Cervical MRI of subacute myelo-optico-neuropathy.

STUDY DESIGN: Case study. OBJECTIVES: Subacute myelo-optico-neuropathy (SMON) is a severe neuro-degenerative disorder caused by poisoning due to over-dose and prolonged oral administration of clioquinol; this disorder was more frequent during 1957-1970. It is characterized by axonal degeneration and gliosis in the cervical gracile fasciculus. Recently, copper-deficient myelo-neuropathies presenting similar symptoms (that is, painful dysesthesia/paresthesia in the lower limbs, ataxia, spastic paraplegia, autonomic disorders and visual impairment) were reported. Magnetic resonance imaging (MRI) of these patients detected T2-weighted hyperintensities in the cervical spinal cord. An unbalanced zinc-copper metabolism was suggested as one of the candidate pathogenesis of clioquinol toxicity because of its metal-chelating ability. The aim of this study was to present MRI findings of old SMON patients and to compare them with those of current copper-deficient myelo-neuropathies. SETTING: Japan. METHODS: We conducted and analyzed cervical and brain MRIs of seven old SMON patients who contracted the disorder during the 1960s. Serum iron, magnesium, copper, zinc and ceruloplasmin levels were also measured. RESULTS: Cervical T2-weighted MRIs showed mild volume loss and faint hyperintensities in the dorsal columns, which might reflect residual gliosis. Brain fast fluid-attenuated inversion-recovery images and tractography were normal. Current levels of serum copper and zinc were within almost normal ranges. CONCLUSION: Although fainter, the abnormal T2 MRI signals we observed were similar to and occurred in the same locations as those reported in copper-deficient myelo-neuropathy patients. We suggest that these findings are useful to study the mechanism of clioquinol toxicity before using it to treat neurodegenerative diseases such as Alzheimer's disease.

Experimental clioquinol intoxication in rats: abnormalities in optic nerves and small nerve cells of dorsal root ganglia.

Pathological abnormalities in the central (CNS) and peripheral nervous system (PNS) were produced in rats by daily administration of 300-400 mg/kg clioquinol for 7-40 days. The changes comprised axonal degeneration of optic nerve fibers and mitochondrial swellings in small nerve cells of dorsal root ganglia. There were occasional myelin splittings in the spinal nerve roots. No apparent changes were observed in the spinal cord or peripheral nerves. Similar changes were occasionally encountered to a lesser extent in control rats by restricting the diet and water to maintain the body weight comparable to the ranges of experimental animals. It seemed that not only clioquinol intoxication but nutritional deficiency also contributed, in part, to the production of these CNS and PNS abnormalities. The possibility of the presence of peripheral neuropathy in subacute myelooptic neuropathy is discussed.

Appearance of intoxication in rats by intraperitoneal administration of clioquinol.

The investigation was undertaken to study the neurological symptoms in rats caused by maintaining high plasma concentration of about 30 nmol/ml or more, of clioquinol. Clioquinol suspension which was prepared using polysorbate 80 was administered intraperitoneally to rats and plasma and tissue concentrations were determined. On administration of clioquinol of 100 and 200 mg/kg, the mean plasma concentrations of clioquinol reached maximum values of 30 and 58 nmol/ml, respectively, after 0.5-1 h and thereafter decreased rapidly. With 400 mg/kg, however, plasma concentration reached maximum value of about 75 nmol/ml and fell slowly. By single and repeated administration of the suspension, clioquinol was distributed in the liver and kidney at a high concentration, and also in the nervous system. In experiments on appearance of neurotoxicity in rats by repeated administration of the suspension, all of 10 rats administered intraperitoneally with 100 mg/kg/d did not develop any neurological symptoms for about 30 d. On the other hand, one of 10 and 7 of 13 rats administered with 200 and 400 mg/kg/d, respectively, developed ataxia in the hind legs or all legs on the 3rd to the 12th day after starting administration. Pathologically, a slight change of the peripheral nerve, central chromatolysis of the anterior horn neuron and severe neuronal degeneration of the Ammon's horn were observed in the rats with ataxia.

Ultrastructural study of a muscle biopsy from a patient with subacute myelo-optic neuropathy.

