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Home , Locoweed, Oxytropis sericea

62 EQUINE VETERINARY EDUCATION / AE / FEBRUAry 2008

Case Report Suspected in a Belgian horse H. NOLLET*, K. PANTER†, K. VANSCHANDEVIJL, L. LEFERE, B. STEGELMEIER† AND P. D EPREZ Department of Internal Medicine, Faculty of Veterinary Medicine, University of Ghent, Belgium; and †ARS Poisonous Research Laboratory, Logan, Utah 84341, USA. Keywords: horse; swainsonine; intoxication; lysosomal; mannosidosis

Summary lunged a hypermetria of the right hindlimb was observed. The symptoms had worsened and the horse was referred for The case of a horse with acute symptoms of excitement, further examination. exaggerated fright reactions and trembling is presented. In addition to these cerebral symptoms, mild cerebellar Clinical findings ataxia and a renal tubular lesion were diagnosed. Suspected swainsonine poisoning was confirmed by the On admission, the horse’s rectal temperature, and heart and presence of the (154 ng/ml) in the serum sample respiratory rates were all within reference ranges. Only the taken immediately after admission. A good recovery respiration was mildly elevated. The sclera of the eye was light was seen after fluid therapy with supplementation of yellow. The horse was extremely stressed. Examination of the potassium, a dopamine drip and administration of cranial nerves was normal, but the reaction of the head during diazepam. The effects of the toxin, by inhibiting the the menace response was exaggerated. When touching the lysosomal enzyme α-mannosidase and mimicking the body, the horse contracted all muscles and jumped away. From genetic mannosidosis, are discussed. time to time there was a sudden short shaking movement over the whole body. When examining the horse on the lunge, a Introduction stiff gait but no paresis was seen. Only a slight hypermetria of all 4 limbs was observed. Swainsonine is a toxic indolizidine especially present in Electromyographic examination of the back and hindlimb species of the genera and , collectively muscles revealed no abnormal potentials indicating known as . The most notable clinical symptom of denervation or muscle pathology. Blood gas analysis revealed a intoxication in horses is a change in behaviour, often metabolic alkalosis (pH: 7.45; bicarbonate: 31 mmol/l; base characterised by many cycles of excitement/depression. excess: 7.7 meq/l). Blood biochemistry showed a very mild This is the first known report of swainsonine poisoning in elevation of urea (9.5 mmol/l; reference range [rr]: 4–8 mmol/l), a horse in Europe. creatine phosphokinase (527 mu/ml; rr 10–146 mu/ml) and a very mild decrease of potassium (3.3 mmol/l; rr 3.5–4 mmol/l). Case details The value for creatinine was at the upper limit of the reference range (16 mg/l; rr 5–16 mg/l). Urinalysis indicated a high level History of γ-glutamyltransferase (110 iu/l; rr <20 iu/l). Normal values for the fractional excretion of sodium, potassium, chloride, calcium and were found. A 20-year-old male horse was admitted to the Internal The following morning serum levels of potassium Medicine department of the Faculty of Veterinary Medicine had decreased to 2.9 mmol/l and urea had increased to of the University of Ghent with symptoms of abnormal 10.9 mmol/l. The serum creatinine concentration remained behaviour since the previous evening. The horse competed unchanged. Clinically the horse was very excited and was formerly at an international jumping level but had been trembling all over its body. When approaching the horse very retired to recreational use a few months prior to carefully, it reacted in a frightened manner and a mild presentation. The owners described the horse as being intention tremor was observed. The ataxia and hypermetria usually quiet to handle. It now showed episodes of trembling were more severe. and fright reactions when touched, and when the horse was An echographic examination of both kidneys did not reveal macroscopic structural abnormalities. Diazepam *Author to whom correspondence should be addressed. (0.05 mg/kg bwt i.v., 4 times a day) was given in an attempt EQUINE VETERINARY EDUCATION / AE / FEBRUAry 2008 63

