Equine motor neuron disease in 2 horses from Saskatchewan

Abstract

Two horses from Saskatchewan were presented with signs of sweating, muscle fasciculations, weight loss, and generalized weakness. The horses were diagnosed with equine motor neuron disease (EMND), by histological assessment of a spinal accessory nerve or sacrocaudalis dorsalis medialis muscle biopsy. This is the first report of EMND in western Canada.

Equine motor neuron disease (EMND) is an acquired neurodegenerative disorder, which sporadically affects horses that have limited access to pasture for long periods of time (1). It was first described in 1990 by Cummings et al (2), who compared the clinical signs and the neuronal degenerative changes to sporadic amyotrophic lateral sclerosis (ALS) in humans. Common clinical signs in horses with EMND include weight loss, muscle wasting, muscle trembling (fasciculations), prolonged recumbency, shifting weight while standing, a short-strided gait, and a base-narrow stance (3,4). Other findings may include elevated tail head carriage, low head and neck carriage, profuse sweating, a ravenous appetite, and a brown pigment retinopathy due to ceroid-lipofuscin accumulation within the retinal pigment epithelium (3,5,6). Affected horses may have mildly to moderately elevated muscle enzymes (creatine kinase and aspartate aminotransferase) and deficiency in serum or plasma concentration of α-tocopherol (1,3), an isoform of vitamin E.

One of the main roles of vitamin E in the body is prevention of oxidant injury to cell membranes by scavenging of free radicals (7). Deficient plasma α-tocopherol concentrations have been linked with neurologic disease in several species (7). Experimental models in which animals have been fed vitamin E-deficient diets have resulted in degenerative lesions in the central and peripheral nervous systems. In Rhesus monkeys (8) and rats (9) these lesions have been found primarily in sensory neurons. Experimental models with adult horses fed vitamin E-deficient diets have resulted in degenerative changes to motor neurons, typical of EMND (10,11). In naturally occurring cases, affected horses have degenerative changes in their somatic motor neurons and axonal degeneration of the ventral horns of the spinal cord, ventral roots, and peripheral nerves (2). These lead to neurogenic muscle atrophy, which is grossly present in severely affected cases. Muscles containing high numbers of type I fibers, such as the sacrocaudalis dorsalis medialis muscle, have high oxidative requirements and therefore undergo the most damage due to oxidative stress (12), leaving them appearing pale, soft, and with a yellow-red discoloration (13).

Equine motor neuron disease was first reported in Canada in Nova Scotia (14) and Prince Edward Island (15) in 1994. Since then, additional cases have been reported in Ontario (1) but to the authors’ knowledge there are no previously published reports from western Canada. This report describes 2 cases of EMND in horses that resided in different parts of Saskatchewan and had no history of travel outside of the province. Veterinarians practicing in western Canada need to be aware of EMND and be familiar with the clinical signs in order to proceed with the appropriate diagnostic tests and treatment for these cases.

Case descriptions

Case 1

A 3-year-old Quarter Horse stallion (Figure 1) was referred to the Western College of Veterinary Medicine, Veterinary Medical Center (VMC) with a 7-day history of lethargy, muscle fasciculations, profuse sweating, and prolonged frequent periods of recumbency. His owners estimated that the stallion had lost 100 kg in the previous 2 wk, despite a normal appetite. He had been housed in a paddock with no access to pasture for most of his life. His diet consisted of mixed alfalfa-grass hay, with oats and corn provided as supplements. The horse was up-to-date on vaccinations and did not have any previous history of disease prior to the onset of clinical signs. He was the only affected horse in a herd of 40 horses.

Figure 1.

A 3-year-old Quarter Horse stallion (Case 1) displaying a base narrow stance, low head carriage, elevated tail head carriage, and profuse sweating.

