Salt (Sodium) Poisoning (With or Without Concurrent Water Deprivation)

Lisle W. George • John R. Middleton

■ Definition and Etiology Salt (sodium) poisoning is a common CNS disease of livestock. Ingestion of sodium-rich solutions over time can cause production-related losses and even death.

The acute toxic doses of oral NaCl have been reported as approximately 2.2 g/kg body weight for cattle and horses and approximately 6 g/kg for sheep.⁵ With water restriction, the toxic dose is considerably lower, and poisoning has resulted from ingestion of 0.9% NaCl in water-restricted cattle.⁶ Chronic toxicity can occur at lower dietary NaCl levels than can acute toxicity. Ingestion of water with NaCl concentrations above 1% uniformly results in toxicosis if no other source of ion-free water is provided.^7,8

Ingestion of water containing 0.7% NaCl impairs the fertility of females,⁸ and water containing 0.25% NaCl suppresses milk production in cattle.⁹ Dairy calves have been poisoned by daily feeding of 4 L of milk replacer containing 2.6% NaCl.¹⁰ Animals are most susceptible to salt poisoning during the summer because of the increased insensitive loss of water at that time. Salt poisoning in ruminants is most frequently a syndrome of concurrent “water intoxication”: a period of restricted access to water, followed by unrestricted access to water.^1,3,4 In such cases, the dietary intake of sodium can be relatively modest, but disease occurs once water enters the extracellular fluid and moves into the brain tissue.

■ Epidemiology Animals are tolerant of high dietary sodium levels if they have concomitant access to fresh drinking water. Feedstuffs that are common sources of excessive sodium include whey, saline-preserved fish or fish meals, bakery by-products, and certain milk replacers.¹¹ Confined calves may be poisoned by improperly formulated milk replacers or oral electrolyte solutions.^11,12 Brine is used extensively as a flush during the drilling of oil wells, and cattle eagerly ingest large amounts of oil well sludge in the western and southwestern United States.^13-15 Effluents from drilling rigs may contain as much as 100,000 ppm NaCl. Drilling effluent is also contaminated by heavy metals and magnesium salts, which complicate the clinical syndrome of salt poisoning.

Concurrent neurologic disease may predispose animals to reduced water intake, as occurred in a group of goats with locoweed (Oxytropis spp.) poisoning who became water deprived because of reluctance to move to a water source. They developed clinical and pathologic evidence of sodium poisoning when moved subsequently to an area where water was easily available.³ Sodium poisoning caused by water restriction may result either from freezing of water sources in northern climates or from intentional water restriction of veal calves.¹² Ingestion of brackish or tidal water is a cause of sodium poisoning in cattle pastured in the coastal regions of the world.

■ Pathogenesis In salt poisoning, disease can occur acutely after ingestion of a large quantity of NaCl or chronically after long periods of reduced water consumption with low to moderate sodium intake. Thus hypernatremia results from an imbalance in sodium and water regulation. Increases in plasma sodium concentration cause movement of intracellular water into the extracellular fluid causing cellular dehydration. Cerebral dehydration is transient but is probably the cause of clinical signs in acute sodium overload.

Within a few hours, osmotic adaptation begins to occur, whereby there is a net flow of fluid from the CSF into the brain interstitium as a result of a reduction in hydraulic pressure caused by the initial cerebral dehydration, and cellular uptake of Na, K, Cl, and organic solutes (osmolytes) increases intracel­lular osmolality, pulling water into cells and restoring cell volume.¹⁸ Hence, with chronic hypernatremia, the animal may not manifest symptoms in the presence of high plasma sodium concentrations because of osmotic adaptation in the brain. In such cases, however, rapidly reducing plasma sodium concentra­tions and thus plasma osmolality during treatment or when the animal drinks large volumes of ion-free water can result in movement of free water into the brain; this causes edema and neurologic deterioration because loss of the accumulated osmolytes occurs more slowly than the relatively rapid loss of excess Na and K ions taken up during osmotic adaptation.

GI signs may also occur when animals ingest large quantities of salt over short periods of time. The hyperosmolality in the intestinal lumen results in saline catharsis and osmotic diarrhea.

■ Clinical Signs Acute ingestion of large amounts of salt

7 10 19 20

causes GI and neurologic signs.'^,,, These include muco- hemorrhagic diarrhea and colic, head-neck extension (“stargaz­ing”), blindness, aggressiveness, hyperexcitability, psychomotor seizures (characterized by paddling and loss of consciousness), vocalization, ataxia, proprioceptive deficits, head pressing, constant chewing movements, nystagmus, muscle twitching, and coma. Death occurs as a result of respiratory failure. Before the onset of neurologic signs, cattle with chronic salt toxicosis may appear to be depressed and dehydrated.

