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Degenerative myelopathy and vitamin A deficiency in a young black-maned lion (Panthera leo)

Correspondence: ¹Corresponding Author: Kimberly A Maratea, Animal Disease Diagnostic Laboratory, Purdue University, 406 South University St, West Lafayette, IN 47907

	Abstract

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Degenerative myelopathy and vitamin A deficiency were diagnosed in a 1-year-old, female, black-maned lion (Panthera leo). Diffuse white matter degeneration characterized by dilated myelin sheaths, Wallerian degeneration, and reactive astrocytosis was present at all levels of the spinal cord. With luxol fast blue–cresyl echt violet stain, bilaterally symmetrical demyelination was observed in the fasciculus cuneatus of the cervical spinal cord and in peripheral white matter of cervical, thoracic, and lumbar segments. Additionally, the ventral gray columns and brain stem nuclei contained rare chromatolytic neurons with abnormal neurofilament accumulation. Leptomeninges of the cervical spinal cord were focally adhered to the dura and thickened by fibrosis and osseous metaplasia. Vitamin A deficiency was diagnosed based on hepatic vitamin A concentration of 1.71 µg/g dry weight. Adequate hepatic vitamin A concentration for yearling to adult domestic animals ranges between 150 and 1,000 µg/g dry weight. Lesions were distinct from those previously described in young captive lions with vitamin A deficiency, which had thickened skull bones and cerebellar herniation. The pathogenesis of vitamin A–associated myelopathy in this lion may be similar to that described in adult cattle, which is believed to result from spinal cord compression secondary to elevated pressure of cerebrospinal fluid.

Key Words: Lions • neurologic disease • spinal cord • vitamin A deficiency • Wallerian degeneration

Vitamin A deficiency is associated with a variety of disorders, including impaired growth, visual deficits, decreased reproductive fitness, decreased disease resistance, altered bone growth, abnormal keratinization of epithelial tissues, and neurologic disease.5,10–12,16,22 Characteristic lesions of vitamin A deficiency in cattle include papilledema, retinal and optic nerve degeneration, and squamous metaplasia of the parotid salivary ducts.5,11,12,16 Common neurologic signs associated with vitamin A deficiency include convulsions, seizures, incoordination, and ataxia.5,7,9,12,16,22 Neurologic manifestions of vitamin A deficiency are attributed to defective bone remodeling and impaired absorption of cerebrospinal fluid (CSF).11,16,22 Multiple cases of suspected or confirmed vitamin A deficiency have been reported in young captive lions.3,4,8,15 Gross lesions included osteodystrophy of skull bones, most notably the tentorium cerebelli, and herniation of the cerebellar vermis.3,4,8,15 Microscopic spinal cord lesions, when present, were confined to the cranial cervical spinal cord and consisted of Wallerian degeneration.8,15 A case of vitamin A–associated degenerative spinal cord disease in a young lion with lesions distinct from those previously reported is described.

A 1-year-old, female, black-maned lion (Panthera leo) was submitted to the Animal Disease Diagnostic Laboratory, Purdue University, for necropsy examination. The animal had a 2-week history of progressive incoordination and ataxia. Terminally, the lion was lethargic and unable to rise and was humanely euthanized. One month before the onset of neurologic signs, the lion developed nasal discharge and was treated with cephalexin for 10 days. Nine months before euthanasia, the lion was vaccinated for feline calicivirus, feline herpesvirus-1 (FHV-1), feline panleukopenia virus (FPV), and canine distemper virus (CDV). Three additional lions and other wild felids, none of which developed clinical signs, were housed at the same private facility.

A complete postmortem examination was performed. No gross lesions were observed. Tissue specimens were fixed in 10% neutral buffered formalin, routinely processed, paraffin-embedded, sectioned, and stained with hematoxylin and eosin and luxol fast blue–cresyl echt violet. Immunohistochemical staining for glial fibrillary acidic protein, phosphorylated neurofilaments, feline leukemia virus (FeLV), and CDV was performed on sections of spinal cord following previously reported protocols.19

Microscopically, diffuse white matter degeneration characterized by variable dilation of myelin sheaths was observed at all levels of the spinal cord (Fig. 1). Many dilated myelin sheaths contained intact axons, whereas others appeared empty on cross-section or contained myelin debris and macrophages. Digestion chambers were commonly seen in longitudinal sections. A few eosinophilic to pale gray, swollen axons (spheroids) were observed in white and gray matter of the brain stem and spinal cord. Rare swollen chromatolytic neurons were observed in ventral gray columns of the spinal cord and within brain stem nuclei. Immunohistochemical staining for neurofilaments demonstrated abnormal accumulation of phosphorylated neurofilaments within the perikaryon of chromatolytic neurons. With luxol fast blue–cresyl echt violet stain, bilaterally symmetrical demyelination was observed in the fasciculus cuneatus and peripheral aspects of lateral and ventral funiculi of the cervical spinal cord and in the peripheral aspects of all funiculi of thoracic and lumbar segments (Fig. 2). Degenerative changes were accompanied by modest astrocytosis and marked reactive astrogliosis, as detected by immunohistochemical staining for glial fibrillary acidic protein (Fig. 3). Mild vacuolation and axonal swelling was detected in several ventral nerve roots.

