Proceedings of a Workshop on - The Havemeyer Foundation

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Havemeyer Foundation Monograph Series No. 11 REVIEW OF THE PATHOLOGICAL CHANGES IN EQUINE RECURRENT LARYNGEAL NEUROPATHY C. Hahn Neuromuscular Diagnostic Laboratory, Royal (Dick) School <strong>of</strong> Veterinary Studies, The University <strong>of</strong> Edinburgh, Easter Bush, Roslin, Midlothian EH25 9RG, UK PATHOLOGICAL CHANGES The lesions associated with recurrent laryngeal neuropathy (RLN) have been well characterised using light and electron microscopy (Cole 1946; Duncan and Griffiths 1974; Duncan et al. 1978; Cahill and Goulden 1986a, b, c, d, e; Duncan et al. 1991). The primary lesions have been demonstrated in nerves, and have been found to be greatest in the distal portions <strong>of</strong> the left and right recurrent laryngeal nerves. Abnormalities have also been noted proximal and distal to the aorta and in the vagus nerve. Changes noted in the right RLN are less severe than those found in the left. The pathology is characterised by a proximal to distal decrease in large myelinated fibres. However, the same trend, including the presence <strong>of</strong> Renaut bodies commonly reported in RLN cases, has been shown in ‘normal’ horses (Lopez-Plana et al. 1993). It is unknown if sensory fibres in the recurrent laryngeal nerves are also affected and vagal sensory ganglia should be examined for neuronal chromatolysis. The primary lesion may be axonal in nature, as indicated by collapsed myelin sheaths without an axis cylinder, increased myelin sheath thickness (potentially due to axonal atrophy), regenerating Schwann cell membrane clusters and paranodal and internodal accumulations <strong>of</strong> axonal debris and organelles. The latter may be an indication that a defect in the axonal transport systems results in the eventual distal axonal degeneration. In addition there is evidence <strong>of</strong> extensive myelin damage. Büngner’s bands, representing Schwann cell membranes, and onion bulbs made up <strong>of</strong> proliferating Schwann cells, are commonly found, as are myelin digestion chambers containing central axon fragments. Teased fibre preparations show a marked variation in internodal length and diameter indicating chronic demyelination and attempted remyelination. Evidence <strong>of</strong> central changes have been sought, however neither Cahill and Goulden (1986) nor Hackett and Cummings (personal communication) were able to identify lesions in the lower motor neuron cell bodies <strong>of</strong> the recurrent laryngeal nerves in the nucleus ambiguus <strong>of</strong> affected horses. Chromatolysis <strong>of</strong> the lower motor neuron may be expected secondary to the axonal damage, this however is influenced by the proximity <strong>of</strong> the lesion (Dyck and Thomas 1993). Likewise chromatolysis or neuronal loss in the nucleus ambiguus would be anticipated if the axonal changes are due to somal (cell body) pathology as has been described in Bouvier des Flandres (van Haagen 1980) and the Siberian husky dogs (O’Brien and Hendriks 1986). Unfortunately, there has been no systematic work in the horse evaluating the peripheral or central pathological changes which accompany damage to long axons. Ultrastructural examination <strong>of</strong> nucleus ambiguus neurons has been attempted but is complicated greatly by the difficulty <strong>of</strong> identifying the boundaries <strong>of</strong> the nucleus in the medulla oblongata. It was believed that there was a difference in the number <strong>of</strong> neurons in horses with RLN compared to normal horses, but small numbers <strong>of</strong> animals examined did not allow a statistical comparison (Hackett personal communication). There have been no histochemical techniques applied to identify somal changes secondary to the hypothesised transport disorder. Lesions in the laryngeal muscles innervated by the recurrent laryngeal nerves are characteristic <strong>of</strong> neurogenic disease. Denervation <strong>of</strong> the adductor muscles precede abductor involvement and typical changes include scattered angular fibres and 9
