Neuroaxonal Dystrophy/Equine Degenerative Myeloencephalopathy
Robert J. MacKay
■ History and Epidemiology Since the original description in 1976, neuroaxonal dystrophy (NAD)1 and the related condition equine degenerative myeloencephalopathy (EDM)2 have been reported throughout the world in horses and ponies of many different breeds and in other equids, including a donkey, Przewalski's Horses, and zebras.3-6 The clinical signs of NAD and EDM are identical, and the associated CNS lesions are thought to be on a continuum wherein EDM lesions are more widely distributed than are those of NAD.3,4 For the rest of this section, the condition is referred to as NAD/EDM.
Clinical signs usually begin within the first year of life: with only a few reported exceptions, all have begun by the age of 3 years.7 A hereditary basis for the condition has been strongly suggested by the results of breeding studies or pedigree analyses in Morgan, Appaloosa, Quarter Horse, and Lusitano horses.4,8,9 The mode of inheritance is suspected to be poly- 4 5 8 10 genic or autosomal dominant with variable penetrance.4,5,8, A familial basis has also been suspected because of clustering of cases among the progeny of particular Standardbreds, Paso Finos, Norwegian Fjord horses, Arabians, Welsh ponies, and Haflingers.6,11
Overcrowding, pelleted feed, poor-quality hay, and lack of access to fresh green forage were thought to be risk factors on two affected premises.12 In another study, significant risk factors were exposure to insecticides/repellents, exposure to wood preservatives such as creosote, and time spent on dirt lots.7 Time spent on green pasture was a protective factor. In contrast, several clusters of cases in Oregon and California occurred in horses on pasture.6,9 In the latter instance, the pasture was growing on volcanic soil that was deficient in selenium and vitamin E.6
With rare exceptions,7,13 NAD/EDM is consistently associated with marginal or low serum/plasma vitamin E concentration.
Published normal ranges of α-tocopherol vary with age, location, season, diet, and use; however, a commonly accepted scheme classifies results greater than 2 μg∕mL as normal, 1.5 to 2 μg∕mL as marginal, and less than 1.5 μg∕mL as deficient.12,14 Healthy horses sharing feedstuffs and environment with affected horses usually also have low levels of vitamin E,5,15 although foals in an Appaloosa family with hereditary NAD/EDM had significantly lower plasma vitamin E than did age-matched normal pasturemates,15 and Quarter Horse foals that developed NAD/EDM had significantly lower CSF vitamin E concentrations than did heathy foals maintained on the same vitamin E-deficient diet.5■ Cause and Pathogenesis NAD/EDM most closely resembles ataxia with vitamin E deficiency of humans and other animals.4,6,14 The neuroprotective effects of vitamin E are related to inhibition of oxidation of CNS membrane lipids and facilitation of axonal transport of macromolecules.14 Direct support for the antioxidant role of vitamin E in horse CNS is provided by the results of global transcriptome analyses of affected and normal spinal cords that suggest a protective role for vitamin E in preventing accumulation of oxidized cholesterol (oxysterol) in the setting of lipid peroxidation and demylina- tion.16 Although familial isolated vitamin E deficiency of humans is caused by mutations in the α-tocopherol transfer protein gene, expression of the messenger RNA of this gene was similar between one unaffected horse and two horses with NAD/ EDM from a group of related Quarter Horse weanlings and yearlings.6 Low serum levels of vitamin E in horses with NAD/ EDM is not explained by impaired intestinal absorption: oral vitamin E tolerance tests were normal in affected horses.15
■ Clinical Signs NAD/EDM is characterized by an acute, occasionally insidious-onset, symmetric ataxia and paresis of the trunk and limbs.
