Vitamin E Supplementation in Horses with Neuromuscular Disorders
- What is vitamin E?
- What equine diseases are directly affected by a deficiency of vitamin E?
- What types of vitamin E supplements exist?
- How can I tell if my horse is deficient in vitamin E?
- Do all horses with an alpha-tocopherol deficiency develop clinical signs of disease?
- What are some diseases associated with vitamin E deficiency?
- What type of vitamin E supplements are avalable?
- What are current recommendations for supplementation?
1. What is vitamin E?
Vitamin E functions as a biological antioxidant, helping to protect cells from the cellular and subcellular damage caused by excess free radicals. Through the vitamin’s protective function as an antioxidant, and potentially other functions in gene regulation, vitamin E is associated with maintenance of normal muscle cell function and motor nerve signals.
2. What equine diseases are directly affected by a deficiency of vitamin E?
Equine diseases that develop due to vitamin E deficiency in young animals includes nutritional muscle degeneration, a neurologic condition called (equine neuroaxonal dystrophy; eNAD) or equine degenerative myeloencephalopathy (EDM). Adult horses deficient in vitamin E may develop disease of muscle tissue (vitamin E responsive myopathy) or nerve tissue (equine motor neuron disease: EDM).
3. WHAT TYPES OF VITAMIN E SUPPLEMENTS EXIST?
Most vitamin E supplements consist of natural or synthetic forms of alpha-tocopherol because alpha-tocopherol is the most biologically available and well researched isoform of vitamin E. Vitamin E, however is a complex nutrient consisting of eight closely-related fat-soluble naturally occurring compounds that form two groups; tocopherols (saturated) and tocotrienols (unsaturated). Within each group, there are four individual isoforms (α, β, γ and δ).
4. How can I tell if my horse is deficient in vitamin E?
Vitamin E is measured as alpha-tocopherol concentrations. A blood sample using serum or plasma is the most readily available way to determine alpha-tocopherol deficiency. After taking the blood sample, it should be refrigerated (4°C) and protected from light (wrapped in foil for example) as soon as possible after obtaining a sample. Blood samples should be centrifuged at 4°C and plasma/serum separated as soon as possible. Since vitamin E deteriorates rapidly, serum/plasma samples should be stored frozen (- 21° F, - 70° C). Because external factors can influence test results, repeating the test may be in order if values are marginal or not in line with clinical signs/supplementation. Normal reference ranges used by most labs for plasma/serum concentrations of alpha-tocopherol in the horse are below. However, we recommend that horses are maintained at levels > 3 μg /ml for optimal health and < 10 μg/ml.
>2 μg/mL Adequate - Note that Cornell labs report this as > 200 ug/dL
1.5-2 μg/mL Marginal
<1.5 μg/mL Deficient
Significant correlations exist between blood serum α-tocopherol concentrations and fat, liver, muscle and cerebral spinal fluid levels in healthy horses. This correlation, however, is not consistently evident in horses with vitamin E responsive myopathy. In cases of vitamin E responsive myopathy, a discrepancy between serum and tissue levels of alpha-tocopherol may indicate that an abnormality exists in the uptake of α-tocopherol into muscle tissues from the blood.
5. Do all horses with an alpha-tocopherol deficiency develop clinical signs of disease?
No; only certain animals demonstrate clinical signs of neuromuscular disease, even if the alpha-tocopherol deficiency exists in an entire herd of horses. Development of neuromuscular disease appears to depend upon the age of the animal when the deficiency develops, the duration of alpha-tocopherol deficiency, genetics of the individual and other concurrent dietary deficiencies or excesses. In many horses, there are no apparent ill effects of short-term alpha-tocopherol deficiency. Therefore, diagnosis of the neuromuscular disorders described below requires not only determination of alpha-tocopherol status, but also supporting clinical signs, histopathology and elimination of other possible diagnoses. There is no benefit to alpha tocopherol deficiency and there are potential long-term consequences to alpha tocopherol deficiency.
