Vitamin E deficiency, in and of itself, does not appear to reliably cause disease in horses. Studies examining the effect of vitamin E deficiencies in exercising or resting horses have revealed no apparent clinical signs resulting from vitamin E deficiency.[49, 52, 57, 60] There are, however, 3 specific diseases that consistently have been associated with α-tocopherol deficiency: EMND, NAD/EDM, and vitamin E-deficient myopathy.
Equine Motor Neuron Disease (EMND)
Equine motor neuron disease is a worldwide acquired neurodegenerative disorder of the somatic lower motor neurons in the ventral horns of the spinal cord and selected brain stem nuclei. Clinical signs include weight loss because of muscle wasting, muscle fasciculations, and prolonged recumbency. A definitive diagnosis is based upon postmortem demonstration of degeneration and loss of motor neurons from the ventral horns of the spinal cord. Antemortem diagnosis of EMND is based upon either histologic evidence of the degeneration of myelinated axons upon biopsy of the ventral branch of the spinal accessory nerve or the finding of neurogenic atrophy of predominantly type I muscle fibers in sacrocaudalis dorsalis medialis muscle biopsy (sensitivity of approximately 90%).[118, 119]
Equine motor neuron disease affects neurons supplying highly oxidative type I muscle fibers, and this oxidative disorder is associated with a dietary deficiency of vitamin E and low plasma concentrations of vitamin E. Horses with naturally occurring EMND require at least 18 months of a vitamin E deficiency before developing clinical signs, and in an experimental model, a 21-month interval of vitamin E deficiency was required before the development of clinical disease. In addition, excessive dietary copper, a potential pro-oxidant, is a risk factor for EMND development.
In the experimental model of EMND, although all horses (n = 8) developed a vitamin E deficiency during the 30-month study, only 4 developed clinical signs of EMND. In naturally occurring EMND, there appears to be an individual susceptibility to oxidative stress in at-risk horses, with clinical signs developing in only a subset of horses maintained in high-risk environments, such as no access to pasture and no vitamin E supplementation. Clinically unaffected horses could suffer from subclinical disease as histologic lesions can be found in vitamin E-deficient apparently unaffected horses, or as discussed previously, it could be that specific polymorphisms in genes involved in vitamin E metabolism determine individual susceptibilities to EMND under the same conditions of deficiency. Indeed, genetic factors outside the major histocompatibility complex were suggested to influence susceptibility to EMND. This effect could also be indirect, in that the α-tocopherol deficiency directly impairs BBB integrity, thereby potentially allowing neurotoxins access to the CNS.
Equine motor neuron disease shares commonalities to the sporadic form of human ALS. Sporadic ALS constitutes 90–95% of all ALS cases, with 5–10% considered familial. The majority of familial ALS cases are associated with mutations in various genes, including Cu/Zn superoxide dismutase (SOD1), a potent free radical scavenger. SOD1 helps to prevent oxidative damage in metabolically active cells, such as neurons. Sequencing of cDNA from SOD1 in EMND affected and unaffected horses did not reveal any putative mutations.
Horses without access to green forage should be supplemented with 1 U/kg BW/day of vitamin E to prevent against EMND development. This dosage is similar to NRC requirements for horses without pasture access (600–800 IU/500 kg horse/day). For EMND-affected cases, 5,000–7,000 IU α-tocopherol/day is recommended. With this treatment, approximately 40% of cases demonstrate clinical improvement within 6 weeks, and some could appear normal within 3 months. It should be noted, however, that return to performance could result in deterioration. Divers et al report that approximately 40% of cases will stabilize, but remain permanently disfigured, while 20% will have continual progression of clinical signs.
Neuroaxonal Dystrophy/Equine Degenerative Myeloencephalopathy
Equine NAD is clinically indistinguishable from EDM. Neuroaxonal dystrophy is a morphologic abnormality of select neurons and their axonal processes in the nervous system. Equine NAD is considered the underlying basis of EDM, with a high likelihood that the pathophysiology of the two diseases is similar. Histologic lesions in both NAD and EDM consist of dystrophic neurons and axons, vacuolization, and spheroid formation, with the only difference being the distribution of the lesions. In previous case reports, the disease was classified as NAD if the lesions were confined to the lateral (accessory) cuneate, medial cuneate, and gracilis nuclei,[126, 127] whereas a diagnosis of EDM was assigned when axonal necrosis and demyelination extended into the dorsal and ventral spinocerebellar tracts and ventromedial funiculi of the cervicothoracic spinal cord.[92, 128-131] Histologic lesions consistent with both NAD and EDM can occur in the same animal.
