Acute paraplegia associated with vasculitis in a dog with leishmaniasis

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CASE REPORTS

Acute paraplegia associated with vasculitis in a dog with leishmaniasis A 14-month-old female crossbreed dog with leishmaniasis, receiving allopurinol, was presented with acute paraplegia. A diagnosis of

in a dog with leishmaniasis, receiving allopurinol.

renal failure with pelvic limb lower motor neuron signs was made and the dog was euthanased. Histopathological examination demonstrated leukocytoclastic vasculitis in multiple organs. Malacia and haemorrhage affecting the spinal cord was associated with multiple foci of vasculitis within the nervous tissue. Rupture and thrombosis of inflamed vessels caused haemorrhage in the spinal cord and subsequent paralysis. A. FONT, J. MASCORT, J. ALTIMIRA*, J. M. CLOSA AND M. VILAFRANCA* Journal of Small Animal Practice (2004) 45, 199–201

Hospital Ars Veterinaria, Carrer Cardedeu 3, 08023 Barcelona, Spain *Histovet, Carrer Montserrat 9, 08192 San Quirze del Valles, Spain JOURNAL OF SMALL ANIMAL PRACTICE

INTRODUCTION In canine leishmaniasis, immune complexes may be deposited on the glomeruli capillary wall and blood vessels as a consequence of the persistent production of circulating antigens. These soluble complexes activate the complement cascade, which elicits an inflammatory response and may cause glomerulonephritis and vasculitis (Slappendel and Ferrer 1998). Glomerulonephritis is a frequent diagnosis in areas where leishmaniasis is endemic but vasculitis is rare (Slappendel and Ferrer 1998). Vasculitis is a clinicopathological process characterised by inflammation and, in some instances, necrosis of blood vessels. It can exist as the major and primary manifestation of a number of clinical syndromes or it may represent a relatively minor component of other primary disease processes (Fauci and others 1978). There are a few reports of necrotising vasculitis involving the central nervous system in dogs where the cause was not determined (Kelly and others 1973, Hoff and Vandevelde 1981, Meric and others 1986). Systemic necrotising vasculitis has been described in two dogs with leishmaniasis (Pumarola and others 1991), but no neurological signs were reported in these cases. In one of the two dogs, vasculitis was found in the choroid plexus of the brain but no lesions were seen in arteries in the spinal cord. This report describes a case of acute paraplegia associated with vasculitis

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CASE HISTORY A 14-month-old, female crossbreed dog weighing 17 kg was presented to the Hospital Ars Veterinaria with a four-day history of anorexia and depression. On physical examination, a generalised lymphadenopathy, splenomegaly and nonpruritic alopecia with dry seborrhoea on the ears were present. At that time, the dog was diagnosed with leishmaniasis by direct observation of Leishmania amastigotes during the cytological examination of the bone marrow. Treatment with allopurinol (Zyloric; Glaxo Wellcome) at a dose of 20 mg/kg/day was instituted. After 25 days of treatment, the dog was in a good condition and the skin lesions had improved. Three months after initiation of treatment, the skin lesions had disappeared completely and the dog appeared healthy. Allopurinol was continued. Five months after initial diagnosis the dog was presented with an eight-hour history of paraparesis progressing to paraplegia. There was a five-day history of loss of appetite and vomiting but no history of trauma. On presentation, the dog was depressed. Temperature, pulse and respiratory rate were normal. Neurological examination revealed paralysis of the hindlimbs with loss of femoral and sciatic nervemediated reflexes, pain sensation and panniculus reflex. The anus was dilated and unresponsive, and the tail was atonic. These findings were indicative of diffuse involvement of the thoracic, lumbar and sacral spinal cord. No other clinical signs were noted. Preliminary haematological and biochemical analyses revealed a packed cell volume of 28 per cent (reference range, 35 to 55 per cent), total protein of 93 g/litre (reference range, 60 to 75 g/litre) and blood urea nitrogen of 99·8 mmol/litre (reference range, 5·4 to 10·7 mmol/litre). A urine sample, obtained by cystocentesis, 199

