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. She is one of at least 65 Japanese believed to have been infected through 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 U.S. and Britain banned it. Most of Japan's known victims were infected before 1987, but Tani received her implant during routine neurosurgery in 1989.
Unlike British victims thought to have contracted CJD by eating contaminated meat, the Japanese are believed to have been infected through implants of the dried brain tissue. Known as dura mater, the tissue 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, a neurologist and 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 HIV, CJD has a long incubation period: It has been known to lie dormant in the brain for 16 years or longer before it awakens to kill its host.
Japan's CJD outbreak reinforces worldwide concerns about the danger of contamination of blood, organs and biological products by emerging infectious diseases--especially emerging viruses that may not be detected until long after their hosts have been distributed to and used in dozens of countries.
In addition to HIV--the virus that causes AIDS--and CJD, 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 UC San Francisco's medical school.
"It's inevitable that more long-incubation viruses will be found," Mintz said. "It's a survival strategy for viruses."
Of particular concern is 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 reputable companies do a good job at anticipating this, and there's a lot of oversight, but the technology is just exploding" and so is the number of donor species, he 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.
Accountability Remains Elusive
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 Disease Control and Prevention 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 Lydodura imports to America, 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 had 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 them 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.
"Everyone says, 'We didn't know, we had no idea,' " said Tetsuji Abe, one of the attorneys for the plaintiffs. "But if they had learned anything from AIDS, they should have known."
1,500 Infected in Hemophilia Scandal
The CJD revelations come on the heels of a scandal in which about 1,500 Japanese hemophiliacs were infected with human immunodeficiency virus after the health ministry allowed pharmaceutical firms to sell high-risk, unsterilized blood products even after safer substitutes were available.
The Japanese language does not include a word for "accountability." But lately the English term has become a buzzword here among Japanese frustrated by a system that has stumbled from crisis to crisis in the 1990s but appears impervious to attempts at change.
Reformers say that's partly because individual decision-makers are rarely held responsible for the behavior of their corporations or government agencies, though symbolic resignations and apologies are expected from a top official in order to quell scandals.
"The basic philosophy of the Japanese bureaucracy is to evade all responsibility," said Dr. Takashi Kitamura, a former researcher at the National Institute for Infectious Diseases in Tokyo, who translated into Japanese the U.S. warnings about the risks posed by dura in light of the Connecticut woman's death and published them in 1987.
A spokesman for the health ministry, Koichi Ando, conceded in an interview that his agency's response to CJD was "not necessarily adequate." He outlined steps that have been 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 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.
The cases here, as with most such lawsuits, focus mainly on what B. Braun and regulators knew and when they knew it. These questions would be of purely legalistic interest were it not for the issue of how quickly authorities will be able to intercept peculiar infectious outbreaks in the future.
CJD transmission was first reported from a cornea transplant, in 1974. By 1978, when it was learned that the disease had also been transmitted by electrodes placed inside the cranium during tests, researchers began discussing the fact that the mysterious agent responsible for CJD wasn't killed off by usual sterilization methods.
The question for the courts is whether B. Braun or others knew or should have known the risks in time to save any of the Japanese patients, the majority of whom had surgery in the mid-1980s.
"It is not clear in this case that they knew," said Kiyohiko Katahira, a medical information specialist at Tokyo Medical and Dental University and an expert witness for the CJD patients. What is clear is that they could have known the risks, certainly as early as 1978, he said. "They could have known by reading published reports in leading medical journals."
But Sato, the neurologist who chaired the investigative commission, said CJD was such an obscure disease that it wasn't likely to register on the Japanese epidemiological radar.
"A neurologist might only see one case in 10 years, if that, so it is not realistic for people to have had a sense of urgency about a threat from dura," he said.
Sato 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 the causes of death listed in some of the records that B. Braun did have were false, according to Japan's NHK television and Nakagawa's office.
By contrast, U.S. manufacturers of dura were identifying donors by number and separately sterilizing tissues taken from each corpse to reduce the risk of disease transmission.
Unlike Japan, the U.S. had never approved Lydodura for sale, and only two CJD deaths believed to have been caused by the product have occurred in the States, Belay said. Cases have also been reported in Australia, France, Germany, Italy, New Zealand, Spain, Britain and Canada. Worldwide, all but half a dozen dura cases are linked to exposure to Lydodura, Belay said.
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.
Long Incubations Pose Challenge
The challenge now facing health officials is how to protect the blood supply and other biological products from contamination caused by diseases with such long incubation periods. One of the CJD victims in Japan is a 17-year-old boy who had brain surgery for a tumor in 1983 as an infant, was pronounced completely cured, then developed his first symptom 15 years later.
There are no confirmed cases of CJD transmission by blood, said Belay, but nevertheless blood donors in the U.S. and Japan now are asked about CJD risk factors. In Japan, those who report having received dura implants are not allowed to donate.
Japanese authorities have identified eight cases of blood donation from people who later developed CJD, but they were able to trace and recall only four of the blood lots.
There is nothing to be done for Takako Tani, who 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, who are 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. On the wall is a family picture from the day in the spring of 1996 when she climbed Diamond Head in Hawaii, just before falling ill.
Sanichi Tani, 51, and his daughters bathe Takako every three days, massage her limbs, put cream on her clenched 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."
His only remaining hope is that Takako will live long enough for him to report to her a successful verdict in her lawsuit. A decision is expected late this year or early next.
In lieu of her testimony, Tani has made public his wife's last diary entry, in disintegrating handwriting that careens across the page:
"May 26. Sunny. Not very hot. Last night I had a scary dream. They were trying to erase all my dreams. It became pitch dark and I was afraid."
Chiaki Kitada in The Times' Tokyo Bureau contributed to this report.