Clinical Signs

The onset of slowly progressive neurologic signs occurs about 10 days to a few months after exposure.^2236-2238 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, attempt to rise, but do so incompletely and fall. Muscular tone and flexor reflexes may be normal, or flaccid paralysis may be evident.²²³⁷ The tail, bladder, and rectum often are paralyzed, and affected animals show signs of incontinence, constipation, and perineal scalding. Slight ventrolateral strabismus has been described, and some animals have been reported to become mute.^2238,2239 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, consistent with denervation of affected muscles.²²⁴⁰ Organophosphate-induced neuropathy also has been reported in horses, where the most striking clinical sign was bilateral laryngeal paralysis.^2241,2242 Degeneration similar to that caused by delayed organophasphate toxicity in other species was most severe in the recurrent laryngeal nerves, but milder changes were present in other peripheral nerves.

Pathology

Laboratory confirmation of the condition usually is based on histopathologic detection of a dying-back axonopathy in the peripheral nervous tissues. Clinical pathologic parameters usually are normal. The RBC cholinesterase 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 haloxon-treated esterase A–deficient animals remain significantly lower than in controls for at least 27 days after administration of 375 mg. In comparison, the enzyme concentrations in the plasma of normal sheep do not decrease after drug treatment.²²⁴³ Cholinesterase levels in exposed animals are not predictive of the later onset of delayed neurotoxicity.²²³⁸

Macroscopic lesions are not usually seen. Microscopic lesions are found exclusively in the central nervous system, 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.²²⁴⁰ Specific lesions include demyelination, internodal axonal swelling, and wallerian degeneration. There also is 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.^2243-2245 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.²²⁴⁵ Delayed organophosphate toxicity is not treatable and is irreversible.

Motor Unit

The motor unit is the smallest functional unit of the peripheral motor system. It comprises a single motoneuron and all the myofibers innervated by that motoneuron.²²⁴⁶ In muscles in which precise control of movement is necessary, each motoneuron innervates only a few muscle fibers, whereas in large postural muscles in which fine control is not required, a single motoneuron innervates many hundreds of muscle fibers. The cell body of the alpha motoneuron lies in the ventral horn of the spinal cord or, in the case of cranial nerves, in cranial nerve nuclei in the brainstem. The myelinated axon of the motoneuron runs within the ventral root to the spinal nerve and peripheral nerves and finally terminates in small, unmyelinated terminal arborizations (Fig. 35-41). Enlargements of the ends of the terminal arborizations form the presynaptic components of the neuromuscular junctions. The postsynaptic part of the neuromuscular junction consists of a specialized region of the muscle fiber membrane. When acetylcholine release from the nerve terminal is sufficient to provoke an action potential in the myofibers, all the myofibers of the motor unit respond equally, an “all or nothing” response. Motor unit disease (lower motoneuron disease) may result from damage to any one of the following: the alpha motoneuron cell body or axon, the Schwann cells that form the myelin sheath of the alpha motoneuron, the neuromuscular junction, or the muscle fiber.

Fig. 35-41 Components of the motor unit. DR, Dorsal root of spinal nerve; DRG, dorsal root ganglion; LMN, lower motor neuron; MS, muscle spindle; TA, terminal arborizations of lower motor neuron axon; VR, ventral root of spinal nerve.

Although they are not part of the motor unit, the neurons that provide the sensory supply to the skeletal muscles may be involved in motor unit diseases in animals. Dysfunction of the peripheral sensory nerves causes clinical signs similar to those seen with motor unit disorders, even when all the components of the motor unit are normal.²²⁴⁷ The cell bodies of sensory neurons lie in the dorsal root ganglia or in the sensory nuclei of cranial nerves. Their axons extend centrally to synapse with lower motoneurons and interneurons in the spinal cord and brainstem and extend distally in peripheral nerves to the stretch receptors in the muscle spindles of skeletal muscles and to proprioceptors in joints (see Fig. 35-41).

Instrumentation

The recording of the electrical activity of nerve and muscle cells requires an electrode system, an amplifier, and a device to display the recording. An electrical stimulator is needed for NCT. A variety of computer-based units are now available for EMG and NCT, with a range of specifications to supply the different needs of investigators and clinicians. The components of a system may be purchased individually, but most clinicians prefer to use a complete unit. Portable units make this technology easy to use in the field, not only in hospital situations. EMG units offer a range of specializations to improve signal amplification while minimizing interference, including high- and low-frequency filters, common mode rejection (to reduce 60-Hz interference from nearby electricity sources), and signal-averaging capabilities to facilitate the recording of nerve action potentials. Data can be stored in the computer memory for later transfer to disc or other external memory and to create paper printouts. An audioamplifier is a useful addition to the system, because many of the potentials recorded by EMG produce characteristic sounds when converted to an audible signal. It is often easier for an experienced electromyographer to make a diagnosis by listening to the audio EMG than by trying to follow a series of rapidly changing potentials displayed on the cathode ray oscilloscope (CRO) screen. Programs that can analyze data (e.g., motor unit potentials) and filters that facilitate the study of periodic motion (gait) are now available.^2248-2250

For recording, three electrodes are required: an active or exploring electrode, a reference electrode, and a ground electrode. A number of different arrangements are possible, but the coaxial needle electrode is typically used. The central wire of the coaxial electrode is the active component, and the surrounding hollow needle is the reference component. The wire is insulated from the needle along its length by a material such as Teflon, except at its tip, where it is exposed. This type of electrode is particularly suited to use in large animals because it minimizes the problem of poor electrical contact encountered with surface electrodes and does not seem to cause undue discomfort. For similar reasons, a subcutaneous needle electrode usually is chosen for the ground electrode, which is placed a short distance from the recording and reference electrodes, usually over a bony prominence. Surface electrodes can be used to study activity in muscles during exercise, both to determine the presence of disease and to direct training exercises where development of particular muscles is desired.^2251,2252

Electromyography

Electromyography usually can be performed in a conscious animal, although some restraint is necessary, such as placing the animal in stocks and administering a sedative agent. General anesthesia may be necessary for EMG in extremely fractious animals, but not without significant risks, particularly when animals are weak and may have difficulty rising after anesthesia. Caudal epidural anesthesia may offer a safer alternative when examination of hindquarter muscles alone is deemed adequate for evaluation.²²⁵³ Common sedatives such as xylazine and acepromazine do not interfere with EMG. An electromyographic examination should include testing of many muscles over the whole body, focusing on those thought to be involved in the disease process. The recording electrode must be inserted into four or five sites in each muscle tested to ensure that focal abnormalities are not missed.

Electromyography alone usually does not provide a definitive diagnosis of the disease process present. EMG does help to localize the lesion and provides information that can then be used in selecting further diagnostic modalities (e.g., NCT) and the most suitable site for muscle or nerve biopsy.

Normal Muscle

INSERTION ACTIVITY

Insertion of the recording electrode into a muscle or its movement in the muscle results in a burst of electrical activity that stops abruptly when movement of the electrode stops (Fig. 35-42). It is accompanied by a harsh, crackling sound. This “insertion activity” is the result of direct stimulation of muscle fibers by the moving electrode.

Fig. 35-42 Electromyogram insertion activity. A, Normal: insertion activity ends abruptly when movement of the exploring electrode stops. B, Abnormal: insertion activity persists after the exploring electrode is at rest.

MOTOR UNIT ACTION POTENTIAL (MUAP)

An MUAP is the electrical activity of a single motor unit (Fig. 35-43). Only the activity of the fibers lying within approximately 1 mm of the electrode tip is recorded.²²⁵⁴ MUAPs may be observed during EMG of normal active muscle. The parameters of an MUAP vary with the motor unit that produced it, with the type of electrode arrangement and electromyograph used, and with the position of the electrodes in relation to the electrical event itself. The important characteristics of the MUAP are the amplitude, duration, and number of phases. Normal MUAPs are biphasic or triphasic with amplitudes of 500 to 3000 μV and durations of 3 to 15 msec.^2254,2255 In very active muscles, many MUAPs are superimposed, producing “interference patterns.” This may be observed in the limb muscles of a standing animal.

Fig. 35-43 Motor unit action potentlals. A, Normal: amplitude is approximately 550 μV. B, Abnormal: amplitude is decreased by approximately 200 μV.

