Polioencephalomalacia (Cerebrocortical Necrosis)

Christopher Cebra • Guy H. Loneragan •

Daniel H. Gould • John R. Middleton

■ Definition and Etiology Polioencephalomalacia (PEM) is a common and important neurologic disease of ruminants^1,2 with a worldwide distribution.

Polioencephalomalacia is a descriptive term for histologic lesions^1,3 that may arise from a variety of etiologies. Literally, the name means softening or necrosis (malacia) of regions of the gray matter (“polio-”) of the brain (“encephalo-”). Thus a definitive diagnosis of PEM requires histologic examination of brain tissue. The possible causes of PEM include, but are not limited to, excessive sulfur consumption (manifested by elevated ruminal sulfide production),^4-8 altered thiamine metabolism,⁹ salt poisoning or water deprivation,¹⁰ amprolium 1113 14

administration,^{11 13} rations composed of molasses and urea,¹⁴ and lead intoxication.¹⁵ Of cases in which a cause can be determined, most involve altered thiamine metabolism, excessive sulfur consumption, or both.

■ Epidemiology PEM has a worldwide distribution. The condition occurs both in individuals and as herd outbreaks. In one instance, approximately 2000 of 2200 sheep grazing were clinically affected with PEM.⁴ No predilection by gender or breed is observed. The condition affects cattle, sheep, goats, deer, camels, and camelids.^5,11,16-19 Although PEM occurs predominantly in animals that eat a high-concentrate supple­ment, the condition can also occur in unsupplemented animals on pasture.

The age ranges for susceptibility to PEM have been reported as 3 weeks to 5 years in sheep, 3 weeks to 8 years in cattle, and 2 months to 2.5 years in goats.

■ Pathogenesis The fundamental lesion with PEM appears to be neuronal edema with necrosis. In most cases, the edema is thought to result from ATP depletion and decreased activity of the sodium-potassium pump in cortical cells. The bony calvaria limits tissue expansion, and neuronal swelling leads to pressure necrosis.

The brain is susceptible to PEM because of its high energy and oxygen requirements. Brain tissue makes up only approxi­mately 2% of body weight but accounts for 20% to 30% of body glucose utilization and 20% of oxygen utilization in adults.²² The brain relies heavily on glucose as an energy substrate, and the blood-brain barrier limits the ability to utilize alternative energy substrates. In comparison with liver or muscle, the brain has relatively small glycogen stores—only approxi­mately a 10-minute supply—and it is entirely dependent on circulating oxygen. Under normal conditions, the extracellular fluid contains approximately 100 times as much glucose as the oxygen required for complete aerobic glycolysis. Thus oxygen delivery or utilization limits the rate of ATP production under most circumstances much more than does glucose availability,²³ and factors that inhibit oxygen utilization (e.g., hydrogen sulfide, lead) affect neuronal ATP production.

Much of the early work on PEM focused on the importance of thiamine (also known as vitamin B₁, thiamin, and aneurin).

The dependence of ruminants on microbial thiamine production led to investigation of factors that might decrease production, absorption, or function. Proposed mechanisms include ruminal production of bacterial thiaminases, produc­tion or ingestion of inactive thiamine analogs, ingestion of preformed plant thiaminases, decreased intake of preformed thiamine by preruminants, impaired absorption or phosphoryla­tion of thiamine by rumen bacteria, increased fecal excretion of thiamine, and decreased ruminal production of thiamine diphosphate. The inactive thiamine analog most frequently reported is amprolium.^11-13

Two types of bacterial thiaminases have been described. Thiaminase I, produced by Bacillus thiaminolyticus or Clostridium sporogenes,²⁶ catalyzes the cleavage of thiamine at the methylene bridge between the pyrimidinyl and the thiazole ring. A basic cosubstrate is necessary to combine with the pyrimidinyl derivative to form a new compound²⁷, and many common medications, including benzimidazoles, levamisole, and pro­mazines, appear to be able to serve as this cosubstrate.

Complete correlation has not been established among production of ruminal and fecal thiaminase, tissue and plasma concentration of thiamine, and development of clinical encephalopathy.^32,33 Some affected animals may show normal amounts of thiamine in the plasma but have greatly decreased levels in the erythrocytes and other tissues, which is evidence of the diversity of causes of PEM.³⁴

Dietary sulfur and sulfates are an important factor in the development of many cases of ruminant PEM. Beef cattle require 0.15% to 0.20% of dietary sulfur on a dry matter basis.³⁵ Sources of sulfur include elemental sulfur,⁴ feed additives such as gypsum and ammonium sulfate,^5,36 feedstuffs such as corn by-products,³⁵ cruciferous crops,^37,38 molasses,¹⁴ and fertil­izers. Water is an important contributor to sulfur intake, usually in the form of sulfates.^7,39,40

There are two primary metabolic pathways of sulfur in the rumen.^40-45 The assimilatory pathway involves reduction of sulfate to sulfides and incorporation into sulfur-containing organic compounds such as cysteine and methionine.⁴³ These are ultimately incorporated into microbial crude protein. The dissimilatory pathway is an energy-producing pathway in which microorganisms use sulfate as a terminal electron acceptor, in a manner similar to how mammals use oxygen.⁴⁶ The end product is liberated sulfide ion.