On presentation to the VMC, the stallion was quiet and responsive, and exhibited generalized muscle atrophy. He had continuous muscle fasciculations, especially of the triceps and quadriceps muscles. He was tachycardic (heart rate: 60 beats/min), hyperthermic (rectal temperature: 38.7°C), had decreased borborygmi on abdominal auscultation, and was sweating profusely throughout the examination. Thoracic auscultation revealed no abnormalities. His head and neck carriage was low with muscle wasting of the cervical musculature and his tail head was elevated. The horse stood with a base-narrow stance and shifted his weight continuously on both forelimbs and hind limbs. At a walk, his gait appeared labored and weak, but no ataxia or proprioceptive deficits were noted. His digital pulses were within normal limits. Based on the history and physical examination findings the initial differential diagnoses included colic, laminitis, exertional rhabdomyolysis, hyperkalemic periodic paralysis (HYPP), and EMND.

Evaluation for colic included nasogastric intubation, which yielded no reflux, and a rectal examination that revealed no abnormalities. An abaxial sesamoid nerve block was performed on all 4 limbs in order to help rule out foot pain causing extreme discomfort. The nerve blocks did not dramatically improve the horse’s stance or gait, ruling out laminitis.

Blood work included a venous blood gas analysis and complete blood (cell) count (CBC), which revealed no abnormalities. The serum biochemistry profile revealed a mild elevation in creatine kinase [450 U/L, reference range (RR): 88 to 439 U/L] and aspartate aminotransferase activity (477 U/L, RR: 6 to 347 U/L), which was attributed to prolonged recumbency and made exertional rhabdomyolysis a less likely diagnosis. Serum magnesium concentration was low at 12 μg/mL [RR: 18 to 35 μg/mL (16)]. Examination by a board-certified ophthalmologist revealed an incipient posterior capsular cataract of the right eye. The fundi of both eyes were normal and no pigment retinopathy was noted. Hair samples from the stallion’s mane were collected to test for HYPP. Results indicated that the stallion was homozygous normal (NN), and therefore negative for the sodium channel α-subunit gene mutation responsible for HYPP (17). Serum selenium concentration was normal at 0.227 μg/mL, while α-tocopherol concentration was deficient at 0.41 μg/mL [normal > 2 μg/mL (18)]. A nerve biopsy was obtained from the left distal branch of the spinal accessory nerve (19) while the horse was restrained with xylazine hydrochloride (Rompun; Bayer Animal Health, Mississauga, Ontario), 0.5 mg/kg body weight (BW), IV, and butorphanol (Torbugesic; Zoetis, Kirkland, Quebec), 0.01 mg/kg BW, IV to induce standing sedation and the site was infiltrated with 2% lidocaine hydrochloride (Zoetis) as local anesthesia. The sample was then fixed in formalin and stained with hematoxylin and eosin (H & E) for histological evaluation. Histopathological analysis revealed significant Wallerian degeneration and a few bundles of unmyelinated nerves, which were interpreted as Büngner’s bands [cords of proliferating Schwann cells (2)]. These findings supported a diagnosis of EMND.

The stallion was treated by his owners with dl-α-tocopherol capsules (10 000 IU/day, PO, brand unknown) (18) for 3 mo and housed on pasture during the summer. Repeat evaluation of the stallion’s serum α-tocopherol levels would have been ideal following 3 to 6 mo of treatment, but was not possible in this case. A follow-up conversation with the owner 1 y later indicated that the stallion’s gait and stance had improved, and the muscle fasciculations and profuse sweating had subsided.

Case 2

A 17-year-old Thoroughbred gelding was referred to the VMC for evaluation and treatment of suspected colic. The horse had a history of weight loss and behavioral changes over the last 2 mo. The owners reported that he had recently become the subordinate horse in the herd; while he was formerly dominant over the other horses. He was up-to-date on vaccinations and had no previous medical problems. The gelding had a good appetite and was fed a diet of grass hay, occasionally supplemented with pelleted complete feed following exercise. He was housed in a dirt paddock with no pasture access.

