The SMON Fiasco

Bryan Ellison & Peter Duesberg

(Excerpt from Inventing the AIDS Virus)

Blaming non-infectious diseases on infectious microbes has occurred many times before. Hidden in foreign-language materials and the footnotes of obscure sources lies the story of SMON, a frightening disease epidemic that struck Japan while the war on polio was accelerating in the 1950s. In many ways, SMON anticipated the later AIDS epidemic. For fifteen years the syndrome was mismanaged by the Japanese science establishment, where virtually all research efforts were controlled by virus hunters. Ignoring strong evidence to the contrary, researchers continued to assume the syndrome was contagious and searched for one virus after another. Year after year the epidemic grew, despite public health measures to prevent the spread of an infectious agent. And in the end, medical doctors were forced to admit that their treatment had actually caused SMON in the first place. Once the truth about SMON could no longer be ignored, the episode dissolved into lawsuits for the thousands of remaining victims. This story has remained untold outside of Japan, ignored as being too embarrassing for the virus hunters. It deserves to be told in full here.

The patient was middle aged, suffering from a mysterious nerve disorder that had already paralyzed both her legs. Reisaku Kono was there to observe the victim because of his work studying poliovirus, which in a few infected individuals would break into the central nervous system, causing progressive paralysis and sometimes a slow, miserable, death. While the condition he examined that day in 1959 was not polio, it bore a certain resemblance to it. And the suspicion was growing that this, too, could be the result of some undiscovered virus, perhaps one similar to poliovirus.
Kono was visiting the patient at the hospital affiliated with Mie University's medical school. Hiroshi Takasaki, a professor of medicine at the university, told Kono about a number of these cases he had recently seen at the hospital. They now realized they were facing an outbreak of something new, not just a minor mystery that doctors would catalog and forget. Just the previous year, medical Professor Kenzo Kusui had published a report of another such case in central Japan: The patient had suffered a similarly strange combination of intestinal problems, manifesting as internal bleeding and diarrhea, with symptoms of nerve degeneration. This illness, stomach pains or diarrhea followed by nerve damage, had been noticed in a few isolated cases as early as 1955, but was now turning into a local epidemic.

More published reports began accumulating after Kono's visit to the hospital. The next five years saw seven major regional epidemics of the new polio-like syndrome, with the annual number of new cases increasing from several dozen in 1959 to 161 victims by 1964 - an alarming rate for those small areas. Scientists jumped to conclusions, believing they had every reason to assume the disease was infectious. Just its sudden appearance was enough evidence to convince them. The disease also broke out in clusters around specific towns or cities, and clusters were seen within families. The first person to develop the condition in each of these families was followed by a relative within several weeks. Many outbreaks were centered around hospitals, places notorious for spreading disease. The annual peak of new patients occurred in late summer, hinting at possible spread of the disease through insects. Those scientists who first thought the disease might be related to some noncontagious occupational hazard were quickly dissuaded once the data showed that the disease lacked the expected preferences. Farmers, for example, who would be more easily exposed to pesticides, had a lower-than-average incidence. Medical workers, on the other hand, had a rather high rate of this condition - further suggesting it was contagious.
However, the scientists investigating the epidemic did notice some important contradictions. For instance, the disease had an odd, amazingly consistent bias for striking middle-aged women, but was less common among men and could hardly be found among children, who normally transmit virtually any infectious disease. Careful medical inspection showed that the symptoms did not coincide with those typically expected for an infection. Blood and other bodily fluids, which usually circulate a virus throughout the body, showed no abnormalities, nor did the patients manifest any fevers, rashes, or other signs of fighting off some invading germ. These important pieces of evidence should have raised doubts about the viral hypothesis.

The virus hunt pressed onward. Scientists were expecting to find a virus that primarily induced diarrhea, as was the case in polio. Looking back on this period, Kono has since become admirably frank about his early biases, shared at the time by his fellow virologists: "I was at that time engaged in poliovirus research, so I suspected such a virus to be the cause."(1) Despite years spent searching for the elusive virus, he never could isolate a single one from any patient. Kono patiently reported his null results as he plodded forward.