to calm the horse. Polyionic isotonic perfusions with extra the western poisoning or locoism is potassium added were administered. Six hours after starting described as the largest poisonous plant problem for livestock the perfusions the horse had not urinated and rectal palpation producers (Marsh 1909; Marsh et al. 1934; Stegelmeier et al. revealed a small bladder; oliguria was suspected and the 1999, 2005). Also, in southern Brazil the toxin is reported to administration of i.v. dopamine (3–7 µg/kg bwt/min i.v.), to produce neurological disorders in goats and ponies (Colodel et increase the renal blood flow and glomerular filtration and al. 2002; Loretti et al. 2003). Locoweeds remain toxic tubular flow, was started. The dopamine drip was continued throughout the season and even the dry, dead stalks of for 3 days until oliguria was converted to polyuria. After 2 days senescent are poisonous (Ralphs 1987). The highest of perfusion, potassium and urea were both normalised and concentrations of swainsonine are found in the flowers and the administration of the polyionic isotonic fluid was , and, consequently, the quantity of plant that an animal discontinued on the fourth day. The horse seemed to be less has to eat to receive a toxic dose will vary (James and van stressed and showed only short episodes of excitement and Kampen 1971). Livestock generally prefer the green-growing longer periods of depression and the diazepam was locoweeds to other forage that is dormant in the late autumn, discontinued. During the following days the serum values of winter and spring. the electrolytes and urea were checked. On the fifth day after The toxin acts by inhibiting the lysosomal enzyme ceasing the perfusions the potassium dropped to 2.8 mmol/l. α-mannosidase resulting in accumulation of partially processed Potassium chloride was again given i.v. until the serum oligosaccharides and glycoproteins in lysosomal vacuoles potassium level was normalised. Clinically, the horse was calm (Dorling et al. 1980), similar to genetic mannosidosis, a but it still showed mild ataxia. Gamma-glutamyltransferase in lysosomal storage disease, described in man, Angus cattle and the urine had decreased to 67 iu/l. On Day 7 after admission, cats (Cooper et al. 1990; DeGasperi et al. 1991). Furthermore, a second needle electromyographic examination and a swainsonine’s inhibition of Golgi mannosidase II alters transcranial magnetic stimulation with evaluation of the glycoprotein synthesis, processing and transport. This results in magnetic motor evoked potentials were performed. Neither dysfunctional cellular adhesion molecules, circulating test revealed any abnormality. During the following days hormones (e.g. insulin) and various membrane receptors (van potassium levels stayed stable and the horse returned home. Kampen and James 1969, 1970; Tulsiani et al. 1984). Four months after the beginning of the problem, Histological studies reveal lysosomal swelling and vacuolisation γ-glutamyltransferase in a control urine sample had within neurons, renal tubules, liver, placenta, lymphocytes etc. normalised (18.0 iu/l). Over this period all clinical signs These lesions are most prominent in neurons and epithelial progressively disappeared and the horse was ridden again. cells. Clinically, the most noticeable feature of intoxication is One year later, the horse was still completely normal. the change in behaviour of normal horses. ‘Loco’ is a Spanish When evaluating the symptoms, 2 distinct problems could word for ‘crazy’ that describes animals poisoned by locoweeds. be described. The abnormal behaviour together with the Depression, proprioceptive deficits, high stepping gait, ataxia and hypermetria indicate a central neurological lesion intention tremors, excitement and over-reaction when (cerebrum and cerebellum) whereas the uraemia, potassium stressed, emaciation, impaired reproduction and occasionally abnormality, the high urinary level of γ-glutamyltransferase death are described in poisoned animals (Panter et al. 1999a,b; and metabolic alkalosis indicate a renal tubular lesion. To Stegelmeier et al. 1999). Nervous signs of intoxication in exclude a brain tumour in this aged horse a CT scan of the horses are especially characterised by many cycles of brain was proposed, but the owner refused. excitement-depression. Previously poisoned stock are described to be more susceptible to infectious disease, Discussion especially respiratory