Excessive salt intake may also interfere with productivity in the absence of acute neurologic signs. In one study, cattle were given either tap water (196 ppm of dissolved salts) or saline (2500 ppm NaCl), and their milk production was measured.⁹ Cows given tap water had greater fluid intake and significantly greater lactational persistence and daily milk production than did cows given saline, despite the fact that the latter group showed normonatremia and normokalemia. This study illustrates the importance of provision of high-quality water for optimization of milk production.

■ Clinical Pathology and Diagnosis The clinical diagnosis of salt poisoning depends on the demonstration of exposure to toxic concentrations (>7000 ppm or 0.7% of sodium), the presence of water deprivation, or the determination of serum or CSF sodium concentrations greater than 160 mEq/L (occasionally exceeding 200 mEq/L).¹² Ratios of CSF sodium to serum sodium that exceed 1: 1 also suggest salt poisoning. The plasma sodium concentration may vary, depending on whether the patient had recently been given ion-free water before measurement. Some animals with acute neurologic lesions may be normonatremic if they have recently drunk to repletion with ion-free water, whereas others that have not had ion-free water may be hypernatremic.

Ruminal sodium concentrations above 0.36% to 0.5% or brain sodium concentrations above 150 mEq/g or 1800 ppm²¹ also suggest salt poisoning in cattle.^12,19,22 Rapid intake of low-sodium water during the rehydration phase of the disease may cause intravascular hemolysis with resultant hemoglo­binuria; such findings raise the index of suspicion of salt poisoning.²

■ Pathology The pathologic changes of salt poisoning include cerebral edema and softening and flattening of the cortical gyri. Microscopic lesions include laminar cortical necrosis, poliomalacia, and, on occasion, meningeal or peri­vascular infiltration of eosinophils, mononuclear cells, or both.

■ Treatment and Control Treatment of animals affected by salt poisoning is difficult. Many animals die even after intensive medical treatment. Prognosis depends on severity of clinical signs at the start of treatment: Animals that already have significant cerebral edema have a guarded prognosis. Therapy should be aimed at limiting the ingestion of nonionic water and attempting to remove intracellular solutes slowly from the brain while simultaneously controlling cerebral edema and attendant CNS signs. To prevent brain swelling and hernia­tion of the brain through the foramen magnum or the tentorium cerebelli, slow reduction of the CSF and plasma sodium is imperative. Slowly lowering plasma Na concentrations over time by means of intravenous fluids is recommended.

Slight underestimation of fluids is preferable to excess fluid administration. Serum sodium should be monitored regularly and correction effected over 24 hours or longer. Oral fluids can be introduced gradually toward the end of the first day of treatment; salt should initially be added to oral fluids to make them isotonic to blood. When IV replacement is not feasible, isotonic to hypertonic oral fluids should be administered at a maintenance level, divided into four to six feedings daily. Access to low-salt water is gradually allowed after 3 to 4 days. Any worsening of clinical signs is an indication to increase the salt level in fluids, and IV mannitol (0.5 to 2.0 g/kg as a 20% solution) or oral glycerin (1 mL/kg diluted 50 : 50 with water) may be necessary to reduce cerebral edema.²

High-sodium crystalloid solutions (HSCS) have been used for individual treatment of severe hypernatremia, which might develop in salt poisoning.²³ Sodium (as dry salt or, if metabolic acidosis is present, as sodium bicarbonate) is added to normal (0.9%) saline to create a final sodium concentration in the HSCS that is 10 to 15 mEq/L lower than the patient's serum sodium concentration. Dry table salt (17 mEq NaCl/g) can also be added to 0.9% saline to achieve the desired sodium concentration in the HSCS.

The use of solutions containing 5% glucose is contraindi­cated because this represents ion-free extracellular fluid, which can exacerbate brain edema. Administration of corticosteroids (dexamethasone, 0.04 to 0.08 mg/kg by slow IV injection twice daily for 2 to 3 days) may be helpful in animals with acute cerebral edema. If the neurologic signs diminish and the plasma sodium level returns to normal, the animal may be given fresh drinking water. Thiamine (10 mg/kg SC) may be a useful adjunctive therapy.

Control measures are centered on ensuring appropriate dietary sodium intake and ad libitum availability of ion-free drinking water. Cattle should be fenced away from polluted ponds and oil wells. Cattle on coastal pastures should have access to fresh ion-free well water. The total daily dietary salt intake should not exceed 4% of dry matter intake. Drinking water must contain less than 7000 ppm of sodium unless the dietary sodium load is reduced correspondingly. Oral rehydrating fluids and milk replacers for calves should be mixed with ion-free water in strict accordance with the manufacturer's recommendations. Assessment of water cleanliness and availability should be a component of a daily animal husbandry plan.