6. What are some diseases associated with vitamin E deficiency?
Nutritional myodegeneration Nutritional myodegeneration (NMD), also referred to as white muscle disease, affects skeletal or cardiac muscle of rapidly growing, active foals and is primarily due to a dietary deficiency of selenium beginning in the uterus. In some, but not all cases, there may also be a vitamin E deficiency. While vitamin E scavenges free radicals within the cell membrane to prevent the formation of damaging compounds, selenium acts to destroy already formed compounds by incorporating them into glutathione peroxidase.
Clinical signs in foals with NMD may include:
- Muscle weakness, difficulty rising, trembling of the limbs, and unable to stand
- Stiffness and firm painful muscles
- Pneumonia, difficulty breathing, foamy nasal discharge
- Rapid heart rate
- Sudden death
Diagnosis of foals with NMD may include elevated serum creatine kinase (CK) and aspartate transaminase (AST), whole blood selenium < 0.07 μg/ml and possible serum alpha-tocopherol < 2 μg/ml.
The cardiac form of NMD is usually not compatible with life. Foals with skeletal muscle disease often show significant improvement within 3 to 5 days of treatment with injectable selenium products as well as general supportive care. Additional oral alpha-tocopherol is suggested to quickly increase antioxidant levels (see below for dosages). Injectable selenium products containing 50 mg/ml (68 IU) of vitamin E as dl-alpha-tocopheryl acetate (all-rac-alpha-tocopheryl acetate) are insufficient for alpha-tocopherol supplementation because its presence at this dose only acts a preservative.
Neuroaxonal Dystrophy / Equine Degenerative Myeloencephalopathy Equine neuroaxonal dystrophy (eNAD) and equine degenerative myeloencephalopathy (EDM) are two closely related disorders distinguished largely by the region of nerve degeneration in the central nervous system. eNAD/EDM occurs in multiple breeds with most cases demonstrating clinical signs by six to twelve months of age. Although the pathophysiology is not completely defined, there is strong evidence of a genetic component that is highly influenced by alpha-tocopherol deficiency during the first year of life. Low serum alpha-tocopherol has been described in most, but not all, of affected foals. Clinical signs may include:
- Symmetric loss of body control (ataxia), which is often more severe in the rear limbs than the front limbs.
- An abnormal base-wide stance while resting, and the abnormal unconscious positioning of the limbs (proprioceptive deficits).
- Sometimes, below normal or lack of skin twitch reflexes occur in the neck, face and chest in addition to an absent laryngeal reflex.15
Diagnosis of eNAD/EDM before death is based on clinical signs, the elimination of other neurological diseases, and the association of low serum alpha-tocopherol concentration. A definitive diagnosis is only available upon histopathologic evaluation of spinal cord and brainstem tissues after death. There is no treatment for NAD/EDM and there have been no reports of spontaneous resolution.
Treatment of suspected eNAD/EDM cases is often accomplished empirically with alpha-tocopherol supplementation (see below for dosages). Unfortunately, strong evidence supports alpha-tocopherol supplementation of affected horses does not lead to neurologic improvement. Horses with NAD/EDM that survive to 2-3 years of age commonly exhibit lifelong, stable neurologic deficits. However, supplementation of dams during pregnancy may lead to decreased incidence of eNAD/EDM during the next foaling season.
For more information on eNAD/EDM: https://www.vetmed.ucdavis.edu/labs/finno-laboratory/equine-neuroaxonal-dystrophy-enad
Vitamin E responsive myopathy A subset of horses with alpha-tocopherol deficiency may develop clinical signs solely related to muscle wasting (atrophy) and weakness without evidence of damage to motor nerves. A wide variety of horse breeds have been diagnosed with vitamin E responsive myopathy (VEM). Whether VEM is an entity unto itself or a predecessor to development of equine motor neuron disease is not yet known.
Clinical signs in horses with VEM may include:
- Loss of muscle mass
- Toe dragging
- Poor performance
- Muscle twitching (fasciculations)
Diagnosis of this disease is based on the histopathologic finding of abnormal “moth-eaten” mitochondrial staining of fresh (not formalin-fixed) sacrocaudalis dorsalis muscle in the absence of neurogenic angular atrophy of muscle fibers. In many, but not all, serum alpha-tocopherol is low. To date, all affected cases have had below normal muscle alpha-tocopherol concentrations.
