Pathological classification of equine recurrent laryngeal neuropathy

Abstract

Recurrent Laryngeal Neuropathy (RLN) is a highly prevalent and predominantly left‐sided, degenerative disorder of the recurrent laryngeal nerves (RLn) of tall horses, that causes inspiratory stridor at exercise because of intrinsic laryngeal muscle paresis. The associated laryngeal dysfunction and exercise intolerance in athletic horses commonly leads to surgical intervention, retirement or euthanasia with associated financial and welfare implications. Despite speculation, there is a lack of consensus and conflicting evidence supporting the primary classification of RLN, as either a distal (“dying back”) axonopathy or as a primary myelinopathy and as either a (bilateral) mononeuropathy or a polyneuropathy; this uncertainty hinders etiological and pathophysiological research. In this review, we discuss the neuropathological changes and electrophysiological deficits reported in the RLn of affected horses, and the evidence for correct classification of the disorder. In so doing, we summarize and reveal the limitations of much historical research on RLN and propose future directions that might best help identify the etiology and pathophysiology of this enigmatic disorder.

Assessing pathological changes within the nucleus ambiguus of horses with recurrent laryngeal neuropathy: An extreme, length‐dependent axonopathy

“…Our data were derived from a large sample size, ensuring the results were free from bias (blinding), and, by using a continuous scale for RLN severity to phenotype individuals, misclassification of disease status was avoided: When using laryngoscopy to phenotype horses for RLN, daily variations in applied grades can cause horses to be classified incorrectly as control, subclinical, or clinical cases . Further, the extensive fiber type grouping that occurs in intrinsic laryngeal muscles supplied by diseased RLns in affected horses very likely means that clinical phenotyping (eg, when using resting or exercising laryngoscopy) is inaccurate …”

“…RLN can now be classified as a distal axonopathy, without an associated degeneration of the cell bodies of the RLns . The advantage of a more specific classification is that it focuses the list of likely etiological mechanisms.…”

“…8,9 Despite the prevalence of the disease being as high as 42%, 10 its etiopathogenesis is unknown; environmental and genetic factors likely interplay to produce the RLN phenotype. [11][12][13] There is extensive characterization of peripheral nerve and muscle pathology in RLN, 14,15 but the presence or absence of an associated neuronopathy (ie, a cell body reaction) within the nucleus ambiguus (which comprises the RLn's axonal cell bodies; see Figure S1 online) is questionable. [16][17][18] In the few studies examining an accompanying presence of neuronopathy in RLN, there were no detectable associated somal reactions or apparent loss of cell bodies within the nucleus ambiguus.…”

“…[16][17][18] In the few studies examining an accompanying presence of neuronopathy in RLN, there were no detectable associated somal reactions or apparent loss of cell bodies within the nucleus ambiguus. [16][17][18] However, these investigations were hampered by unblinded analyses, possible phenotyping inaccuracies (a single laryngoscopic examination used to grade RLN severity 14,19 ) and unmatched control groups.…”

Species‐specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1)

“…We also confirmed that the K40 horse SOD1 variant was present in an equine ancestor, 4-4.5 million years ago by blasting the SOD1 exon 2 sequence of the modern horse genome to the ancient horse genome, 9 and it appears that evolutionary pressures have not resulted in the removal of this residue; to the best of the authors' knowledge there is no publically available horse genomes where a different residue can be found at the 40 th codon, and within our laboratory we have identified this residue at the 40 th codon in over seven different horse breeds (Supplementary Figure 1). 11 An important pathological feature of ALS-models is higher cellular ROS levels in cells expressing mutant SOD1 variants. Indeed in dogs, to develop the DM phenotype, advancing age as well as the expression of the K40 SOD1 protein is typically needed, 3 highlighting that the K40 residue might only be pathogenic under certain circumstances.…”