Originally created 04/08/00

Brain membrane patch causes disease



KOSEICHO, Japan -- At first, she thought it was a bad case of jet lag. Then her vision began to blur, and she got lost on the walk to the nearby post office. Her handwriting became childlike, and she was tormented by hallucinogenic nightmares.

Within four months of her first headache, Takako Tani quite literally lost her mind to Creutzfeldt-Jakob disease, or CJD, the human form of the fatal brain-wasting malady known as "mad cow" disease. It was 1996. She was 41.

What horrifies Japan most about what happened to Tani is that it almost certainly was preventable. Unlike British victims thought to have contracted CJD by eating contaminated meat, Tani is one of at least 65 Japanese believed to have been infected through medical implants of contaminated brain tissue collected from European corpses.

For reasons that are being probed in the Japanese media, courts and parliament, the imported tissue continued to be used in Japan even after 1987, when regulators in the United States and Britain banned it. Most of Japan's 65 known victims were infected before 1987, but Tani received her implant during routine neurosurgery in 1989.

The dried brain membrane tissue, called dura mater, was widely used as a surgical patch for the membrane covering the brain until synthetic substitutes were developed. During the 1980s, as many as 100,000 Japanese received dura, and an untold number of them may have been exposed to CJD. Statistically speaking, 35 to 40 more people are likely to develop the disease during the coming decade, said Dr. Takeshi Sato, head of a commission that investigated the outbreak.

But it is impossible to know who may be infected. There is as yet no screening test and, like AIDS, CJD has a long incubation period: It has been known to lie dormant in the brain for at least 16 years before it awakens to kill its host.

Japan's CJD outbreak reinforces worldwide concerns about the danger of contamination of blood, organs and other biological products by emerging infectious diseases -- especially emerging viruses that may not be detected until long after their hosts have have been distributed to and used in dozens of countries.

Prevailing scientific opinion holds that Creutzfeldt-Jakob disease is caused by small proteins called prions. In addition to HIV, other viruses with long incubation or latency periods include herpes, chickenpox, hepatitis B and hepatitis C. The latter was identified only in 1989 and is a concern in blood and organ transplants, said Dr. Lawrence Mintz, an infectious-diseases specialist and professor at the University of California at San Francisco medical school.

"It's inevitable that more long-incubation viruses will be found," Mintz said.

Of particular concern is the the potential for unknown viruses to be transmitted from animals to humans through genetically engineered biopharmaceuticals. Some companies use animals as factories for producing human substances, such as insulin or hormones, by inserting human genes into the animals.

"When you put a human gene into a mouse, you can't be sure that there isn't something mousy in that final product that hasn't yet been discovered or isn't appreciated as a pathogen in man but may turn out to be so," Mintz said.

The globalization of the medical industry means that small countries must grapple with these issues -- even if they lack the regulatory resources to keep up.

"If HIV can happen, if mad cow disease can happen, I can't rule out the possibility of any other infectious disease of a similar nature occurring in any country," said Dr. Ermias Belay, an epidemiologist and CJD expert at the Centers for Disease Control and Prevention in Atlanta. "The only way to potentially control emerging infectious diseases is by anticipating them and getting ready for the unknown."

What worries critics in Japan is whether their nation's regulatory and medical establishments are up to the job.

"When the next Ebola virus emerges and there's a warning about some strange new, dangerous disease, the Japanese Health and Welfare Ministry will probably say, `This is still under study and has not been confirmed in Japan, so we cannot take any action,' " fumed opposition lawmaker Tomoko Nakagawa, who is battling to have a parliamentary investigation into the CJD outbreak launched this month.

In a country where the ritual apology has been elevated to an art form but accountability remains elusive, she notes that no one has yet apologized or accepted responsibility for the CJD affair.

Not the German manufacturer, B. Braun Melsungen, which maintains that there is no proof that its product, Lydodura, caused CJD. This despite findings by the Centers for Diseases Control and Prevention in Atlanta that at least 85 patients worldwide have developed CJD after dura implants and that the vast majority of cases were associated with Lydodura.