MINIATURE ENDPLATE POTENTIALS (MEPPS)

The neuromuscular junctions of the myofibers of one muscle tend to lie in a band across the midpoint of the muscle fibers; this region is called the endplate zone. The spontaneous release of quanta of acetylcholine from the nerve terminal at a neuromuscular junction results in local electrical responses in the muscle fiber. This activity can be recorded when the recording electrode lies close to the neuromuscular junction in the endplate zone (Fig. 35-44). MEPPs are monophasic-negative potentials having amplitudes of 10 to 20 μV and durations of 0.5 to 1 msec.²²⁵⁶ MEPPs are local electrical responses in the muscle fiber that are not propagated throughout the whole fiber and thus do not result in fiber contraction. MEPPs are present even in resting muscle and are normal. MEPPs may be absent in disorders in which acetylcholine release is lacking from the nerve (neuropathies), in those with an abnormality in transmission across the neuromuscular junction (junctionopathies), and in some myopathies. MEPPs cannot be detected when the recording electrode is not close to a neuromuscular junction.

Fig. 35-44 Miniature endplate potentials (MEPPs). MEPPs are a normal electromyographic finding.

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Age of the patient has been shown to have an effect on EMG findings, even in animals that are clinically healthy. Insertional activity, spontaneous activity, and motor unit morphology all have been shown to differ in elderly horses (>18 years old) compared with young and adult horses, with the elderly horses displaying a greater amount of EMG activity usually considered to indicate muscle pathology.²²⁵⁷ This factor must be taken into account when interpreting EMG findings.

Abnormal Muscle

FIBRILLATION POTENTIALS AND POSITIVE SHARP WAVES

These activities result from the electrical activity of single muscle fibers (Fig. 35-45). The muscle activity may be spontaneous or the result of mechanical stimulation of the fiber by the electrode. It is thought that the occurrence of spontaneous individual fiber contraction is a manifestation of an increase in the excitability of the muscle fiber membrane. Fibrillation potentials and positive sharp waves occur in both neuropathies and myopathies. The presence of either activity is not pathognomonic for the type of pathologic condition present.

Fig. 35-45 Abnormal electromyographic potentials. A, Positive sharp waves. B, Fibrillation potentials.

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Fibrillation potentials are biphasic spikes with an initial positive phase. Their peak-to-peak amplitude is less than 1 mV and their duration less than 5 msec.²²⁵⁶ Fibrillation potentials are recorded when the recording electrode lies a short distance from the muscle fiber whose activity is being recorded.

Positive sharp waves have an initial positive phase with amplitude of up to 1 mV and duration under 5 msec, followed by a negative phase with lower amplitude and a duration of 10 to 100 msec.²²⁵⁶ They are recorded when the recording electrode tip lies close to the electrically active myofiber.

In addition to EMG changes induced by primary myopathic and neuropathic disease, electrolyte disturbances such as hypocalcemia and hypomagnesemia also have been shown to result in EMG abnormalities, both inducing spontaneous muscle activity and altering the waveform characteristics of MUAPs.²²⁵⁹ Therefore, a complete history, physical examination and serum chemistry are essential for correct interpretation of EMG findings.

Nerve Conduction Testing

Nerve conduction studies usually require that the animal be sedated or under general anesthesia, because the procedure is somewhat painful. Routinely used sedatives and anesthetic agents do not interfere with the results of testing. Two stimulating needle electrodes, the anode and cathode, are placed on or close to the nerve to be stimulated. A short pulse of current is applied to the nerve. A compound nerve action potential (CNAP) is evoked in the nerve by the applied current and is propagated along the nerve in the same manner as a naturally occurring action potential. Either the CNAP is recorded directly from the nerve itself, or the compound muscle action potential (CMAP) evoked in the muscle innervated by that nerve is recorded. To ensure that all the nerve fibers are stimulated, the stimulus intensity is varied to determine the maximum stimulus (i.e., the current that just evokes the maximum CNAP or CMAP). A supramaximum stimulus (150% to 200% of the maximum stimulus) is applied when making recordings.^2255,2260

Definition and Etiology

Botulism spores are ubiquitous in the soil in most areas of the United States and cause isolated occurrences of botulism in humans, animals, birds, and fish.²²⁶⁶ The clinical signs of botulism result from the effect of the neurotoxin, an exotoxin produced by Clostridium botulinum, on the myoneural junction, leading to progressive muscular weakness.^2267-2272 Seven neurotoxin types have been identified: A, B, C, D, E, F, and G.^2273,2274 In North America, horses are most often affected by type B botulism (>85% of cases) and occasionally by types A and C toxins.^2275,2276 Types A and B botulism are associated with forage or hay and do not involve an animal carcass. Type A cases have been reported in California, Utah, Idaho, Oregon, and Ohio, but almost never in the mid-Atlantic region.²²⁷⁵ Type C toxin is typically associated with a decomposing carcass,²²⁷⁶ feeding poultry litter,²²⁷⁷ or situations where ravens or crows feed on a decomposing carcass, then transport toxin to the feed buckets or feed troughs of horses.^2277,2278

Type D botulism occurs more frequently in South America and South Africa and has been linked to phosphorus-deficient cattle chewing bones of decaying carcasses to restore their phosphorus stores.^2279,2280 Feeding poultry litter to cattle in North America,^2281,2282 Europe, Israel,^2283-2285 and Australia²²⁸⁶ has been associated with type D botulism, often in massive outbreaks.^2287-2294 More recently, type D botulism was confirmed in a group of beef cattle in Canada being fed bakery waste,²²⁹⁵ then later in dairy cattle in Canada.²²⁹⁶

Recently, types C and D botulism have been reported in Switzerland horses.²²⁹⁷ Type E botulism in humans^2273,2274 is typically associated with fish, but rarely reported in animals. Birds that eat fish with type E botulism have recently been reported in areas surrounding lakes Erie and Ontario.²²⁹⁸ Types F and G have rarely been reported in humans.²²⁷⁴

Clinical botulism occurs by one of three routes: (1) ingestion of the preformed toxin (the most common form in cattle and adult horses), (2) ingestion of spores, leading to toxicoinfectious botulism (shaker foal syndrome), and (3) wounds contaminated with botulism spores and subsequent production and absorption of the neurotoxin. Wound botulism occurs in horses, most often in castration sites,²²⁹⁹ umbilical hernia repairs (typically with hernia clamps), or deep puncture wounds that occur with injections of counterirritants.²³⁰⁰ Horses are much more susceptible to botulinum toxin than cattle. If botulinum-containing forage is fed to both horses and cattle, the horses will develop clinical signs first, and usually more horses will be affected than cattle.²³⁰¹ This likely results from degradation of toxin by the rumen microbes,²³⁰² whereas horses have more time to absorb the toxin from the intestinal tract before the toxin reaches the colon, the site of microbial degradation.

Clinical Signs in Foals (“Shaker Foal Syndrome”)

The owner’s chief complaint is often that the foal is found lying down more than normal. When forced to rise, it stands for a few moments, develops generalized muscle tremors (“shaker foal syndrome”), then drops to the ground, usually in lateral recumbency.^2303,2304 Some foals present with colic, whereas others present with pneumonia or respiratory distress.²³⁰⁵ Closer physical examination usually reveals a well-nourished foal that is bright, alert, and has normal vital signs and normal clinical pathologic findings, which help to differentiate botulism from other diseases. Affected foals often drool milk from their mouth when suckling the mare. Decreased tongue tone is evidenced by the tongue being easier to pull from the mouth than normal and the foal slowly retracting the tongue when released.²³⁰⁶ Mild mydriasis and weak eyelid tone may be detected in most foals. Progressive symmetric myasthenia, along with the absence of fever and other signs of systemic disease leading to recumbency, remains the predominant clinical sign. Constipation and ileus are consistent findings.²³⁰⁷ As the disease progresses, the heart rate and respiratory rate increase, which may progress to inhalation pneumonia and terminate in respiratory failure. A small proportion of foals will stabilize at a certain level of neuromuscular weakness and then gradually recover over 10 to 14 days with intensive nursing care. Although botulism may occur at any age, the peak age of occurrence is 4 weeks, with 70% of cases occurring between 2 and 6 weeks of age.²³⁰⁸

Clinical Signs in Adult Horses History

Generalized muscle weakness (myasthenia) and dysphagia are typically the first clinical signs of botulism in adult horses detected by an alert horse owner. Astute individuals may detect subtle early signs of botulism, including changes in the horse’s attitude (slight depression) and decreased exercise tolerance. This is especially true after a few cases of botulism have occurred on their premises.²³⁰⁹ Other early signs include slowness to eat, with reduced ability to swallow hay and water. Colic may be the initial clinical sign, presumably from ileus and accumulation of gas.^2310-2313 Occasionally, the pain will be severe enough that an experienced clinician recommends general anesthesia with surgical intervention, later to determine the pain was attributable to botulism. Draft horses have reduced work capacity, leading to progressive weakness, dysphagia, and recumbency. Some owners may not seek veterinary attention until the horse is recumbent.

