Infections in Humans
Infections in Animals
Bovine spongiform encephalopathy (BSE) feline spongiform encephalopathy (FSE), variant Creutzfeldt-Jakob disease (vCJD) and spongiform encephalopathy of exotic ruminants appear to be related diseases. All four diseases appeared at the same time, during an epidemic of BSE in the United Kingdom. The causative agent(s) are generally thought to be prions; a minority opinion is that they may be virinos or retroviruses.
BSE appears to have originated in the United Kingdom in 1985. Infected cattle have since been found in numerous European countries, including Portugal, Ireland, Switzerland, Belgium, Spain, Germany, France, Slovakia, Italy, the Netherlands, Denmark, Slovenia, Greece, the Czech Republic, Finland, Austria and Poland. Albania, Bulgaria, Croatia, Cyprus Republic, Estonia, Hungary, Latvia, Lithuania, Luxembourg, Romania, San Marino Republic and Turkey are also likely or confirmed to have BSE. Israel and Japan reported their first cases in 2002. Cases have also been seen in imported cattle in Liechtenstein, the Falkland Islands and Canada. BSE has not been detected in Australia, New Zealand, the United States or South America. As a result of control measures, the current epidemics in the United Kingdom and Switzerland appear to be diminishing.
FSE and Spongiform Encephalopathy of Exotic Ruminants
FSE has been found almost exclusively in the United Kingdom, with a single isolated case in a cat in Norway. Spongiform encephalopathy of exotic ruminants has been detected only in captive ruminants in the United Kingdom. These two diseases have been declining in parallel with the BSE epidemic.
Variant Creutzfeldt-Jakob disease
The vast majority of cases of vCJD have occurred in the United Kingdom. Six cases have been reported from France and one each from Ireland, Italy and the United States. The patient in the United States lived in the United Kingdom from 1979 to 1992 and was probably infected there during the BSE epidemic.
BSE, FSE, vCJD and spongiform encephalopathy of exotic ruminants all seem to be transmitted orally. BSE is thought to have mutated from the scrapie agent, found in sheep. The first cases of BSE appeared in the U.K. in 1985 and have been linked to changes in the rendering practices for livestock feed. These changes may have allowed infectious meat or bone meal from scrapie-infected sheep to be fed to cattle. Rendering of contaminated cattle carcasses and wastes seems to have amplified the agent. A minority of researchers believes that BSE has always existed in cattle but was unrecognized until the outbreak in the U.K.
The BSE agent is found mainly in nervous tissues. In naturally infected cattle, it has been detected only in the brain, spinal cord, and retina. In experimentally infected calves, it is also seen in the distal ileum. This agent has never been found in muscle, blood, or milk, and natural infections do not seem to spread laterally between cattle. The offspring of BSE-infected cattle have an increased risk of developing BSE, but it is not known whether this is due to vertical transmission.
Spongiform Encephalopathy of Exotic Ruminants
The outbreak of spongiform encephalopathy of exotic ruminants paralleled the BSE epidemic, and may have been due to the same agent. Experimentally, this spongiform encephalopathy can be transmitted both orally and parenterally. Vertical transmission is uncertain: two offspring of affected animals developed the disease, but vertical transmission has not been seen in experimental infections.
The BSE agent or a related agent may also have been the source of FSE. In domestic cats, the source of infection was thought to be pet food that contained cattle offal. Wild cats in zoos may have been infected when they were fed cattle carcasses.
Variant Creutzfeldt-Jakob disease
The first cases of vCJD in humans appeared almost 10 years after the first cases of BSE in cattle. The source of vCJD has not been definitively identified but appears to be beef, most likely products contaminated by nervous system tissue. Genetic factors may play a role in infection: to this date, all patients with clinical disease have been homozygous for methionine at codon 129 of the prion protein gene.
The prototype agent, scrapie, is highly resistant to disinfectants, heat, ultraviolet radiation, ionizing radiation and formalin. Effective disinfection is possible with a single porous load autoclave cycle of 134-138°C for 18 minutes. Infectious tissues should either be autoclaved under the same conditions or incinerated. A 4% sodium hydroxide or 10% sodium hypochlorite solution is effective if it is applied for more than 1 hour at 20°C. Overnight disinfection is recommended for equipment.
The incubation period in humans has not been established, but appears to be at least several years. The first case of vCJD appeared in 1994, almost a decade after BSE first appeared in cattle.
Variant CJD is similar to the classic (genetic) form of CJD, but the clinical signs usually appear in younger patients; the median age of onset is 26 years of age for vCJD, and 68 years for classical CJD.