Meanwhile the epidemic was growing and the 1964 Olympic Games were approaching. Ninety-six new cases had been diagnosed the previous year, and the increased number of cases was being accompanied by new symptoms. Some victims, for example, were now suffering debilitating blindness. Preparing to host tourists from around the world for the 1964 Olympics, Japan could ill afford to have an uncontrolled plague. To make matters worse, forty-six new patients suddenly appeared around the city of Toda, one of the locations for Olympic events. Embarrassingly dubbed the "Toda disease," this outbreak directly threatened Japan's reputation and tourist industry while focusing public fear on the epidemic. Etsuro Totsuka, later to become a lawyer for victims of the disease, summarized the public mood at the time: "Even I was quite worried at the time, as a university student studying physics. The general public, including me, was extremely worried; we didn't know how to prevent it, and there was no cure."(2)

In May of 1964, at the 61st General Meeting of the Japanese Society of Internal Medicine, the disease was raised as a formal topic. Kenzo Kusui, one of the first doctors to report patients stricken with this condition, chaired that session. The participating researchers gave the disease a formal name, Subacute Myelo-Optico-Neuropathy (SMON), and they agreed on a standardized clinical diagnosis. The Japanese Ministry of Health and Welfare quickly provided a research grant and launched a formal commission to investigate the epidemic under the leadership of Magojiro Maekawa, a medical professor at Kyoto University. Kono was one of several virologists named to the commission, thereby establishing its mandate as a formal search for a virus.

The same year brought the first sign of a possible breakthrough. Masahisa Shingu, a virologist at Kurume University and a fellow member of the commission, announced his discovery of a virus in excretions from SMON patients. The virus was classified as an echovirus - an acronym for enteric cytopathogenic human orphan virus. The viruses were called orphans because they had been discovered accidentally during polio research but caused no disease. Echoviruses were known for infecting the stomach or intestines, and Shingu found evidence of infection in various SMON sufferers. He excitedly drew the conclusion that this orphan virus had finally been matched with a disease. Perhaps, he speculated, this virus could also occasionally break into the nervous system, much like poliovirus. He published the finding in 1965, unabashedly boasting he had isolated the syndrome's cause.

But Kono, knowing the potentially disastrous results of blaming the wrong microbe for the disease, took a more cautious attitude. In 1967, after three years of research trying to confirm Shingu's claims, Kono could only report to a SMON symposium that he had not isolated the virus from patients, nor could he find even indirect evidence that the patients had previously been infected. Kono's better judgment saved Japanese science from stampeding in the wrong direction. He was fully vindicated four years later when other researchers announced the same lack of evidence to suggest any danger from Shingu's virus.

In the midst of this fruitless investigation, the Maekawa team made a surprising observation that was tragically brushed aside. According to surveys of hospitals, about half the SMON patients had previously been prescribed a diarrhea-fighting drug known by the brand name Entero-vioform, and the other half had received a compound marketed under the name Emaform. Both drugs were prescribed for problems of the digestive tract - the early symptom of SMON. The suspicion naturally arose that these drugs might play some role in the syndrome, but the commission, intent on the viral hypothesis, bowed to the consensus view of SMON as contagious and quickly dismissed this, noting that two different drugs should not cause the same new disease. Had the commission researchers checked further, however, they would have discovered that the two drugs were merely different brand names applied to the same drug, a fact that did not surface for several years.

The SMON commission dissolved in 1967, a failure. The cumulative total of reported SMON cases had meanwhile reached nearly two thousand by the end of 1966, a significant but not terrifying number. If not for the quiet growth of the disease epidemic, the floundering virus hunt might have killed public interest in SMON research altogether.

Almost immediately after the official commission was dissolved, two rural areas in the Okayama province began reeling from a new explosive outbreak of the syndrome. Dozens of elderly women, and some men in their thirties, began filling the nearby hospitals, totaling almost 3 percent of the local population by 197I. Scientific attention was again focused on SMON, with the specter of a resurgent epidemic recharging the virus hunt.

Two researchers issued reports in 1968 describing a new virus found in tissues of SMON patients, stirring a wave of excitement. The agent fell under the classification of "Coxsackie" viruses, a type of passenger virus known to infect the digestive tract and originally discovered as a by-product of polio research. It was another false alarm: The virus proved to be an accidental laboratory contamination.

