History
A 3-month-old sexually intact male mixed-breed lamb was submitted for necropsy at the Federal University of Santa Maria Laboratory of Veterinary Pathology after a 6-day history of neurologic signs. Two lambs from the same farm had previously died after developing similar clinical signs. All affected individuals were part of a herd of 20 sheep; the animals were raised in an extensive grazing system and all lambs were dewormed with doramectin and moxidectin 20 days before the onset of clinical disease.
Clinical and Gross Findings
Antemortem physical examination of the lamb performed by the referring veterinarian revealed progressive clinical changes characterized by severe signs of depression and anorexia followed by incoordination, circling, bilateral blindness, and recumbency. Owing to the worsening of the clinical signs and because of the possibility of rabies, euthanasia was elected. Gross findings were restricted to the brain (Figure 1). The frontal telencephalic lobes were bilaterally swollen and soft, with flattening of gyri. Serial cross sections of the entire brain revealed extensive, pale yellow, granular areas of malacia affecting the frontal telencephalic cortex. The cortical gray matter was multifocally separated from the subcortical white matter by a cleft containing translucent fluid. No other gross changes were observed.
Photograph of the frontal lobe of a 3-month-old mixed-breed lamb in a herd of 20 animals that was euthanized after development of severe signs of depression and anorexia followed by incoordination, circling, bilateral blindness, and recumbency. Two lambs from the same herd had died after developing similar clinical signs. Notice that the frontal cerebral cortex contains extensive, pale areas of malacia (asterisk). There is a 2-mm-wide edematous cleft separating the cortex from adjacent subcortical white matter (arrow).
Citation: Journal of the American Veterinary Medical Association 251, 7; 10.2460/javma.251.7.799
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→
Histopathologic Findings
Sections of the brain, including the frontal, parietal, and occipital cerebral cortex and subcortical white matter, basal nuclei, thalamus, midbrain, cerebellum, and brainstem, were examined microscopically. There was widespread laminar neuronal necrosis characterized by angular neurons with shrunken and hypereosinophilic cytoplasm and pyknotic nuclei throughout the frontal and parietal telencephalic cortex (Figure 2). Blood capillaries were conspicuous as a result of endothelial swelling and were often surrounded by small numbers of foamy macrophages (gitter cells) and fewer lymphocytes and plasma cells. The gray matter was finely vacuolated because of edema and contained widespread reactive astrocytosis (astrocytic hypertrophy) and astrogliosis (astrocytic proliferation). The interface between the cortical gray matter and the subcortical white matter was occasionally collapsed by a cleft containing scattered foamy macrophages, hemorrhage, and edema fluid.
Photomicrograph of a section of cerebral cortex from the lamb in Figure 1. Notice the necrotic neurons (arrowheads) and foamy macrophages or gitter cells (arrows) among prominent capillaries and fragmented gray matter. H&E stain; bar = 50 μm.
Citation: Journal of the American Veterinary Medical Association 251, 7; 10.2460/javma.251.7.799
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: extensive cerebrocortical necrosis (polioencephalomalacia [PEM]). Case summary: PEM in a lamb.
