Definition and Etiology

Chronic ingestion of a variety of different plants worldwide can result in an acquired neurovisceral storage disease. These include plants of the Astragalus and Oxytropis genera (locoweeds) in the western United States, Canada, and Australia; Ipomoea (shrubby morning glory) in Mozambique; the darling pea in Australia (Swainsona species), and Sida carpinifolia in Brazil (Table 35-14).^1763-1770 Horses are most susceptible to intoxication, but cattle, sheep, goats, and deer also can be affected.

Table 35-14 Species of Astragalus and Oxytropis Found in Western United States

From Knight AP: Compend Cont Educ (Pract Vet) 9:F418, 1987.

Conditions that promote locoweed poisoning are hot, dry weather and a scarcity of alternative forage. Horses may be more prone to graze on locoweed than cattle, particularly when other green forage is scarce, and may increase their consumption over a single season.¹⁷⁷¹ Chronically exposed livestock can become habituated and feed selectively on the plant over successive grazing seasons.¹⁷⁷²

The following toxic components have been identified:

Locoine, swainsonine n-oxide, and indolizidine alkaloids, which interfere with the activity of α-mannosidase and of Golgi mannosidase II.^{1764,1765,1773,1774}

β-Galactosidase and β-glucosidase.¹⁷⁷⁵

Aminonitrile, a compound that caused abortion and teratogenesis.

Miserotoxin, a compound that causes a respiratory disease complex.

Selenium accumulation (selenium toxicity may contribute to the neurotoxicity and fetal deformities).

Oxytropis and Astragalus plants are legumes that have herbaceous stems and alternate pinnately compound leaves. ¹⁷⁷⁶ The fruits are characteristic leguminous pods that contain kidney-shaped seeds with pods marked by characteristic longitudinal grooves.¹⁷⁷⁶ The plant is eaten because it is the first vegetation available in the spring. The Oxytropis and Astragalus species found in the United States are listed in Table 35-14. Symptoms do not usually develop in cattle until 3 weeks after the animals first begin grazing the plant and may not occur until long after ingestion of the plant has stopped. The toxicity of the locoweed may vary from year to year and even within one season.¹⁷⁷¹ Despite its relative unpalatability, some sheep may become habituated to the plant and selectively eat forage containing up to 20% Astragalus plants.¹⁷⁷²

Clinical Signs

Experimentally and naturally poisoned horses show clinical signs by 2 to 3 weeks after continuous ingestion of locoweed.^1769,1771 The clinical signs include ataxia, conscious proprioceptive deficits, and depression, with alternating periods of frenzied or manic activity. There is sometimes a high-stepping, stringhalt-like gait.¹⁷⁷⁷ At rest the horses show intentional head tremor, flaccidity of the nose and lips, repetitive movements with the lips and tongue, and dysphagia.¹⁷⁷⁷ The clinical signs worsen when affected horses are handled or transported. Signs in goats are similar, including ataxia, hypermetria, hyperesthesia, and muscle tremors.¹⁷⁶⁶ Forcing the head backward can result in falling, nystagmus, opisthotonos, seizures, and tetany.¹⁷⁷⁸ Tranquilization usually is ineffective for controlling the apparent hyperexcitability. Horses that survive locoweed poisoning retain an altered behavior. Abortions, stillbirths, and neonatal deaths can occur in all species exposed to these toxic plants, regardless of whether the dams have clinical signs of neurologic disease.^{1764,1766-1768}

Neurologic signs in adult cattle include conscious proprioceptive deficits, hypermetria, weakness, depression, dull staring eyes, and loss of herding instinct. Heavy losses from abortions or malformed calves have also been described. The indolizidine alkaloids are secreted in the milk and may cause unthriftiness and weak suckling behavior in calves. Calves that have been exposed to the toxin in utero are weak and fail to thrive. Some may have flexural contractions of the limbs and lateral rotation of the carpus.^1779-1782 Ingestion of locoweed by certain cattle at high altitudes may result in the development of cor pulmonale.^1779,1780 Many cattle with mild signs of locoweed poisoning recover completely by 60 days after removal from the offending pastures. Ruminants with advanced chronic intoxication apparently have permanent loss of neural tissue.

Poisoned sheep have a star-gazing attitude and appear to be blind, nervous, and stiff. The normal flocking behavior is absent.¹⁷⁶⁵ Affected sheep may exhibit ptyalism. Testicular atrophy has been reported in rams.¹⁷⁸³ Affected animals have intercurrent pyogenic infections such as pneumonia, keratoconjunctivitis, and foot rot. This is thought to be related to the immunosuppressive effect of the plants on the T lymphocytes.¹⁷⁸⁴ Depression and reluctance to move induced by locoweed toxicity may predispose animals to other problems, such as water deprivation.¹⁷⁸⁵

Clinical Pathology

Microscopic examination of stained blood smears may reveal the presence of vacuolation in the cytoplasm of the lymphocytes. These changes are found in the majority of lysosomal storage disorders, but might be considered diagnostic of locoweed poisoning in animals with characteristic clinical signs and historical evidence of exposure. Serum concentrations of alkaline phosphatase (ALP) and aspartate transaminase (AST) may be helpful markers for toxicity; elevated concentrations were detected in sheep exposed to swainsonine in Oxytropis sericea.¹⁷⁸⁶ Definitive diagnosis can be established by assaying sera from affected animals for α-mannosidase and swainsonine.¹⁷⁸⁷

Pathology

The microscopic abnormalities of the soft tissues of acutely poisoned animals are similar to those of the inherited lysosomal storage diseases of cattle, including cytoplasmic vacuolation of neurons, particularly Purkinje’s cells, and cells in various other tissues.^1766,1777 Paraffin-embedded tissues can be examined using lectin histochemistry to characterize the stored material within the vacuoles.^1766,1788 Vacuolation of renal tubular epithelial cells may occur as early as 4 days after the start of daily feeding of 0.34 kg of locoweed to horses and may be present in animals exposed to toxic plants but clinically normal.^1766,1789 Pulmonary lesions associated with chronic ingestion of locoweed that may predispose to high-altitude disease (brisket disease) in cattle (see Chapter 31) include alveolar emphysema, bronchiolar constriction and hypertrophy, and interlobular edema and fibrosis. Pyloric or gastric ulcers have been reported in affected cattle.^1782,1789 Placental edema, fetal ascites, and hydrops allantois have been described in exposed pregnant cattle.

Treatment

There is no known effective long-term therapy for locoweed poisoning. Animals remain affected for a prolonged period after removal from the plants and may be permanently afflicted. Some recommend either tranylcypromine (60 mg PO), a monoamine oxidase inhibitor, and protryptyline (60 mg PO) or reserpine (3.125 g/500 kg IM once or 1.25 mg PO per animal once daily) for treatment of chronically affected animals.¹⁷⁹⁰ However, the efficacy of these treatments is unknown. Addition of a mineral supplement and a natural clay (clinoptilolite) to the diet of cattle ingesting locoweed did not prevent toxicity.¹⁷⁹¹

Prevention

Nonaddicted livestock normally do not eat locoweed if other forage is available. The intoxication may be prevented by supplemental feeding during the early spring and late summer. One report has described conditioning aversion to locoweed in horses using lithium chloride administered simultaneously with grazing of Oxytropis sericea.¹⁷⁹² Whether this is a practical management tool in large numbers of animals has yet to be determined.

Perennial Ryegrass Staggers

Ingestion of toxic stands of perennial ryegrass (Lolium perenne) results in ataxia and tremors in horses, cattle, and sheep. The condition is recognized in livestock of New Zealand, Australia, Northern Europe, United States, South America, and Great Britain.^1793-1808 The case-attack rate may reach 100%, but the mortality rate is typically less than 50%.¹⁸⁰² Conditions that favor toxicity include late seasonal growth, ambient temperatures over 23° C (73.4° F), and closely grazed pastures. For these reasons, the disease is seen exclusively between June and September in the Northern Hemisphere and between December and June in the Southern Hemisphere. The condition may appear 5 to 10 days after grazing on highly toxic pastures. For a pasture to develop toxicity, the ryegrass must constitute a majority of the forage growth.

Perennial ryegrass produces tremorgenic toxins when infested with the endophytic fungus Acremonium loliae or Acremonium coenophialum. The fungal infection confers resistance to the Argentine stem weevil, so there is a selective pressure for toxigenic cultivars. Strains of Acremonium-resistant ryegrass have been propagated but are difficult to maintain because of the devastating effects of the stem weevil infestation. The chemicals produced by Acremonium-infected plants are classified as indole terpenes. These compounds are chemically related to the fungal tremorgens, penitrem A and fumotremogen. A number of separate toxic compounds have been isolated, including lolitrems A and B, paxilline, and peramine. Paxilline is a biosynthetic precursor of lolitrem B, which is related chemically to peramine. Peramine has the major antagonistic effects against the Argentine stem weevil. The lolitrems have the greatest tremorgenic effect on livestock.¹⁸⁰⁹ Concentrations of more than 2000 ppb of lolitrem B in forage or 1.68 mg/kg of forage have been associated with toxicity for sheep and cattle, respectively.¹⁸¹⁰ The concentration of lolitrem varies seasonally in the same grass, and toxic pastures may become nontoxic over the course of the grazing season.¹⁸¹¹

A relationship also exists between the frequency of poisonings and the proportion of plants infested by the Acremonium fungus. Infection rates below 25% are associated with sporadic cases, whereas plots containing 90% infection rates are associated with large outbreaks of staggers. Intoxication is most common on dry pastures where the perennial ryegrass is growing slowly under relatively low ambient temperatures. The Acremonium fungus can be identified by microscopic examination of boiled leaves. The fungus is in greatest prevalence in the summer and is found in the uppermost part of the leaf. To identify the fungus, the ryegrass leaves are immersed in a stain containing 0.06 g aniline blue in 50 mL of lactic acid in 250 mL of distilled water, 50 mL of glycerine, and 50 g of phenol. The mixture is boiled 5 minutes and mounted in lactophenol (20 g phenol, 16.7 mL lactic acid, 40 mL glycerine, and 20 mL water). For biologic assay of lolitrem, chloroform: methanol extracts of suspect plants are injected into mice. The recipients are then examined every few hours for tremors.

The endophyte-infested grasses also produce ergovaline or other ergopeptine alkaloids that exert prolactin-like activity. The resulting clinical signs are diarrhea, fever, tachypnea, and reduced weight gain.

High-peramine, low-lolitrem cultivars of Lolium* have been propagated. Such cultivars have partial protection against the stem weevil but do not cause staggers in pastured animals.¹⁸¹²

Annual Ryegrass Staggers

Annual ryegrass toxicity is caused by corynetoxin, which is manufactured in the seed heads of annual ryegrass (Lolium rigidium) and related grasses. The seed head is infested by the nematode Anguina agrostis (Anguina funesta). The parasitic infestation forms a gall that becomes secondarily infected by the bacterium Clavibacter toxicus (Corynebacterium rathayii).^1813,1814 The Corynebacterium organisms produce corynetoxin; this neurotoxin has been purified using high-performance liquid chromatography (HPLC) and can be detected using an enzyme-linked immunosorbent assay (ELISA). The structure of corynetoxin is similar to that of the antibiotic tunicamycin.¹⁸¹⁵ The corynetoxin is a glycolipid that inhibits the synthesis of lipid-linked oligosaccharides and blocks protein glycosylation.^1816,1817 Bacterial proliferation in the gall results in the formation of a yellow to orange exudate, which contains the toxin. The toxic material usually leaks out over the seed but occasionally remains encapsulated within the gall and cannot be detected by external examination. Galls that have a normal external appearance are toxic if the interior of the defect maintains a deep-orange color. Loss of color is associated with a decrease in the amount of toxicity. A method of evaluating toxic pastures based on enumeration of contaminated seed heads and ELISA to detect corynetoxin has been developed.