In 1969 the Japanese Ministry of Health and Welfare, anxious about the expanding epidemic, again decided to form an official investigating body. With more than ten times the funding of the old 1964 commission, the SMON Research Commission became the largest Japanese research program ever devoted to a single disease. Its first meeting was held in the heavily affected Okayama province in early September. The consensus view among Japanese scientists had completely focused on some unknown virus as the probable cause of the disease. The naming of Kono, Japan's most respected virologist, as chairman symbolically established the new commission's priorities.

So far, after more than a decade of persistent research, the virologists had come up painfully empty-handed. Kono, though himself a virologist, now saw the need to explore alternative hypotheses. Kono divided the commission's work into four sections, each led by top Japanese medical officials. An epidemiologist was put in charge of a group conducting nationwide surveys on the extent, distribution, and associated risk factors of the disease. Kono himself headed the virology group. A pathologist headed a group focused on analyzing autopsy results, and a neurologist led a group classifying neurological and intestinal SMON symptoms. Altogether, forty top scientists participated in the commission during 1969.

Although Kono had opened the door for alternative research directions, the virus hunt accelerated - for just at this time, some key scientific claims by English and American virologists were beginning to have a profound impact on virus research worldwide, and particularly on SMON research in Japan. The first came in the early 1960s from virologist Carleton Gajdusek of the American National Institutes of Health, who reported finding evidence of the first "slow virus" in humans. (A slow virus is a virus alleged to produce a disease long after the original infection, that is, after a long "latent period.") He believed it to be the cause of kuru disease among New Guinea natives. Kuru was a slowly progressing neurological disease that led to the debilitation of motor skills. The patients presented with symptoms of tremor and paralysis similar to Parkinson's disease. Gajdusek claimed to have found the kuru virus, but his methods were highly unusual by any scientific standards. He had never actually isolated a virus but instead had ground up the diseased brains of dead kuru victims and injected these unpurified mixtures into the brains of living monkeys. When some of the monkeys showed deficits in motor skills, Gajdusek published his findings in the world's oldest scientific journal, Nature, and was lauded by his fellow virologists. The second alleged discovery came from London's Middlesex Hospital in 1964, directly inspired by Gajdusek's claims. Two researchers found a virus that was believed to cause the childhood cancer, Burkitt's lymphoma. It was the first virus ever claimed to cause human cancer and the first known human virus thought to have an incubation time between infection and disease measured in years, rather than days or weeks.

These claims were made by very large and respected research establishments; therefore, Kono could not afford to ignore them. Other medical experts on the SMON commission warned him that the SMON symptoms did not resemble those of standard virus infections, suggesting the condition was not contagious. Kono, however, brushed aside this advice, arguing that if scientists were unwilling to consider the possible existence of nonclassic viruses then "Dr. Gajdusek could not have established a slow virus etiology for kuru."(3) Imitating Gajdusek's methods, he injected unpurified fluids from SMON patients into the brains of experimental mice and monkeys, hoping to cause the disease and isolate the guilty virus. Frustrated, but not willing to give up, he decided the American researchers were better equipped to find such a virus. He mailed the same fluid samples directly to Gajdusek, who repeated the inoculations into the brains of his own chimpanzees; after three years, they, too, remained perfectly normal. With that, Kono finally abandoned the search for a "slow virus."

With their virus research faltering, a few of the investigators began looking for bacteria. One lab found that SMON patients had imbalanced levels of the beneficial bacteria normally growing in everyone's intestines, but it could not isolate any new invading microbe. Kono's own lab, as well as two other researchers, did notice unusually large amounts of a mycoplasma, one type of bacterial parasite, in disease victims. However, since mycoplasma are found in a large percentage of human populations and are usually known for being either relatively harmless or causing some pneumonias, Kono and his fellow researchers decided against pursuing this further.

By 1970, one fact stood out more agonizingly than any other: Twelve years of microbe research into the SMON epidemic had yielded nothing but dead ends. Yet the pressure continued to mount as the death toll rose. The year 1969 alone claimed almost two thousand new SMON victims, the worst toll ever. Kono and his commission were running out of options.
Fortunately for the Japanese people, several researchers on the commission were not virus hunters, and these scientists actually rediscovered the evidence for a toxin-SMON hypothesis.

