A report of 97 cases of Creutzfeldt-Jakob disease (CJD) in Japan caused by use of contaminated cadaveric dura mater grafts performed between 1978 and 1991 is another grim reminder of the possibility of iatrogenic CJD (JAMA 2004;291:295–296). It also highlights the continued necessity to report all suspected or confirmed CJD and variant CJD (vCJD) cases to public health authorities, prion disease detection experts say.
Unfortunately, because of late recognition of the problem and the long latency period – the upper limit for onset of iatrogenic CJD now exceeds 22 years – the Japanese outbreak probably is not yet over. As of September 2003, five additional cases were being investigated for suspected dural graft-associated CJD.
The first Japanese case was diagnosed in 1985, but at that time no one realized what was going on. In fact, according to Ermias Belay, MD, a medical epidemiologist in the Division of Viral and Rickettsial Diseases at the CDC's National Center for Infectious Diseases, the first realization that a problem existed seems to have occurred in the US in 1987.
In that year, a physician reported a CJD death in a 28-year-old pregnant Connecticut woman. Because of her young age – atypical for sporadic CJD – the CDC decided to investigate the case. It turned out that she had had a dural graft produced by a German company B. Braun Melsungen AG – LYODURA® – placed as part of a neurosurgical procedure 22 months earlier. The grafts had never been distributed in the US, but this particular tissue had been sent from Canada.
The CDC contacted the German manufacturer and learned that the company's method for processing the grafts differed from US practice. “They commingled dura from several cadavers, presenting an opportunity for contamination from just one person who might have had CJD. Not only that, they did not keep records of the identity of donors or any knowledge of prions,” Dr. Belay said. The only decontamination process was radiation, which does not inactivate prions.
The CDC pushed for a change in the processing of dura based on that one case. “People thought we were nuts because this was an isolated case,” said Dr. Belay. Nonetheless, in 1987 the German company changed its procedures: no more commingling of dura, improved record keeping, and using decontamination by sodium hydroxide, which would inactivate prions. “There is no case that we know of associated with this particular dural mater graft that could have been produced after 1987,” Dr. Belay said.
Still, the shelf life of the grafts was five years, so some contaminated grafts doubtless were used after 1987, likely accounting for the additional cases.
By 1987 in Japan, eight cases of dura-associated CJD were detected, probably the result of similar German grafts placed between 1978 and 1982, but the Japanese still had not recognized the problem, according to Dr. Belay.
DISCOVERING THE PROBLEM
It was not until around 1996, when the Japanese government had instituted surveillance for CJD in response to the bovine spongiform encephalopathy (BSE) problem and recognition of vCJD in the UK that Japanese public health authorities learned of the shockingly large number of dura mater-associated cases in their country and immediately reported them to the World Health Organization.
The result: a 1997 report on the first 43 Japanese cases (MMWR 1997;46: 1066–1069). The January report of 97 cases adds another 54 cases, with onset up to 2002, to that total. Eighty-six of those 97 patients were documented as having received the German grafts. The brand name of the graft was uncertain for the other 11 patients. Dural graft-associated cases of CJD have also been reported elsewhere in the world.
Why so many in Japan? Dr. Belay said the Japanese outbreak appeared to have been enhanced by two factors: extensive use by neurosurgeons there (possibly more than elsewhere) of dura mater grafts and extensive use of the German product. An estimated 20,000 grafts per year might have been used during between 1983 and 1987, according to the Morbidity and Mortality Weekly Report (MMWR).
In one of the 97 Japanese cases reported in the MMWR, the graft was used in a spinal rather than intracranial procedure. And according to Richard T. Johnson, MD, Distinguished Service Professor of Neurology, Microbiology, and Neuroscience at Johns Hopkins University in Baltimore, MD, in two other unrelated cases, dura mater was injected to occlude vessels during vascular surgery, resulting in two more cases of dura-associated CJD.
CASES IN THE US
Back in the US, a second case of dura mater-associated CJD was detected in 1992, and an additional two were reported later. In the second case, a German graft was used. The third case involved an older man who received a dural graft processed in the US, but an investigation revealed that the donor was a young man with no neurologic disease; he died in a car crash. Sporadic CJD may have occurred coincidentally.
In the fourth US case, in a 39-year-old man (again, rather young for the sporadic form of CJD), the disease was believed to be associated with another brand of dura mater, made by another German company (Neurology 2001;56: 1080–1083). This brand was also suspected in a few Japanese cases, but it was not possible to document a specific source. No commingling was involved in processing of this brand of dura, however.
GUIDELINES FOR DURAL PROCESSING
In 1997, the Transmissible Spongiform Encephalopathy (TSE) Advisory Committee of the FDA introduced more stringent guidelines for dural processing in the US, such as neuropathologic examination of cadaver brains for the presence of prions and characteristic lesions, no matter what the cause of death.
Many European countries as well as Japan and Canada eventually banned the use of dural grafts. In the US, according to Dr. Belay and others, the TSE advisory committee was considering doing the same in 1997 but relented when neurosurgeons pleaded with the committee not to take the material away. However, other tissues can be used safely, including bovine pericardium (although there is some theoretical risk of disease transmission with this) and several synthetic plastics. Tellingly, the distribution of dura mater grafts in the US declined from 4,500 in 1997 to 900 in 2002.
NO COMPLACENCY WARRANTED
Inasmuch as CJD is also known to have been transmitted via human growth hormone and corneas, it would be comforting to think that all types of iatrogenic transmission of CJD, or vCJD for that matter, are now known, but Dr. Belay is not so sure. “We were surprised by the cases from a particular brand. These kinds of surprises may be waiting, we don't know.”
Indeed, there is newer evidence that vCJD at least may be transmissible through blood transfusions. Last month, The Lancet included two reports on the subject. One, already released to the media in December 2003, concerned a 69-year-old man who developed vCJD and who six years earlier had received red cells from someone who developed vCJD a few years later.
Another study in the same issue compared the degree of tissue infectivity among macaque monkeys given tissue containing the BSE agent either orally or intravenously. The investigators found that the degree of organ infectivity was similar regardless of the route of entry of the prion protein, with tonsil tissue most strongly infected.
NEED FOR BETTER DETECTION
Neuropathologist Pierluigi Gambetti, MD, Director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University, hopes neurologists will become more vigilant about looking for suspected CJD.
The Center examines about 50 percent of the cases of TSE, which are expected to be about 300 per year or 1 case per million people per year. But the problem is the other 50 percent: “People don't send us the tissues for the other 50 percent of cases,” Dr. Gambetti observed. Hence the figures for the registry are not complete. Dr. Gambetti's center is has data from 1997 on the Center Web site, www.cjdsurveillance.com.
“We're trying to raise the awareness of US neurologists and pathologists to refer to us cases of suspected CJD so we can examine up to 80 percent of these cases by tissue analysis as they do in Europe,” Dr. Gambetti said. “In Europe, small countries can examine perhaps 100 percent. Big countries like Germany and the UK examine nearly 80 percent. The rest are examined by clinical findings alone. So we want to at least examine the chart in cases where the family refuses an autopsy to get close to 100 percent.”
The UK's National CJD Surveillance Unit in Edinburgh has up-to-date figures for sporadic, iatrogenic, and familial CJD, Gerstmann-Sträussler-Scheinker syndrome (another familial prion disease), and vCJD from 1990 through part of 2004 on their Web site, www.cjd.ed.ac.uk