Outbreaks of staggers may occur in animals grazing the same pasture for months because the toxin is not inactivated by the rumen microflora, and daily doses may accumulate in sheep for as long as 9 weeks.¹⁸¹⁸ Thus, repeated exposure leads to an accumulation of the toxin and delayed onset of clinical disease. Also, the concentration of the toxin increases in the seed heads during the summer and is greatest as the plant dries and the seeds ripen.^1819,1820 Finally, toxic ryegrass may occur only in patches in the pastures, and the grazing patterns of the animals is altered by changes in the climatic conditions, the growth of the ryegrass, or introduction of new sheep. This could explain why outbreaks occur shortly after onset of inclement weather or after introduction of new sheep to the pastures.

Pathologic changes associated with annual ryegrass staggers include hemorrhage in the cerebellum, liver, and spleen. Ultrastructural changes include swelling of the capillary endothelial cells, dilation of the endoplasmic reticulum in the endothelial cells, mitochondrial degeneration, swelling of the astrocytic end feet, protein leakage across the blood-brain barrier, pyknosis and death of granular cell nuclei of the cerebellum, and changes in the neuropil adjacent to the damaged capillaries. These changes indicate that the toxin may access the central nervous system (CNS) by damaging the blood-brain–cerebrospinal fluid (CSF) barrier. CNS neurons could be affected because of vascular damage or direct activity of the toxins.¹⁸²¹

Clinical Signs and Pathologic Lesions

The clinical signs of annual and perennial ryegrass staggers are similar. For both disorders the case-attack rate usually is high, but mortality varies and can range from 0% to over 90%. The clinical signs may occur within 48 hours to several weeks after cattle are introduced to toxic pastures. The animals appear normal at rest but tremble when they are excited. The gait is stiff, and limbs are hypermetric. There are fine and coarse tremors of all major muscle groups, especially those of the shoulder and flank areas. The tremors worsen as the animal becomes excited. Other clinical signs include intentional head tremor, truncal sway, and base-wide stance. With continued stimulation, affected animals kneel and then fall over. While down, animals have stiff extension of the legs with occasional flailing and may display opisthotonos or convulsions. Frothy exudate from the mouth also has been described. After approximately 10 to 20 minutes of struggle, the animal recovers, stands, and walks back to the herd or flock. New cases and deaths can continue for as long as 1 week after the animals have been removed from the toxic pasture.

Differential Diagnosis

Grass staggers is easily recognized by clinical signs. The specific plant involved must be identified by examination of the pasture forage. Tremorgenic diseases of adult cattle are common throughout most of the world. In addition to ryegrass pastures, tremorgenic plants include Swainsona luteola and Swainsona galegifola; Solanum dimidiatum and Solanum fastigiatum; Astragalus species; red buckeye; Phalaris species (canary and reed canary grass); Eupatorium rugosum (white snakeroot); Cynodon dactylon (Bermuda grass); Dallis grass infested with the fungus Claviceps paspali; Polypogon monospeliensis (annual beard grass); Pennisetum clandestinum (kikuyu grass); and the mycotoxins of Penicillium cyclopium.¹⁸²⁰ Hypomagnesemia has been reported to cause cerebellar degeneration under some circumstances. The storage diseases (α- and β-mannosidosis, generalized glycogenosis, globoid cell leukodystrophy, neuronal lipodystrophy) may also be important differential diagnoses for ataxic animals with tremor and cerebellar signs.

Treatment

There is no specific treatment for grass staggers. If the animals are removed from toxic pastures as soon as signs are first seen, the mortality rate is low despite the high number of affected animals. Several months may elapse before the neurologic signs resolve completely. Treatment with high doses of magnesium chloride has been recommended, although others have shown it to be ineffective for controlling the muscular spasms.¹⁸²² Pastures may lose toxicity after rain and growth of new grass. In subtropical regions, cattle should not be introduced to toxic pastures until the late fall or winter, when less toxic growth becomes abundant.

Prevention

Ammoniation of dried feed has been recommended as a method of reducing the toxicity of hay. This treatment simultaneously increases the digestibility and protein equivalency of the forage.¹⁸²³ For preventing annual ryegrass staggers, high-risk pastures can be identified by visually examining seed heads for infected galls. ELISA is sufficiently sensitive to identify one infected seed gall per 100 g of dried seed heads and also can accurately predict toxicity in pastures.¹⁸²⁴ The most practical strategy for controlling annual ryegrass toxicity is to break the nematode’s life cycle by killing the ryegrass for two or three growing seasons. Otherwise, pastures remain perpetually toxic. Integrated control measures that have been recommended for prevention of annual ryegrass toxicity include applying herbicides in the spring, seeding the pastures with legumes, burning the infected pasture grasses during early autumn, and applying ryegrass-selective herbicides in the summer months, combined with heavy winter grazing.¹⁸²⁵

Prevention of perennial ryegrass staggers using endophyte-free cultivars has been recommended. Such resistant biotypes of ryegrass lack resistance to the Argentine stem weevil and consequently are less productive than other biotypes. The most convenient solution has been to minimize exposure of the animals until fall rains stimulate less toxic pasture growth. Newer cultivars containing fewer tremorgens may be useful in the future.

CERVICAL VERTEBRAL STENOTIC MYELOPATHY (WOBBLER SYNDROME; CERVICAL STENOTIC MYELOPATHY; CERVICAL VERTEBRAL INSTABILITY)

BONNIE R. RUSH

Clinical Signs

Cervical vertebral stenotic myelopathy (CVSM) is a common cause of symmetric spinal ataxia in horses. Neurologic gait deficits are caused by spinal cord compression by stenotic and malformed cervical vertebrae.¹⁸⁶³ A neurologic examination is performed to assess the symmetry of deficits and the severity of weakness, ataxia, and spasticity.¹⁸⁶⁴ Gait analysis is performed at the walk; neurologic deficits can be accentuated by circling, elevation of the head, and maneuvering over obstacles and inclines. Ataxia or proprioceptive loss is manifested by circumduction of the hindlimbs, posting (pivoting on the inside hindlimb during circling), and truncal sway. In most cases, pelvic limb ataxia is more pronounced than forelimb deficits. Moderately to severely affected horses have lacerations on the heel bulbs (wobbler heels) and medial aspect of the forelimbs from overreaching and interference. Stumbling and toe dragging indicate weakness. The hooves of horses with prolonged clinical signs of CVSM are chipped, worn, or squared at the toe. At rest, affected horses may have a base-wide stance and may demonstrate delayed responses to proprioceptive positioning. When prompted to back, horses may stand base wide, lean backward, drag their hindlimbs, and step on their hindfoot with a forelimb. The musculature of the neck may appear disproportionately thin compared to the rest of the body, and in some horses, prominent articular processes of the fifth and sixth cervical vertebrae may be evident.¹⁸⁶⁵

Occasionally, weakness and stumbling are more pronounced in the forelimbs. This is usually observed in horses with stenosis of the caudal cervical vertebrae (C6-C7) caused by compression of the cervical intumescence. Alternatively, arthropathy of the caudal cervical vertebrae may produce cervical pain and forelimb lameness from peripheral nerve compression, without producing clinical signs of spinal cord compression.¹⁸⁶⁶ Affected horses typically travel with a short cranial phase of the stride and a low foot arc of the forelimbs and may stand or travel with their head and neck extended. Rarely, diskospondylosis of the cervical vertebrae will produce a short-strided gait and cervical pain, with or without spinal ataxia. Horses with diskospondylosis or arthropathy of the caudal vertebrae may demonstrate increased rate and depth of respiration with cervical manipulation because of pain.

The condition has been reported in most light and draft breeds.¹⁸⁶⁷ Thoroughbreds are particularly predisposed to CVSM, which affects approximately 2% of the population. Between 10% and 50% of thoroughbreds have characteristic developmental malformations of the cervical vertebrae without spinal cord compression.^1868,1869 Male horses are more frequently affected than females. Most horses with CVSM are 6 months to 3 years of age at presentation. Nonetheless, age (≥4 years) does not preclude a diagnosis of CVSM; spinal cord compression caused by vertebral abnormalities is routinely diagnosed in adult horses, including geriatric horses.

The onset of neurologic gait deficits is typically insidious, with progression of ataxia for several weeks, followed by stabilization (plateau) of clinical signs.^1867,1870 Owners may report a traumatic incident with the onset of clinical signs of CVSM. The event may be the result of mild neurologic deficits, with the injury exacerbating the clinical signs of spinal cord compression. Asymmetric ataxia and paresis may be occasionally observed in horses with dorsolateral compression of the spinal cord by proliferative, degenerative articular processes and periarticular soft tissue structures.

Pathophysiology

CVSM appears to be a manifestation of developmental orthopedic disease. Developmental disease of the appendicular skeleton, such as physitis, joint effusion, osteochondrosis, and flexural limb deformities, occurs more often in young horses with CVSM.¹⁸⁷¹ A direct cause-and-effect relationship between osteochondrosis and CVSM has not been identified; however, the association between the frequency of occurrence of osteochondrosis and CVSM indicates that the two conditions have a similar pathophysiology.

The etiology of osteochondrosis and CVSM appears multifactorial, consisting of genetic and environmental influences. It is unlikely that CVSM is heritable by simple mendelian dominant recessive patterns.¹⁸⁷² The mode of inheritance more likely involves multiple alleles and variable penetrance, which determine genetic predisposition to CVSM. A high plane of nutrition, micronutrient imbalance, rapid growth, trauma, and abnormal biomechanical forces probably contribute to the development of CVSM in genetically predisposed animals.

Dietary copper, zinc, and carbohydrates are thought to play a role in the pathogenesis of osteochondrosis and CVSM. Low dietary copper (12 ppm) and high dietary zinc (1000 to 2000 mg/kg of dry weight) concentrations cause osteochondrosis in foals, whereas copper supplementation (55 ppm) reduces the incidence of osteochondrosis of the axial and appendicular skeleton.^1873,1874 Copper supplementation does not eliminate developmental orthopedic disease, suggesting the existence of other etiologic factors. Excessive carbohydrate in the diet is hypothesized to contribute to the pathogenesis of osteochondrosis through endocrine imbalance.^1875,1876

Spinal cord compression can be dynamic or static in horses with CVSM.^1870,1877 Dynamic compression occurs because of vertebral instability and causes intermittent spinal cord compression during ventroflexion of the neck; compression is relieved when the neck is in the neutral position. Pathologic changes most often observed in horses with dynamic compression are instability between adjacent vertebrae, malformation of the caudal vertebral epiphysis (caudal epiphyseal flare), and malformation or malarticulation of the articular processes. Osteochondrosis of the articular processes is not always present at the site of spinal cord compression in horses with dynamic compression.¹⁸⁷⁰ The intervertebral sites most frequently affected by dynamic compression are C3-C4 and C4-C5.

