Vitamin E-related Diseases – What do we need to know?

Vitamin E-related Diseases – What do we need to know?

Kile S. Townsend, DVM, MS, DACVIM (LAIM)

There are several neurological and muscular conditions in horses that are related to vitamin E. In this session, we will particularly focus on three specific vitamin E-related conditions in the horse: Equine Motor Neuron Disease (EMND), Vitamin E Deficient Myopathy (VEM), and Equine Degenerative Myeloencephalopathy/Neuroaxonal Dystrophy (EDM/eNAD).

Vitamin E is a group of fat-soluble compounds found in nature. Vitamin E is broadly known to be essential for neuromuscular function by acting as a potent antioxidant. Vitamin E status is relevant to immune function, reproduction, gene transcription, neuromuscular homeostasis, and exercise. Vitamin E can also modulate gene expression, inhibit platelet aggregation, and stabilize membranes. There are many ways to characterize vitamin E into different subgroups, but the relevant isoform for equine veterinary medicine is known to be RRR-α-tocopherol (it is also the most researched). RRR-α-tocopherol is the most biologically active isoform of vitamin E, and it also is known to have the most potent antioxidant properties. Horses obtain vitamin E solely from dietary intake.

Equine Motor Neuron Disease (EMND) EMND is a spontaneous, acquired neurodegenerative disease of adult horses that is likened to amyotrophic lateral sclerosis (ALS aka Lou Gehrig’s disease) in human medicine. It usually affects adult horses >9 years of age (median ~ 10 years) but has been known to affect horses as young as 2 years old. It is caused by vitamin E deficiency for ≥ 18 months and has been experimentally induced in animals by denying access to vitamin E for 21+ months. Vitamin E deficiency results in neurodegeneration and the major lesions are present in alpha motor neurons in the spinal cord (ventral horn cells) and brain stem nuclei (V, VII, XII, and nucleus ambiguous). This neurodegeneration is coupled with muscle wasting, most severe in muscles with predominantly type I muscle fibers. It is believed that type I muscle fibers are more affected due to the higher oxidative requirements and are therefore more susceptible to oxidative damage.

Clinical signs of EMND include acute onset trembling, inappropriate or excessive recumbency, shifting of the weight of the hindlimbs, propulsive walking, short-strided gait, weakness, weight loss (often with good appetite), “horse-on-a-ball” posture, low head carriage, and marked muscle atrophy. Beware of mistaking clinical signs of EMND for other common equine afflictions that lead to recumbency, including rhabdomyolysis or colic. Pigment retinopathy is observed upon careful ophthalmic examination in approximately 40% of cases. There is no sex predilection to this disease and Quarter Horses and Thoroughbreds are said to be overrepresented.

In order to treat this disease, administration of 5000-7000 IU of water-soluble, natural α-tocopherol/day is recommended and about 40% of horses have shown some clinical improvement within 6 weeks. In order to prevent EMND, horses without access to green forage should be supplemented with 1 U/kg BW/day of vitamin E. The Nutritional Research Council (NRC) requirements for horses without pasture access is 600–800 IU/500 kg horse/day. Divers et al. have reported that about 40% of horses will stabilize clinical signs with treatment, but these horses remain permanently afflicted. The remainder of horses, treated or not, will continue to deteriorate.

Diagnosis of EMND is supported by low serum vitamin E concentrations and telltale clinical signs, but definitive antemortem diagnosis can be achieved via biopsy of the ventral branch of the spinal accessory nerve (histologic evidence of the degeneration of myelinated axons) or the finding of neurogenic

atrophy of predominantly type I muscle fibers in sacrocaudalis dorsalis medialis muscle biopsy. The sacrocaudalis dorsalis medialis muscle biopsy has a sensitivity of approximately 90% but should be examined by a veterinary pathologist with experience evaluating striated muscle. Electromyography can also aid in diagnosis of this disease antemortem. It is important to note that horses on pasture may be affected by EMND and this disease should not be entirely ruled out based on evidence of access to lush grass-based pasture.

Vitamin E Deficient/Responsive Myopathy (VEM) Horses affected with VEM develop muscle wasting and associated weakness (myasthenia). This condition has been recognized as distinct from EMND because the muscle biopsies from affected horses yielded no evidence of neurogenic atrophy but had a characteristic “moth-eaten” staining appearance of the mitochondria. Some (but not all) horses with VEM also have low serum vitamin E and most horses will have low muscle vitamin E levels.