Treatment: Horses with VEM respond remarkably to alpha-tocopherol supplementation and can make a complete recovery.
Equine Motor Neuron Disease
Equine Motor Neuron Disease (EMND) is an acquired neurodegenerative disorder affecting motor nerves supplying highly oxidative type 1 muscle fibers. EMND is associated with low plasma concentrations of alpha-tocopherol and a dietary deficiency of alpha-tocopherol of at least 18 months duration.
Clinical signs in horses with EMND may include:
- Generalized muscle wasting
- Standing with fore and hindlimbs close together
- Muscle fasciculations
- Shifting of weight between hind-limbs
- Low head carriage
- Prolonged periods of laying down (recumbency)
Diagnosis prior to death is based upon either histopathologic evidence of the degeneration of myelinated axons (nerves) upon biopsy of the ventral branch of the spinal accessory nerve or the finding of neurogenic atrophy of predominantly type 1 muscle fibers in sacrocaudalis dorsalis medialis muscle biopsy.
Treatment: EMND is treated with 5000-7000 IU alpha-tocopherol per day. This is reported to produce clinical improvement in about 40% of cases within 6 weeks. Some horses may appear normal within 3 months of this treatment. It should be noted, however, that return to performance may result in deterioration. One study reports that approximately 40% of cases will stabilize, but remain permanently disfigured, while 20% will have continual progression of declining clinical signs.
7. WHAT TYPE OF VITAMIN E SUPPLEMENTS ARE AVALABLE?
The only equine vitamin E supplements currently available contain only alpha-tocopherol. Alpha-tocopherol can be obtained from natural or synthetic sources, but the chemical structure of each is different. Natural alpha-tocopherol is composed of one isomer (d-α-tocopherol [RRR α-tocopherol]), and it is the most bioactive form in animal tissues. Synthetic alpha-tocopherol is a mixture of eight isomers (dl-α-tocopherol [all-rac-α-tocopherol]), of which only one is identical to the natural isomer. These eight isomers vary greatly in relative biopotency. Furthermore, when synthetic or natural alpha-tocopherol is formulated as a feed additive, it is manufactured as an esterifed form (alpha-tocopherol acetate) to prolong shelf life. In order for alpha-tocopherol acetate to be utilized in the horse’s body, that ester has to be removed and the alpha-tocopherol made water-dispersible by the action of bile salts (micellization). These additional steps may limit alpha-tocopherol acetate absorption in horses. It is important to realize when interpreting studies that the absorption and metabolism of alpha-tocopherol in healthy horses may differ from the metabolism of alpha-tocopherol in deficient horses.
To account for differences in biopotency, the relative strengths for different forms of alpha-tocopherol are expressed as international units (IU) in which 1 mg of synthetic acetate equals 1 IU, 1 mg of natural acetate equals 1.36 IU, and 1 mg of natural alcohol equals 1.49 IU. Therefore, based on human and rodent studies (which may not apply to horses) relative to synthetic vitamin E (dl-α-tocopheryl acetate);
- Natural-source alpha-tocopherol acetate (d-α-tocopheryl acetate) is 1.97 times more potent.
- Natural-source alpha-tocopherol alcohol (d-α-tocopherol) is 2.52 times more potent.
- Water dispersible liquid formulations of alpha-tocopherol are about 6 times more bioavailable.
Water dispersible forms commercially available include:
Nano•E, Kentucky Equine Research, Versailles, KY Elevate WS, Kentucky Performance Products LLC, Versailles, KY Emcelle, Stewart Products, Bedford TX
8. What are current recommendations for supplementation?
Alpha-tocopherol deficiency: Natural-source water-dispersible forms of vitamin E at 10 IU/kg body weight is recommended based on biopotency. A 5000-IU dose/horse more than doubles serum vitamin E levels within 12 hours. It requires over a month to increase alpha-tocopherol to the normal range using natural-source powdered alpha-tocopheryl acetate.
