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In a case of atypical myopathy submicroscopic examinations revealed intact ground structure and large number of solitaer, regular multilamellar bodies. The author suggests, in accordance with literary data, this typical alteration to be due to the applied short term Chloroquine treatment.

Previous studies in this laboratory have demonstrated 2,5-dimethylpyrrole adduct formation during in vitro exposure of protein amino groups to the neurotoxic n-hexane metabolite 2,5-hexanedione (2,5-HD). The present investigation reports in vivo pyrrole adduct formation in neural and nonneural protein from 2,5-HD-treated animals. Adult, White-Leghorn hens were given daily doses of either 200 or 70 mg 2,5-HD/kg, po, for up to 55 or 135 days, respectively. Additional animals were given 70 mg/kg for 63 days and then allowed to recover for 72 more days. Protein separation by gel electrophoresis followed by staining with a pyrrole-specific reagent yielded evidence of widespread adduct formation in protein from serum, liver, kidney, brain, and purified myelin. Binding was particularly strong in serum albumin nd myelin basic protein. Quantitation of the adduct in these tissues revealed that its formation reached peak levels at 20 days in high dose and 30 days in low-dose animals. Levels subsequently declined, suggesting the presence of a clearance mechanism capable of removing altered protein during continuing 2,5-HD exposure. Protein from animals on the recovery regimen contained no detectable pyrrole adduct. Pyrrole adduct formation was also detected in neurofilament protein preparations, although protein yields were too low to allow assessment of clearance. Hens at both dosages displayed clinical signs indicative of CNS and PNS neuropathy. Histologic findings included axonal swelling and degeneration in peripheral nerve and some spinal cord nerve tracts. A hypothesis is proposed involving differential clearance of pyrrole adduct from neural vs nonneural tissue to explain the mechanism of action and target organ specificity of 2,5-hexanedione.

This report has presented an overview of my approach to assessing neuromuscular toxicity using primarily in vitro techniques. Our current work on triethyltin toxicity exemplifies the use of these in vitro methodologies and the data they yield. Our neurophysiological and neurochemical experiments along with reports in the literature have directed our attention to several possible mechanisms for explaining the myopathic and neuropathic manifestation of TET intoxication. These mechanisms include (a) a compromise in the bioenergetic capacity of neurons and/or myofibers via disruption in mitochondrial function and (b) the direct effect of TET on the cell membrane and/or Na+-K+-ATPase. These hypotheses are currently being explored using additional biochemical and electrophysiological techniques in the isolated vascular perfused phrenic nerve-hemidiaphragm.

Administration of drinking water containing 0, 0.02%, 0.04% and 0.08% of caffeine to female rats throughout gestation and lactation affects several behavioral parameters in the offspring. Righting reflexes, swimming ability development, motor coordination and muscle tone were affected. The activity of these animals, as measured with an open-field test at weaning (i.e., at the end of the treatment), was reduced. The effects observed were dose-dependent. However, for righting reflexes the dose-dependency was direct (the highest dose producing maximal effects), whereas in all the other tests, the dose-dependency was inverse, the lowest dose producing maximal effects and the highest dose producing no effects. This might reflect the presence of subclasses of receptors having different affinities for adenosine, mediating opposite effects and antagonized by caffeine. On the other hand, perinatal caffeine effects are certainly not mediated by blockade of phosphodiesterases, since cAMP levels at the end of the treatment were dose-dependently reduced. This study shows therefore that administration of caffeine to rat dams is able to influence the neurobehavioral development of the offspring. Moreover, all the doses utilized and corresponding to 27, 58 and 108 mg/kg, were able to produce all or some of the mentioned effects, indicating that further testing with doses lower than 27 mg/kg is required to find a dose which does not affect the offspring.