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FIG 1. Wedge-shaped area of haemorrhage causing degeneration of nervous tissue within the spinal cord (arrow). Haematoxylin and eosin (H&E). Bar=500 µm

indicated significant proteinuria (4+), with a specific gravity of 1·015 and normal sediment. A clinical diagnosis of glomerular disease with renal failure was made. Due to the acute onset of paraplegia and the presence of glomerular disease, biochemical and coagulation profiles were carried out. Abnormalities included mild hypoalbuminaemia (20·4 g/litre; reference range, 27 to 36 g/litre), hypergammaglobulinaemia (30·9 g/litre; reference range, 4 to 10 g/litre), high creatinine (592·3 µmol/litre; reference range, 45 to 150 µmol/litre) and marked hyperphosphataemia (8·4 mmol/litre; reference range, 0·6 to 1·3 mmol/litre). The urinary protein/creatinine ratio was 6·4 (reference range, < 1). The dog’s haemostatic status demonstrated normal activated partial thromboplastin time (15·8 seconds; control time, 14 seconds), prothrombin time (9 seconds; control time, 9·4 seconds) and thrombin time (14·5 seconds; control time, 14·7 seconds), with a normal fibrinogen level (4 g/litre; reference range, 2 to 4 g/litre). Antithrombin III activity was normal (106 per cent; reference range, 92 to 116 per cent). The prognosis for recovery with treatment was considered poor in view of the leishmaniasis with advanced renal failure and neurological complications, and the dog was euthanased. On postmortem examination, a large area of haemorrage within the nervous tissue (Fig 1) was observed in the spinal cord at the level of the second lumbar vertebra (L2), which was associated histologically with a partially organised thrombus and with a mixed inflammatory cell infiltrate. Sections of the spinal cord immediately caudal to this focus of haemorrhage also 200

FIG 2. Spinal cord section showing leukocytoclastic vasculitis. Note the vessel wall necrosis, inflammatory cells showing karyolysis and karyorrhexis, and incipient haemorrhage into the nervous tissue (top right). H&E. Bar=20 µm

revealed thrombi, discrete haemorrhage within the parenchyma, fibrin and severe malacia of the adjacent nervous tissue. The haemorrhagic areas affecting the nervous tissue were associated with necrosis of the wall of numerous blood vessels, together with karyorrhectic leucocytic debris within the degenerate wall (leukocytoclastic vasculitis) (Fig 2). The sciatic nerve showed diffuse moderate vacuolation of axons. Sections of striated muscle (quadriceps) revealed multiple foci of leukocytoclastic vasculitis and complete necrosis of small vessels between striated muscle bundles. Discrete inflammatory cell infiltrates were present adjacent to these lesions, as well as focal haemorrhages at the interstitium, and caused degenerative changes to the surrounding myocytes (loss of transversal striation, eosinophilia). In these areas, particles showing morphological as well as immunohistological characteristics of Leishmania amastigotes were identified within the cytoplasm of macrophages. The lymph nodes, renal interstitium, spleen and liver were infiltrated by plasma cells and macrophages with Leishmania amastigotes within the cytoplasm. Membranous glomerulonephritis was present. Immunohistochemistry demonstrated Leishmania antigen within the cytoplasm of macrophages in these inflammatory infiltrates.

DISCUSSION It is unusual to find dogs with leishmaniasis and clotting complications such as thrombosis, haemorrhages or disseminated intravascular coagulation (Pumarola and