Vitamin A Deficiency

■ Definition and Etiology Vitamin A (retinol) is found in green plants and can be synthesized from plant carotenoid precursors in the liver and intestinal mucosa. Precursors of vitamin A are usually fed in cattle rations as β-carotene or as retinoids. Vitamin A deficiency occurs primarily in growing ruminants in feedlots. Deficiency develops under these condi­tions because the growing animal has a higher requirement for the vitamin, and feedlot-reared animals may have limited access to succulent plants. Exposure to ultraviolet light inactivates vitamin A in stored feedstuffs. Diets that are naturally low in vitamin A include cereal grains, beet pulp, and cottonseed hulls. Conditions in which the immune system is challenged, as when exposure to pathogens is high, also increase the requirement for vitamin A. Other scenarios conducive to vitamin A deficiency include prolonged grazing on dry pastures or cereal grains other than corn, exclusive feeding of cereal grains that have been stored at high temperature and humidity, or prolonged feeding of mineral oil as a preventive for frothy bloat.

■ Epidemiology The vitamin A requirement for common livestock species ranges from 40 to 110 lU/kg daily.^1-3 The minimum recommended daily dose of vitamin A for growing calves up to 1 year of age, for pregnant sheep, and for growing horses is 40 IU/kg. Pregnant cattle and pregnant and lactating horses require 40 to 50 IU (13.76 to 17.2 μgZkg) of vitamin A daily.² Lactating cattle require 80 IU (27.5 ug/kg) of vitamin A daily. Horses are susceptible to vitamin A deficiency, but the condition is rare; this situation is thought to be the result of differing conditions of management rather than an inherent resistance to the deficiency. The daily dietary requirement for carotene in cattle, sheep, and swine is 0.12 mg/kg.² Pasture forage, silage, and properly cured hay (may also be increased (>200 mm Hg).¹⁹

■ Pathology The major pathologic changes in the fundus of vitamin A-deficient calves include papilledema, small flame­shaped hemorrhages around the optic disk, venous congestion in the area of the swollen optic disk, degeneration of the retinal ganglion cells, focal retinal thinning, and fusion of parts of the retina to the choroid plexus.¹⁵ Other changes associated with vitamin A deficiency include doming of the frontal bones, enlargement of the carpi, cerebellar and cerebral compression, partial transtentorial herniation of the cerebellum, cystic dilation of the hypophyseal cleft, focal ruminal hyperkeratosis, and increased keratinization of the squamous epithelium of the penile and the preputial mucous membrane. Corneal ulceration and clouding have been observed in the eyes of calves with naturally occurring deficiencies.¹⁸ Vitamin A deficiency also can cause anasarca, squamous metaplasia of the salivary ducts, degeneration of the germinal testicular epithelium, degenerative changes in the intestinal epithelium in lambs, and reduction in intramuscular fat in cattle.^20-22

Microscopic changes in the CNS include attenuation of the optic nerve with necrosis and demyelination. Focal accu­mulations of phagocytic cells containing lipofuscin and hemosiderin are present in the necrotic area. The optic nerve is attenuated along its entire length. The meninges are thickened by fibrosis and mononuclear cell inflammation. The microscopic changes in the bones include wider-than-normal spacing of the central canals and reduction of osteoclastic lacunae.

■ Treatment and Control Cattle with severe blindness caused by damage to the retina or optic nerves do not regain their vision when treated with vitamin A; however, cattle with acute encephalopathy and simple papilledema may respond favorably after a short period of vitamin supplementation.² Affected cattle should receive 440 IU/kg of vitamin A parenter­ally and then 6000 IU/kg parenterally every 50 to 60 days until the diet has been enriched. High-dose oral therapy is important because carotene and oil suspensions of vitamin A are not efficiently utilized when administered by parenteral injection.²³ Administration of large doses orally is important because conversion of β-carotene to vitamin A is inhibited in deficient calves. The recommended concentration of vitamin A in milk replacers for preruminant calves is 11,000 IU/kg dry matter.¹⁴

Prophylactic dietary supplementation of vitamin A should be considered in all cattle that lack access to green feed. Dietary supplements could include leafy, freshly cured hay, green pasture, or alfalfa meal. Concentrate feeds formulated with exogenous, stabilized vitamin A are commercially available. Recommended concentrations (per kilogram of dry matter) of vitamin A in feed are 2200 IU for feedlot cattle, 2800 IU for pregnant cows, and 3900 IU for lactating cows.⁴

Hydrocephalus and Hydranencephaly of Ruminants

■ Definition and Etiology Hydrocephalus/hydranencephaly is an apparently common abnormality of the CNS in large ruminants. It is probably 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.¹ Hydrocephalus may be classified as hypertensive or normotensive.²

Normotensive Hydrocephalus (Hydranencephaly)

Normotensive hydrocephalus that develops as a result of a failure of cell growth or cellular necrosis is called hydranen­cephaly.² Most cases of hydranencephaly in domestic livestock are caused by in utero infection of the fetus by viral pathogens such as bluetongue, BVD, Akabane, Cache Valley, Aino, border disease, and Schmallenberg viruses.^1,3-13 The pathogenesis and epizootiology of bluetongue and BVD are discussed in detail in Chapter 32. The neurologic effects of border disease virus infection are discussed earlier in this chapter.