disease, probably due to an altered immune function (Stegelmeier et al. 1998). Many of the clinical A possible differential diagnosis of the neurological problems signs and lesions are reversible if the animal is removed from together with the renal abnormalities is an intoxication. the source of locoweed; however, with chronic poisoning, However, no toxin described in our countries could explain the irreversible neurological lesions occur and the damage can be symptoms. From a review of the literature, intoxication by permanent (Marsh 1909; James and van Kampen 1971). swainsonine, present in locoweeds, is reported to induce The serum sample of the horse taken on admission (about comparable symptoms (Oehme et al. 1968; James et al. 1969; 12 h after the beginning of the symptoms) was tested by a James and van Kampen 1971; O’Sullivan and Goodwin 1977; competitive binding assay with jack bean α-mannosidase and Loretti et al. 2003; Pfister et al. 2003). was found positive for swainsonine (154 ng/ml). The half-life Swainsonine is a toxic indolizidine alkaloid especially of swainsonine in the serum is 16–20 h (Stegelmeier et al. present in species of the genera Astragalus and Oxytropis, 1995a). This means that an animal suspected of locoweed collectively known as locoweeds. The name is derived from the poisoning must have a blood sample taken within 2 days of gray swainson pea ( canescens), from which the eating locoweed for swainsonine to be detected. Blood toxin was first isolated (Huxtable and Dorling 1982). Other samples from the same horse were also examined for publications reported swainsonine intoxication by ingestion of swainsonine one day, one week and 4 months later. When the the plants Sida carpinifolia (Colodel et al. 2002; Loretti et al. last sample was taken the horse was again clinically normal. 2003) or Ipomoea carnea (de Balogh et al. 1999). Throughout All 3 samples were below the detectable limits (<30 ng/ml). 64 EQUINE VETERINARY EDUCATION / AE / FEBRUAry 2008

While the presence of the swainsonine in the first serum thereafter because animals may retain a preference for the sample, together with the typical neurological signs and the plants from year to year. renal abnormalities, are very suspicious for ingestion of feed The most effective management strategy is to deny containing swainsonine, locoweed ingestion was never livestock access to locoweeds during critical periods when they confirmed. The horse was fed by ensilated grass-hay and are more palatable than the associated forage (the late spent a few hours a day on pasture. Plants of the genera autumn, winter and spring) (Ralphs and James 1999). Rotating Astragalus and Oxytropis are present in Belgium, although the cattle from pastures with locoweeds to those without can also available literature does not state whether these variants be effective to prevent poisoning. Herbicides can control produce swainsonine. The possible introduction and spread of existing locoweed populations and provide ‘safe’ pastures for toxic adventive species into Belgium by the increasing rates of critical periods. However, locoweed in will germinate human travel has to be taken into consideration. The presence when environmental conditions are favourable. Repeated of these plants was not confirmed in the silage or pasture. application of herbicides will be necessary to control locoweed Usually it takes several weeks of grazing the plants to re-emergence. The method of conditioned food aversion by become intoxicated. The horse showed symptoms in February associating the eating of the locoweeds with a distasteful 2005. Temperature and moisture conditions are ideal in mild experience (e.g. a bolus of lithium chloride) seemed also to be winters so that locoweeds may retain green leaves and are an effective management system in cattle and horses grazing very palatable to eat, especially when grasses are depleted. on heavily infested pastures (Ralphs and Provenza 1999; Dried locoweed that can be present in the ensilated grass hay Pfister et al. 2002). could also be the source of the intoxication. Another source of To the authors’ knowledge, this is the first report of a swainsonine intoxication is the production of the toxin by swainsonine intoxication in a European horse. The reason for certain moulds that can be present in the