Polioencephalomalacia / Cerebrocortical Necrosis / Thiamine Deficiency

Polioencephalomalacia (PEM), also known as cerebrocortical necrosis (CCN), is a non-infectious, metabolic, and neurological disease of sheep and goats characterized by diffuse or focal necrosis of the cerebral cortex. It results primarily from a deficiency of thiamine (vitamin B1), which is essential for carbohydrate metabolism, particularly in the brain. Thiamine deficiency leads to impaired glucose oxidation, accumulation of lactate, and subsequent cerebral edema and necrosis. The disease is most commonly seen in growing lambs and kids, but can affect adults, especially those on high-concentrate diets or with ruminal acidosis. PEM is a significant cause of morbidity and mortality in intensively managed flocks and herds, with economic losses due to treatment costs, reduced growth, and death. The condition is classified as a metabolic disorder of the forestomach, as it is often precipitated by dietary changes that alter ruminal thiamine production or increase thiaminase activity.

The primary cause of PEM is a deficiency of thiamine (vitamin B1), which can arise from several mechanisms: (1) Inadequate dietary intake of thiamine, though this is rare in ruminants because ruminal microbes synthesize thiamine; (2) Increased destruction of thiamine by thiaminases produced by certain ruminal bacteria (e.g., Bacillus thiaminolyticus, Clostridium sporogenes) or from dietary sources such as bracken fern (Pteridium aquilinum) and certain molds; (3) Impaired ruminal synthesis due to ruminal acidosis, which alters the microbial population and reduces thiamine production; (4) Ingestion of thiamine antagonists, such as amprolium (a coccidiostat) or certain plant compounds (e.g., thiaminase in bracken fern); (5) High dietary sulfur intake, which can cause sulfur-induced PEM, a distinct but clinically similar condition, where excess sulfur interferes with thiamine metabolism or directly causes cerebral necrosis. In sulfur-induced PEM, the mechanism involves the production of hydrogen sulfide in the rumen, which is toxic to the cerebral cortex. Other less common causes include lead poisoning, salt poisoning (water deprivation), and sodium ion toxicosis, which can also cause cerebrocortical necrosis but are not true thiamine deficiencies. In sheep and goats, PEM is often associated with sudden changes to high-concentrate diets, grain overload, or feeding of moldy feeds.

PEM occurs worldwide and affects both sheep and goats, but is more commonly reported in sheep. It is most frequently seen in growing lambs and kids between 2 and 6 months of age, particularly those on high-concentrate diets or creep feeding. Outbreaks can occur in feedlots, intensive fattening operations, and show flocks. In goats, PEM is often associated with feeding of high-grain diets or sudden dietary changes. The disease can also occur in adult animals, especially pregnant or lactating ewes and does on high-energy diets. There is no breed predilection, but any breed can be affected. Morbidity can be high in affected groups, with up to 10-20% of animals showing clinical signs, and mortality can reach 50% if untreated. Economic losses arise from treatment costs, reduced weight gain, and death. Seasonal patterns may be observed, with more cases in winter and spring when animals are housed and fed conserved forages and concentrates. Flock management practices, such as feeding moldy hay or silage, or the use of amprolium in coccidiosis prevention, can increase the risk.

Thiamine is a cofactor for several enzymes critical for glucose metabolism, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. In the brain, glucose is the primary energy source, and thiamine deficiency impairs the tricarboxylic acid (TCA) cycle, leading to decreased ATP production and accumulation of pyruvate and lactate. The resulting energy deficit causes cellular dysfunction and edema, particularly in the cerebral cortex. The accumulation of lactate contributes to local acidosis and further neuronal damage. The cerebral cortex is highly sensitive to thiamine deficiency, leading to bilateral symmetrical necrosis, which is characteristic of PEM. In sulfur-induced PEM, the mechanism is slightly different: excess sulfur in the rumen is converted to hydrogen sulfide by sulfate-reducing bacteria. Hydrogen sulfide is absorbed and directly toxic to the cerebral cortex, causing necrosis similar to thiamine deficiency. The clinical signs and pathological lesions are identical, but thiamine levels may be normal. In both cases, the blood-brain barrier is disrupted, leading to vasogenic and cytotoxic edema, increased intracranial pressure, and herniation of the brainstem, which can be fatal.