Clinical signs typically appear between the ages of 1 and 12 months but have occurred in neonates and mature horses.3,4 Posture and gait are wide based, and affected limbs demonstrate notable hypometria (spasticity). Signs are typically considerably more severe in the pelvic limbs, and the thoracic limbs may be clinically normal. In two reports, it was noted that limb weakness was observed only in horses with moderate or severe ataxia and was not recognized in many horses that were mildly ataxic.4,6 Some horses with NAD/EDM adopt a two-beat lateral (“pacing”) gait at walking speed. Long spinal reflexes such as the cervicofacial, laryngeal adductor (slap), and cutaneous trunci reflexes may be reduced or absent, especially in long-standing cases. Neurogenic muscle atrophy is not characteristic of NAD/EDM, and cases were reported in horses with body condition scores of 5 to 6 out of 9.4,6 Signs of brain dysfunction were not reported until the early 2010s. Of 88 Quarter Horses with NAD/EDM (NAD), 77 were described as dull or obtunded and minimally responsive to light flashes, sudden movement, or loud noises.6 An EEG obtained from one affected horse revealed dominant states of drowsiness to slow-wave sleep. Reduced or absent menace responses were noted in 33 of the 88 Quarter Horses and in 4 of 6 Lusitanos with NAD/EDM.4,6 Vision, pupillary light reflexes, ophthalmologic examination findings, and electro- retinograms were normal.Signs may not worsen after initial onset; others progress for days to months before stabilizing. Only rarely does the condition progress to recumbency.
■ Laboratory Findings There is no antemortem diagnostic test for NAD/EDM. Plasma/serum vitamin E concentrations of NAD/EDM horses and pasturemates are often marginal or low. Because vitamin E concentrations within individual horses vary considerably over time (especially if they are low), it is recommended that three blood samples be taken over the course of 24 hours.14,15 Samples must not be visibly hemolyzed and should be stored so that the blood is not in contact with the rubber stopper.
Plasma CK and AST activities may be slightly to moderately high because of increased recumbency.9■ Diagnosis Diagnosis during life is presumptive only and is made primarily by suggestive signalment and clinical signs with exclusion of competing diagnoses. NAD/EDM should be suspected in horses with symmetric limb ataxia that began within the first year of life and for which results of standard neurologic workups (cervical vertebral radiographs, CSF analysis, immunoassay for S. neurona antibody) have not implicated another diagnosis. Low or marginal serum/plasma vitamin E concentration (≤2 pg/mL) is supportive of the diagnosis.
■ Necropsy Findings Necropsy reveals no abnormal gross findings. Histologic changes develop in the spinal cord and brainstem.4,6,9,13 Lesions in the lateral and medical cuneate, gracilis, and thoracic nuclei are characterized by spheroid formation with vacuolation, loss of somata, astrogliosis, and lipofuscin pigment accumulation. In addition, axonal necrosis and demyelination of the dorsal and ventral spinocerebellar tracts, the cuneocerebellar tracts, and and the ventromedial funiculi of the cervicothoracic spinal cord may be present. Calretinin immunohistochemical staining was used to show that the cell bodies of degenerated axons in NAD/EDM-affected horses probably are located in the dorsal root ganglia.17 No histologic lesions were found to explain observations of dull mentation18 and abnormal menace responses4,6 in reported case series.
■ Treatment and Prevention It is unlikely that NAD/ EDM can be cured even if treated early. Slight to no improvement was observed in affected horses given vitamin E supplements of 2000 to 8000 IU daily.9,12 The type of vitamin E and the method of supplementation have important effects on its bioavailability. Natural vitamin E (RRR-α-tocopherol) is up to twofold more active than synthetic vitamin E (d,l-α-tocopherol or all-rac-α-tocopherol). Absorption requires fat, and so bioavailability of vitamin E is negligible or low unless it is given with feed or vegetable oil.
In accordance with the notion that NAD/EDM is associated with some interaction between inherited metabolic defect and vitamin E deficiency, vitamin E supplementation appears to be at least partially effective prophylaxis and is recommended in circumstances that involve familial predisposition, processed feed, lack of access to pasture, and exposure to insecticides or wood preservatives. In one study, the incidence of NAD/EDM was reduced from 36% over 3 years to 9% by supplementation of foals with 1500 IU vitamin E daily.12 Similar results were observed in two other clusters of cases.6,12 Sensible genetic, nutritional, and other management practices alone could greatly reduce or eliminate the risk of NAD/EDM.