Variant Creutzfeldt-Jakob disease (vCJD) is a rare and fatal human neurodegenerative condition. Like Creutzfeldt-Jakob disease (CJD), vCJD is classified as a transmissible spongiform encephalopathy (TSE) due to its characteristic spongy degeneration of the brain and its ability to be transmitted.
CJD exists in four distinguishable forms which are generally characterized by how each form is spread.² Variant CJD or vCJD was first described in March 1996 and is referred to as the human form of CJD. Sporadic CJD is the most common form of CJD, while genetic CJD is caused by a rare inherited abnormal gene. Iatrogenic CJD is caused by iatrogenic transmission of the disease, which today still remains a threat. Well documented cases of CJD transmission via surgery, organ transplantation, and blood transfusion exist.8 Factors of transmission can include contaminated surgical equipment/ medical instruments, electrodes or other neurosurgical instruments that come in contact with the brain, corneal or dura mater grafts or transplants, or through the administration of human-derived pituitary growth hormones and gonadotropin.¹,10
The incubation period for vCJD is unknown, but is suspected to be years, and possibly even decades in some cases.³ The median number of days from onset of symptoms to diagnosis is 327 days and from onset to death is 407 days.4 The overall median age at death is 28.5 years with a range from 14 to 74.
The early clinical presentation of vCJD is usually psychiatric symptoms, which most commonly are displayed as depression or even as a schizophrenia-like psychosis.5 Neurological symptoms will increase as time passes. Some signs, include unsteadiness, difficulty walking, and involuntary movements. By the time the patient dies, they will become completely immobile and mute.
There is currently no cure for vCJD and no treatment that conclusively slows the progression of the disease.6
The Stats Behind the Disease
According to vCJD Worldwide, the total number of primary cases range from one to four cases in most countries. However, France has 21 cases reported and the United Kingdom (UK) has an astounding 162 cases.9 The UK is the hot spot for the disease due to an outbreak of contaminated beef materials which spread bovine spongiform encephalopathy (BSE) or mad cow disease when it entered the food chain.7
The U.S. has had three reported cases as of February, and the third is suspected to have contracted the disease as a child when living in Saudi Arabia. (For more information on this patient and the other two U.S.-reported cases, visit the CDCs vCJD Fact Sheet Web page at www.cdc.gov/ncidod/dvrd/vcjd/factsheet.htm.) As of March 2, 112 deaths have been confirmed to be definitive vCJD cases, and there are another 46 probable cases.² It is interesting to note that three cases in which vCJD was transmitted by blood transfusion have now occurred in the UK. Two of those patients have since died.7, 9
The CJD/Surgical Suite Dance
Epidemiologic evidence in the U.S. suggests that CJD transmission via medical devices is very rare, but it has occurred. According to a presentation concerning the new HICPAC guidelines on disinfection and sterilization presented by William A. Rutala, PhD, MPH, professor, division of infectious diseases, department of medicine at the University of North Carolina Health Care System, Chapel Hill, six cases of CJD associated with medical devices were reported which include two confirmed cases involving depth electrodes reprocessed by benzene, alcohol, and formaldehyde vapor and four cases of CJD were reported following brain surgery leaving neurosurgical instruments suspect for transmission.
It has been noted that only critical or semicritical devices contaminated with high risk tissue from high risk patients requires special treatment,10,11 however, it also has been found that prions are resistant to conventional disinfection and sterilization.10
Prions exhibit unusual resistance to conventional chemical and physical decontamination methods, writes Rutala in a journal article addressing this topic. He notes that recommendations for CJD-related cross-transmission have been based primarily on prion inactivation studies,11 but he and his colleagues recommend that in addition to inactivation data, epidemiological studies should be carried out and a focus should include the infectivity of human tissues and the efficacy of removing microbes by cleaning.
According to review conducted at the London School of Hygiene and Tropical Medicine, researchers note that the difficulty in determining the scale of a vCJD-related epidemic lies within deciphering whether the occurrence stems from the number of times a single instrument is reused, the infectivity of a contaminated instrument, and/or the effectiveness of cleaning.12 Rutala did note that no known failure of steam sterilization has been reported.10
The Ongoing Residual Battle
Effective cleaning, disinfection, and sterilization is a very real challenge for the millions of insidious pathogens that could be lurking on a surgical instrument. Add to that challenge a resistant prion, and the sterile processing department (SPD) has a real fight on their hands.
The Health Protection Agency of Porton Down, Salisbury, UK conducted a surface decontamination study to address this very issue.13 The aim of the study was to assess the levels of total protein contamination on a wide range of surgical instruments. The researchers wanted to determine the true effectiveness of routine cleaning and disinfection in their hospitals.
Random trays of wrapped and autoclaved instruments were analyzed for residual protein and total organic matter at two laboratories. The instruments were at the stage/condition that they would normally be when returned to an operating room for use.
