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What to Make of News Reports of Possible Exposure to CJD?

Valeo, Tom

doi: 10.1097/01.NT.0000436537.02549.30
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Neuroinfectious disease experts say that publicity around 15 patients who were possibly exposed to Creutzfeldt-Jakob disease, through contaminated surgical equipment, may be overblown — and the risk of infection is low.

The 15 people in three states who may have been exposed recently to the type of prion proteins that cause Creutzfeldt-Jakob Disease (CJD) face a very low risk of infection, according to experts on the disease.

The patients underwent surgical procedures that involved rented equipment manufactured by Medtronic Inc., including a metal reference frame and a brace used during surgical navigation. The equipment was used on a patient later discovered to have CJD, who died in August.

Infection from the instruments “is a potential problem, but in terms of the magnitude of risk involved, it doesn't warrant the degree of publicity it's getting,” said Joseph R. Berger, MD, the Ruth L. Works professor and chairman of the department of neurology at the University of Kentucky College of Medicine. “The infection is unique and uniformly fatal, so I can see how it could play into the public's worst fears, but I think it's clearly an overblown story.”

The patient, who apparently had sporadic CJD rather than the familial form or variant CJD (bovine spongiform encephalopathy), underwent neurosurgery at Catholic Medical Center in Manchester, NH earlier this year, according to a Sept. 4 statement from public health officials in New Hampshire. The rented equipment was sterilized using standard procedures, which are not considered sufficient to remove all prion proteins.

Subsequently eight patients had surgery with the instruments at Catholic Medical Center, five had spinal cord surgery this summer at Cape Cod Hospital in Hyannis, Massachusetts, and two had surgery involving the equipment at Veterans Affairs Hospital in West Haven, CT. Spinal cord surgery carries a much smaller risk of transmission than brain surgery, according to the Massachusetts Department of Public Health, which issued a statement about the cases in that state.

A similar situation developed in August of 2012 after a patient who had brain surgery at Greenfield Memorial Hospital in South Carolina was later discovered to have a familial form of CJD. Eleven other patients had surgery involving the same instruments, which had been sterilized using standard procedures. Those patients were notified, but so far none have been infected.

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The New Hampshire patient with CJD will be autopsied at the National Prion Disease Pathology Surveillance Center at Case Western Reserve University School of Medicine in Cleveland. The autopsy will be “extremely important” for assessing the risk faced by those exposed to the contaminated equipment, according to Wen-Quan Zou, MD, PhD, associate director of the Center.

“Not only will the autopsy make the definite diagnosis on this case, but it also will determine whether the prions are type 1 or type 2, and if the disease is the familial or sporadic form of CJD,” said Dr. Zou, who is also an associate professor in the departments of pathology and neurology at Case Western Reserve University. “Certain prions are highly infectious compared to others in vitro.”

Infectious human prion proteins exist in two main conformational states recognized by differences in the extent of their N-terminal truncation following proteolytic cleavage. Type 1 yields an N-terminus at glycine 82, Dr. Zou explained, and type 2 yields an N-terminus at serine 97. The differences are believed to affect the disease phenotype.

“Prions from some familial prion diseases are less transmissible than those from sporadic CJD,” Dr. Zou said.

Prions associated with some of Gerstmann-Sträussler-Scheinker (GSS) syndrome or familial CJD cases have not been transmitted yet to animals, suggesting that prions in these cases are less infectious, he added.

A polymorphism at codon 129 of each exposed patient's gene for prion protein also could affect their susceptibility to infection, Dr. Zou added.

“There are many examples of this, but the mechanism remains unclear,” he said. “For instance, variant CJD that is associated with consumption of food contaminated by mad cow disease has always affected subjects that carry a gene for prion protein with methionine/methionine (M/M) polymorphism at codon 129, whereas sporadic CJD has been mainly observed in subjects carrying PrP-129 M/M exhibiting PrPSc type 1.” (PrPSc refers to scrapie, one of the first diseases known to be caused by the infectious spread of misfolded prion protein.)

If the autopsy shows that the index case carries the 129 M/M variant, those exposed who carry the 129 M/M variant will be more susceptible to infection.

