Feature Story

Fact vs. folklore: dealing with CJD

March 2001
Mark Uehling

Looking for CJD: as easy as 14-3-3

It was an ordinary FedEx box, addressed to Stephen DeArmond, MD, PhD, professor of neuropathology at the University of California San Francisco. An unsuspecting assistant to Dr. DeArmond opened the package, which came from a pathologist practicing in the United States.

"They had decapitated the person and sent the whole head in," reports an astonished Dr. DeArmond. "That shouldn’t be done. For Creutzfeldt-Jakob disease we usually get brains sent to us in formalin."

Has the unending European controversy over mad cow disease, or bovine spongiform encephalopathy, confused pathologists in this country? While there were 98 cases of human disease in Europe as of Feb. 2, there have been no instances—not one—of the beef-based new variant CJD, or nvCJD, in the United States. Dr. DeArmond and others do not feel the U.S. can breathe easily just yet. But he does suggest that what may have infected American pathology is not nvCJD but an unfortunate mix of fear and rumor-mongering.

The transmissible spongiform encephalopathies are spawning regrettable confusion in the lab. "Pathologists are afraid of prion diseases," Dr. DeArmond says. "There’s a fear that it’s like a 1950s science-fiction monster that leaps out of the body. The agent is a protein. It isn’t something from outer space."

But the folklore around the disease—nurtured by a grain of truth, as rumors often are—is that its agent is somewhat otherworldly. BSE and CJD are both caused by self-replicating proteins called prions, and these controversial compounds are, for lack of a better word, unusual. As one National Institutes of Health document notes: "Prions resist inactivation by nucleases, UV-irradiation at 254 nm, treatment with psoralens, divalent cations, metal ion chelators, acids (between pH 3 and 7), hydroxylamine, formalin, boiling, or proteases."

Fine, says Dr. DeArmond. But the devilish prion can still be inactivated. "People are saying even nuclear weapons can’t destroy it," Dr. DeArmond says, "which is baloney. It’s a carbon-based protein. It can be burned to carbon dioxide and water. It can be denatured with detergents. Sodium hydroxide breaks it up and makes it ineffective. So does bleach."

At a meeting of the Creutzfeldt-Jakob Disease Foundation, Dr. DeArmond says he was distressed to learn many relatives of victims of CJD complain about the unwillingness of pathologists to perform autopsies on their next of kin. "It’s unethical not to do your duty as a pathologist," says Dr. DeArmond. "Especially when there is no danger and you can do it in a simple way."

His own technique is to place a bag around the head and to put absorbent papers inside the bag; the papers will absorb any cerebrospinal fluid that may leak out. "The minimum which is very helpful is that a small incision is cut in the skull, a window of 2-3 sq. cm. Then I ask for a pretty healthy cube of tissue, frontal lobe or parietal lobe, whatever’s easiest to get to. And they can put the bone patch back in, sew it up, and they’re finished."

Failing that, he says, a needle biopsy will work once a simple burr hole has been drilled in the skull. "It doesn’t have to be more than a quarter of an inch in diameter. Again, catch any fluids that would come out. And then take out a chunk of brain with a needle biopsy. We’ve been successful in making a diagnosis off that kind of preparation too."

Dr. DeArmond says he and his longtime collaborator, neurologist and 1997 Nobel laureate Stanley Prusiner, MD, have just published a book chapter about exactly how to handle an autopsy in which CJD is suspected. (Lippincott Williams and Wilkins is the publisher for Disinfection, Sterilization and Preservation.) Says Dr. DeArmond, "We cover all of the precautions to take and how to decontaminate the autopsy suite and how to keep spillage of anything to a minimum, and if it does occur, how to take care of it."

In Cleveland, at Case Western Reserve University, Pierluigi Gambetti, MD, takes exception to Dr. DeArmond’s explanation for a dearth of autopsies. For Dr. Gambetti, neuropathology professor and director of the National Prion Disease Pathology Surveillance Center, the dearth of CJD autopsies can be traced to financial reasons. "Some of the superstitions are not very real," Dr. Gambetti says. "They may disappear if there is compensation."

But Dr. Gambetti shares Dr. DeArmond’s concern that few of all cases are being forwarded to his center, which has been tracking CJD since 1997. As any neuropathologist can elaborate, CJD is scarce enough already. The incidence is believed to be about 1:1,000,000. That works out to about 280 cases annually in the United States, according to a recent letter in JAMA reviewing death certificates over a 20-year period.