PHYSICAL EXAMINATION

Decreased Tongue Tone

Characteristic early signs of botulism include reduced tongue strength. Assessment of tongue strength is best done by keeping the jaws closed with the left arm under the jaw, then placing the hand on the top of the nasal bones. The tongue is gently retracted with the other hand through the interdental space and allowed to hang down, then slowly released. Most normal horses quickly retract the tongue into the mouth after release with one or two “tugs” or attempts to retract the tongue.²³¹⁰ The strength of the normal tongue retraction response varies significantly from horse to horse and must be considered when assessing tongue strength in a suspect horse. In more advanced stages of the disease, but before recumbency, the horse will retract the tongue very slowly, if at all (Fig. 35-46). This procedure, the “tongue stress test,” if done properly, represents one of the earliest and most sensitive clinical signs of botulism in horses.

Fig. 35-46 Horse with very weak tongue. The tongue may hang over the lips for several seconds, up to a minute or longer in severe cases. This test is not specific for botulism, but is characteristic, and with other compatible clinical signs, strongly suggests botulism.

Botulism Grain Test

The horse is offered 8 ounces of sweet feed in a large, flat feeding tube on the ground. The horse is timed and observed for ability to consume the feed. Most normal horses will consume an 8-oz cup of grain (sweet feed) in less than 2 minutes, often in less than 1 minute.²³¹³ In outbreaks of equine botulism, owners should be taught to perform the grain test and the tongue stress test to detect early signs of botulism and allow early treatment of affected horses. As the ability to retract the tongue diminishes, the time required for the horse to eat sweet feed increases. Grain mixed with some saliva often falls out of the mouth through the horse’s lips while eating. This creates a row of grain in the feed tub and a ring on the horse’s lip. This is very characteristic of botulism and is one of the earliest clinical signs²³¹³ (Fig. 35-47).

Fig. 35-47 A, Abnormal “grain test,” showing sweet feed mixed with saliva falling out of the side of the mouth. B, Note the trail of grain on the bottom of the bucket.

Dysphagia

Horses with beginning dysphagia may eat hay but have difficulty swallowing it. Inability to swallow water occurs after the loss of the ability to swallow hay. Horses seem to respond differently to the inability to drink water; many refuse to attempt to drink, whereas others immerse their muzzles under the surface of the water. Decreased tongue strength and dysphagia typically occur before onset of obvious muscle weakness. Recumbent horses with botulism are very difficult to assess with regard to swallowing ability because the struggle to stand takes priority over eating and drinking. During an outbreak of botulism in a herd of horses, if one horse is recumbent, it is always advisable to assess tongue tone on the other horses to detect early cases of botulism.

Clinical Signs in Cattle

Other Large Animal Species

Type C botulism has been reported in bighorn sheep in California²³²⁵ and in sheep in South Africa associated with feeding poultry litter.^2326,2327 The later report indicates the importance of sampling both the rumen and the cecal contents for botulinum toxin testing, because in this case the rumen samples were negative but the cecal contents were positive for preformed toxin.

Differential Diagnosis

Clinical Pathology and Diagnostic Approach

Laboratory support for a diagnosis of botulism requires one of the following: (1) demonstration of preformed toxin in the patient’s serum or gastrointestinal (GI) contents or in a wound; (2) demonstration of Clostridium botulinum spores in the GI contents or feed materials, with compatible clinical signs; or (3) the detection of an antibody response to C. botulinum in patients recovering from suspected botulism. A definitive diagnosis may be obtained by demonstration of preformed toxin in plasma or GI contents, but this is rarely possible in adult horses. Preformed toxin has been identified in about 30% of GI contents of shaker foals, but rarely in adult horses. Finding botulinum spores in the intestinal or rumen contents, with clinical signs compatible with botulism, is strongly supportive of botulism because botulinum spores are rarely detectable in the rumen or GI contents of normal cattle or horses.

Botulinum toxin is relatively stable in tissues or plasma frozen at −20° C (−4° F) for several weeks. The mouse bioassay, the most sensitive test for botulism currently available, requires a minimum of 5 mL of plasma or serum from an affected animal as early in the clinical course as possible. Detection of toxin in the serum is likely only in animals with peracute onset and rapidly progressive clinical signs (onset to death in less than 48 hours). The serum (1 mL) is injected into two ICR Swiss Webster mice. If clinical signs of botulism occur in the mice (“wasp waist”), four additional mice are injected with the suspect serum. Two of the mice receive either a monovalent or a polyvalent botulism antiserum, depending on the history, along with the test serum. If mice are protected by a specific antitoxin, the test is definitive for the presence of botulinum toxin of that type.²³²⁹ Unfortunately, because horses are very susceptible to botulinum toxin, the level of circulating toxin in an affected horse is often below the threshold of detection of the mouse bioassay. Few reports have demonstrated preformed toxin (type B) in plasma (or serum) from an acutely affected foal or horse.^2330,2331

A tentative diagnosis may be based on the presence of botulinum spores and toxin in feedstuffs recently consumed by animals having clinical signs compatible with botulism.²³⁰¹ Spores of C. botulinum type B are found in the feces of approximately 34% of adult horses (three fecal samples per horse) with clinical signs compatible with botulism. C. botulinum toxin and spores can be found in the feces of approximately 20% and 70%, respectively, of foals affected with botulism. Spores are rarely detected in fecal samples from normal foals or adult horses.²³¹⁰ The presence of neutralizing botulinum antibody is a recently recognized indicator of botulism in nonvaccinated animals.^2321-2324 The polymerase chain reaction (PCR) for the detection of botulinum neurotoxin gene type B was reported to be more sensitive than the mouse bioassay in a natural case of type B botulism in Australia.^2332,2333 At present, however, this technique remains a research tool that is not readily available for routine diagnostic purposes. In the author’s experience, electromyographic evaluation has not been very rewarding to confirm a diagnosis of botulism in horses.²³⁰¹

Typically, botulism is a diagnosis by exclusion, ruling out other diseases that may result in similar clinical signs. Both hematologic and routine plasma biochemical findings in early to moderate cases of botulism show few abnormalities. Hyperglycemia is often present²³³⁴ and expected in cases of botulism, because elevated blood glucose is expected in many life-threatening diseases of cattle. If significant abnormalities are present, a disease other than botulism should be strongly considered. The gradual progression of clinical signs over 1 to 4 days, including dysphagia, decreased tongue tone, and muscular weakness leading to recumbency, is fully compatible with botulism.

