Definition and Etiology

Hydrocephalus/hydranencephaly is a common occurrence in large ruminants. It is underdiagnosed because many of the affected animals die of complications, and the primary condition is overlooked during clinical and pathologic examinations. One study reported that 97 of 155 calves with CNS lesions had hydrocephalus.¹²⁰⁹ Hydrocephalus may be classified as hypertensive or normotensive.¹²¹⁰

Akabane Virus Infection

The akabane virus is a member of the Sindbis serologic subgroup of the Bunyaviridae family of the Arboviridae.¹²¹¹ It has been isolated from cattle in Africa, Japan, Israel, Korea, and Australia.^1212-1217 The host range of akabane virus includes sheep, cattle, and goats. Infection of pregnant, nonimmune dams results in hydranencephaly or arthrogryposis of the fetus.¹²¹⁸ The disease is thought to be transmitted to the cow by various Culicoides species. Experimentally infected calves develop porencephaly and encephalitis when exposed to the akabane virus between gestational days 62 and 96.¹²¹⁹ Studies in naturally infected cattle showed that infection of calves between days 76 and 104 of gestation resulted in hydranencephaly or porencephaly, whereas infection between days 103 and 174 of gestation resulted in arthrogryposis.¹²²⁰ Lambs are susceptible when exposed to the virus on gestational days 30 to 36.¹²¹⁷ Fetuses that survive the in utero infection are born with arthrogryposis. The CNS lesions apparently are the result of a direct necrotizing effect of the virus on the developing neurons. The pathologic changes of the CNS in experimentally infected calves and lambs are similar to those of naturally acquired infections.^1214,1217 Adults occasionally abort when infected by the virus but do not develop clinical disease.

A syndrome of arthrogryposis, facial deformities, kyphoscoliosis, hydranencephaly, and hypoplasia of multiple regions of the brain and spinal cord has been described in Corriedale sheep in Australia. Although resembling the disorder caused by congenital akabane virus infection, breeding trials supported an autosomal recessive inheritance for the disease.¹²²¹

Aino Virus Infection

The aino virus causes stillbirths, premature calving, and congenital malformations, including arthrogryposis, cerebellar hypoplasia, and hydranencephaly, in calves of Japan and Australia.^1222-1224 Aino virus is antigenically and biologically distinct from akabane virus, but the clinical syndromes of fetal infection by the two viruses are indistinguishable.

Chuzan Virus Infection

Hydrocephalus, hydranencephaly, and cerebellar hypoplasia have been attributed to infection of pregnant cattle with the Chuzan virus.^1225-1227 This virus is a relative of the akabane and aino viruses and is classified as a new member of the Palyam subgroup of the genus Orbivirus. The virus has been isolated from Culicoides oxystoma, which may serve as the major vector. The clinical signs are characteristic of hydrocephalus.

Cache Valley Virus Infection

A flock outbreak of arthrogryposis, myositis, hydranencephaly, and a variety of other brain malformations (micrencephaly, cerebellar hypoplasia, porencephaly) in newborn lambs in the southwestern United States was attributed to in utero infection with the Cache Valley virus (family Arboviridae).^1228,1229 Cache Valley virus was first isolated from mosquitoes from Utah and has since been isolated from caribou, horses, sheep, and cattle elsewhere. Antibodies have been found in white-tailed deer in the southwestern United States, but the role of this mammal in the survival of the virus and the transmission of the disease to livestock is unknown.¹²³⁰ In one survey of sheep in the western United States, the seroprevalence for the Cache Valley virus was 19.1%.¹²²⁸ Vectors for the virus include Anopheles, Aedes, Culex, and Coquellettidia mosquitoes.¹²³¹ Infection before 30 days of gestation may cause embryonic death, whereas infection between days 30 and 52 causes fetal malformations.¹²³¹

Bluetongue Virus Infection

The bovine fetus is most susceptible to the development of hydranencephaly from bluetongue virus when the dam is infected at approximately 125 days of gestation.^1232,1233 Abortions occur when nonimmune dams are infected at other times of gestation. Serotype 11 or serotype 17 of the virus is most frequently isolated from calf and lamb neonates in field epizootics.¹²³³ Calves infected in utero may develop one or more associated birth defects, including hydranencephaly, arthrogryposis, brachygnathia, prognathia, and excessive gingival tissue. In vitro studies have not supported the role of infected calves as reservoirs for the virus.¹²³⁴ Similar abnormalities and fetal deaths have been reported following vaccination of pregnant ewes with live attenuated virus.¹²³⁵ (See Chapter 32 for additional information.)

Bovine Viral Diarrhea Virus Infection

Hydranencephaly, hydrocephalus, and cerebellar hypoplasia have been associated with fetal infection of cattle with the BVD virus.^1236-1239 Precolostral serum antibody titers for the virus in affected calves vary; some titers range from 1:32 to 1:256, but other calves may have persistent viremias yet no demonstrable antibody. The BVD antibody titer in CSF may range from 1:4 to 1:32. The virus can be isolated from approximately 12% of affected calves.

Other Infectious Agents

A single case of hydrocephalus in a calf aborted at 7 months of gestation was associated with necrotizing encephalitis caused by Neospora caninum.¹²⁴⁰

Clinical Signs

Hydrocephalic animals often are born dead or are weak and die shortly after birth. The most obvious signs in animals that survive include failure to bond to the dam, depression, diminished learning ability, partial failure of suckling, droopy head and ears, muscular fasciculations, head tremor, conscious proprioceptive deficits, blindness, ventrolateral strabismus, nystagmus, dysphonia, tongue flaccidity or paralysis, retention of food material in the cheeks and lips, limb spasticity, hyperreflexia, psychomotor seizures, recumbency, and coma. Occasionally, doming of the calvarium or protrusion of fluid-filled cystic structures through an open fontanelle is seen.¹²⁴⁶ Affected neonates often do not ingest sufficient amounts of colostrum and frequently die of septicemia.

In virally induced cases of hydranencephaly, associated skeletal deformities may be observed, including abnormally curved ribs, kyphoscoliosis, flexural deformities of the limbs, domed skulls, and brachygnathia. Patients with hydrocephalus caused by compressive lesions around the ventricular system may show unilateral or bilateral signs of increased intracranial pressure. The clinical signs of unilateral lesions include head tilt (toward the lesion side), ipsilateral mydriasis, and contralateral menace deficit. Signs of hydrocephalus in foals are similar to those in calves. The cause of the condition in horses is unknown.

Antemortem diagnosis of brain malformations has been facilitated by CT and MRI. However, these techniques are rarely warranted or available for use in large animal species. A more practical technique for using ultrasonographic imaging, transorbital echoencephalography, has recently been described and has proved effective for the diagnosis of hydranencephaly.¹²⁴⁷

Clinical Pathology

The diagnosis of hydrocephalus in calves and lambs is typically based on the presence of characteristic clinical signs and a domed skull. Whenever hydranencephaly is suspected, blood should be collected for virus isolation, serologic testing, and quantitative immunoglobulin determination. Presuckle serum samples from bovine fetuses that have been infected by the akabane or bluetongue virus in the latter part of gestation may be seropositive. Immunologically competent calves that are infected with the bluetongue virus have serum neutralization indices ranging from 2.5 to 4.¹²³⁰

Necropsy Findings

The pathologic lesions of hydranencephaly are similar regardless of the etiologic agent. They include microcephaly, cerebellar hypoplasia, hydrocephalus, hydranencephaly, and porencephaly of the cerebral and the cerebellar cortex. Microscopic lesions of hydranencephaly include segmental loss of dorsolateral ventricular ependyma, thinning of the periventricular white matter, porencephalic cysts, and nonsuppurative meningoencephalitis. Lesions in other parts of the CNS may include loss of ventral horn cells in the spinal cord and demyelination in the spinal cord. Nonsuppurative inflammatory changes may be seen in cases caused by viral infections. Polymyositis has been described in affected calves; however, it is unclear if these lesions are caused by viral infection or occur secondary to the denervation. The skeletal deformities associated with virally induced hydranencephalies include rigid extension or contraction of one or more limbs (arthrogryposis), abnormally curved ribs, domed skull, thickening of the calvarium, kyphoscoliosis, and brachygnathia.

Treatment

Except for one report of successful surgical intervention in a calf with a meningocele, no satisfactory therapy is available for the treatment of hydrocephalus or hydranencephaly in large animals.

Definition and Etiology

Lead poisoning in ruminants is characterized by an acute encephalopathy. In contrast, lead poisoning in horses is characterized by chronic polyneuritis. Blindness, ataxia, and depressed sensorium are significant clinical signs in cattle, sheep, and goats, whereas in horses the poisoning is associated with weight loss, dysphagia, and secondary aspiration pneumonia. Cattle most often are poisoned because of their tendency to lick or chew on foreign objects, their access to lead-containing materials, and their propensity to drink contaminated petroleum distillates.¹²⁵³

Clinical Signs

The signs of lead poisoning in ruminants are characteristic of central nervous system (CNS) derangement. During the first stages of lead poisoning, affected cattle stand alone and are depressed.¹²⁵⁴ They may show hyperesthesia, muscular fasciculations, and rapid, spastic twitching of the eyelids or other facial muscles. Progression of the disease is associated with ataxia, conscious proprioceptive deficits, blindness, head pressing, odontoprisis, coma, and convulsions.^1255,1256 Despite the blindness, the pupillary reflexes usually are normal. Some animals may display episodic running, hyperesthesia, and bellowing. Others may die suddenly without premonitory signs. The more acute and severe the toxicity, the more acute, severe, and excitatory are the clinical signs.¹²⁵⁷ Animals with subacute or chronic lead poisoning have signs that are less excitatory and more indicative of CNS depression and have a longer clinical course. Affected cattle may accumulate frothy saliva at the commissures of the lips. Gastrointestinal (GI) signs of bloat, diarrhea, rumen atony, and colic occur in about 60% of lead-poisoned cattle, and the presence of such signs increases the index of suspicion for lead toxicity versus other causes of cerebral dysfunction.¹²⁵⁸ Other substances ingested with the lead may contribute to GI disturbances. The clinical signs of lead poisoning in horses include weight loss, lack of coordination, laryngeal or pharyngeal paralysis, dysphonia, roaring, conscious proprioceptive deficits, loss of anal tone, facial paralysis, and difficulty with mastication.¹²⁵⁹ Aspiration of pharyngeal debris caused by dysphagia may result in pneumonia. Fine muscular tremors occur intermittently. The poisoned animals die in psychomotor seizures. Horses with lead poisoning are emaciated at death.¹²⁶⁰

In cattle, lead produces microscopic changes of the myocardium that result in arterial hypertension (120 to 150 mm Hg) and electrocardiographic abnormalities. These electrical changes, which occur by 30 days after exposure, include increased duration and amplitude of the P wave (0.16 second and 0.06 mV, respectively), prolongation of the PR interval (0.14 to 0.16 second), decreased QT interval (0.32 second), and inverted T wave in lead II.¹²⁶¹

Clinical Pathology

Diagnosis of lead poisoning is based on measurement of increased blood and tissue concentrations of lead. Tissue levels of lead in naturally poisoned cattle can reach 20 to 100 ppm in the liver, 30 ppm in the kidneys, and 5000 ppm in bone. Reported reference blood lead concentrations vary considerably, ranging from 0.05 to 2.5 ppm.^{1255,1256,1262} Suggested toxic ranges also vary considerably among laboratories. Reference values from earlier colorimetric studies are consistently higher than those from later tests using spectrophotometry.¹²⁶³ Modern techniques usually report 0.3 ppm as the maximum normal blood lead concentration. When interpreting the results of a lead measurement, consideration of the reference ranges obtained with similar methodology is essential. Table 35-12 compares the lead concentrations of various tissues of experimentally poisoned and control calves. Heparin is the anticoagulant of choice when collecting blood for lead measurement because it does not chelate the lead. The lead concentration of ruminal fluid from acutely poisoned cattle ranges from 0 to 11,875 ppm.¹²⁵⁵

Table 35-12 Mean Lead Concentration (and Range) in Calf Tissues after Exposure to Different Dosages of Lead Acetate for 7 to 20 Days

Livestock that are chronically poisoned with low concentrations of lead may have a normal blood lead concentration but a high concentration in the bone. In these cases the poisoning can be diagnosed by administration of calcium disodium ethylenediamine tetraacetic acid (EDTA), which solubilizes the bone lead stores and increases the concentration of lead in the plasma. The soluble lead-EDTA complexes are excreted in the urine. The urinary lead concentration may rise by 40-fold over pretreatment levels within a few hours. Table 35-13 shows the lead concentrations in the urine and blood of naturally exposed horses and the temporal changes that occur after treatment with calcium disodium EDTA (75 mg/kg). In cases of chronic lead poisoning, radiographs of the abdomens of smaller patients may reveal lead-containing radiodense foreign material in the GI tract.¹²⁶⁴ “Lead lines” also may be present in the long bones of young animals chronically exposed to lead.

Table 35-13 Urine and Blood Lead Concentrations* in Horses with Chronic Lead Poisoning before and after Intravenous Treatment with Calcium Disodium EDTA^†

When blood lead concentrations are normal in chronically poisoned animals, measurement of free erythrocyte porphyrins and erythrocyte concentrations of α-aminolevulinic acid (ALA) are the preferred methods of diagnoses. The concentration of porphyrins is increased in the blood, urine, and feces of animals with lead poisoning. The reference range of blood porphyrin concentrations in normal calves is 21.6 ± 11.6 to 45.6 ± 10.3 μg/dL for whole blood and 113 and 142.8 ± 32.4 μg/dL for erythrocytes.^{1256,1265,1266} In chronically exposed, asymptomatic cattle, the free erythrocyte porphyrin concentrations are frequently greater than 2000 μg/dL. A field test has been developed for determining blood porphyrins.¹²⁶⁶

Reference ranges for ALA dehydrase are 45.8 ± 20.6 U, whereas activities ranging from 28 to 33 U have been reported in naturally exposed calves.¹²⁶⁰ The urinary concentration of δ-ALA is increased and range above 500 μg/mL.^{1261,1267,1268} Measurement of ALA in the erythrocytes is more reliable than measurement in urine.¹²⁶⁹

Environmental sources of lead can be detected by direct measurement of the lead concentration of the soil or pasture forage. Forage from toxic pastures contains more than 30 ppm of lead, and in some cases the level may exceed 300 ppm.^1268,1270

The hematologic abnormalities of lead poisoning are subtle. Most poisoned livestock have a normal hemogram. If present, lead-related changes are characteristic of a hemolytic anemia with an inappropriately large-bone marrow response. The morphologic abnormalities of erythrocytes include anisocytosis, poikilocytosis, polychromasia, hypochromia, Howell-Jolly bodies, metarubricytes, and basophilic stippling.^1255,1271 The shape changes begin within hours after ingestion of the lead and peak by 100 days.^1255,1271 Blood changes do not occur in all cases of the disease and are not necessarily specific indicators of lead poisoning in cattle, in which elevated blood lead may be present without hematological abnormalities.¹²⁷² However, hematologic abnormalities tend to be more consistent in chronic lead toxicity and in lead-poisoned horses.