Static compression is defined as continuous spinal cord impingement regardless of cervical position. It occurs predominantly in the caudal cervical region, C5-C6 and C6-C7. Static compression is exacerbated by thickening of the dorsal lamina, hypertrophy of the ligamentum flavum, and degenerative joint disease (DJD) of the articular processes. Both static and dynamic compression are associated with narrowing of the vertebral canal from C3-C6, regardless of the site of spinal cord compression, indicating that generalized vertebral canal stenosis is an important factor in the pathophysiology of CVSM.¹⁸⁷⁸

Histopathologic examination of the spinal cord identifies myelin degeneration (ventral and lateral funiculi), malacia, focal neuronal loss, and fibrosis at the sites of compression. Wallerian degeneration occurs in ascending white matter tracts cranial to the affected site and in descending tracts distal to the site of spinal cord compression.¹⁸⁷⁹

Diagnosis

Radiographic examination and cerebrospinal fluid (CSF) analysis are indicated in horses with symmetric tetraparesis and ataxia to differentiate CVSM from other spinal cord disorders. The most important differential diagnoses for horses with symmetric tetraparesis and ataxia include equine herpesvirus myeloencephalitis, equine protozoal myeloencephalitis, equine degenerative myeloencephalopathy, and spinal cord/vertebral trauma. Cytologic CSF findings usually are unremarkable in horses with CVSM. When CSF findings are abnormal, the alterations are consistent with acute spinal cord compression, such as mild xanthochromia and mild increases in protein concentration.

Survey radiographs of the cervical spine are obtained in standing, sedated horses. Cervical radiographs are evaluated by subjective assessment of vertebral malformation and objective determination of vertebral canal diameter.¹⁸⁷⁸ The five categories of cervical malformation subjectively assessed in horses with CVSM are DJD of the articular processes, subluxation between adjacent vertebrae, flare of the caudal physis of the vertebral body, abnormal ossification patterns, and caudal extension of the dorsal laminae^1878,1880 (Figs. 35-26 and 35-27). Although the presence of characteristic vertebral malformations supports the diagnosis of CVSM, subjective evaluation of survey radiographs does not reliably discriminate between horses affected and those unaffected by CVSM.^1868,1878 DJD of the articular processes of the caudal cervical vertebrae is the most common and severe malformation observed in affected horses.¹⁸⁷⁸ However, degenerative arthropathy occurs in 10% to 50% of nonataxic horses and is the most common and severe vertebral malformation in horses without CVSM.^1869,1878 Subjective evaluation of degenerative arthropathy of the articular processes may lead to a false-positive diagnosis of CVSM.¹⁸⁶⁸

Fig. 35-26 Survey radiograph of fifth (C5) and sixth (C6) cervical vertebrae. Bony malformations include flare of the caudal physis (curved arrow, C5), caudal extension of the dorsal lamina (small arrows, C5), and subluxation and malalignment of the C5-C6 articulation. Solid line, Intervertebral canal diameter of C5-C6 articulation; double-headed arrow, intravertebral canal diameter of C5.

Fig. 35-27 Survey radiograph of fifth and sixth cervical vertebrae. Degenerative joint disease, bony proliferation, and a facet fracture (arrows) can be seen on the articular processes of the C5-C6 articulation.

The vertebral canal diameter is objectively assessed by determining the sagittal ratio.¹⁸⁷⁶ The sagittal ratio is obtained by dividing the minimum sagittal diameter of the vertebral canal by the width of the corresponding vertebral body. The minimum sagittal diameter is measured from the dorsal aspect of the vertebral body to the ventral border of the dorsal laminae, and the vertebral body width is measured perpendicular to the vertebral canal at the widest point of the cranial aspect of the vertebral body (Fig. 35-28). The sagittal ratio eliminates error caused by magnification because the vertebral canal and vertebral body are in the same anatomic plane. The sagittal ratio should exceed 52% from C4 through C6 and 56% at C7 in horses weighing more than 320 kg. The sensitivity and specificity of the sagittal ratio for identification of CVSM-affected horses are approximately 89% for vertebral sites C4 through C7.¹⁸⁸¹ Accurate measurement of the sagittal ratio requires a precise, lateral radiograph of the cervical vertebrae. Oblique views yield indistinct margins of the ventral aspect of the vertebral canal, resulting in erroneous values for minimum sagittal diameter and vertebral body width. Intervertebral ratios have been suggested to improve the ability to identify the site of spinal cord compression.¹⁸⁸² This measurement is obtained by determination of the minimum distance from the craniodorsal aspect of the vertebral body to the caudal aspect of the vertebral arch of the immediately rostral vertebra. This value is divided by the width of the vertebral body. Reference values for this technique have not been published.

Fig. 35-28 Survey radiograph of fourth and fifth cervical vertebrae. The sagittal ratio is determined by dividing the minimum sagittal diameter (double-headed arrows) by the width of the corresponding vertebral body (lines).

The semiquantitative scoring system developed by Mayhew et al.¹⁸⁸⁰ should be used in foals under 1 year of age to assess cervical radiographs for diagnosis of CVSM. The scoring system combines objective measurement of the vertebral canal diameter and subjective evaluation of vertebral malformation. Stenosis of the vertebral canal is assessed by determining the intervertebral and intravertebral minimum sagittal diameters. These values are corrected for radiographic magnification by dividing them by the length of the vertebral body (see Fig. 35-26). Foals that measure below the mean are assessed 5 points, and foals that measure 2 standard deviations (SD) below the mean or fall below the mean at multiple sites are assessed 6 to 10 points (Table 35-15). Cervical vertebral malformation is determined by subjective assessment of five categories: encroachment of the caudal epiphysis of the vertebral body dorsally into the vertebral canal; caudal extension of the dorsal lamina to the cranial physis of the next vertebra; angulation between adjacent vertebral bodies; abnormal ossification of the physis; and DJD of the articular processes. The maximum score allotted for each category of bony malformation is 5 points. A total score of 12 or higher (maximum, 25) confirms the radiographic diagnosis of CVSM. Stenosis of the vertebral canal and malalignment between adjacent vertebrae are the most discriminating parameters in this semiquantitative scoring system to differentiate CVSM-affected foals from normal foals.

Table 35-15 Mean Minimum Sagittal Diameters* and Corrected Minimum Sagittal Diameters of Cervical Vertebrae in Foals without Neurologic Disease

From Mayhew IG et al: Diagnosis and prediction of cervical vertebral malformation in thoroughbred foals based on semi-quantitative radiographic indicators, Equine Vet J 25:435, 1993.

SD, Standard deviation.

Survey radiographic examination of the cervical vertebrae determines the likelihood of spinal cord compression. Myelographic examination is required for definitive diagnosis of CVSM, identification of the location of affected vertebral sites, and classification of compressive lesions. The clinician should use radiographic interpretation to classify the patient into one of the following categories:

Myelographic examination is performed under general anesthesia with the patient in lateral recumbency.¹⁸⁸³ The landmarks for cisternal puncture at the atlantooccipital site are the cranial border of the wings of the atlas, the caudal border of the occipital protuberance, and the dorsal midline. The poll region is aseptically prepared and the head flexed at a 90-degree angle to the cervical vertebral column. The spinal needle (3½-inch, 18-gauge needle with stylet) is introduced and directed toward the lower jaw. The needle is advanced until the dura mater is penetrated, which often produces a “popping” sensation. Clear CSF should drip rapidly or flow from the hub with successful placement of the needle. An equal volume (20 to 40 mL) of CSF is removed before injection of a contrast agent. From 20 to 40 mL of contrast medium produces sufficient positive-contrast opacity to identify spinal cord compression in adult horses.¹⁸⁸³ The bevel of the spinal needle is directed caudally, and contrast medium is injected at a constant rate over 5 minutes. The head and neck are elevated under a wedged platform for 5 minutes at 30 to 45 degrees to facilitate caudal flow of the contrast medium. Iohexol (350 mg iodine/mL) and iopamidol (370 mg iodine/mL) are the most popular nonionic, water-soluble contrast media used for equine myelographic studies.^1884-1886 These second-generation agents cause less neurotoxicity and meningeal irritation than metrizamide.¹⁸⁸⁷

It is difficult for investigators to agree on myelographic criteria for definitive diagnosis of CVSM. In many cases the site of compression (or lack thereof) is obvious, and all recommended criteria would produce the same result. However, there is a population of horses for which myelographic interpretation is more difficult. Many reports recommend a 50% or greater decrease in the sagittal diameter of the dorsal contrast column, paired with obliteration of the ventral contrast column.¹⁸⁸³ The decrease in the sagittal diameter of the contrast column is determined by comparing the value at the intervertebral space to a midvertebral site cranial or caudal to the suspected intervertebral space. The 50% reduction should be interpreted conservatively, given the propensity for false-positive diagnosis; a 70% reduction may be more reliable.¹⁸⁸² Some investigators prefer to use a diagnostic criterion of less than 2 mm of dorsal contrast column (or smaller) to reduce false-positive results on myelographic studies, but this criterion will increase the risk of false-negative diagnosis. Most recently, a 20% reduction in dural diameter (height of dural sac) at a given intervertebral junction, compared with the dural diameter at the level of the midvertebral body, has been suggested as the most reliable indication of spinal cord compression.¹⁸⁸²

A complete myelographic examination should include neutral and stressed (flexed and extended) views of the cervical vertebrae.^1863,1883 Horses with dynamic spinal cord compression show obliteration of the dorsal and ventral contrast columns during ventroflexion of the neck (Fig. 35-29), whereas spinal cord compression is not apparent with the neck in the neutral position. Static vertebral canal stenosis is characterized by constant spinal cord compression regardless of cervical position (Fig. 35-30). In some cases of static compression, ventroflexion of the neck stretches the ligamentum flavum and relieves spinal cord compression, whereas hyperextension exacerbates compression. In horses with obvious sites of spinal cord compression on neutral myelographic views, excessive flexion and extension of the neck should be avoided while obtaining dynamic views to prevent exacerbation of spinal cord injury.

Fig. 35-29 Myelographic examination of C3 through C6 with the cervical spine in ventroflexion. Dynamic instability and spinal cord compression are present at the C3-C4 and C5-C6 articulations. The ventral contrast columns are obliterated, and the dorsal contrast columns are narrowed (to less than 2 mm) at C3-C4 and C5-C6 (arrows).

Fig. 35-30 Myelographic examination of C5 through C7 with the cervical spine in neutral position. Static spinal cord compression is demonstrated by obliteration or narrowing (to less than 2 mm) of the dorsal and ventral contrast columns at C5-C6 and C6-C7 (arrows).

Horses should be monitored for 24 hours after the myelographic procedure for depression, fever, seizure, and worsening of neurologic status.¹⁸⁸⁸ Worsening of neurologic status after myelography may result from spinal cord trauma during hyperflexion, iatrogenic puncture of the spinal cord, or chemical meningitis. Administration of phenylbutazone (4.4 mg/kg PO every 24 hours) 1 day before through 1 day after myelographic examination attenuates fever and depression associated with chemical meningitis.

Treatment

Conservative management of CVSM-affected horses consists of administration of antiinflammatory therapy (glucocorticoids, dimethyl sulfoxide [DMSO], and nonsteroidal antiinflammatory drugs [NSAIDs]) and exercise restriction. Antiinflammatory therapy alone may reduce the edema associated with spinal cord compression; however, full recovery is unlikely without dietary or surgical intervention.

