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Of the metabolites of hexane, 2,5-hexanedione (2,5 HD) has the strongest neurotoxic effect. There is a wealth of experimental studies in animals showing an axonotoxic mechanism consisting of an accumulation of 10 nm neurofilaments. Only few studies deal with a possible action of 2,5-HD on Schwann cells, glia cells or both. Pure neurons, pure glia and mixed cultures prepared from dorsal root ganglia (DRG) of chick embryos were studied in this model. DRG were chosen because they constitute a linkage between the peripheral and central nervous system and provide the additional advantage of containing only few defined glial and neuronal cell types. Additionally, pure neuronal cultures of sympathetic ganglia and mixed cultures of spinal cord and brain were prepared. In cultures of the different parts of the nervous system investigated, we observed at a concentration of 0.25% 2,5-HD massive toxic alterations of glial cells, whereas neurons and neurites were virtually unaffected.

Pure neurons were prepared from dorsal root ganglia (DRG) of 8 day old chick embryos (E8). The substances tested in this model were pure n-hexane, 2.5-hexanedione (2.5 HD) and methyl-ethyl-ketone (MEK). Differentiated cultures were exposed to these neurotoxins after two days in culture and then examined over a period of up to one week. For all three substances a specific neurotoxic effect could be demonstrated: (i) n-Hexane mainly altered the neurites, leading to focal swellings and in a second step to degenerative changes in glial cells; (ii) 2.5 HD had a minor effect on neurons and proved to be mainly gliatoxic; (iii) MEK primarily affected the neurons by swelling and disintegration of the cell body.

A 31-year-old woman developed an acute, potentially fatal rhabdomyolysis of undetermined origin. Muscle biopsy revealed selective lysis involving exclusively type 2a fibers. Myoadenylate-deaminase (MAD) deficiency was proven by a negative histochemical reaction as well as by an enzymatic biochemical determination. The significantly greater energetic dependence of type 2a fibres on MAD explains their selective damage. The patient's mother also suffers from a similar muscle disease of still unclarified origin.

The effects of lipoic acid on hexacarbon neurotoxicity in rats were investigated. Rats were exposed by inhalation to n-hexane for 24 hours/day, 7 days/week, up to a total period of 9 weeks. Eight animals were exposed to 700 ppm n-hexane only, and eight animals were exposed to 700 ppm n-hexane and additionally received 100 mumol/kg lipoic acid PO daily. Clinical status of the animals was evaluated by examination of general condition, motor performance tests and neurophysiological measurements of caudal nerve motor conduction velocity. Results showed that animals exposed to 700 ppm n-hexane developed severe motor neuropathy leading to paralysis by the 6th week. Motor distal latencies of these animals were severely prolonged. In contrast, in animals treated with lipoic acid the onset of motor neuropathy was delayed for approximately 3 weeks as could be demonstrated by motor performance tests and measurements of motor distal latencies.

The toxicity of organic solvents at different concentrations was examined to determine their effect on pregnant rats and their offspring. A very serious effect which inhalational exposure to n-hexane, methyl-ethyl-ketone and a mixture of the two organic solvents produced in pregnant rats was a concentration-dependent increase of intrauterine mortality. In cases of only prenatal exposure, the persistence of reduced body growth was an important result obtained at all concentrations we investigated (first solvent experiment, 500 ppm; second solvent experiment, 800 ppm; and third solvent experiment, 1000 to 1500 ppm; 23 hr day). In these cases, a delay in the maturation of cerebellar cortex was also observed. In cases of pre- and postnatal solvent exposure, the effects of malnutrition were added to the solvent-induced retardation. This resulted in an extreme delay in tissue maturation accompanied by a retarded cell maturation. The solvents examined had no teratogenic effect in pregnant rodents and their offspring. Neurotoxicity was restricted to the known structures of the adult animals, whose axons were damaged. They did, however, show a concentration-dependent embryotoxic and fetotoxic effect.