Lead toxicity has a variety of effects on endocrine function in cattle. Elevated levels of serum T₃, T₄, estradiol, and cortisol have been demonstrated in cattle with elevated blood lead levels.¹²⁷³ Parameters of liver function also are affected; serum alanine and aspartate transaminase (ALT and AST) levels are increased, whereas serum lipids, total protein, and albumin are decreased.

In poisoned animals the concentrations of protein and WBCs in CSF are increased, ranging from 50 to 100 mg/μL of protein and 5 to 50 mononuclear cells/mL, respectively. Such changes are relatively nonspecific and found with other causes of polioencephalomalacia.

Pathophysiology

Lead enters the body through the GI tract or less often through the respiratory tract. Metallic lead and the sulfide form are less well absorbed than the acetate, phosphate, carbonate oxide, and hydroxide salts. Metallic lead is poorly absorbed and causes toxicity only when a lead foreign body becomes entrapped in the stomach for prolonged periods. Interaction between lead and other minerals may occur. For example, high levels of dietary calcium reduce the GI absorption of lead. Concomitant exposure to lead and cadmium results in a worsening of the clinical signs of lead poisoning.¹²⁷⁴

Acute toxic single doses of lead range from 200 to 600 mg/kg for calves and 600 to 800 mg/kg for adults.^1275,1276 Although intestinal absorption of lead is relatively inefficient, significant amounts can cross into the blood if sufficient quantities are ingested. Approximately 1% to 2% of the total oral dose of lead is absorbed by 24 hours.¹²⁵⁵ Increases in the blood lead concentration are observed as early as 3 hours after dosing. Most of the lead absorbed from the digestive tract (90%) is bound irreversibly to erythrocyte proteins, resulting in a low lead concentration in the plasma but higher concentrations in whole-blood specimens.¹²⁷⁷ At the end of the erythrocytes’ lifespan, the cell-bound lead is metabolized from the erythrocyte proteins and deposited in the bone as the triphosphate salt. A smaller amount of dissolved lead is deposited into the soft tissues as the diphosphate. A portion of the soft tissue lead is excreted through the GI tract via the secretions (pancreatic juices, bile) and direct diffusion. The half-life of blood lead in adult cattle is extremely variable and unpredictable, ranging from 48 to 2507 days in one study.¹²⁷⁸ Phenotypic or genotypic factors may affect metabolism and storage of lead; for example, beef cattle store more lead in the liver than the kidneys compared to dairy cattle.¹²⁷⁹ The variable time for clearance of lead has an obvious implication for public health, because all carcasses of animals suspected or known to be exposed to lead must be tested before being cleared for human consumption.¹²⁸⁰

Lead also crosses the placental barrier and accumulates in fetal bone, liver, and kidneys, but does not substantially accumulate in milk. Infertility, abortions, and fetal malformations may result from exposure to lead.¹²⁵⁷ The concentration of lead in milk from lactating cattle fed a daily dose of 13 mg of lead acetate remains less than 5.9 parts per billion (ppb).¹²⁸¹ In one study a logarithmic relationship between blood and milk lead concentrations was found. At blood concentrations below 3.6 μg/dL, milk lead concentrations were 0.8 μg/mL. However, cattle with higher blood lead levels (4.8 μg/dL) had exponentially greater concentrations in milk (2.2 μg/kg).¹²⁸² Lead cannot be detected in milk by 7 months after exposure.¹²⁸³

The toxic effects of lead include inhibition of free sulfhydryl groups found in many enzymes, interference with zinc-containing metalloproteins, and steric inhibition of enzyme activity.¹²⁷¹ Enzymes of heme synthesis are particularly susceptible to injury. These include δ-ALA dehydratase and ferrochelatase. Interference with ferrochelatase inhibits the formation of heme from protoporphyrin, resulting in a buildup of unmetabolized porphyrins, including protoporphyrin I, uroporphyrins, and coproporphyrins. The last two molecules are excreted in the urine and feces, respectively.¹²⁵⁴ Protoporphyrin I is retained in the erythrocyte.

Interference with the activity of ALA dehydrase may be partly responsible for the brain damage associated with lead poisoning. The enzyme δ-ALA dehydrase combines two molecules of δ-ALA into a single porphobilinogen molecule. This enzyme is exquisitely sensitive to lead. Inhibition of the enzyme leads to accumulation of ALA, which is excreted into the urine. Concentrations of the synthetic product porphobilinogen in the erythrocytes are reduced.^{1266,1267,1269,1284}

Because of the interference with heme metabolism and the altered function of other erythrocyte proteins, the erythrocyte half-life is shortened, which may result in a normochromic, normocytic anemia in a small proportion of chronically poisoned animals.¹²⁸⁴ Iron is not adequately used and is stored in sideroblasts in the bone marrow.¹²⁶⁶ Lead also interferes with the activity of pyrimidine-specific 5′-nucleotidase.¹²⁸⁵ Loss of activity of this enzyme results in basophilic stippling.

After absorption, lead rapidly enters the brain at a dose-dependent rate. The lead deposition in the CNS results in acute cerebellar hemorrhage and edema from capillary dysfunction.¹²⁷⁷ Abnormalities of brain cerebroside content and catecholamine metabolism have also been described in animals with lead poisoning; however, the role of these changes in the pathogenesis of the clinical signs is unknown. The pathogenesis of lead encephalopathy is multifactorial. Encephalitic signs probably originate from a combination of decreased microvasculature, cellular necrosis, brain swelling, neurotransmitter dysfunction, and decreased glucose uptake by the brain.¹²⁸⁶

The molecular effects of lead on the myocardium are unknown. Hypertension caused by chronic poisoning is thought to result from an inhibition of sodium-potassium adenosine triphosphatase or an alteration of the juxtaglomerular apparatus.¹²⁶¹

Ingestion of lead also results in aberrations of other minerals. For example, long-term exposure to lead results in competitive inhibition of selenium uptake, thereby diminishing the absorption of selenium by as much as 26%.¹²⁷⁶ If selenium intake is marginal, lead toxicosis could manifest as an outbreak of white muscle disease. Lead-induced selenium deficiency may contribute to the pathogenesis of myocardial disease and immune system dysfunction.

Epidemiology

Sources of lead are legion, including lead arsenate defoliants, batteries, used motor oil, linoleum, roofing felt, paint, machinery grease, caulking compounds, improperly compounded mineral supplements, and foliage near lead smelters and battery-recycling plants.^{1254,1260,1268,1287-1293} Blood lead levels of animals residing in highly contaminated urban environments may be significantly greater than those of their rural-dwelling counterparts, and high lead levels have been reported in grasses growing near busy roadways, but the clinical significance of these findings is unclear.^{1290,1294,1295} Contamination of preserved feeds, such as silage, can occur before or during processing or during storage. Factors that can increase the likelihood of ingestion of lead-contaminated foodstuffs include lack of alternative feed, hunger, and phosphorus deficiency.¹²⁵⁷ The single lethal dose of lead for cattle is estimated to range from 220 to 600 mg/kg for calves, 600 to 800 mg/kg for adult cattle, and 400 mg/kg for goats.^1257,1275 Poisonings from cumulative intake are associated with substantially lower daily doses. Although cattle can detect fairly low levels of lead on pasture and have an aversion toward contaminated herbage, continued exposure may lessen this aversion, making animals more prone to ingest contaminated material.¹²⁹⁶ Lead poisoning has been induced in cattle by feeding 5 to 6 mg lead/kg body weight/day for 3 years or 6 mg/kg of lead (lead acetate) for 7 days.^1268,1297 Lead poisoning has been reported in cattle exposed naturally to 6 to 7 mg/kg/day of lead on foliage and in calves given oral lead acetate at 2.7 to 20 mg/kg/day.¹²⁹⁷ The interval for development of clinical signs ranges from 5 to 20 days and is related to the dose and the ionic form of lead administered.¹²⁹⁷ Ensiling of contaminated forage results in percolation and concentration of lead at the bottom of the silo.¹²⁹⁸

The toxicity of lead is apparently influenced by dietary factors. Calves on a milk diet are more susceptible to lead poisoning than calves fed hay and grain.¹²⁶² There appears to be a direct correlation between high levels of vitamin D and enhanced lead absorption, which may explain the greater occurrence of the poisoning during the summer. Elevated copper concentrations in forage, such as may be found in pastures fertilized using pig slurry, may potentiate accumulation of lead in animals consuming it.¹²⁹⁹

The estimated cumulative toxic dose of lead for horses is 2.9 mg/kg/day.¹³⁰⁰ Poisonings have been reported in horses grazing pastures contaminated with 320 to 440 ppm of lead from a metal smelter; this amounted to a daily intake of 2 g (∼6.4 mg/kg). Metallic lead and the “galena” (insoluble sulfide salt) are less toxic than the acetate and carbonate lead salts.¹³⁰¹

Necropsy Findings

The macroscopic brain lesions of lead poisoning are mild and include brain edema, congestion of vessels of the cerebral cortex, and yellowish discoloration and flattening of the cortical gyri. Lesions tend to be most severe in the occipital lobes. Microscopic changes in the brain include capillary prominence, endothelial cell swelling, edema of the Purkinje cell layer of the cerebral cortex, laminar cortical neuronal necrosis, and edema of the white matter.¹³⁰² The lesions are predominantly located on the tips of the gyri. Whether these lesions are caused by a direct effect of lead on the neurons or from vascular damage is unclear.¹²⁷⁷ Intranuclear acid-fast inclusion bodies in the renal tubular epithelial cells have been described in experimentally poisoned cattle. Chronic lead exposure also may interfere with normal functioning of the immune system, resulting in an increased susceptibility to infections.¹³⁰³

Treatment

Therapy for lead poisoning should include removal of the lead from the digestive tract, chelation therapy with calcium disodium EDTA, and fluid and nutritional support of the patient. Treatment with calcium disodium EDTA (calcium versenate) has been shown to be superior to treatment with penicillamine or dimercaprol (BAL). The EDTA chelates osseous but not soft tissue—bound lead.¹²⁷⁴ After chelation the unsaturated bone stores reequilibrate with the lead remaining in the soft tissues. In cases of acute lead poisoning, several days are required before reequilibration results in a decreased blood lead concentration. The dose of calcium disodium EDTA is 66 mg/kg/day, divided into several doses daily for 3 to 5 days.¹³⁰⁴ After five daily treatments, a 2-day nontreatment period is recommended to reequilibrate the soft tissue and bone lead. After the 2 days’ rest, daily treatments are given for another 5 days. The decision to continue therapy with EDTA should be based on the results of posttreatment blood lead analyses and renal function tests. Another recommendation is for administration of two IV injections of calcium disodium EDTA (110 mg/kg per dose) given 12 hours apart for 2 days.¹³⁰⁵ Therapy then is withheld for 2 days, after which the EDTA treatments are reinstituted for 2 more days. The comparative efficacy of this regimen is unknown.

The EDTA also chelates other divalent cations. Consequently, prolonged administration of the drug results in trace-mineral deficiencies, especially of zinc. For this reason, after prolonged EDTA therapy, oral supplementation with zinc should be considered to prevent the development of parakeratosis.

Meso-2,3,-dimercaptosuccinic acid may be a more effective agent for lead chelation, particularly when it comes to removing lead from soft tissue.¹³⁰⁶ However, experience with this drug is still limited. There appears to be no advantage to using this drug in conjunction with calcium disodium EDTA.

Reports have indicated that thiamine therapy is an effective adjunctive treatment with EDTA in cases of acute lead poisoning of cattle.^{1275,1307,1308} Administration of 2 mg/kg thiamine daily was more effective than treatment with disodium EDTA (62 mg/kg twice daily for 4 days) or thiamine plus disodium EDTA in inducing remission of clinical signs of experimentally induced lead poisoning.¹³⁰⁹ For clinical treatment of lead poisoning, thiamine dosages of 500 mg for small ruminants and 1 g for cattle weighing 300 kg or 5 mg/kg have been recommended.¹³⁰⁷ Administration of daily doses of thiamine (100 mg/calf/day or 5 mg/kg) has protected experimentally exposed calves from clinical signs of lead poisoning and reduced lead deposition in the soft tissues.^{1308,1310,1311} The nature of the protective effects of thiamine is unclear. Apparently, either lead interferes with thiamine synthesis, or the tissue distribution and deposition of lead are reduced by the formation of rapidly excreted lead-thiamine complexes.

In ruminants, ingested lead is best removed from the digestive tract by means of a rumenotomy.¹²⁷⁵ Magnesium sulfate laxatives are administered concomitantly to form insoluble lead sulfides. Because of the possibility of additional lead absorption from the GI tract, oral administration of chelators is contraindicated.

Patients that respond slowly to chelation and thiamine therapy should be given supportive care. These measures should include provision of 40 to 80 mL free water/kg/day for maintenance, oral hyperalimentation, and administration of diazepam or phenobarbital for convulsions (see Table 35-9).

Prevention and Control

Toxic pastures can be made safe by removing contaminated forage. This is best done by cutting, baling, and burying native grasses; burning the stubble; and applying agricultural lime at the rate of 1 ton per acre where the lead concentration of topsoil exceeds 175 ppm.¹²⁶⁶ In the case of negligent poisonings, vigorous attempts at laboratory confirmation of the clinical diagnosis should be made. The source of the lead should be established, and the affected animals should be carefully documented. In the United States, insurance liability responsibilities may be covered under homeowner or farm insurance.

Definition and Etiology

Leukoencephalomalacia (LEM) is an intoxication of horses caused by ingestion of corn contaminated with the fungus Fusarium moniliforme.^1331-1335 Fumonisin toxins (B1, B2, and B3) produced by F. moniliforme interfere with sphingolipid metabolism, disrupting endothelial cell walls and basement membranes.¹³³⁶ Although all three substances are toxic, fumonisin B1 is believed to be mainly responsible for LEM.¹³³⁷ Outbreaks of multifocal neurologic signs and hepatic disease occur in groups of horses exposed to tainted feedstuffs.