Because sulfur and sulfate demonstrate low cellular toxicity, it is unlikely that sulfur-associated PEM results from sulfate or sulfur toxicity. However, sulfides are highly toxic.^57-59 The chances of sulfur-associated PEM are higher after sulfide toxicity.^6,8,49 It has been proposed that the pathogenesis of sulfur-induced PEM involves inhibition of cytochrome c oxidase, an enzyme in the electron transport chain; this chain is important for regenerating the intermediaries of aerobic glycolysis and the final round of ATP production. Because oxygen availability already limits aerobic glycolysis in the brain, inhibition of the electron transport chain could profoundly alter neuronal ATP production.

For highly toxic sulfide to reach the brain, it must escape hepatic oxidation. This is achieved by two mechanisms. A surge in ruminal sulfide generation usually follows a period of adaptation to high-sulfur diets. This surge may overwhelm the hepatic detoxification capacity. Because cattle inhale the majority of eructated ruminal gas,⁶⁰ it has been proposed that eructated hydrogen sulfide may be inhaled and absorbed via the pulmonary tree, bypassing hepatic circulation and leading to neurotoxicity in the brain; however, this concept has been questioned.⁶¹

In feedlot cattle, a summer peak in PEM cases was associated with consumption of water containing 2500 mg/L of sulfate.⁷ The total sulfur intake of these steers was estimated to be 0.6% on a dry matter basis during the hottest days of the year.

The recommended maximum tolerance level of sulfur is 0.4% of dry matter intake.³⁵ Other effects of excessive sulfur intake are decreases in feed intake and weight gain. Accurate diagnosis of sulfur toxicity requires measurement of sulfur in all food and water sources. Sulfur from water must be included when total sulfur intake is calculated. One third of the molecular weight of sulfate is sulfur. Accordingly, if an animal drinks 30 L of water a day containing 2000 mg/L of sulfate, this contributes 60,000 mg of sulfate, or 20 g of sulfur. Furthermore, if this animal consumes an average of 10 kg of dry matter daily at 0.15% sulfur, the feed or forage contributes 15 g of sulfur, and thus the total sulfur intake is 35 g, or 0.35% on a dry matter basis. This scenario illustrates that water may be a substantial contributor to total daily sulfur intake.

Some authors have suggested that sulfides result in thiamine destruction, thereby directly implicating a thiamine deficiency in the pathogenesis of sulfur-associated PEM. Rumen thiamine production was slightly reduced by the inclusion of excessive sulfur in the ration.⁶⁴ However, the authors deemed the measured reduction to be clinically insignificant; they suggest that sulfur-associated PEM occurs independent of thiamine metabolism. One study suggested that the reductions in activities of pyruvate dehydrogenase, α-ketogluterate dehydrogenase, and cytochrome c oxidase in the cerebral cortex is associated with the pathogenesis of sulfur-induced PEM.⁶⁵

PEM induced by feeding of molasses and urea is thought to be related to the high sulfur content of the molasses and to the depletion of propionate and other glucogenic precursors¹⁴; it is not considered to be caused by thiamine destruction. The tissue thiamine concentrations of animals with molasses-related PEM are normal,⁶⁶ and signs are preventable by concomitant feeding of glycerol, which is converted to glucose in the rumen. Outbreaks of PEM in range cattle have been associated with ingestion of the plant Kochia scoparia.⁶7⁶⁹ The pathogenesis of this condition is unknown; however, some authors have sug­gested that the plant has the capacity to accumulate sulfur.⁴⁰

Some cases of PEM cannot be linked either to problems with thiamine or to sulfur toxicity. Other compounds, such as lead, affect electron transport in a manner similar to that of sulfides and therefore also impair ATP production. Water intoxication creates a similar histologic lesion, but the patho­genesis of edema is related more to the generation of osmotic compounds and fluid shifts with rapid fluctuations in blood and neuronal osmolality (see Salt Poisoning [With or Without Concurrent Water Deprivation] section).