Strikingly, however, tissue from only 35 percent of the known CJD cases last year was forwarded to the Cleveland surveillance center. That means the remaining 65 percent of CJD cases are unexamined for their similarity to or divergence from the known types of the disease. As such, there can be no certainty about exactly what forms of CJD are present in the United States.

Here’s what Dr. Gambetti can report with authority. From 1997 through last year, 480 cases of suspected CJD have been submitted to Dr. Gambetti and his colleagues. Of those, 292 have been confirmed as CJD, but not the nvCJD strains linked to beef or beef byproducts in Europe. Such nondietary cases are generally termed sporadic (at least 85 percent of cases), hereditary (five to 10 percent), and iatrogenic (one percent or less).

Part of the reason for the lack of more data about CJD in the United States is that Congress has been stingy, allotting a fraction of the amount of money spent elsewhere. Other countries may budget six or seven times the $149,000 earmarked for Dr. Gambetti’s center. The shortage of funds worries Dr. Gambetti, but he is too much the diplomat to grouse about it.

He will say only that the shortfall in helping him monitor CJD in the United States could be reversed if there were more funds not only for autopsies but also for the shipment of bodies. Dr. Gambetti’s cosponsor, the Centers for Disease Control and Prevention, has tried to increase the annual budget. "I am sure they are hard at work to try to increase the funding. So am I," says Dr. Gambetti. If he could see as many as 80 percent of the CJD cases in the U.S., Dr. Gambetti speculates, he could say with confidence that the form of the disease linked to diet is unlikely to be here.

Dr. Gambetti does appear to be displeased with the casual ways in which reporters and relatives of CJD patients bandy about the terminology. He reminds a reporter that bovine spongiform encephalopathy, or BSE, is the disease conclusively identified in about 180,000 British cattle. BSE, as all the world knows, then found its way into the British food supply and was thereafter exported-in meat and bone meal-around the world.

At press time, 98 Europeans were confirmed to be victims of nvCJD, the new variant of the traditional Creutzfeldt-Jakob disease. All of those cases are believed to be linked to consumption of cattle or beef byproducts. Of those, 94 arose in England, three in France, and one in Ireland. In the U.S., of course, there are no cases of BSE in cattle or of nvCJD in humans so far.

But Dr. Gambetti confirms that during the last 12 months a mere 2,600 U.S. cattle were checked for BSE amid a total of more than 37 million cows sent to slaughter. Regulations of the U.S. livestock industry are beyond the scope of this article, but the Food and Drug Administration has far less authority to crack down on Joe Bob’s County Stockyard, where brains may be illegally mixed into the cattle feed, than it can on the likes of Merck or Pfizer.

Indeed, a variety of news organizations and consumer rights groups have painted a somewhat distressing portrait of feedlot and slaughterhouse regulation in the United States. Most of the rules are voluntary and sporadically enforced. All of which makes Dr. Gambetti’s mission-and the vigilance of U.S. pathologists at large-all the more urgent.

In the western U.S., for example, there are well-documented chronic wasting syndromes in elk and mule deer that are transmissible spongiform encephalopathies, pathological cousins to BSE. The worst-case epidemiological scenario is that a rancher in Wyoming sees an infected elk, hit by a passing vehicle, lying dead at the side of the road. The rancher throws the elk in his truck and takes it home and (confident of never being visited by the FDA) feeds it to his cattle. Unbeknownst to the rancher, if the elk had a chronic wasting syndrome, the farmer could transmit the disease to his cows-just as British cows originally received BSE from sheep with scrapie.

All the experts interviewed for this article said such a scenario was a remote but scientifically plausible route for an endemic, food-based new strain of CJD to reach the U.S. population. Dr. Gambetti reports he and his team in Cleveland have already examined three young men, known to have eaten venison, from the Rocky Mountain states. All had CJD.

The good news is that none had the acquired or nvCJD variety, first characterized in Britain and confirmed with an exhaustive workup. Besides autopsy or biopsy, the workup includes, in part, an analysis of the DNA extracted from blood, brain, or other to search for the presence of mutation in the prion protein gene and find a polymorphism for methionine at codon 129. Says Dr. Gambetti of the cases from the Rocky Mountain area: "We keep a special eye on these cases. We look very carefully at every case as a potential example of nvCJD. That is what the major effort of this center is."

