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Welden Panziera Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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Daniel R. Rissi Athens Veterinary Diagnostic Laboratory, Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Glauco J. N. Galiza Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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Paula R. Giaretta Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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Ronaldo M. Bianchi Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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Talissa Bazzi Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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Claudio S. L. Barros Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, RS, Brazil.

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History

Two 1-year-old mixed-breed calves were euthanized and submitted for necropsy at the Laboratory of Veterinary Pathology, Federal University of Santa Maria, Santa Maria, Brazil after a 3-day period of sternal recumbency. The calves were part of a herd of 200 cattle that had been vaccinated against foot-and-mouth disease approximately 2 months before the onset of clinical signs.

Clinical and Gross Findings

Physical examination conducted by the referring veterinarian revealed bilateral pelvic limb paresis progressing to paralysis and permanent recumbency. To investigate the possibility of rabies, the calves were euthanized before a detailed physical examination could be performed. Gross findings were similar in both calves and consisted of extensive, irregular, firm cutaneous masses, which were each approximately 20 cm in diameter on the right hip area. These lesions affected the deep dermis and extended into the subcutaneous tissue and underlying skeletal muscles such as the gluteus medius and piriformis muscles. On cut surface, the masses were white and firm and had multifocal to coalescing, soft, fairly nodular yellow foci ranging in size from 0.2 to 2 cm in diameter. The lesions also extended to the lumbar vertebrae and infiltrated the lumbar spinal canal at the L2-L4 region, occupying the epidural and subdural spaces and also compressing the underlying spinal cord and nerve roots. Multiple cross sections of the affected segments of spinal cord and meninges were examined (Figure 1). In these sections, the spinal cord had focally extensive areas of softening (myelomalacia) and hemorrhage. No changes were observed in other organs.

Figure 1—
Figure 1—

Photographs of formalin-fixed cross sections of the lumbar spinal cord (between L2 and L4) from 2 euthanized calves that had a 3-day history of bilateral hind limb paresis progressing to paralysis and apparently permanent recumbency. In panel A, notice the thickening of the epidural (arrows) and subdural (arrowheads) spaces as a result of infiltration of pale tan to dark brown, firm nodules admixed with the preexisting adipose and fibrous tissue. In panel B, dark brown, soft foci of hemorrhage and necrosis (arrowheads) are observed affecting the dorsal and dorsolateral spinal cord funiculi and the gray matter.

Citation: Journal of the American Veterinary Medical Association 249, 5; 10.2460/javma.249.5.483

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

Histopathologic findings were similar in both affected calves. The subcutaneous tissue of the right hip area as well as the underlying skeletal muscles, lumbar vertebrae, epidural and subdural spaces, and spinal cord were expanded and partially or completely effaced by extensive areas of pyogranulomatous inflammation with proliferation of fibrous connective tissue (Figure 2). Most pyogranulomas had a necrotic and mineralized core containing large numbers of neutrophils surrounded by foamy and epithelioid macrophages and fewer multinucleated giant cells, lymphocytes, and plasma cells. In addition, clear spaces of variable sizes (ranging from 30 to 300 µm) were observed in the central necrotic areas. The dura mater and epidural spaces were thickened and obliterated as a result of deposition of fibrous connective tissue and infiltration by scattered lymphocytes and plasma cells. The affected sections of spinal cord (L2-L4 segments) had extensive areas of hemorrhage and necrosis with accumulation of foamy macrophages in the white and gray matter. The adjacent gray matter had scattered necrotic neurons with shrunken and hypereosinophilic cytoplasm and pyknotic nuclei. The remainder of the white matter had multifocal dilated periaxonal spaces containing either swollen axons (spheroids) or foamy macrophages (digestion chambers), consistent with Wallerian degeneration. No intralesional fungal or bacterial organisms were observed in multiple histologic sections stained with periodic acid-Schiff reaction and Grocott methenamine silver, Giemsa, or Ziehl-Neelsen acid-fast stains.

Figure 2—
Figure 2—

Photomicrograph of a section from the epidural area of one of the calves in Figure 1. There are extensive empty spaces (consistent with the space once occupied by the oil vaccine adjuvant that was extracted during processing of tissues for histologic examination) surrounded by large numbers of neutrophils and necrotic debris that are in turn surrounded by epithelioid macrophages and scattered lymphocytes and plasma cells. H&E stain; bar = 100 µm.

