Polioencephalomalacia is a common neurological disease of ruminants that results from thiamine deficiency or sulfur toxicosis. Clinical signs include stargazing, head pressing, ataxia, cortical blindness (absent menace response, present pupillary light reflex), dorsomedial strabismus, and progression to seizures and death. Antemortem diagnosis is based primarily on clinical signs and response to treatment; during postmortem examination, the brain may fluoresce under ultraviolet light. Treatment is parenteral administration of thiamine.
Polioencephalomalacia (PEM) is an important neurological disease of ruminants that occurs worldwide. Cattle, sheep, goats, deer, and camelids are affected. PEM is a pathological diagnosis and a common end point of several conditions. Historically, PEM has been associated with altered thiamine status; more recently, an association with high sulfur intake has been noted. Other toxicoses or metabolic diseases (eg, acute lead poisoning, or salt toxicosis due to excess salt consumption or water deprivation) can result in PEM as well.
Etiology, Pathogenesis, and Epidemiology of Polioencephalomalacia in Ruminants
Polioencephalomalacia (also called cerebrocortical necrosis) occurs sporadically in individual animals or as a herd outbreak. Younger animals are affected more frequently than adults. Pastured animals can develop PEM; however, animals on high-concentrate diets are at higher risk, as are cattle exposed to excessive amounts of sulfur through their water or their feed (rations with by-products of corn or beet processing), or both. Patterns of PEM occurrence depend on the etiological factors involved.
PEM has been associated with two types of dietary risks: altered thiamine status and high sulfur intake.
Thiamine-Associated Polioencephalomalacia
Thiamine inadequacy in animals with PEM has been suggested by several observations, including decreased concentrations of thiamine in tissues or blood and deficiency-induced alterations of thiamine-dependent biochemical processes (decreased blood transketolase activity, increased thiamine pyrophosphate effect on transketolase, and increased serum lactate). However, these biochemical features of altered thiamine status are not always present in cases of PEM, and decreased thiamine concentrations have also been observed in patients with diseases other than PEM. Decreases in the activity of thiamine-dependent enzymes that play a role in ATP production result in altered glucose mechanisms in the brain by affecting lipid synthesis, acetylcholine, and other neurotransmitters (1). These alterations result in encephalomalacia (softening of the brain) and associated clinical signs.
Preruminant (neonatal) animals depend on dietary thiamine. In adult ruminants, thiamine is produced by rumen microbes. Thiamine inadequacy can be due to alteration of the rumen microbial population—eg, if the animal is fed a high-concentrate feed or has a sudden change in diet. Alteration of the microbial population can either destroy thiamine or form antimetabolites that interfere with thiamine function. Thiaminase I, produced by Bacillus thiaminolyticus and Clostridium sporogenes, and thiaminase II, produced by B aneurinolyticus, catalyze the cleavage of thiamine. The latter microorganism proliferates under conditions of high grain intake.
Cases of PEM can also occur when animals ingest substances that interfere with thiamine's action, such as plant thiaminases—contained in the nardoo fern (Marsilea drummondii), bracken fern (Pteridium aquilinum), and rock fern (Cheilanthes sieberi)—or thiamine analogues (eg, amprolium). Although PEM has been produced experimentally by feeding animals high doses of extracts from these plants, field cases are uncommon, because these plants are unpalatable.
Overall, there is no linear relation among the presence of ruminal and fecal thiaminase, decreased concentrations of thiamine in tissue and blood, and development of PEM.
A beneficial response to thiamine administration in patients with PEM is sometimes considered evidence of thiamine inadequacy. Thiamine-responsiveness often occurs if treatment is initiated early in the course of disease. However, the assumption that a response indicates that thiamine deficiency is the true etiology should be made with caution.
Sulfur-Associated Polioencephalomalacia
Polioencephalomalacia associated with high sulfur intake is recognized with increasing frequency. Historically, it was believed that sulfur-related PEM resulted from an overproduction of ruminal sulfide in response to decreased sulfur ingestion by rumen microbes. However, more recent research suggests that high dietary sulfur increases the metabolic demand for thiamine, resulting in secondary thiamine deficiency (1).
When cattle transition to diets high in sulfur, ruminal sulfide concentrations peak 1–4 weeks after the change. This pattern is probably due to alterations in ruminal microflora. The occurrence of PEM peaks during the period when ruminal sulfide concentrations are highest.
A variety of sulfur sources, including drinking water, feed ingredients, and forage, can result in excessive sulfur intake. Many geographical areas have surface and deep waters with high concentrations of sulfate. When evaporation occurs, especially in warm weather, sulfate concentrations in water increase. Water consumption by cattle also increases greatly with warmer weather, and this combination of increased drinking and higher sulfate concentrations leads to increased sulfur intake by cattle.
