Atypical myopathy is a seasonal (Spring and Autumn), acute, non exertional rhabdomyolysis seen in pasture kept horses. Recently ingestion of hypoglycin A, a toxin found in Sycamore tree seeds has been implicated as an underlying cause. The toxin causes a multiple acyl-Co A dehydrogenase deficiency in the fatty acid metabolism depleting energy sources. Type I muscle fibres are more susceptible and so signs relate predominantly to damage to respiratory and postural muscles. A presumptive diagnosis can be made from a history of grazing pastures with adjacent Sycamore trees, typical clinical signs (progressive muscle weakness and stiffness, myoglobinuria, tachycardia, tachypnoea and recumbency) and blood work (marked elevation in CK and AST). The disease is frequently fatal (74%) and progresses rapidly. Treatment includes stabling and nursing care, intravenous fluids, anti-inflammatories and appropriate nutrition including anti-oxidants. Co-grazing horses should also be examined, removed from pasture and treated with anti-oxidants. Advice should be given to owners to reduce the probability of grazing horses ingesting Sycamore seeds.

Introduction

Atypical myopathy has been recognised in pasture kept horses since the 1940s as a seasonal, acute, non-exertional rhabdomyolysis (Votion 2012) but it is only in recent years that significant progress has been made in identification of the underlying aetiology. A collaborative effort with improved surveillance, identification of spatial and temporal distribution and epidemiological risk factors together with detailed clinical evaluation of cases has led to a strong evidence of a causative agent, hypoglycin A toxicity.

Identification of suspected causative agent

Epidemiology studies of Atypical Myopathy supported ingestion of a toxin with sporadic cases, sometimes clusters without the characteristics of a contagious disease. Staining of muscle biopsies of affected horses revealed lipid accumulation (Valberg 2014). Subsequent examination of metabolites present in the urine and serum of affected horses was consistent with an acquired enzyme defect (multiple acyl-Co A dehydrogenase deficiency; MADD) in the fatty acid metabolism pathway (Westermann 2011) leading to depletion of energy sources. In humans MADD can develop from ingestion of hypoglycin A in unripe fruit from the Jamaican Ackee tree. This led to consideration of plants within the same family, the maple trees, as a potential cause of disease in horses. The box elder Acer negundo in the USA and sycamore maple Acer pseudoplatanus inEurope have since been confirmed as a source of hypoglycin A. Hypoglycin A is an amino acid that becomes a potent inhibitor of acyl-CoA dehydrogenase, a key enzyme in fatty acid metabolism. The toxic metabolites of hypoglycin A have been detected in the serum and urine of affected horses (Valberg 2012; Votion 2013). The concentration of hypoglycin A in the seeds is highly variable (Unger 2014) which may explain the sporadic nature of the disease.

Many questions remain unanswered; this is an area of active research to determine the ‘perfect storm’ that is required for this disease to occur as the majority of horses grazing on pasture near sycamore trees do not develop the disease. Induction of disease through administration of hypoglycin A would fulfil Koch’s postulates, establish the toxic dose and explain the relationship with the known risk factors.

Leaves of a sycamore tree; small shoots (spring) and seeds (autumn) contain the hypoglycin A toxin and are ingested by horses. Assess pasture and local area for presence of sycamore trees and consider removal or strategies to limit risk.

Diagnostic approach

A minimum database of information should be compiled to aid an early clinical diagnosis. This should include a thorough history, evaluation of all co-grazing horses and clinical investigation of affected animals.

1. History

Horses have a history of grazing pastures containing or surrounded by Sycamore maple trees (or Box elder maple in the USA) for more than 12 hours per day (Valberg 2014). Disease peaks are temporally associated with the periods when seeds and germinating seeds would be on the land (spring and autumn time). Single or multiple cases can occur in an outbreak. The presence of leaves and dead wood on the pasture with a recent history of high winds or inclement weather is common (Van Galen 2012a; Van Galen 2012b). It is assumed this is associated with dispersal of the seeds.

2. Clinical signs

Atypical myopathy is predominantly seen in younger horses and ponies but can occur in any age group, often in animals in good body condition. The clinical signs are due to muscular degeneration, with the type I muscle fibres (slow twitch) most severely affected. The abnormalities therefore reflect predominantly damage to postural and respiratory muscles and cardiac muscle in some cases (Van Galen 2013).