The most successful conservative treatment option for CVSM-affected foals (<1 year of age) is the “paced diet” program.¹⁸⁸⁹ This program is designed to correct endocrine imbalance associated with high-carbohydrate diets. After a carbohydrate meal, high serum insulin and low serum thyroxine concentrations promote cartilage proliferation and retention without promoting maturation. This dietary program is restricted in energy and protein (65% to 75% of National Research Council [NRC] recommendations) but maintains a balanced vitamin and mineral intake (minimum 100% of NRC recommendations). Vitamins A and E are provided at three times the NRC recommendations, and selenium is supplemented to 0.3 ppm. Roughage is provided by pasture or low-quality grass hay (6% to 9% crude protein). Solitary stall confinement is recommended to minimize repetitive spinal cord compression from dynamic instability.

Horses with cervical pain and forelimb lameness caused by cervical vertebral arthropathy may benefit from intraarticular administration of corticosteroids and chondroprotective agents.^{1870,1890-1892} Arthrocentesis of the cervical vertebral articulations (facets) is performed with ultrasound guidance using a 6-inch, 18-gauge spinal needle in the standing, sedated, or recumbent horse.¹⁸⁹³ The cranial facet of the caudal vertebrae will appear superficial to the caudal facet of the cranial vertebrae. The articular space is accessed at the cranioventral opening of the articular facet, which is angled approximately 60 degrees from the ultrasound beam. The needle should be introduced 5 cm cranial to the facet and inserted at a 30-degree angle to the skin surface. Joint penetration should be confirmed by aspiration of synovial fluid. If the neck is extended, the transverse process of the cranial vertebrae may obscure the path to the articulation. Intraarticular triamcinolone (6 mg/joint) or methylprednisolone (100 mg/joint) has produced a positive clinical response in approximately 50% of horses with arthrosis of the articular processes. An antimicrobial agent (e.g., amikacin, 250 mg) can be administered prophylactically with intraarticular corticosteroids or chondroprotective agents. The goal of intraarticular antiinflammatory therapy should be to improve cervical mobility, reduce cervical pain, and eliminate forelimb lameness. It is unlikely that intraarticular therapy will significantly improve clinical signs of spinal ataxia.

Surgical intervention is the most widely reported treatment for CVSM and is indicated to stop repetitive trauma to the spinal cord.^1894-1897 The goals of surgical intervention are to stabilize the cervical vertebrae and decompress the spinal cord. Cervical vertebral interbody fusion (ventral stabilization) provides intervertebral stability for horses with dynamic spinal cord compression. The affected cervical vertebrae are fused in the extended position to provide immediate relief of compression and prevent repetitive spinal cord trauma (Fig. 35-31).

Fig. 35-31 Intraoperative radiograph of third and fourth cervical vertebrae during cervical vertebral interbody fusion. The stainless steel basket is placed in the ventral aspect of the vertebral bodies, spanning the intervertebral disk and vertebral endplates, at the C3-C4 articulation.

Dorsal laminectomy (subtotal Funkquist type B) is performed to decompress static lesions by removing portions of the dorsal lamina, ligamentum flavum, and joint capsule at the compressed site.¹⁸⁹⁵ This procedure provides immediate decompression of the spinal cord; however, fatal postoperative complications may occur.¹⁸⁹⁶ Interbody fusion in horses with static compression causes remodeling and atrophy of the articular processes, resulting in delayed decompression of the spinal cord over weeks to months.¹⁸⁹⁸ Decompression is immediate with dorsal laminectomy. Because of the relative safety of interbody fusion, however, some surgeons believe it is the technique of choice for both dynamic and static compressive lesions.¹⁸⁹⁶

Cervical vertebral interbody fusion improves the neurologic status in about half the horses with CVSM, with some horses returning to athletic function.^1894,1896 An improvement in one or two neurologic grades of five is expected. The most important patient factor for determining the postoperative prognosis is the duration of clinical signs before surgical intervention; horses with clinical signs for less than 1 month before surgery are more likely to return to athletic function than those with clinical signs for longer than 3 months.¹⁸⁹⁶ In addition, the number of compressive sites, severity of the compression, and severity of postoperative complications contribute to the long-term prognosis.¹⁸⁷⁰ Subtotal laminectomy and cervical vertebral interbody fusion for static compression of the caudal cervical vertebrae are associated with fatal postoperative complications, including vertebral body fracture, spinal cord edema, and implant failure.¹⁸⁹⁶

Postoperatively, horses should be maintained on strict stall rest for 3 weeks and fed from a hay net to minimize motion at the surgical site. Intraarticular injection of the intervertebral articulations with corticosteroids immediately after surgery may lead to more rapid decompression.¹⁸⁷⁰ The duration of convalescence and rehabilitation after cervical vertebral interbody fusion is approximately 6 to 12 months. An individualized exercise program, determined by the projected use of the horse and the animal’s neurologic status, should be designed to promote muscular strength. Extended exercise at slow speed, including ponying and lunging on inclines, is recommended during rehabilitation. A neurologic examination should be performed to determine the horse’s ability to return to athletic function after surgery. It is unlikely that significant improvement in neurologic status will occur beyond the 1-year postoperative period.¹⁸⁹⁶

Definition and Etiology

Equine degenerative myeloencephalopathy (EDM) is a symmetric, noncompressive spinal cord disease of young horses characterized by demyelination in the dorsal funiculi of the cervical spinal cord and in the brainstem.¹⁸⁹⁹ A similar disorder in which lesions are found only in the gracile and cuneate nuclei of the medulla oblongata also has been described, termed neuraxonal dystrophy to differentiate it from the more common EDM.¹⁹⁰⁰ Signs most often develop in horses less than 1 year of age (mean, 5 months), but onset of signs can occur as late as 12 years.^1899,1901 The incidence of EDM in Arabian horses is disproportionately high.¹⁸⁹⁹ The disease has been recognized in zebras, donkeys, Welsh ponies, and horses of the Przewalski, thoroughbred, standardbred, Appaloosa, quarter horse, Paso Fino, Paint, Haflinger, Norwegian Fjord, Trakehner, Hanoverian, and Morgan breeds.^1902-1909 EDM has also been observed in Mongolian wild horses.¹⁹⁰³

The disease may be related to a dietary deficiency of vitamin E, but EDM also has a familial pattern of distribution. These observations suggest a genetic etiology, but the mode of inheritance is not clear.¹⁹¹⁰

Clinical Signs

Affected horses show a symmetric proprioceptive (sensory) ataxia characterized by knuckling, stumbling, circumduction, abduction, interference, abnormal limb protraction, spasticity, hypermetria, and inability to turn sharply or lift the inside forefoot during sharp turns. When the animal is forced to turn sharply in a circle, the inside hindfoot pivots instead of lifting off the ground. Affected animals appear clumsy and cannot stop rapidly from a gallop. When stopped suddenly, they step on the rear of the forelimbs and end in a dog-sitting posture. Affected animals usually have severe conscious proprioceptive deficits that can be detected by postural placement tests. Some patients are unable to back or move easily down an incline. They may fall or stumble when light pressure is applied to the tuber coxae or withers. Signs are often more severe in the hindlimbs than in the forelimbs; in some cases, signs are only apparent in the hindlimbs.¹⁹¹¹

Other clinical signs that may be observed with EDM are deficits of the local cervical and cervicoauricular reflexes, absence of response to the “slap test”¹⁹¹² (see Chapter 8), and paralysis of the laryngeal adductor muscles. Absence of these findings, however, does not completely exclude a cervical spinal cord disease.¹⁹¹³ In rare cases, animals with EDM may present in acute recumbency without a prior history of neurologic disease (M.O. Smith, unpublished data).

The most important differential diagnoses for EDM are cervical stenotic myelopathy (“wobbler syndrome”), equine herpesvirus myeloencephalopathy, and equine protozoal myeloencephalitis.

Clinical Pathology and Radiographic Findings

EDM is best differentiated from cervical stenotic myelopathy by plain and contrast radiographic examination of the spinal column. The cervical spinal canal, CSF protein concentration, and white blood cell count of horses with degenerative myeloencephalopathy are normal. Serologic testing and CSF analysis is indicated to rule out herpesvirus and protozoal myelopathies. The acute clinical course of herpesvirus myelopathy and the presence of signs such as cranial nerve involvement and lower motor neuron lesions in protozoal disease help to differentiate these entities from EDM. The plasma vitamin E concentration may be below the reference range (1.70 to 10.50 μg/μL) in some unsupplemented affected horses.^1903,1904 For analysis, optimal methods of blood collection include collection of unhemolyzed blood in a clot tube and storage in an upright position in a refrigerator. The refrigerated specimens should not be allowed to contact rubber stoppers and should not be stored for longer than 72 hours unless the red cells are removed and the plasma is gassed with nitrogen and frozen at −16° C (3.2° F). The concentration of vitamin E in specimens handled in this manner remains constant for at least 3 months.¹⁹¹⁴

Pathophysiology

Some suggest that EDM is associated with a low plasma concentration of vitamin E from 6 weeks to 10 months of age.^{1904,1915,1916} Oral absorption of vitamin E does not appear to be deficient in affected horses.¹⁹¹⁶ Vitamin-replete, clinically normal horses have a plasma concentration ranging from 1.7 to 9.5 μg/mL; vitamin E concentration is approximately 2 μg/mL higher in the spring and summer than in winter. Horses fed diets that lack fresh green forage have a low plasma concentration of vitamin E. Such diets include poor-quality, sun-baked hay and pelleted rations. In one study testing vitamin E supplementation, the case-attack rate declined from 40% to 10% in the first year after supplementation, and the severity of disease in subsequent foal crops was diminished. Moreover, supplementation of five affected horses with 6000 IU vitamin E daily improved their neurologic condition. Horses’ susceptibility to development of low vitamin E concentrations also appears to be age related. Foals sired by affected stallions tend to have lower plasma α-tocopherol concentrations than those sired by normal stallions. These lower concentrations are first noted by 6 weeks of age, but the differences disappear by 10 months. The causes of the differences in the two groups of animals are unknown. An alternative explanation for the role of vitamin E in EDM is a defect in vitamin E absorption, transportation, or metabolism.¹⁹⁸⁰ The nature of such a defect has yet to be elucidated.

Vitamin E deficiency is apparently not the sole etiologic factor in EDM, however, because one report documented normal vitamin E levels in the sera of 40 affected horses examined at a veterinary hospital.¹⁹¹⁷ Subsequent epidemiologic studies indicated that risk factors for the disorder include heredity, application of insecticides on foals, exposure to dirt lots without pasture, and exposure to wood preservatives. Access to green pasture had a protective effect on foals.¹⁹¹⁶ This study may indicate that the changes in the central nervous system are related to the patient’s inability to respond adequately to oxidative stress such as phenols, anthelmintics, and insecticides. The key role of vitamin E as an antioxidant may explain the link between the disparate etiologies proposed for EDM.

The deficiency occurs most often in related horses, suggesting a genetic predisposition.^1900,1916 The importance of heredity in the development of EDM is supported by studies in a number of breeds, including Appaloosa, Haflinger, and Morgan horses.^{1900,1907,1918} A higher incidence has been documented in both foals sired by certain stallions and foals born to mares that already produced an affected foal.^1901,1904 However, the mode of inheritance is not clear.

