Wintersweet (Chimonanthus praecox) toxicity in 5 sheep

1 INTRODUCTION

The ingestion of wintersweet (Chimonanthus praecox) may lead to ataxia, seizures, and death in ruminants because of the presence of calycanthine, a highly toxic alkaloid, in the leaves, branches, fruit and seeds.¹ Although calycanthine toxicity is a known pathology in ruminants, case reports of the ingestion of wintersweet and similar plants rarely have been reported in literature. Wintersweet is a fragrant, deciduous shrub native to China and is known for its anti-inflammatory, antinausea, antioxidant, and antihyperglycemic associations.² Consequently, wintersweet has been utilized for its medicinal properties against rheumatoid arthritis, coughs, hand-foot-and-mouth disease, diarrhea, dizziness, nausea and fever among many other conditions.^2-4 It exhibits delicate, yellow flowers with a purple center that bloom in the winter and spring, often when the shrub is leafless. It can grow in a wide range of soil conditions and is used in many gardens and landscaping for ornamental purposes.^{3, 5}

Wintersweet contains many secondary metabolites including 13 alkaloids that have been isolated from the seeds, leaves, branches, rind and fruit of the plant.² Calycanthine is 1 of the most prominent of such alkaloids and has long been recognized as a neurotoxin in humans with limited studies identifying neurologic clinical signs in ruminants when consumed.^{6, 7} Calycanthine is a convulsant that acts centrally by inhibiting the release of and receptors for the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA).^5-7

To our knowledge, this case is the first report of wintersweet toxicosis in ruminants in the United States, and published accounts of calycanthine toxicosis in small ruminants are scarce overall. A detailed case report of wintersweet ingestion in 4 goats was reported in New Zealand.¹ Italian epidemiological records from 2000 to 2011 mention a record of wintersweet ingestion in cattle leading to limb rigidity, dyspnea and death.⁸ Similar clinical signs including ataxia, convulsions and death were first reported in herds of cattle and sheep in Tennessee in 1888 after ingesting Calycanthus floridus var glaucus, a plant in the same taxonomic family as wintersweet and known to contain calycanthine.⁹ An additional report of Calycanthus spp. ingestion with similar subsequent clinical signs was recorded in the southeastern United States,¹⁰ but clinical information is limited and no other published case reports were found. Our case report describes the history, clinical findings, emergency treatment and diagnostic test results of 5 sheep after known ingestion of wintersweet leaves.

2 CASE HISTORY

A 2-year-old 75 kg Polled Dorset ewe (Ewe A) and a 6-month-old 41.5 kg Polled Dorset wether (Wether A) presented on a farm with intermittent generalized, tonic-clonic seizures and opisthotonos of a 1-hour duration since the owner first observed them that morning. The sheep resided in a herd of 20 sheep that were kept in a fenced pasture in Wake County, North Carolina and typically consumed a diet of pasture grass and orchard or Timothy hay along with 0.34 kg/animal of a labeled sheep ration (Mule City Sheep Feed, Mule City Specialty Feeds, Benson, North Carolina). All sheep had received yearly vaccinations against common clostridial diseases (Covexin 8, Merck Animal Health, Madison, New Jersey). The day before veterinary intervention, the sheep had been relocated into a new pasture. Upon observing 5 of the sheep browsing on an ornamental shrub (Figure 1) in the new pasture, they were moved back to their original pasture. The shrub was not flowering and only the leaves were observed to be consumed by the sheep. Later that evening, ataxia was observed by the owner in 2 sheep (Ewes B and C), which developed into convulsions and death soon after. One additional wether (Wether B) developed convulsions, opisthotonos and muscle fasciculations overnight but recovered by the morning. All of the other sheep in the herd appeared clinically normal.

3 CLINICAL FINDINGS

On initial presentation, both Ewe A and Wether A were laterally recumbent and exhibiting generalized, tonic-clonic seizures. Physical examinations in both sheep identified opisthotonos, bilateral mydriasis, pyrexia (40.5-41.5 C), tachycardia (140-160 beats per minute) with strong contractility, absent pupillary light reflexes with intact palpebral and menace reflexes. Both had normal mucous membrane color, capillary refill time of 1-2 seconds and increased respiratory rate.