On general clinical examination horses have depressed mentation, tachycardia, trembling, sweating and congested mucous membranes. The horses have muscle weakness and stiffness, which may rapidly progress towards recumbency. Cardiac arrhythmias may be noted (50% have cardiac damage; Verheyen 2012).
Urine is frequently dark brown due to muscle breakdown leading to myoglobinuria. Secondary renal damage will cause haematuria and casts may also be present. A catheterised sample will aid in diagnosis if a free catch is not available.
Rectal examination can reveal a distended bladder and dry, mucous covered or impacted faecal material in the small and large colon that can result in colic signs.
Haematology and biochemistry profile identifies marked elevation in muscle enzymes (CK, AST). The increase will be marked (Creatine kinase: 100,000’s- 1,000,000’s; ref range <150U/l) consistent with a severe primary myopathy. This should be differentiated from the mild to moderate elevation seen secondary to recumbency or colic. Sequential samples are recommended if onset of clinical signs is recent. Other abnormalities frequently encountered include acid base imbalance (lactic acidosis and respiratory alkalosis), electrolyte disorders, hyperglycaemia, hyperlipaemia and leucocytosis (neutrophilia). Horses are often hypovolaemic (increased PCV and TP) and may be azotaemic (pre renal and potentially renal secondary to myoglobin damage). Cardiac troponin I may be elevated reflecting myocardial damage (Van Glanden 2012a).
Photograph illustrating colour of normal adult horse urine (left) compared to myoglobinuria (right)

In the context of a supportive history the clinical findings should lead to a strong suspicion of Atypical Myopathy. However careful consideration should still be given to other conditions that may present in a similar manner.

Important Differential Diagnosis

Other severe rhabdomyolysis syndromes e.g. nutritional myopathy, polysaccharide storage myopathy.
Endotoxaemic or hypovolaemic shock e.g. colic, colitis
Abnormal gait or recumbency e.g. laminitis, neurological disease
Acute equine grass sickness

A definitive diagnosis is unlikely to change management of the individual animal in the short term (due to the timeline) but is important for management of the property, co-grazing horses and furthering knowledge of the disease.

A muscle biopsy taken from the shoulder will identify degeneration, necrosis and excessive intramuscular lipid storage which rules out a nutritional or polysaccharide storage myopathy. This can also be performed post mortem on the intercostal muscles. Macroscopically pale musculature will be visible in the intercostals, diaphragm, myocardium and postural muscles.

A definitive diagnosis is based upon characteristic changes in serum acylcarnitines and urine organic acids (metabolic by products that occur due to inhibition of fatty acid metabolism) which can be measured in human metabolic disease laboratories. Examples include Service de Genetique Humaine, CHU de Liege, University of Liege, Belgium (contact Dr D.-M. Votion; Van Galen 2013) and Baylor Institute of Metabolic Disease (www.baylorhealth.edu/research/institutes-centers/IMD/Pages/tests%20and%20forms%2005-11.pdf; Valberg 2014).

Normal equine references have been published (Sponseller, B.T. et al 2012)

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References

Unger, L. et al (2014) Hypoglycin A Concentrations in Seeds of Acer Pseudoplatanus Trees Growing on Atypical Myopathy- Affected and Control Pastures J Vet Intern Med 28; pp 1289-1293

Van Galen, G. et al (2012a) European outbreaks of atypical myopathy in grazing equids (2006-2009): Spatialtemporal distribution, history and clinical features Equine Veterinary Journal 44 pp 614-620

Van Galen, G. et al (2012b) European outbreaks of atypical myopathy in grazing horses (2006-2009): Determination of indicators for risk and prognostic factors Equine Veterinary Journal 44; pp 621-625

Van Galen, G. and Votion, D.M. (2013) Management of cases suffering from atypical myopathy: Interpretations of descriptive, epidemiological and pathophysiological findings. Part 1: First aid, cardiovascular, nutritional and digestive care. Equine Veterinary Education 25; 5; pp 264-270

Votion, D.M. (2012) The Story of Equine Atypical Myopathy: A Review from the Beginning to a Possible End International Scholarly Research Network Article ID 281018

Votion, D.M. et al (2013) Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy Equine Veterinary Journal 46; pp 146-149

Valburg, S. J. (2012) Seasonal pasture myopathy/ atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree Equine Veterinary Journal 45; pp 419-426

Valberg, S. (2014) Review of the Discovery of the Basis for a Seasonal Pasture Myopathy/Atypical Myopathy AAEP Proceedings Vol 60 pp 184-187

Verheyen, T. et al (2012) Cardiac Changes in Horses with Atypical Myopathy J Vet Intern Med 26; pp 1019-1026

Westermann, C.M. et al (2011) Decreased oxidative phosphorylation and PGAM deficiency in horses suffering from atypical myopathy associated with acquired MADD Molecular Genetics and Metabolism 104; pp 273-278

This article was written for VetGrad.co.uk and previously published in September 2015.

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