The first signs are usually psychiatric symptoms, including anxiety, depression, and social withdrawal. Some patients also develop persistent painful sensory symptoms. Frank neurologic signs, including gait disturbances, ataxia, incoordination, slurring of speech and tremor usually appear several months later. Chorea, dystonia, myoclonus and dementia typically develop late in the course of disease. Variant CJD usually progresses over years, compared to months for classic CJD.
Person to person transmission of either vCJD or classic CJD has not been seen during casual contact. In rare cases, classic CJD has been transmitted during medical procedures such as corneal and dura mater grafts. It may be possible to spread CJD by liver transplants, blood transfusions, pituitary-derived human growth hormone injections and contaminated brain electrodes.
The definitive diagnosis of vCJD is by microscopic examination of brain tissue, usually at necropsy. Numerous amyloid plaques surrounded by vacuoles are found; such plaques are seen in only 5 to 10% of cases of classic CJD. Large amounts of prion protein can be found around the plaques by immunohistochemistry.
A tentative diagnosis can be made before death by the history, clinical signs and cortical atrophy on magnetic resonance imaging (MRI) of the brain. The abnormal prion protein may be found in tonsil biopsies by Western blot and immunohistochemistry. The electroencephalogram (EEG) is sometimes normal during the early stages of disease, but later develops characteristic abnormalities.
Treatment and Vaccination
No treatment or vaccine is available. The possible benefits of quinacrine are being investigated.
Morbidity and Mortality
From 1993 to October 2002, 138 cases of vCJD were reported worldwide. Only small increases were seen in vCJD cases during the first 6 years. The full extent of the outbreak is not yet known; mathematical models predict from fewer than one hundred to hundreds of thousands of cases, depending on the exact length of the incubation period and other factors.
Most cases of vCJD have occurred in the United Kingdom. One case has been confirmed in a resident of the United States who lived in the United Kingdom from 1979 to 1992. Genetic factors may play a role in infection: to this date, all patients with clinical disease have been homozygous for methionine at codon 129 of the prion protein gene. The mortality rate is 100%.
BSE is seen in cattle and can be experimentally transmitted to cats, mink, mice, pigs, sheep, goats, marmosets and cynomolgus monkeys. FSE has been found in domestic cats and captive wild cats, including tigers, a puma, an ocelot and a cheetah. Spongiform encephalopathy of exotic ruminants has been seen in captive nyala, gemsbok, Arabian oryx, eland, kudu, scimitar-horned oryx, ankole and bison. Variant Creutzfeldt-Jakob disease is a disease of humans.
All spongiform encephalopathies have incubation periods of months or years. The incubation period of BSE is more than a year and often several years. The peak incidence of disease occurs in 4 to 5 year old cattle.
Spongiform encephalopathies are usually insidious in onset and tend to progress slowly. The clinical signs are usually neurologic. Once the symptoms appear, these diseases are relentlessly progressive and fatal.
The clinical signs of BSE may include hyperesthesia, hindlimb ataxia, pelvic swaying, hypermetria, tremors, falling, recumbency, and behavioral changes such as apprehension, nervousness, and occasionally frenzy. Intense pruritus is not usually seen. Nonspecific symptoms include loss of condition, weight loss, and decreased milk production. Decreased rumination, bradycardia, and altered heart rhythms have also been reported. The disease progresses to recumbency and coma, and death occurs from weeks to months later. Rare cases may develop acutely and progress rapidly within days.
Spongiform encephalopathy of exotic ruminants
In exotic ruminants, the clinical signs may include loss of condition, unsteadiness, incoordination, and self-mutilation by biting. Asymptomatic cases have been described. This disease appears to progress more rapidly than most spongiform encephalopathies; the mean period from the onset of symptoms to euthanasia is 13.5 days.
The clinical signs of FSE can include behavioral changes, tremors, and ataxia. Cats may become aggressive or tend to creep aimlessly around their home and hide. In later stages, somnolence is common and convulsions may occur. Excessive salivation, hyper-responsiveness to loud noises, and dilated pupils have also been seen. Death occurs in approximately 6 to 8 weeks.
There is no evidence that BSE or FSE is communicable during casual contact.
Spongiform encephalopathies can be diagnosed by histopathology or by detecting PrPSc (a disease-specific isoform of the membrane protein PrP) in the brain. Accumulations of PrPSc can be found in unfixed brain extracts by immunoblotting and in fixed brains by immunohistochemistry. The diagnosis can also be confirmed by finding characteristic fibrils of PrPSc (scrapie-associated fibrils) with electron microscopy in brain extracts. Some of these tests can be used on frozen or autolyzed brains.