Pathophysiology

Botulinum toxin acts primarily presynaptically at the peripheral cholinergic neuromuscular junction by blocking the evoked release of acetylcholine.²²⁶⁸ The three steps involved in the neuromuscular blockage are (1) a primary step in which toxin heavy chain binds rapidly and irreversibly to receptors on the presynaptic nerve terminal, (2) an internalization process involving receptor-mediated endocytosis of the toxin light chain, and (3) a final blocking step to prevent the release of acetylcholine from the vesicle,²²⁷² leading to a flaccid paralysis. Once toxin is bound at the motor endplate, improved neuromuscular function is achieved only by the regeneration of new endplates; thus the prolonged time of a week to 10 days for clinical improvement after antitoxin therapy. Each neurotoxin serotype has its own specific receptor, an endopeptidase,^2335,2336 which may explain differences in species susceptibility to different toxin types. (For more detail about the neurotransmission, see Dasgupta.²²⁶⁹)

Toxicoinfectious botulism occurs in foals and was initially reported as “shaker foal syndrome.” Foals may ingest botulinum spores with their food material as “normal” contaminants. The spores then produce toxin in vivo in the GI tract, resulting in neurologic disease.^{2303,2304,2315} Toxin is detectable in the feces of approximately 30% of shaker foals, but only in the acute clinical phase of the condition.²³¹⁰ Normal intestinal flora of adult horses, humans, and other animals inhibit intraintestinal growth of botulism spores, limiting the occurrence of toxicoinfectious botulism to neonates.²³³⁷ In human infants less than 6 months of age, C. botulinum may colonize the GI tract, which lacks competing microbial microflora. After their ingestion, botulism spores vegetate to produce botulinum toxin, which may be detectable in the stool for several weeks.²³³⁸

Most cases of type B equine botulism are associated with spores in the hay and rarely with commercial grain contaminated by decomposed animal carcasses. Commercial feeds (grains) are seldom proven to be the source of botulism toxin for horses. The origin of botulism affecting only one or two horses on a farm is often not identified. When several horses are involved, the source is typically found to be the forage, as in outbreaks in California (hay cubes),²³¹⁴ Ohio (contaminated wheat fed to work horses),²²⁹⁵ North Carolina (baled alfalfa hay),²³⁰⁹ England (big baled hay),^2330,2339 Sweden (big bale ensilage),²³⁴⁰ and Australia (oaten chaff).²³⁴¹ Silage and hay contaminated with type B botulinum toxin and spores are the typical sources of exposure for horses.²³¹⁰ Hay stored in plastic bags or tubes has become a common factor in many outbreaks of botulism in the United States and England.^2342,2343

Conditions of low acidity (pH >4.5), low oxygen, and high water content favor spore germination and toxin production. Small-grain forage, such as ryelage, oatlage, wheatlage, and barley,²³⁴⁴ frequently provides these conditions and is a major risk factor for bovine botulism. The small-grain forages have a narrow window of harvest; if harvested too early or too late, fermentation is inadequate, and the pH remains high, helping botulism spores to vegetate, producing botulinum toxin. Spoiled hay or poorly fermented silage also represents potential sources of botulism exposure for horses.²²⁸¹ Silage with high pH (>4.5) is a well-known source of botulism for horses and is not a recommended equine feed because horses are much more susceptible to botulism toxin than cattle.²³⁰¹

Necropsy Findings

Typically, no obvious gross or histologic lesions are associated with botulism in most species. Myositis or aspiration pneumonia may be present in some foals and adult horses because the deglutition reflex is abnormal. Patches of edema among the cervical muscles of an adult horse suggest type C botulism because some horses are unable to lift their head when affected with this toxin type.

Treatment and Prognosis

Equine botulism is usually fatal unless affected animals are promptly treated with specific antitoxin.²³¹⁰ In a series of 91 foals, yearlings, and adults with presumed type B botulism, none was treated with antitoxin and only two of the foals survived.²³⁴⁵ On the other hand, a recent report of 30 foals affected with botulism had a survival rate of greater than 98% when treated with antitoxin.²³⁴⁶ Neutralization of circulating toxin with a specific or multivalent botulinum antiserum should be the first and immediate therapeutic objective. Every hour between initial examination and antitoxin treatment results in a poorer prognosis for survival. Only one dose of antitoxin is needed because the half-life of botulinum antitoxin of equine origin is about 12 days in normal horses. Unfortunately, the antitoxin has no effect on the toxin after binding to the cell receptor; thus the importance of immediate treatment.²²⁶⁹ Once an adult horse is recumbent, the prognosis for survival is greatly reduced, with less than 15% survival. Because the prognosis for survival in recumbent horses is poor, these animals should not be treated with antitoxin, unless the owners are fully appraised of the poor prognosis, the extensive nursing care that will be required, and the huge financial costs of an attempt to save these recumbent animals.

The recommended dose of antitoxin is 200 mL (30,000 IU) for a foal and 500 mL (70,000 IU) for an adult horse. A single dose of antitoxin should provide passive protection for more than 60 days. Horses with mild, slowly progressive disease may survive without antitoxin, as long as the patient is confined to a stall to restrict muscular activity as much as possible. Frequent attempts to force the horse to rise are also contraindicated to avoid further depletion of acetylcholine stores and exacerbation of the clinical signs. Antimicrobials may be given for specific secondary complications (e.g., aspiration pneumonia). If antimicrobials are used, those that may potentiate neuromuscular weakness should be avoided (e.g., aminoglycosides).^2347,2348 Metronidazole, often effective against anaerobic bacteria,²³⁴⁹ is not effective against botulism and has predisposed laboratory animals and human patients to develop botulism.²³⁵⁰ Mineral oil is often recommended as a cathartic for horses with ileus to prevent impaction colic. Parasympathomimetics (e.g., neostigmine) and 4-aminopyridine are countraindicated for the treatment of botulism in animals.²³¹⁰

Most equine patients cannot swallow, so supportive alimentation is required. A high-quality protein slurry composed of 4 lb of alfalfa meal and up to 12 L of water should be administered twice daily by nasogastric tube using a bilge pump to support a 1000-lb horse. Hydration should be monitored by daily determinations of packed cell volume (PCV) and total plasma protein (TPP). Alfalfa meal gruel with adequate water was shown to maintain dysphagic horses for more than 2 weeks.²³¹³ Expensive mixtures of electrolytes and semipurified nutrients are not necessary for oral alimentation.²³⁵¹ If the horse or foal is recumbent, it should be fed in a sternal position and supported during gastric emptying. Recumbent foals are prone to developing ileus and may accumulate a large amount of fluid in their stomach, which must be relieved by nasogastric intubation. Additionally, recumbent male horses require bladder catheterization several times daily because they are unable or unwilling to urinate. If not catheterized, severe cystitis or bladder necrosis may result. Because most animals continue to attempt to eat, muzzling may be necessary to prevent aspiration of food or bedding, which can lead to aspiration pneumonia.

Foals often require intragastric feeding with either mare’s milk, goat’s milk, or a commercial milk replacer (Foal-Lac; Borden) through an indwelling nasogastric tube (Levin Tube, 16 Fr, 1.27 m; Davol). Additional therapy often includes histamine receptor (H₂) blockers such as ranitidine or cimetidine, along with sucralfate to help prevent gastric ulcers, which occur frequently in shaker foals.²³⁰⁸ Ophthalmic lubricating ointments (Lacri-Lube; Allergan Pharmaceuticals) are often needed to prevent corneal abrasions that may result from decreased eyelid tone. Recumbent foals must be turned frequently to help prevent decubital ulcers and muscle necrosis. Parenteral antibiotics (e.g., potassium penicillin, ceftiofur sodium) are indicated to help reduce secondary infections, especially inhalation pneumonia. Approximately 50% of foals with botulism will require supplemental oxygen, and 30% will require mechanical ventilation.²³⁵² In foals requiring mechanical ventilation, 87.5% survived.²³⁵²

Recovery from botulism depends on toxin dose and the resulting severity of the clinical disease. Dysphagic horses that are able to stand will gradually regain the ability to swallow over 3 to 7 days. The more complete the dysphagia, the longer is the time required for recovery. An occasional horse will remain dysphagic for more than 2 weeks. Most adult horses are able to eat hay and swallow grain and water by 7 to 10 days after treatment with antitoxin. Return to full strength often takes more than 1 month. Very few adult horses that become recumbent and are unable to rise for 24 hours recover unless they are provided meticulous nursing care. Decubital ulcers and secondary respiratory problems are the major complications. Recumbent foals are usually able to stand after 7 to 10 days of intensive nursing care.²³⁰⁸

Prevention

A toxoid for Clostridium botulinum type B, BotVax B, is available from Neogen Corporation (Lexington, Ky). Three doses of vaccine 1 month apart are required to successfully immunize horses according to current recommendations.²³⁵³ Alternatively, three vaccinations given at 10-day to 12-day intervals may provide protective antibody after 3 weeks, if necessary for emergency situations (e.g., outbreaks).²³⁵⁴ Annual revaccination of pregnant mares 4 to 6 weeks before foaling is highly recommended. Horses from an endemic area should be revaccinated annually. The colostrum from vaccinated mares receiving boosters 6 to 8 weeks before foaling should contain adequate antibody to protect the foal for 8 to 12 weeks.²³⁵⁵ Foals vaccinated with toxoid in the first few days of life should be immunoresponsive and should develop antibodies to the toxoid, even in the presence of passive antibody.²³⁵⁴ Foals or weanlings given only two doses of toxoid may not be protected.