Clinical Signs

The clinical signs of LEM occur suddenly. Occasionally, animals die acutely, without other overt signs,¹³³⁸ but most horses show a variety of neurologic signs before death. These include somnolence, flaccidity of the facial and pharyngeal muscles, muscle fasciculations over the neck and withers, ataxia, conscious proprioceptive deficits, head pressing, mania, facial desensitization, pharyngeal paralysis, blindness, seizures, and a tendency to circle or lean to one side.^1338,1339 Most animals die while convulsing.¹³³¹ The few horses that recover usually have permanent neurologic dysfunction. Hepatic involvement occurs in many cases, as evidenced by elevated serum liver enzymes, although hepatic failure is uncommon. Signs of liver disease include icterus, petechiation on mucous membranes, and swelling of the muzzle or lips. Gastrointestinal disease caused by fumonisin toxins has been reported and may manifest as signs of colic.

Unique constellations of clinical signs may predominate within any one outbreak of the disease. Fumonisin toxins cause a variety of clinical syndromes in other species, but horses appear to be particularly susceptible and can show signs when exposed to toxin concentrations as low as 5 to 10 ppm, almost 10 times less than the concentration needed to cause mild signs of inappetence and decreased weight gain in cattle.

Clinical Pathology and Diagnosis

Fumonisin toxicosis has no unique clinicopathologic findings, therefore antemortem diagnosis relies on recognition of the clinical signs with a history of exposure to moldy corn. Specific changes in the cerebrospinal fluid (CSF) of affected horses have not been reported. Serum liver enzymes (aspartate transaminase [AST], γ-glutamyltransferase [GGT], sorbitol dehydrogenase [SDH]) and bilirubin may be elevated. Nonspecific changes in serum chemistry associated with dehydration (increased hematocrit, prerenal azotemia) and recumbency (elevated serum creatine kinase [CK]) also may be present. Anemia, leukocytosis, and leukopenia all have been reported, but none is a consistent finding.

Differential diagnoses include craniocerebral trauma, the arboviral encephalitides, hepatic encephalopathy, equine protozoal myeloencephalitis, Theiler’s disease, and botulism.

Epidemiology

Leukoencephalomalacia occurs worldwide.^1333,1340 Corn becomes contaminated during growth rather than in storage, and climatic factors that stress the plants, such as drought, excess moisture, or heat, contribute to the likelihood of mold development. Most cases of equine disease occur during the winter and early spring.^1332,1338 In experimental studies the toxic dose of infected corn ranged from 5 to 15 kg (10 to 30 lb), but the amount of corn required to cause the disease is likely to vary considerably depending on the amount of toxin in the grain.¹³³⁴ A direct link between the onset and severity of clinical signs and the dose of toxin has not been established in naturally occurring cases, but experimental data suggest a dose-related effect.¹³⁴¹ Repeated exposure to the toxin, rather than a single large dose, seems to be associated with the development of clinical signs.¹³⁴² Experimental studies with infected corn demonstrated an onset of clinical signs on the ninth day after the beginning of the feeding period. Older animals develop clinical signs of LEM more rapidly than younger animals and thus appear to be most susceptible to the effects of the mycotoxin.¹³³⁴

The rates of disease in exposed horses vary widely, from 14% to 100% in some reports.^1343-1346 Ruminants apparently are more resistant than horses to the effects of the neurotoxin, but this is not a complete resistance because camels and water buffalo have died after ingesting toxic corn. Diplodiosis, a similar neuromycotoxicosis of cattle caused by ingestion of Diplodia maydis, occurs in Africa; however, the toxicologic relationship between these conditions is unknown.

Pathology

The major pathologic features in the central nervous system (CNS) result from the vascular damage caused by fumonisin toxins, including liquefactive necrosis and degeneration or malacia of the white matter of one or both cerebral hemispheres.^1347,1348 The size of the lesions may vary from 0.5 cm in diameter to complete necrosis of the entire cerebral cortex.¹³³¹ Flattening of the cortical gyri, enlargement of the cerebral cortex, vascular congestion, cortical softening, yellowish discoloration of the white matter, hemorrhage, and cavitation of the cerebral cortex may be present^{1331,1338,1340} (Fig. 35-14). A gelatinous fluid can be seen in many of the cavitary lesions.¹³³⁸ Hemorrhage in the CNS also has been reported.¹³⁴³ Lesions in the visceral organs, including hepatic congestion, centrilobular hepatic necrosis, hemorrhagic enteritis, and cystitis are found in some horses. The relationship between these lesions in the CNS and those in the liver, urinary bladder, and GI tract is unknown.

Fig. 35-14 Characteristic appearance of a malacic lesion in the brain of a horse that died of moldy corn poisoning.

Courtesy Dr. R.H. Whitlock.

Treatment

There is no known specific treatment for LEM, but successful treatment of horses was reported using antiinflammatory medications such as dimethyl sulfoxide (DMSO) (1 g/kg given as 10% solution by slow IV infusion once daily for 3 days) or flunixin meglumine (0.25 to 1 mg/kg), as well as antibiotics and supportive care (thiamine, 5 g IV every 12 hours).¹³⁴⁹ In other cases, survivors usually have permanent neurologic dysfunction.

Definition and Etiology

Ingestion of stagnant pond water containing certain species of blue-green algae may result in a peracute intoxication of livestock. Blue-green algae poisoning is characterized by convulsions, ataxia, bloody diarrhea, and sudden death.^1350-1353 Although often a fatal toxicity, some affected animals can make a full recovery.^1351,1354 The algal toxins have been responsible for high losses of livestock and illness in humans and for deaths of domestic dogs.^1355,1356 The algal toxins may also be responsible for occasional die-offs of fish and aquatic birds. Toxic algal species include Microcystis aeruginosa, Anabaena flos-aquae, Aphanizomenon flos-aquae, Anacystis cyanea, Gloeotrichia echinulata, Nodularia sphaerocarpa, and Oscillatoria agardhii. Of these, the first three are most toxic.¹³⁵⁷ Blue-green algae poisoning most often results in sudden death. Affected animals rarely move far from the source of the toxin. Some of the algae produce hepatotoxins, and animals develop liver failure, diarrhea, and photosensitivity. The development of toxic stands of blue-green algae requires specific environmental conditions, including a water pH above 6, organic pollution, and a water temperature ranging from 15° C to 30°C (59° F to 86°F).

Clinical Signs

Clinical syndromes of blue-green algae poisoning in livestock may be separated into acute and chronic forms. Acutely affected animals may show signs resembling those of milk fever,¹³⁵⁴ including muscle tremors, reluctance to rise or move, ataxia, cold extremities, weak rapid pulse, mydriasis, muscle tremors, salivation, colic, rumen atony, mild bloat, pallor, increased capillary refill time, vomiting, ataxia, conscious proprioceptive deficits, and bloody diarrhea. Some of the toxins are absorbed through the oral mucosa. Consequently, the full range of clinical signs, culminating in death from respiratory arrest, can occur within minutes of ingestion of the toxic water. If clinical signs are seen before death, affected animals tend to be afebrile but have significantly increased pulse and respiratory rates. Many animals die suddenly without premonitory symptoms.^1358,1359 The deaths often occur in the vicinity of the pond, and dead animals may be covered by the green scum.

In the chronic form of blue-green algae intoxication, affected animals show ataxia, depression, anorexia, hemorrhagic diarrhea, icterus, and photosensitization, which occur secondary to hepatic necrosis.¹³⁵⁹ Death from respiratory arrest and circulatory shock may occur within 2 to 72 hours after the toxin is ingested.

Clinical Pathology

The diagnosis of blue-green algae poisoning depends on recognition of a relationship between livestock deaths and ingestion of pond water, identification of toxic algae in the pond water, recognition of hepatic disease in chronically affected animals, and elimination of the possibility of similar clinical conditions, such as cyanide or acute poisoning. Diseases that kill animals suddenly should be considered as differential diagnoses (see Chapter 14). Blue-green algae poisoning should be considered whenever a group of cattle simultaneously develop marked massive hepatic necrosis.

The vegetative cells of the algae can be identified by microscopic examination of rumen contents. The intestinal contents should be split. Half the contents should be placed in 10% neutral buffered formalin for microscopic analysis, and the other half should be refrigerated (not frozen) for mouse bioassay tests or chromatographic identification of the toxin using high-performance liquid chromatography (HPLC).¹³⁶⁰ The blood of animals poisoned by microcystin, the toxic principle of Microcystis aeruginosa, shows changes characteristic of hepatic necrosis, including increased concentrations of bilirubin, AST, GGT, alkaline phosphatase (ALP), and arginase. The animals may be secondarily hypocalcemic, which complicates the clinical picture.¹³⁵⁴

Pathophysiology

Blue-green algae grow more slowly than other algae in cold water; therefore, highly flushed systems cannot achieve a toxic bloom. The blue-green algae can fix atmospheric nitrogen dissolved in the water, and they have intracellular gas vesicles that accumulate the nitrogen when photosynthesis decreases. If mixing occurs because of the wind, the amount of light reaching the algae decreases because of the turbulence. The buoyancy of the cells increases because of decreased photosynthesis. At night the winds become calmer, and the algae lose their ability to regulate density. The cells float to the surface of the water and form a scum, which is concentrated on the leeward side. For these reasons, poisonings tend to occur in the period of stable weather just after a frontal system has passed.

Direct ingestion of the toxicant is necessary to cause clinical signs. No significant level of toxin was detected in milk of cows fed the toxin experimentally, so calves are not exposed through their dams’ milk.¹³⁶¹

All species of blue-green algae probably produce toxins, which can be classified into the following three groups:

Aphanizomenon, Oscillatoria, and Anabaena species. Aphanizomenon produces two alkaloid toxins that have a structure resembling that of saxitoxin, the agent of paralytic shellfish poisoning. Toxins from Anabaena species are named anatoxin-a and anatoxin-a(s) and are structural analogs of cocaine. Toxins from Oscillatoria species resemble those of Anabaena; they can be absorbed unchanged through the mucous membranes and kill by depolarizing blockade of the neuromuscular junction.^{1358,1359,1362-1364}

Peptide hepatotoxins. These substances are produced by strains of Microcystis, Oscillatoria, and Anabaena algae. Microcystin-LR is the most frequently isolated hepatotoxin.^1365-1369 On a weight basis, this toxin is 20 times more active than cyanide or strychnine. A single intraperitoneal injection of 1 to 2 μg in a mouse is lethal. At least nine structural variants of microcystin have been identified. These toxins act exert their toxic effects on mitochondria.¹³⁷⁰ The toxins can cross the placenta and cause lesions in the fetus.

Lipopolysaccharides. These substances may be produced by most species of blue-green algae.

Necropsy Findings

The pathologic lesions of blue-green algae poisoning are either severe centrilobular hepatic necrosis in animals that die of the chronic poisoning or generalized petechiation and body cavity effusions in animals that die peracutely.¹³⁵⁸

Epidemiology

Blue-green algae intoxication occurs worldwide and affects mammals, birds, and fish. The bloom is most abundant during the late summer and early autumn when warm, sunny conditions favor algal growth. Growth is most abundant in ponds with an alkaline pH and in high concentrations of nitrogen, phosphates, carbonates, or organic matter. Release of the toxin is associated with death of the algae and production of a “rotting fish” odor. Most poisonings occur on the leeward side of the pond, where the algae are concentrated by the action of the prevailing wind. Ingestion of approximately 1080 to 1500 mL of heavily contaminated water can be fatal for cattle.¹³⁵⁰ Toxicity varies daily and in different parts of the pond or lake.

Treatment

Therapy for blue-green algae poisoning is symptomatic and usually unsuccessful. Experimentally poisoned calves have not recovered, even after 30 hours of artificial respiration, although recovery of cows naturally intoxicated has been reported.^1351,1363

Prevention

Methods for control of the disease include restriction of access to infested ponds and treatment of the pond with copper sulfate or algacides.¹³⁵² Prevention of blue-green algae poisoning depends on the proper construction of farm ponds and the prophylactic treatment of the water with bluestone (copper sulfate) to achieve a final concentration ranging from 0.5 to 1.0 ppm in acid water and 1.5 to 2.0 ppm in alkaline water. The bluestone is either dissolved in water and sprayed over the pond or dragged through the pond in a burlap sack in lanes that are 5 to 10 feet apart.¹³⁵² This amounts to 1.22 kg/acre foot in alkaline water. Cattle should be fenced from the pond for several days after the copper sulfate treatment. The treatment should be repeated whenever the toxic bloom recurs. To prevent algal bloom without application of copper sulfate, farm ponds should be constructed so that they are 80 × 20 feet in length and width and 10 feet in depth. Surrounding drainage areas should be fenced from the livestock. Water should be pumped from the pond to the cattle in polyethylene pipes and delivered into raised water troughs. The water for the troughs should be pumped from the center and bottom of the pond.

Definition and Etiology

Intracarotid drug injection is common in horses because the jugular vein and the common carotid artery are closely apposed in the caudal third of the neck. The condition is rarely seen in cattle because the omohyoideus muscle lies between the carotid artery and the jugular vein in the posterior part of the neck. Hypertonic or caustic drugs, including phenothiazine tranquilizers, chloramphenicol, chloral hydrate, barbiturate anesthetics, phenylbutazone, calcium gluconate, sodium iodide, and chloramphenicol, cause cortical necrosis when injected into the carotid artery.^1373,1374

Clinical Signs

The onset is peracute. When the drug is injected into the carotid artery, the animal recoils backward and falls over. Some horses strike or rear violently or run wildly without regard to obstructions. Other animals fall down and become comatose without showing severe motor activity. Severely affected animals may die after a variable period, but others regain their footing and recover completely. Residual neurologic deficits may occur in surviving animals. These deficits include contralateral blindness, facial hypalgesia, head tilt (toward the side of the lesion), and a largely contralateral, conscious proprioceptive deficit. If the injection has damaged the ascending vagosympathetic pathways, the animal may display Horner’s syndrome, with signs that include ptosis, miosis, and enophthalmos. Horses with Horner’s syndrome also sweat profusely over the head and neck of the ipsilateral side, whereas cattle with the syndrome fail to sweat on the planum nasale on the ipsilateral side of the lesion.