Emergency treatment was administered to both sheep after physical examinations were performed. Treatment consisted of xylazine 0.05 mg/kg IV (AnaSed, Akorn Pharmaceuticals, Lake Forest, Illinois), thiamine hydrochloride 0.5 mg/kg SC (VetOne, Boise, Idaho), flunixin meglumine 2.2 mg/kg IV (Banamine, Merck Animal Health, Rahway, New Jersey), clostridium perfringens C & D antitoxin SC (Colorado Serum Company, Denver, Colorado) to both sheep. Approximately 240 mL each of charcoal-kaolin suspension (ToxiBan, Lloyd Laboratories Inc, Malolos, Philippines) was administered PO via a stomach tube between seizure episodes. Treatment was limited to available medications on the veterinary truck and no benzodiazepines were available.

Wether A died after attempts to stabilize it. During stabilization of Ewe A, blood was collected from the jugular vein between seizures for further analysis at the hospital but the ewe died on the farm soon after Wether A. A CBC disclosed mild lymphopenia (1404 cells/μL) and presence of toxic neutrophils but was otherwise unremarkable. A serum biochemistry panel identified hyperglycemia (136 mg/dL), increased serum creatinine concentration (1.7 mg/dL), markedly high creatine kinase activity (14 734 IU/L), mild hypernatremia (151 mEq/L), hypokalemia (3.5 mEq/L), hyperchloremia (107 mEq/L), and moderately low bicarbonate (15 mEq/L). Abnormal biochemical variables are summarized in Table 1. Hyperglycemia was attributed to stress. Electrolyte abnormalities were suspected to be associated with dehydration and seizure activity. Prerenal factors such as dehydration were suspected as the cause of the mild azotemia. Markedly increased creatine kinase activity supported the occurrence of tonic-clonic seizure activity.

Necropsy of Ewe B was performed on the farm and was macroscopically normal. Rumen contents included plant material and no foreign bodies. Wether A was submitted to the Rollins Animal Disease Diagnostic Laboratory in Raleigh, North Carolina for necropsy and rabies testing. Necropsy identified multifocal petechiation and ecchymotic hemorrhages of the SC tissue, thymus, brain, heart, and parietal pleura for which differential diagnoses included bacterial septicemia, heat stroke or incidental perimortem changes. Rumen contents were consistent with plant material and no foreign material was observed. Plant material was well digested with no leaf fragments present to identify the species that had been consumed. Evidence of endoparasitism within the intestine was also present but considered incidental. Aerobic lung culture and rabies testing were both negative. The cause of death was inconclusive but calycanthine toxicity was highly suspected given history of observed ingestion and subsequent clinical signs. Photos of the plant in question were submitted to an arborist at the JC Raulston Arboretum at North Carolina State University. Rumen contents were submitted to the Animal Health and Food Safety Laboratory System at the University of California at Davis, California and were positive for calycanthine using liquid chromatography—mass spectrometry, with presence determined at reporting limit >200 parts per billion (ppb). Based on history of observed ingestion, clinical signs and calycanthine presence within the rumen, the 5 sheep were diagnosed with calycanthine toxicosis as a result of ingesting wintersweet.

4 DISCUSSION

Wintersweet is a plant of the Calycanthaceae family containing 9 other flowering shrubs that grow in warm temperate and tropical environments and all contain the calycanthine alkaloid. Although wintersweet is native to China, its presence in the US landscaping creates a risk to ruminants that may have access to these plants. The Calycanthaceae family is divided into 3 genera: Chimonanthus which contains wintersweet and 5 other species and has a geographical distribution in eastern Asia, Idiospermum which contains 1 species native to Queensland, Australia, and Calycanthus which contains 1 species in eastern Asia and 2 species native to the western and the southeastern United States, Calycanthus occidentalis and Calycanthus floridus, respectively.¹¹ Calycanthus floridus is known commonly as Carolina allspice, bubby bush, eastern sweetshrub or spice bush and grows readily in sunny, moist environments from Pennsylvania to Florida. Calycanthus occidentalis, known commonly as spice bush or western sweetshrub, is found along canyons, stream sides and moist environments up to 5000 ft in elevation in the California coast, Sierra Nevada, and Cascade Mountain ranges as well as the Sacramento Valley and occasionally in Washington.¹² Both species exhibit large, burgundy to purple flowers that produce a sweet odor and thus often are cultivated in ornamental gardens, similar to wintersweet. Both species contain calycanthine and are known to cause a strychnine-like toxicity in humans and ruminants.^{9, 12, 13} The ranges of both Calycanthus species in the United States overlap known agricultural areas, and producers, veterinarians and hobby farmers in these areas should be aware of the potential toxicity that can affect their animals.