BSE can also be diagnosed by transmission tests in mice. However, an incubation period of several months often makes this technique impractical. New commercial tests to detect BSE (PrPSc) in cattle brain samples include a modified immunoblot, a chemiluminescent ELISA test, a sandwich immunoassay and a two-site noncompetitive immunometric procedure.
Serology is not useful for diagnosis, as antibodies are not made against the agents of spongiform encephalopathies.
Treatment and Vaccination
No treatment or vaccination is available. Spongiform encephalopathies are uniformly fatal once the symptoms appear.
Morbidity and Mortality
In 1992, the annual incidence of BSE in United Kingdom cattle was 1%; however, the number of cases has been decreasing in recent years. The incidence of FSE is unknown. This disease was seen in a total of 81 domestic cats (as well as a few wild felids) in the United Kingdom, but many cases may have been missed. Spongiform encephalopathies are always fatal once the symptoms appear.
No gross lesions are found in spongiform encephalopathies, except emaciation or wasting of the carcass in some cases.
The typical histopathologic lesions are confined to the central nervous system. Neuronal vacuolation and non-inflammatory spongiform changes in the gray matter are pathognomonic. Astrocytosis is prominent in some diseases but not others. Amyloid plaques are seen in some spongiform encephalopathies but are rare in BSE and not found in FSE. These lesions are usually but not always bilaterally symmetrical.
“Bovine Spongiform Encephalopathy.” Animal Health Australia. The National Animal Health Information System (NAHIS). 7 November 2001
“Bovine Spongiform Encephalopathy.” In Manual of Standards for Diagnostic Tests and Vaccines. Paris: Office International des Epizooties, 2000, pp.
“Bovine Spongiform Encephalopathy.” In The Merck Veterinary Manual, 8 th ed. Edited by S.E. Aiello and A. Mays. Whitehouse Station, NJ: Merck and Co., 1998, pp. 897-8.
Brown P., R.G. Will, R. Bradley, D.M. Asher and L. Detwiler. “Bovine Spongiform Encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns.” Emerg. Infect. Dis. 7, no. 1 (Jan–Feb 2001):6-16. 10 Dec 2002 <http://www.cdc.gov/ncidod/EID/vol7no1/brown.htm>.
“Central nervous system. Viral diseases. Prion diseases (Transmissible spongiform encephalopathies).” In The Merck Manual, 17 th ed. Edited by M.H. Beers and R. Berkow. Whitehouse Station, NJ: Merck and Co., 1999. 10 Dec 2002 <http://www.merck.com/pubs/mmanual/section13/chapter162/162d.htm>.
Irani, D.N. “Bovine Spongiform Encephalopathy.” Johns Hopkins Department of Neurology. Resource on Prion Diseases. 7 November 2001
Irani, D.N. “Feline Spongiform Encephalopathy.” Johns Hopkins Department of Neurology. Resource on Prion Diseases. 7 November 2001
Irani, D.N. “Spongiform Encephalopathy of Exotic Ruminants.” Johns Hopkins Department of Neurology. Resource on Prion Diseases. 7 November 2001 <http://www.jhu-prion.org/animal/ani-seoer-hist.shtml>.
“New variant CJD: Fact Sheet.” Centers for Disease Control and Prevention, April 2002. 10 Dec 2002
“Prions and Transmissible Spongiform Encephalopathies.” In Foodborne Pathogenic Microorganisms and Natural Toxins Handbook. U.S. Food & Drug Administration, Center for Food Safety & Applied Nutrition, Feb 2002. 8 Dec 2002 <http://www.cfsan.fda.gov/~mow/prion.html>.
“Probable variant Creutzfeldt-Jakob disease in a U.S. Resident --- Florida, 2002.” Morbidity and Mortality Weekly Report 51, no. 41 (Oct 18, 2002):927-929. 10 Dec 2002 <http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5141a3.htm>.
“Questions and answers regarding Bovine Spongiform Encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD).” Centers for Disease Control and Prevention, January 2001. 10 Dec 2002
“Transmissible Spongiform Encephalopathies.” July 2000 United States Department of Agriculture Animal and Plant Health Inspection Service. 7 November 2001 <http://www.aphis.usda.gov/oa/pubs/fsspongiform encephalopathy.html>.
“Update 2002: Bovine Spongiform Encephalopathy and variant Creutzfeldt-Jakob disease.” Centers for Disease Control and Prevention, Sept 2002. 10 Dec 2002 <http://www.cdc.gov/ncidod/diseases/cjd/bse_cjd.htm>.
Copyright 2003, ISU
Center for Food Security and Public Health
Iowa State University College of Veterinary Medicine
Ames Iowa USA 50011
Phone: 515 294 7189
Fax: 515 294 8259