Botulism toxoid is considered highly efficacious when administered properly and is regarded as one of the safest and most effective vaccines for horses. Occurrence of clinical botulism in fully immunized horses has not been reported. No multivalent vaccine or licensed type C toxoid for horses is available in North America at this time. However, horses have been vaccinated and immunized with a type C toxoid approved for use in mink. This vaccine has been used for several years in endemic type C areas, such as southwestern United States.

Definition and Etiology

The etiology of polyneuritis equi in horses is unknown. Inflammatory changes occur in various nerve roots, particularly those of the cauda equina and cranial nerves. All nerve roots may be affected to a greater or lesser degree, which has led to the use of the term polyneuritis equi as a more descriptive name for the condition than its previous name of “cauda equine neuritis.”^2356-2358

The disease usually occurs in adult horses,^2356-2361 although it has been described in a yearling filly.²³⁵⁹ No breed or gender predilection has been noted.²³⁶⁰

Several hypotheses have been proposed for the cause of this disease. The lesions it causes bear some histopathologic resemblance to experimental allergic neuritis of rats, coonhound paralysis of dogs, and Guillain-Barré syndrome in humans, all of which are suspected of having an autoimmune basis.^2361,2362 Other proposed etiologies include a hypersensitivity reaction after systemic infection, aberrant migration of helminth larvae, and association with equine herpesvirus type 1 (EHV-1) and equine viral arteritis (EVA) infections.^{2359,2360,2363-2365} However, conclusive evidence supporting any of these theories is lacking.

Clinical Signs and Differential Diagnosis

The clinical signs of polyneuritis equi reflect the involvement of the lower motoneurons and sensory neurons at the level of the nerve roots. In the initial stages of the acute form, horses show signs of hyperesthesia, particularly around the tailhead, and rub and chew at this area.²³⁶¹ Sometimes pain is apparent, and horses become apprehensive of handling.²³⁶⁶ The condition can progress to hypoesthesia or anesthesia of the affected areas.^{2356,2357,2363} In the chronic form a gradually progressive paresis of the tail, bladder, rectum, and anal sphincter develops, which may terminate in paralysis.

Common signs include weakness or paralysis of the tail.^2367,2368 The anus may be hypotonic or atonic and distended.^{2356,2366-2369} Fecal retention or incontinence is sometimes a feature.^{2356,2357,2363,2366,2370} Urinary incontinence occurs in many horses because of involvement of parasympathetic fibers in the sacral nerves and is the lower motoneuron type (i.e., bladder is atonic, distended, and easily expressed manually). In severe cases, overflow incontinence develops, and urine dribbling may cause vaginal hyperemia and scalding of the perineum in mares and scalding of the thighs in animals of either gender.^{2356,2357,2363,2367-2371} Retention of urine predisposes to urinary tract infections.²³⁶⁹ In males the penis may be relaxed and protruding, with decreased sensation in the perineal skin.^{2356,2357,2369} Impotence resulting from incomplete erection and inability to achieve intromission was the presenting complaint in one stallion with polyneuritis equi.²³⁷² The preputial skin, which derives its innervation from spinal cord segments L2 to L4 through the genitofemoral nerve, usually retains normal sensory function.²³⁷³ When the nerve roots of the lumbosacral enlargement of the spinal cord are involved, hindlimb weakness with ataxia is seen.^{2360,2361,2363,2366} Weakness and ataxia have been observed in all four limbs of some horses.^{2357,2361,2367,2370} The gait may be stiff,^2366,2369 and denervation atrophy of muscles may result.²³⁶⁶

Cranial nerves can be involved. The signs depend on the individual nerves affected and the severity of the disease. The motor branch of the trigeminal nerve is reported to be most often involved, resulting in atrophy of the temporal and masseter muscles, with drooling and dysphagia.^{2367,2370,2371,2374} Involvement of the facial nerve results in unilateral or bilateral facial paralysis, which can cause keratitis and corneal ulceration.^{2361,2363,2367,2370,2374} Head tilt and other signs of cranial nerve dysfunction may also occur.^{2357,2367,2374}

Any disorder that affects the cauda equina may cause similar signs. These include instabilities of the caudal spine caused by luxations or fractures, EHV myelitis, sorghum intoxication, and infectious diseases that involve the cauda equine, as well as some primary diseases of the lower urinary tract.^2375-2377

Clinical Pathology

Cerebrospinal fluid (CSF) may have a mononuclear and neutrophilic pleocytosis, sometimes with more than 100 cells/μL.²³⁵⁹ The CSF protein concentration usually is moderately to markedly increased.^{2360,2370,2374} Electromyographic abnormalities occur in polyneuritis equi as a result of denervation of affected muscles. A recent study suggests that the presence of circulating antibodies to P2 myelin protein may prove to be a useful diagnostic test, but further research is required to confirm this.^2378,2379

Pathophysiology

The finding that some horses with polyneuritis equi possess antibodies to P2 myelin protein supports the theory that this disease has an autoimmune etiology.^2378,2379 An initial traumatic or infectious insult might cause the release of autoantigens from nerve tissue and disrupt the blood-nerve barrier so as to permit an autoimmune reaction.²³⁶⁶ Experimental inoculation of P2 protein in rats produces an antibody response and an allergic neuritis that shares some pathologic features with polyneuritis equi.²³⁸⁰ However, such autoantibodies may represent an epiphenomenon and may not be central to the pathogenesis of the disease.

Necropsy Findings

The main lesions are in the nervous system. The cauda equina is thickened, discolored, and covered with edematous tissue and fibrous material.^{2361,2371,2381} There may be adhesions of the nerve roots or the spinal cord to the meninges and the periosteum of the vertebral canal.^2356,2369 Subdural or epidural petechiation and hemorrhage are sometimes seen.^{2356,2363,2366}

At the microscopic level the major finding is a granulomatous inflammation that is most intense in the extradural part of the nerve roots. On rare occasions, microabscesses are found at the center of the granulomatous lesions.^2356,2361 The epineuria, perineuria, and endoneuria are thickened and are infiltrated to varying degrees by lymphocytes, plasma cells, lymphoblasts, macrophages, giant cells, eosinophils, and in rare cases, neutrophils.* Intraneural inflammation, necrosis, and endoneurial thickening can obliterate nerves.^{2356,2363,2366} Axonal degeneration and demyelination are present.²³⁶¹ Often, myelinated axons are absent in the affected nerves. Mildly affected nerves have axonal swelling and ballooning of myelin sheaths. Nerve bundles are separated by large amounts of fibrous tissue. There is minimum to moderate evidence of nerve regeneration.²³⁶¹

Lesions can also be found in the spinal cord itself, having occurred secondary to the nerve root lesions, such as wallerian degeneration in the dorsal columns and axonal reaction in the ventral horn cells.²³⁶⁶ Inflammatory lesions in dorsal root ganglia and in trigeminal ganglia have been found in some horses with this disease.²³⁶⁷

Treatment and Prognosis

Treatment with corticosteroids at antiinflammatory doses early in the course of the disease may be helpful.^{2359,2363,2371,2382} However, no therapy has consistently been shown to be effective. Immunosuppressive drugs, such as azathioprine, may be useful in the treatment of polyneuritis equi, but their use for this disease has not been reported.²³⁸³ General supportive care should be given, including fluid therapy when necessary, and the bladder and bowels should be manually evacuated. Because of the slow progression of signs in some horses, these animals may be maintained on supportive care for a long time. Because of the severity of the clinical signs, the gradual deterioration, and the poor prognosis, euthanasia usually is the eventual choice.