Alfalfa, by virtue of its high protein and sulfur-containing amino acid content, can serve as a substantial source of sulfur. In addition, although grasses tend to be low in sulfur content, some circumstances can result in high sulfate concentrations. Certain weeds, including Canada thistle (Cirsium arvense), kochia (Kochia scoparia), and lamb's-quarters (Chenopodium spp), can accumulate sulfate in high concentrations.
Cruciferous plants normally synthesize sulfur-rich products and serve as important sources of excess sulfur. These include turnips, rape, mustard, and oil seed meals.
By-products of corn, sugar cane, and sugar beet processing commonly have a high sulfur content, apparently because of the addition of sulfur-containing acidifying agents. PEM has been associated with the use of these by-products as feed ingredients. Corn-based ethanol production has led to increased availability of corn by-products that can vary widely in sulfur content. Wet distillers' grains plus solubles have been shown to have sulfur content ranging from 0.44% to 1.74% as dry matter.
Clinical Findings of Polioencephalomalacia in Ruminants
Polioencephalomalacia can be acute or subacute. Patients with the acute form often manifest blindness and ataxia, followed by recumbency, tonic-clonic seizures, and coma. Those with a longer duration of acute clinical signs have poorer responses to treatment and higher mortality rates.
Patients with the subacute form of PEM initially separate themselves from the group and stop eating, and their ears and face twitch. They subsequently develop cortical blindness and dorsomedial strabismus (see video), stargazing (see stargazing image), and head pressing (see head pressing image), and then they progress to recumbency. Cortical blindness is characterized by an absent menace response and a normal bilateral pupillary light reflex.
Courtesy of Dr. Pippa Gibbons.
Courtesy of Dr. Michel Lévy.
The subacute form of PEM is frequently followed by recovery with only minor neurological impairment, though blindness can persist once ataxia and other clinical signs have resolved. However, occasionally, the subacute form progresses to a more severe form with recumbency and seizures.
Lesions
Gross lesions in PEM are inconsistent and frequently subtle, especially early in the disease. Acutely affected patients can have brain swelling with gyral flattening and coning of the cerebellum resulting from herniation into the foramen magnum. Affected cortical tissue can have a slightly yellow discoloration. The brains of acutely affected patients may also show autofluorescent bands of necrotic cerebral cortex on meningeal and cut surfaces of the brain under ultraviolet illumination. As the pathological process progresses, affected cerebrocortical tissue exhibits macroscopically evident cavitation; sometimes, this cavitation is severe enough to cause apposition of the pia meninges to white matter. (See cortex image.)
Courtesy of Dr. Daniel H. Gould.
The initial histological lesions are necrosis of cerebrocortical neurons. The neurons are shrunken and have homogeneous, eosinophilic cytoplasm. Nuclei are pyknotic, faded, or absent. Cortical spongiosis is sometimes present in the early phases of the acute form. Vessel cells undergo hypertrophy and hyperplasia. At later stages, affected cortical tissue undergoes cavitation, as macrophages infiltrate and necrotic tissue is removed. A pattern observed in brains of cattle with early, severe, acute sulfur-related PEM features multifocal vascular necrosis, hemorrhage, and parenchymal necrosis in deep gray matter, including the striatum, thalamus, and midbrain.
Diagnosis of Polioencephalomalacia in Ruminants
Presumptive: clinical signs and response to thiamine administration
Definitive: necropsy
The described pattern of clinical signs should arouse suspicion of PEM. At necropsy, macroscopically evident cerebrocortical autofluorescent areas under ultraviolet illumination provide a presumptive diagnosis of PEM; however, in animals with sulfur-associated PEM, autofluorescent areas are not typically present. Characteristic histological lesions are confirmatory.
Differential diagnoses for cattle include the following diseases that affect the cerebral cortex:
acute lead poisoning
salt toxicosis (due to excess salt consumption or water deprivation)
coccidiosis with nervous system involvement
Differential diagnoses for sheep and goats include the following:
type D clostridial enterotoxemia (focal symmetric encephalomalacia)
salt toxicosis (due to excess salt consumption or water deprivation)
acute lead poisoning
Patients with vitamin A deficiency also present with blindness; however, the neurological examination of the vitamin A–deficient patient will reveal both an absent menace response and an absent pupillary light reflex, because the lesion is localized to the retina and optic nerve. The absence of a pupillary light reflex can help distinguish vitamin A deficiency from PEM.