View larger version (181K): [in this window] [in a new window]   Figure 1 A longitudinal section of cervical spinal cord; black-maned lion. Wallerian degeneration of axons in the white matter is characterized by distension of myelin sheaths, axonal loss and fragmentation, and formation of digestion chambers (arrows) filled with myelin debris and gitter cells. Hematoxylin and eosin stain. Bar = 50 µm.

View larger version (109K): [in this window] [in a new window]   Figure 2 Transverse sections of cervical (top) and thoracic (bottom) spinal cord; black-maned lion. Pale areas in the white matter indicate demyelination. Luxol fast blue–cresyl echt violet stain. Bar = 1.5 mm.

View larger version (181K): [in this window] [in a new window]   Figure 3 A longitudinal section of cervical spinal cord; black-maned lion. Cell bodies and processes of reactive astrocytes stain intensely dark (arrows). Immunohistochemistry for glial fibrillary acidic protein. Bar = 25 µm.

View larger version (159K): [in this window] [in a new window]   Figure 4 Cervical spinal cord; black-maned lion. The leptomeninges (l) are focally adhered to the dura (d) and thickened by fibrosis and osseous metaplasia (arrow). The dorsal aspect of the spinal cord (s) is observed in the lower right. Hematoxylin and eosin stain. Bar = 150 µm.

Virus isolation and fluorescent antibody tests for CDV, FHV-1, and FPV and serologic tests for CDV, FeLV, and feline immunodeficiency virus conducted on blood collected at necropsy were negative. Immunohistochemical tests for CDV and FeLV gp70 did not detect viral antigen in spinal cord. Assays for trace minerals and vitamins E and A were performed on liver tissue. Vitamin A deficiency was diagnosed based on the low hepatic vitamin A concentration of 1.71 µg/g dry weight (DW). Adequate hepatic vitamin A concentration for yearling to adult domestic animals ranges between 150 and 1,000 µg/g DW, whereas concentrations below 30–40 µg/g DW are considered deficient.17 Felids have a higher dietary requirement for vitamin A than other species because they do not convert ß-carotene to vitamin A (retinol) and must receive retinol from animal products.17 Although published reference values are not available for lions, previous studies have reported hepatic vitamin A concentrations of 908 µg/g (3,026 IU/g) and 4,060 µg/g (13,535 IU/g) in 2 captive lions,20 and 6,075 µg/g DW (5,400 IU/g wet weight [WW]) in a wild lion.4 One IU vitamin A = 0.30 µg all-trans retinol17 was used as a conversion factor for hepatic vitamin A concentrations originally expressed as IU/g, and the formula WW x 3.75 = DW18 was used to convert values originally expressed as WW. Original values are listed in parentheses following the converted values. Hepatic copper concentration was 12.1 parts per million (ppm) WW. Reported reference ranges for hepatic copper concentration are 19–45 ppm WW in tigers and 37–45 ppm in domestic cats.18

Degenerative myelopathy is uncommonly reported in domestic animals and has not been described in lions. The etiology is often unknown. In domestic cats, degenerative myelopathy has been associated with chronic FeLV infection and cobalamin (vitamin B₁₂) deficiency.5,21 FeLV-associated myelopathy occurred in cats infected for more than 2 years.6 Consistent expression of FeLV p27 antigen was present in spinal cord neurons, endothelial cells, and glial cells.6 Exocrine pancreatic insufficiency secondary to chronic pancreatitis was proposed to be the underlying cause of cobalamin deficiency and degenerative myelopathy in a 9-year-old cat.21 Serum cobalamin concentration was not evaluated in this lion; however, lesions were not observed in the pancreas or gastrointestinal tract. Dietary deficiency is considered unlikely in a carnivore because animal products are the primary source of dietary cobalamin.2 CDV infection has been described in lions and other large felids.1 Lesions consisted of mild polioencephalitis, lymphocytic meningitis, and microgliosis.1 Although common in dogs, demyelination was not a feature of CDV infection in the large felids.1

Diffuse myelopathy in this lion was distinct from lesions previously described in young captive lions with confirmed or presumptive vitamin A deficiency.3,4,8,15 In previous cases, most bones of the cranial vault and mandibles were grossly thickened.3,4,8,15 Bony thickening was typically most severe in the tentorium cerebelli and was accompanied by herniation of the cerebellar vermis.3,4,8,15 Less common lesions were syringomyelia,8,15 cerebellar hemorrhages,4,15 thickened leptomeninges,8 and Wallerian degeneration confined to the brain stem and cervical spinal cord.8,15 Similar lesions have been described in calves and growing pigs with vitamin A deficiency.7,16,22 Gross alterations of cranial bones and cerebellar herniation were not observed in this lion.