Pathophysiology

The CNS lesions are caused by vascular endothelial damage. Intracarotid drug injection results in intense vasospasm and profound alterations of the blood-brain barrier (BBB). The vascular damage causes endothelial cell swelling, increased vascular permeability, mural necrosis, hemorrhage, intercellular edema, and thrombosis.¹³⁷³

Necropsy Findings

Pathologic lesions include diffuse cerebral edema and brain swelling. Microscopic lesions include arteriolar hyalinization, hemorrhage, edema, necrobiosis, and status spongiosus. Vacuolation of the neuropil, perivascular hemorrhage, fibrin, and edema are also seen.

Treatment

No effective treatment exists for an accidental intracarotid drug injection. Violent horses should be placed in a padded stall, sedated with diazepam, and treated with dexamethasone (1 to 2 mg/kg). Administration of mannitol or other osmotic diuretics should be avoided in the first 24 hours because of active bleeding in the CNS and loss of the BBB. Administration of a hypertonic dehydrating agent at that time may result in distribution of the osmotically active drugs into the CNS parenchyma, resulting in a large increase in intracranial pressure. Although most animals eventually recover from the effects of an intracarotid injection, fatalities have been reported.^1373-1375

Prevention

Intracarotid injection of drugs is best prevented by the use of large-bore needles or catheters for intravenous injections. This allows better visualization of pulsating oxygenated blood when the carotid artery has been accidentally punctured. In the horse, venipunctures should be performed in the anterior one third of the jugular furrow because the artery and vein are separated by the omohyoideus muscle in this area. Needles should be inserted into the vein while they are separated from the syringe.

Definition and Etiology

Coenurosis is caused by invasion of the CNS by Coenurus cerebralis, the intermediate stage of the tapeworm Taenia multiceps. The adult worms live in the intestine of domestic dogs and some wild carnivores, where they shed eggs into the feces. Ruminants eat the eggs from contaminated pastures. The eggs hatch in the small intestine of the ruminant, and the larval stages travel through the blood to the CNS, where they mature into C. cerebralis. The life cycle is completed when the ruminant dies and the brain is eaten by a scavenging carnivore. Coenurus cysts then develop into sexually mature adults in the bowel of the carnivore host.

Many animals, including sheep, goats, cattle, horses, wild ruminants, and humans, are susceptible to C. cerebralis infestation.^1376-1378 Outbreaks of coenurosis may occur in previously uninfected sheep that are suddenly exposed to contaminated fecal matter from carnivores. Cases initially occur as early as 2 weeks after the sheep are exposed and continue for as long as 4 months.

Clinical Signs

Signs can occur acutely, during the migratory phase of the larval stage in the intermediate host. Lambs 6 to 8 weeks old are most often affected by this form and develop fever, dullness, and mild neurologic deficits.¹³⁷⁹ Occasionally, acute encephalitis occurs, leading to sudden onset of severe neurologic signs and death within a few days. More frequently, the clinical presentation of coenurosis is that of a space-occupying brain lesion; signs include depression, anorexia, ataxia, unilateral or asymmetric loss of vision, facial hemiplegia, head tilt, circling, high-stepping forelimb gait, and hyperesthesia. When the spinal cord is the site of cyst development, hindlimb ataxia and paresis to paralysis is the main clinical sign.¹³⁸⁰ As the disease progresses, the sheep assume lateral recumbency and become comatose.^1381,1382 In advanced cases the calvarium directly over the parasite enlarges and softens.¹³⁷⁸

Pathophysiology

Lesions of the CNS may result from three separate pathogenic mechanisms. These include encephalitis from invasion of the CNS by large numbers of larvae, hypertensive hydrocephalus resulting from interference with CSF drainage, and development of large cerebral cysts that increase intracranial pressure. Full development of the Coenurus cyst requires 6 to 7 months. Mature cysts may reach 5 cm in diameter and displace the bones of the calvarium.

Necropsy Findings

In the acute form of coenurosis, the main finding is coagulation necrosis and inflammation associated with the pathway of the larval form as it migrates through the CNS.¹³⁸³ This may be visible grossly as yellow to red tracks through the brain parenchyma. Coagulation necrosis and surrounding inflammatory cells, such as degenerate granulocytes, macrophages, and histiocytes, are found microscopically. The mature cysts, up to 7 cm in diameter, are thin walled and contain clear fluid or, occasionally, purulent fluid. Protoscolices, up to many hundreds, can be visualized microscopically within the cysts, which are surrounded by severe and mainly nonsuppurative inflammation. The cysts deform and compress the underlying brain tissue.

Diagnosis

The combination of a characteristic clinical syndrome and location in an endemic area supports a presumptive diagnosis. Radiographs in the lateral and posteroanterior planes may detect radiolucent areas in the calvarium. The optimum diagnostic views in the posteroanterior projection occur whenever the base of the nose is level with the upper margin of the orbit. Computed tomography (CT) effectively demonstrates the presence of cysts but rarely is practicable in large animal species.¹³⁸⁴

Treatment

Praziquantel,* 50 to 100 mg/kg orally daily for 3 to 5 days, is effective for the treatment of coenurosis in sheep that do not yet have neurologic signs.^1380,1385 Concomitant administration of a nonsteroidal antiinflammatory drug (NSAID) or dexamethasone may enhance the posttreatment survival rate.

The cyst can also be removed surgically,¹³⁸⁶ with success rates as high as 90% reported.¹³⁸⁷ A craniotomy is performed over the site of the cyst. Approximately 70% of the cysts are located extradurally and can be removed easily with minimal dissection. The other cysts are located on the surface of the pia arachnoid, in which case the dura mater is incised. The cyst usually bulges from under the incised dura and can be removed. When the cyst is located in the cerebral cortex, ultrasound probes placed on the surface of the brain may be used to locate the pocket of fluid.^1388-1390

Prevention

In endemic areas the carcasses of affected animals should not be fed to dogs, and dogs in endemic areas should be treated repeatedly with a vermifuge to minimize the possibility of pasture contamination. Appropriate management practices have virtually eliminated this disease from North American sheep flocks. Lyophilized antigens from in vitro—cultured larvae have protected sheep; however, this preparation is not commercially available.

Definition and Etiology

Ceroid lipofuscinosis is a lysosomal storage disease that has been reported in South Hampshire, Swedish Landrace, and Rambouillet sheep, Nubian goats, Devon cattle, and horses.^1391-1396 The disease is known to be inherited as an autosomal recessive trait in many cases¹³⁹⁷ and is believed to be so in others.¹³⁹⁶ It is characterized by the intracellular accumulation of abnormal autofluorescent lipopigments in lysosomes of neurons and other cells throughout the body. The storage material has been shown to consist predominantly of the subunit c of mitochondrial c synthase.^1398,1399 The mechanism of neuronal dysfunction is hypothesized to be mediated by N-methyl-D-aspartate (NMDA) receptor excitotoxicity.¹⁴⁰⁰ Affected animals display progressive ataxia and postural abnormalities, blindness due to retinal involvement in many cases, sensory depression, and terminally, coma. Lesions seen on CT scans include enlargement of the lateral ventricles and reduced thickness of the cerebral cortex.¹⁴⁰¹

Gross pathologic lesions in the CNS may include moderate enlargement of the lateral ventricles, flattening of cerebral gyri, and a yellow to brown discoloration of the brain parenchyma. Accumulation of protein storage material in neuronal lysosomes is evident on microscopic examination and is accompanied by neuronal necrosis and astrocytosis, which may be severe. The lesions sometimes have a lamellar appearance.¹⁴⁰⁰ The disease is ultimately fatal, and no practical method of treatment is currently available.

Clinical Signs

Generalized seizures may consist of muscle contractions that are tonic, clonic, or alternating between tonic and clonic. Affected animals may fall and display various autonomic signs, such as salivation, urination, and defecation. During the seizure there may be dorsiflexion of the head and neck and rotation of the eyes. Postictal depression may last minutes to days. Blindness lasting minutes to weeks may be present postictally.¹⁴⁴⁰ Partial seizures may consist of tonic or clonic contractions of isolated muscle groups without loss of consciousness. Seizure disorders have been described in Romagnola,¹⁴⁴¹ Swedish Red,¹⁴⁴² Brown Swiss¹⁴⁴³ Hereford,¹⁴⁴⁴ Angus,¹⁴⁴⁵ Brahman,¹⁴⁴⁶ and crossbred¹⁴⁴⁷ cattle. A recent study in Angus cattle suggests that the previously described epilepsy may, in fact, be a cerebellar disease, with episodes of severe cerebellar dysfunction, rather than a true seizure disorder of cerebral origin (see also Bovine Familial Convulsions and Ataxia).¹⁴⁴⁸ Attacks in a 6-month-old Brown Swiss bull were prompted by undue excitement and declined in number with age.¹⁴⁴⁹ Young progeny exhibited similar attacks, suggesting that the trait was transmitted as an autosomal dominant genetic character.

Epilepsy has been poorly documented in horses but occurs in Arabians and in some ponies.¹⁴⁵⁰ There is anecdotal evidence of the existence of the condition in Paso Fino horses of the western United States. A condition known as “benign epilepsy” is seen in foals of many breeds, especially Arabians, but unlike true epilepsy, is usually outgrown. The condition in Arabians is termed “juvenile idiopathic epilepsy.” It occurs in animals of Egyptian lineage, is responsive to antiepileptic drugs (AEDs), and usually resolves by 1 to 2 years of age.¹⁴⁴⁰ Idiopathic epilepsy in mares has been associated with elevated levels of estrogen.¹⁴⁵¹

An epileptic condition in an 8-year-old Hereford cow has been described.¹⁴⁴⁴ The seizures began at 6½ years of age. Tonic-clonic convulsions could be elicited by administration of pentylenetetrazol at doses of 4 mg/kg, which was well below the convulsant dose for normal animals. EEG showed high-frequency spike bursts, spike and wave, and polyspike and sinusoidal wave abnormalities (Fig. 35-15). No microscopic abnormality could be found in the CNS of the affected animal. Partial epilepsy has been described in a 5-year-old Nubian goat with a 3½-year history of episodic convulsions. Between episodes the goat appeared to be healthy. The seizures appeared more often at times of peak endogenous plasma estrogen concentrations and could be induced by administration of ketamine. The clinical signs included repetitive tremors of the forelimbs and hindlimbs, head tremors, and mastication without loss of consciousness. The postictal depression lasted for several hours.¹⁴⁵²

Fig. 35-15 Electroencephalographic (EEG) recording of a tonic-clonic seizure in an epileptic cow elicited by injection of pentylenetetrazol (6 mg/kg IV, marker on time channel). High-frequency EEG changes began at the first arrow, the convulsion began at the second arrow, and vocalization began at the third arrow. Electrodes: left and right frontal (F₃, F₄), central (C₃, C₄), parietal (P₃, P₄), and occipital cortex (O₃-O₄). Calibration: 10 sec and 1 mV; recording bandwidth: 1 to 75 Hz.

From Strain GM, Olcott BM, Turk MAM: J Am Vet Med Assoc 191:833, 1987.

The EEG evaluation of seizure disorders may be performed using evocative drug challenges with pentylenetetrazol, ketamine, or other seizure-inducing agents and established techniques, but care must be taken to prevent injury to the animal. Although EEG may be of some value in investigation of epilepsy and other brain disorders,¹⁴⁵³ the need for sedation or anesthesia in large animals, combined with the paucity of data available for comparison, limits its usefulness.

Because of the rarity of epilepsy in large animals, specific drug therapies have not been established; however, Table 35-9 presents several drugs that could be administered. These drugs usually are highly protein bound in plasma and can be displaced or functionally altered by other drugs, including tetracycline and chloramphenicol. Because of these potential interactions, these agents should not be used concomitantly with the anticonvulsants.

All anticonvulsant treatments are begun at a low dose, which is increased daily or every second or third day until the seizures have been controlled. If seizures cannot be controlled without causing depression or ataxia, a second anticonvulsant is added. The dose of the second drug is gradually increased until the seizures stop. This combination treatment is continued for 2 to 4 weeks. Thereafter, the first anticonvulsant is tapered until it is discontinued. If seizures reappear, the dose of this drug is increased until they disappear again. After 1 month the trough blood concentration of all anticonvulsants is monitored. Therapeutic trough concentration of phenobarbital is 15 to 40 μg/mL of plasma and for diphenylhydantoin 5 to 20 μg/mL. Any attempt to withdraw anticonvulsant therapy should be made gradually, because rebound seizures may occur with too rapid withdrawal. Dosage recommendations have been established for potassium bromide in horses.¹⁴⁵⁴ A loading dose of 120 mg/kg daily for 5 days, followed by 90 mg/kg once daily, results in serum concentrations in the range found to be effective for seizure control in other species. However, the efficacy of potassium bromide for seizure control in large animals has yet to be established.

In many animals, epilepsy may be incurable because of its genetic basis. In these cases, treatment is rarely indicated. Horses with epilepsy should not be ridden or used for sporting purposes. Specific methods of control, other than breeding selection against affected animals, are unavailable.

Mares with estral-related seizures may be treated with an ovariectomy. All ruminants experiencing seizures should also immediately be treated with thiamine (10 to 20 mg/kg IM or SC three times daily, or diluted in 5% dextrose or isotonic fluid and given slowly IV) in case the seizural problem is caused by polioencephalomalacia (see previous discussion). The plasma sodium, magnesium, potassium, and calcium levels should be measured in all animals experiencing seizures of unknown origin. Infrequent seizures generally do not justify anticonvulsant treatment, and economic considerations often limit the amount of drug therapy possible. Status epilepticus can be treated with IV diazepam in 5-mg doses until the seizures are controlled or by titrated doses of phenobarbital or pentobarbital.