CJD affects only about one person in a million, according to the Centers for Disease Control and Prevention — about 300 per year in the United States. There have been no known cases in the U.S. caused by transmission of the protein with neurosurgical instruments, and only four overseas, none since 1976, the CDC added.

Most cases occur either from inheriting the mutated protein, or spontaneously, with fewer than 5 percent of all CJD transmissions involving tissue transplants or contaminated surgical equipment, according to the World Health Organization.







Human growth hormone derived from human pituitary glands has been linked to 26 cases of CJD, according to the National Institutes of Health, but the risk of new cases has disappeared since genetically engineered synthetic HGH is now used, according to Dr. Berger. About 7,700 people in the U.S. were exposed to HGH derived from cadavers.

However, because the incubation period is so long, and CJD “is one of the great imitators,” some cases may remain undiagnosed, Dr. Berger added.

“It can be very difficult to make the diagnosis,” he said. “CJD may present with parkinsonian or stroke manifestations, or unexplained cortical blindness, or ataxia. The stereotypical EEG changes are often not present early in the disease. Spinal fluid abnormalities, like an elevated 14-3-3, may not be evident, and when you do see them they may not be diagnostic since similar changes could occur in other diseases as well.”

Many years ago when Dr. Berger examined a number of cases of CJD to determine the original diagnosis he found most of the patients presented with behavioral and psychiatric changes. “Two of the patients I had been asked to consult on were hospitalized on the psychiatry ward,” he said. “One had been there for several weeks before they sought a neurologic consultation. I can understand very well how the diagnosis might be missed. The characteristic clinical findings may not be evident.”



A 2012 paper in the Archives of Neurology found that patients with CJD were most often misdiagnosed as having neurodegenerative disorders, autoimmune or cancer-related reactions, infections, or problems involving toxins. “The most common individual misdiagnoses were viral encephalitis, paraneoplastic disorder, depression, vertigo, Alzheimer disease, stroke, unspecified dementia, central nervous system vasculitis, peripheral neuropathy, and Hashimoto encephalopathy,” the authors found. The mean time from onset to diagnosis was nearly 8 months — about two-thirds of the way through their disease course.

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Lead author Michael D. Geschwind, MD, PhD, associate professor of neurology and Michael J. Homer chair in neurology at the University of California, San Francisco (UCSF), said standard sterilization methods do not remove prions adequately to eliminate the risk of transmission with surgical instruments. Even special sterilization methods involving higher autoclave temperatures for longer times are not guaranteed to remove all prions.

“This is why at UCSF, we decided many years ago to destroy/incinerate all neurosurgical equipment used in suspected CJD cases, rather than using prion sterilization techniques and reusing the equipment,” he said via e-mail. “We see too many patients with CJD and other prion diseases, and the risk was felt not to be worth it.”

After a patient is exposed to contaminated surgical equipment each subsequent patient faces a lower risk of infection, Dr. Geschwind added. “After each use the equipment would have been cleaned by standard methods, and each standard sterilization/cleaning would likely remove more prions, diminishing the risk, so the further down the line a patient is from the index case, the lower the theoretical risk,” he said. “The patients exposed temporally closest to the CJD surgery would be at highest risk.”

However, other surgical equipment cleaned along with the prion-contaminated neurosurgical instruments could conceivably pick up some prions, and therefore carry some risk of contamination.

“This equipment would likely have far fewer prions, so these patients would be at much lower risk of getting prions, but at risk nevertheless,” Dr. Geschwind said.

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•. Paterson RW, Torres-Chae CC, Kuo A, et al. Differential diagnosis of Jakob-Creutzfeldt disease. Arch Neurol 2012;69(12):1578–1582.
    •. Massachusetts Department of Public Health statement about contaminated products:
      •. New Hampshire Department of Health and Human Services statement about contaminated products:
        •. Korth C, Kaneko K, Groth D, et al. Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human protein transgene. Proc Natl Acad Sci 2003: 100(3):4784–4789.
          •. Bishop MT, Will RG, Manson JC. Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci 2010; 107(26):12005–12010.
            © 2013 American Academy of Neurology