others 1991, Font and others 1993, 1994). In the case presented here, no laboratory evidence of a hypercoagulable state or disseminated intravascular coagulation was seen. The neurological findings were indicative of diffuse or multifocal involvement of the thoracic, lumbar and sacral spinal cord. Thrombosis and rupture of inflamed vessels had resulted in haemorrhage in the spinal cord, causing severe degeneration of the nervous tissue at the level of L2 and subsequent paralysis. There was clear evidence of vasculitis affecting small blood vessels of the spinal cord causing haemorrhage within the spinal tissue. Although similar vascular lesions may have occurred at sacral and caudal segments of the spinal cord, causing an absent panniculus reflex, dilated anus and flaccid tail, these segments were not collected for histopathological examination. Leukocytoclastic vasculitis was also identified as affecting small-sized vessels in the interstitium of the striated muscle. Necrotising vasculitis of small arteries and arterioles can be caused by infectious agents that damage vessels either directly or indirectly by immune mechanisms, drug-induced immune reactions, toxic substances and metabolic disease (Easley 1979). In addition to classic immune complex-mediated vasculitis, cell-mediated immunity may also be involved in vascular damage. Any mechanism inducing endothelial cell injury may initiate the acute inflammatory response by induction of the complement and kinin cascades, resulting in thrombosis and/or vasculitis (Easley 1979). It is not known why vasculitis is uncommon in dogs with leishmaniasis. However, vascular disease is recognised

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infrequently antemortem and this could explain the apparent low incidence of vasculopathy in canine leishmaniasis. Vasculitis may reflect the wide spectrum of immunological responses to the infection (Pumarola and others 1991). Leishmaniasis in this dog may have been the cause of the vasculitis, as occasionally described (Pumarola and others 1991), although drug-induced vasculitis due to a generalised hypersensitivity reaction or toxicity to allopurinol could also be considered. In recent years, allopurinol combined with meglumine antimoniate or allopurinol alone has been used for the treatment of canine leishmaniasis (Liste and Gascon 1995, Denerolle and Bourdoiseau 1999). The drug is available in most countries, is effective, inexpensive, well tolerated and has few adverse side-effects (Slappendel and Ferrer 1998). Meglumine antimoniate in combination with allopurinol produces better results than antimony alone or allopurinol alone for the treatment of canine leishmaniasis (Denerolle and Bourdoiseau 1999). Meglumine antimoniate should be administered by subcutaneous injections daily. In this case, the owner had problems related to the administration of the drug and so allopurinol alone was used. The therapy was only partially effective. Clinical remission was achieved with the initial treatment of allopurinol and, although the treatment was administered continuously without interruption for five months, the dog relapsed. Therapy appears to have failed in this dog although long-term administration of allopurinol is an effective way of maintaining clinical remission in most dogs with leishmaniasis (Ginel and others 1998, Cavaliero and others 1999).a Most of the allopurinol is oxidised within two to four hours to oxypurinol, the major active metabolite. The halfclearance time of oxypurinol is far more prolonged than that of allopurinol and it markedly increases when renal function is impaired (Puig and others 1989). Human patients with renal dysfunction may be JOURNAL OF SMALL ANIMAL PRACTICE

predisposed to allopurinol-induced adverse effects (Singer and Wallace 1986). In humans, the pathogenesis of adverse reactions to allopurinol is thought to involve a combination of immunological processes, genetic predisposition and accumulation of the drug (Singer and Wallace 1986). Harmful effects of allopurinol treatment have been ascribed to toxicity, hypersensitivity, drug interaction and idiopathic reaction, and to direct consequences resulting from the normal therapeutic action of the drug, such as xanthine stones (Puig and others 1989).aaa Hypersensitivity typically manifests within several weeks of starting the medication and presents as fever, skin rashes, eosinophilia, and kidney and liver dysfunction (Singer and Wallace 1986). Some adverse reactions to allopurinol may be mediated by lymphocyte reactivity to oxypurinol (Emmerson and others 1988). Plasma oxypurinol monitoring could prevent allopurinol side effects, although it may not prevent allopurinol hypersensitivity (Puig and others 1989). In humans receiving allopurinol, vasculitis and necrotising arteritis involving the central nervous system have been reported as a hypersensitivity reaction (Rothwell and Grant 1996). In the present case, although an association between vasculitis and allopurinol therapy was not proven, allopurinol could be implicated in the development of this unusual vascular lesion, although the time course is not typical of the disorders described in humans. Longterm treatment with allopurinol should be considered as a potential cause of vasculitis and, due to the serious side effects seen in human patients, this drug should be used with caution in dogs. Conclusions In the dog discussed in this report, multiple foci of leukocytoclastic vasculitis were identified in the vessels of the nervous tissue, explaining the presence of acute paraplegia. The unusual findings in this case were thrombosis and rupture of inflamed vessels, causing haemorrhage in the spinal