The loss of fetal neurons in utero results in flexural con­tractions of the limbs (arthrogryposis), which may manifest as dystocia. Affected neonates may be stillborn or born alive but weak, blind, unable to stand, and unable to nurse. They may exhibit a dysphonia, which resembles a bark. Neonates that are unable to nurse fail to ingest colostrum and often die from septicemia.

AKABANE VIRUS INFECTION. The Akabane virus is a member of the Simbu serogroup of the Orthobunyavirus genus in the Peribunyaviridae family.³ It has been isolated from cattle in Africa, Japan, Israel, Korea, and Australia.^4-9 Hosts of Akabane virus include sheep, cattle, and goats. Infection of pregnant, nonimmune dams results in hydranencephaly or arthrogryposis of the fetus.¹⁴ The disease is thought to be transmitted to the cow by various Culicoides spp. Experimentally infected calves develop porencephaly and encephalitis when exposed to the Akabane virus between gestational days 62 and 96.¹⁵ Studies in naturally infected cattle showed that infection of calves between days 76 and 104 of gestation resulted in hydranen- cephaly or porencephaly, whereas infection between days 103 and 174 of gestation resulted in arthrogryposis.¹⁶ Lambs are susceptible when exposed to the virus between gestational days 30 and 36.⁹ The CNS lesions are apparently the result of a direct necrotizing effect of the virus on the developing neurons. The pathologic changes in the CNS of experimentally infected calves and lambs are similar to those of naturally acquired infections.^6,9 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 it resembles the disorder caused by congenital Akabane virus infection, results of breeding trials indicated autosomal recessive inheritance for the disease.¹⁷

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.^18-20 Aino virus is antigeni- cally and biologically distinct from Akabane virus, but the clinical syndromes of fetal infection by the two viruses are indistinguishable.

CHUZAN VIRUS INFECTION. Hydrocephalus, hydranen- cephaly, and cerebellar hypoplasia have been attributed to infection of pregnant cattle with the Chuzan virus.^21-23 This virus is a relative of the Akabane and Aino viruses and is a 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 (microcephaly, cerebellar hypoplasia, porencephaly) in newborn lambs in the southwestern United States was attributed to in utero infection with the Cache Valley virus (family Peribunyaviridae).^24,25 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 deer in the survival of the virus and the transmission of the disease to livestock is unknown.²⁶ In one survey of sheep in the western United States, the seroprevalence for the Cache Valley virus was 19.1%.²⁴ Vectors for the virus include Anopheles, Aedes, Culex, and Coquellettidia mosquitoes.²⁷ Infection before 30 days of gestation may cause embryonic death, and infection between days 30 and 52 causes fetal malformations.²⁷

BLUETONGUE VIRUS INFECTION. Hydranencephaly, arthro­gryposis, or both may occur in ruminants when the dam is infected at specific times during gestation; abortions or fetal resorption can also occur. Serotypes 11 and 17 are the serotypes most frequently isolated from neonatal calves and lambs in field epizootics.^28,29 Bluetongue virus serotype 8 has caused devastat­ing disease in ruminants in Central and Northern Europe; of importances is that neonates infected in utero may be born viremic, thereby providing Culicoides spp. with more abundant viremic hosts during the subsequent spring.³⁰ Calves, lambs, and kids infected in utero may be born normal or manifest one or more associated birth defects, including hydranencephaly, arthrogryposis, brachygnathia, prognathia, and excessive gingival tissue (see Chapter 32 for additional information).

BOVINE VIRAL DIARRHEA VIRUS INFECTION. Hydranen- cephaly, hydrocephalus, and cerebellar hypoplasia have been associated with fetal infection of cattle with the BVD virus.^31-34 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 without demonstrable antibody.

SCHMALLENBERG VIRUS INFECTION. The Schmallenberg virus is an enveloped RNA virus belonging to the genus Ortbobunyavirus.¹'⁰ The Schmallenberg virus is a member of the Simbu serogroup, which includes the well-known teratogenic Akabane virus. It is named after a town in west-central Germany where, in the autumn of 2011, signs of this viral disease first emerged in local cattle. Diagnosticians at the Friedrich-Loeffler Institute (the Federal Research Institute for Animal Health) subsequently identified this virus as a cause of transient fever, depression, reduced milk production, and occasional diarrhea in cattle. The virus was subsequently detected in several countries in continental Europe, the British Isles, the Mediter­ranean Basin, and Turkey.¹² During the fall of 2011, infections in small ruminants in the region were predominantly asymptomatic; however, once ruminant birthing commenced in late 2011 and early 2012, it became apparent that the virus had induced significant fetal morbidity and mortality, primarily in sheep but in goats and cattle as well.