Definition and Etiology

Narcolepsy is a CNS disorder characterized by excessive daytime sleepiness, episodes of muscular weakness (cataplexy), and rapid eye movement (REM)–onset sleep.^1455-1457 Narcoleptic attacks differ from convulsions in that they do not involve tonic-clonic muscular activity.¹⁴⁵⁵ Cataplexy, a sudden episode of paralysis of the voluntary muscles, frequently is induced by stimulation of the patient and can range from atonic, areflexic paralysis of all nonrespiratory muscles to weakness of facial neck and forelimb muscles. Episodes of cataplexy last seconds to minutes. Environmental factors that can stimulate cataplectic attacks include active restraint, feeding, or changing the stall environment, grooming, or saddling horses in preparation for work.^{1455,1458-1460} Excessive daytime sleepiness and REM-onset sleep are difficult to document in large animals, so cataplexy is the most frequently recognized manifestation of sleep disorder in these species.¹⁴⁶¹ The disorder is considered an intrusion of aspects of REM sleep into the waking stage, especially the active descending paralysis of skeletal muscle. This intrusion results in indistinct boundaries between wakefulness and REM and non-REM sleep. Cataplectic attacks result from sequential activation of pontine α₁-adrenergic and muscarinic cholinergic systems. The numbers of muscarinic and dopaminergic receptors also are increased.^1456,1462

Attacks of narcolepsy and cataplexy are considered a paradoxic form of sleep because the EEG is characteristic of an alert, awake animal, but the REM is characteristic of deep sleep.¹⁴⁵⁵ Both neonatal-onset and adult-onset syndromes have been described in horses.¹⁴⁶³ Narcolepsy has been reported in quarter horses, a Shetland pony, thoroughbreds, Morgans, Paint horses, Arabians, Appaloosas, standardbreds, Welsh ponies, Suffolk sheep, Spanish fighting bulls, a Guernsey bull, and a Brahman bull.^{1459,1464-1468} A familial occurrence has been reported in American miniature horses.¹⁴⁶⁹

Clinical Signs

The clinical signs of narcolepsy include staggering, drooped head, kneeling posture, flaccidity of the lips, closure of the eyes, loss of the menace reflex, stertorous breathing, and proprioceptive deficits. During severe narcoleptic attacks the animal assumes lateral recumbency and appears comatose. The sensorium returns to normal after a time. In the periods between attacks, the patient appears normal.

The EEG changes of narcolepsy and cataplexy have been reported in cattle.¹⁴⁶⁴ The waveforms vary between low-voltage high-frequency (LVHF) and high-voltage low-frequency (HVLF) patterns, with LVHF corresponding to the actual period of narcoleptic attack (Fig. 35-16). The normal EEG sleep patterns of the horse are usually unavailable, so the technique has limited application for diagnosis of the condition in equine species.

Fig. 35-16 Electrophysiologic examination of a narcoleptic Brahman bull. The electroencephalogram shows low-voltage, high-frequency waves in all leads (i.e., left and right frontal [F₃, F₄], central [C₃, C₄], and parietal [P₃, P₄]). The electrooculogram (EOG) shows bursts of activity characteristic of rapid eye movement (REM) sleep, and the electromyogram (EMG) reflects data from extrinsic ocular muscles.

Cataplexy can be induced by IV administration of centrally acting cholinomimetics such as physostigmine salicylate (0.05 to 0.1 mg/kg) or α₁-adrenergic blockers such as prazocin (0.02 to 0.06 mg/kg), but attacks cannot be evoked in all animals. Signs can be reversed for several hours by antimuscarinic drugs such as atropine sulfate (0.02 to 0.1 mg/kg IV once for acute signs). Diagnostic drugs must be used with caution because of possibly inducing colic, especially in horses. Pathologic lesions have not been reported in narcolepsy of large animals. In humans, narcolepsy can be caused by lesions in the rostral brainstem.¹⁴⁵⁵

Treatment and Prevention

The tricyclic antidepressant imipramine can be used to treat narcolepsy or cataplexy. Lifelong treatment is required, which must be considered when deciding whether to treat affected large animals. Side effects of imipramine in horses can be serious, including tachycardia, muscle fasciculations, sensitivity to noise, and hemolysis.¹⁴⁷⁰ Such side effects can occur even when the blood level of imipramine is below the therapeutic range. This drug must be used with caution, and oral dosage in horses should not exceed 2 mg/kg; lower doses should be used when possible.¹⁴⁵⁷ Results of oral imipramine therapy are inconsistent¹⁴⁵⁷; duration of effect is about 5 hours.

Definition and Etiology

Listeriosis is an acute meningoencephalitis caused by the gram-positive bacterium Listeria monocytogenes. The disease has a worldwide distribution but occurs most often in temperate climates. Listeriosis typically affects ruminants, fowl, and humans but is rare in horses. The prevalence of listeric meningoencephalitis in infected herds does not usually exceed 1% of the adult animals at risk.¹⁴⁸⁷

Clinical forms of listeriosis include septicemia of neonates, abortion, neonatal death, ophthalmitis, septicemia and diarrhea of ewes, and neurologic disease.¹⁴⁸⁸ Usually, only one clinical form is recognized during an outbreak, and only one serovar can be isolated from the clinically affected animals. Neurologic listeriosis may manifest as a multifocal brainstem disorder, as a diffuse meningoencephalitis, or as a spinal cord myelitis. The condition usually affects individual animals but occasionally can affect several members of a herd.¹⁴⁸⁹ Asymptomatic intramammary infections apparently occur and may be responsible for outbreaks of listeriosis in humans. Repeated intramammary inoculation of 10⁶ to 10⁷ colony-forming units (CFUs) of L. monocytogenes into cattle resulted in 500 to 50,000 CFUs of Listeria in the milk for as long as 12 months.¹⁴⁹⁰

Clinical Signs

The neurologic signs of listeriosis in adults reflect dysfunction of the caudal brainstem, cerebellar peduncles, or spinal cord.¹⁴⁹¹ Signs common to most Listeria infections of the central nervous system (CNS) include fever, anorexia, depression, conscious proprioceptive deficits, head pressing, and centrally located cranial nerve deficiencies. Depressed consciousness is the result of lesions of the reticular activating system. Conscious proprioceptive deficits are caused by interference with the descending motor pathways and the ascending proprioceptive fibers in the brainstem and may precede or accompany cranial nerve dysfunction. The fever occurs early in the disease course and often disappears after 3 to 5 days. Head pressing and propulsive walking or compulsive circling are caused by lesions of the basal ganglia.

Cranial nerves (CNs) V through XII usually are dysfunctional in listeric animals. Patients with loss of the trigeminal nerve (CN V) show dropped jaw or asymmetric jaw closure and facial analgesia or anesthesia. Facial analgesia is best detected by stimulation of the nasal septum with a pencil or piece of straw. Animals with lesions of CN VI exhibit a medial strabismus on the ipsilateral side of the lesion. Animals with lesions of CN VII have ptosis, loss of menace response, absent palpebral reflex, drooped ear, loss of levator nasolabialis muscle function, and decreased lip tone (Fig. 35-18). Small ruminants with CN VII loss have a deviated philtrum. The paralysis of the orbicularis oculi muscle results in exposure keratitis and, in chronic cases, panophthalmitis.¹⁴⁹² The loss of levator nasolabialis function is best detected by observation of the muscular contraction on the dorsum of the nose during inspiration. Loss of lip and cheek muscle tone is best detected by observation of drooling of saliva from the ipsilateral side of the mouth and by palpation of the lips and nostrils.

Fig. 35-18 Clinical appearance of the neurologic form of listeriosis in a Charolais bull. Note the dropped right eye and ear and the drooling of saliva from the right side of the mouth.

Courtesy Dr. W.D. Wilson.

Animals with CN VIII lesions display a nystagmus that changes as the position of the head is altered. Other signs include a head tilt toward the side of the lesion and a tendency to circle or fall to the lesion side. The nystagmus may be horizontal, vertical, or rotatory and usually is inconstant. Goats may lie on their backs with the head curved toward the trunk and tilted with the lesion side toward the ground. If the spinal reflexes can be tested, the affected animals show a mild to moderate hypertonia and hyperreflexia in the limbs opposite the side of the lesion. Lesions of the cerebellar peduncles (juxtarestiform body) may cause paradoxic vestibular signs in which the head tilt and circling are directed away from the side of the lesion and proprioceptive deficits are on the same side as the lesion.¹⁴⁹³ This should be suspected whenever the head tilt is directed toward the side opposite that of the other dysfunctional cranial nerves. Animals with acute loss of CNs IX, X, and XII develop stertorous breathing and dysphagia. Animals with dysfunctional CN XII have paresis or paralysis of the tongue. With unilateral lesions the tongue protrudes from the side of the mouth ipsilateral to the lesion. Progression of listeriosis is associated with decreased consciousness, coma, and convulsions.

Lambs may selectively develop spinal myelitis without brainstem disease. This condition results in flaccid paraparesis or hemiparesis without attendant signs of brainstem dysfunction.¹⁴⁹⁴ The clinical signs of myelitis include tetraparesis, tetraplegia, paraparesis, paraplegia, conscious proprioceptive deficits, and recumbency. The sensorium and appetite are normal in some affected animals and greatly depressed in others.¹⁴⁹⁵

Clinical Pathology

The clinical signs of multifocal brainstem disease with fever in a ruminant are suggestive of listeriosis, Haemophilus somnus infection (cattle), or aberrant parasite migration. Examination of the cerebrospinal fluid (CSF) should be helpful for confirming a diagnosis of listeriosis, but the cell and protein concentrations of the specimens do not correlate with the severity of the clinical signs or the prognosis. The protein concentration in the CSF may be more than 40 μg/dL, and the CSF white blood cell (WBC) counts may be more than 12 mononuclear cells/μL.^{1487,1496,1497} Many cattle with advanced signs of listeriosis develop metabolic acidosis as a result of salivary bicarbonate loss.

Pathology

Pathologic confirmation of listeriosis is based on identification of multifocal microabscesses in the brainstem and isolation of L. monocytogenes from infected brain tissue. The agent is only rarely isolated from CSF and is best recovered from refrigerated nervous tissues. Enrichment of the Listeria organisms may be accomplished by refrigerating slices of brain at 4° C (39.1° F) for 3 months while culturing the tissues weekly. In contrast to septicemic listeriosis of monogastric animals, peripheral monocytosis is not observed in infected ruminants.

Pathophysiology

Listeria organisms produce a hemolysin, listeriolysin-O, a thiol-activated toxin (molecular weight, 58 kD) that is correlated with pathogenicity. The molecular role of the toxin in dissemination of the infection and in cell death is not known.

It is unclear whether infection of the brain by L. monocytogenes occurs hematogenously or by ascent from the cranial nerve rootlets.¹⁴⁹⁸ Morphologic studies of naturally occurring cases of encephalitic listeriosis have demonstrated the bacterium in the axons of the trigeminal nerve rootlets, indicating a possible centripetal migration.^1498,1499 Similar findings have been reported in animals infected experimentally.¹⁵⁰⁰ Younger animals may be susceptible because eruption of the permanent teeth may expose trigeminal nerve rootlets. A model for experimental induction of listeriosis by inoculation of the bacterium into the pulp cavity of sheep has been described.¹⁵⁰¹ Infection of the CNS without bacteremia has been detected, indicating that centripetal migration of the bacterium is possible.¹⁵⁰² Some investigators consider axonal migration as an unlikely mode of pathogenesis because of a lack of nutritional dependency of L. monocytogenes for nervous tissue and the ready ability to produce multifocal brain microabscesses by intravenous (IV) inoculation of the bacteria into susceptible hosts.^1498,1503

Epidemiology

L. monocytogenes has 16 major serologic types based on comparison of somatic and flagellar antigens. Most clinical infections are caused by serovars 1/2a, 1/2b, 4a, and 4b. Listeria ivanovii, usually associated with abortions in sheep, also has been classified as L. monocytogenes serovar 5. The serovar 1/2 (a and b subtypes) is most prevalent in livestock. The 1/2b subtype appears to be exclusively related to encephalitic infections, whereas other subtypes, including 1/2a, can be associated with any of the clinical forms of listeriosis.¹⁵⁰⁴ The pathogenicity of serovar 1/2a is hemolysin dependent. Serogroup 1/2 (a or b type) is most often isolated from feedstuffs. Serovar 4b is responsible for most infections in humans.¹⁵⁰⁵

The case-attack rate in ruminants may reach 9% but rarely is greater than 2%.¹⁵⁰⁶ Listeriosis occurs sporadically in weaned lambs confined to a drylot and appears in only a small proportion of the lambs at risk. The encephalitis usually occurs from 4 to 32 days after weaning and at 6 to 12 weeks of age. Between 0.7% and 1.6% of all lambs at risk may develop the infection.¹⁵⁰⁷ In untreated cases the fatality rate is almost 100%.¹⁴⁹¹ The survival rate in treated animals is considerably higher than in untreated patients. The disease in sheep and goats tends to be more acute and results in a higher case-fatality rate than in cattle. Occasional outbreaks of listeriosis may occur in sheep without access to silage.^1491,1508 In these cases the source may be the feces of carrier animals or rotting vegetation on the pastures or feed bunks. During an outbreak of listeriosis, the bacterium can be isolated from the feces of a large percentage of normal animals.¹⁵⁰⁹ It is unclear whether this high rate of asymptomatic infections represents a true carrier state or is simply the result of a high environmental contamination by nonpathogenic isolates.¹⁵⁰⁹ The agent infects the udder but rarely causes clinical mastitis. In sheep, excretion of the bacterium in the milk is greatest during the immediate postlambing period.^1510,1511

Listeria monocytogenes can survive for long periods in the environment and in asymptomatic carriers. The bacterium can multiply at low environmental temperatures and is resistant to environmental influences. L. monocytogenes is shed in the feces of asymptomatic carriers, especially at the end of pregnancy and at lambing. Once in the environment, the bacterium can survive for 2 years in dry soil. It is resistant to freezing and thawing in the soil but does not survive for more than 1 to 2 weeks in properly preserved silage. The bacterium proliferates in rotting vegetation in which aerobic conditions exist and the pH is above 5.4.^1512-1514 Common sources of contaminated forage include spoiled silage at the ends of trench silos, decaying forage at the bottom of feed bunks, or rotting hay at the periphery of hay stacks.^1512,1515 The incidence of listeriosis may be increasing because of the greater use of trench silos and bulk handling methods that result in a greater amount of spoilage than in conventional upright silos. Although L. monocytogenes can be isolated from silage with a pH below 4, fewer bacteria are found in well-preserved forage.¹⁵¹⁶

A selective enrichment medium has been developed for identifying and enumerating the Listeria organisms in silage. This medium permits semiquantitative enumeration of Listeria bacteria in 10 g of silage. Hemolysin production is measured by overlaying the colonies with bovine blood agar and reincubating the plates. Using this method, outbreaks of listeriosis have been correlated with silage containing 1 million Listeria organisms and more than 1 million enterobacteria per gram of silage. The pH of such silage characteristically is above 7.8.¹⁵¹⁷

There is a significant public health concern about Listeria contamination of milk products. The 4b serotype of L. monocytogenes is most often responsible for infections in humans.¹⁵¹⁸ Outbreaks have been traced to ingestion of pasteurized milk, cole slaw, and soft, ripened cheese. The occurrence in cheese has led to concerns that the bacterium may survive the pasteurization process¹⁵¹⁹; however, heat resistance by Listeria organisms does not appear to be a significant factor in milk-related human exposures. One study indicated that intracellular Listeria bacteria survived after exposure to temperatures as high as 73.9° C (165° F) for 16.4 seconds. Complete killing of the Listeria organisms required temperatures as high 76.4° C (169.5° F) for 15.4 seconds. These temperatures exceeded the minimum temperatures required by the U.S. Food and Drug Administration (71.7° C [161° F] for 15 seconds).¹⁵²⁰ The public health implications of these findings are unclear.