VEM is typically found in horses with a shorter duration of vitamin E deficiency than those with EMND. Clinical signs include loss of muscle mass, toe dragging, poor performance, muscle weakness, and muscle fasciculations in some cases. There is no known breed or sex predilection and its relationship to EMND is not known at this time.

Treatment for VEM consists of vitamin E supplementation (water-soluble, natural form) and in one report all horses recovered completely after vitamin E therapy for several weeks.

Equine Degenerative Myeloencephalopathy/Neuroaxonal Dystrophy (EDM/eNAD) This disease can be confusing because of the variable and diverse clinical presentations of the disease as well as the nomenclature. Equine NAD (eNAD) is clinically indistinguishable from EDM. Neuroaxonal dystrophy refers to a morphologic abnormality of select neurons and their axonal processes within 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. When classifying these diseases histologically, they both have dystrophic neurons and axons, vacuolization, and spheroid formation, the only (and subtle) difference between the two is the distribution of the lesions within the central nervous system (CNS). Essentially, experts have concluded that eNAD should be considered a localized form of EDM in which degenerative changes in the spinal cord are subtle and easily overlooked.

EDM has been reported in several breeds of equids (Quarter Horse, Arabian, Appaloosa, Thoroughbred, Standardbred, Morgan, Paso Fino, Grant’s zebra, Przewalski horses, and Warmbloods) and clinical signs typically occur in the first 14 months of age. In some Warmblood horses, there is increasing recognition of onset of signs of disease between 5-15 years of age. There is no known sex predilection, and a heritable component is suspected in some breeds.

Clinical signs are classically described as symmetric tetraparesis and ataxia. The onset of this paresis and ataxia is typically within the first 14 months of life. Recently, clinical signs such as topline muscle wasting and a dull haircoat have been reported along with personality changes in the horse. Owners/trainers often report changes in behavior and personality. Some horses appear unusually dull or sedate during examination while others inappropriately spooky or reactive for their level of handling/training. Dynamic gait evaluation typically reveals proprioceptive deficits and signs of mild-to-moderate ataxia and paresis consistent with a cervical or diffuse myelopathy. Most horses are graded 1 to 2/5 on the modified Mayhew ataxia scale at the time of first evaluation, although some horses show more severe deficits (2.5 to 3/5). Repeated evaluations over months might show a progression of neurologic disease

(Johnson, 2021). Some horses are presented for inappropriate behavior under saddle, lameness, or poor performance.

Diagnosis of EDM is difficult and has to be made based on exclusion of other similar candidate diseases. The top differentials include compressive myelopathy, usually due to cervical vertebral stenotic myelopathy (CVSM) or infectious myelitis, usually due to equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona. CVSM must be ruled out with radiography/myelography and EPM with CSF analysis and serum: CSF antibody titer testing for Sarcocystis neurona. Vitamin E deficiency has been associated with EDM, and vitamin E concentration should be assessed in suspect cases. Low vitamin E concentration (less than 2 ppm or 200 mg/dL) is supportive of EDM diagnosis, particularly when other causes of neurologic disease have been excluded. However, adequate vitamin E levels do not preclude diagnosis of EDM (Johnson, 2021). It has been suggested that vitamin E deficiency in utero may contribute to development of this disease. The use of ‘phosphorylated neurofilament heavy’ (pNF-H) for diagnosis of equine neurologic disease, including EDM, is currently being investigated. Current evidence suggests that abnormally high concentrations of pNF-H in serum and CSF are suggestive of EDM if diseases such as EPM have been excluded. However, pNF-H testing has a low sensitivity for EDM diagnosis, and many confirmed cases have normal pNF-H concentrations in blood, spinal fluid, or both (Johnson 2021). Comorbidities are both possible and probable in some cases and can confuse diagnosis of this disease. In some cases, if neurological evaluations are repeated over months to years, a progression of neurologic disease can be demonstrated.