Equine Recurrent Laryngeal Neuropathy groups <strong>of</strong> atrophied fibres adjacent to hypertrophied fibres with central nuclei (Duncan and Griffiths 1974; Duncan et al. 1991). The first muscle groups affected appear to be the adductor muscles and within the adductor group the cricoarytenoideus lateralis is among the earliest and most severely affected muscles (Lopez Plana et al. 1993). The chronic, repetitive nature <strong>of</strong> the disease is further exemplified by the presence <strong>of</strong> muscle fibre type grouping, as muscle fibre type is controlled by the innervating neuron. Together, these pathological changes have been classified as a distal axonopathy, with the greater pathology in the left recurrent laryngeal nerve being explained by its greater length. One hypothetical cause <strong>of</strong> distal axonopathy is a defect in the neuronal soma, as the axon depends on the cell body for metabolic support and sustaining or trophic influences. Indeed, many <strong>of</strong> the peripheral nerve lesions that are typical in equine motor neuron disease, a disease primarily affecting the cell body, are also observed in RLN including axonal atrophy, proliferated Schwann cell cords (Büngner’s bands), loss <strong>of</strong> myelinated fibres and an increase in endoneurial collagen. HYPOTHETICAL AETIOLOGIES Despite years <strong>of</strong> work we appear to be no closer to clarifying the aetiology <strong>of</strong> this common equine disease. Hypotheses range from mechanical causes such as tension and stretch to the recurrent laryngeal nerve and its blood supply during neck movement, growth, or the caudal shift <strong>of</strong> the heart during embryonic development, to environmental factors, including toxins (reviewed by Cahill and Goulden 1987). The latter have been viewed as unlikely causes <strong>of</strong> RLN as the neuropathological changes are limited to the recurrent laryngeal nerves. Myelinopathies and the inherited and metabolic primary axonopathies affect multiple nerves and in other species would be expressed as part <strong>of</strong> a polyneuropathy and be progressive. Comparable pathology has indeed been noted in foals (Duncan 1992; Harrison et al. 1992) and clinical signs <strong>of</strong> left-sided hemiplegia have been demonstrated to be clinically progressive (Dixon et al. 2002). Interestingly, however, there have been no reports <strong>of</strong> left hemiplegic horses progressing to develop right-sided clinical signs (Dixon, personal communication). On the other hand, it is clear that horses affected with RLN do not show classical clinical signs <strong>of</strong> polyneuropathy such as megaoesophagus, tetraparesis and muscle atrophy. Notwithstanding, involvement <strong>of</strong> other long peripheral nerves (common, deep and superficial peroneal and tibial nerves) has been reported by some workers (Cahill and Goulden 1986a; Kannegieter 1989), but was not found by Duncan et al. 1978). Similarly, neurogenic muscle changes have been reported to exist in the extensor digitorum longus (Cahill and Goulden 1986d) in 3 out <strong>of</strong> 4 horses suffering from RLN. The above observations however have been isolated, uncontrolled and have not taken into account that age-related pathological changes can be demonstrated in distal limb nerves <strong>of</strong> horses (Wheeler and Plummer 1989). A detailed study <strong>of</strong> the peripheral nerves in RLN affected and control animals has not been undertaken. It should be remembered that axonal degeneration, characterised by distal degeneration that spreads proximally (‘dying back’), is the most common pathology seen in peripheral nerve diseases caused by a wide variety <strong>of</strong> toxic, metabolic, and infectious insults. Some <strong>of</strong> these processes affect the cell body, and it may be that the axonal dying back process may be initiated in order to conserve energy. How a cell can eliminate part <strong>of</strong> itself while leaving the rest intact is unknown. Localised axonal degeneration that resembles dying back can also occur in cell culture if the distal portion <strong>of</strong> the axon is deprived <strong>of</strong> nerve growth factor, and a similar process may be involved in disease states. Other forms <strong>of</strong> axonal degeneration that seem distinct from typical dying back occur in various human neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Pathological changes <strong>of</strong> the recurrent laryngeal nerve in RLN has been described in great detail using light and electron microscopy but the tools <strong>of</strong> the burgeoning science <strong>of</strong> molecular pathology have not been utilised. A detailed examination <strong>of</strong> changes in gene regulation and cytokine expression will have to be applied if further details <strong>of</strong> the pathogenesis are to be uncovered. REFERENCES Cahill, J.I. and Goulden, B.E. (1986a) Equine laryngeal hemiplegia. I. A light microscopic study <strong>of</strong> peripheral nerves. N. Z. vet. J. 34, 161-169. Cahill, J.I. and Goulden, B.E. (1986b) Equine laryngeal 10
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