At laboratory A, the instruments showed that 17 percent (35 of the 206 instruments) were above an acceptable threshold, and up to 2.228 mg of extractable protein was extractable from one instrument in particular. The residual matter washed from the instruments at each of the testing laboratories ranged from 0.62 mg to 3.5 mg. On one instrument (a split stem) the researchers note 45 mg of residual organic matter.
They concluded from these findings that an uncomfortably large proportion of instruments at the point-of-use show levels of protein that could pose a direct cross-infection risk via prion agents and other organic contamination.
Scientists at the University of Southampton were concerned about such residual soiling, especially that containing CJD-specific infectious matter following standard reprocessing procedures.14 Removal of all proteinaceous material from surgical devices can be severely hampered, they note, if the contaminant is allowed to dry onto the instrument surface for any length of time. The team found that not only the amount of time between contamination and the initial prewash of the instrument was key, but the kinetics of drying at different temperatures also played a role.
Their research shows that all pre-soaks did in fact significantly reduce by up to 96 percent the prion-infected tissue contamination.
Perhaps more interestingly, however, is that they found that controlling the temperature while in transit from the OR to the SPD allows more time before high protein absorption levels occur.
In addition to temperature, some components commonly used on instruments may not be advisable for use. Researchers at the Trust Sterile Services found that in cases where spongiform disease is a possibility, alcohol, and probably formaldehyde, should not be used to decontaminate neurosurgical instruments because alcohol actually firmly binds blood to stainless steel.15
In search for effective, instrument-friendly, and routinely applicable reprocessing procedures, UK scientists have been feverishly investigating a number of decontamination methods and products. In one such study, various reagents and processing conditions were screened for efficacy of decontamination and active principles such as detachment, destabilization or degradation of surface-bound prion protein.16
The biochemical marker for TSE infectivity, which is pathological prion protein (PrP(Sc)), was attached to steel surfaces, and residual contamination with PrP(Sc) and its protease-resistant core PrP27-30 were still present on the wire surface after reprocessing was monitored.
This investigation revealed that, under appropriate conditions, relatively mild reagents such as a commercially available alkaline cleaner (with a pH ranging from 11.9 to 12.2), a disinfectant containing 0.2 percent peracetic acid, and low concentrations of Sodium hydroxide (NaOH) (pH of 8.9) or 5 percent Sodium dodecyl sulfate (SDS) (pH of 7.1), exert potent decontaminating activities on the PrP(Sc)/PrP27-30 that was attached to the steel surfaces.
Another study infecting the surface of steel wires with infectious brain materials was conducted and this time the wires were implanted in the brains of healthy hamsters.17 The PrP(Sc) did bind to the steel wires and did cause disease after the contaminated wires were implanted in the brains of the hamsters.
Prior to implantation, decontamination studies were performed by reprocessing the contaminated steel wires with different disinfection agents and procedures. The scientists found that only the group of hamsters implanted with wires that were reprocessed with an alkaline detergent, followed by sterilization with a modified cycle in a hydrogen peroxide gas plasma sterilizer (4 injections), showed no clinical signs of disease and remained alive. However, two animals from the group receiving sodium hydroxide followed by autoclaving (at 134 degrees Celsius for 18 minutes) died.
Finally, according to one French study, a formulation of copper metal ions in combination with hydrogen peroxide was found to dramatically reduce the level of PrP(Sc).18 This hypothesis has been tested on instruments used on prioninfected brains and the reduction of infectivity was confirmed.
Infiltrating the Blood Supply
As mentioned earlier, three people have been contaminated with vCJD through blood transfusion in the UK. These cases, first reported in 2004, found that a group of 23 known recipients exist who have survived at least 5 years after receiving a transfusion from donors who subsequently developed vCJD.19 Scientists say the risk to the remaining recipients is probably high, and these patients should be followed closely.
Measures can be taken to reduce the incidence of vCJD transmission through blood products. These measures include:20
- A close epidemiological surveillance of the population in countries with cases of vCJD and/or BSE
- The deferral of blood donors who traveled or resided, for specific periods of time, to countries with BSE, or who received transfusion or tissue transplant
- The removal of leucocytes in plasma used for fractionation
- The removal of the prion agents during the complex industrial fractionation process used to prepare plasma products
In addition, numerous investigations have demonstrated that ethanol fractionation, depth filtration, and chromatography, can effectively remove several logs of prions.
As one French scientist notes, The risk of transmission of vCJD by human plasma products appears remote, but caution should prevail since the biochemical nature of the infectious agent in human blood is still unknown.
The U.S. Food and Drug Administration (FDA) conducted its own risk assessment on the probability of transmissible vCJD through blood products.21 Based on the risk assessment, the U.S. Public Health Service states that the risk of vCJD to patients who receive U.S. licensed pdFVIII products is most likely to be extremely small, although we do not know the risk with certainty, the report notes. vCJD risk from other plasma-derived products, including Factor IX, is likely to be as small or smaller, FDA notes. For more information on FDAs assessment, visit www.fda.gov/cber/blood/vcjdrisk.htm.