Several factors predispose sheep and goats to PEM: (1) Dietary factors: sudden introduction of high-concentrate diets, grain overload, feeding of moldy feeds, or diets high in sulfur (e.g., brassicas, certain hays, water high in sulfates); (2) Management practices: intensive feeding systems, creep feeding, and feedlot operations; (3) Use of thiamine antagonists: amprolium in coccidiosis prevention, or ingestion of bracken fern; (4) Ruminal acidosis: conditions that lower ruminal pH, such as grain overload, can alter the microbial population and reduce thiamine synthesis; (5) Stress: weaning, transportation, or overcrowding can precipitate disease; (6) Age: young growing animals are more susceptible due to higher metabolic demands; (7) Genetic factors: some breeds may be more susceptible, but this is not well documented; (8) Concurrent disease: conditions that reduce feed intake or cause diarrhea can lead to thiamine deficiency.

Clinical signs of PEM typically develop acutely and progress rapidly. Early signs include depression, anorexia, and mild ataxia. As the disease progresses, animals may show: (1) Head pressing against objects; (2) Circling, often in one direction; (3) Blindness, with normal pupillary light reflexes (cortical blindness); (4) Opisthotonos (head drawn back); (5) Nystagmus; (6) Muscle tremors and twitching of the ears and face; (7) Recumbency and inability to rise; (8) Convulsions, which may be intermittent; (9) Coma and death if untreated. In some cases, animals may show a 'star-gazing' posture. The onset can be peracute, with sudden death, or acute, with signs developing over 24-48 hours. In sulfur-induced PEM, the clinical signs are similar, but there may be a history of high-sulfur diet. On physical examination, body temperature is usually normal or slightly elevated, heart rate and respiratory rate may be increased due to stress, and rumen motility may be reduced. The FAMACHA score is not directly relevant to PEM, but if the animal has concurrent anemia, it may be assessed.

Differential diagnoses for PEM in sheep and goats include: (1) Listeriosis (Listeria monocytogenes): causes encephalitis with cranial nerve deficits, circling, and fever; histopathology shows microabscesses in the brainstem, not cortical necrosis; (2) Polioencephalomalacia due to lead poisoning: similar clinical signs, but history of lead exposure and elevated blood lead levels; (3) Salt poisoning (water deprivation): causes cerebral edema and cortical necrosis, but history of water deprivation and elevated serum sodium; (4) Pregnancy toxemia (ketosis): occurs in late gestation, with elevated BHB levels, but neurological signs are less prominent; (5) Hypocalcemia (milk fever): occurs in lactating animals, with muscle weakness and recumbency, but responds to calcium therapy; (6) Hypomagnesemia (grass tetany): occurs in lactating animals on pasture, with muscle tremors and convulsions, but low serum magnesium; (7) Rabies: rare, but causes progressive neurological signs and behavioral changes; (8) Tetanus: causes muscle rigidity and spastic paralysis, but no cortical signs; (9) Brain abscess: due to bacterial infection, often with fever and unilateral signs; (10) Hepatic encephalopathy: due to liver failure, with depression and ataxia, but liver enzymes are elevated.

The diagnostic approach to PEM involves: (1) Flock history: recent dietary changes, high-concentrate feeding, use of amprolium, or high-sulfur water; (2) Physical examination: assess mentation, vision, cranial nerve function, and gait; (3) Response to thiamine therapy: a rapid improvement within 12-24 hours after IV thiamine administration is highly suggestive of PEM; (4) Blood tests: measure thiamine levels (though not routinely available), blood glucose (may be normal or low), and serum electrolytes (to rule out salt poisoning); (5) Cerebrospinal fluid (CSF) analysis: may show increased protein and lactate, but is not specific; (6) Necropsy: gross examination of the brain may show flattening of cerebral gyri, and histopathology reveals bilateral symmetrical cerebrocortical necrosis with edema and neuronal degeneration; (7) In sulfur-induced PEM, measure ruminal hydrogen sulfide levels or water sulfate content; (8) Rule out other causes of neurological disease through differential testing, such as PCR for Listeria, lead levels, and serum sodium.