Pathologic Lesions

The lesions of listeric meningoencephalitis are most common in the pons and the trapezoid bodies, but they can be located anywhere in the brainstem. Neurologic structures most often affected include the reticular formation and CNs V and VII to X. Macroscopic lesions are limited to mild meningeal congestion and clouding of the CSF. Microscopic lesions include perivascular cuffing with mononuclear cells, multifocal asymmetric brainstem microabscesses, and mononuclear cell meningoencephalitis.¹⁵²¹ The microabscesses are composed predominantly of neutrophils. Other microscopic changes include degeneration of the neuropil and neuronophagia. To enhance the speed and accuracy of pathologic diagnosis, a peroxidase-antiperoxidase method has been developed for use with formalin-fixed nervous tissue. The test detects degraded bacterial proteins, as well as intact bacteria in the suspect tissue. Bacterial antigen is exclusively located in areas of malacia or in the microabscesses.¹⁵²²

Treatment

The recovery rate is best if treatment is administered early in the disease course. Animals that are recumbent, comatose, or convulsive rarely survive despite intensive antibiotic and supportive therapy. In most cases, treatment must be administered for a prolonged period because recovery may take as long as 1 month. L. monocytogenes is susceptible to most of the common antimicrobial drugs. Recommended treatment is either oxytetracycline, 10 mg/kg intravenously (IV) twice daily, or penicillin G.¹⁴⁹² Specific recommendations for penicillin therapy include an initial dosage of 40,000 IU/kg (IV potassium penicillin G) three or four times daily for 7 days and then 22,000 IU/kg (procaine penicillin) intramuscularly (IM) once daily for 14 to 21 additional days.¹⁴⁹²

The plasma concentrations of bicarbonate and potassium should be measured and specific corrective fluid therapy administered. Maintenance fluids also may be administered by gavage. Good footing and nursing care are helpful in the short term but may not influence the overall recovery rate.¹⁵²³

Prevention

Serologic responses to flagellin and listeriolysin-O develop after oral administration of virulent L. monocytogenes and correlate with protection against listerial bacteremia.¹⁵⁰² Cell-mediated immune responses also are important in protection against virulent challenge. Vaccines of attenuated or killed bacteria have been used successfully to protect sheep and goats. Although these vaccines reduce the incidence of listeriosis in vaccinated flocks, they are not commercially available in the United States.

Although the case-attack rate of listeriosis is low, occasional epizootics may occur in cattle, sheep, or goat herds, invariably associated with high rates of environmental contamination. In such cases the hay and silage should be examined culturally for L. monocytogenes. Rotten vegetation should be discarded, and cattle should be fenced from contaminated areas.

Definition and Etiology

Thromboembolic meningoencephalitis (TEME) is a fulminant neurologic disease of cattle that arises from septicemia caused by the pleomorphic, nonencapsulated, gram-negative bacterium Histophilus somni (formerly Haemophilus somnus).¹⁵²⁴ The disease was first reported in Colorado in 1956,¹⁵²⁵ but characterization of the etiologic agent, H. somni, was not completed until 1960.¹⁵²⁶ The disease is economically significant for livestock owners. One study in feedlots of western Canada indicated that the average economic loss from TEME resulted in 15 sick animals and five deaths annually, amounting to $3190 in lost revenue.¹⁵²⁷ In addition to TEME, disease syndromes that have been associated with H. somni infection include pneumonia, infertility, metritis, vulvitis, orchitis, conjunctivitis, otitis, and mastitis.^1528-1530 The bacterium has been isolated from unthrifty calves, but its causative relationship to that syndrome is unclear.

Cross-agglutination, complement fixation tests and countercurrent immunoelectrophoresis have shown the existence of common surface antigens among isolates of H. somni.¹⁵³¹ Nevertheless, differences in the susceptibility of heterologous isolates of H. somni to antibody and complement have been identified.¹⁵³² Isolates from septicemic animals are serum resistant, whereas those from preputial or vaginal mucosa of healthy animals tend to be serum susceptible.

Clinical Signs

Only the neurologic syndrome (TEME) is discussed here. Descriptions of other clinical syndromes of H. somni infection are discussed in Chapters 31, 39 and 43. The neurologic signs of TEME occur peracutely and may be preceded for 1 to 2 weeks by a dry, harsh cough and dyspnea.¹⁵³³ Death may occur within 36 hours after the onset of neurologic signs. The initial signs of TEME are fever (40° C to 41.6° C; 104° F to 107° F), anorexia, depression, and ataxia.^1534-1536 In addition to depression, affected animals show a number of conscious proprioceptive deficits, including knuckling, circumduction, crossing over, and interference.¹⁵³⁶ Affected animals may fall while attempting to walk. Signs specifically associated with lesions of the cerebellum and caudal brainstem include head tilt, nystagmus, strabismus, blindness, muscular tremors, opisthotonos, coma, and convulsions.¹⁵³⁷ Auscultatory abnormalities in the chest include harsh bronchovesicular sounds and pleural friction rubs. Localization of the bacterium in the joints or lungs may result in lameness, joint swelling, and fluctuant swellings over the joint surface. Other signs observed in some animals include retinal hemorrhages, hyphema, and hypopyon.^1535,1538

After recovery from the pneumonia, some affected animals may develop pleuritis, necrotic laryngitis, and weight loss.¹⁵³⁹ Some symptomatic animals and as many as 10% of inapparently infected cattle may develop suppurative arthritis of the hock and the stifle joints.

Clinical Pathology

Examination of CSF may be helpful in substantiating a clinical diagnosis of TEME. Specific CSF changes characteristic of hemorrhage include high erythrocyte counts, xanthochromia, and increased concentrations of protein (>100 mg/dL) and neutrophils (>500 WBCs/μL). In untreated cases of TEME, the bacterium may be isolated from pleural fluid, lung sections, aspirated tracheal exudate, urine, blood, and preputial washings. The bacterium can be isolated from 25% to 34% of all fatally infected cattle.¹⁵³⁷ Histophilus organisms die rapidly on swabs or transport media, so specimens should be inoculated directly onto a growth medium as soon as they are collected from the patient.¹⁵³⁰ The inoculated medium should be incubated in an atmosphere containing 5% carbon dioxide. Isolation of H. somnus from joint fluid and CSF usually is unsuccessful.¹⁵⁴⁰ The kidneys and brain should be collected at postmortem examination because these tissues contain the highest concentrations of H. somni.¹⁵⁴⁰

Initial changes in the peripheral WBC count include neutropenia, left shift, and toxic changes in the neutrophils. A test for serum agglutinins has been developed. Cattle that develop acute TEME invariably have antibody titers greater than 1:400 and show a fourfold increase by 2 to 4 days after infection.¹⁵⁴¹ Serum agglutination titers greater than 1:1024 are seen in convalescent cattle; lower titers may be seen with inapparent infection or vaccination.¹⁵⁴²

Pathophysiology

Infection of cattle by H. somni probably occurs through the respiratory tract. Bacterial proliferation in the lungs and other soft tissues by serum-resistant isolates results in bacteremia. Circulating Histophilus organisms are phagocytosed by neutrophils but are not killed. Blood-borne bacteria also adhere to and may be phagocytosed by the cells of the vascular endothelium. The infected endothelial cells then degenerate and desquamate, exposing the subendothelial collagen and initiating the blood-clotting cascade and thrombosis.¹⁵⁴³ Death of neutrophils in the tissues is thought to enhance the tissue damage.^1544,1545 The sites of the body most affected by the thrombosis are the brainstem, spinal cord, synovial membranes, pleura, and lungs. Although the name “thromboembolic meningoencephalitis” implies the presence of disseminated coagulopathy, only local thrombus formation likely occurs at the specific vascular lesion. Immunologic mechanisms may play a role in the vascular lesion. Thrombosis occurs most often in animals with high levels of specific agglutinating antibodies and is not seen in colostrum-deprived calves with H. somni septicemia, indicating the importance of antigen-antibody complexes for the development of vasculitis.¹⁵⁴⁶

Cattle probably develop immunity to H. somni infection; however, the presence of serum antibodies does not always confer substantial protection against challenge exposure by virulent bacteria.

Epidemiology

Most cattle develop Histophilus infection by inhalation of contaminated respiratory secretions from carrier animals. Although TEME occurs most frequently in feedlot cattle,¹⁵³⁶ outbreaks in the western United States and Canada have been reported in both pasture and dry-lot environments.^1534,1547 The disease occasionally may occur in adult cattle.¹⁵²⁷ Outbreaks of the neurologic form of TEME tend to occur in the winter months, after shipment or overcrowding, or after additions to the herd in the previous 7 months. Outbreaks usually are preceded by a poorly defined respiratory infection.¹⁵²⁷ In feedlot outbreaks the disease frequently is restricted to herdmates in a single pen or pasture.

Transmission of H. somni from asymptomatic carriers to uninfected calves may be enhanced by concomitant infection with infectious bovine rhinotracheitis virus.¹⁵³⁵ The anatomic site of bacterial infection in the carrier animals is unknown. Histophilus organisms can be readily isolated from the vaginal and urethral epithelium and from urine, the preputial cavity, and accessory sex glands, but the relationship between these isolates and those found in TEME is unknown.¹⁵⁴⁸ Although random bacteriologic surveys of cattle indicated that 71% of bulls may have H. somni in the preputial orifice, the concentration in the nasal secretions and upper respiratory tract epithelium in cattle with TEME is low.¹⁵⁴⁸ Consequently, some investigators have suggested that the urogenital tract may constitute the primary colonization site in chronically infected cattle.¹⁵⁴⁸ Differences exist in serum susceptibility of isolates from the CNS and from the urogenital tract.¹⁵³²

The seroprevalence rate may be as high as 100% in some endemic herds and may range from 25% to 56% in herds in which the CNS disease is uncommon. In comparison, the case-attack rate of TEME ranges from 2% to 7.4%.¹⁵⁴⁹ Repeated annual outbreaks can occur in some herds. Estimates of the proportion of carrier animals in feedlots range from 3.2% to 8.8%.

Necropsy Findings

Cattle with the neurologic lesions do not tend to develop fibrinous pneumonia. Macroscopic pathologic lesions of the CNS include disseminated multifocal hemorrhages and 0.1-cm to 0.3-cm infarctions in the spinal cord, brainstem, and cerebral cortex. Bacterial colonies frequently are observed in thrombosed blood vessels and the surrounding infarcted tissues. Ocular lesions are characterized by conjunctivitis, multifocal retinal hemorrhages, and areas of retinal edema. The CSF is cloudy and xanthochromic. A focal fibrinous meningitis is seen, and suppurative otitis may be seen in some cases.

The earliest microscopic lesion of TEME is a vasculitis that progresses to septic infarction and abscessation. The lesions usually are found in the CNS but in severe cases may be disseminated throughout the body.

Nonneurologic lesions of H. somni infection include suppurative arthritis, synovitis, suppurative pleuritis, and bronchopneumonia. Changes associated with the bronchopneumonia include infarction, cranioventral pulmonary consolidation, and hemorrhagic interstitial pneumonia. Simultaneous pulmonary infections with H. somni and Pasteurella multocida result in particularly severe pathologic changes.¹⁵⁵⁰ These lesions include ecchymotic to petechial hemorrhages over the serous surfaces, purulent exudate in the joints, and ulceration of the laryngeal and tracheal mucosa with pseudodiphtheritic membrane formation.¹⁵⁵¹

Treatment and Prognosis

During an outbreak, cattle must be examined frequently and should be treated when the neurologic signs first appear. H. somni is susceptible to many antibiotics and antimicrobial drugs. Drugs that have been reported to be effective for the treatment of TEME include tetracyclines, penicillin, aminoglycosides, and ampicillin. Parenteral oxytetracycline is regarded as the most cost-effective treatment for infected commercial cattle; dosage is 10 mg/kg of a conventional formulation given IV twice daily for 3 days or 20 mg/kg of a long-acting formulation given IM every other day for three treatments. After oxytetracycline therapy, daily treatment with procaine penicillin (10,000 to 20,000 IU/kg IM) should be continued until complete recovery is observed. Some advocate the addition of chlortetracycline (2.2 mg/kg) to the feed for 10 successive days.¹⁵⁵² This method of mass therapy for a TEME epizootic is considered more efficacious than vaccination when the mortality is less than 2%.¹⁵⁵²

Prevention and Control

Antibody responses protective against respiratory challenge have been generated by vaccinating cattle with anionic, heat-stable proteins derived from the bacterial cell wall.¹⁵⁵³ In comparison, cattle vaccinated with cationic cell wall proteins developed precipitating antibodies but were not protected against challenge exposure.¹⁵⁵³ Bactericidal antibodies may constitute important mechanisms for host resistance against H. somni.^1545,1550 Vaccination of cattle with commercial products affords substantial protection from experimentally induced H. somni septicemia and neurologic disease^1533,1554 for as long as 95 days after vaccination.¹⁵³³ (See Chapter 48 for more information about vaccines.)

Mass prophylactic treatment of affected cattle with a parenterally administered, long-acting oxytetracycline formulation may be efficacious for preventing TEME in cattle that have been stressed and exposed to carrier animals.¹⁵⁵⁵ Oxytetracycline feed additives also may be useful for preventing H. somnus infection.¹⁵⁵¹ One field study indicated that administration of modified live virus vaccines for infectious bovine rhinotracheitis and bovine viral diarrhea on arrival at a feedlot significantly increased the incidence of TEME.¹⁵⁵⁰ Such data indicate that modified live virus vaccines should be administered cautiously to cattle exposed to H. somni.