Recent studies have indicated that a defect in axonal transport of proteins, particularly certain proteins vital to synaptic function, may be a key mechanism in the pathogenesis of EDM.¹⁹¹⁹

Pathology

The microscopic lesions are present throughout the spinal cord, involving both white matter and gray matter, and are most pronounced in the dorsal spinocerebellar tracts.¹⁹⁰³ These lesions include diffuse axonal degeneration of ascending and descending spinal cord funiculi and prominent myelin loss. Gliosis and astrocytosis develop in response to myelin breakdown. Horses with acute, rapidly progressive disease have evidence of active myelin destruction and vaculoation, whereas those with a more gradual course of disease have prominent astrogliosis. Considerable accumulation of lipofucsin-like pigment has been reported in some affected horses.¹⁹⁰⁹ The form of EDM termed neuraxonal dystrophy (e.g., in Morgan horses) is characterized by lesions almost entirely confined to the lateral caudate nucleus in the medulla. Because of the clinical signs in these horses, however, it is suspected that subtle lesions may be present within the spinal cord.

Treatment and Control

EDM is a chronically progressive disorder, although the clinical signs may stabilize after 2 to 3 years of age. The signs are irreversible, and most patients eventually are euthanized because they present a hazard to other livestock and humans.

Some improvement of clinical signs has been reported in horses treated with vitamin E. The current recommended vitamin E level for horse feed is 80 to 100 IU/kg/day.¹⁹²⁰ In suspected cases of EDM, supplementation with 6000 IU of D,L-α-tocopherol acetate in feed is recommended, a level that appears to be safe. This dose should be mixed with 60 mL corn oil and fed in 1 L concentrate ration daily.¹⁹²⁰ Once clinical signs are present, the prognosis for complete recovery is guarded to poor. Supplementation has been recommended for foals at risk of developing the disease (e.g., family history of EDM) and foals maintained on poor-quality pasture.^1904,1916

Clinical Signs

Affected animals are adults with a mean age of 9 years (range, 2 to 23 years).¹⁹²³ Clinical signs vary depending on the stage or duration of the disorder; therefore the signs are best summarized by dividing the disease into subacute and chronic forms. A subclinical form also occurs, although these cases cannot be currently diagnosed antemortem.

Clinical Pathology

Horses with acute or subacute EMND have mild to moderately elevated levels of creatine kinase (CK) and aspartate transaminase (AST). The serum vitamin E is low (<1 μg/mL) in almost all acute and subacute cases. Levels of α- and γ-tocopherol are low in the gray matter of affected horses. Superoxide dismutase (SOD) activity in red blood cells also is severely decreased, believed to result from increased consumption of SOD. Other clinicopathologic abnormalities may be present in particular individuals, including elevated serum γ-glutamyltransferase (GGT) activity; low vitamin A, β-carotene, and ascorbic acid levels; and high liver iron and spinal cord copper levels. Many horses have abnormal glucose absorption, and some have enhanced glucose utilization.¹⁹²⁴ This supports the observation that many horses have ravenous appetites and that most have normal fat deposition at necropsy.

The protein CSF level is elevated in almost half of affected horses, and intrathecal immunoglobulin G (IgG) is increased in many cases. Increased IgG is thought be a response to neuronal death rather than a primary pathophysiologic event.

Pathophysiology

The sites of lesions in EMND are the ventral horn cells (lower motor neurons) of the spinal cord gray matter; the nuclei of cranial nerves V, VII, and XII; and the nucleus ambiguous; all undergo noninflammatory degeneration. Neurogenic atrophy occurs in muscles innervated by degenerate neurons, particularly those with predominantly type 1 myofibers, which have a higher oxidative requirement than type 2 fibers and thus are more susceptible to oxidative damage. The dysfunction and death of motor neurons is an oxidative disorder, presumably caused by vitamin E deficiency and the resulting inability to protect against oxidative (prooxidant) stress. Clinical signs occur when approximately 30% of the motor neurons are affected.¹⁹²⁵ Some of these neurons may regain function with vitamin E treatment, which may explain why some horses do not have continual progression of clinical signs, as occurs in ALS in humans. Human motor neuron disease, although an oxidative disorder, is more complex that EMND, and the causes have yet to be determined.

Pathology

Gross lesions are limited to pallor of the medial head of the triceps brachii and vastus intermedius muscles. Severe atrophy is present in these muscles and many others, including the sacrocaudalis dorsalis medialis muscle of the tail, which shows severe denervation atrophy and fibrosis. Scattered areas of myofiber necrosis are present in many muscles. A pigment retinopathy¹⁹²⁶ and deposition of lipopigment in the spinal cord vasculature are found in horses with EMND, apparently related to similar pigment depositions in other species with vitamin E deficiency. A vitamin E–supplemented diet may result in resolution of pigment deposition in the spinal cord vasculature but not the retina.

Epidemiology

EMND is a sporadic disease, with only single animals in a barn usually affected, although a few outbreaks of the disease have been reported. All breeds of horse can be affected, as can ponies. The apparent prevalence of EMND in certain breeds probably reflects the prevalence of the breed in specific populations of horses, and no familial or heritable predisposition has been identified. Affected horses usually are housed in facilities with little or no access to pasture for more than a year before signs appear.^1923,1927 The diet of affected animals in North America is deficient in green foodstuffs and frequently consists of pelleted or sweet feed and poor-quality grass hay, without alfalfa or other sources of vitamin E supplementation.^1928,1929 In the United Kingdom a few horses with EMND have been on pasture, have no laboratory or necropsy evidence to support malabsorption, but are deficient in vitamin E.¹⁹³⁰ The explanation for this remains elusive. No other management practices, such as worming and vaccination regimens, insecticide use, amount of exercise, or type of bedding, have been related to development of the disease. The highest prevalence of EMND in North America occurs in the northeastern United States and Canada, although sporadic cases have been reported across the continent. This regional distribution is believed to relate to the frequency of predisposing management practices in high-incidence areas rather than other environmental factors.

Diagnosis

The diagnosis of EMND can be made from the following observations and testing:

Treatment

Oral vitamin E supplementation at 5000 to 7000 IU daily may result in improvement in some clinically affected horses, although full recovery is unlikely. This therapy cannot reverse the neuronal death, and all affected horses are permanently weakened. Use of a source of pure vitamin E is preferable to a multi–vitamin-mineral supplement. Natural vitamin E products are preferred over synthetic products, but both will raise serum levels.

Prevention

All horses without green forage (grass of good quality or green hay) for prolonged periods (>1 year) should be routinely tested for the plasma vitamin E concentration and supplemented with vitamin E. If this were a standard policy, most if not all cases of EMND could be prevented.

Definition and Etiology

Vertebral fractures are relatively common causes of spinal cord injury in food animals. In horses with various neurologic disorders, however, spinal fractures represented only about 3% of cases in two studies.^1933,1934 Because of differences in management, temperament, and regional spinal strength, the pathogenesis and predominant anatomic location of spinal injury sites differ among the livestock species.

Clinical Signs

The clinical presentation of a spinal fracture varies, depending on the site of the traumatic lesion, severity of the spinal cord compression, and involvement of specific anatomic tracts.

LUMBAR SPINE

Animals with lumbar injury have an attitude, gait, and posture similar to those with thoracic lesions. Fig. 35-32 shows the characteristic posture of a calf with a fracture at the L6 vertebra. Fig. 35-33 illustrates myelographic findings of cord compression at L6. The forelimbs are normal. Lesions at the L1 to L3 spinal cord segments result in normal or hypertonic and hyperreflexic hindlimbs. Conversely, hypotonia and hyporeflexia of the hindlimbs may be seen in animals with lesions at segments L4 to S2.¹⁹⁵⁰ Marked spasm of the longissimus dorsi muscle has been described in horses with a lesion between the T11 and T12 segments.¹⁹⁵¹ Lesions of segments L4 to L6 result in cutaneous desensitization of the medial surface of the rear leg and diminished or absent patellar reflex because of dysfunction of the femoral and saphenous nerves. Lesions of segments L6 to S2 result in desensitization of the hindlimb and diminished withdrawal (flexor) reflexes. The panniculus response is absent when the skin posterior to the lesion is stimulated. Damage to the spinal rootlets may cause regional swelling. Tail tone and anal tone are normal. The bladder is distended, but the sphincter tone is normal.

Fig. 35-32 Characteristic posture of a calf with a compressive fracture of the sixth lumbar (L6) vertebra and hematomyelia. The calf was fed a diet of grass hay and corn and developed nutritional osteodystrophy.

Courtesy Dr. R.H. Whitlock.

Fig. 35-33 Myelogram of a calf with nutritional osteodystrophy showing a mild compression fracture of the L6 vertebra and complete obstruction of dye flow posterior to L5 (arrow).

Clinical Pathology and Radiographic Findings

Radiography is the usual method of diagnosing a spinal fracture. In young horses, slipped physeal plates are often seen in the atlas.^1951,1953 Shortening of the lumbar vertebrae is consistent with either an oblique overriding fracture of the vertebral body or a compression fracture.^1950,1953 Abnormally shaped vertebrae may signify an anomalous vertebral arch. Myelographic examination may detect stenosis in segments distant from the fracture site.¹⁹⁵⁴

Examination of cerebrospinal fluid (CSF) collected through a lumbosacral puncture may be useful for ancillary diagnosis of a spinal fracture. Fracture-induced changes in the CSF may be classified as either acute (0 to 1 day) or chronic (>1 day). The acute changes include diffuse blood contamination, a high red blood cell (RBC) count, a normal to high white blood cell (WBC) count, and a high protein concentration. The CSF changes in patients with more chronic injuries include a normal to slightly increased WBC count, normal to increased RBC count, increased protein concentration, and xanthochromia. These changes are not pathognomonic for spinal fracture, however, so should be interpreted with caution.

Pathology and Pathophysiology

Neurologic dysfunction after spinal trauma is similar to that of brain trauma and is a result of both immediate and secondary events. Immediate causes of injury include shearing forces that result in tearing of tissue, hemorrhage, and impingement of bone fragments on the spinal cord, particularly when the fracture is unstable. Trauma initiates a cascade of secondary biochemical events that further injure nervous system tissue, including adenosine triphosphate (ATP) depletion, which deprives cells of their ability to maintain their ionic environment through the action of sodium-potassium ATPase pumps. Rapid intracellular accumulation of calcium and sodium ions causes cytotoxic edema and neuronal depolarization. Release of the excitatory neurotransmitter glutamate and activation of the arachidonic acid and xanthine oxidase pathways further compound cellular damage. Other injurious substances generated after traumatic injury include nitric oxide, oxygen free radicals, lactic acid, arachidonic acid metabolites, and a variety of cytokines. Local vasogenic reflexes, mostly mediated by α-adrenergic receptors, result in decreased blood flow in the gray and white matter. Platelets aggregate in the hypoperfused capillaries and form microthrombi and infarcts. Regional ischemia caused by hypoperfusion results in lipid peroxidation of the axons, myelin degradation, and demyelination.¹⁹⁵⁵

Treatment and Prognosis

It is important to recognize that the radiographic appearance of a spinal fracture is not a reliable prognostic indicator, because the vertebral components are likely to be in a different position from that at the time of injury. Not all vertebral body fractures result in neurologic disease. The prognosis is best judged on the basis of repeated neurologic examinations. Provided the animal is not suffering inhumanely and the pain can be adequately controlled, repeated neurologic examinations should be made over the first several hours. The longer the patient remains recumbent and neurologically impaired, the more unfavorable the prognosis.