Fetal infection with Schmallenberg virus may result in abortion or stillbirth; newborns may be weak, may have sig­nificant neurologic deficits, or may be normal and healthy. On the basis of the pathophysiologic features of Akabane viral infections, the outcome of fetal infection with Schmallenberg virus is considered to probably depend on the timing of viral infection in relation to the stage of fetal development.^10,11 Infection early in gestation, within the first trimester, appears to result in the most significant fetal deformities, with arthro­gryposis of one or more limbs, torticollis, spinal malformations (scoliosis, kyphosis, lordosis, or a combination of these), brachygnathia inferior, and a multitude of CNS malforma- tions.^10,11 Hydranencephaly, porencephaly, and hydrocephalus are among the more common neurologic malformations. According to the OIE, the clinical disease in ruminants can best be categorized as an arthrogryposis/hydranencephaly syn­drome.¹⁰ Fetal limb, neck, and spinal skeletal anomalies can result in dystocia. To date, there have been no reports of Schmallenberg virus causing human infections, and the virus is not currently considered to be a zoonotic threat.

As is the case with other members of the Orthobunyavirus genus, Schmallenberg virus is an arthropod-borne virus, and Culicoides spp. midges (e.g., Culicoides obsoletus) are currently considered the vector in Europe.¹³ Other vectors, however, may also be involved. Vertical transmission of the virus from infected ruminant dam to ruminant fetus is considered to be the primary means of spread within animals. Horizontal transmission is a possible but less likely means of transmission.

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.³

Hypertensive Hydrocephalus

An increase in CSF volume that results from compressive or obstructive lesions in the ventricular system or from decreased CSF absorption is called hypertensive hydrocephalus.⁰ Obstructive lesions of the ventricular system trap the CSF in the ventricles, causing an increase in CSF volume and pressure. Ischemia and CNS degeneration result from the high CSF pressure. The sites of obstruction are most often the lateral apertures, mesen­cephalic aqueduct, lateral ventricles, interventricular foramina, and fourth ventricle. The obstructions may be either congenital or acquired. Causes of acquired obstructive hydrocephalus include cerebral abscess, cholesteatoma (in equines), equine infectious anemia, Coenurus cerebralis infestation, meningitis, and lymphosarcoma. Hypertensive hydrocephalus may also be caused by acute inflammatory disease such as meningitis and vitamin A deficiency. In these diseases the increased pressure is the result of impaired CSF resorption.

Congenital Hypertensive Hydrocephalus

Congenital hypertensive hydrocephalus is a hereditary condi­tion in Hereford, Charolais, Ayrshire, Dexter, Holstein, and Jersey calves.^36-38 The condition has also been recognized in Arabian foals.³⁹

■ Clinical Signs Hydrocephalic animals are often 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 calvaria or protrusion of fluid-filled cystic structures through an open fontanelle is observed. Affected neonates often do not ingest sufficient amounts of colostrum and frequently die of septicemia.

In virally induced cases of hydranencephaly, associated skeletal deformities such as abnormally curved ribs, kypho­scoliosis, flexural deformities of the limbs, domed skulls, and brachygnathia may be observed. 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 deficit of the menace response. 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 involving ultrasonography, trans­orbital echoencephalography, has proved effective for the diagnosis of hydrocephalus and hydranencephaly in calves younger than 3 months of age.⁴⁰

■ 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 hydranen- cephaly is suspected, blood should be collected for virus isolation, serologic testing, and quantitative immunoglobulin determination. Presuckle serum samples from neonates that have been infected by the Akabane or bluetongue virus in the latter part of gestation may be seropositive.²⁶

■ Pathology The pathologic lesions of hydranencephaly are similar regardless of the etiologic agent. They include microcephaly, cerebellar hypoplasia, hydrocephalus, hydran- encephaly, 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 occur in cases caused by viral infections. Polymyositis has been described in affected calves; however, it is unclear whether 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 calvaria, kyphoscoliosis, and brachygnathia.

Obstructive or compressive lesions may be observed with congenital or acquired hypertensive hydrocephalus.

■ 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 hydranen- cephaly in large animals.

Ammoniated Forage Toxicosis (Cow Bonkers)

Application of anhydrous ammonia to poor-quality forage improves the nutritional density of the material and reduces certain toxic fungal metabolites, specifically the prolactin-like toxins of the endophytic fungus Acremonium Coenophialum in fescue hay.¹ Ammoniation increases dry matter intake, enhances digestibility, and increases the relative value of the protein content of the feed. However, overammoniation of the forage, at a rate exceeding 3% of the forage on a dry matter basis, may result in toxicosis. Studies now suggest that several dialkylimidazoles may be responsible for the neurotoxic effects of ammoniated feedstuffs, superseding previous theories that 4-methylimidazole is the primary neurotoxin.^2,3 Ammoniated feedstuffs containing high levels of molasses are more toxic than similarly treated grass hay. The toxin may be concentrated in milk; consequently, calves suckling from normal-appearing dams may show clinical signs of intoxication.