Definition and Etiology

Vestibular disease of horses is an acute, asymmetric condition with one of several causes: extension of pyogenic bacterial infections from the guttural pouch, polyneuritis equi, viral labyrinthitis, and traumatic skull fractures.^1579-1581 Idiopathic labyrinthitis probably represents an acute viral inflammation of the vestibular system that is severe,¹⁵⁸⁰ but spontaneous recovery is common. Lightning strike also has been suspected as the cause of vestibular signs in horses.¹⁵⁸²

Vestibular disease may also be caused by pyogenic inflammation of the petrous temporal bone or membranous labyrinths. Staphylococci, streptococci, and Aspergillus species have been isolated from cases of suppurative otitis in horses.^1579,1583 Two forms of suppurative otitis media-interna have been identified.^1579,1583 In the least severe form, the pyogenic inflammation localizes in the petrous temporal bone but does not spread into the calvarium or rupture the tympanum. This infection results in vestibular signs. This mild form of otitis media-interna also causes dysfunction of CNs VII and VIII.

Clinical Signs

The clinical course of peripheral vestibular disease may be chronic with acute exacerbations. Recovery is common with appropriate therapy. The more severe form occurs when the pyogenic inflammation extends outward into the temporohyoid joint and stylohyoid bone.¹⁵⁸³ The inflammatory process fuses the tympanohyoid joint, which fractures during strong contractions of the muscles of the pharynx and neck. The fracture line extends into the calvarium, resulting in hematoma formation in the CNS. Pyogenic agents from the original septic site may then gain access to the CNS and cause meningitis. The clinical signs are peracute, and mortality is high. Extension of the fracture lines along the cranial vault and osteomyelitis result in dysfunction of CNs VII and VIII and the cerebrum. Affected horses show a rapid deterioration in mental status immediately after the initial onset of clinical signs. Involvement of the temporohyoid bone can be recognized on radiographic examination of the head and pharynx. The radiographic changes include thickening and pathologic fracture of the stylohyoid bone and tympanosclerosis.

Early clinical signs may appear to be unrelated to the CNS. The horse may appear to be uncomfortable and may shake the head or rub the affected ear for 2 to 3 weeks before the onset of vestibular signs. Otorrhea is not usually observed. The neurologic signs appear suddenly. Horses with mild disease develop ataxia, head tilt, facial paralysis, and nystagmus. The nystagmus is not changed by movement of the head (rapid phase away from the side of the lesion). There also is a ventrolateral strabismus on the side of the lesion. The affected animals circle or more often lean against the stall walls for support. Frequently, a mild conscious proprioceptive deficit is worse on the affected side. Horses with severe calvarium fractures fall and become recumbent. They lie with the side of the lesion facing the floor. Because of the proximity of the facial nerve to the vestibular apparatus in the petrous temporal bone, most affected horses also show signs of facial palsy, including drooped ear and lips, drooling of saliva, ptosis, exposure keratitis, and deviation of the philtrum toward the opposite side of the lesion (Fig. 35-19). If extensive bleeding into the calvarium has occurred, the animal becomes blind in the eye contralateral to the side of the hematoma. Pressure in the cerebral cortex may result in mydriatic pupils on the ipsilateral side. Lesions located central to the geniculate ganglion denervate the lacrimal glands and result in keratitis sicca.

Fig. 35-19 Head tilt and right-sided facial paresis in a horse with peripheral vestibular disease.

Courtesy Dr. W.D. Wilson.

Horses with lesions of the peripheral vestibular system remain appetent and alert. In comparison, animals with vestibular disease accompanied by petrous temporal bone fractures and meningitis tend to be depressed, febrile, and inappetent. Animals that develop septic meningitis secondary to a temporal bone fracture show rapid deterioration of mental status, rigidity, or flailing of the limbs with mild stimulation, stiffness of the neck, hyperesthesia, fever, otorrhea, and dysphagia.¹⁵⁸⁴

Diagnosis and Treatment

Ancillary diagnostic measures for vestibular disease in horses include skull radiographs and endoscopic examination of the guttural pouch to exclude the possibility of tympanosclerosis, fractured hyoid bone, or fungal otitis. Otic examination in the horse in difficult because of the external ear anatomy in this species and the resistance of horses to this type of examination. Chemical restraint and the use of video otoscopy can facilitate both otoscopic examination and the sampling of material from the external ear for microscopic examination and culture.¹⁵⁸⁵ The rate of tear secretion may be tested with a Schirmer tear test strip. The normal rate of tear secretion is approximately 21 mm/min, whereas deficient tear production is less than 17 mm/min. Brainstem auditory-evoked response testing may help to establish the localization of vestibular signs as peripheral in origin rather than central.¹⁵⁸⁶

Antibiotic treatment of peripheral vestibular disease should include high doses of penicillin (20,000 to 40,000 IU/kg IV four times daily) or, as an alternative, a third-generation cephalosporin or trimethoprim-sulfonamide combination. The alternative drugs should be considered when infection by penicillin-resistant bacteria is suspected. One study reported clinical improvement in patients treated with chloramphenicol (10 mg/kg orally four times daily).¹⁵⁸³

Patients with early cases of vestibular disease may benefit from treatment with nonsteroidal antiinflammatory drugs (NSAIDs). Administration of corticosteroids in the acute stages of the disease may ameliorate the clinical signs, but the beneficial antiinflammatory effects of these drugs should be weighed against the potential for nonspecific immune suppression and ultimate extension of pyogenic foci into the CNS along cracks in the calvarium.

Affected horses should be kept in a quiet, heavily bedded stall with good footing. Exposure keratitis may be treated by performing a tarsorrhaphy or by repeatedly administering petrolatum ophthalmic-lubricating ointments. Horses with keratoconjunctivitis sicca may be treated with 0.25% pilocarpine eyedrops four times daily.¹⁵⁸⁷

Horses that recover after long-term antibiotic therapy should be used cautiously because subtle neurologic deficits that interfere with coordinated motor activities could precipitate catastrophic accidents. Relapses may occur in some seemingly recovered patients.

Definition and Etiology

Nigropallidal encephalomalacia is a disease of adult horses characterized by facial dystonia, variable ataxia, mild depression, and food retention in the mouth. The disease is caused by ingestion of large quantities of the plants Centaurea solstitialis (yellow star thistle) or Centaurea repens (Russian knapweed).^1592-1595

Clinical Signs

The signs appear suddenly but always after long-term ingestion of large quantities of the plants. Characteristic signs of nigropallidal encephalomalacia common to all cases include weight loss, mild to moderate depression, conscious proprioceptive deficits, yawning, lowered head, protruding tongue, tremor of the tongue and lips, and facial hypertonicity when feed is offered. The facial hypertonicity causes a retraction of the lips, resulting in a fixed grimace with the mouth and lips held half-open (Fig. 35-20). The patient may display constant chewing movements, and prehension, mastication, and deglutition of food are uncoordinated and inefficient. Affected horses can grasp food in their incisors but are unable to chew adequately and propel the food to the back of the mouth. Food retained in the mouth and cheek pouches may protrude from the commissures of the lips. Affected animals may attempt to drink by immersing their muzzles deeply into the bucket to force the water into the back of the pharynx. Once the food or water is in the posterior part of the pharynx, the animal is able to swallow. Affected animals die of starvation or dehydration. Horses that appear to be depressed usually can be aroused by mild stimulation. Motor and sensory deficits include hypertonicity, ataxia, conscious proprioceptive deficits, and occasionally hypermetria. There also may be a transient tendency to walk propulsively or to circle. Occasionally the animals are hyperexcitable. After several days the signs stabilize, and the disease does not progress. Affected animals usually do not recover.

Fig. 35-20 Characterisitc facial expression of a horse with nigropallidal encephalomalacia. When the animal is offered feed, the marked dystonia of the facial muscles, caused by loss of upper motor neuron inhibition, becomes obvious.

Courtesy Dr. G.P. Carlson.

Diagnosis

The CSF of affected horses may show increases in WBC count (75/μL).¹⁵⁹⁴ There are no characteristic changes in the complete blood count (CBC) or the serum chemistries. Magnetic resonance imaging (MRI) was used to make an antemortem diagnosis in one horse with nigropallidal encephalomalacia.¹⁵⁹⁶

Pathophysiology

The toxic principle in the plants has been isolated and chemically characterized. The toxic molecule is called repin, a sesquiterpene lactone with high affinity for neural tissue.^1597-1600 Long-term feeding of alcoholic extracts containing repin to monkeys has resulted in collapse, convulsions, and death.¹⁶⁰¹ Studies in rats suggest that repin exerts its neurotoxic effects by inhibiting dopamine release.¹⁶⁰⁰ Additional neurotoxic compounds, including aspartic and glutamic acids, also have been isolated from Centaurea plants.¹⁶⁰²

Necropsy Findings

At necropsy, sharply demarcated areas of yellowish malacia are visible grossly in the substantia nigra and globus pallidus (extrapyramidal system). Lesions are bilaterally symmetric in more than 50% of cases but are asymmetric in a substantial proportion of affected animals. Lesions in other brainstem nuclei are found in a small number of animals.^1593,1603 Microscopic lesions include neuronal necrosis, vacuolation with gliosis, liquefactive necrosis, and cavitation in well-developed lesions.¹⁵⁹⁷

Epidemiology

Nigropallidal encephalomalacia has been reported in horses of the United States, Australia, and South America. Yellow star thistle is a common plant in unirrigated pastures in the arid regions of the western United States. The plant is resistant to the effects of saline or alkaline soil conditions and has a minimum moisture requirement. Russian knapweed belongs to the sunflower family and grows predominantly on flood plains, where it can extract deep subterranean moisture. In the United States the plants tend to remain green during the dry months, so most poisonings occur during the summer or late autumn. Most horses are reluctant to eat Centaurea plants unless other vegetation is unavailable, but some develop a craving and selectively seek it out. Horses that develop nigropallidal encephalomalacia usually are being fed a poor-quality, high-roughage diet. Affected horses range from 4 months to 10 years of age (median, 2 years).¹⁵⁹⁷ The case-attack rates of yellow star thistle poisoning range from 3% to 31% of horses on infested pastures.¹⁵⁹⁷ Feeding studies have reported that as much as 59% to 200% of the body weight of yellow star thistle and 59% to 63% of Russian knapweed must be eaten over 3 to 11 weeks to cause clinical disease.^1593,1597 Continuous protracted exposure to the weeds seems to be important for expression of clinical disease. The dried plants retain their toxicity.

Treatment and Prevention

There is no known treatment for the poisoning. Prevention is best aimed at correcting the nutritional problem by daily supplementation with 10 to 15 lb of alfalfa hay and by not pasturing horses in areas where the thistle grows.

Definition and Etiology

Horner’s syndrome results from interruption of ocular sympathetic pathways. Sympathetic fibers originate from neuronal cell bodies located in the mesencephalic tectum. Axons descend to the first to third thoracic (T1 to T3) segments of the spinal cord, where they enter the gray matter, synapse, and exit through the ventral spinal nerves. From there the nerves pass through the cervicothoracic and middle cervical ganglia (stellate ganglia) and ascend in the cranial vagosympathetic trunk.¹⁶⁰⁵ The nerves enter the cranial ganglion in the petrous temporal bone, where they synapse. The postganglionic fibers are distributed to the sweat glands of the head, ciliary muscles, periorbital smooth muscles, and periarteriolar musculature. Fibers of the vagosympathetic trunk or the cranial cervical ganglion can be injured as they pass through the neck or over the caudodorsal aspect of the guttural pouch.

Specific causes of Horner’s syndrome include mycotic guttural pouch infections; traumatic lesions of the basisphenoid area; cervical trauma; abscesses, tumors, or space-occupying lesions in the anterior aspect of the thorax^1606,1607; periorbital abscesses or tumors; parotid duct obstruction and inflammation¹⁶⁰⁸; esophageal rupture; and complications associated with surgical ligation of the carotid artery. Intracranial lesions involving the central components of the sympathetic pathway in the ipsilateral brainstem are rare but have been reported as a consequence of metastatic neoplasia.¹⁶⁰⁹ Horner’s syndrome also has occurred after IV injection of certain drugs, including xylazine, vitamin E or selenium, and phenylbutazone.^1610-1612 Horner’s syndrome has also been seen in horses with polyneuritis equi (cauda equina neuritis) syndrome and equine protozoal myeloencephalitis of the cervical spinal cord.^1613,1614 Tumors that have resulted in Horner’s syndrome include sclerosing respiratory epithelial carcinoma, squamous cell carcinoma, and melanoma.^{1606,1607,1610,1615,1616}

Clinical Signs

The clinical signs of Horner’s syndrome in horses vary but include miosis, enophthalmos, ptosis, regional hyperthermia, excessive sweating on the ipsilateral side of the face, congested mucous membranes, inspiratory stridor, and dermatitis caused by chronic sweating. Ptosis may be detected by palpation of decreased eyelid tone. The palpebral reflex and the menace response are normal. Facial sweating often disappears 6 to 14 days after sympathectomy. If concomitant damage to the cervical sympathetic nerves is present, sweating of the skin of the neck also may be seen. This is not observed in animals with lesions solely in the tectotegmentospinal pathway. Regional hyperthermia is caused by vasodilation, which results from deficient vasomotor tonus. Sweating is thought to be caused by vasodilation and increased cutaneous blood flow.^1617,1618 Increased sweating can be induced by β₂-agonists, including IV clenbuterol (200 μg) or isoprenaline (2 mg) or local application of 10% phenylephrine.¹⁶¹⁹ Dysfunction of adjacent neurologic structures may result in simultaneous facial nerve paralysis and laryngeal hemiplegia. Bilateral Horner’s syndrome has been reported in a horse with metastatic neoplasia affecting the sympathetic innervation of the head bilaterally.¹⁶¹⁶ This horse had a mixed pattern of both preganglionic and postganglionic denervation caused by widespread metastases at multiple sites along the nerves.