Chronic treatment of rats with dithiobiuret (DTB) produces a delayed onset muscle weakness and, as suggested by a preliminary study, a distal axonopathy. An inhibition of glycolysis resulting in an energy deficit has been suggested as a possible mechanism of neurotoxin-induced distal axonopathies. To determine whether chronic DTB administration (1 mg/kg/day X 7 days; sacrificed on Day 7) might be associated with a perturbation of glucose metabolism in neuronal tissues, lactate production was measured in brain and spinal cord homogenates prepared from rats which exhibited hindlimb skeletal muscle weakness. Kinetic and statistical analysis showed that glucose-dependent lactate production in these homogenates was not different from that of controls. Lactate production was also determined in brain homogenates prepared from rats intoxicated with acrylamide (50 mg/kg/day X 9 days; sacrificed on Day 9), p-bromophenylacetylurea (200 mg/kg/day X 2 days; sacrificed on Day 14) or 2,5-hexanedione (400 mg/kg/day X 21 days; sacrificed on Day 21). The results indicated that whereas 2,5-hexanedione produced a slight decrease in Vmax, acrylamide and p-bromophenylacetylurea did not cause changes in glucose-dependent lactate production. These findings do not support the suggestion that an inhibition of glycolysis represents a common biochemical lesion associated with neurotoxins which cause delayed onset muscle weakness and distal axonopathy.

Six barbiturates with diverse time-action characteristics--thiopental, pentobarbital, butabarbital, phenobarbital, diphenylbarbiturate, and barbital--were evaluated for "anticonvulsant" and "neurotoxic" effects. For the former, the MES test, clonic seizures induced by pentylenetetrazol, 90 mg/kg, s.c., and maximal seizures produced by pentylenetetrazol, 200 mg/kg, s.c., were employed. For the latter, we used a rotorod technique. Time to peak activity in the MES test was employed as the time for other tests. Pentobarbital required at least neurotoxic doses to produce substantial "anticonvulsant" activity, its protective index ranging from 0.79 to 0.98 in the three tests. Among the drugs tested, phenobarbital and diphenylbarbiturate exhibited the most favorable protective indices, ranging from 2.71 to 3.41 for phenobarbital and from 3.85 to 5.0 for diphenylbarbiturate. Barbital, another drug with a prolonged duration of action, exhibited a range from 0.84 to 2.81. Although a prolonged duration of action is an important characteristic for antiepileptic activity, this property does not confer per se a favorable protective index.

A motor polyneuropathy developed in a woman with subcorneal pustular dermatosis of 16 years' duration, who had received at least 300 gm of dapsone over a five-year period and 80 gm during the four-month period of progression of her neurologic symptoms. Although the patient believed her muscle power had returned to normal four months after the drug was stopped, a slight peripheral neuropathy remained. Electrodiagnostic and clinical features during the period of greatest weakness and the subsequent 16 months were consistent with a polyneuropathy of the axonal type. The neurotoxicity of dapsone appears to be dose-dependent, but the mechanism by which it occurs is unknown.

Daily dosing with 1-3 mg/kg dithiobiuret for 4-5 days causes progressive, generalised muscle weakness which is fatal in about 50% of cases on day 4 or 5. Survivors recover mobility by day 7 and appear normal, although still weak. Striking changes in the motor nerves and motor end plates can be observed before and during the development of this weakness, using the zinc iodide-osmium staining technique. The terminal internodes of intramuscular axons become densely stained: later this may extend back into the main intramuscular (i.m.) nerves, and is often followed by axonal degeneration. Many motor end plates lose their branching form and become globular, and profuse terminal sprouting develops before any nerve degeneration appears. Following axonal degeneration, collateral sprouting becomes prominent, and, within four weeks of beginning the dose regime, restores the normal appearance of the innervation. This pattern of response was observed clearly in the whole mounts of the sternocostalis muscle: similar but less marked changes occurred in the lumbrical muscles, while in the soleus and tibialis anterior muscles, loss of end plates seemed to be a more common response. Despite marked differences in the severity of the functional disability, the i.m. changes were similar in juvenile and adult rats. These changes are related to previous electrophysiological findings on the possible mechanism of action of dithiobiuret.

The possibility that dietary exposure to triphenyl phosphate (TPP) may result in detectable neuromotor dysfunction was investigated. Young male Sprague-Dawley rats were fed diets containing TPP at levels of 0, 0.25, 0.50, 0.75 or 1.0% for 4 months. At approximately monthly intervals, a battery of behavioral tests was administered to assess different facets of neuromotor function including motility, balance, coordination and muscular strength. Treatment-related decrements in growth, in the absence of changes in food consumption, were found at all dietary levels above 0.25%. However, none of the behavioral measures used in this study were affected by the dietary treatment. It was concluded that there is no evidence of neuromotor toxicity following subchronic dietary exposure to TPP in the rat.