Affected animals are hyperesthetic and ataxic. At rest they assume a sawhorse stance, but when excited, they become hyper­active, appear to be blind, and circle propulsively. Other clinical signs include vocalization, dysphonia, and walking or running into objects. The periods of frenzy may result in recumbency and convulsions. The spasmodic episodes last for 15 to 20 minutes. Afterward, the affected animals rest quietly with occasional muscle tremors. Recurrences of the mania may be precipitated by loud noises or other startling stimuli. The concentrations of ammonia in the blood and CSF may be increased. Although specific treatments have not been identified, one report indicated that affected calves benefited from acepromazine (0.045 mg/kg IV) and thiamine (1.14 mg/kg IM). Thiamine dosages higher than described in this report⁴ (such as 10 to 20 mg/kg SC q12h) have been used for treatment of other neurologic diseases and may be considered for use in this disease.

Lead Poisoning

■ 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 are most often 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.¹

■ Epidemiology Sources of lead are numerous and include lead arsenate defoliants, lead acid 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.^2-10 High lead levels have been reported in grasses growing near busy roadways, but the clinical significance of these findings is unclear.^7,11,12 Factors that can increase the likelihood of ingestion of lead-contaminated feedstuffs include lack of alternative feed, hunger, and phosphorus deficiency.¹³ The acute lethal dose of lead for cattle is estimated to range from 220 to 600 mg/kg in calves, 600 to 800 mg/kg in adult cattle, and 400 mg/kg in goats.^13,14 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.¹⁵ The interval for development of clinical signs ranges from 5 to 20 days and is related to the dose and ionic form of lead administered.¹⁵ Ensiling of contaminated forage results in percolation and concentration of lead at the bottom of the silo.¹⁶

The toxicity of ingested lead is apparently influenced by dietary factors. Calves on a milk diet are more susceptible to lead poisoning than are calves fed hay and grain.¹⁷ There appears to be a direct correlation between high levels of vitamin D and enhanced lead absorption, which may explain the greater occurrence of poisoning during the summer. Elevated copper concentrations in forage, such as may be found in pastures fertilized with pig slurry, may potentiate accumulation of lead in animals consuming it.¹⁸

The estimated cumulative toxic dose of lead for horses is 2.9 mg/kg/day.¹⁹ Poisonings have been reported in horses grazing on 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 “galena” (insoluble sulfide salt) are less toxic than acetate and carbonate lead salts.²⁰

■ Pathogenesis 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.²¹

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 within 24 hours.²² Most of the lead absorbed from the digestive tract (90%) is bound to erythrocyte proteins, which results in a low lead concentration in the plasma, but higher concentrations in whole-blood specimens.²³ At the end of the erythrocyte’s life span, the cell-bound lead is metabolized from the erythrocyte proteins and deposited in the bone as the triphosphate salt. The half-life of blood lead in adult cattle is extremely variable and unpredict­able, ranging from 48 to 2507 days in one study.²⁴ Phenotypic or genotypic factors may affect metabolism and storage of lead. 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.²⁵

Lead also crosses the placental barrier and accumulates in fetal bone, liver, and kidneys but does not substantially accu­mulate in milk. However, cattle with higher blood lead levels may have greater concentrations in milk.²⁶

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.²⁷ Enzymes of heme synthesis are particularly susceptible to injury. These include δ-aminolevulinic acid dehydratase and ferrochelatase. Interference with ferrochelatase inhibits the formation of heme from protoporphyrin, which results in a buildup of unmetabolized porphyrins.

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.²⁸ Iron is not adequately used and is stored in sidero­blasts in the bone marrow.²⁹ Lead also interferes with the activity of pyrimidine-specific 5'-nucleotidase, which results in basophilic stippling of red blood cells.³⁰

After absorption, lead rapidly enters the brain at a dose­dependent rate. The lead deposition in the CNS results in acute cerebellar hemorrhage and edema from capillary dysfunc­tion.²³ The pathogenesis of lead encephalopathy is multifactorial. Encephalitic signs probably originate from a combination of microvascular damage, cellular necrosis, brain swelling, neurotransmitter dysfunction, and decreased glucose uptake by the brain.²⁸

Ingestion of lead also results in competitive inhibition of selenium uptake, thereby diminishing the absorption of selenium by up to 26%.³1 If selenium intake is marginal, lead toxicosis could manifest as overt selenium deficiency.

■ Clinical Signs The signs of lead poisoning in ruminants are characteristic of CNS derangement. During the first stages of lead poisoning, affected cattle stand alone and are depressed.² 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, cortical blindness, head pressing, odontoprisis, coma, and convulsions.^22,32 Some affected animals display episodic running, hyperesthesia, and bellowing. Others die suddenly without premonitory signs. The more acute and severe the toxicity, the more acute, severe, and excitatory are the clinical signs.¹³ Affected cattle may accumulate frothy saliva at the commissures of the lips. GI signs such as bloat, diarrhea, rumen atony, and colic occur in approximately 60% of lead- poisoned cattle; the presence of such signs is more indicative of lead toxicity than of other causes of cerebral dysfunction.³³ Infertility, abortions, and fetal malformations may result from exposure to lead.¹³