The mainstay of immediate treatment of spinal injuries is maintaining whole-body homeostasis, particularly the maintenance of cardiovascular integrity and blood pressure.¹⁹⁵⁶ Ischemia local to the spinal cord plays a key role in development of the injury, but global cardiovascular failure compounds this effect. Most recoveries from spinal cord contusion occur spontaneously and are not appreciably influenced by drug administration. Some recommend treating acutely affected animals with DMSO (0.25 to 1 g/kg IV in 5% dextrose as a 40% DMSO solution) and dexamethasone (0.1 to 0.2 mg/kg four times daily for 2 to 4 days), but supportive data from controlled studies are not available. Analgesics or tranquilizers should be administered with care to ambulatory patients that have thoracolumbar spinal lesions because an ataxic patient may slip and worsen the spinal cord contusion. If signs of pain are severe, NSAIDs or narcotic analgesics may be administered. Epidural catheterization can be an effective method for delivery of analgesics over several days in animals with severe pain.¹⁹⁵⁷ In animals with pelvic lesions, the bladder should be evacuated either by manual palpation per rectum or by insertion of a catheter and use of a closed urinary drainage system. Attention to aseptic procedure during catheter maintenance may reduce the number of iatrogenic bacterial infections. The urine should be cultured and examined repeatedly. Bladder infections should be treated with an appropriate antibiotic. In animals with paralysis of the rectal musculature, the feces should be removed manually. Lubricants (1 to 2 quarts of warm detergent or methylcellulose) may be administered with an enema.

If the spinal fracture appears stable and the animal can stand with assistance, the patient may be placed in a water tank and supported for prolonged periods. Goats are most amenable to treatment for spinal fractures, whereas adult horses and cattle may present insurmountable nursing problems and should be euthanized if they are unable to rise after several days or have intractable pain. Slings are commercially available or can be fashioned from canvas or burlap and wool or cotton. The time spent in the sling varies, depending on the animal’s temperament and degree of neurologic dysfunction. Some horses become frantic while suspended in the device and cannot be supported without the risk of severe injury to the patient and the handlers. The sling should not be used for recumbent animals that cannot support themselves while harnessed. Such animals can sustain severe (even fatal) respiratory compromise or secondary myositis. Nevertheless, daily slinging of animals with mild neurologic signs may reduce secondary medical complications and facilitate recovery.

Recumbent cattle should be floated in a tub of warm water. Watertight tubs for use with large cattle are commercially available* (see Down Cows at end of chapter).

Cervical fractures and luxations of small ruminants may be stabilized by incorporation of the head, neck, and anterior thorax in a fiberglass cast. The cast should extend from the middle part of the thorax to the tip of the nose. The feed and water supply of all animals with cervical fractures should be placed so that the animal can reach it without bending the neck. Surgical methods for stabilization of cervical fractures have been described in horses. The effectiveness of such treatments for restoration of neurologic function after traumatic injury or fracture of the spinal column is variable, but good results may be achieved when presurgical signs are mild and the repair is stable.^1958-1961

Fractures of the dorsal spinous processes, transverse processes, and some small, oblique fractures of vertebral bodies may produce minimal instability of the spine. Such injuries may respond well to conservative treatment, such as stall confinement. Bone sequestra can result in the formation of draining tracts, however, and may require surgical removal to facilitate healing.¹⁹⁶²

The dietary intake of copper, molybdenum, and calcium should be measured in cattle. If the daily intake is inadequate, the minerals should be fed in supplements. Animals with metabolic bone disease should not be restrained because of the risk of inducing additional pathologic fractures.

Definition and Etiology

Most abscesses of the spinal cord originate from a preexisting vertebral body osteomyelitis. The bone usually is infected hematogenously. Extension of bacteria from the lungs, the heart, or a septic injection site is common. Neonates frequently develop vertebral abscesses secondary to septicemia.^1965,1966 Bone lesions may develop from sequestra broken from fractured vertebrae. Epizootics of spinal abscesses can result from injection of contaminated vaccines or mineral supplements near the spinal column. Similarly, spinal abscesses may be seen along with other diseases in groups of animals that are immunocompromised, such as cattle with bovine immunodeficiency virus infection.¹⁹⁶⁷ Infectious agents isolated from spinal abscesses of ruminants include Corynebacterium pseudotuberculosis, Aracanobacterium pyogenes, Mannheimia haemolytica, Staphylococcus aureus, and Fusobacterium necrophorum.^{1965,1968-1970} Agents typically found in vertebral infections of foals include β-hemolytic streptococci, Salmonella species, Actinobacillus equuli, Escherichia coli, Rhodococcus equi, and Klebsiella pneumoniae.^1970-1974 Agents less often associated with vertebral body osteomyelitis of horses and cattle include Mycobacterium bovis, Mycobacterium avium, Aspergillus species, Eikenella corrodens, and Brucella abortus.^1975-1977 In rare cases, septic arthritis of the atlantooccipital joint may result from extension of a mycotic guttural pouch lesion.^1978,1979

If the infectious agent remains localized in the vertebral body, the patient usually shows signs consistent with a transverse myelopathy. If the infection erodes through the dura mater, the animal develops signs of septic meningitis. If the bone infection is extensive, the vertebrae may fracture suddenly, resulting in signs characteristic of spinal trauma.

Clinical Signs

The neurologic deficits of animals with vertebral body abscesses without pachymeningitis are similar to those described previously for spinal fractures.¹⁹⁶⁹ Animals with mildly compressive cervical abscesses show a characteristic “weather vane” attitude, appear stiff, and are reluctant to eat food from the ground.^{1969,1971,1972} Ruminants with this lesion hold the neck in extension and attempt to prehend the food with the tongue while the head is held more than 30 cm (12 inches) from the ground.¹⁹⁶⁹ Additional signs of spinal abscess include heat, pain, swelling, or crepitus over the affected areas and associated signs of bacteremia. Abscesses in the thoracolumbar spine cause hindlimb weakness and ataxia of variable severity, from mild gait abnormalities to complete recumbency. Stud males may be unable to breed because of weakness and pain.¹⁹⁸⁰ Animals with pachymeningitis show characteristic signs of meningeal inflammation such as hyperesthesia, intermittent spasmodic muscle contractions, and recurrent profuse sweating^1971,1975 (see earlier section on meningitis). Differential diagnoses include trauma, aberrant parasite migration, tumor and pathologic fractures, hemorrhage into or around the spinal cord (e.g., postanesthetic myelopathy), myopathies, caprine arthritis-encephalitis, and fibrocartilaginous embolism.¹⁹⁸¹ Spinal abscesses can be mistaken for other painful conditions, such as orthopedic disorders or traumatic reticuloperitonitis.¹⁹⁸²

Clinical Pathology and Radiographic Findings

Radiographs are the best method for obtaining a definitive diagnosis of spinal abscessation. A random pattern of hyperlucency and increased bone density characteristic of osteomyelitis is seen in the affected vertebrae, with or without adjacent soft tissue mass lesions indicative of abscessation^1976,1983 (Fig. 35-34). Diskospondylitis usually results in detectable osteolysis in the intervertebral joints.¹⁹⁷¹ Occasional cases of extradural abscesses without radiographic evidence of osteomyelitis have been described in calves and lambs.¹³³¹ Nuclear scintigraphy can be used when the bone lesions are not well defined in plain film radiography.¹⁹⁷⁷ In addition, myelography can be used to detect the specific site of the spinal cord compression.

Fig. 35-34 Cervical radiograph of a sheep with osteomyelitis and diskospondylitis at the C2-C3 intervertebral space (arrows). The sheep recovered fully after application of a full-length cast of the head, neck, and trunk and after continuous therapy with parenteral penicillin G for 1 month.

A complete blood count (CBC) may indicate the presence of a chronic inflammatory focus. Specific changes in the CBC include hyperfibrinogenemia, neutrophilia, monocytosis, nonresponsive anemia, and left shift. The plasma globulin levels are increased in adults but may be increased or decreased in neonates, depending on the adequacy of colostral immunoglobulin transfer.

The changes in the cerebrospinal fluid (CSF) depend on the location of the abscess in the nervous system tissue and the meninges. Changes are present in CSF caudal to the lesion, but not cranial to the lesion; thus, CSF should be obtained by lumbar puncture and not cisternal puncture.¹⁹⁸¹ In most cases the abscess does not infiltrate through the pachymeninges, and the CSF is normal or shows xanthochromia and mild increases in the protein concentration (60 to 120 mg/dL), with mild to no increase in nucleated cell count.¹⁹⁸⁴ The CSF of animals with pachymeningitis contains high numbers of WBCs (>100 neutrophils/μL) and a greatly increased protein concentration (>200 mg/dL). The CSF may clot after collection because of high concentrations of fibrinogen. Bacteria may be observed in a Gram-stained smear of CSF sediment. Horses with spinal brucellosis may have a rising serum agglutination titer or one above 1:160.¹⁹⁷⁵ Because of a high number of nonspecific reactions in equine sera, titers below 1:40 are considered nondiagnostic.¹⁹⁸⁵ Horses with spinal tuberculosis may be identified by an intradermal skin test using purified protein derivative or tuberculin.¹⁹⁷⁶

Pathophysiology

Hematogenously derived abscesses arise because of embolization of septic thrombi into the metaphyseal arteries. These vessels have a sluggish blood flow because they become tortuous as they approach the physis. The metaphyseal vessels communicate with the ventral vertebral plexus, which in turn drains into the post cava, the portal vein, and the pulmonary veins. The ventral vertebral plexus does not have valves; blood flow reverses with an increase in abdominal or pleural pressure. Regurgitated blood from infected sites in the body cavities showers the vertebrae and spinal cord with bacteria.^1968,1977

Necropsy Findings

The most common sites of involvement are the costovertebral and intervertebral articulations and the vertebral body epiphyses.¹⁹⁸⁶ Lumbar vertebrae frequently are involved. The bone is uneven, deformed, and softened. The abscessed area is interspersed with calcified trabeculae and pockets of necrotic debris. Sequestration of necrotic bone may be seen in some cases. The meninges may be adherent to the abscessed site, and occasionally a fistulous tract may be seen from the center of the abscess pocket to the subarachnoid space. In other cases the abscess is compartmentalized away from the CSF, but the proliferating bone impinges on the spinal cord.

Treatment and Prevention

If spinal abscessation is recognized early, prolonged antimicrobial therapy generally is effective. Selection of the appropriate antimicrobial agents should be based on the results of cultures from the patient’s blood, urine, feces, and CSF. When bacteriologic culturing is inconclusive, a broad-spectrum antimicrobial should be chosen. Amikacin (7.5 to 10 mg/kg IM four times daily) or gentamicin (1 mg/kg IM three times daily) combined with potassium penicillin G (10,000 IU/kg IV three or four times daily) should be administered. After 1 or 2 weeks of this therapy, a trimethoprim-sulfonamide combination (2 to 3 mg/kg trimethoprim, 10 to 15 mg/kg sulfadiazine PO twice daily) in horses or procaine penicillin G (10,000 to 20,000 IU/kg SC or IM daily) in cattle can be administered for 2 to 3 months.

Small ruminants with cervical diskospondylitis may show a good response after 2 to 4 weeks of procaine penicillin G (10,000 IU/kg IM twice daily). Phenylbutazone, flunixin meglumine, or aspirin may be administered for pain relief. Immobilization of the head and neck in a fiberglass cast extending from the thorax to the nose may provide support to smaller patients with a cervical abscess. Surgical drainage of the abscess and curettage of the necrotic bone may be feasible in smaller animals with sufficient economic value to justify the procedure.^1974,1987 Surgical intervention in adult cattle and horses is usually difficult because of the size of the epaxial musculature and the inaccessibility of the spine in large animals.