Laboratory findings in PEM are not specific but can support the diagnosis: (1) Blood thiamine levels: may be low (<40 ng/mL), but this test is not widely available; (2) Erythrocyte transketolase activity: reduced, with an increase after thiamine addition (TPP effect); (3) Blood glucose: may be normal or slightly low; (4) Serum electrolytes: sodium may be elevated in salt poisoning; (5) CSF analysis: increased protein (50-100 mg/dL) and lactate, with normal cell count; (6) In sulfur-induced PEM, ruminal hydrogen sulfide concentration >2000 ppm, or water sulfate >500 ppm; (7) Complete blood count: usually normal; (8) Blood gas analysis: may show metabolic acidosis due to lactate accumulation; (9) Liver function tests: may be normal; (10) Fecal egg count: not directly relevant, but may be performed to rule out parasitic causes of neurological signs.

Imaging is not commonly used in the diagnosis of PEM in small ruminants, but advanced imaging can be helpful: (1) Ultrasonography: not useful for brain imaging, but can be used to assess rumen motility and contents; (2) Radiography: not useful for brain, but can rule out skull fractures or other lesions; (3) Computed Tomography (CT): can show cerebral edema and areas of decreased attenuation in the cerebral cortex, but is rarely available in field settings; (4) Magnetic Resonance Imaging (MRI): can show bilateral symmetrical hyperintensity in the cerebral cortex on T2-weighted images, but is not practical for routine diagnosis. In practice, diagnosis is based on clinical signs, history, and response to thiamine therapy.

Histopathology of the brain is the definitive diagnostic tool for PEM. Grossly, the brain may show flattening of cerebral gyri, and the cut surface may reveal yellowish discoloration of the cerebral cortex. Microscopically, there is bilateral symmetrical necrosis of the cerebral cortex, characterized by: (1) Neuronal degeneration and necrosis, with shrunken, eosinophilic neurons; (2) Spongiosis (vacuolation) of the neuropil; (3) Edema and congestion of blood vessels; (4) Astrocytic swelling; (5) In chronic cases, there may be gitter cell infiltration (macrophages) and gliosis. The lesions are typically limited to the cerebral cortex, with sparing of the brainstem and cerebellum. In sulfur-induced PEM, the lesions are identical. Other tissues may show no significant changes. Cytology of CSF may show increased protein and lactate, but no inflammatory cells.

Treatment of PEM should be initiated immediately upon suspicion. The primary treatment is thiamine hydrochloride, administered intravenously at a dose of 10-20 mg/kg, followed by intramuscular or subcutaneous administration at 10 mg/kg every 12 hours for 2-3 days. In severe cases, the initial IV dose can be repeated after 6 hours. Supportive therapy includes: (1) Intravenous fluids: isotonic crystalloids (e.g., lactated Ringer's solution) at a rate of 20-40 mL/kg/hour to correct dehydration and maintain perfusion; (2) Corticosteroids: dexamethasone at 0.1-0.2 mg/kg IV to reduce cerebral edema, but use with caution as it may be contraindicated in pregnant animals; (3) Mannitol: 1-2 g/kg IV over 20-30 minutes to reduce intracranial pressure, but may be used in severe cases; (4) Diazepam: 0.1-0.5 mg/kg IV to control seizures; (5) If sulfur-induced PEM is suspected, remove the source of sulfur and administer thiamine as well; (6) In cases of ruminal acidosis, administer sodium bicarbonate (1 mEq/kg IV) and rumen transfaunation. Nursing care is essential: provide a quiet, dark environment, and ensure access to food and water. If the animal is recumbent, provide soft bedding and turn it regularly to prevent pressure sores. Prognosis is good if treatment is initiated early, but poor if the animal is comatose or has severe cortical necrosis.

The prognosis for PEM depends on the severity and duration of clinical signs. Animals treated early, within 24 hours of onset, have a good prognosis, with recovery rates of 70-80%. However, animals that are recumbent, comatose, or have severe seizures have a guarded to poor prognosis, with mortality rates exceeding 50%. Even if animals recover, they may have permanent neurological deficits, such as blindness, which can affect their ability to thrive. In a flock setting, the prognosis for the group is good if management changes are implemented to prevent recurrence. Negative prognostic indicators include: (1) Lack of response to thiamine therapy within 24 hours; (2) Severe cortical necrosis on histopathology; (3) Concurrent diseases; (4) Recumbency for more than 48 hours. Long-term, affected animals may have reduced growth rates and may be culled.