Calycanthine was first isolated from the fruit of Calycanthus floridus var. glaucus in 1888, after a local report of “hundreds of cattle and sheep” convulsing and eventually dying after consumption of the fruit.⁹ Since then, calycanthine has been most widely isolated from the seeds of the Calycanthaceae plants, but the alkaloid also has been extracted from the leaves and fruit of certain species, including wintersweet.^{2, 3, 12} Reports of neurological clinical signs after consumption of the branches and bark have been recorded, but it has not been biochemically isolated.^{1, 14}

Calycanthine is a centrally-acting convulsant that acts primarily by inhibiting the release of the inhibitory neurotransmitter, GABA, from calcium channels and GABA-mediated chloride currents at GABA_A receptors, resulting in overexcitation of neurons.^5-7 The dose-dependency required for calycanthine to cause clinical signs in ruminants is not well studied, but 50% lethal doses (LD₅₀) for mice (44 mg/kg intraperitoneal [IP]), rats (17 mg/kg IP) and rabbits (8 mg/kg IP) have been reported to cause similar clinical signs in these species.^{6, 7}

Clinically and practically, diagnosis of calycanthine toxicosis in ruminants is based primarily on history of ingestion and clinical signs rather than on diagnostic testing. Reported clinical signs of calycanthine toxicosis have included ataxia, muscle fasciculations, opisthotonos, mydriasis, pyrexia, hyperesthesia, cardio-respiratory impairment and eventual death.^{1, 10, 14} The sheep in our report both exhibited increased heart and respiratory rates rather than decreases in these vital signs. However, all other clinical signs observed in these cases were consistent with those reported in the literature. Differential diagnoses included enterotoxemia, polioencephalomalacia, ryegrass staggers, lead poisoning, tetanus or ingestion of other toxic plants. Other than examination of the rumen contents at necropsy, calycanthine toxicosis is reportedly diagnostically unremarkable. Previous accounts have reported normal serum biochemistry, hematology, urinalysis and necropsy findings other than the presence of mild generalized petechia on various organs.¹⁰

Treatment of calycanthine toxicosis in ruminants only has been rarely published and is based on control of clinical signs. By extrapolating from treatment of strychnine toxicosis, recommended treatment has included administration of activated charcoal, sedation with chloral hydrate (50-70 mg/kg IV to effect) or pentobarbital (30 mg/kg IV to effect) and minimization of stimulation.¹⁰ In a case report of wintersweet toxicosis in goats in New Zealand, treatment success was achieved with initial administration of activated charcoal and diazepam (1.7 mg/kg IV to effect), dexamethasone (0.33 mg/kg IM), vitamin B₁ (5 mg/kg IM), vitamin B₁₂ (50 μg/kg IM) and magnesium sulfate (1.33 mg/kg SC) followed by several days of supportive care.¹ Treatment of the 2 sheep in our case series followed similar principles but both died soon after receiving treatment. Poor outcome could be a consequence of many factors including advanced clinical signs and poor physiologic condition by the time treatment was instituted, amount of plant consumed, body condition, or health history. The recovery of Wether B compared to the death of the other sheep also could be related to similar factors.

Our case report further documents calycanthine toxicity in ruminants. Producers and veterinarians should be aware of the toxic potential of wintersweet because of its prevalence in ornamental gardens, and other calycanthine-containing plants because of their native distribution in areas of the western and southeastern United States where livestock also may be present.

CONFLICT OF INTEREST DECLARATION

Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION

Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION

Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION

Authors declare human ethics approval was not needed for this study.