On the pattern of change in peripheral nerves produced by isoniazid intoxication in rats

Pegum (1952) first reported in a letter to the Lancet that patients on isoniazid (isonicotinic acid hydrazide, I.N.H.) therapy might suffer from peripheral neuropathy. This observation was subsequently confirmed by Jones and Jones (1953), by Gammon, Burge, and King (1953) and by Biehl and Skavlem (1953). It became clear from the work of Biehl and Vilter (1954) that high doses of isoniazid (20 mg./kg./ day) regularly produced symptoms of neuritis in patients, that their excretion of vitamin B6 under isoniazid medication rose to three times the normal rate and that large doses of pyridoxine were fully protective against developing neuropathy. The action of isoniazid had already been shown to be competitive against the phosphorylation of pyridoxine and its inhibitory action upon microorganisms was competitively reversed, particularly by pyridoxamine and by pyridoxal (Boone and Woodward, 1953; Lichstein, 1955). The reason for the occurrence of only 40% incidence of neuritis in patients on a high daily dose of isoniazid became clear when it was shown by Biehl (1956; 1957) that, on the basis of finding a bimodal distribution of the percentage of administered isoniazid found free in the urine, patients could be divided into two clear groups, slow inactivators and rapid inactivators. Mitchell, Riemensnider, Harsch, and Bell (1958) suggested that this polymorphism for isoniazid metabolism might be genetically determined, and evidence in support came from Harris, Knight, and Selin (1958) who found a much higher incidence of rapid inactivators amongst Japanese than amongst Caucasians. This idea has been confirmed by Evans, Manley, and McKusick (1960), who showed that the slow inactivator state is recessive, and that a 'dosage' effect of the allele controlling the dominant character can be demonstrated. Polyneuritis tends to occur more frequently in slow inactivators than in rapid inactivators (Biehl, 1957). The nature of the changes in human peripheral nerves is not well understood and only two cases in which post-mortem studies have been done have been reported (Zbinden and Studer, 1955a). The only changes noted were Wallerian degeneration in peripheral nerves. The spinal cord and brain in each case appeared normal. Zbinden and Studer (1955b) made an experimental study using rats, rabbits, and guineapigs. The first species regularly showed degeneration of peripheral nerves within 15 days of being on a diet containing 250 mg. /kg. of isoniazid. Functional disturbances did not appear, however, until after seven to eight months of continuous dosing. They found that pyridoxine (50 mg./day) and pyridoxal phosphate both had a significant effect in mitigating the severity of the changes, whereas other vitamins of the B group had none. Neither guinea-pigs nor rabbits showed significant peripheral nerve lesions. Schlaepfer and Hager (1964a, b, c) have studied various ultrastructural features of the peripheral nerve degeneration in rats. In the early stages the changes in sciatic nerve showed granularity of axoplasm and mitochondrial swelling which are indistinguishable from those found in early Wallerian degeneration (Vial, 1958). It is thus clear that isoniazid produces degeneration of Wallerian type in rats and in man and that the clinical evidence suggests that recovery, presumably by reinnervation, is the rule. It is also apparent that the spinal cord and central nervous system generally are not significantly affected and in this respect the pattern of the process would seem to be different from that found in organo-phosphorus neurotoxicity (Cavanagh, 1954; 1964a, b; Cavanagh and Patangia, 1965). On the other hand evidence has been put forward suggesting that the neuropathy that complicates acute intermittent porphyria is also different from that due to organo-phosphorus compounds (Cavanagh and Mellick, 1965). The purpose of this study is to determine whether or not isoniazid neuropathy resembles either of these two patterns of neurological disease.