Triaryl Phosphate Poisoning (Chronic Organophosphate Poisoning; Dying-Back Axonopathy)
■ Definition and Etiology Ingestion of triaryl phosphates causes a neurologic disturbance of livestock characterized by a delayed neuropathy that results in incoordination and paralysis.
Common sources of the triaryl phosphate esters include motor lubricants, hydraulic oils, industrial solvents, plasticizers, and automotive brake fluid. Chronic organophosphate poisoning also occurs in some families of sheep after treatment with organophosphorous anthelmintics.1Triaryl phosphates have few effects on the glial cells,2 but they have profound neurotoxic effects on the longest axons.3 These fibers degenerate first at the distal, nonterminal areas. The degenerative lesions then spread proximally from the terminal nerve rootlets into the spinal cord until the cell body dies (dying-back axonopathy). Ingestion of 5 to 10 g/kg of triaryl phosphate causes paralysis by 19 to 36 days after exposure.4
■ Clinical Signs The onset of slowly progressive neurologic signs occurs approximately 10 days to a few months after exposure.5-7 The clinical signs of chronic organophosphate intoxication are rough hair coat, bloat, dyspnea, muscular weakness, and incoordination of the rear legs. The animals may slip on their hindlimbs and assume a dog-sitting posture. The limbs are circumducted and lack normal conscious proprioceptive responses. Affected animals become recumbent. When they attempt to rise, they do so incompletely and fall. Muscular tone and flexor reflexes may be normal, or flaccid paralysis may be evident.6 The tail, bladder, and rectum are often paralyzed, and affected animals show signs of incontinence, constipation, and perineal scalding. Slight ventrolateral strabismus has been described, and some affected animals have been reported to become mute.7,8 Most animals retain a normal appetite and sensorium during the development of the paralysis.
Electromyographic changes in experimentally poisoned animals include increased insertional activity, positive sharp waves, and fibrillation potentials in the muscles of the hindlimb, which are consistent with denervation of affected muscles.9 Organophosphate-induced neuropathy has also been reported in horses, in which the most striking clinical sign was bilateral laryngeal paralysis.10,11 Degeneration similar to that caused by delayed organophosphate toxicity in other species was most severe in the recurrent laryngeal nerves, but changes present in other peripheral nerves were milder.■ Clinical Pathology Clinical pathologic parameters are usually normal. The RBC cholinesterase level is low or undetectable at clinical onset but may return to normal concentrations by the time the animals display profound paralysis. The specific concentration of cholinesterase depends largely on the type of organophosphate and the patient's genetic ability to metabolize the toxic compounds. Whole-blood cholinesterase concentrations in esterase A-deficient animals remain significantly lower than in controls for at least 27 days after administration of haloxon (375 mg). In comparison, the enzyme concentrations in the plasma of normal sheep do not decrease after drug treatment.12 Cholinesterase levels in exposed animals are not predictive of the delayed onset of neurotoxicity.7
■ Pathology Laboratory confirmation of the condition is usually based on histopathologic detection of a dying-back axonopathy. Macroscopic lesions are not usually observed. Microscopic lesions are found exclusively in the CNS, and their severity appears to be dose dependent. The lesions begin distally and progress retrograde along the long, unsynapsed proprioceptive and motor tracts. The dorsospinal, cerebellar, gracile, and cuneate tracts are most susceptible to the effects of the toxins.9 Specific lesions include demyelination, internodal axonal swelling, and wallerian degeneration. There is also a vacuolation of the large neurons of the ventral motor nucleus of the spinal cord. The mechanism of neurotoxicity is unknown, but alteration of a cell membrane protein found in neurons and some other cells has been implicated.12-14 This protein has been designated a “neuropathy target esterase” and is thought to be “aged” by phosphorylation induced by the toxicosis.
Newer compounds in the triaryl phosphate group are less capable of causing delayed neurotoxicity, which offers some hope that the incidence of this type of toxicity may decline in the future.14
■ Treatment and Prevention Delayed organophosphate toxicity is not treatable and is irreversible. Prevention is centered on eliminating access to potential sources triaryl phosphates and ensuring secure storage and disposal of automotive lubricants and fluids.