The horse presented with generalized muscle fasciculations, profuse sweating, and stood with a hunched back and base-narrow stance. His head carriage was low and his tail head carriage was elevated. He was tachycardic (heart rate: 60 beats/min), tachypneic (respiratory rate: 32 breaths/min), and had increased borborygmi on abdominal auscultation. Tacky mucous membranes and a slightly elevated packed cell volume (45%) were consistent with dehydration; however, the concentration of total solids (75 g/L) was normal. The referring veterinarian had performed a CBC and serum biochemistry, which revealed a mild elevation of aspartate aminotransferase activity at 366 U/L (RR: 175 to 340 U/L) as the only abnormality. A nasogastric tube was passed and no gastric reflux was obtained. Rectal examination revealed no abnormalities. An abdominocentesis yielded peritoneal fluid that was normal based on cytological analysis.

Following the initial examination, the horse was treated with flunixin meglumine (Flunixin injection; Zoetis), 1.1 mg/kg BW, IV, once for pain control and intravenous fluids (Lactated Ringer’s Solution; Baxter, Mississauga, Ontario), 90 mL/kg BW per day to replace fluid deficits and to provide maintenance fluid needs. The horse was monitored overnight for signs of colic. Once he was placed in a stall and allowed to lie down, his tachycardia resolved and the profuse sweating stopped. The muscle fasciculations were present only when the horse was standing. As no further colic signs were observed, the primary differential diagnosis was EMND. Other differentials included laminitis, exertional rhabdomyolysis, and pheochromocytoma, but all were considered less likely than EMND based on monitoring of physical examination findings and the serum biochemistry results from the referring veterinarian.

Examination by a board-certified ophthalmologist revealed incipient posterior cataracts bilaterally and normal fundi with no apparent pigment retinopathy. A serum vitamin and mineral panel revealed deficient levels of both serum magnesium at 10.10 μg/mL [RR: 18 to 35 μg/mL (16)] and α-tocopherol at 0.86 μg/mL [normal > 2 μg/mL (18)]. A muscle biopsy for histopathological evaluation was obtained from the left sacrocaudalis dorsalis medialis (SCDM) muscle (19) under standing sedation with xylazine hydrochloride (Bayer Animal Health), 0.5 mg/kg BW, IV, and butorphanol (Zoetis), 0.01 mg/kg BW, IV, and local anesthesia with 2% lidocaine hydrochloride (Zoetis). The SCDM muscle contained muscle fibers with moderate size variation, anguloid atrophy, angular atrophy, centrally displaced nuclei, and sarcoplasmic masses, which is consistent with neurogenic atrophy that occurs in EMND cases (20). Electromyography (EMG) was performed under general anesthesia (21). Spontaneous fibrillation potentials consistent with muscle fiber denervation were detected in several muscles on the left side of the horse including the extensor carpi radialis (Figure 2), gluteal, quadriceps, triceps, and neck muscles. Complete examination of the right side was not undertaken due to the positioning of the horse in right lateral recumbency.

Figure 2.

Electromyogram reading demonstrating fibrillation potentials in the left extensor carpi radialis muscle, which is consistent with the muscle fiber denervation that occurs with EMND. Each line represents the recording from an electrode within a muscle and the wave forms indicate spontaneous firing of the muscle due to loss of innervation.

Given the results of the muscle biopsy examination and EMG, an antemortem diagnosis of EMND was established. The horse was given a guarded to poor prognosis for return to his previous level of function and the owners elected euthanasia. On postmortem examination, there were no gross abnormalities. Histologic examination revealed minimal degenerative lesions in the extensor carpi radialis muscle (Figure 3). Abundant lesions of Wallerian degeneration in both spinal accessory nerves (Figure 4) and degenerative lesions of ventral motor neurons in both cervical (Figure 5) and lumbar intumescences of the spinal cord confirmed the diagnosis of EMND (13).