Clinical Signs

The clinical signs of tumorous invasion are indistinguishable from those described previously for spinal fractures. The onset of the neurologic dysfunction varies. Some neurofibromas, melanomas, and lymphosarcomas invade centripetally along the peripheral nerve rootlets. These patients develop slowly progressive dysfunction of the peripheral nerve or spinal cord, which eventually leads to tetraplegia or paraplegia (Figs. 35-35 and 35-36). In rare cases the onset of tetraplegia in cattle with a neurofibroma or lymphosarcoma may be peracute and unaccompanied by prodromal neurologic symptoms. Lymphosarcoma has a predilection for the lumbar segments of the spinal cord and the cauda equina in cattle over 5 years of age. A diagnosis of tumorous spinal invasion should be considered in cases of progressive neurologic disease characterized by flaccid tail and anus, dysuria, urine scalding, distended bladder, perineal analgesia or anesthesia, and paraparesis. Although most animals with spinal tumors are mature to older adults, immature animals can be affected rarely, mainly by embryonal tumors.^{1994,1999-2001}

Fig. 35-35 Characteristic appearance of a paraplegic cow with lymphosarcoma of the L6 to cauda equina spinal rootlets and the cauda equina.

Courtesy Dr. R.H. Whitlock.

Fig. 35-36 Spinal cord from a cow with lymphosarcoma. The mass is an accumulation of neoplastic lymphocytes that surround the spinal rootlets, filum terminale, and cauda equina.

Clinical Pathology

Examination of CSF may be useful when the tumor has infiltrated the cauda equina and is located in the lumbosacral cistern. In these cases, tumor cells may be biopsied as the needle is inserted into the lumbosacral space. In other cases the CSF may be normal, or albuminocytologic dissociation can be expected (elevated CSF protein with normal to mildly elevated nucleated cell count) with or without variable degrees of hemorrhage and xanthochromia. After necropsy, various immunohistochemical techniques can be used to identify the tumor type when routine histologic examination is insufficient.^2000,2001

Treatment

There is currently no treatment for most spinal tumors of large animals. One study reported survival of 57 days after three treatments with L-asparaginase at 10,000 IU/m². The body surface area was estimated using the following formula:

where 10^b is a constant that is routinely used for the calculation of surface area in dogs.

The nearly 2-month period of survival allowed the investigators to successfully superovulate the cow. When treating food animals with L-asparaginase, the benefits of the antimetabolite drug must be weighed against the potential for teratogenicity of the fetus, toxicity for humans, and the certainty of relapse in the patient.²⁰⁰²

HORSES

Strongylus vulgaris Migration

Migration of S. vulgaris in the CNS causes two major clinical syndromes: acute embolization of parasitic emboli and slow perivascular migration of living parasites in the CNS. The two forms have a common pathogenesis. Aberrantly migrating fourth-stage or fifth-stage larvae in the intima of the aorta or left ventricle damage the endothelium, stimulate the clotting cascade, and cause formation of a thrombus that often contains the parasitic larva.²⁰²⁰ Embolization of the thrombus to the brain results in fulminating encephalitic signs.²⁰⁰⁹ As the embolus is degraded, the parasite migrates from the blood vessel into the CNS, resulting in the progressive brainstem disease. The cranial brainstem (diencephalon) is most often affected. The thrombosis and migration are accompanied by multifocal infarction, edema, hemorrhage, and necrosis²⁰⁰⁷ (Fig. 35-37). Microscopic findings include linear tracts of hemorrhage lined by neutrophils, macrophages, eosinophils, and reactive glial cells. Anesthesia of the hindquarters has been described in some affected horses.²⁰¹⁰ Donkeys are also susceptible to the aberrant migration.²⁰²⁹ CSF changes associated with S. vulgaris migration in equids include xanthochromia, refractive index over 1.3353, protein concentration ranging from 32 to 550 mg/dL, and increased WBC count (42 to 10,000/μL). The differential counts range from 70% to 80% neutrophils, 12% to 19% mononuclear cells, and 1% to 2% eosinophils.

Fig. 35-37 Parasitic lesions in the brainstem of a horse. The arrows indicate the major lesion, but other, smaller lesions are distributed over the entire brainstem.

Courtesy Dr. R.H. Whitlock.

Hypoderma lineatum and Hypoderma bovis (Warble Flies)

Hypoderma lineatum and H. bovis are parasites that typically affect cattle but occasionally migrate aberrantly in the horse. Warble flies hatch from pupae in the early spring and mature during the summer. The flies deposit the eggs of H. lineatum on the lips, where they hatch and are swallowed. The ingested worms burrow through the intestine and along the adventitia of blood vessels until they reach the CNS.²⁰⁰⁸ The flies deposit the eggs of H. bovis on the legs, where they hatch and burrow into the skin. The subcutaneous parasites then migrate as first-instar larvae to the spinal column, where they penetrate the epidural space along the peripheral nerves.²⁰⁰⁴ Peroneal nerve paralysis from a local parasitic invasion has been reported in a pony.

Micronema deletrix

Micronema deletrix is thought to be a free-living rhabditid nematode that gains access to the CNS by penetration through the skin of the face and the lips, gums, and tongue.^2005,2006 The parasites migrate into the brain through the vascular system and cause diffuse encephalitis. Nematodes are found in the tunica adventitia and tunica media of blood vessels.²⁰⁰⁵ Clinical signs of M. deletrix depend on the localization of the parasite. Spinal cord invasion is apparently less common than migration through the brainstem, cerebellum, thalamus, forebrain, and deeper layers of the cerebral cortex. Clinical signs include asymmetric ataxia, loss of conscious proprioception, depression, behavioral changes, propulsive walking, head pressing, head tilt, circling, nystagmus, recumbency, convulsions, and coma. Affected animals may have granulomatous masses in the nares, pharynx, and maxilla. These could be helpful in formulating a differential diagnosis when parasitic migration is suspected. CSF changes in affected horses include pleocytosis (25 to 80 nucleated cells/μL), a normal to high protein concentration (69 to 114 mg/dL), and xanthochromia.²⁰⁰³ The cellular types were mostly lymphocytes and macrophages ranging from 78% to 91% of the nucleated cells. Eosinophils were observed in the CSF of one horse.

Draschia megastoma

Draschia megastoma has been found in the brainstem of a horse from the southern United States.²⁰¹¹ The adult worm is embedded in a pyogranulomatous lesion of the equine stomach, and the eggs are shed into the stomach. They hatch in the small intestine to form first-stage larvae, which are passed in the feces and ingested by the larvae of Musca flies. The third-stage larvae migrate to the mouthparts of the fly and are deposited on the mucous membranes of the host as the fly feeds.

Setaria

Setaria parasites are common filarid parasites of cattle that migrate aberrantly when they infect horses, sheep, or goats. These parasites have a worldwide distribution, and clinical cases are especially common in India and the Orient, where the common name for the disease is “kumri” (weak back).²⁰²⁵ There are at least four Setaria species, of which S. equina, S. digitata, and S. labiatopapillosa are most common. The parasite is found in the connective tissues and peritoneal cavity of cattle, where it produces circulating microfilariae. Mosquitoes and possibly other bloodsucking insects become infected by the microfilariae and thus transmit the parasite.²⁰²⁴ The parasite has a predilection for the spinal cord in horses. The clinical signs of reported cases include hypotonic tail, bladder paralysis, ataxia, and conscious proprioceptive deficits.²⁰¹² Changes in the CSF associated with Setaria infestation include xanthochromia, pleocytosis (25 to 84 cells/dL), and a slightly increased protein concentration (∼114 mg/dL). The cells of one horse contained a small proportion of eosinophils and basophils, but this finding was inconsistent with other reports.²⁰⁰³

SHEEP AND GOATS

Parelaphostrongylus tenuis

Disease caused by P. tenuis occurs predominantly in sheep and goats of the northeastern United States and western Canada.^{2013,2016,2018,2019} The case-attack rate ranges from 10% to 59%.²⁰¹⁴ The disease appears to be spreading because of the increased range of the primary host, the white-tailed deer. Migration of the parasite in the CNS of deer is relatively innocuous, but aberrant migration occurs in domestic small ruminants. The result of this migration is severe signs of spinal cord and brainstem disease.²⁰¹⁴ The life cycle of the worm is complex. Adult worms are found in the cranial subarachnoid space, venous sinuses, and spinal subarachnoid space of the deer, where they reproduce.²⁰¹⁵ Eggs are deposited into the venous blood and migrate into the lungs, where they embryonate. The larvae penetrate into the airways and are coughed into the pharynx, swallowed, and passed in the feces. They then penetrate into snails and slugs. Sheep and goats are infected when they eat the snails. After ingestion by the ruminant, the larvae penetrate the gastrointestinal wall and enter the CNS by migration along the nerve rootlets. Because of the complex life cycle of the parasite and the indirect life cycle in invertebrate hosts, the neurologic disease in sheep and goats is seen exclusively in late fall and winter. The pathologic lesions of the CNS of affected animals include asymmetric irregular tracts of disrupted necrotic tissue with macrophage infiltration. Coiled larvae occasionally may be seen in the tissues of some affected animals and may be excreted in the feces; however, these are difficult to distinguish from the larvae of Müllerius worms.

The clinical signs of P. tenuis infection are acute. In untreated animals the disease is progressive. The CSF of animals with Parelaphostrongylus infection contains increased concentrations of protein (56 to 157 mg/dL), RBCs (300 to 41,000/μL), and WBCs (17 to 700/μL). The differential cell counts contain a large number of eosinophils (7% to 97%).²⁰³⁰

CATTLE

Setaria digitata

Infection of the spinal cord of cattle by S. digitata has been described in India.²⁰¹⁷

Diagnosis of Parasitic Infestation of Central Nervous System

Parasitic myeloencephalopathy must be considered in all cases of acute asymmetric disease of the spinal cord, cerebellum, or brainstem. Identification of eosinophils in the CSF may be helpful; however, this pattern is not seen in every neuroparasitic diseases. For example, Hypoderma infestations often are extradural, and CSF changes reflect only increased pressure. The CSF of horses with acute S. vulgaris migration could be normal or could show xanthochromia, increased concentrations of RBCs or WBCs, and increased protein concentration.²⁰⁰⁹

Treatment

Although severe reactions often are associated with death of the CNS parasites, administration of parasiticides in conjunction with heavy antiinflammatory therapy is recommended. Such treatment prevents further migration of the parasite yet mitigates the host inflammatory responses.

The recommended treatment for neural S. vulgaris infection is either thiabendazole (440 mg/kg PO daily for 2 days) or mebendazole (30 mg/kg daily for 2 days). Horses should also be given a combination of corticosteroids and NSAIDs for 10 days after administration of the parasiticides.

Some experts speculate that ivermectin may be a valuable broad-spectrum treatment for all CNS parasitic infections. The drug has a prolonged plasma half-life after parenteral or oral administration (2.7 days) and may exert an antiparasitic effect for as long as 14 to 21 days after subcutaneous administration.^2031-2033 Although ivermectin diffuses across the blood-brain barrier, the plasma concentrations after oral administration are low, and the drug should be administered parenterally to achieve optimum efficacy. Unfortunately, significant side effects occur (0.92% overall adverse reaction rate) after parenteral administration to horses.^2034,2035 Consequently, until ivermectin is proved to be effective by pharmacologic and clinical studies, alternative parasiticides should be considered for initial treatment of parasitic CNS disease in horses.

