Page 232 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Nervous System Toxicity Chapter | 12 199

VetBooks.ir Axonopathy (Plumb, 2015). Although reported rarely in humans, no
published reports of peripheral neuropathy in veterinary
The second class of structural lesions caused by neurotox-
patients were found.
icants is axonopathy. Despite damage to the axon, the
A more common, yet fortunately still rare, cause of
neuronal cell body remains intact, but the portion of the
neurotoxicosis in veterinary medicine is metronidazole. A
axon distal to the lesion degenerates, resulting in a
nitroimidazole antibacterial and antiprotozoal agent used
“chemical transection” distal to the lesion that is function-
to treat Giardia and anaerobic intestinal bacterial over-
ally identical to a physical transection of the axon. This is
growth in small animals (Plumb, 2015), metronidazole
also known as Wallerian or axonal degeneration. Changes
can result in a sensory peripheral neuropathy manifesting
in the Nissl substance, the protein synthetic material com-
as proprioceptive deficits (Gupta et al., 2000) as well as
prised of free polyribosomes and rough endoplasmic retic-
CNS effects including ataxia, nystagmus, head tilt, and
ulum, become evident histologically in response to this
seizure activity (Plumb, 2015). Myelinated fibers are most
degeneration. These changes include chromatolysis (dis-
commonly affected (Anthony et al., 2001). The mecha-
solution of the Nissl substance) as well as margination of
nism is unknown for both peripheral and central effects.
the Nissl and the nucleus to the periphery of the cell
Oral and/or IV diazepam has been associated with has-
body. Not surprisingly, those neurons with axons of great-
tened recovery of metronidazole toxicity in dogs (Evans
est length are most susceptible to axonal damage. To
et al., 2003).
highlight the susceptibility of distal axons, a subclassifica-
A final example of a class of agents that can cause
tion of axonopathy affecting these axons has been termed
axonopathy are the OPs compounds, commonly used as
“central peripheral distal axonopathy.” This is in contrast
insecticides, which can result in signs of neuropathy
to “central peripheral proximal axonopathy,” which
7 10 days postexposure, termed OP-induced delayed
involves axons proximal to the spinal cord (Anthony
neuropathy or OPIDN. An example of historical
et al., 2001). A third subclassification of axonopathy has
significance was the delayed neuropathy associated with
been termed “dying back axonopathy,” which represents
the intentional contamination of Jamaican ginger alcohol
progressive death of the axon toward the cell body over
(“Jake”) with tri-ortho cresyl phosphate (TOCP), an OPs
time and continued injury. In the peripheral nervous sys-
compound, during the Prohibition Era. The TOCP was
tem (PNS), the prognosis for at least partial regeneration
present in lindol, a substitute solvent added to the Jake to
is good, but this is less true in the central nervous system
cut costs. The resulting upper motor neuron spasticity and
(CNS). Secondary demyelination is also possible with
paralysis were irreversible and affected more than 50,000
axonal injury (Mandella, 2002). Both sensory and motor
people (Woolf, 1995). In addition to humans, hens have
axons can be affected.
also been shown to be very sensitive to OPIDN
Many agents cause axonopathies, yet just a few are
(Damodaran et al., 2001). The neuropathy associated with
particularly relevant to veterinary medicine. The first
OPs is thought to involve slow axonal transport macromo-
example, commonly used as an antineoplastic drug, is the
lecules, such as actin and tubulin, which involve move-
vinca alkaloid vincristine, which is derived from the peri-
ment of the neuronal cytoskeleton at a rate of 1 4 mm/
winkle plant, Vinca rosea or Catharanthus rosea.
day (Anthony et al., 2001).
Vincristine exerts its therapeutic effect by binding to
tubulin, inhibiting microtubular formation, disrupting the
formation of the mitotic spindle, and arresting cell divi-
Myelinopathy
sion at metaphase (Roder, 2004a). Neurotoxicity in the
form of axonal degeneration can occur as a result of the Myelin is produced by the oligodendrocytes of the CNS
disruption of fast axonal transport (rate of 400 mm/day and Schwann cells of the PNS. It is a lipid and forms a
normally), which relies on the functional integrity of the sheath around certain axons, namely those of the cranial
microtubules (Anthony et al., 2001). Cats are more sensi- and spinal nerves. It functions to increase the speed of
tive to the neurotoxic potential of vincristine. With dis- impulse conduction by creating isolated areas of height-
continuation of therapy and appropriate supportive care, ened electrical excitability, termed nodes of Ranvier
animals exhibiting signs of peripheral neuropathy may (Spencer, 2000). Myelin gives white matter its character-
improve over several weeks to months (Roder, 2004a). istic appearance. Toxicants that result in myelinopathy
Colchicine, an antimetabolite derived from the autumn may affect the myelin itself or target the cells that pro-
crocus (Colchicum autumnale) and the glory lily duce myelin. The insult may result in loss of myelin
(Gloriosa spp.), also inhibits spindle formation (Burrows (demyelination) or edema of the myelin sheath and subse-
and Tyrl, 2013; Roder, 2004a). It is used in veterinary quent separation of myelin lamellae. Remyelination of
medicine for the treatment of amyloidosis associated with segmentally demyelinated areas can occur more so in the
Shar Pei fever (Loeven, 1994) as well as hepatic fibrosis PNS than the CNS. When peripheral nerves are