ensiled hay, such as the difference in prevalence between the United States and and Metarhizium anisopliae (Croom Europe is unclear. However, as with other plants, such as et al. 1995; Sim and Perry 1997). According to the owner, no Senecio jacobaea, an increase in described cases of poisoned macroscopic signs of growth of moulds was seen in the horses is seen, probably partly due to environmental ensilated hay. However, no mycological examination could be management whereby less herbicide is used. Also, such performed on the hay. management factors as overgrazing of pastures can be Horses are described as being more sensitive to locoism predisposing. We can conclude that by finding the toxin in this than cattle. Also sensitisation occurs, which means that once Belgian horse we have to assume that swainsonine poisoning they have eaten the plant they are more sensitive to the toxic has to be included in the differential diagnosis of equine effects than prior to exposure. Habituation may be manifested neurological diseases in Belgium and perhaps in the by ingestion of all plant parts (Ralphs et al. 1990). This may surrounding countries, especially when symptoms of ataxia, include eating soil containing the roots of locoweed after hypermetria, hyperaesthesia and muscle tremors are presented. other parts of the plants have been grazed. Van Kampen and James (1972) reported that histological References lesions already developed within 4 or 5 days after animals Colodel, E.M., Gardner, D.R., Zlotowski, P. and Driemeier D. (2002) began consuming locoweed. Vacuolation was first seen in the Identification of swainsonine as a glycoside inhibitor responsible proximal convoluted tubules of the kidney and urinary bladder for Sida carpinifolia poisoning. Vet. human Toxicol. 44, 177-178. with slightly later lesions identified in the pancreas, thyroid, Cooper, A., Hatton, C.E., Thornley, M. and Sardharwalla, I.B. (1990) spleen, lymph nodes and cerebellum. Toxicokinetic studies by Alpha- and beta-mannosidoses. J. Inherited Metab. Dis. 13, 538-548. Stegelmeier et al. (1995b) found that these tissues also Croom, W.J. Jr., Hagler, W.M. Jr., Froetschel, M.A. and Johnson, A.D. accumulate relatively high amounts of swainsonine. (1995) The involvement of slaframine and swainsonine in slobbers Mild cases generally resolve in 1–2 weeks. The inhibition of syndrome: a review. J. anim. Sci. 73, 1499-1508. α-mannosidase is relatively transient and quickly reversible de Balogh, K.K., Dimande, A.P., van der Lugt, J.J., Molyneux, R.J., once animals stop eating locoweed (Stegelmeier et al. 1994). Naude, T.W. and Welman, W.G. (1999) A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique. J. However, regeneration of affected neurons in the brain and vet. diag. Invest. 11, 266-273. spinal cord may not occur completely, making horses a DeGasperi, R., al-Daher, S., Daniel, P.F., Winchester, B.G., Jeanloz, R.W. potential liability to human safety if ridden (James and van and Warren, C.D. (1991) The substrate specificity of bovine and Kampen 1971). Patients with chronic locoism with long- feline lysosomal alpha-mannosidases in relation to alpha- standing clinical signs generally do not recover completely and mannosidosis. J. biol. Chem. 266, 16556-16563. the owner has to watch closely for future aberrant behaviour Dorling, P.R., Huxtable, C.R. and Colegate, S.M. (1980) Inhibition of since these horses are notorious for throwing a fit when lysosomal alpha-mannosidase by swainsonine, an indolizidine alkaloid isolated from Swainsona canescens. Biochem. J. stressed or put into confined quarters, such as horse trailers. 191, 649-651. An effective treatment for swainsonine poisoning does not Huxtable, C.R. and Dorling, P.R. (1982) Poisoning of livestock by exist (Staley 1978). Animals will recover from locoism provided Swainsona spp.: Current status. Aust. vet. J. 59, 50-53. they are removed from the toxin before extensive cellular James, L.F., van Kampen, K.R. and Staker, G.R. (1969) Locoweed degeneration has occurred in the brain. Further consumption (Astragalus lentiginosus) poisoning in cattle and horses. J. Am. vet. of locoweed should be prevented immediately, and every year med. Ass. 155, 525-530. EQUINE VETERINARY EDUCATION / AE / FEBRUAry 2008 65

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