In contrast to the disease in horses, cattle do not sweat on the planum nasale of the affected side. This can be explained by the mediation of normal sweat gland secretion by α-adrenergic receptors in the bovine.¹⁶¹⁸ The other signs seen in cattle are similar to those in horses. The clinical signs of experimentally induced Horner’s syndrome in sheep and goats are limited to a mild ptosis.¹⁶¹⁸ Retrobulbar tumors may cause Horner’s syndrome, but in these cases the eyeball proptosis results from the excessive retrobulbar pressure.¹⁶¹⁵

Diagnosis

The specific site of the denervation of the ocular sympathetic system usually can be located by pharmacologic testing.¹⁶⁰⁵ Hydroxyamphetamine (1% solution) instilled into the eye will result in release of norepinephrine from intact postganglionic sympathetic neurons, causing pupillary dilation, but no response when the postganglionic neurons are damaged. A positive response to this test indicates a preganglionic sympathetic lesion, and a lack of response indicates a postganglionic lesion. In animals with a postganglionic lesion, topical administration of 0.1 mL of 1:1000 epinephrine solution directly activates the iris musculature and produces mydriasis by 20 minutes, whereas the onset of dilation occurs at about 40 minutes in animals with preganglionic lesions. Similarly, 2.5% to 10% phenylephrine solution will produce pupillary dilation in an eye with a postganglionic sympathetic lesion, but not in a normal eye. The increased sensitivity to these direct-acting sympathomimetics in animals with postganglionic sympathetic lesions results from the phenomenon of “denervation supersensitivity,” with numbers and sensitivity of norepinephrine receptors in the iris muscle increasing over days to weeks after postganglionic nerve injury. A positive response is therefore expected only after the nerve lesion has been present for at least several days. Parenteral administration of 1 mL of 1:1000 epinephrine solution causes affected horses to sweat profusely over the affected side of the face.¹⁶¹⁰ However, this test does not differentiate between preganglionic and postganglionic lesions.

The guttural pouches of horses and the pharynx of all patients should be examined endoscopically to exclude the possibility of pharyngeal or laryngeal paralysis or guttural pouch disease. The jugular furrows should be palpated for swellings. Insertion of a nasogastric tube during palpation may be helpful for detecting subtle lesions on the left side of the neck. Radiographs of the cervical vertebrae should be obtained to exclude spinal cord disease. The thorax should be examined using auscultation and percussion and, if indicated, radiographs taken. The gait and proprioceptive responses should be examined to evaluate the function of the spinal cord. The skin temperature may be measured using thermography^1607,1620; on the affected side it is 1° C to 2.5° C (33.4° F to 37.5° F) higher than normal.

Treatment

The treatment for Horner’s syndrome depends on the underlying cause of the denervation. Except for Horner’s syndrome related to IV injection of xylazine, the neurologic signs often are irreversible, even if the primary cause of the condition has been eliminated. When xylazine is administered IV, the condition disappears spontaneously. The situation differs from inadvertent perivascular drug injections, in which permanent neurologic sequelae may occur. The necrotizing effects of perivascular drug injections can be minimized if treatment is administered immediately. These treatments should include aseptic infusion of large volumes of saline at the perivascular injection site and systemic administration of NSAIDs or dexamethasone, or both. Abscesses should be drained, and fungal infections of the guttural pouch should be treated as described in Chapter 31.

Definition and Etiology

In one retrospective survey, mycotic infections of the guttural pouch were the third most common disease of the upper respiratory tract of horses.¹⁶²¹ The clinical signs occur because fungal infections in the medial part of the pouch extend dorsally and damage CNs IX through XII and the internal carotid artery. Mycotic guttural pouch infection usually occurs in older animals; however, horses as young as 3 months have been affected.¹⁶²²

Clinical Signs

Initially the horse may display head shaking and unilateral nasal discharge. Additional clinical signs are nasal catarrh, dysphagia, head shyness, head shaking, roaring, dysphonia, protrusion of the tongue from the mouth, and epistaxis^1622-1624 (Fig. 35-21). Other clinical signs include parotid pain, abnormal head posture, facial sweating, shivering, Horner’s syndrome, colic, hemiparesis to hemiplegia of the tongue on the affected side, and facial paralysis.^1622-1628 Epistaxis may be fulminant and life threatening. The abnormal head posture is characterized by a tendency to hold the head in extension or lower to the ground than normal. Atrophy of the brachiocephalicus and trapezius muscles occurs secondary to denervation of the accessory spinal nerve. Horner’s syndrome occurs secondary to damage of the cranial cervical ganglion and sympathetic trunk. The sensorium is intact unless aspiration pneumonia develops or the fungus embolizes into the brain.^1629,1630 Occasionally, affected horses die peracutely as a result of exsanguination from a ruptured internal carotid artery. Endoscopic examination of the larynx of affected horses may reveal dorsal displacement of the soft palate, inability to swallow, and unilateral or bilateral laryngeal hemiplegia. Mycotic guttural pouch infection can be definitively diagnosed by endoscopically identifying the characteristic fungal mass in the dorsomedial compartment (Fig. 35-22). Radiographic examination of the pouches shows a poorly defined border of the pouch in the abnormal area. Extension of a mycotic infection from the guttural pouch to the brain through the internal carotid artery has been reported.¹⁶³⁰ The infection caused disseminated necrosis and hemorrhage that was most severe in the thalamus, cerebral cortex, and hippocampus. The clinical signs were fever (38.3° C; 100.9° F), epistaxis, dysphagia, laryngeal hemiplegia, pharyngeal paralysis, circling, unilateral blindness, mydriasis, facial paralysis, and apprehension.

Fig. 35-21 Regurgitation of food material from the nose of a dysphagic horse with pharyngeal paralysis. The horse had a mycotic infection of the guttural pouch.

Fig. 35-22 Appearance of a mycotic lesion in the dorsomedial compartment of the guttural pouch. Arrows outline the mycotic plaque.

Pathophysiology

The guttural pouch is separated into two compartments by the stylohyoid bone and the occipitohyoideus muscle. CNs IX through XII and the internal carotid artery are located in the dorsomedial aspect of the medial compartment and are susceptible to damage from mycotic infections. Extension to the cranial nerves occurs because of inflammation and direct destruction of these structures by the fungal elements. Pathologic studies have shown swelling of the myelin sheaths and Schwann cells. Some sections demonstrate necrosis of the nerves and invasion by fungal elements.¹⁶³¹

In chronic infections the fungal lesion may extend into the tympanic bulla and cause vestibular disease. Extensive growth of the lesion also results in temporomandibular osteoarthropathy and fusion of the temporomandibular joint or osteoarthritis of the atlantooccipital joint. Excessive muscular force on the fused joint can result in avulsion fractures of the petrous temporal bone and calvarium. Hemorrhage or spread of infection into the vestibular apparatus and calvarium results in acute vestibular disease, cerebral hemorrhage, and septic meningitis (see Peripheral Vestibular Disease of Horses). In rare cases, fungal elements may reach into the lateral compartment, invade the wall of the internal maxillary artery, and affect the facial nerve. Facial nerve paralysis also has been observed and results from abscessation of the parotid lymph nodes secondary to a fungal guttural pouch infection.¹⁶²³ In other rare cases, Horner’s syndrome may be caused by mycotic lesions in the cranial cervical ganglion. The syndrome also may occur iatrogenically during surgical ligation of the external carotid artery.¹⁶³² Occasionally, the mycotic infection may extend into the brain and cause encephalitic signs.¹⁶²⁹

Treatment

Before the onset of neurologic disturbances, the internal carotid artery may be occluded using a ligature or by insertion of a balloon-tipped catheter.¹⁶³³ During the exploration the fungal mass is debrided surgically. The surgical procedure is effective for preventing fatal epistaxis but may not reduce the potential for progression of the infection, resulting in nerve deficits or extension of the infection to the CNS. Some studies have shown excellent resolution of the mycotic lesion in horses that underwent carotid artery occlusion with or without additional antifungal therapy,^1634-1636 but in other animals the lesion may progress despite complete arterial occlusion.¹⁶²⁸ Moreover, optic neuropathy and blindness of the ipsilateral eye are common postsurgical sequelae.¹⁶³⁷ Neurologic signs may be permanent, although improvement or recovery over many months has been reported in some horses.¹⁶³⁶ Affected horses often are euthanized for humane reasons. (See Chapter 31 for treatment of guttural pouch mycosis.)

CEREBELLAR HYPOPLASIA CAUSED BY CONGENITAL BOVINE VIRAL DIARRHEA VIRUS INFECTION

A complete discussion of bovine viral diarrhea–mucosal disease (BVD-MD) can be found in Chapter 32. BVD virus infection of susceptible pregnant cattle from 90 to 170 days’ gestation results in abortion or stillbirth, hydranencephaly, or cerebellar hypoplasia in the fetus.^1638,1639 These signs are also seen in calves born to susceptible dams vaccinated during gestation with a modified live BVD vaccine.¹⁶⁴⁰ The BVD virus infects the developing germinal cells of the cerebellum and kills Purkinje’s cells in the granular layer, resulting in necrosis and inflammation.¹⁶⁴¹ Such cerebellar lesions tend to be most severe by 21 days after inoculation of the susceptible pregnant dams.¹⁶³⁸ The microscopic lesions include necrosis of the external germinal cells, focal parenchymal hemorrhages, and folial edema. After infection the acute inflammatory responses subside by 42 days, when the microscopic changes include cavities ranging from 1 to 7 mm in diameter, thinning of the neuropil, atrophy of the cerebellar folia, axonal torpedoes, and mild reactive astrocytosis. Calves infected with vaccine virus between 90 and 118 days’ gestation may develop hydrocephalus and hydranencephaly.¹⁶⁴²

The signs of cerebellar dysfunction usually are present at birth and include truncal ataxia, falling backward, opisthotonos, base-wide stance, coarse intentional head tremors, hypermetria, hyperreflexia, and nystagmus or strabismus (Fig. 35-23).^1643,1644 If severely affected, the animal may be unable to stand or lie in sternal recumbency. Excitatory stimuli in these animals precipitate wild oscillations and side-to-side movements of the head, which can be mistaken for convulsions. The affected calves may have a deficient menace response and appear to be blind, especially with concomitant hydranencephaly or microphthalmia. The neurologic condition rarely improves after birth. Other fetal changes that may be induced by the BVD virus include thymic atrophy, retinal degeneration, corneal opacity, failure to grow, and abortion.^1638,1643 The diagnosis of cerebellar hypoplasia is based on identification of the specific clinical signs and the recognition of BVD antibodies in precolostral blood specimens. The virus may be cultured from the blood of some affected calves. Viral antigen has been detected in the spleen, kidneys, and lymph nodes of aborted fetuses.¹⁶⁴⁴ The virus cannot usually be isolated from immunocompetent calves after antiviral antibody responses develop but may be recovered repeatedly from immunoincompetent, seronegative calves. Bluetongue virus may also occasionally cause cerebellar lesions in calves and lambs.

Fig. 35-23 Characteristic head position and base-wide stance of a calf with cerebellar hypoplasia.

Clinical Signs

The onset of clinical signs ranges from 2 to 3 hours after birth to 3 months of age. Calves may be born dead at or near term or may be aborted. Some aborted calves have a dorsiflexion of the spine. Most affected calves are born alive and rapidly develop intermittent signs of cerebellar dysfunction with multiple “tetaniform seizures” that last 3 to 12 hours. Two forms of seizures have been described. One form is characterized by a generalized stiffness and inability to protract the legs, elevation of the tailhead, and head-neck extension with mild head tremor. The animals are hyperesthetic. A more severe form is characterized by lateral recumbency, loss of consciousness, opisthotonos, hypertonicity, tonic-clonic seizures, and trismus. Animals may improve greatly if supported during the tetaniform activity. The frequency of the seizures declines over several months, but animals are left with a permanent ataxia characterized by cerebellar signs. The attacks may be precipitated by sudden, violent auditory, olfactory, visual, or tactile stimuli. These could include driving by dogs, shipment, flashing lights, loud sounds, or painful tactile stimulation. These features of the attacks, combined with a lack of electroencephalographic (EEG) evidence of seizure activity in the cerebrums of affected calves, suggest that these episodes may be exacerbations of cerebellar signs rather than true seizures.¹⁶⁶² There is no response to treatment with electrolytes, mineral supplements, or B-complex vitamin injections. Seizure-like activity can be controlled by administration of barbiturates or inhalational anesthetics.

Most animals improve when turned out to grass pastures, but episodic relapses associated with excitement may occur for as long as 2 years. Affected animals gradually recover and by 2 years of age either show only mild cerebellar signs or are completely normal. There are no specific diagnostic tests for the disease.

Pathology

The gross appearance of the brain is normal. Microscopic lesions are restricted to the cerebellar cortex and include swelling and vacuolation of Purkinje’s cells, chromatolysis, loss of neurofibrils, and formation of axonal torpedoes. The axonal structures have been defined as “argyrophilic axonal swellings.” They are located in the granular layer of the lingula, uvula, and adjacent parts of the vermis. An early report stated that these lesions were not seen in affected animals under 6 weeks of age, but a more recent study found lesions in affected animals of all ages.^1661,1663

Diagnosis

Diagnosis is based on the presence of typical clinical signs, particularly when several related animals are affected. Differential diagnoses include cerebellar hypoplasia caused by congenital BVD virus infection, hypomyelinogenesis, congenital brain malformations affecting structures in the caudal fossa, congenital storage diseases, and the various cerebellar abiotrophies described in cattle.¹⁶⁶² Imaging studies (e.g., CT, MRI) are expected to be within normal limits.¹⁶⁶² Definitive diagnosis can be made only on histologic examination postmortem.

Treatment and Control

There is no known treatment for bovine familial convulsions and ataxia. Affected animals can be fattened and slaughtered but should not be used as breeding stock because the disease is genetically transmitted. Elimination of carrier animals from the breeding population will effectively control the propagation of this disease.

Pathology

The diagnosis of a clinical case of mannosidosis can be substantiated pathologically by observation of cytoplasmic vacuolation in the neurons of the cerebrum, cerebellum, brainstem, and spinal cord.¹⁶⁷⁵ There is also a mild to marked internal hydrocephalus. The microscopic appearance of the brain of affected calves is characterized by vacuolation of the neurons and astrocytes and by reactive astrocytosis.¹⁶⁷⁵ The vacuolation is not restricted to the nervous system, however, and can be seen in Kupffer’s cells, pancreatic exocrine cells, fibrocytes, and macrophages of the spleen and lymph nodes.¹⁶⁸¹ The vacuoles are lined by a single membrane and are thought to be part of the Golgi apparatus.¹⁶⁸¹ Associated neuronal changes include axonal swelling and spheroids.

Because of the hereditary nature of the disease, the ancestry of affected animals should be traced, and the biochemical phenotypes of related individuals should be tested. Both biochemical and molecular testing facilitate early detection of carrier animals, enabling their elimination from breeding programs.¹⁶⁸² Although bone marrow transplantation has been shown to correct the defect in the feline and murine models of α-mannosidosis,^1683-1685 there is currently no effective and practical treatment for α-mannosidosis of cattle.