Clinical Signs

Spastic paresis is characterized by intermittently increased extensor tonus in the pelvic limb as the animal attempts to walk.^{2127,2131,2136,2141} The gastrocnemius and superficial digital extensor muscles are spastically contracted in all calves, whereas the biceps femoris, adductor, quadriceps, semitendinosus, and semimembranosus muscles are less often affected.^{2128,2131,2141,2142} The extensor tone is normal when the calf is recumbent and relaxed but becomes excessive when the animal stands and attempts to bear weight. The excessive extensor motor activity results in an inability to flex the hock during protraction of the pelvic limb. To prevent the toes from dragging, the limb is circumducted, resulting in a pendulum-like motion.²¹⁴² At rest the limb is held stiffly abducted and is repeatedly circumducted. The foot is held off the ground, and the gastrocnemius muscles appear to be underdeveloped. The tail is elevated from the ischiorectal fossa as the animal attempts to move. Eventually there is atrophy of the hindquarters. The spasticity is progressive, and affected animals experience difficulty rising and grazing. If untreated, the animals are stunted and usually are culled.

The excessive pull of the extensor tendons produces radiographically detectable changes in the bones of the hock, including osteoporosis, lipping of the dorsal aspect of the tibial epiphysis, plantar displacement of the proximal part of the tibial diaphysis and epiphysis, and excessive straightening of the tuber calcis.^{2127,2128,2143}

The etiology and pathogenesis of spastic paresis are unknown. Some investigators have documented the presence of subtle demyelinating lesions of the red nucleus but were unclear about the contribution of these changes to the clinical syndrome.^2132,2134 Changes observed in affected calves include nonsuppurative encephalitis and reduced concentrations of dopamine and 5-homovanillic acid in the cerebrospinal fluid.²¹⁴⁴ There are no histologic or biochemical alterations of the myofibrils.²¹⁴⁵ Neuropharmacologic studies have indicated that the disease may be related to overstimulation of the gamma motoneurons of the spinal cord.²¹⁴⁶ A genetic basis for the disease has been postulated because affected offspring tend to have a common paternity^{2127,2130,2132}; however, breeding experiments and progeny evaluation of cattle have not demonstrated heritability. The condition has been seen in female calves only, in one case, and occurred in a single year; calves with the same parentage born in previous and subsequent years were not affected, and calves in the same environment but with different parentage were unaffected.²¹³⁹ This suggests that a conjunction of environmental and genetic factors may determine disease pathogenesis. Consequently, some authors do not recommend culling a bull merely because an offspring has developed the condition,²¹⁴⁷ whereas others disagree with this recommendation.²¹⁴⁸

Treatment

Surgical techniques for correction of the spasticity include sectioning of the spinal afferents at segments L4 through L6, neurectomy of the tibial nerve rootlets supplying the medial and lateral heads of the gastrocnemius muscle, and superficial digital flexor tenotomy proximal to the tuber calcis.^{2129,2141,2149-2151} The tenotomy procedure is performed by incising proximal to the tuber calcis and transecting the superficial head of the gastrocnemius tendon completely (this tendon twists around the superficial digital flexor tendon from medial to lateral, coursing distally) and partly nicking the superficial digital flexor tendon.^2150,2152

To perform a tibial neurectomy, an incision is made in the groove separating the heads of the biceps femoris. The tibial nerve is identified as the more caudal of the branches off the ischiatic nerve. Some surgeons have recommended a concomitant sectioning of the caudal cutaneous sural nerve.

Success rates of 82% for the neurectomy technique and 40% for the tenotomy procedure have been reported.^2149,2153 Although recurrences may be common, some authors found high rates of sustained improvement over several months with the neurectomy technique.²¹⁴⁹ Results are poorer when animals under 2 months of age are treated.

Despite the reported success of these procedures, these treatments are not routinely performed in most countries because of the possible heritability of the condition and the need for specialized instruments and general anesthesia. Administration of lithium gluconate (4 mg/kg IM or PO daily for 10 to 30 days) is reportedly efficacious when used to treat calves in the early stages of spastic paresis.²¹³⁵

Clinical Signs

During the attack the leg may be held spastically in flexion, but more often it is held in rigid extension. The attacks are episodic, which differentiates them from the spasms of spastic paresis. The two diseases are otherwise similar in appearance. Each spasm is accompanied by kyphosis, which initially lasts 15 to 30 seconds and often is terminated by a fine tremor in the hindquarters or the digit. The intensity and duration of the spasms progressively increase over time. Both hindlimbs are affected. During a spasm the animal usually extends or flexes only one leg at a time. Some animals with advanced disease arch the neck and back dorsally and lift the contralateral forelimb during an attack.²¹⁵⁴ At first the signs appear to typify a response to a painful focus, and affected animals may be misdiagnosed as having laminitis, colic, or peritonitis. Gait and proprioceptive responses appear normal.

Treatment

There is no specific treatment for periodic spasticity, although mephenesin has been recommended, at a dosage of 30 to 40 mg/kg daily for 3 days. Although the pharmacologic effect of mephenesin lasts only 6 to 8 hours, severe symptoms were reportedly reduced for as long as several months after a single course of therapy.²¹⁵⁸ Methocarbamol also has been recommended, but reports of efficacy are anecdotal only.

Definition and Etiology

Tetanus is characterized by muscular rigidity and death from respiratory arrest or convulsions. The disease is caused by the exotoxins produced by the anaerobic, spore-forming, gram-positive bacterium Clostridium tetani. Tetanus has a worldwide distribution, and all species of domestic livestock are susceptible. The bacterium is typically isolated from the bowel contents of herbivores, but fecal contamination is considered to be only partly responsible for soil contamination.²²⁰⁵ The agent also can be found in dirt with no documented contact with domestic livestock. This indicates that C. tetani should be considered a primary soil contaminant. Tetanus usually is a disease of individual animals; however, herd outbreaks of tetanus after tail docking or castration have been described.^2206,2207 During outbreaks of tetanus, C. tetani can be isolated from the feces of a large proportion of the cattle, indicating that in some cases the disease may be caused by proliferation of C. tetani in the patient’s gastrointestinal tract.^2206,2207

Clinical Signs

The incubation period of tetanus varies and depends on the size of the wound, the redox potential in the contaminated tissue, the number of bacteria inoculated, and the host’s antitoxin titer. In most susceptible animals the signs occur from 2 weeks to 1 month after the bacterial inoculation. During the first 24 hours, horses may develop intractable colic, and ruminants may bloat.²²⁰⁸ The first signs in some animals may be a vague stiffness and lameness of the infected limb, which are related to a local effect of the absorbed toxin (localized tetanus). By 24 hours, generalized spasticity usually is evident. Affected animals display a stiff gait and an extended head posture.²²⁰⁹ The hypertonia is most evident in the antigravity muscles. Thus the limbs are held in a characteristic posture that resembles the legs of a sawhorse (sawhorse stance). The lips are retracted toward the poll, and the ears are pulled slightly down and caudal. The tail is elevated from the ischiorectal fossa. There is excessive muscle tone of all facial musculature. The jaws are clamped tightly shut (trismus), and the legs are held rigidly extended.

Muscular spasms can be elicited by auditory, ocular, or tactile stimulation. The limbs and head are very resistant to passive flexion. Retraction of the eye and a rapid flashing of the third eyelid across the cornea occurs after a menacing gesture or a slap over the neck.^2208,2210 This sign is more consistently observed in horses than in ruminants. Aspiration pneumonia may develop as a result of impaired deglutition. Severely affected animals become recumbent and lie on their side with the head and legs in full extension and the ears held almost parallel to the thoracic spinal cord (Fig. 35-40). Progression of the disease is associated with increased tonic muscular activity, which results in pyrexia in all species and profuse sweating in horses.^2207,2211 Frothy saliva accumulates at the commissures of the lips because the animals are unable to swallow, and respiratory incursions whip the mucinous saliva into a foam. The respiratory muscles (diaphragm and intercostals) are affected, and the animals develop hypoxia. Ventrolateral strabismus and dilated, fixed pupils may occur in advanced tetanus of cattle. Animals die while in a terminal convulsion. Death is attributable to hypoxemia and heart failure secondary to systemic hypertension and aspiration pneumonia. Survivors begin to show some improvement after 2 weeks, but the clinical signs may persist for as long as 1 month, and lameness may be permanent.

Fig. 35-40 Characteristic appearance of tetanus in a lamb. This condition developed subsequent to application of an elastrator band to the scrotum.

Clinical Pathology

There are no reliable clinicopathologic tests for confirmation of a diagnosis of tetanus. Attempts should be made to culture C. tetani from the suspected site of entry.

Pathophysiology

In horses, puncture wounds of the foot or the soft tissues are the most frequent sites of infection, whereas dairy cattle are infected most frequently through the uterus. Other sites for growth of C. tetani include lesions induced by elastrator bands, tail docking, dehorning, bull rings, or infected umbilical stalks.²²¹² Proliferation of C. tetani in the forestomachs of normal cattle may produce sufficient concentrations of toxin to result in clinical signs.^2213,2214 Outbreaks of tetanus have been correlated with ingestion of millet. This diet has been postulated to promote the growth of C. tetani in the large bowel²²¹⁵ and probably accounts for the lack of visible wounds in some animals affected with tetanus.^2206,2210

When inoculated into the anaerobic site, C. tetani spores germinate into the vegetative form. Factors that enhance the sporulation and growth of C. tetani include necrotic tissue, pus, concomitant bacterial infection, and foreign bodies. Spores inoculated into the tissues are highly resistant to normal host defenses and may remain dormant for months or years before developing into the vegetative state. The production of the tetanus toxins occurs at the end of the logarithmic growth phase of the vegetative form and is governed by a plasmid-associated gene.^2216,2217 The bacterium produces at least three toxic proteins: tetanospasmin, tetanolysin, and a nonspasmogenic toxin. Tetanolysin promotes the spread of the infection by increasing the amount of local tissue necrosis.²²¹¹

Tetanospasmin is a lipoprotein exotoxin that diffuses from the site of production into the vascular system, where it is distributed hematogenously to the presynaptic part of the motor endplates. Once bound to the nerves, the toxin is internalized and transported to the central nervous system along the axons of the alpha motoneurons through the membrane-bound smooth endoplasmic reticulum.^{2209,2218,2219} After reaching the ventral horn of the spinal cord, the toxin crosses the synaptic cleft to presynaptic inhibitory interneurons (Renshaw cells) in the intermediate gray column.²²²⁰ Tetanospasmin probably inhibits the release of glycine and γ-aminobutyric acid (GABA) from the Renshaw cells, resulting in disinhibition of the gamma motoneurons. The inhibition of these cells results in hypertonia and muscular spasms.

The nonspasmogenic toxin is thought to produce overstimulation of the sympathetic nervous system. Systemic hypertension seen in tetanus can be related to excessive catecholamine production by the adrenal medulla. Other physiologic changes identified in humans and laboratory animals include increased plasma cortisol concentrations and neuromuscular blockade. Whether these changes are caused by the effects of the toxin or these are secondary changes occurring in response to a painful and life-threatening problem is unclear. There are no characteristic postmortem lesions associated with tetanus.