The Drug Connection

As the race to find a SMON virus was capturing all the attention, other scientists were turning up some important clues to the mysterious syndrome. One pharmacologist, Dr. H. Beppu, visited the hard-hit Okayama province in 1969 to investigate the increasing outbreak and independently discovered the same coincidence the Mackawa group had years earlier - that SMON victims had taken certain drugs to treat diarrhea. Unlike the Maekawa group, Beppu investigated and found that Entero-vioform and Emaform - the diarrhea-fighting drugs found present in an earlier SMON study - turned out to be different brand names for a substance known as clioquinol, a freely available medical drug used against some types of diarrhea and dysentery. Beppu fed the chemical to experimental mice, hoping to see nerve damage like that in SMON, but was disappointed when the mice merely died. He missed the significance of his own results. Clioquinol was sold because it was believed not to be absorbed into the body, instead remaining in the intestines to kill invading germs. The death of Beppu's animals, however, proved that the drug not only entered the body, but could kill many essential tissues in the animal. His experiment led the SMON commission to rediscover this clioquinol connection the following year. "He later confessed to feeling stupid, because he gave up the experiment when the animals died," Totsuka explained of Beppu. "He wanted to prove a neurological disorder, but only proved the drug's severe toxicity."(4)

Meanwhile the SMON commission's first priority lay in conducting a nationwide survey of SMON cases reported since 1967, gathered by sending questionnaires to doctors and hospitals throughout Japan. In the fall of 1969, shortly after the commission began analyzing survey data, the head of the clinical symptoms section came across several SMON patients with a strange green coating on their tongues, a symptom unnoticed before nationwide data were gathered. At first other researchers on the commission suggested that this new symptom might be caused by Pseudomonas bacteria, which can release colorful blue and green pigments. One of the investigators did isolate such a bacterium from some patients but not from others, and the inexplicable symptom merely became a part of the revised SMON definition. The green tongue observation achieved new importance in May of 1970, when one group of doctors encountered two SMON patients with greenish urine. Enough of the pigment could be extracted to perform chemical tests. Within a short time the substance was determined to be an altered form of clioquinol, the same drug previously found by the Maekawa commission and by Beppu.
This raised two very troubling questions. Clioquinol had been marketed for years on the assumptions that it only killed amoeba in the intestinal tract and could not be absorbed into the body; its appearance on the tongue and in the urine now proved this belief wrong. Could the medicine therefore have unexpected side effects? And why would SMON patients manifest the drug by-products so much more obviously than the rest of the population? This latter question particularly bothered one neurology professor at Niigata University, Tadao Tsubaki. Making an educated guess, he openly formulated the hypothesis abandoned by earlier investigators - that SMON might be the result of clioquinol consumption, not of a virus.

As expected, the interpretation of SMON as a noncontagious syndrome did not become popular among the virus hunters. And the suggestion that clioquinol might be guilty met even stronger resistance, for the drug was being used to treat the very abdominal symptoms found in SMON. Doctors, naturally, were reluctant to believe they were exacerbating these abdominal pains and thus adding the severe insult of nerve damage to the injury. Totsuka recalled that "doctors and scientists wanted to believe in a virus, because they prescribed clioquinol. One of the drug's main side effects was constipation and abdominal pain. Now because the drug caused pain, doctors again prescribed the drug."(5) Doctors, ignorant of clioquinol's side effects, assumed the stomach pains resulted from the primary sickness and kept increasing the dose in a vicious cycle.
Tsubaki knew he had to gather strong evidence before they could shoot down the virus-SMON hypothesis. Pulling together several associates, Tsubaki arranged for a small study of SMON patients at seven hospitals. By July of 1970 he had already compiled enough data to draw several important conclusions: 96 percent of SMON victims had definitely taken clioquinol before the disease appeared, and those with the most severe symptoms had taken the highest doses of the medication. The number of SMON cases throughout Japan, moreover, had risen and fallen with the sales of clioquinol.