Dr. Gambetti continues, reflecting on the surveillance aspect of his work. "We have to keep our eyes open for something that is different. We don’t know how different it could be. The nvCJD is really very different from sporadic CJD. We could see a new variant that is not that different. We have to keep our eyes wide open."

One of the neuropathologists sending material to Cleveland is Daron G. Davis, MD, associate professor of neuropathology at the University of Kentucky, Lexington. He agrees with Drs. DeArmond and Gambetti that vigilance for all forms of CJD will be essential to establishing, once and for all, whether the beef-based nvCJD form of the disease occurs in the United States. "Pathologists need to be picking up on cases of dementia that essentially run their course within a year to 18 months," says Dr. Davis.

Besides myoclonic jerks and the hallmark spiked EEG patterns, pathologists should be on the lookout for "rapid onset dementia, where you take people who are quite competent and functional, and they go downhill in a short period of time. They may not necessarily have been seen by a neurologist."

The University of Kentucky’s Sanders-Brown Center on Aging attracts a large number of complex dementing neurological cases for clinical and postmortem evaluation. Often, demented individuals are assumed to have Alzheimer’s disease. Dr. Davis says, "CJD is so uncommon, the chances of a clinician seeing one of these patients in their practice is fleetingly small. I have received calls from clinicians and families where they are seeking an autopsy where the illness was believed to be Alzheimer’s. I become very suspicious the dementing illness is CJD when they relate the patient’s clinical course, which often progresses from a fully functional individual to a densely demented subject in less than 12 months."

Dr. Davis differs with Drs. Gambetti and DeArmond in one respect: He is not sure if a general pathologist should be performing autopsies on patients suspected of having CJD, though he "strongly supports" the performance of postmortem examination in such cases. "The actual physical performance of the autopsy is only a small part of the procedure," he says. "The tissues must be processed and the instruments and materials used in the autopsy must be properly decontaminated or otherwise disposed of." In his own morgue, Dr. Davis performs the brain removal himself, though he does have an assistant present. "The assistant does not handle any contaminated tissue or instruments," Dr. Davis says. The instruments are sequestered and soaked in 2N sodium hydroxide for 24 hours and then autoclaved in a steam autoclave for several hours at 134°C. Tissue samples are processed according to published guidelines.

Dr. Davis continues, "Surgeons doing biopsies or procedures on demented patients should sequester the surgical instruments used in the procedure. The hospital operating room sterilization procedure for those instruments should be sufficient to disinfect potential CJD cases. Our chief of staff is a neurosurgeon who is keenly aware of the potential for iatrogenic transmission of the prion agent. He has instituted a number of infection control guidelines for instrument sterilization in our medical center and our adjoining VA hospital to prevent inadvertent iatrogenic transmission of CJD."

Unfortunately, he says, few hospitals have in place similar procedures for their operating room instrument sterilization for such cases. Some of today’s high-tech surgical instruments would not survive soaking in sodium hydroxide, or those with plastic parts may be destroyed in the autoclave. Use of disposable surgical instruments in such cases would be advantageous; the instruments could be incinerated after a one-time use, Dr. Davis notes.

There are more tips and advice from the National Institutes of Health in the form of Paul Brown, MD. He is a leading neuroscientist and neurologist and director of the U.S. Public Health Service Laboratory of Central Nervous System Studies. It was his work in the laboratory, transmitting spongiform encephalopathies across one species and then another, that helped the FDA (and later the Red Cross) decide to block blood donations from U.S. citizens who had spent more than six months in Britain between 1980 and 1996.

At the time of the FDA announcement, the American Red Cross estimated that 10.7 percent, or a million units, of the current blood supply would be lost. Some experts predicted that ban would affect as many as 285,000 U.S. citizens, or 2.2 percent of the nation’s donors. Other estimates have pegged the loss of blood at five percent of the U.S. supply. "No evidence exists that the disease has been transmitted by blood transfusion, but current studies cannot exclude this possibility," the FDA said.

Dr. Brown, for his part, keenly feels the need for pathologists to help with monitoring the U.S. population for nvCJD and for any new strains that may appear. "Judging from what happened in Great Britain, any patient suspected of having CJD under the age of 50 ought to be gone after with a lot of enthusiasm to get an autopsy," says Dr. Brown. "If you can’t get an autopsy, get a postmortem biopsy. That’s a point you ought to make very strongly."