The types of lesions that develop in vitamin A–deficient animals are variable and depend on duration and severity of deficiency, hepatic vitamin A reserves, and the stage of skeletal growth at the onset of deficiency.11,12,16,22 Elevation of CSF pressure is the earliest detectable change associated with vitamin A deficiency in calves and correlates clinically with the onset of papilledema.11,12 The increase in CSF pressure is caused by decreased bulk absorption of CSF at the arachnoid villi9,11,13 and is accompanied by progressive thickening of the dura mater11,13,14 and leptomeninges.14 Proposed mechanisms for resistance to CSF outflow include impaired function of arachnoid villi attributable to structural alterations in the arachnoid villi themselves or the dura mater in which they are embedded and restriction of CSF space caused by progressive meningeal thickening.11,13,14 In calves, the magnitude of increased CSF pressure correlates inversely with the degree of deficiency,11 but does not correlate with bony changes, which develop inconsistently.13 When present, significant cranial bone thickening probably contributes to elevated CSF pressure by restriction or mechanical blockage of CSF flow11 and may predispose to severe lesions such as cerebellar herniation and hydromyelia. Because dietary supplementation of deficient cattle results in rapid reduction of CSF pressure and partial to complete reversal of clinical signs, increased CSF pressure is presumed to be the primary mechanism of neurologic disease,10,11,16 and Wallerian degeneration may be observed in the peripheral spinal cord of these animals.16 Diffuse white matter degeneration of the spinal cord without obvious thickening of skull bones has also been described in 5–6-month-old grower pigs with vitamin A deficiency.7

Microscopic lesions in the spinal cord were consistent with the clinical signs in the lion. A diagnosis of vitamin A deficiency was based on a nearly depleted hepatic vitamin A concentration of 1.71 µg/g DW. Because approximately 90% of total body vitamin A is stored in the liver, hepatic levels are the most reliable indicator of vitamin A status.12,17 Spinal cord compression secondary to elevated CSF pressure may explain the mainly peripheral distribution of Wallerian degeneration observed in this lion. Demyelination and neuronal chromatolysis most likely occurred secondary to axonal degeneration. Neuronal chomatolysis accompanied by abnormal accumulation of phosphorylated neurofilaments in the perikaryon is associated with decreased transport of neurofilaments to axons and can occur when axonal injury occurs close to the cell body.23 Focal leptomeningeal thickening and osseous metaplasia may be directly caused by vitamin A deficiency or represent a degenerative response to persistently elevated CSF pressure. Meningeal thickness and dural mineralization in the remaining spinal cord were similar to those in a 17-year-old lion with no history of neurologic disease, but may be excessive in a 1-year-old lion. Perivascular cuffing was restricted to several blood vessels in the pontine white matter and most likely represents a nonspecific response to local injury.

The significance of low hepatic copper concentration in this lion is unknown. Enzootic ataxia is a delayed-onset form of copper deficiency that causes degenerative spinal cord disease in lambs and goat kids up to 6 months of age.22 Microscopic lesions of enzootic ataxia consist of neuronal chromatolysis and white matter degeneration in the caudal brain stem and spinal cord.22 In the spinal cord, dorsal spinocerebellar tracts and tracts adjacent to the ventromedian fissure are most severely affected.22 In this lion, however, myelopathy was diffuse and the peripheral white matter was most severely affected. To the authors' knowledge, neurologic disease caused by copper deficiency has not been demonstrated in cats or wild felids. Mild myositis and myocarditis were most likely unrelated to the spinal cord lesions, because they were not associated with skeletal muscle atrophy or peripheral nerve lesions. Squamous metaplasia was not observed in this lion and has not been described in previous cases of vitamin A deficiency in lions.

Diffuse myelopathy has not been previously reported in lions with vitamin A deficiency. The distinct lesions in this lion suggest that neurologic manifestations of vitamin A deficiency in some lions may resemble those described in marginally deficient calves and adult cattle. Vitamin A deficiency should be considered in the differential diagnosis of lions with clinical histories of progressive ataxia and incoordination and microscopic evidence of degenerative myelopathy.

	Acknowledgments

 
We thank the Nutrition and Toxicology sections of the Michigan State University Diagnostic Center for Population and Animal Health for performing the vitamin and mineral analyses, respectively; Dr. Brian Summers for consulting on this case, and Dr. Kerrick Deardorf for referring this interesting case.

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From the Animal Disease Diagnostic Laboratory and Department of Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, IN 47907 (Maratea, Hooser, Ramos-Vara).

	References

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