Doxorubicin (Adriamycin) is an autofluorescent anthracycline antibiotic that acts as a DNA intercalator. Following intraneural microinjection of 3 micrograms of doxorubicin into rat tibial nerve, fluorescence microscopy indicated that it is transported retrogradely to anterior horn cell bodies. Subsequently, these motor neurons underwent a progressive subacute degeneration that occurred over a period of 35-39 days. Combined electrophysiological and neuropathological methods indicated that dorsal root ganglion cells were relatively unaffected by this dose of toxin. The selective motor neuron degeneration produced by this agent raises the possibility that abnormalities of nucleic acid metabolism may be involved in the aetiology of motor neuron diseases.

Neurologic complications of gold are rare and include peripheral neuropathy, a Guillain-Barré-type syndrome, cranial nerve palsies and encephalopathy. Three cases of cranial neuropathy complicating chrysotherapy for rheumatoid arthritis are described. One also had a sensorimotor neuropathy associated with segmental demyelination and axonal degeneration, and another developed an encephalopathy which, on contrast enhanced computed tomographic scanning, showed reversible cerebral and cerebellar white matter lesions. Early recognition and prompt withdrawal of chrysotherapy are the mainstay of management of this lesser known complication.

Two cases of the association myasthenia/systemic lupus erythematosus are described. This association is rare but of particular interest from a pathogenic point of view. The discussion includes the suggestion of an immunological disturbance which might be the common denominator of the two disorders. Recent data concerning the role of the thymus and of "suppressor" T cells support such a hypothesis.

In attempts to degenerate motor neurons experimentally by way of retrograde axoplasmic transport, ricinus communis agglutinin (RCA), a potent protein inhibitor, was intraneurally injected into the rat sciatic nerve. Immunohistochemically, RCA was shown to be intra-axonally carried up to motor neuronal soma and to the dorsal root ganglia of L4-6. Within a few days, these dorsal root ganglion cells and large motor neurons giving rise to sciatic nerve efferents in the lumbar spinal cord degenerated, whereas small internuncial neurons and glia remained unaffected. The degeneration of motor neurons was characterized by a profound diffuse chromatolysis and subsequent dissolution, after which a mild gliosis remained. The retrograde axoplasmic flow of neurotoxic substance and motor neuron degeneration observed here may be a phenomenon implicated in the pathogenesis of human motor neuron diseases.

In this paper we present sequential morphologic changes produced in rat muscle mitochondria. Respiratory toxins such as crotoxin (rattle-snake venom) and 2,4-dinitrophenol (DNP-an uncoupler of oxidative phosphorylation) were injected in rat quadriceps muscle and the mitochondrial alterations were studied at various time intervals. The series of mitochondrial changes consisted of rounding and swelling of mitochondria, unfolding of the cristae as straight lines, formation of the concentric rings, appearance of paracrystalline inclusions, formation of multiple vesicles and finally vacuole formation. These changes were comparable to the range of mitochondrial alterations seen in the human material examined. Similarity of the time-related mitochondrial changes in the rat to the spectrum of changes observed in human muscle biopsies suggests that the mitochondrial alteration in the human muscle disorders is a stepwise process in which respiratory alterations and calcium ion may play a role.

Dietary exposure of rats to three different concentrations of zinc pyridinethione (ZPT; 166, 332, 498 ppm) caused delayed onset failure in a treadmill test and, at the higher concentrations (332 and 498 ppm), death. Daily treatment with d-penicillamine (d-PEN) increased the latency period for treadmill failure and lethality. Comparable levels of toxicity were achieved only after d-PEN treated rats had consumed 2-3 times more ZPT than rats not treated with d-PEN. In contrast to ZPT, administration of d-PEN did not affect the onset of treadmill failure associated with acrylamide, p-bromophenylacetylurea or 2,5-hexanedione. Thus, d-PEN provided protection which was selective for ZPT.