Definition and Etiology

A syndrome of ataxia and cystitis in horses, cattle, and sheep has been linked to the feeding of Sorghum species.^2384-2389 The underlying mechanism is probably toxic damage to the central nervous system, but the precise toxin responsible is not known. This disease does not appear to be linked to the breed, gender, or age of an animal.²³⁸⁵

Clinical Signs

The first sign observed usually is ataxia of the hindlimbs, usually followed by urinary incontinence. Affected animals have a swaying hindlimb gait and a tendency to knuckle over. Occasionally, affected horses may walk with a hopping gait, in which both hindlimbs are lifted off the ground simultaneously (Fig. 35-48). Signs in horses tend to worsen on backing, and animals may fall or even become recumbent.²³⁸⁵ During an outbreak of the disease in cattle, 3 of 54 affected cows became recumbent, and two of these died.²³⁸⁶ The perineal muscles are relaxed, and urine dribbles from a flaccid, distended bladder.^2385,2386 In mares the vulva opens and closes repeatedly; in stallions and geldings the penis is relaxed and protrudes from the prepuce.²³⁸⁵ Paresis of the tail may be present in both horses and cattle. Loss of skin sensation over the hindquarters has been described in a cow, suggesting involvement of both sensory and motor nervous pathways.²³⁸⁶ Head shaking, ataxia, weakness, recumbency, opisthotonos, and death have been reported in sheep, and mortality can approach 50%.²³⁸⁴

Fig. 35-48 Characteristic “rabbit hopping” gait of a horse with lathyrism. This horse was believed to have eaten sweet peas (Lathyrus species). Horses may also simply show ataxia and paraparesis.

Courtesy Dr. G.P. Carlson.

Cystitis in affected animals may be severe and occurs secondary to urine retention. Dribbling of urine onto the skin of the perineum and hindlimbs results in scalding of the skin and dermatitis. Pyelonephritis is a common sequela to chronic cystitis and may be fatal.^2385,2387 Sometimes the clinical signs may be chronic; in one outbreak, horses had been showing signs for as long as 3 years.²³⁸⁵

Abortion in mares, arthrogryposis as a congenital deformity of foals and lambs, and neurologic abnormalities in newborn lambs also have been linked to the feeding of Sorghum plants.^2384,2385

Clinical Pathology

Diagnosis of sorghum toxicity is made by the presence of typical clinical signs in association with a history of feeding Sorghum plants. No specific diagnostic test is available. Cystitis and pyelonephritis are identified by typical findings on routine urinalysis, serum biochemistry, and urine culture.

Pathophysiology

The precise nature of the toxic substance in Sorghum plants that causes this syndrome is unknown. Most Sorghum species are cyanogenetic plants that contain hydrocyanic acid at potentially toxic concentrations.²³⁸⁹ Chronic exposure to cyanide has been suggested as the cause of the neuropathologic changes found in affected animals.²³⁸⁵ Similarities in the clinical signs of this syndrome and those of neurolathyrism in humans have led to the suggestion that the toxic principle in Sorghum plants may be a lathyrogen-like substance.²³⁹⁰

Epidemiology

The cyanide content of Sorghum plants is increased by drought or freezing and also is higher in new shoots and wet plants.^2389,2390 In one survey of the disease in horses, most cases occurred during the wet season and involved young, growing plants.²³⁸⁵ The period of grazing before the onset of signs ranges from 1 week to many months.^2385,2386

Necropsy Findings

Wallerian degeneration, swelling of axons and myelin sheaths, and demyelination in a small number of nerve fibers throughout the length of the spinal cord, in the cerebellum, cerebellar peduncles, and the pons have all been described, together with the presence of phagocytic gitter cells.^2384-2386 These changes are not associated with specific tracts.²³⁸⁶ Ultrastructural studies of brains and spinal cords of affected sheep have revealed that the axonal swelling (spheroids) are composed of aggregates of neurofilaments, mitochondria, vesicular bodies, and dense bodies, enclosed within a thin myelin sheath.²³⁸⁴

Treatment and Prognosis

Withdrawal of Sorghum plants from the diet of affected animals results in a gradual improvement in the clinical signs over weeks to months, although recovery may not be complete.^2384,2386 Death is a potential sequela, however, and mortality can be high in some cases.²³⁸⁴ There is no specific treatment for affected animals. Supportive therapy includes antibiotics for treatment of bacterial urinary tract infections.

Control

Avoidance of feeding Sorghum plants as a predominant part of the diet or the sole diet is the only method of control. This plant has considerable feed value and should not present a major hazard when used as part of a diversified feeding regimen.

Definition and Etiology

Stringhalt is a disorder of unknown etiology that produces a characteristic hyperflexion of one or both hock joints in affected horses. The sporadic form usually affects a single hindlimb and is often associated with traumatic injury, although in some cases no inciting cause is identified. The epidemic form affects both hindlimbs and sometimes the forelimbs. This form also is called bilateral stringhalt, rather than “epidemic” stringhalt. Laryngeal paresis from involvement of the recurrent laryngeal nerves also has been described in this form of the disease. This form of stringhalt occurs often as an outbreak in groups of horses grazing poor-quality, weed-infested pastures; it is suspected to have a toxic etiology.

Clinical Signs

Affected horses appear normal at rest but have a characteristic involuntary hyperflexion of the tarsocrural joint when moving. The disorder may be unilateral or bilateral and can vary in severity from a slight exaggeration of normal movement to a motion wherein the rear foot strikes the belly. A grading system has been proposed, with the severity of signs classified from grade I to grade V.²³⁹¹ In grade I, mild signs are noted just as the horse begins to move; in grade V, animals are reluctant to move and have a “bunny-hopping” gait when forced to do so. The signs generally worsen on turning or backing and may also be more severe when the animal is frightened, after a period of rest, or in cold weather.^2392-2394 Knuckling of the forelimbs may occur in the epidemic form of the disease, sometimes with evidence of laryngeal weakness in the form of dyspnea or “roaring.” Atrophy of muscles in the affected limbs is usually a feature of stringhalt and is most severe in distal limb muscles.

Clinical Pathology

No abnormal clinical pathologic findings are associated with stringhalt. Electromyography of affected muscles reveals increased insertion activity and abnormal spontaneous activity, such as fibrillation potentials and positive sharp waves, consistent with denervation.^2395,2396 Nerve conduction velocity is slowed in the peroneal nerves of affected limbs, indicating demyelination, and improves as animals recover clinically.²³⁹¹

Pathophysiology

The etiology and pathophysiology of stringhalt are unknown. The sporadic form occurs in individual animals. In some sporadic cases, a history of traumatic injury to the limb, particularly to the dorsoproximal metatarsus, precedes the development of stringhalt by several months,^2397,2398 although in other cases the cause is unknown. Explanations for the development of stringhalt after traumatic injury include tendinous adhesions and alterations in the function of nervous or muscular components of the myotactic reflex in the affected muscles.^{2393,2399,2400} Outbreaks of stringhalt among horses in Australia and the United States have been associated with ingestion of certain plants, particularly Hypochoeris radicata (catsear), but a causal role for a plant toxin has not been proved experimentally.^2401-2403 Other related plants that have been associated with the development of stringhalt include Taraxacum officinale (dandelion) and Malva parviflora (cheeseweed mallow).²³⁹⁴ Lathyrism, a toxicity caused by plants of the Lathyrus (flatpea) family, can cause signs similar to stringhalt (see earlier discussion). Detailed pathologic studies of horses affected by the epidemic form of stringhalt have revealed that the lesion is a distal axonopathy in peripheral nerves that selectively affects large-diameter myelinated axons.^2402,2404 The pathologic changes are widespread and involve nerves of the forelimb and the recurrent laryngeal nerves, as well as those supplying the hindlimbs. Neurogenic myofiber atrophy is present in muscles innervated by the affected nerves, with type II fibers being more severely affected than type I fibers. Recovery in affected horses is presumed to result from axonal regeneration, a process that requires an intact neuronal cell body.²⁴⁰²

Epidemiology

The sporadic form of stringhalt occurs in individual animals worldwide and at any time of year. The epidemic form occurs in outbreaks in which several horses in the same location are affected; it has a seasonal incidence, being most prevalent in the late summer or early autumn after a period of very dry weather. Outbreaks have been reported in Australia (thus the alternative name for the epidemic form, “Australian stringhalt”) and in the western United States.^2405,2406

Necropsy Findings

Lesions are limited to the peripheral nerves and muscles.²⁴⁰² There is a loss of large-diameter myelinated fibers in a number of peripheral nerves, especially those innervating the hindlimbs and the recurrent laryngeal nerves. The pathologic changes in the nerves include demyelination, fibrosis, and proliferation of Schwann cells. Longer nerves are more severely affected. Muscles innervated by the affected nerves show evidence of denervation atrophy, particularly of type II myofibers.

