Equine grass sickness (EGS) is a frequently fatal, multisystem neuropathy killing approximately 1% of grazing horses in high-risk areas. Until recently, the disease pathogenesis has remained largely unknown, resulting in difficulties in diagnosis and lack of treatment options, with devastating consequences for clinicians and horse owners.
Horse grazing on grass and clover in a spring pasture.
Significant recent breakthroughs have been made in our understanding of EGS pathogenesis, but further work is required to develop effective methods to prevent and treat this devastating disease.
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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 characterised by marked depletion of SVs, Ω 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 hypothesised that these neurotoxins are responsible for the dysautonomias seen in cats, dogs, hares, rabbits, llamas and alpacas.
Consistent with this hypothesis, a striking similarity has been identified 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 differences between the clinical signs is the predominance of gastrointestinal signs in horses with more pronounced signs of respiratory muscle paralysis and muscular weakness/rigidity in humans.
The hypothesis for this difference is that an enteric route of intoxication is proposed in EGS as opposed to a haematogenous and lymphatic spread in human snakebite victims.
The initial depolarising block induced by nPLA2s may 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.
In order to definitively prove this hypothesis, the presence of the nPLA2 in biological samples from affected horses needs to be demonstrated. Work is underway to utilise proteomics, lipidomics and metabolomics to confirm this. 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 remains unidentified. 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 also raises novel therapeutic options. Interestingly, snake envenomation is associated with induction of a pro-regenerative intercellular signalling axis.
This involves melatonin-melatonin receptor 1 (MT1) interactions which 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, which is currently used to treat insomnia in people in the U.S., has been shown to be a strong promoter of the neuroregeneration after paralysis induced by venom from Bungarus species (venomous snakes) in mice. This led to a proposal to trial Ramelteon in envenome 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 sub-acute EGS cases is currently underway at the Dick Vet Equine Hospital, University of Edinburgh.
Significant recent breakthroughs have been made in our understanding of EGS pathogenesis, but further work is required to develop effective methods to prevent and treat this devastating disease.
Press release by Equine Disease Quarterly - Article by Sophie McCullagh, BVSc MRCVS HBLB Resident in Equine Internal Medicine The Royal (Dick) School of Veterinary Studies – University of Edinburgh, United Kingdom