Clinical, electrophysiological, and the nerve and muscle biopsy findings from a case treated with amiodarone are reported. Marked distal motor and sensory impairment and distal muscular atrophy were observed clinically. The electrophysiological examination revealed normal motor and sensory conduction velocities in the median nerve; the sensory action potentials were polyphasic and reduced in amplitude. Electromyography revealed denervation potentials and severe loss of motor units in the M. extensor digitorum brevis and in the M. tibialis anterior. The light and electronmicroscopical study of a N. suralis biopsy displayed total loss of large myelinated fibers and an almost total reduction of small myelinated fibers. The number of unmyelinated axons was markedly reduced. Fibrocytes and degenerative axons polymorphous inclusion bodies were present in Schwann cells. The muscle biopsy revealed both neurogenic and myopathic changes. Lipid storage was also present in the muscle fibers. Physical and chemical analysis of the nerve and muscle biopsy revealed the content of iodine to be more than 40 times increased. The findings indicate damage of axons, schwann cells and muscle fibers. It is suggested that the lipid storage in nerve and muscle tissue might be related to the accumulation of the drug or its metabolites.

Disulfiram is known to produce toxic encephalopathy and peripheral neuropathy. The case of a 37-year-old alcoholic who attempted to commit suicide by taking 22.5 g disulfiram is described. During the first 6 days after the intoxication he was stuporous and had cerebellar ataxia and dysarthric speech. Then he became comatose, and as he recovered from coma, he showed peripheral neuropathy including diplegia faciei and severe tetraparesis. Denervation potentials were detected in both facial muscles and distal muscles of the upper and lower limbs, while conduction velocity was normal. Axonal degeneration was verified by sural nerve biopsy. In addition neurofilamentous axonopathy was documented. The recovery from his paresis lasted 2 years.

A very high prevalence of polyneuropathy was observed in shoe and leather workers from the area of Florence. In addition, normal workers showed abnormally low maximal nerve motor conduction velocity. A linear decrease of motor conduction velocity was observed as a function of age and of the length of exposure to solvents. The worker population showed a steeper decrease with age than controls. A higher prevalence of polyneuropathy was observed when the amount of glue used by each worker per day was higher, and when the air volume of the plant was smaller. The subjective symptoms most frequently associated with polyneuropathy were muscle spasms, leg weakness and pain, and arm paresthesiae. Cases of polyneuropathy were more frequent in the workers exposed to solvents and in the older age group. A solvent aetiology of the disease is suggested, and glue substitution and proper hygienic conditions are recommended.

Dapsone produces a potentially reversible toxic neuropathy, with its primary effect on the soma and axons of motor neurons as opposed to myelin. There is very little evidence to suggest involvement of sensory axons in most cases; if present, it would appear minimal. A "dying back" of motor axons is postulated to produce the clinical features of primarily distal weakness and wasting. Recovery appears to occur via axon regeneration and peripheral sprouting. The sporadic occurrence of this neuropathy may be due to slow acetylation of dapsone in some patients.

The muscle-relaxing effect of antibiotics, particularly that of aminoglycosides and polymyxins after oral, intravenous, intramuscular and local application is described. After local application of Isoptomax eye drops, one patient suffered from relaxation of the muscular system of the neck and throat. The phenomenon did not recede until several hours after therapy was discontinued. The mechanism of action is described and a possible treatment discussed with reference to the relevant literature.

The case of a patient with Charcot-Marie-Tooth syndrome and diffuse large-cell lymphoma, in whom a severe generalized weakness developed after the intravenous administration of vincristine (2 mg) during combination chemotherapy, is reported. Spontaneous resolution of the severe weakness occurred when teniposide was substituted for vincristine in the chemotherapy regimen.

The L-isomer of beta-N-methylamino-L-alanine (BMAA), present in free form in seed of Cycas circinalis, elicits in spinal cord cultures a pattern of acute postsynaptic neuronal vacuolation comparable to that induced by beta-N-oxalylamino-L-alanine (BOAA), an excitotoxic amino acid of greater potency isolated from seed of Lathyrus sativus. The neuronotoxic properties of these compounds may be linked to the etiology of motor-system degenerative disorders (amyotrophic lateral sclerosis and lathyrism, respectively) found in human groups that have used these plant seeds for food.