Page 233 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

200 SECTION | II Organ Toxicity

VetBooks.ir remyelinated, the process involves more Schwann cells intoxication in horses. Sensory function is spared. Clinical
signs may include dysphagia and secondary weight loss,
compared to the initial myelination. As a result, the nodes
ataxia, dysphonia, laryngeal paralysis (“roaring”), and
of Ranvier in remyelinated peripheral nerves are closer
(Anthony et al., 2001). facial nerve deficits. The CNS and other organs may be
Two examples of toxicants that result in intramyelinic affected resulting in seizures, depression, secondary aspi-
edema and separation of the myelin lamellae are hexa- ration pneumonia, colic, and death (Gwaltney-Brant,
chlorophene and bromethalin. The former is an antibacte- 2004c).
rial agent frequently marketed decades ago as pHisoHex
and that is still commercially available for the treatment FUNCTIONAL TOXICOSES
and prevention of Staphylococcal infections. The latter is
a rodenticide that is marketed under a variety of trade Most neurotoxicants exert their functional effects via the
names including Assault, Sudden Death, and Vengeance. exquisitely orchestrated mechanisms involved in neuro-
The mechanism by which hexachlorophene and brometha- transmission yet leave no structural footprint of their
lin cause intramyelinic edema is due to the uncoupling of activity. This can occur at all levels within the nervous
oxidative phosphorylation (Anthony et al., 2001; Dorman, system including the CNS, PNS, and autonomic nervous
1
2004). This uncoupling results in decreased Na /K 1 system (ANS). Nervous impulses are chemically mediated
-ATPase activity, weakened ion gradients, and retention across synapses by the release of neurotransmitters from
of water in the myelin lamellae (van Lier and Cherry, the presynaptic terminal. These neurotransmitters then
1988). The use of mannitol or diuretics early in the course move across the synaptic cleft, bind to their postsynaptic
of the disease may reverse mild changes, but continued target receptor, and affect either an excitatory or inhibi-
swelling of the lamellae results in a dramatic increase in tory response in the postsynaptic neuron or muscle
intracranial and cerebrospinal fluid (CSF) pressure that is (Anthony et al., 2001). Functional neurotoxicants may
typically unresponsive to therapy. Clinical signs in an exert their action by preventing synthesis, storage, release,
acute toxic exposure include muscle tremors, hyperther- binding, reuptake or degradation of the neurotransmitter.
mia, generalized seizures, hyperexcitability, hyperesthesia Interference with axonal transmission via sodium, potas-
and death within several hours of ingestion (4 18 h) for sium, chloride or calcium channels, and the subsequent
bromethalin. Cats are more sensitive to bromethalin than alteration of action potentials, can also result in functional
dogs are with a minimum lethal oral dose of 0.45 mg/kg toxicoses (Spencer, 2000; Hansen, 2006). Continual
versus 2.5 mg/kg in the dog (Dorman, 2004). At lower development of new pharmaceuticals targeting these end-
dosages, hind limb ataxia and paresis can develop in dogs points will lead to an increased likelihood of intoxication
and cats within 2 7 days of ingestion. Signs may include in veterinary patients with accidental exposures, particu-
decreased or absent proprioception, loss of response to larly in an overdose situation and/or if species differences
deep pain, upper motor neuron bladder paralysis, patellar in pharmacokinetics exist.
hyperreflexia, and varying degrees of CNS depression. Examples of neurotransmitters include: acetylcholine
These sublethal effects may be spontaneously reversible (ACh); the catecholamine neurotransmitters (dopamine,
with time (1 2 weeks). Histologic lesions consistent with norepinephrine and epinephrine); the amino acid deriva-
bromethalin and hexachlorophene toxicosis include tives serotonin (5-hydroxytryptamine; 5-HT), GABA, gly-
spongy degeneration (diffuse vacuolation) of the white cine, histamine, aspartic acid, and glutamic acid; and
matter of the CNS. Confirmation of a fatal bromethalin various neuropeptides including enkephalins, substance P
toxicosis can be accomplished by identifying the parent (a neurokinin), orexins, endorphins, vasopressin (anti-
compound and/or its more toxic metabolite, desmethyl- diuretic hormone), and thyroid releasing hormone
bromethalin, in the liver. Because of their relative inabil- (Beasley, 1999; Spencer, 2000). The complex array of
ity to metabolize bromethalin into desmethylbromethalin, neurotransmitters provides many targets for neurotoxicity.
guinea pigs are resistant to its toxic effects. Treatment of A more detailed discussion follows regarding some of the
exposed susceptible species is largely aimed at initial more common neurotransmitters involved in veterinary
decontamination via induction of emesis (in those species neurotoxicoses.
that can vomit) and administration of multiple doses of
activated charcoal prior to the onset of clinical signs Acetylcholine
(Dorman, 2004).
Another toxicant that results in myelinopathy is inor- ACh is the neurotransmitter that mediates effects at the
ganic lead. The peripheral neuropathic manifestation of neuromuscular junction, at the preganglionic neurons of
lead intoxication is secondary to the segmental degenera- both the parasympathetic and sympathetic nervous sys-
tion of myelin in distal motor fibers and is most com- tems of the ANS, and at many of the postganglionic neu-
monly seen in veterinary medicine with chronic rons of the parasympathetic nervous system. It is the