This clioquinol hypothesis explained all the strangest features of the SMON syndrome, such as its preference for striking middleaged women, its absence in children (who received fewer and smaller doses of the drug), and its symptomatic differences from typical viral infections. It also shed new light on the supposed evidence that SMON was infectious: its tendency to appear in hospital patients, to cluster in families, to afflict medical workers, and to break out more heavily in the summer - all of these reflected the patterns of clioquinol use. The epidemic itself had begun shortly after approval for pharmaceutical companies to begin manufacturing the drug in Japan.
In 1970 there were thirty-seven SMON cases in January and nearly sixty more cases during the month of July. The Japanese Ministry of Health and Welfare decided not to wait any longer, and promptly released the information about clioquinol to the press. The news of Tsubaki's research reached the public in early August, and the number of new SMON cases for that month dropped to under fifty, presumably because some doctors stopped prescribing clioquinol to their patients. On September 8 the Japanese government banned all sales of the drug, and the total new caseload for that month sank below twenty. The following year, 1971, saw only thirty-six cases. Three more cases were reported in 1972, and one in 1973. The epidemic was over.

For the next few years, the commission's research focused on confirming the role of clioquinol. In 1975 it released a comprehensive report. Systematic epidemiological surveys matched use of the drug with outbreaks of the syndrome, and experiments were performed on animals ranging from mice to chimpanzees. As it turned out, the drug induced SMON-like symptoms most perfectly in dogs and cats. Meanwhile, the investigators began uncovering individual case reports of SMON symptoms from around the world, wherever clioquinol had been marketed. Totaling roughly one hundred cases, the published reports ranged from Argentina in the 1930S to Great Britain, Sweden, and Australia in more recent times, often with the doctor specifically pointing out the association with the use of clioquinol or similar compounds. Ciba-Geigy, the international producer of the drug, had received warnings of these incidents years before the Japanese epidemic, a fact that later became the basis of a successful lawsuit against the pharmaceutical company.

Clioquinol, often marketed under the brand name Enterovioform, has been available for decades throughout many countries in the world. But while doctors outside Japan have published a few reports of SMON-like conditions, no real epidemic of the disease has ever broken out in Europe, India, or other countries with widespread use of the drug. Much of the difference lies in the heavier consumption of clioquinol in Japan, where the stomach, rather than the heart, is considered the seat of the emotions. The general over-prescription of drugs in that country further worsens the problem, such that many SMON victims had histories of using not only clioquinol but also multiple other medications, often at the same time. Government health insurance policies have encouraged this over-medication, paying doctors for every drug prescribed to the patient. As a result, the proportion of the Japanese health insurance budget spent on pharmaceutical drugs grew from 26 percent in 1961 to 40 percent in 1971, a level many times higher than in other nations. By the time the Japanese government decided to ban clioquinol, many of the hardest-hit SMON patients had each consumed hundreds of grams over the course of several months. And whereas the outside world mostly used clioquinol to prevent diarrhea when traveling abroad, the Japanese usually received the drug as hospital patients, having an already weakened condition.
Years later, at a 1979 conference, Reisaku Kono asked, "Why had research on the etiology of SMON not hit upon clioquinol until 1970?" The question has two answers; both pointed out by Kono himself:

There were at least two occasions when physicians suspected that clioquinol might have something to do with SMON. I know of a certain professor rebuking one of his staff physicians for connecting clioquinol with SMON. In 1967 the study group of the National Hospitals on SMON reported as follows: Entero-vioform (clioquinol's brand name), mesaphylin, Emaform (home producer of clioquinol), chloromycetin and llosone were often prescribed to SMON patients, but no link was found between Entero-vioform and SMON. This report referred to Entero-vioform in particular so that clioquinol must have been suspected by someone in the study group. Dr. Tsugane, who was responsible for the survey, said that the survey was not thorough enough to unearth clioquinol as a causative agent. One of the reasons could have been that clioquinol had been used as a drug for the intestinal disorders of SMON, and it was hard to believe that clioquinol was toxic rather than a remedy. (6)

Referring here to the tentative fingering of clioquinol by the Maekawa group, Kono observed that too many medical doctors refused to recognize the possibility of an iatrogenic disease (one caused by the doctor's treatment). They understandably disliked the idea that a drug might cause some of the very symptoms for which it was prescribed in the first place.