A man, aged 46, who had been taking Clioquinol in high doses for a long period, developed a characteristic neurological syndrome of subacute myelo-optic neuropathy rather abruptly. Electron microscopical examination of the muscle biopsy, obtained five months after the onset of the disease, revealed severe degenerative changes of the presynaptic nerve endings and some unique paracrystalline inclusions in the sole plate region. The latter may represent the morphological expression of the toxic agent which is held responsible for the subacute myelo-optic neuropathy.

The neuropathology of subacute myelo-optico-neuropathy, "SMON", in the humans: --with special reference to the quinoform intoxication.

The detailed neuropathology of the 16 autopsy cases of the acute to chronic "SMON" of different ages together with those reported before and at the "SMON" Research Commission has been described and reviewed. This was compared with the alreadyknown neurological disorders, particularly systemic and/or pseudosystemic degeneration of the long tracts of the spinal cord with polyneuropathy together with the "SMON"-like diseases caused by certain neurotoxic and/or neurotropic agents. It has been concluded that "SMON" can be belonged to a subgroup of some endemic diseases within the main group of combined degenerations associated with complex nutritional deficiency or toxic interference of tissue metabolism. Since an excess and mal-administration of quinoform in quantity, time and space were identified in a great majority of the autopsy cases, quinoform could comprize the most important etiology for the "SMON" onset. This view also was supported by the almost complete reconstruction of the neuropathology of the human "SMON" in the experimental animals intoxicated with quinoform which disclosed a precise neurotropism from the autoradiograms of the same animals. As compared with the similar lesions in SLE,hepatocerebral diseases, etc., the pathogenesis and clinicopathological relationship of "SMON" was speculated. The accerelating and/or modifying factors for the SMON" onset aside from quinoform were discussed.

Neurotoxity of iodoxyquinoline: a further study on beagle dogs.

Eight beagle dogs were treated orally with iodoxyquinoline (chinoform, clioquinol) again, and all of them manifested similar neurologic symptoms to those observed in our previous experiments on mongrel dogs, beagle dogs, cats and a monkey. The neurologic symptoms were identical both clinically and pathologically with those of subacute myelo-optico-neuropathy (abbreviated to SMON) in man. In the present study, the neurologic manifestations evolved with less total chinoform doses (5.1-13.8 g/kg) in shorter periods (19-47 days) and there was no difference between each group on the increasing dosage and on fixed dosage. It is discussed in the present paper that onset of the neurologic symptoms is associated with unconjugated chinoform levels in the blood.

Prognosis of SMON patients.

The following points have become clear on prognosis of SMON through the analysis of 981 cases collected. 1) The prognosis of the old whose ages were 60 year old or over is not favorable, when compared with that of the young. However, there is no prognostic difference between male and female. 2) The cummulative death rate of SMON which was calculated by the life table method is approx twice as much as the generally expected value. 3) Approximately 80% of the patients showed some sort of improvement 7 to 12 months after the onset of the disease. The rate for 13 months or over if nearly the same. 4) The abdominal symptoms found at the time of the onset of the disease decreased markedly in the course of the disease. 5) Among neurological symptoms, the prognosis of motor disorders is more favorable. The complete recovery of sensory disturbances was extremely rare, but approx 60% showed more or less favorable in the course of the illness. Approximately 40% of the cases with visual disturbances completely recovered or showed favorable improvement, whereas 9% of them became worse. As for the prognosis of visual impairment, it is more serious than other symptoms. 6) The patients who had been administered clioquinol over long period displayed a higher rate of severe or moderate motor, sensory and visual disturbances, compared with the group with short-term administration of clioquinol. The death rate was also higher in the former group. 7) The rate of relapse as a whole was 16.7% and 68% of them was seen within 18 months after the onset. There is no difference in relapse according to sex. There was seen a high rate of relapse in the group of longterm administration of clioquinol. 8) A 10.5% of total cases were either unable to walk or in need of assistance in walking, whereas the rate of patients who cannot get dressed or who cannot defecate unassisted was lower. 9) Approximately 65% returned to the job in 12 months or more after the onset. The employment rate was not different according to sex, whereas it was lower along with the age advances. 10) Approximately 20% were not received medical treatment. The rate of non-treated patients is higher in the younger patients. The rate of hospitalized patients was higher in the older patients.