There is no definitive treatment for EDM and horses that are predisposed to EDM or with a clinical diagnosis of EDM should receive oral water-soluble, natural α-tocopherol supplementation. Improvement in clinical signs has been seen in some cases with long-term treatment, but in general, the prognosis for complete recovery is poor. In a group of Quarter Horses affected with EDM, dietary vitamin E supplementation did not improve neurologic deficit. However, vitamin E administration to pregnant mares appeared to decrease but not prevent disease development among offspring born the following year (Aleman et al. 2011).

Not all horses in which vitamin E deficiency is identified exhibit clinical signs or disease. It is important to supplement vitamin E in at risk horses and serum vitamin E testing is recommended prior to starting supplementation. Some horses require higher levels of supplementation than other (individual variation), so testing baseline vitamin E levels is important for monitoring. It is known that healthy horses on pasture maintain a serum vitamin E level of 3-4 µg/mL, so that is the recommended target in the average horse.

Measurement of vitamin E in serum or plasma is the easiest way to determine if a horse ahs vitamin E deficiency. Blood samples should be refrigerated (4°C) and protected from light (wrapped in foil for example) as soon as possible after obtaining a sample. The serum/plasma should be separated via centrifugation as soon as possible. Vitamin E deteriorates rapidly in the samples, so samples should be stored frozen (-70° C). Samples can be sent to the MU-VMDL (https://vmdl.missouri.edu/) or other veterinary diagnostic laboratories for analysis (Michigan State University and Cornell University have VMDLs that are often utilized). Reports of vitamin E results usually come with reference ranges/interpretations. Often, laboratories will report vitamin E levels as >2 μg/mL = Adequate, 1.5-2 μg/mL = Marginal, <1.5 μg/mL = Deficient.

References Divers TJ, Mohammed HO, Cummings, JF. Equine Motor Neuron Disease, Veterinary Clinics of North America: Equine Practice, Volume 13, Issue 1, 1997, Pages 97-105, ISSN 0749-0739, https://doi.org/10.1016/S0749-0739(17)30258-4.

Divers TJ, Mohammed HO, Hintz HF, de Lahunta A. Equine Motor Neuron Disease: A Review of Clinical and Experimental Studies, Clinical Techniques in Equine Practice, Volume 5, Issue 1, 2006, Pages 24-29, ISSN 1534-7516, https://doi.org/10.1053/j.ctep.2006.01.005.

Edwards LA, Donnelly CG, Reed SM, Valberg S, Chigerwe M, Johnson AL, Finno CJ. Serum and cerebrospinal fluid phosphorylated neurofilament heavy protein concentrations in equine neurodegenerative diseases. Equine Vet J. 2022 Mar;54(2):290-298. doi: 10.1111/evj.13452. Epub 2021 May 9. PMID: 33969539.

Finno, C. and Valberg, S. (2012), A Comparative Review of Vitamin E and Associated Equine Disorders. J Vet Intern Med, 26: 1251-1266. https://doi.org/10.1111/j.1939-1676.2012.00994.x.

Johnson, Amy. “How to Diagnose Equine Degenerative Myeloencephalopathy in Sport Horses.” HOW-TO SESSION: MEDICAL REASONS FOR POOR PREFORMANCE. AAEP PROCEEDINGS / Vol. 67 / pp.209-213. 2021.

McGorum, B.C., Mayhew, I.G., Amory, H., et al. Horses on pasture may be affected by equine motor neuron disease. Equine Veterinary Journal, 38: 47-51. 2006. https://doi.org/10.2746/042516406775374207.

Miller MM, Collatos C. Equine degenerative myeloencephalopathy. Vet Clin North Am Equine Pract. 1997 Apr;13(1):43-52. doi: 10.1016/s0749-0739(17)30254-7. PMID: 9106342.

Mohammed, H.O., Divers, T.J., Summers, B.A. et al. Vitamin E deficiency and risk of equine motor neuron disease. Acta Vet Scand 49, 17 (2007). https://doi.org/10.1186/1751-0147-49-17.

Riis, R.C., Jackson, C., Rebhun, et al. Ocular manifestations of equine motor neuron disease. Equine Veterinary Journal, 31: 99-110. 1999. https://doi.org/10.1111/j.2042-3306.1999.tb03801.x

Equine

Alison LaCarrubba, DVM, ABVP (Equine Practice)

Equine Ambulatory and Equine Internal Medicine Services University of Missouri College of Veterinary Medicine Columbia, Mo.

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