Clinical cases of NAD/EDM have been reported in several breeds, including Standardbreds, Paso Finos, Quarter horses,[128, 132] Mongolian horses, Appaloosas, Haflingers, Arabians, Morgans, Lusitanos, Thoroughbreds,[134, 137] Paint horses, Tennessee Walking Horses, Norwegian Fjord Horses, a Welsh Pony, and various mixed breeds.[129, 131] There is no sex predilection and age of onset ranges from birth[134, 139] to 36 months, although most cases demonstrate clinical signs by 6–12 months of age. There is strong evidence of a genetic component, in that many of the clusters of case reports involve related horses.[127, 129, 130, 135, 136] The mode of inheritance appears to be autosomal dominant with variable expression or polygenic. A study of risk factors associated with the development of EDM found that foals from dams that had an EDM-affected foal were at a significantly higher risk (25× more likely) of developing EDM than foals from other dams.
Clinical signs in all cases include symmetric ataxia that is often more severe in the pelvic limbs than in the thoracic limbs, abnormal base-wide stance at rest, and proprioceptive deficits. In some reports, hyporeflexia of the cervicofacial and cutaneous trunci is described in addition to an absence of laryngeal adductor reflex.[128, 133] Horses with NAD/EDM that survive to 2–3 years of age commonly exhibit lifelong, stable neurologic deficits.
The developing nervous system is dependent on adequate vitamin E for normal development and vitamin E appears to play a role in the pathophysiology of NAD/EDM. Although vitamin E deficiency occurs in some cases of equine NAD/EDM,[128, 130, 133] low α-tocopherol levels are not present consistently in all cases. Serum α-tocopherol concentrations were not significantly different between EDM-affected horses and control horses in some studies.[131, 140] It does appear that vitamin E supplementation of susceptible horses, such as those on the same farm as previously diagnosed horses, does lower the severity and overall incidence of NAD/EDM.[133, 140] Foals from an EDM-affected stallion compared with controls from an unaffected stallion had significantly lower plasma α-tocopherol concentrations, and it was concluded that vitamin E is a factor in the development of EDM in the first year of life in genetically predisposed foals. Blythe et al determined that foals with EDM do not demonstrate significant differences in oral vitamin E absorption as compared with controls. Overall, there is very strong evidence that NAD/EDM is an inherited disorder, and it could be that the serum concentration of α-tocopherol acts as an environmental modifier to determine the overall severity of the phenotype of horses affected with NAD/EDM.
An antemortem diagnosis of NAD/EDM is based solely upon clinical signs, the elimination of other causes of neurologic disease, and a possible association with a low serum α-tocopherol concentration. At this time, a definitive diagnosis is only available upon histopathologic evaluation of spinal cord and brainstem tissue at postmortem. There is no treatment for NAD/EDM, and there have been no reports of spontaneous resolution. Suspected cases are often treated empirically with vitamin E supplementation because of the association of low serum vitamin E concentrations with the disease. Unfortunately, there is strong evidence that vitamin E supplementation of affected cases does not lead to neurologic improvement.[132, 143] Although the neurologic abnormalities appear to stabilize by 2–3 years of age, these horses are neurologically abnormal and often unfit for any performance activity. Prevention of the disease has been reported in genetically susceptible herds by supplementing susceptible animals with 1,000–2,000 IU/450 kg/day vitamin E.[133, 140] Recent evidence, however, supports that supplementation is not necessarily entirely effective in preventing NAD/EDM, in that vitamin E supplementation appeared to decrease the severity of disease in foals born in a susceptible herd with previously diagnosed NAD/EDM cases, but it did not completely prevent new cases.
Vitamin E-Deficient Myopathy
Some horses with clinical signs of EMND and a deficiency in vitamin E are not diagnosed antemortem with EMND because they lack evidence of neurogenic atrophy in the sacrocaudalis dorsalis (SC) muscle. A recent study suggests that many such undiagnosed cases are the result of a specific myogenic presentation of vitamin E deficiency. Sacrocaudalis muscle from horses with a clinical presentation of EMND lacked evidence of neurogenic atrophy, but did, however, contain characteristic abnormal moth-eaten staining pattern of mitochondria. Muscle α-tocopherol concentrations from affected horses were all low, but serum α-tocopherol concentrations were inconsistently low. This vitamin E-deficient myopathy has likely been missed previously because formalin-fixed biopsy specimens are most often evaluated for a diagnosis of EMND and mitochondrial staining is not possible with this fixative. The observed generalized weakness in the horses with abnormal mitochondrial stains was suggested to be due to a reversible manifestation of skeletal muscle/mitochondrial oxidative stress associated with vitamin E deficiency. All horses recovered completely after vitamin E therapy. Vitamin E-deficient myopathy could be an entity unto itself or a predecessor to development of EMND, but this distinction was not evaluated in the study as all horses successfully responded to vitamin E therapy, precluding a postmortem examination.