Not the Japanese distributor, which has said it never received an order from B. Braun to recall Lydodura from hospital shelves here in 1989, after the second report of a CJD case in a dura recipient.

Not the Health and Welfare Ministry, which admits that it received a February 1987 report from the Atlanta centers that Lydodura was the suspected culprit in a CJD case involving a 28-year-old Connecticut woman, a safety alert two months later from the U.S. Food and Drug Administration announcing that it was banning imports to America of Lydodura, and subsequent reports of more deaths. The ministry says it had no duty to ban Lydodura sales in Japan because the CJD link was unproven.

Not the Japanese medical establishment, which says the manufacturer is responsible because it did not recall the Lydodura that was used in Tani's surgery in January 1989 and a 61-year-old woman's operation in 1991. Their surgeries occurred after articles appeared from August 1987 onward in prominent Japanese medical journals about the emerging threat of CJD from dura.

The families of 15 CJD patients -- only three of whom are still alive, including Tani -- have filed civil lawsuits in Tokyo and Osaka against B. Braun, its Japanese distributor, and the Health and Welfare Ministry.

Tani's husband, Sanichi, also has filed a criminal complaint of attempted murder against the current and former presidents of the distributor, Nihon BSS. So far, however, prosecutors have not indicted anyone, nor has any official in the health ministry or any doctor been reprimanded.

A spokesman for the health ministry, Koichi Ando, acknowledged in an interview that his agency's response to CJD was "not necessarily adequate." He outlined steps that must be taken to improve information dissemination and oversight. However, he said the ministry, which had licensed sales of Lydodura in Japan, had no legal duty to act in 1987 based on a U.S. report of a single death, when the link to CJD had not been scientifically proved.

The Japanese media have had a field day revealing the embarrassing details of just how uninformed the nation's regulators were.

The Asahi newspaper filed Freedom of Information Act requests in the United States -- an increasingly common journalistic strategy here because it's nearly impossible to pry unflattering documents out of Japanese agencies -- and got hold of an urgent fax sent by a senior Japanese health ministry official to the FDA in 1996.

The official wanted to know whether it was true that the FDA had issued safety alerts against Lydodura in 1987, and asked what other measures the Americans had taken to deal with dura mater. Japan finally banned dura imports in 1997.

Neurologist Sato, who chaired the investigative commission, suggested that the Japanese media, which have focused on the lapses of the domestic establishment, should also probe the failure of German regulators to police the manufacturing practices of B. Braun, which he considers to be the main culprit.

According to epidemiologist Belay, Sato and FDA documents, B. Braun collected brain membranes from corpses in a number of European countries and dumped them together into a tank for processing. That meant that tissue from a single CJD-infected donor could contaminate an entire batch. Moreover, the company did not have a system for tracking individual donors, and German authorities later learned that some of the causes of death listed in some of the records that B. Braun did have were false, according to Japan's NHK television.

B. Braun, in a statement, said it improved its donor screening and sterilization procedures in 1987, as soon as the first CJD case was reported, and ordered all distributors worldwide to recall the products in 1989, after a second death was reported in New Zealand.

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Meanwhile, Takako Tani lies in a coma at home here in Koseicho, a rural town about a 30-minute train ride from Kyoto. She is cared for around the clock in shifts by her husband and three daughters, now in their early 20s.

The nightmare period, when she could not find the toilet in her own home and screamed in terror at night in the barred room of the psychiatric hospital where she was finally diagnosed, is over.

Though she has shown no signs of recognizing her family for nearly four years, they refuse to warehouse her in a hospital. Classical music plays all day in her sunny room, which is decorated with bright paper cutouts made by her daughters, cards and posters from well-wishers and the pink flowers she loved.

Sanichi Tani, 51, and his daughters bathe Takako every three days, massage her limbs, put cream on her crabbing hands, feed her through a tube, suction out her nose up to 30 times a day, and take her to sit outside in good weather. She is unresponsive, though sometimes she moans. Still, Tani wants to believe this tender care has kept his wife alive for four years, whereas most CJD patients are dead within one.

"I don't know how much love I have, but I am trying." he said. "She did everything for our family for 20 years, so I feel I must repay her as best I can."