Before implementing supplementation, it is important to measure serum alpha-tocopherol concentrations. Measuring the alpha-tocopherol will reveal an underlying deficiency and allow effective monitoring of supplementation. The National Research Council (NRC) has set the upper safe diet concentration at 20 IU/kg of body weight, which is based on biopotency of synthetic vitamin E (10,000 IU/500 kg horse). Above this level, blood clotting and impaired bone mineralization have been reported. Furthermore, in healthy exercising horses, high dosages of vitamin E supplementation (10x NRC requirements) was shown to be potentially detrimental to beta-carotene absorption and thus not recommended.
Healthy horses: Current NRC daily recommendations for vitamin E in horses are 1 -2 IU/kg body weight, however, these NRC recommendations do not discriminate between natural or synthetic sources. Research-based evidence proving the need for additional alpha-tocopherol supplementation above 500 IU/day is lacking in healthy young and middle-aged horses receiving adequate dietary vitamin E intake. Synthetic or natural esterified forms of alpha-tocopherol are the most cost-effective means to provide vitamin E to horses with normal alpha-tocopherol status. It is important to periodically check serum alpha-tocopherol concentrations. If an adequate response to supplementation does not occur, the dose or formulation of alpha-tocopherol should be altered accordingly.
FOR MORE INFORMATION PLEASE SEE;
Dr. Carrie Finno’s podcast with Q&A from audience members for the Horse Magazine : https://thehorse.com/188244/equine-essentials-the-importance-of-vitamin-e/
1. Mustacich DJ, Bruno RS, Traber MG. Vitamin E. Vitam Horm 2007;76:1-21.
2. Lindholm A, Piehl K. Fibre composition, enzyme activity and concentrations of metabolites and electrolytes in muscles of standardbred horses. Acta Vet Scand 1974;15:287-309.
3. Blythe LL, Craig AM. Degenerative Myeloencephalopathy In: Robinson NE, ed. Current Therapy in Equine Medicine. 3 ed. Philadelphia, PA: W.B. Saunders, 1992;559-561.
4. Craig AM. Antioxidants: Disease associated with deficiencies and therapeutic usages in equine practice, in Proceedings. 38th Am Assoc Equine Pract 1992;579-580.
5. Muirhead TL, Wichtel JJ, Stryhn H, et al. The selenium and vitamin E status of horses in Prince Edward Island. Can Vet J 2010;51:979-985.
6. Steiss JE, Traber MG, Williams MA, et al. Alpha tocopherol concentrations in clinically normal adult horses. Equine Vet J 1994;26:417-419.
7. Roneus BO, Hakkarainen RV, Lindholm CA, et al. Vitamin E requirements of adult Standardbred horses evaluated by tissue depletion and repletion. Equine Vet J 1986;18:50-58.
8. Pusterla N, Puschner B, Steidl S, et al. alpha-Tocopherol concentrations in equine serum and cerebrospinal fluid after vitamin E supplementation. Vet Rec 2010;166:366-368.
9. Higgins JK, Puschner B, Kass PH, et al. Assessment of vitamin E concentrations in serum and cerebrospinal fluid of horses following oral administration of vitamin E. Am J Vet Res 2008;69:785-790.
10. Divers T, Mohammed H, Hintz HF, et al. Equine motor neuron disease: a review of clinical and experimental studies. Clin Tech Equine Pract 2006;5:24-29.
11. Perkins G, Valberg SJ, Madigan JM, et al. Electrolyte disturbances in foals with severe rhabdomyolysis. J Vet Intern Med 1998;12:173-177.
12. Maylin GA, Rubin DS, Lein DH. Selenium and vitamin E in horses. Cornell Vet 1980;70:272-289.
13. Rotruck JT, Pope AL, Ganther HE, et al. Selenium: biochemical role as a component of glutathione peroxidase. Science 1973;179:588-590.
14. Valberg SJ. Diseases of Muscle In: Smith BP, ed. Large Animal Internal Medicine. 3rd ed. St. Louis: Mosby, 2002;1272-1273.
15. Mayhew IG, Brown CM, Stowe HD, et al. Equine degenerative myeloencephalopathy: a vitamin E deficiency that may be familial. J Vet Intern Med 1987;1:45-50.
16. Blythe LL, Craig AM. Equine Degenerative Myelencephalopathy: Part I. Clinical signs and pathogenesis. Comp Cont Educ Pract Vet 1992;14:1215-1221.