All pathologists may not know it’s possible, he says, to get "postmortem biopsies not even making a hole in the skull but going through the eye socket or the nose," Dr. Brown adds. "You can get a piece of tissue and make a diagnosis." The family and referring clinician should understand, however, that, because the microscopic changes in CJD may be focal, the absence of typical lesions in a biopsy does not rule out the diagnosis. In such cases, it may be possible to establish CJDonly by autopsy examination.

Dr. Brown speculates that because large numbers of U.S. military personnel were stationed in Britain, pathologists in Veterans Affairs hospitals and other military institutions ought to be especially attuned to the possibility of a case of nvCJD. American military personnel in England ate British beef until 1996. "People at Walter Reed, people around the country in the military, ought to be particularly sensitive to the possibility, because if a case turns up in the U.S. as a group, the military would be the odds-on favorite to be the group in which such a case occurs," Dr. Brown contends.

Dr. Brown seems sufficiently well-insulated from the political realm to be able to say that the $149,000 budget for the nation’s CJD surveillance effort in Cleveland is "pitiful. There isn’t any budget for CJD surveillance," he says sharply.

In that sense, Dr. Brown suggests that the European approach may be superior. There aggressive efforts to find first BSE, in cattle, and now CJD, are paying off. At a cost of nearly $8 billion and counting, at least 4.5 million cattle across Europe have been slaughtered, with the disposal of the carcasses itself proving difficult.

Farmers anywhere are loath to admit their cows are sick, but European public health officials have long stopped issuing blanket guarantees of the safety of meat. European consumers, rational or hysterical depending on one’s perspective, have stopped eating beef in droves.

Dr. Brown acknowledges the situation in Europe has created political support for autopsies and other research funding. Which is not to say that Europe handled the situation adroitly, in Dr. Brown’s view. "The fault, if there is a fault, lies with governments who were warned by the scientists after we [scientists] were wrong about the human consequence of BSE, that there was every likelihood that BSE was going to turn up in Europe. And the governments stonewalled that. They said, ’No, it’s not going to happen, and if it does happen, we don’t want to know about it.’"

Dr. Brown continues: "If the governments had been educating the people throughout the 1990s that [human nvCJD] is a possibility that was not only possible but probable and said that they should be prepared and not surprised by some cows in various countries in Europe, the panic would never have occurred."

On the scientific front, Dr. Brown reports, there is no remaining doubt in mainstream circles that classically benign scrapie prions, for reasons as yet unknown, were made virulent when processed and fed first to cattle and then, tragically, to people.

But much remains unknown. Can calves get nvCJD from their bovine mothers? How much of mis- or unlabeled British cattle feed, trans-shipped from country A to B to C, may have wound up in the United States? What triggers an ordinarily harmless and abundant brain protein to fold into a prion with such catastrophic results? Some of those puzzles will have to be answered in the lab. Others may never be resolved.

On European farms, the most recent news is generally good, Dr. Brown reports. BSE cases are tapering off. That augers well for the emergence of new nvCJD cases in Europe: The raw numbers and geographic patterns of BSE and nvCJD have been closely correlated. As sick cattle are identified and destroyed, presumably, the source of nvCJD will slowly die off. "Barring the occurrence of endemic disease either from cow to calf or lateral transmission from whatever source, eating placentas," says Dr. Brown, "or sorting up dust in a barn, yes, I think we can anticipate that both of these diseases will vanish from the face of the earth."

Dr. Brown says, "The number of cattle with disease this past year, 2000, was 1,400, down from 2,100 the previous year. This coming year it’s predicted to be less than a thousand. As it gets closer to zero, we’ll probably see some ups and downs."

Dr. Brown, like Dr. DeArmond, is aware of the doomsday scenarios around BSE and CJD-speculation that it might be lurking out there on the landscape undetected. As he points out, without BSE or some other spongiform encephalopathy in the U.S. cattle herd, that idea is a phantasm. "What we can say with certainty, at this level of spontaneously occurring BSE, if that is happening, it’s not producing outbreaks of BSE. We’re not seeing it. And if we don’t have BSE, we’re not going to see variant CJD because the two things are caused by the same agent."

Mark Uehling is a freelance writer in Chicago. Cases of suspected CJD can be sent to Dr. Gambetti at Case Western Reserve University, Division of Neuropathology, Rm. 418, 2085 Adelbert Rd., Cleveland, OH 44106.