■ ClinicalSigns PEM appears to manifest both subacutely and acutely.^1,8 In the subacute form, signs may develop within hours or over several days. In the early stages of the disease, the affected animals detach from the herd or flock, become anorectic, and stagger. Neurologic signs are symmetric. Affected animals are blind, walk with the head held erect, and demon­strate a slight hypermetric gait. Progression of the condition is associated with bilateral cortical blindness, head pressing, opisthotonos, bilateral dorsomedial strabismus, miosis, repetitive chewing, profuse ptyalism, and odontoprisis.^1,5,69-71 Despite the defective menace response, the animals usually have normal palpebral reflexes. Affected animals may also develop a variable nystagmus. The rectal temperature is normal unless excessive muscular fasciculations have developed. The pulse and respira­tory rates are usually increased. An odor of hydrogen sulfide may be detected on the breath if the PEM is associated with excessive sulfur consumption.

Although most of these animals respond favorably to aggres­sive therapeutic intervention, clinical signs may progress to recumbency, tonic-clonic convulsions, and death. In facilities with certain types of fencing, such as cables, affected animals may push or press on their airway with such force that they die of asphyxiation.

In the acute form of PEM, animals are found recumbent and comatose.^1,8 These animals often exhibit episodic tonic- clonic convulsions, and they remain recumbent and hypertonic between seizures. The prognosis is poor for acutely affected animals and those with advanced subacute manifestations. Survivors may remain irreversibly decorticated and are culled because of poor performance, chronic anorexia and ataxia, or blindness. However, mildly affected animals may remain productive members of the herd.

Because the clinical manifestations of PEM may be subtle and nonspecific, they can be confused with other disorders. PEM is often confused with lactic acidosis that develops after consumption of excessive amounts of readily fermentable carbohydrates. Animals with lactic acidosis may appear ataxic and obtunded, in addition to having a foul-smelling, watery stool and a distended, fluid-filled rumen. PEM can occur concurrently with carbohydrate engorgement but may go undiagnosed, or PEM may be confused with lactic acidosis or primary ruminal tympany in acutely affected animals that have remained laterally recumbent for some time.

The major differential diagnoses for PEM include entero­toxemia type D (focal symmetric encephalomalacia in small ruminants), salt poisoning/water deprivation, head trauma, bacterial meningoencephalitis, coccidiosis with nervous system involvement, vitamin A deficiency, ethylene glycol poisoning, locoism, rabies, and IBR encephalitis.

■ Clinical Pathology Although a definitive diagnosis requires histologic examination of brain tissue, a presumptive diagnosis before death may be based on the history and clinical signs or response to therapy. If PEM is diagnosed, the investiga­tion should proceed at the animal, herd, and environmental level to identify evidence supportive of sulfide toxicity, thiamine deficiency, lead toxicity, or water deprivation/salt toxicosis.

Sulfide concentrations in the ruminal fluid and gas cap in experimentally induced sulfur-associated PEM have been shown to be high.^49,72 However, unpublished data supported a finding of a decrease in gas cap sulfide concentrations in naturally developing PEM associated with increased sulfur consumption.⁷³ This is probably caused by the rapid metabolism of sulfate to sulfide in the rumen and resultant absorption or eructation of hydrogen sulfide. Animals with naturally developing PEM are likely to have been anorectic for some time, which results in a decrease in oxidized and reduced forms of ruminal sulfur.

In clinically healthy penmates of affected cattle, the con­centration of hydrogen sulfide in the rumen gas cap can be estimated; this is an effective chute-side diagnostic procedure whose results can indicate excessive sulfur consumption.⁸ This method provides real-time results that may aid direction of further animal and environmental investigations. In short, an area in the left paralumbar fossa is prepared for ruminocentesis. An 18-gauge, 3.5-inch spinal needle is inserted through the body wall and into the rumen gas cap. A modified gas sampler is attached to the spinal needle by means of an extension set, and a known amount of gas is drawn through a hydrogen sulfide detector tube.⁷² It is important to adjust the values to account for any dead space of the sampling instrument, such as the extension set and other modifications. Hydrogen sulfide concentrations greater than 1000 ppm are indicative of excessive 74

sulfur consumption.⁷⁴

Blood samples may be analyzed for lead concentration and possibly estimation of thiamine status. Thiamine status is generally evaluated with one of several available methods, including determining the total blood thiamine concentration through a thiamine-dependent Lactobacillus bioassay.⁷⁵ The erythrocyte thiamine pyrophosphate concentration may be measured by high-performance liquid chromatography.⁷⁶

