Equine Grass Sickness Update

Equine grass sickness (EGS) is a frequently fatal multisystem neuropathy that kills approximately 1% of grazing horses in high-risk areas. Until recently, the disease pathogenesis has remained largely unknown. As a result, the disease has been difficult to diagnose, and treatment options have been limited, with devastating consequences for clinicians and horse owners.  

Recent Research on EGS

Recent studies have shown that EGS is associated with major changes in skeletal neuromuscular junction (NMJ) ultrastructure that are not consistent with the effects of botulinum neurotoxins, which were previously proposed as the cause of EGS. Instead of the dense packing of synaptic vesicles (SV) at the active zones of the presynaptic membrane seen in botulism cases, EGS is characterized by marked depletion of SVs, omega-shaped invaginations in the presynaptic membrane, accumulation of neurofilament-like material in terminal boutons, and ultimately, bouton degeneration. Montecucco and Bano highlighted that these NMJ changes were very similar to those seen in animals envenomed with snake venom containing neurotoxic phospholipase A2 (nPLA2) leading to a proposal that nPLA2 is the likely cause of EGS. It is also hypothesized that these neurotoxins are responsible for the dysautonomias seen in cats, dogs, hares, rabbits, llamas, and alpacas. 

Consistent with this hypothesis, researchers have identified a striking similarity between the clinical signs seen in envenomed human patients and horses with EGS. Both horses and humans show signs of abdominal pain, abdominal distension, and lack of bowel movement early in the disease course. 

Progression leads to involvement of cranial nerves and axial muscles, resulting in some of the characteristic clinical signs associated with EGS, including bilateral ptosis (eyelid drooping) and dysphagia, which often results in aspiration pneumonia. Dysautonomia also leads to abnormal heart rate, resulting in the profound tachycardia observed in equine patients despite management of pain and hydration status. Human patients also report abnormal taste and smell, which is likely but not confirmed in EGS cases.  

The main difference in clinical signs between horses and humans is the predominance of gastrointestinal signs in horses with more pronounced signs of respiratory muscle paralysis and muscular weakness/rigidity in humans. Researchers hypothesize that this difference is due to the enteric route of intoxication proposed in EGS as opposed to a hematogenous and lymphatic spread in human snakebite victims. The initial depolarizing block induced by nPLA2s might account for the previously unexplained skeletal muscle fasciculations and the marked small intestinal dysmotility that is grossly visible during exploratory laparotomy in acute EGS horses, with uncoordinated contractions leading to a failure of peristalsis.  

Next Steps

To definitively prove this hypothesis, researchers must confirm the presence of the nPLA2 in biological samples from affected horses. Work is underway to utilize proteomics, lipidomics, and metabolomics to this end. This is proving very challenging as PLA2s are ubiquitous, diverse in size and structure, and likely bind rapidly to target receptors, resulting in low tissue/plasma concentrations. The exact nPLA2 responsible for the disease also remainsunidentified. Based on the epidemiology of the disease, plausible sources of the nPLA2 include ingestion of a microbial or plant PLA2 or microbial production in vivo by gastrointestinal microbes. As well as providing an explanation for the EGS-associated NMJ abnormalities and clinical signs, this hypothesis raises novel therapeutic options. Interestingly, snake envenomation is associated with induction of a pro-regenerative intercellular signaling axis. This involves melatonin receptor 1 (MT1) interactions that lead to reinnervation as early as five days after envenomation in mice and after several weeks in envenomed human patients. Ramelteon, a highly selective MT1 agonist currently used to treat insomnia in people in the U.S., is a strong promoter of neuroregeneration after paralysis induced by venom from Bungarus species (venomous snakes) in mice. This led to a proposal to trial Ramelteon in envenomed humans to determine whether this drug can reduce clinical consequences and promote neuroregeneration.  

Due to its use in insomnia treatment, large meta-analyses have been carried out into the use of ramelteon in humans, indicating that it is generally well-tolerated with common adverse effects including drowsiness, dizziness, and nausea. Murine models also suggest good safety margins with intravenous administration. A treatment trial of intravenous ramelteon in acute and subacute EGS cases is currently underway at the University of Edinburgh’s Dick Vet Equine Hospital. 

Final Thoughts

Researchers have recently made significant breakthroughs in our understanding of EGS pathogenesis, but further work is required to develop effective methods to prevent and treat this devastating disease. 

Related Reading

• Researchers Identify Probable Cause of Equine Grass Sickness
• Equine Grass Sickness: A Global Concern?
• Track-Grazing Better for Equine Welfare Than Strip-Grazing

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