Comments
The clinical history and pathological findings for the lamb of the present report were consistent with those described for ruminants with PEM or cerebrocortical necrosis.1,2 Although these are both descriptive terms that denote neuronal necrosis with softening of the cerebral gray matter, they have been historically used to name a set of diseases characterized by similar neuropathologic changes caused by different and often unknown causes.1–4 Polioencephalomalacia is an acute or subacute condition that has been described as affecting multiple ruminant species, including cattle, sheep, goats, buffalo, and deer.1,5,6 The disease has a worldwide distribution and has been associated with a wide variety of causes, including thiamine deficiency (ingestion of thiaminases, dietary changes, or treatment with anthelminthics or amprolium), sulfur toxicosis, lead toxicosis, salt toxicosis (water deprivation), bovine herpesvirus-1 or -5 infection, and hyperacute Phalaris spp toxicosis.2,7 As exemplified by the case described in the present report, the cause of PEM remains undetermined in a diagnostic setting for most cases.2
Thiamine has an important role in carbohydrate and energy metabolism, and a disruption of glycolysis or ATP production has been proposed as a potential underlying mechanism for the development of PEM.8,9 The ruminal flora in adult ruminants is able to synthesize adequate amounts of thiamine, but certain conditions may inactivate or reduce its production, resulting in thiamine deficiency.1,10 Thiamine deficiency-induced PEM (naturally occurring or experimentally induced) has been associated with ingestion of thiaminase-producing plants such as bracken fern (Pteridium aquilinum),5 horsetail (Equisetum arvense),5 pigweed (Amaranthus blitoides),11 and Nardoo fern (Marsilea drummondii).12 Other conditions that may possibly cause thiamine deficiency include increased ruminal acidity as a result of subtle changes in high-energy diets,8 use of thiamine antagonists (eg, amprolium) or anthelminthics (eg, promazine, levamisole, and benzimidazole), and ingestion of animal carcasses.7,8,13 In the present report, affected sheep in the herd had a history of routine anthelmintic treatment 20 days before the onset of clinical signs; although a suspected etiologic diagnosis could be drawn from this information, confirmation would be difficult given the lack of standard scientific tests capable of supporting that hypothesis.5,10 Thiamine deficiency has been associated with PEM because affected ruminants frequently have low thiamine concentrations in tissues or high ruminal activities of thiaminases. In addition, these affected animals may respond positively to treatment with thiamine, supporting its active role in the development of PEM.3,4 However, the concentration of thiamine in tissues may be within the reference interval in affected individuals, which raises questions regarding the role of thiamine deficiency in the pathogenesis of PEM.9,14,15
Sulfur toxicosis develops as a result of ingestion of sulfur or sulfur compounds in formulated rations, drinking water, molasses, urine acidifiers, and sulfurrich plants, such as Kochia scoparia (fireweed or burning bush) and Brassica spp.8,16,17 Salt toxicosis (water deprivation) in ruminants following excessive ingestion of salt and restricted water intake has been rarely reported.2,18 Salt toxicosis develops after dehydrated individuals regain access to water and start drinking, which results in a relative, acute decrease in blood sodium concentration that is followed by rapid movement of water into the CNS and subsequent development of edema.8 Lead poisoning is more common in cattle than in small ruminants. Sources of lead include insecticides and herbicides, lead-acid batteries, leaded gasoline, lubricants, linoleum, lead paint, caulking compounds, shotgun pellets, automobile exhaust, and smelter discharges.8 These products can be indirectly ingested as contaminants of pastures or foodstuffs or can be directly ingested by ruminants.8 Histologically, acid-fast intranuclear inclusions can be observed in the epithelial cells of the renal tubules and can be helpful in determining the etiologic diagnosis of PEM caused by lead toxicosis.2
Clinical signs in the lamb of the present report were typical of PEM. Affected animals frequently isolate from other animals in the group and develop neurologic abnormalities related to telencephalic lesions; these abnormalities are characterized by blindness, recumbency, opisthotonus, hyperesthesia, seizures, strabismus, and nystagmus.8,10 Death typically occurs within 3 to 5 days after onset of clinical signs.10 Gross findings are typically restricted to the brain and may vary according to the duration and severity of clinical disease.2 Animals that die after a short time may have cerebral edema characterized by narrowing of sulci and flattening of cerebrocortical gyri, which can be pale and slightly soft.2,17 In addition to these changes, lesions in subacute cases develop secondarily to severe laminar neuronal necrosis and may include marked cerebrocortical pallor or separation from the underlying white matter, similar to findings for the lamb of the present report. Furthermore, there may be subtentorial herniation or cerebellar herniation through the foramen magnum because of severe widespread cerebral edema. Atrophy of cerebral gyri and cortical gray matter can be observed in animals that survive for > 2 weeks after onset of clinical signs.2,17 The gross lesions of PEM in fresh and formalin-fixed specimens may be highlighted under UV light because of the accumulation of mitochondrial derivatives.17 Major clinical differential diagnoses for the lamb of the present report included rabies, focal symmetrical encephalomalacia, listeriosis, and cerebral coenurosis; however, the gross and microscopic changes convincingly supported the diagnosis of PEM.1,10
Prevention of PEM is difficult because of the variety of possible causes, but preventative measures should target management of dietary intake by susceptible animals and allow an adequate period of adaptation to high-concentrate rations. Thiamine supplementation is useful, but may not prevent clinical disease. Affected individuals need to be identified early in the course of disease to be successfully treated.1 Although most animals with PEM may respond favorably to parenteral administration of thiamine hydrochloride, this treatment has not been regarded as highly effective in many cases.1,16
References
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