Blister Beetle  Poisoning: Cantharidin toxicosis in Equines

Awareness is the best prevention

  There are more than 200 species of blister beetles, each varying in size, shape and color, but the most common is genus iEpicauta which commonly contaminates alfalfa hay causing toxicosis in horses.  Blister beetles range from 0.5-1.5 inches in length and can be black, brown, gray or even yellow and black in color.  Most have non-bulging eyes that follow the contour of their head, and the head is often bent downward.  The legs are long, with claws on the tarsus that have blades, teeth or spines.  The most important feature found commonly among all species is that the first portion of the thorax is narrower than either the head or wing  and there are six abdominal plates on the beetle's underside.  Early identification in alfalfa bales may help to prevent ingestion by horses, therefore preventing cantharidin toxicosis.

Horses are particularly susceptible to cantharidin, with the minimum lethal dose 1 mg/kg of the horse's body weight.  Experimentally, as little toxin as 0.45 mg/kg of body weight  has been fatal.  One of the most important characteristics of this toxin is that it can exert its effects in the absence of the blister beetle bodies.  Also, cantharidin withstands degradation by heating or drying, making it difficult to remove the toxin even during processing of alfalfa bales or alfalfa pellets where the beetles are commonly found.

  Cantharidin is odorless and colorless, so it is important to monitor alfalfa hay for early detection of the blister beetles or their parts, as a preventive measure.  If gone unnoticed within the alfalfa hay, once ingested it is highly irritating, causing acantholysis of the gastrointestinal tract, especially of the esophagus and nonglandular portion of the stomach, and of vesicles in skin or mucous membranes of horses.  Cantharidin acts by altering mitochondrial metabolism via its inhibition of protein phosphatase, which is involved in the control of cell proliferation, activity of membrane-associated channels and receptors, and modulation of protein kinases and phosphatases.  The inhibition of protein phosphatase 2A causes an increase in permeability of endothelial cells in a time- and concentration-dependent fashion by enhancing the phosphorylation of endothelial regulating proteins.

  Clinical signs begin to appear 6-8 hours after ingestion of cantharidin.  The affected horse may experience colic due to the irritation and vesicle formation in the gastrointestinal tract or because of decreased contractility, hypomotility and ileus.  Also, it may be restless, irritable, sweating, have diarrhea and/or submerge its muzzle in water, (a common sign of cantharidin toxicosis).  Cantharidin toxicosis also causes mucosal hemorrhage and inflammation of the urinary tract, which may manifest itself as signs of hematuria, stranguria and/or dysuria.  The cardiovascular system is less frequently affected but, clinically, a horse may present with syndoronous diaphragmatic flutter (SDF).  This is caused by alteration in membrane potential of the phrenic nerve and its discharge in response to electrical impulses generated during myocardial depolarization.  The nervous system is less commonly affected, but an affected horse may present with aggressive behavior, seizure-like muscle activity secondary to colic, or muscle fasciculations.  Most commonly, the horse presents with colic, depression, fever, dehydration, gastritis, esophagitis, and oral ulcers.

  Laboratory findings can also be helpful in diagnosing cantharidin toxicosis.  Serum calcium is usually markedly decreased and may remain low for prolonged periods.  This hypocalcemia may be manifested clinically as SDF, tremors, or abnormal facial expressions, such as clamped jaws with lips drawn back.  The serum magnesium concentration is also usually low, while creatinine kinase can increase markedly within the first 24 hours after ingestion.  In acutely affected horses, urinalysis reveals markedly decreased specific gravity, often less than 1.101, and hematuria with or without myoglobinuria.  Also, in acute cases, horses are frequently hyperglycemic and analysis of peritoneal fluid may reveal increased protein, greater than 4 g/dl, with normal numbers of white blood cells and fibrinogen levels.  If the toxin has caused renal tubular necrosis and/or hypoproteinemia, there may be increases in serum urea nitrogen, approximately 50-70 mg/dl, and increases in creatinine, approximately 2-10 mg/dl.  Total protein may be normal or increased during the first 24 hours, but then drops dramatically.  Most commonly, the horse's laboratory findings include hypocalcemia, hypomagnesemia, and azotemia.

  Cantharadin toxicosis can be confirmed using high pressure liquid chromatography (HPLC) to detect and quantify cantharidin in the urine of live or dead horses, and in the gastric contents, liver, or kidneys of dead horses.  It is best to submit at least one pint of stomach contents or 20 ml of urine on ice for analysis.

  At necropsy. erosions in the oral cavity, esophagus and stomach may be seen, as well as ulcerated to pseudomembranous enteritis. The most commonly reported gross pathologic lesions include necrosis and ulceration of the squamous lining of the distal esophagus, forestomach and urinary bladder.

 Histologically, sheets of epithelium lifted from the serosal surface with normal epithelium in between can be seen, as well as  hemorrhagic, ulcerative cystitis that appears as desquamation of epithelium, hyperemia, and marked hemorrhage in the bladder.  Renal tubular necrosis is also visible.  Occasionally, ventricular myocardial necrosis, which appears as foci or streaks in the papillary muscles and under the epicardium, may be seen both grossly and histologically.

  There is no specific antidote for cantharidin toxicosis, so the treatment is usually directed at cantharadin removal, reduction, and immediate symptomatic therapy.  The fatality rate can be as high as 65%, but with aggressive therapy, can be reduced to 20%.  Horses with a toxic dose can die within 3-18 hours of onset, but, if they survive for 72 hours, recovery is more likely.  Calcium and magnesium supplementation for prolonged periods of time is almost always indicated, but their administration should be carefully monitored and linked to serum chemistries.   If the horse is exhibiting signs of gastritis, often indicated by submerging the muzzle in water repeatedly, sucralfate can be administered as a protectant.  Non-steroidal anti-inflammatories (NSAIDs) can alleviate pain and protect against endotoxemia, but should be used with caution because NSAIDs are toxic to the kidney if the horse is dehydrated and if renal damage has occurred.  The horse should also be stall rested for 5-10 days.

  Prevention is the most effective way to avoid cantharidin toxicosis.  The first cutting of hay is often free from blister beetles because the adults do not emerge until late May or June (in the southwest and southern plains, if cut before mid-May).        Also, it is important not to crimp the hay during cutting so that the beetles can escape rather than get trapped and incorporated into the hay.  Cutting the alfalfa at 10% or less can decrease the chance of poisoning because beetles are attracted to flowering plants.  Scouting the fields for beetles and treating with a short residual insecticide before cutting helps to prevent blister beetle infestation.  Sevin XLR has been has been used for prevention of infestation by blister beetles and other toxic insects.  Carbaryl and parathion have also been commonly used to kill blister beetles, but have a pre-harvest waiting period that does not give them adequate residual activity to kill blister beetles that enter the field from spray time until just before harvest.

  Blister beetle, or cantharidin, toxicosis is an important disease that should be considered when horses present with colic or acute death soon after ingestion of alfalfa.  A definitive diagnosis may be determined if there is a history of feeding alfalfa or alfalfa-containing products, laboratory findings of hypocalcemia with or without hypomagnesemia, identification of blister beetles in hay or GI contents, and gross identification of ulcers in the distal esophagus, stomach and urinary bladder on necropsy.  Confirmation using HPLC to determine the presence and amount of cantharidin in stomach contents or urine can be used.  In order to prevent cantharidin toxicosis, proper cutting of alfalfa, surveying of fields and use of an insecticide, if necessary, are recommended.

-by Cindy Echevarria, Ross Student

-edited by Dr. Steve Hooser, ADDL Toxicologist

References:

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