Figure 3.

Right extensor carpi radialis muscle (Case 2). Multiple fibers are hypereosinophilic, homogeneous (arrows) and vacuolated (arrowhead), representing degenerative lesions. Hematoxylin and eosin (H&E) stain.

Figure 4.

Left accessory nerve (Case 2). The chain of digestion chambers (arrows) is filled with axonal debris and activated macrophages. Such examples of Wallerian degeneration were abundant in both the left and right accessory nerves. H&E stain.

Figure 5.

Spinal cord, cervical intumescence (Case 2). This ventral motor neuron (arrow) shows advanced degenerative change of peripheral chromatolysis, accumulation of eosinophilic inclusions and swollen nucleus. H&E stain.

Discussion

The 2 cases of EMND presented with similar clinical signs of muscle fasciculations and sweating, history of recent weight loss and no access to pasture (3). Interestingly, fundic examination in both horses showed no evidence of a pigment retinopathy, which has been reported commonly in cases of EMND (5). The breeds of the horses in this report are not unusual as Quarter Horses are reportedly the most commonly affected breed and Thoroughbreds are overrepresented amongst reported EMND cases (1,3). Equine motor neuron disease has been diagnosed in adult horses as young as 3 y old (3), but the risk of developing the disease peaks at 16 y (1,22). Experimental models have demonstrated that the disease can be reproduced after 18 (11) to 21 mo (10) of feeding a diet completely deficient in vitamin E. In order for this disease to occur in a 3-year-old horse, as in Case 1, his diet would likely have had very low or no vitamin E for most of his life.

Several differential diagnoses were considered during initial examination of the horses described here. Colic, laminitis, and exertional rhabdomyolysis were considered in both cases, as they are common differential diagnoses in horses presenting with tachycardia, profuse sweating, and occasionally, muscle fasciculations (23). Equine hyperkalemic periodic paralysis (HYPP) was included as a differential diagnosis in Case 1 as it mainly occurs in Quarter Horses and one of the most common clinical signs is muscle fasciculations (24). Pheochromocytoma is a catecholamine secreting adrenal medullary tumor, which results in clinical signs such as prolonged tachycardia, tachypnea, profuse sweating, muscle tremors, and anxiety (25). This was considered in Case 2 until the tachycardia and sweating resolved when the horse was able to lie down. Botulism and equine grass sickness are other differential diagnoses that could also have been considered for these cases. Equine grass sickness is a poly-neuropathy, which results in clinical signs similar to EMND, as well as dysphagia and ptosis. Grass sickness has only been reported once in North America to date (26), and in contrast to horses with EMND, horses with grass sickness are commonly kept on pasture (27). Botulism should also be considered in cases of muscle weakness; however, the lack of dysphagia in the presented cases put it lower on the differential list (28). The low magnesium in both cases was considered to be an incidental finding and not the primary cause of the clinical signs. Primary hypomagnesemia is rare in horses (29) and causes mineralization of several body tissues (30). Low serum magnesium has been associated with severe illness and endotoxemia in hospitalized horses (31), which was not present in either of these cases.

Different diagnostic techniques were used to confirm a diagnosis of EMND in the 2 cases reported here. Histopathology of the spinal accessory nerve was the first reliable antemortem diagnostic test for definitive diagnosis of EMND (32). When interpreted by an experienced pathologist, this test has a specificity of 94% and a sensitivity of 92% (32). In Case 1, the spinal accessory nerve biopsy was obtained by an experienced board-certified equine surgeon, with the horse restrained under standing sedation and local anesthetic infiltration at the surgical site. This procedure is technically challenging and in some cases may require general anesthesia (32). In Case 2, antemortem diagnosis of EMND was made by evaluation of frozen and formalin-fixed SCDM muscle biopsy specimens. Frozen specimens are thought to yield higher test sensitivity than formalin-fixed samples (20). The SCDM muscle biopsy procedure is technically easier than the spinal accessory nerve biopsy (19) and therefore is preferred by many clinicians. The SCDM muscle is used for diagnosis because it is easily accessible and it contains a high percentage of type 1 muscle fibers, causing it to be more severely affected by denervation atrophy than other muscles (19). Denervation atrophy of the SCDM muscles ultimately leads to fibrotic contracture and elevation of the tail head. The sensitivity and specificity of the SCDM muscle biopsy for diagnosing EMND is approximately 90% (19).