Another method of evaluating thiamine status is to determine erythrocyte transketolase activity.⁷⁷ In this test, the specific activity in the active (holoenzyme) and inactive (apoenzyme) forms is compared with the activity of the two forms after addition of thiamine to the homogenates. A large increase in specific transketolase activity after addition of the thiamine pyrophosphate suggests thiamine deficiency. Theoretically, in animals with thiamine-associated PEM, the concentration of holoenzyme is decreased and that of the apoenzyme is increased. If thiamine deficiency is identified in an affected animal, caution should be used in interpreting the results, because a period of anorexia may result in a decrease in ruminal 7879 de novo synthesis. ^8,9

Changes in CSF of affected animals are usually vague. They include mild pleocytosis (5 to 50 WBCs/dL) with vacuolation and increased protein concentrations (>50 mg/ dL).^9,80 Electrophysiologic studies of affected animals show a normal latency and decreased amplitude of the late peaks of the visual evoked potentials. These changes reflect decreased numbers of neurons capable of responding to the photic stimulation.⁸¹

Environmental investigations should include evaluation of all feed and water sources for sulfur concentrations or the possibility of lead contamination. The diet should also be checked for molasses, salt, and urea content.

■ Pathology In cases of sulfur-associated PEM, rumen contents may have an odor of hydrogen sulfide. In other cases, there may be evidence of grain overload, coccidiosis, or respiratory disease. Some of these lesions are related to management conditions, but they may also be related directly or indirectly to PEM. The macroscopic pathologic brain lesions of PEM include cortical swelling and softening, flattening, and yellowish discoloration of the gyri. Necrotic areas of the cerebral cortex demonstrate autofluorescence under ultraviolet light (365 nm).^82,83 In severe cases, the cerebellum herniates through the foramen magnum or the occipital cortex under the tentorium cerebelli. Necropsy months after recovery may reveal cerebral atrophy and submeningeal cortical cysts. The major microscopic lesion is a diffuse laminar necrosis. Other changes include intracellular and intercellular edema, neuronal necrosis, and neuronophagia.^3,70

■ Treatment and Prognosis Regardless of the under­lying cause, animals with the subacute form of PEM often respond favorably to parenteral administration of thiamine hydrochloride. These animals may remain blind and may have depressed sensorium for weeks or months.⁸⁴ Thiamine should be administered at 10 to 20 mg/kg IM or SC three times daily. In severe cases, IV administration of the first dose might be war­ranted. If given intravenously, thiamine should be administered slowly to avoid adverse reactions. If no improvement occurs initially, the treatment should be continued for at least 3 days. In some patients, recovery may take as long as 7 days, but most patients show improvement within 24 hours. A single administration of sodium dexamethasone (0.1 to 0.2 mg/kg IM or IV) or mannitol (1 g/kg of mannitol in a 20% solution IV) may help reduce cerebral edema. Anecdotal reports indicate that feedlot animals that have recovered from PEM are at increased risk for respiratory disease; therefore prophylactic antimicrobial administration may be indicated. Convulsions may be controlled with phenobarbital, pentobarbital, or diazepam (see Table 35.4). Animals with the acute form of PEM usually have more severe cortical and deep gray matter lesions than do animals with the subacute form.⁸ Animals with the acute form generally do not respond to therapeutic regimens. Ruminants with PEM secondary to the molasses-urea diet do not appear to respond to treatment with thiamine. They may respond more favorably to parenteral administration of glucose or enteral or parenteral administration of a glucose precursor.

■ Prevention and Control Ultimately, the best way to prevent outbreaks is to manage the dietary intakes of susceptible animals appropriately. Ruminants should be allowed an adequate period of adaptation to high-concentrate rations. All feedstuffs and water sources should be carefully analyzed on a routine basis to estimate total sulfur intake. If excess sulfur consumption is a factor, steps should be taken to remove sources such as high-sulfur hay, ammonium sulfate, and molasses. If the excess sulfur intake is unavoidable, steps can be taken to limit its effects. Older members of the cow herd could be used to graze the high-sulfur pastures, and younger, more susceptible animals could be kept in lower-sulfur pastures or given hay supplementa­tion. Personnel should be trained to identify PEM early and treat it appropriately.

Thiamine may be given as supplementation (3 to 10 mg/ kg of feed) in rations in which the concentrate/fiber ratio is high, but this has little or no effect in preventing PEM. Other recommendations for preventing PEM include addition of brewer's yeast to the ration and gradual adaptation of ruminants (at least 2 weeks) to high-concentrate diets. Gypsum, if present as a feed-limiting additive, should be removed from the diet. Elimination of supplementation and rotation of pastures have been sufficient for controlling some outbreaks.²⁰ Supplementa­tion with cobalt in trace-mineral salt mixes may be necessary in deficient areas.