination of the brain under the microscope.
Characteristically, multiple minute protein aggregates surrounded by holes are seen, with a daisy-like appearance, described as "florid plaques" (see photograph, p.8). All 23 cases tested to date were in people with a particular genetic characteris- tic found in only 40% of the general population. It is possible, however, that nvCJD may occur in people with other genetic features in the future.
New evidence
Cases of nvCJD and BSE started to increase in the same countries at around the same time which led to the hypothesis that they were linked.
Scientific evidence further support- ing a link includes the identification of microscopic features similar to nvCJD in the brains of monkeys inoculated with BSE, and the demon- stration that nvCJD is associated with a molecular marker that distin- guishes 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 show- ing that the transmission characteris- tics of BSE and nvCJD in mice are almost identical, strongly suggesting that they are due to the same
causative agent. In addition, trans- genic mice carrying an important human gene have been shown to be susceptible to BSE, and no other convincing hypothesis for the occur- rence of nvCJD has been proposed.
Intensive CJD surveillance in five European countries with low poten- tial exposure to the BSE agent has failed to identify any cases. In con- clusion, the most likely cause of nvCJD is exposure to the BSE agent, probably in food contaminated by affected cattle brain or spinal cord.
We do not have sufficient informa- tion at present to make any well- founded prediction about the future number of nvCJD cases.
WHO global surveillance
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Since 1991 WHO has convened seven scientific consultations on issues related to animal and human TSEs. The potential future public health implications of nvCJD were examined by a WHO consultation in May 1996 and reviewed in February 1998. As exposure to the BSE agent may extend to populations outside the United Kingdom and western Europe, strengthened global surveil- lance of CJD and its variants was recommended in 1996 in order to determine the number and distribu- tion of any future cases. Surveillance has already been established in many European countries, Australia, Canada and the United States of America, and WHO is initiating surveillance in other, mainly devel- oping, countries. It is anticipated that these activities will provide information that is important for enhancing the protection and plan- ning of public health worldwide. •
Or Martin Zeidler is with the Department of Clinical Neurology, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland Or Daniel Hahn's address is 30A Clapham Road, London SW9 OJQ, England