Adult rats were exposed to the solvents n-hexane and methylethylketone (MEK) in different concentrations. Lung tissue was examined systematically after various periods by electron microscopy. The direct toxic effect to pneumocytes could be demonstrated as definite regressive alterations, such as fatty degeneration and changes of lamellar bodies of type II pneumocytes as well as increased detachment of cells. Besides these findings, after chronic inhalation of solvents conspicuous aggregation of lamellar discharge material of type II pneumocytes can be seen, and probably, as a result of an irritated fat metabolism, large lysosome-like bodies with densely packed lipid material appear in type I pneumocytes. The most distinguished changes could be demonstrated after exposure to a mixture of n-hexane and MEK, while they were less obvious after n-hexane alone. The observation suggests a profound enzymatic irritation of metabolism.

A severe potentiating effects of methyl-ethyl-ketone (MEK) on the peripheral and central neurotoxicity of n-hexane could be demonstrated in a chronic inhalation study in rats.

Treatment with the histamine H2 receptor antagonist, cimetidine, alone and/or in combination with the histamine H1 receptor antagonist, chlorpyramine, in 13 patients showed that cimetidine alone was ineffective. 7 of 9 patients taking the combination of H1 and H2 receptor antagonists responded well to the treatment; in 1 patient, medication was ineffective and in 1 patient, success was doubtful. In 3 patients with chronic cluster headache, the effect faded after 4 weeks. The results are discussed.

Four men aged 16 to 19 years who had sniffed contact glue ("Pattex") thinner almost daily for 3 to 7 years developed a pronounced polyneuropathy. They had to be admitted nearly at the same time. A uniform neurological syndrome similar to Landry's paralysis with progressive ascending symmetrical pareses had developed. Motor deficiencies and atrophies affected the lower extremities more frequently and more severely. Only minimal sensory disturbances were found. The disease shows remarkable similarity to the "glue-sniffing neuropathy" described in the US and Japan which is attributed to n-hexane.

The pathomechanism of the Spanish mass oil poisoning, which affected more than 20,000 people in the spring of 1981 and has so far caused more than 500 deaths, has not yet been clarified. Subsequent to a toxic-allergic initial phase of the disease with fever as well as lung and skin manifestations, 10 to 20% of the patients, after passing through an interval of reduced symptoms, entered a second disease phase characterized by marked vasculitis and fibrosis in diverse organ systems. The most frequent manifestation type involved in this connection was a severe neuromyopathy with pronounced joint contractures and skin alterations. A survey of the disease course is presented on the basis of our own examinations at the Centro Especial Ramon y Cajal as well as morphological studies on nerve-muscle and brain tissue, chemical analysis studies with oil samples from affected families and the literature available so far.

Predisposing factors and concomitant diseases were examined in cluster headache patients. A positive or negative correlation to a particular disease, e.g. gastrointestinal ulcerative disease, could not be showen. Factors indicating a genetic predisposition could also not be found. In the Freiburg Personality Inventory cluster and migraine patients had an essentially normal profile; however, both groups evidenced a tendency towards psychosomatic reactions.

The effects of long-term continuous and intermittent inhalation exposure to selected concentrations of n-hexane and mixtures of n-hexane and methyl-ethyl-ketone (MEK) on the nervous system of rats were investigated. Animals exposed continuously (24 h/d, 7 d/week) to 500 ppm n-hexane displayed complete hindlimb paralysis after 9 weeks. Histological examination showed hexacarbon-specific axonal lesions in peripheral nerves, particularly tibial branches to calf muscles, and in the gracile tract at cervical levels of the spinal cord. Similar clinical and pathological signs of neuropathy appeared one week earlier in animals treated with a mixture of 500 ppm n-hexane/MEK (4:1 or 3:2) and 5 weeks earlier with 700 n-hexane/MEK mixture (5:2) or 700 ppm of n-hexane alone. Rats exposed to the latter concentrations intermittently, 8 hours daily for 40 weeks, did not develop clinical or morphological signs of a hexacarbon neuropathy.