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.³⁴ Aspiration of pharyngeal debris caused by dysphagia may result in pneumonia. Fine muscular tremors occur intermittently. The poisoned animals die in psychomotor seizures. Horses that die of lead poisoning are emaciated.³

■ 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. When interpreting the results of a lead measurement, the reference ranges obtained with similar methods must be considered. Heparin is the anticoagulant of choice for 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.²²

In livestock that are chronically poisoned with low concentra­tions of lead, the lead concentration may be normal in blood but high in 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. In cases of chronic lead poisoning, radiographs of the abdomens of smaller patients may reveal lead-containing radiodense foreign material in the GI tract.³⁵ “Lead lines”—radiopaque transverse bands at the metaphyses— may also be visible on radiographs of the long bones of young animals chronically exposed to lead.

When blood lead concentrations are normal in chronically poisoned animals, measurement of free erythrocyte porphy­rins and erythrocyte concentrations of δ-aminolevulinic acid 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 pg/dL for whole blood and 113 and 142.8 ± 32.4 pg/dL for erythrocytes.^29,32,36 In chronically exposed cattle without symptoms, the free erythrocyte porphyrin concentra­tions are frequently greater than 2000 pg/dL.

Reference ranges for aminolevulinic acid dehydrase are 45.8 ± 20.6 U, whereas activities ranging from 28 to 33 U have been reported in naturally exposed calves.³ The urinary concentration of δ-aminolevulinic acid exceeds 500 pg/mL.^4,37 Measurement of aminolevulinic acid in the erythrocytes is more reliable than measurement in urine.³⁸

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.^4,39

The hematologic abnormalities of lead poisoning are subtle. Most poisoned livestock have a normal hemogram. Lead-related changes, if present, are characteristic of hemolytic anemia with an inappropriately robust regenerative response. The mor­phologic abnormalities of erythrocytes include anisocytosis, poikilocytosis, polychromasia, hypochromia, Howell-Jolly bodies, metarubricytes, and basophilic stippling.^22,27 The shape changes begin within hours after ingestion of the lead and peak by 100 days.^22,27 Blood changes do not occur in all cases of the disease and are not necessarily specific indicators of lead poisoning in cattle, in which blood lead levels may be elevated without hematologic abnormalities.⁴⁰ 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 triiodothyronine, thyroxine, estradiol, and cortisol have been demonstrated in cattle with elevated blood lead levels.⁴¹ Parameters of liver function are also affected; serum alanine and aspartate transaminase (AST) levels are increased, whereas serum lipids, total protein, and albumin levels are decreased.

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

■ Pathology 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.⁴²

■ Treatment and Control Therapy for lead poisoning includes 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. The EDTA chelates osseous lead but not soft tissue-bound lead. 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.⁴³ After five daily treatments, a 2-day nontreatment period is recommended to reequilibrate the soft tissue and bone lead. After the 2-day 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.⁴⁴ Therapy is then 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 so as to prevent the development of parakeratosis.

Reports have indicated that thiamine therapy is an effec­tive adjunctive treatment with EDTA in cases of acute lead poisoning of cattle.^14,45,46 Administration of thiamine (2 mg/kg 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.⁴⁷ For clinical treatment of lead poisoning, thiamine dosages of 500 mg for small ruminants and 1 g for cattle weighing 300 kg have been recommended⁴⁵; an alternative dosage is 10 to 20 mg/kg SC q12h. Administra­tion of daily doses of thiamine (100 mg/day or 5 mg/kg) has protected experimentally exposed calves from clinical signs of lead poisoning and reduced lead deposition in the soft tissues.^46,48,49 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.¹⁴ Magnesium sulfate laxatives are administered concomitantly to form insoluble lead sulfides. 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 (as discussed in the Meningitis section).

Toxic pastures can be made safe by removal of contaminated forage. This is best done by cutting, baling, and burying native grasses and then burning the stubble. 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.

Helichrysum argyrophyllum (Golden Guinea Everlasting, Vaal Sewejaartjie) Poisoning

Both naturally occurring and experimental poisoning of sheep and cattle in South Africa by plants of the genus Helichrysum results in blindness and a variety of CNS signs.^1,2 The clinical signs of intoxication include progressive tetraparesis, depression, nystagmus, mydriasis, blindness, intentional head tremor, and stargazing attitude. Older sheep may develop lens cataracts 2 to 3 months after eating the plants. The case-attack rate ranges from 1% to 29%. Plants are toxic only in the flowering stage. Helichrysum spp. have been shown to contain substances that bind at the GABA-benzodiazepine receptor, which is suggestive of a mechanism for toxic effects on the nervous system.³

Pathologic findings include widespread status spongiosus of brain white matter, particularly in subependymal areas and in the cerebellar peduncles and brainstem.² Myelin edema is present in some cases. Edematous swelling of the optic nerve causes compression of the nerve in the optic canal, with secondary damage to nerve axons and myelin. The toxic principle in Helichrysum plants also causes a primary retinopathy in some animals.