Another, more fundamental, reason for overlooking clioquinol lay in the prevailing attitude of the virologists. As expressed by Kono, "We were still within grasp of the ghosts of Pasteur and Koch!"(7) SMON, a vaguely polio-like syndrome, had first appeared in the midst of a war against polio. The polio virologists, Kono included, were naturally inclined to search for a new virus as the cause of the new disease. The Japanese government, having funded poliovirus research, simply kept up the momentum by funding the same virologists to study SMON. Thus, the virus hunters received the lion's share of research moneys and attention, and with that the power to direct the SMON research program. Had it not been for Kono's foresight in also appointing nonvirologists to the commission, the epidemic might have lasted much longer.
At least the epidemic had ended, with the truth universally recognized. The virologists had learned their lesson, and the search for SMON viruses was over.

Or was it? Incredibly, against all evidence, the SMON virus hunt suddenly came back to life within weeks of the epidemic's end. The fight over the cause of the syndrome was to drag on for several more years, with the virus hunters simply ignoring the fact that SMON itself had disappeared after the ban on clioquinol.

The Virus Hunt Revived

In February of 1970, while the SMON Research Commission was still scrambling to find the cause of the epidemic and a few researchers were just beginning to notice the greenish pigments in some patients, Assistant Professor Shigeyuki Inoue at Kyoto University's Institute for Virus Research claimed discovery of a virus in the spinal fluid and excretions of SMON patients. He added the extracts to laboratory culture dishes of hamster tumor cells and found that the new agent killed the cells. With more experimentation, Inoue classified the microbe as a new herpes virus. He was able to isolate this particular virus from nearly all SMON patients he tested, more than forty in all, and found antibodies against the virus in other victims. 

Reisaku Kono moved promptly to test these new observations. He used Inoue's own virus isolate and cell cultures, and within three months of Inoue's first report found that the virus could kill some cells. These particular cells, however, were extremely sensitive, prone to spontaneous death even in the uninfected cultures. Kono began to suspect the virus was harmless. He also could not isolate the virus from any SMON patients, unlike Inoue's lab. Perhaps, he openly wondered, the alleged virus might not exist at all.

A number of scientists sided with Kono, insisting they could neither find the virus in SMON victims nor cause cell death in culture dishes by adding virus samples from Inoue's lab. Nor could Inoue's extracts induce symptoms when injected into mice. Indeed, Kono and some of these other investigators could never even find the virus at all, reinforcing the growing question of whether it truly existed. The virus could not even be detected in the samples sent them from Inoue. An occasional mouse injected with Inoue's supposed virus would become sick, but the symptoms did not resemble those of SMON. Kono won allies among his peers when many of them could not reproduce Inoue's observations. a troubling problem for any scientific claim.
Nevertheless, Inoue had meanwhile rapidly achieved celebrity status for his "SMON virus" during 1970, before the clioquinol announcement that August. The Japanese news media had prematurely publicized his results, creating the widespread impression that the cause of SMON had been determined. Hysteria over the contagious plague swept through much of the country, causing frightened family members of SMON patients to avoid contact with their "infected" relatives, and leading many of the victims to commit suicide. "Patients were isolated, many committed suicide, and there was national panic," reflected Totsuka on the horror he witnessed. "I met families who lost relatives. I heard from most or all of my goo clients; most of the patients said they very much feared and dreaded the disease. Everybody told me about that, about those sufferings. Once they found out about the drug, they were somewhat relieved, because it was not infectious."(8)

The new virus-SMON hypothesis had indeed achieved a life of its own, causing a few scientists to Jump on the Inoue bandwagon; months after clioquinol had been banned and the epidemic had virtually disappeared, several labs excitedly issued reports claiming they could reproduce Inoue's findings. Inoue himself further insisted he had caused SMON-like symptoms in mice - including weight loss, paralysis, and nerve damage - either by injecting the virus into their brains or feeding the virus to other immune-suppressed mice unable to fight off the infection. Inoue and a collaborating scientist also both claimed to have photographed the virus directly with electron microscopes, although Inoue's colleague eventually retracted his own report as having been mistaken.