The neurodegeneration that occurs in EMND is associated with a deficiency in plasma α-tocopherol levels (3). Alpha-tocopherol is a potent anti-oxidant and has several important roles in the body including immune function, gene transcription, and neuromuscular function (18). When a deficiency of vitamin E manifests itself as EMND, neurodegeneration occurs in the areas of the body that have high oxidative requirements, such as the motor neurons supplying the type I muscle fibers (12,13). A neuronal loss of approximately 30% is required before clinical signs will manifest as EMND (33). It has been hypothesized that both neuronal loss and dysfunctional motor neurons may be present in the diseased state (6). The affected horses that recover may be those with a higher proportion of neuronal dysfunction, rather than neuronal loss, and the dysfunctional motor neurons may be capable of recovery (6). In cases in which the horse is able to continue to eat and remain mobile, treatment may be beneficial.

Treatment usually involves supportive care, which may include administration of corticosteroids in acute cases, and increasing dietary vitamin E through supplementation and the addition of fresh green forage in the diet (4,12). The recommended dose for supplementation is 5000 to 7000 IU of vitamin E/horse per day, with the highest safe level being 10 000 IU of vitamin E/horse per day (18), which was the dose used in Case 1. This dose is expected to increase the serum α-tocopherol concentration to normal levels within 2 to 4 wk of initiation (4). It is important to consider the type of vitamin E in the supplement, as vitamin E in its natural form (RRR-α-tocopherol) is up to twice as bioavailable as the synthetic formulations (all-rac-α-tocopherol and dl-α-tocopherol) (18). Clinical improvement is noticeable in 40% of cases within 6 wk of treatment and of these, some will appear normal within 3 mo (4). However, it should be considered that improvement of clinical signs at rest can be deceiving and owners should be warned that the horse may deteriorate if it is put back into work, potentially leading to injury of both the horse and the rider (4). In 20% of EMND cases clinical signs progress to prolonged recumbency and debilitation, which often leads to euthanasia (4). The stallion in Case 1 was expected to be a breeding animal and due to the severity of his clinical condition, the highest safe dose was used in an attempt to promote his recovery. In Case 2 the horse was to be used for riding, and due to the unpredictability of his recovery, he was euthanized.

Equine motor neuron disease occurs sporadically and the etiology has not been fully determined. It is still unknown why some horses are affected and others are not when they are on the same farm and fed the same diet. One study evaluated vitamin E levels in clinically normal horses kept on the same property and in the same housing conditions as EMND-affected horses. This study showed that clinically normal horses had low vitamin E concentrations, but the EMND-affected horses from these farms had significantly lower plasma vitamin E concentrations than the clinically normal controls (3). Genetic factors have been considered and based on the genetic mutation responsible for human familial ALS, the coding sequence of the equine copper/zinc superoxide dismutase (SOD1) gene was evaluated in a group of affected horses, but no similar mutations were detected (34). A heritable component of EMND has not been completely ruled out, however, and it could be argued that the stallion in Case 1 should not be used as a breeding animal.

Veterinarians in western Canada need to be aware of EMND as horse husbandry during long winters typically involves feeding stored hay, which contains less vitamin E than fresh forage (35), and therefore may predispose those horses to dietary vitamin E deficiency. By familiarizing themselves with the clinical signs of EMND, veterinarians can proceed with appropriate diagnostics and treatment.