An outbreak of neuropathies among Berlin solvent sniffers was closely related to the denaturation by methyl-ethyl-ketone (MEK) of the mixture used. The solvent was composed of n-hexane, toluene and ethyl-acetate. Nervous system responses to chronic repeated exposure to 10,000 ppm pure n-hexane, 10,000 ppm MEK/n-hexane (ratio 1:9) and 6000 ppm pure MEK were investigated in rats. Motor neuropathy of the dying back type with giant swelling of axons in the peripheral and central nervous system developed in animals exposed to MEK/n-hexane and n-hexane. Severe potentiation of n-hexane neurotoxicity and shortened onset of morphological and clinical signs were demonstrated in animals exposed to MEK/n-hexane. MEK alone did not produce neuropathy under these conditions. The findings suggest that commercial solvent mixtures containing MEK/n-hexane should be avoided.

The effects of the solvents n-hexane, butanone (methyl-ethyl-ketone, MEK) and a mixture of both in the intrapulmonary nerve system of rats were studied by light and electron microscopy. The alteration in the fine structures of the tissue consisted in a disseminated swelling of axons due to a striking multiplication of neurofilaments. Nonspecific axonal alterations could be demonstrated as well. The latter consisted in clusters of phospholipid material within the axoplasm of nerve fibers and the cytoplasm of Schwann cells plus an accumulation of glycogen granules in the axoplasm. Additionally, single degenerative changes of Schwann cells were observed. An enzyme-associated metabolic damage with a concomitant impairment of axonal flow is discussed as a possible underlying pathomechanism.

Hexacarbon-containing solvents can induce specific functional and morphological disorders in the peripheral and central nervous system. The neurological manifestations consist in polyneuropathy syndromes and neuromyelopathies. Such clinical pictures have been observed both after exposure at industrial work and after abuse of hexacarbon-containing solvents as narcotics. An outbreak of neuropathies among solvent-sniffers after denaturation of the hexacarbon-containing solvent with methyl-ethyl-ketone led to the assumption that the neurotoxic properties of n-hexane can be considerably potentiated with methyl-ethyl-ketone. Experimental studies on laboratory rats have shown that solvent mixtures with n-hexane and methyl-ethyl-ketone bring about an earlier onset of clinical-neurological deficits and hexacarbon-specific morphological changes than exposure to n-hexane alone. First results of a combined exposure to lead and n-hexane solvents also indicate an intensified effect of the combined neurotoxins.

In West Berlin in the autumn of 1975 through the following 5 months we observed 18 juvenile patients who had a toxic polyneuropathy and had sniffed a glue thinner. The neurological picture consisted of a symmetrical, progressive, ascending, mainly motor, polyneuropathy with pronounced muscle atrophy and characteristic vegetative alterations. The height of the disease was reached after 1 1/2-2 1/2 months and was characterized by tetraplegia in 7 patients. After 8 months all patients still had a motor deficit. Nerve biopsy showed paranodal axon swelling, dense masses of neurofilaments and secondary myelin retraction. The neurological and morphological data correspond to the "glue sniffer's neuropathy" and the n-hexane and MBK polyneuropathy after industrial exposure, as described in 10 cases to date. However, there was no MBK in the glue thinner. The polyneuropathies occurred in close time relation with the denaturation of the thinner with MEK (2-butanone). It is concluded from the data n-hexane and MBK have a common toxic mechanism with primary axonal changes and that there is an additional synergistic effect of MEK.

25 cases of clinically severe toxic polyneuropathy were observed among young people in Berlin who were addicted to sniffing methylethylketone-containing solvents. The peripheral motor defects took 2 1/2 to 3 years to regress. In severe cases there were additional spastic signs. This form of neurotoxic effect can be reproduced in animals. It is due to a disorder of axonal transport which destroys peripheral and central axons.

In the present study, a comparison relating to various social aspects was made between 74 opiate addicts who had abused or continued to abuse solvents and 500 fixers without sniffing experience (SE). The results show clear differences between the two groups with reference to age, sex, social status, socialization conditions, family structure, education, vocational training, drug sequence and criminality as well as attitude and motivation towards withdrawal therapy. Contrary to hitherto existing assumptions, solvent abuse among children and juveniles can lead to opiate addiction, given a certain set of social circumstances. Polytoxicomanic opiate addicts with sniffing experience can be differentiated as a marginal group with particularly unfavorable developmental conditions and a specific course of addiction. The results make it clear that a stronger differentiation is necessary within the group of heroin addicts, which has often been regarded as being homogeneous.