Treatment and Prognosis

Individual cases rarely recover spontaneously. Surgical therapy by tenotomy or tenectomy of the lateral digital extensor tendon has been the treatment of choice in sporadic cases, resulting in a guarded to favorable prognosis for recovery.^{2392,2393,2407} Conservative treatment using gradually increasing exercise or intraarticular administration of corticosteroids also has been advocated for animals with a history of trauma to the affected limb.^2397,2398 One study found no apparent significant difference in outcome between horses that underwent surgery and those managed conservatively.²³⁹⁷ Steroid therapy was successful in the one case reported, whereas exercise alone resulted in improvement in two of four horses but complete recovery in only one horse.²³⁹⁷

In the epidemic form, most horses recover in weeks to months without treatment.²⁴⁰¹ Because a toxic etiology is suspected, it is usually recommended that the horses be removed from the pasture they were grazing when they developed signs. Administration of phenytoin (10 to 15 mg/kg orally once or twice daily) resulted in clinical improvement and reduced abnormal electromyographic activity within 24 hours of starting therapy and reached full effect by 1 week.^2396,2408 Horses that did not recover spontaneously while receiving phenytoin showed reappearance of signs within a few days. Mild sedation is a possible side effect of this treatment. Other drugs reported to have variable beneficial effects include mephenesin and baclofen.^2409-2411

Control

Because plant toxicity is suspected as the cause of the epidemic form of stringhalt, control is best effected by not grazing horses on weed-infested pasture and by using weed control and good pasture management where horses are being grazed. Judicious exercise regimens may be helpful in reducing the likelihood of stringhalt in horses that have sustained traumatic injuries to the dorsoproximal region of the metatarsus.²³⁹⁷

Definition and Etiology

An ascending lower motoneuron paralysis has been described in horses, sheep, cattle, and goats in Australia, associated with infestation by the tick Ixodes holocyclus.^2412-2417 In the United States a similar disease occurs in dogs, humans, cattle, New World camelids, and wild animal species as a result of infestation with several Dermacentor species.^2418,2419 A similar problem occurs in small ruminants in Africa, where Ixodes rubicundus and Rhipicephalus evertsi evertsi are the tick species implicated.²⁴²⁰

Clinical Signs

Progressive generalized paresis develops over one to several days, terminating in recumbency. Death from respiratory paralysis may occur in as little as 24 hours in severe cases.²⁴¹² Animals may be found recumbent or may be paraparetic and ataxic in the early stages of disease. When signs are mild to moderate, differential diagnoses include a variety of neurologic and nonneurologic diseases, such as rabies, colic, uterine torsion, trauma, myelopathies, myopathies, and metabolic disorders. These do not usually progress to the profound muscular flaccidity seen in tick paralysis.²⁴²¹ Reflex withdrawal from a noxious stimulus and the blink reflex both are reduced to absent, although sensory function appears normal. The major differential diagnosis for fully developed tick paralysis is botulism. Tick paralysis often is fatal when caused by I. holocyclus, but animals affected by Dermacentor species recover if the ticks are removed before the animals are moribund. Diagnosis is made on the basis of the clinical signs and finding ticks on the affected animal.

Clinical Pathology

There are no pathognomonic findings in affected animals except for the presence of ticks on the patient. Electromyography in tick paralysis in dogs in North America reveals minimal spontaneous activity and lack of evoked compound muscle action potentials in response to motor nerve stimulation.²⁴²² Findings in large animals can be expected to be similar. Cerebrospinal fluid is normal in tick paralysis, helping to differentiate it from some, but not all, myelopathies.

Pathophysiology

The cause of tick paralysis is believed to be a neurotoxin in the saliva of female ticks that is inoculated into the host when the tick feeds. Nymphs and larvae also may cause the disease.^{2413,2415,2416} In the case of I. holocyclus the toxin has been named holocyclotoxin. The toxin elaborated by Dermacentor species has been less well characterized. The pathogenesis of the disease is blockage of transmission at the neuromuscular junction as a result of reduced release of acetylcholine. Mortality is common in tick paralysis caused by I. holocyclus despite tick removal.

Epidemiology

The disease occurs worldwide, associated with different tick species in different areas. In North America the region from the Pacific coastal range to the Continental Divide provides especially favorable conditions for the proliferation of Dermacentor andersoni.²⁴¹⁸ Tick paralysis in the United States and Canada occurs mainly in the Pacific Northwest and the Rocky Mountains, although the range of the tick species involved covers a much wider area.²⁴²¹ The disease tends to be seasonal in North America, with most cases occurring in the spring, when ticks are most active. Smaller animals, such as sheep and New World camelids, are more often affected than cattle, probably because they receive a larger dose of the tick neurotoxin relative to their body size.²⁴²¹ Tick factors probably influence disease severity, and genetic variation within I. holocyclus may play a role in toxin potency.²⁴²³ A short-lived immunity has been demonstrated in dogs exposed to ticks. Tick paralysis is most common in the early part of the season and in younger animals, suggesting that a similar phenomenon may occur in other species.²⁴²¹ The significance of host immunity is supported further by the finding that D. andersoni has reduced virulence in hamsters after the ticks are prefed on cattle previously exposed to the same species of tick compared with ticks prefed on naive cattle.²⁴²⁴

Necropsy Findings

There are no pathognomonic findings at necropsy, although the presence of ticks should increase suspicion of this disease. Death usually results from respiratory paralysis.

Treatment and Prognosis

Treatment is symptomatic after removal of the ticks, which is essential. Lack of improvement suggests that ticks remain on the animal, except in cases of I. holocyclus infestation, where signs persist and may worsen despite removal of all ticks. Spraying or dipping affected animals facilitates tick removal. In small animals, shaving the hair coat may be necessary to ensure detection and removal of all ticks. Areas such as the axillae and groin, in particular, provide good sites of attachment for ticks. The prognosis is good in the case of Dermacentor-induced paralysis when tick removal and supportive care are instituted before animals are moribund. Fatalities occur frequently in the case of Ixodes-induced paralysis despite removal of ticks. Cooling of the patient has been suggested in treatment of I. holocyclus toxicity because anecdotal clinical reports suggest that patients may be more likely to survive when cool. In vitro studies revealed that binding of holocyclotoxin at the neuromuscular junction is reduced in a cooler environment.²⁴²⁵ However, such an approach may increase risk of severe complications in patients that are paralysed and cannot thermoregulate. A better approach may be to avoid warming the patient excessively.

Administration of hyperimmune serum has been shown to be beneficial in the treatment and prevention of this disease in dogs and in one llama.^2417,2426 Adverse reactions such as anaphylaxis, bradycardia, and hypotension occur in a small number of dogs and cats treated with hyperimmune serum, but these can be avoided by premedication of atropine.²⁴²⁷ No report of such treatment in other species was found.

Control

Environmental control to reduce tick populations and routine use of acaricides may decrease the incidence of tick paralysis.

Suprascapular Nerve

Mechanical damage to the suprascapular nerve results in paralysis of the infraspinatus and supraspinatus muscles.²⁴⁶¹ Early denervation is characterized by a slight outward bowing of the scapulohumeral joint as weight is placed on the limb. Neurogenic atrophy develops after several months, and the scapular spine becomes prominent (Fig. 35-49). The common name for this condition is “Sweeney.”

Fig. 35-49 “Sweeney” (neurogenic atrophy) of the left supraspinatus and infraspinatus muscles in a Charolais bull. The lesion was caused by trauma related to running through a cattle chute.

Brachial Plexus

Damage to the brachial plexus may result in any combination of dysfunction of the biceps and coracobrachialis muscles (musculocutaneous nerve), as well as the pectoral, subscapularis, and triceps muscles.