Flatpea (Lathyrus sylvestris, Lathyrus collis) Poisoning

Ingestion of flatpea results in a CNS disorder. The condition may manifest within 5 days after consumption of a diet of which 50% is flatpea vines. Toxicosis has been induced in sheep ingesting forage of 35% flatpea vines.¹ Livestock can develop a tolerance for the plant through rumen microbial detoxification. Nevertheless, acclimatized animals can be rendered susceptible by treatment with monensin or by a change ₂

in rumen microflora.²

The toxic constituent of the plant, 2,4-diaminobutyric acid, is known to inhibit ornithine transcarbamylase, an enzyme responsible for urea detoxification. Consequently, the blood ammonia concentration in clinically affected animals is increased.

The clinical signs of flatpea intoxication are depression, muscular tremors, and spasmodic torticollis. Affected animals become recumbent and are reluctant to rise. When stimulated to move, they display circling, head pressing, and odontoprisis. The urine may appear dark brown. The clinical disorder often culminates fatally in a seizure. During the interictal periods, affected animals may rest, rise, and resume normal behavior and gait. Treatment is empirical and supportive and could include 1 to 2 L of vinegar PO, diazepam (0.1 mg/kg IV) or midazolam (0.1 mg/kg IV or IM) every 4 to 6 hrs as needed and removal from the offending forage.

Lathyrus sylvestris is a leguminous plant with a high protein content that might be an adequate substitute for alfalfa in areas where the latter grows poorly.³ L. sylvestris harvested in the vegetative state has been fed to lambs in combination with alfalfa and as a sole diet without ill effect.⁴ Similarly, when fed as part of a mixed silage in which the concentration of diaminobutyric acid was approximately 1%, L. sylvestris produced an acceptable weight gain in cattle without signs of toxicity.⁵

Nitrofurazone Toxicosis

Nitrofurazone is an antimicrobial that has been fed to cattle for the treatment and control of respiratory or GI diseases. Treatment of food-producing animals with the nitrofurans is now prohibited by the U.S. Food and Drug Administration. Nervous system signs of nitrofurazone toxicosis occur after 1 to 3 weeks of continuous feeding at dosages exceeding 15 to 30 mg/kg.^1,2 Lower dosages (7.1 mg/kg) reduce feed intake but do not result in neurologic signs. Nitrofurazone inhibits enzymes of the oxidative glycolytic pathways and is thought to interfere with brain metabolism of carbohydrates.

Clinical signs of nitrofurazone toxicosis include hyperir­ritability, propulsive running, muscular tremors, blindness, convulsions, and death. With lower doses, the convulsions may appear intermittently, but as the condition progresses, the signs become continuous.

Coenurosis (Sheep Gid;

Coenurus cerebralis Infestation; Taenia multiceps Infestation)

■ Definition, Etiology, and Epidemiology Coenurosis is caused by invasion of the CNS by C. cerebralis, the larval 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.^1-3 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.

■ Pathogenesis Lesions in the CNS may result from three separate pathogenic mechanisms: 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.

■ Clinical Signs Clinical signs can occur acutely, during the migratory phase of the larval stage in the intermediate host (e.g., the ruminant). Lambs 6 to 8 weeks old are most often affected by this form and develop fever, dullness, and mild neurologic deficits.⁴ Acute encephalitis occasionally 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 or paralysis are the main clinical signs.⁵ As the disease progresses, the sheep assume lateral recumbency and become comatose.^6,7 In advanced cases, the calvaria directly over the parasite enlarges and softens.³

■ Pathology In the acute form of coenurosis, the main finding is coagulation necrosis and inflammation associated with the larval migration path through the CNS.⁸ This may be visible grossly as yellow to red tracks in 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 reveal radiolucent areas in the calvaria. The optimum diagnostic views in the posteroanterior projection occur whenever the base of the nose is level with the upper margin of the orbit. CT, if available, effectively demonstrates the presence of cysts.⁹

■ Treatment and Control Praziquantel (50 to 100 mg/kg PO q24h for 3 to 5 days) is effective in the treatment of coenurosis in sheep that do not yet have neurologic signs.^5,10 Concomitant administration of an NSAID or dexamethasone may enhance the posttreatment survival rate. The cyst can also be removed

1115

surgically by craniotomy.^{11 15}

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.

Ceroid Lipofuscinosis

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.^1-5 The disease is known to be inherited as an autosomal recessive trait in many cases⁶ and is believed to be so in others.⁷ 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.^8,9 Affected animals display progressive ataxia and postural abnormalities, blindness due to retinal involvement in many cases, sensory depression, and, in the terminal stage, coma. Lesions seen on CT scans include enlargement of the lateral ventricles and reduced thickness of the cerebral cortex.¹⁰

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.¹¹ The disease is ultimately fatal, and no practical method of treatment is currently available.