A meeting of the SMON Research Commission was finally held in July of 1972 to resolve the controversy. Until that time, Inoue's results had received attention and concern equal to the ciioquinol research. But based on the inability of many scientists to produce the same results, which must be done for any scientific hypothesis to be accepted, the members at the meeting decided not to focus any more research efforts on the Inoue virus. Samples were frozen for future study, and the group thereafter devoted its resources to studying clioquinol.

Despite the absence of confirming evidence, and despite the disappearance of SMON following the ban on clioquinol, Inoue and his supporting colleagues continued to publish reports of evidence for the virus hypothesis. This publicity carried the Inoue hypothesis overseas, leading the 1974 edition of the Review of Medical Microbiology, an American textbook, to incorporate the Inoue virus hypothesis of SMON.

Shocked and angered by the favorable publicity surrounding Inoue's hypothesis, Kono wrote a letter to the British medical journal Lancet; the letter was published in August of 1975. The international popularity of virus research had whetted scientists' appetite for Inoue's hypothesis, but Kono also knew he was battling a nearly complete ignorance of the SMON episode outside Japan:

Inoue et al. published several papers on SMON virus, and a standard textbook adopted Inoue's virus theory as confirmed. However, research in the laboratories of the SMON Research Commission in Japan failed to confirm Inoue's results. Unfortunately, this negative information has not been published in English.(9)

The epidemic's toll had officially ended in 1973 with 11,007 victims, including thousands of fatalities. Angered upon learning of Ciba-Geigy's disregard of previously reported clioquinol toxicity, many of these patients filed a lawsuit in May of 197I against the Japanese government, Ciba-Geigy of Japan, fifteen other distributors of the drug, and twenty-three doctors and hospitals. The ranks of the plaintiffs soon swelled to some forty-five hundred, with legal action initiated in twenty-three Japanese district courts. The largest group of SMON victims sued jointly in the Tokyo District Court. When frustrations mounted over the slow and indecisive actions of their lawyers, nine hundred of the plaintiffs broke away to form a second group. The aggressive investigations conducted by this new legal team reinvigorated the case, bolstering the positions of the plaintiffs in parallel lawsuits. Etsuro Totsuka, one of the thirty members of this legal team, has described the fight:

We were the only team gathering information outside Japan, inviting foreign experts to testify in Japanese courts, discovering the United States FDA had restricted clioquinol ten years before Japan, and waging an international campaign against Ciba-Geigy... 

We found many foreign doctors who had reported clioquinol side effects before. They were contacted by Ciba-Geigy, and except in one or two instances were persuaded not to help us. By the time I saw the doctors, they had already been contacted by the other side. They had been invited on trips, some to Ciba-Geigy's headquarters... We felt they were already compensated, under the condition not to tell us anything.(10)

The two sides slugged it out for several years, but the testimony by members of Kono's SMON Research Commission proved devastating, and a string of legal victories followed in the courts. 

Today most scientists and laymen outside Japan have never heard of the virus-SMON controversy, even in the face of the lawsuit against the distributors of clioquinol, television documentaries in Germany and England on clioquinol, and two conferences during the 1970s on iatrogenic (medically caused) disease. The story that SMON research had ignored the evidence of a toxic cause for fifteen years and had sacrificed thousands of human lives to a flawed virus hypothesis is too embarrassing to the virus-hunting establishment to record. *

References:
1. R. Kono, "The SMON Virus Theory," Lancet, ii (1975): 370-371; I. Shigematsu, H. Yanagawa, S.I. Yamamoto, and K. Nake, "Epidemiological Approach to SMON (Subacute Myelo-Optico-Neuropathy)," Japanese Journal of Medicine, Science, and Biology, 28 Supplement (1975): 23-33
2. E. Totsuka, personal communication, 1 May 1992.
3. T. E. Soda, Drug-lnduced Sufferings: Medical, Pharmaceutical, and Legal Aspects (Amsterdam: Excerpta Medica, 1980). 
4. Totsuka, personal communication, 1 May 1992.
5. Ibid.
6. Soda, Drug-lnduced Sufferings.
7. Ibid.
8. Totsuka, personal communication, 1 May 1992.
9. Kono, "SMON Virus Theory," 370-371.
10. Totsuka, personal communication, 1 May 1992.
11. Soda, Drug-lnduced Sufferings.