Confirmation of etiology or pathogenesis requires laboratory testing of samples from affected patients or their environment. Assessment of thiamine status is difficult, and results should be interpreted with caution. Few laboratories are capable of routinely measuring thiamine content of blood and tissues, transketolase activity, or the thiamine pyrophosphate effect on transketolase. Demonstration of clinical improvement after thiamine administration is not adequate evidence for a specific diagnosis.
The possibility of sulfur-associated PEM is assessed by measuring the sulfur content of the water and dietary ingredients and then estimating the total sulfur intake on a dry-matter basis. The maximal concentration of dietary sulfur tolerated by cattle and sheep depends on the type of diet. For diets consisting of > 85% concentrate, the maximal tolerable concentration of total sulfur is 0.3% dry matter. For diets consisting of ≥ 45% forage, the maximal tolerable concentration of total sulfur is 0.5% dry matter. Because multiple factors are involved in determining the actual risk of developing PEM, these percentages should not be considered absolute maximal concentrations. Many cattle adapt adequately to sulfur intake amounts that exceed the maximal tolerable concentration, although negative effects on performance can occur when a slow transition in the feed is made.
Treatment and Prevention of Polioencephalomalacia in Ruminants
Primary: thiamine administration
Supportive care: dexamethasone and mannitol for cerebral edema; anticonvulsants for possible seizures
Dietary investigation and modification, as necessary
The treatment of choice for PEM, regardless of etiology, is thiamine administration (10 mg/kg, slowly IV or IM for the initial dose, then every 6–8 hours, IM or SC, for 3–5 days). Treatment must begin early in the disease course to achieve benefits. If brain lesions are particularly severe or if treatment is delayed, full clinical recovery may not be possible. Beneficial effects are usually evident within 24 hours; however, if there is no initial improvement, treatment should be continued for ≥ 3 days.
Dexamethasone (0.1–0.2 mg/kg, IV, once) or mannitol 20% (0.25–1 g/kg , IV, once) can be administered in an effort to decrease cerebral edema; however, clinical trials for confirmation are not available (1, 2, 3, 4). These dosages represent extralabel use, and appropriate withdrawal intervals must be assigned. Supportive care and treatment for seizures may also be necessary. Treatment for ruminants with seizures may include diazepam (0.5–1 mg/kg, IV [5]) as needed to control seizures. Appropriate restraint is needed to ensure human safety when administering drugs to ruminants actively having seizures. Oral phenobarbital has also been reported for use in small ruminants with seizures; however, it may be less effective than intravenous phenobarbital for acute episodes. In addition, oral phenobarbital dosing for maintenance therapy must be determined through therapeutic drug monitoring and, therefore, may be impractical and not cost-effective in larger ruminants (6).
Dietary supplementation of thiamine (3–10 mg/kg of feed) has been recommended for prevention of PEM; however, the efficacy of this approach has not been carefully evaluated. During a PEM outbreak, sufficient roughage should be provided to promote ruminal production of thiamine.
When sulfur-associated PEM is suspected, all possible sources of sulfur, including water, should be analyzed, and the total amount of sulfur consumed via dry matter should be estimated. Dietary ingredients or water with high sulfur concentrations should be avoided; if this is not possible, then a more gradual introduction to such dietary components can improve the likelihood of successful adaptation.
Key Points
Polioencephalomalacia is a neurological disease that affects ruminants. It occurs in herd outbreaks or in individual animals.
Clinical signs include cortical blindness, dorsomedial strabismus, stargazing, and recumbency. Seizures and death can occur.
Diagnosis is suspected based on clinical signs and response to thiamine administration.
Treatment is thiamine administration and dietary modification when appropriate.
References
Dore V, Smith G. Cerebral disorders of calves. Vet Clin North Am Food Anim Pract. 2017;33(1):27-41. doi:10.1016/j.cvfa.2016.09.004
Constable PD, Hinchcliff KW, Done SH, Grünberg W. Veterinary Medicine: A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats. 11th ed. Elsevier; 2017:1309.
Smith BP, Van Metre DC, Pusterla N, eds. Large Animal Internal Medicine. 6th ed. Elsevier; 2020:1053.
Mayhew IGJ, MacKay RJ. Nutritional diseases. In: Large Animal Neurology. 3rd ed. Wiley-Blackwell; 2022:481-502.
Fajt VR, Brown KR, Pugh DG. Commonly used drugs and veterinary feed directive in sheep, goats, and cervids. In: Pugh DG, Baird AN, Edmonson MA, Passler T, eds. Sheep, Goat, and Cervid Medicine. 3rd ed. Elsevier; 2021:517-538. doi:10.1016/B978-0-323-62463-3.00030-X
Chigerwe M, Aleman M. Seizure disorders in goats and sheep. J Vet Intern Med. 2016;30(5):1752-1757. doi:10.1111/jvim.14566