For more information on the epidemiology of vCJD in general, visit the CDC Web page located at www.cdc.gov/ncidod/dvrd/vcjd/epidemiology.htm.
1. WHO Fact Sheet: variant Creutzfeldt-Jakob disease (vCJD) www.who.int/mediacentre/factsheets/fs180/en/.
2. The National Creutzfeldt-Jakob Disease Surveillance Unit, based at the Western General Hospital in Edinburgh, Scotland www.cjd.ed.ac.uk/vcjdworld.htm.
3. CDC. Fact Sheet: vCJD. www.cdc.gov/ncidod/dvrd/vcjd/factsheet.htm.
4. Andrews NJ. Incidence of Variant Creutzfeldt-Jakob Disease Deaths in the UK: January 1994 December 2006. Feb. 2007. www.cjd.ed.ac.uk/vcjdqdec06.htm.
5. WHO Fact Sheet: variant Creutzfeldt-Jakob disease (vCJD) www.who.int/mediacentre/factsheets/fs180/en/.
6. Parry A, et al. Long term survival in a patient with variant creutzfeldt- jakob disease treated with intraventricular pentosan polysulphate. J Neurol Neurosurg Psychiatry. 2007 Feb 21.
7. Seitz R, et al. Impact of vCJD on blood supply. Biologicals. 2007 Jun;35(2):79-97.
8. Sutton JM, et al. Methods to minimize the risks of Creutzfeldt-Jakob disease transmission by surgical procedures: where to set the standard? Clin Infect Dis. 2006 Sep 15;43(6):757-64.
9. National Creutzfeldt-Jakob Disease Surveillance Unit. Western General Hospital, Edinburgh, Scotland. www.cjd.ed.ac.uk/vcjdworld.htm.
10. Rutala WA, Weber DJ. Creutzfeldt-Jakob disease: recommendations for disinfection and sterilization. Clin Infect Dis. 2001 May 1;32(9):1348-56.
11. Weber DJ, Rutala WA. Managing the risk of nosocomial transmission of prion diseases. Curr Opin Infect Dis. 2002 Aug;15(4):421-5. Review.
12. Garske T, et al. Factors determining the potential for onward transmission of variant Creutzfeldt-Jakob disease via surgical instruments. J R Soc Interface. 2006 Dec 22;3(11):757-66.
13. Murdoch H, et al. Surface decontamination of surgical instruments: an ongoing dilemma. J Hosp Infect. 2006 Aug;63(4):432-8.
14. Lipscomb IP, et al. Effect of drying time, ambient temperature and pre-soaks on prioninfected tissue contamination levels on surgical stainless steel: concerns over prolonged transportation of instruments from theatre to central sterile service departments. J Hosp Infect. 2007 Jan;65(1):72-7.
15. Prior F, et al. Alcoholic fixation of blood to surgical instruments-a possible factor in the surgical transmission of CJD? J Hosp Infect. 2004 Sep;58(1):78-80.
16. Lemmer K, et al. Decontamination of surgical instruments from prion proteins: in vitro studies on the detachment, destabilization and degradation of PrPSc bound to steel surfaces. J Gen Virol. 2004 Dec;85(Pt 12):3805- 16.
17. Yan ZX, et al. Infectivity of prion protein bound to stainless steel wires: a model for testing decontamination procedures for transmissible spongiform encephalopathies. Infect Control Hosp Epidemiol. 2004 Apr;25(4):280-3.
18. Solassol J, et al. A novel copperhydrogen peroxide formulation for prion decontamination. J Infect Dis. 2006 Sep 15;194(6):865-9.
19. Wroe SJ, et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt- Jakob disease associated with blood transfusion: a case report. Lancet. 2006 Dec 9;368(9552):2061-7.
20. Burnouf T, Padilla A. Current strategies to prevent transmission of prions by human plasma derivatives. Transfus Clin Biol. 2006 Nov;13(5):320-8.
21. FDA. Potential Risk of Variant Creutzfeldt-Jakob Disease (vCJD) From Plasma-Derived Products. www.fda.gov/cber/blood/vcjdrisk.htm.
A Treatment May Be On Its Way
vCJD is presently a non-treatable neurodegenerative disease, only diagnosed definitively post mortem. No treatment is currently available to prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease.
Researchers in the MRC Prion Unit of the Department of Neurodegenerative Disease at the Institute of Neurology in London however, have found that targeting a protein within the culprit isoform at the onset of debilitating signs of the disease can stop progression of the disease.
"We previously showed that targeting endogenous neuronal prion protein (PrP(C)) the precursor of its disease-associated isoform, PrP(Sc) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss," the researchers write. "We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology.
"Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc).
"These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms," they conclude.
Source: Giovanna R. Mallucci, et al. Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice. Neuron, Vol 53, 325-335, February 1, 2007.