17. Dill SG, Correa MT, Erb HN, et al. Factors associated with the development of equine degenerative myeloencephalopathy. Am J Vet Res 1990;51:1300-1305.
18. Aleman M, Finno CJ, Higgins RJ, et al. Evaluation of epidemiological, clinical, and pathological features of neuroaxonal dystrophy in Quarter Horses. J Am Vet Med Assoc 2011;239:823-833.
19. Lekeux P, Kirschvink N. Antioxidants and Horse health In: Robinson NE, ed. Current Therapy in Equine Medicine. 6 ed. St. Louis, MO: Saunders, 2009;73-78.
20. Bedford H, Valberg SJ, Firshman A, et al. Reversible generalized muscle atrophy and weakness associated with sacrocaudalis dorsalis medialis myopathy and vitamin E (alpha-tocopherol) deficiency in horses. Am J Vet Med Assoc;In press.
21. Divers TJ, Mohammed HO, Cummings JF, et al. Equine motor neuron disease: findings in 28 horses and proposal of a pathophysiological mechanism for the disease. Equine Vet J 1994;26:409-415.
22. Divers TJ, Cummings JE, de Lahunta A, et al. Evaluation of the risk of motor neuron disease in horses fed a diet low in vitamin E and high in copper and iron. Am J Vet Res 2006;67:120-126.
23. Divers TJ, Valentine BA, Jackson CA, et al. Simple and practical muscle biopsy test for equine motor neuron disease, in Proceedings. 42nd Am Assoc Equine Pract 1996;180-181.
24. Jackson CA, De Lahunta A, Cummings JF, et al. Spinal accessory nerve biopsy as an antemortem diagnostic test for equine motor neuron disease. Equine Vet J 1996;28:215-219.
25. Divers T, De Lahunta A, Hintz HF, et al. Equine Motor Neuron Disease. Equine Vet Educ 2001;13:63-67.
26. Weber P, Bendich A, Machlin LJ. Vitamin E and human health: rationale for determining recommended intake levels. Nutrition 1997;13:450-460.
27. Acuff RV, Thedford SS, Hidiroglou NN, et al. Relative bioavailability of RRR- and all-rac-alpha-tocopheryl acetate in humans: studies using deuterated compounds. Am J Clin Nutr 1994;60:397-402.
28. Pagan JD, Lennox M, Perry L, et al. Form of α-tocopherol affects vitamin E bioavailability in Thoroughbred horses, in Proccedings. Nordic Feed Science Conference 2010;112-115.
29. Stewart RH, Rush BR. Cervical Vertebral Stenotic Myelopathy In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine. 2nd ed. St. Louis, MO: Saunders, 2004;594-598.
30. Orsini JA, Divers TJ. Manual of equine emergencies. 2nd ed. Philadelphia, PA: Saunders, 2003.
31. Bertone JJ. Equine Clinical Pharmacology. 1 ed. Philadelphia, PA: Saunders, 2004.
32. NRC. Nutrient Requirements of horses. 6 ed. Washington, D.C.: National Research Council, 2007.
33. Mustacich DJ, Vo AT, Elias VD, et al. Regulatory mechanisms to control tissue alpha-tocopherol. Free Radic Biol Med 2007;43:610-618.
34. Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 2002;23:687-702.
35. Williams CA, Carlucci SA. Oral vitamin E supplementation on oxidative stress, vitamin and antioxidant status in intensely exercised horses. Equine Vet J Suppl 2006:617-621.
36. Brown JC, Valberg SJ, Hogg M, Finno CJ. Effects of feeding two RRR-α-tocopherol formulations on serum, cerebrospinal fluid and muscle α-tocopherol concentrations in horses with subclinical vitamin E deficiency. Equine Vet J. 2017 Nov;49(6):753-758.
37. Bookbinder L, Finno CJ, Firshman AM, Katzman SA, Burns E, Peterson J, Dahlgren A, Ming-Whitfield B, Glessner S, Borer-Matsui A, Valberg SJ. Impact of alpha-tocopherol deficiency and supplementation on sacrocaudalis and gluteal muscle fiber histopathology and morphology in horses. J Vet Intern Med. 2019 Nov;33(6):2770-2779.