After treatment, animals should be monitored closely for 48-72 hours. Serial neurological examinations should be performed to assess improvement. Blood thiamine levels, if available, can be monitored. In a flock outbreak, it is important to review the diet and management practices to identify the cause. If high-sulfur water is suspected, test the water source. If amprolium is used, consider alternative coccidiostats. For animals that recover, provide a balanced diet and avoid sudden dietary changes. In the flock, consider prophylactic thiamine supplementation in the feed or water at a dose of 3-5 mg/kg of feed for at least 2 weeks after an outbreak. Monitor for any new cases and treat promptly. Long-term follow-up should include regular assessment of growth and performance.

Clinical pearls: (1) Always consider PEM in any sheep or goat with acute neurological signs, especially if on high-concentrate diets; (2) The response to thiamine therapy is both diagnostic and therapeutic; (3) Cortical blindness with normal pupillary light reflexes is a classic sign; (4) In sulfur-induced PEM, thiamine may not be effective, so remove the sulfur source; (5) Use dexamethasone cautiously in pregnant animals; (6) Provide supportive care to prevent secondary complications. Pitfalls: (1) Delaying treatment while waiting for diagnostic tests; (2) Using thiamine at inadequate doses or for too short a duration; (3) Confusing PEM with listeriosis, which requires antibiotic therapy; (4) Overlooking the possibility of lead poisoning or salt poisoning; (5) Failing to address the underlying dietary cause, leading to recurrence; (6) Using corticosteroids in animals with infectious diseases, which can worsen the condition.

Based on Plumb's Veterinary Drug Handbook and AASRP guidelines, the following protocols are recommended: (1) Thiamine hydrochloride: 10-20 mg/kg IV initially, then 10 mg/kg IM or SC every 12 hours for 2-3 days. Withdrawal times: meat 0 days, milk 0 days (but check label); (2) Dexamethasone: 0.1-0.2 mg/kg IV or IM once, may repeat after 12 hours. Withdrawal times: meat 7 days, milk 72 hours; (3) Mannitol: 1-2 g/kg IV over 20-30 minutes, may repeat after 6 hours. Withdrawal times: meat 0 days, milk 0 days; (4) Diazepam: 0.1-0.5 mg/kg IV, as needed for seizures. Withdrawal times: meat 7 days, milk 72 hours; (5) Lactated Ringer's solution: 20-40 mL/kg IV over 1-2 hours, then maintenance at 2-4 mL/kg/hour. Withdrawal times: none; (6) Sodium bicarbonate: 1 mEq/kg IV slowly, if acidotic. Withdrawal times: none; (7) For sulfur-induced PEM, remove the sulfur source and consider oral administration of poloxalene (1-2 mL/kg) to reduce ruminal hydrogen sulfide. Withdrawal times: meat 0 days, milk 0 days; (8) Prophylactic thiamine in feed: 3-5 mg/kg of feed for 2 weeks. Withdrawal times: none.

Landmark studies and consensus guidelines on PEM in small ruminants include: (1) A review by Radositis et al. (2007) in Veterinary Medicine, which provides a comprehensive overview of PEM, including etiology, pathogenesis, and treatment; (2) A study by Gould (1998) on sulfur-induced PEM in cattle and sheep, which highlighted the importance of dietary sulfur as a cause; (3) A clinical trial by Niles et al. (2002) comparing thiamine and dexamethasone treatment in sheep with PEM, showing improved recovery with early thiamine administration; (4) The AASRP (American Association of Small Ruminant Practitioners) guidelines for the use of thiamine in small ruminants, which recommend the dosages mentioned above; (5) A field study by Smith and Sherman (2009) in Goat Medicine, which describes PEM outbreaks in goats and emphasizes the role of dietary management; (6) A meta-analysis by Constable et al. (2017) on the efficacy of thiamine in ruminants, concluding that early treatment significantly reduces mortality. These sources provide evidence-based recommendations for the diagnosis and treatment of PEM in sheep and goats.