Lesions of the brachial plexus are caused by trauma to the shoulder, deep penetrating axillary wounds, or traction on the forelimbs of a fetus during relief of a dystocia. Because of their tendency to rear and jump over objects, horses are most susceptible to brachial plexus injuries. The condition may occur in small ruminants after automobile accidents, carnivore attacks, or blows from larger animals.

Radial Nerve

The radial nerve is motor to the extensor muscles of the forelimbs. The nerve courses over the lateral aspect of the elbow joint and is vulnerable to traumatic insult at that point. Radial nerve paralysis most often arises from direct trauma to the nerve, during prolonged anesthesia, or during restraint in lateral recumbency with inadequate padding of the forelimb.^2463,2464 Degeneration of the triceps muscles also plays a significant role in many cases of radial nerve paralysis.²⁴⁶³

The limb position varies, depending on the location of the lesion in the radial nerve. Lesions at or near the elbow joint result in high radial nerve paralysis, characterized by a dropped elbow, failure of limb protraction with scuffing of the toe, and flexion of all distal limb joints (Fig. 35-50). The foot is knuckled over at rest, and the animal is unable to bear weight on the leg. Lesions of the distal radial nerve result in knuckling of the carpus, fetlock, and pastern joints. The animal can support weight on the affected limb if the metacarpus and distal limb are held in extension. The triceps reflex is depressed to absent. Chronic dysfunction of the radial nerve results in neurogenic atrophy of the extensor muscles of the forelimb. Detectable sensory deficits resulting from radial nerve paralysis tend to be vague and probably vary from patient to patient.

Fig. 35-50 High radial nerve paralysis in a horse showing knuckling of the carpus and digit and dropped elbow.

Courtesy Dr. R.H. Whitlock.

Femoral Nerve

The femoral nerve is distributed to the quadriceps femoris muscles and the skin of the rear limb extending from the medial thigh to the medial part of the coronet (saphenous nerve). Traumatic overextension of the hip and stifle joint from a fall or other injury or forced posterior delivery can damage the femoral nerve. The clinical signs of femoral nerve paralysis are related to an inability to extend and fix the stifle.²⁴⁶¹ The reciprocal apparatus is unable to fix the hock, resulting in collapse of the limb during weight bearing and constant flexion of all distal digital joints. Chronic lesions of the femoral nerve result in atrophy of the quadriceps femoris muscles and the muscles of the posterior part of the gluteals. The patellar reflex is absent or depressed, and the patella often is displaced laterally. There is analgesia to anesthesia of the medial part of the rear limb extending from the proximal thigh to the medial malleolus of the tibia.

Sciatic Nerve

The sciatic nerve innervates the extensor muscles of the hip, the flexor muscles of the stifle, and most of the muscles of the distal limb.

Sciatic nerve paralysis occurs most often in postpartum cows after forced fetal extraction. Loss of function of the lumbar branches of the nerve most likely plays a major role in the so-called calving or obturator paralysis syndrome.²⁴⁶⁷ Injection of irritating drugs into the space between the greater trochanter and the ischial tuberosity may cause a sciatic neuritis. This occurs most frequently in neonates but can occur rarely in adult cattle and small ruminants. Other causes of sciatic nerve damage are pelvic fractures, tumors, or abscesses located along the course of the nerve.

The sciatic nerve innervates most of the musculature of the rear limb, so the motor deficits associated with denervation are profound. At rest the limb is hanging behind the animal. The stifle is dropped and extended (Fig. 35-51). The foot is constantly knuckled. If the limb is positioned properly, the animal usually can bear weight for a limited period because of the normal function of the quadriceps muscles and the action of the reciprocal apparatus. Chronic denervation of the sciatic nerve results in neurogenic atrophy of the caudal thigh muscles and all of the muscles distal to the stifle.

Fig. 35-51 Characteristic posture of a cow with partial sciatic nerve paralysis. The condition pictured here was induced during correction of a severe dystocia. Note the flexion of the hocks, fetlocks, and stifle. These signs differentiate the condition from peroneal paralysis.

Courtesy Dr. R.H. Whitlock.

The sciatic nerve divides into the tibial and the peroneal nerves in the distal limb. Therefore, except for the medial part of the thigh and rear limb, there is analgesia and anesthesia of the entire limb distal to the stifle.

Peroneal Nerve

The peroneal branch of the sciatic nerve is distributed to the flexor muscles of the hock joint and the extensor muscles of the digit. The nerve becomes superficial and is exposed to damage as it crosses over the lateral condyle of the fibula.²⁴⁶⁸ The condition is typically seen in all species of large animals and is common in postpartum dairy cattle that have been recumbent as a result of hypocalcemia or other causes and in horses because of postanesthetic myopathy. Neurologic deficits of the peroneal nerve result in a hyperextended hock joint and flexion of the fetlock and pastern^{2461,2468,2469} (Fig. 35-52). Many cows knuckle at the fetlock even when the foot is flat on the ground, and others may be able to bear weight only when the limb is manually placed in the proper position.

Fig. 35-52 Calf with peroneal nerve paralysis. Note the flexed fetlock and digit and the hyperextended carpus. This condition was caused by injection of antibiotics into the peroneal nerve on the caudolateral aspect of the leg.

Courtesy Dr. R.H. Whitlock.

There is desensitization of the skin over the craniolateral aspect of the limb extending from the stifle to the hoof.

Tibial Nerve

The tibial nerve supplies the extensor muscles of the hock joint (gastrocnemius) and the digital flexors.

Tibial paralysis is most often observed in periparturient cattle or neonates that have been given an injection of an irritant drug in the caudal leg at the level of the stifle. Tibial paralysis also is seen in sheep and goats and is a common sequela to dog-bite injuries. With tibial paralysis, the hock is overflexed and is pulled higher than normal when the limb is protracted. The toe does not drag on the ground, and the limb is dropped suddenly perpendicular to the ground at the end of the stride. At rest the pelvis is asymmetric, with the affected side held lower than normal.²⁴⁶¹ Chronic loss of tibial nerve function results in atrophy of the gastrocnemius and digital flexor muscles. There is anesthesia to analgesia of the skin of the caudomedial aspect of the leg.

Obturator Nerve

The obturator nerve supplies motor impulses to the adductor muscles. The nerve is well protected in the equine and small ruminants, and therefore damage is rare in these species. The cow has a shallow acetabulum and a poorly developed round ligament. Consequently, the condition is often seen in peripartum cows. Reports of obturator nerve paralysis of cattle accompanied by knuckling and inability to support weight on the rear limbs probably represent a combination of sciatic and obturator nerve deficits. Coxofemoral luxation is a common complication of obturator paralysis in cattle housed in stalls with slippery flooring. Such luxation can be recognized by the identification of crepitus during passive manipulation of the hip joint. There may be a difference in the length of the rear limbs.

Obturator nerve paralysis is most common in cattle and is almost always a result of dystocia. The nerve injury is located in the pelvis at the level of the obturator foramen. Of all dystocias, 9.2% result in paraplegia.²⁴⁷⁰

The obturator nerve innervates the adductor, pectineus, and gracilis muscles. Only minimum deficits are observed if the cow is placed on a surface that has good traction. Clinical signs of an obturator nerve deficit include a hopping gait when the animal attempts to run and severe abduction or splay-leggedness when the animal is placed on a slippery surface (Fig. 35-53). In severe cases the cow may be sternally recumbent with the rear limbs extending laterally to each side. Experimental studies have indicated that the so-called calving paralysis syndrome is actually a result of a combination of lesions of the lumbar root (L6) of the sciatic nerve and the obturator nerve. Experimental sectioning of the obturator nerve alone does not produce paralysis, provided the animal has a nonslip footing.^{2461,2467,2471} Obturator nerve paralysis does not result in a cutaneous sensory deficit.

Fig. 35-53 Cow with obturator nerve paralysis caused by relief of a difficult dystocia. Note the base-wide stance, yet the apparent ease with which the cow is able to stand on the deep bedding. Note also that rope hobbles are being applied to prevent further abduction and possible luxation of the coxofemoral joint.

Damage of one or more peripheral nerves during parturition or milk fever may play a large role in the so-called downer cow syndrome (see later discussion).^2472,2473 The incidence of the condition ranges from 4% to 28% of all cases of milk fever and is associated with a mortality rate ranging from 20% to 67%.^2474-2477