Citation: Journal of the American Veterinary Medical Association 249, 5; 10.2460/javma.249.5.483

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: severe, focally extensive, pyogranulomatous panniculitis; myositis; osteomyelitis; and spinal pachymeningitis with intralesional vacuoles (consistent with oil adjuvant droplets) and secondary hemorrhagic myelomalacia.

Case summary: spinal cord compression associated with vaccine granulomas in 2 calves.

Comments

The history of previous vaccination at the affected tissue site, the clinical signs, and the gross and histopathologic findings for the 2 calves of the present report are similar to previous descriptions of compressive myelopathy associated with postvaccinal granulomas in cattle.1–5 Given the clinical suspicion of vaccine-associated granulomas during necropsy, the presence of the typical intralesional clear vacuoles (consistent with the space once occupied by the oil vaccine adjuvant that was extracted during processing of tissues for histologic examination), and the absence of infectious organisms (as revealed by use of special stains), no bacterial culture of samples of the lesions was performed.

Degenerative conditions of the spinal cord in cattle have been associated with multiple causes, including compressive and space-occupying lesions affecting the spinal canal (vertebral or epidural abscesses), neoplasms (most commonly lymphoma), physical trauma, and congenital or degenerative vertebral abnormalities.6–9 Spinal damage secondary to compression caused by postvaccinal granulomas is an uncommon cause of ischemic myelopathy in cattle, although most reported cases involve this species. There have been also a few reports of this condition in humans following IM or epidural injections,10,11 in guinea pigs under experimental conditions,12,13 and in dogs and cats,14 although no spinal involvement has been documented.7

Similar to previous descriptions,1–5 paresis and paralysis in the calves of the present report likely were caused by cutaneous, muscular, and spinal lesions that developed secondary to vaccination in an inappropriate area of the body,3,4 which resulted in an inflammatory reaction to the vaccine oil adjuvant similar to the response to a foreign body. Moreover, the interval of 60 days since vaccination to the onset of clinical signs in the calves of the present report was similar to what has been described in previous reports of compressive myelopathy associated with postvaccinal granulomas in cattle.1–3,5 Adjuvants act nonspecifically to increase immune responsiveness to antigens and are a key component of many veterinary vaccines that contain inactivated bacteria and viruses.15–17 The main substances used as vaccine adjuvants in the pharmaceutical industry include mineral salts, oils, hydrophilic and hydrophobic block polymers, hydrocarbons, and surface active agents.15,16 In some instances, these compounds can trigger adverse effects such as granulomatous inflammation, anaphylaxis, iatrogenic infections, endotoxin-induced tissue damage, acute demyelinating polyradiculoneuropathy, and neoplasia.3 The vaccine adjuvant used in the foot-and-mouth disease vaccine that was responsible for the lesions observed in the cases described in the present report was a water-in-oil emulsion; although adverse effects can potentially occur with this type of adjuvant, it is commonly used in vaccines for cattle.4,15 Even though this particular vaccine is not commercially available in the United States, similar reactions can develop in cattle following vaccination with other products that contain certain types of adjuvants.2–4

The location and chronic nature of the inflammatory response in the calves of the present report reflected the injection site and the severity of the adverse reaction to the vaccine adjuvant. The spinal cord involvement denoted the infiltrative ability of the inflammatory reaction. Migration through the tissues is a well-known property of water-in-oil adjuvants, and the mechanism suggested for the invasion of the spinal canal is diffusion through the intervertebral foramen.3 Compressive and chronic lesions of the spinal cord usually affect the white matter,7,9 and this characteristic was observed in transverse sections of spinal cord from the affected calves. However, the damage was so extensive that areas of the gray matter were also involved. Histologic features in the spinal cord were similar to those outlined in previous descriptions of this condition1–5; moreover, the presence of intralesional vacuoles associated with the absence of microbial infection was indicative of a reaction to the vaccine adjuvant.

Differential diagnoses for hind limb paresis and paralysis in cattle should include infectious diseases (eg, rabies and botulism), toxicosis (eg, poisoning with Senna occidentalis or ionophore antimicrobials), vitamin E and selenium deficiency, physical trauma, and neoplasms that invade the spinal canal.1–5 The neck should be the preferred site for vaccination in cattle, and the paravertebral region should be avoided, especially in situations where the biological products in the vaccine can be potential irritants. Furthermore, appropriate procedures must be followed to avoid this type of disorder and the economic losses resulting from it.3–5

References

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