[SMON--a model of the iatrogenic disease]

Abstract

The subacute myelo-optico-neuropathy (SMON) was hazard caused by clioquinol, an antiseptic, prescribed for the treatment of diarrhea and other bowel symptoms. Its overdosing and long-term taking led to the occurrence of SMON, for which physicians should be responsible. Clioquinol, originally a disinfectant powder for external use, was diverted later to a drug for internal use to sterilize the bowel where no intestinal absorption or action after absorption was expected. An annotation on the 6th Revision of the Japan Pharmacopoeia (1954) allowed irregular increase in its dosage depending on the severity of illness. An annotation on the 7th Revision (1961) ignoring the 6 papers published in the 1930's, 1940's or 1950's claimed that its metabolism was poorly known, yet neglected significant side effect and substantial absorption from the intestine. Its characterization as a superficial disinfectant helped the annotators be less interested in its absorption and its internal actions and side effects. Attention paid by clinicians to a polyneuropathy-like syndrome that complicated an uncontrollable hemorrhagic diarrhea (1958) and an encephalomyelitis or a paralysis of the lower half of the body associated with diarrhea or other bowel symptoms (1960, 1961) started the recognition of a new disease. During the dispute induced by the mass occurrence of the disease in several instances postmortem examination with neuropathologic expertise, especially of T. Tsubaki, Y. Toyokura and H. Tsukagoshi (1964), characterized SMON as a non-inflammatory new disease of the spinal cord, optic nerve and peripheral nerve with a pseudo-systemic degeneration of posterior and lateral columns and, therefore played a decisive role in establishing the truth of SMON. The discovery of the green hairy tongue (the tongue coated with green hairs) of SMON by T. Takasu, A. Igata and Y. Toyokura (January 1970) aroused researchers' interest in the green color of SMON and thereby began solving the cause of SMON. The discovery of the green urine in SMON patients by A. Igata, M. Hasebe and T. Tsuji (May 1970) especially facilitated the identification of the green substance in SMON that was achieved by M. Yoshioka and Z. Tamura (June 1970). The green color was derived from a chelate compound of clioquinol with ferric iron. The early epidemiological analysis related clioquinol taking to the occurrence of SMON well enough for the Japanese Government to take an administrative measure for the temporary suspension of selling clioquinol containing drugs and the postponing of their use (September 1970). Extensive and intensive multidisciplinary investigations conducted for the subsequent 20 months led to the conclusion by the SMON Investigation and Research Committee (Head: R. Kono) that the neurological disorders of patients who were diagnosed as SMON for the most part were caused by taking clioquinol (March 1972). Close clinical observation of patients opened a way to recognize a new disease and elucidate its cause. Expert specialized technical knowledge and skills established the firm knowledge of the new disease. The study of SMON began as a personal research and after its achievement was exposed to the public a great many investigators in different fields concerted efforts to solve problems. Both steps were indispensable for completing the study.