cord and subsequent paralysis. This indicates that, in dogs with leishmaniasis receiving allopurinol, necrotising arteritis should not be overlooked as a possible cause of acute paralysis. References CAVALIERO, T., ARNOLD, P., MATHIS, A., GLAUS, T., HOFMANNLEHMANN, R. & DEPLAZES, P. (1999) Clinical, serologic, and parasitologic follow-up after long term allopurinol therapy of dogs naturally infected with Leishmania infantum. Journal of Veterinary Internal Medicine 13, 330-334 DENEROLLE, P. & BOURDOISEAU, G. (1999) Combination allopurinol and antimony treatment versus antimony alone and allopurinol alone in the treatment of canine leishmaniasis (96 cases). Journal of Veterinary Internal Medicine 13, 413-415 EASLEY, J. R. (1979) Necrotizing vasculitis: An overview. Journal of the American Animal Hospital Association 15, 207-211 EMMERSON, B. T., HAZELTON, R. A. & FRAZER, I. H. (1988) Some adverse reactions to allopurinol may be mediated by lymphocyte reactivity to oxypurinol. Arthritis and Rheumatism 31, 436-440 FAUCI, A. S., HAYNES, B. F. & KATZ, P. (1978) The spectrum of vasculitis: Clinical, patholic, immunologic and therapeutic considerations. Annals of Internal Medicine 89, 660-676 FONT, A., CLOSA, J. M., MOLINA, A. & MASCORT, J. (1993) Thrombosis and nephrotic syndrome in a dog with visceral leishmaniasis. Journal of Small Animal Practice 34, 466-470 FONT, A., GINES, C., CLOSA, J. M. & MASCORT, J. (1994) Visceral leishmaniasis and disseminated intravascular coagulation in a dog. Journal of the American Veterinary Medical Association 204, 1043-1044 GINEL, P. J., LUCENA, R., LOPEZ, R. & MOLLEDA, J. M. (1998) Use of allopurinol for maintenance of remission in dogs with leishmaniasis. Journal of Small Animal Practice 39, 271-274 HOFF, E. J. & VANDEVELDE, M. (1981) Case report: Necrotizing vasculitis in the central nervous systems of two dogs. Veterinary Pathology 18, 219-223 KELLY, D. F., GRUNSELL C. S. G. & KENYON, C. J. (1973) Polyarteritis in the dog. Veterinary Record 92, 363-366 LISTE, F. & GASCON, M. (1995) Allopurinol in the treatment of canine leishmaniasis. Veterinary Record 137, 23-24 MERIC, S. M., CHILD, G. & HIGGINS, R. J. (1986) Necrotizing vasculitis of the spinal pachyleptomeningeal arteries in three Bernese mountain dog littermates. Journal of the American Animal Hospital Association 22, 459-465 PUIG, J. G., CASAS, E. A., RAMOS, T. H., MICHAN, A. A. & MATEOS, F. A. (1989) Plasma oxypurinol concentration in a patient with allopurinol hypersensitivity. Journal of Rheumatology 16, 842-844 PUMAROLA, M., BREVIK, L., BADIOLA, J., VARGAS, A., DOMINGO, M. & FERRER, L. (1991) Canine leishmaniasis associated with systemic vasculitis in two dogs. Journal of Comparative Pathology 105, 279-286 ROTHWELL, P. M. & GRANT, R. (1996) Cerebral vasculitis following allopurinol treatment. Postgraduate Medicine Journal 72, 119-120 SINGER, J. Z. & WALLACE, S. L. (1986) The allopurinol hypersensitivity syndrome. Arthritis and Rheumatism 29, 82-87 SLAPPENDEL, R. J. & FERRER, L. (1998) Leishmaniasis. In: Infectious Disease of the Dog and Cat. Ed C. E. Greene. W. B. Saunders, Philadelphia. pp 450-458

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