equine degenerative myeloencephalopathy


migration disorder


neuroaxonal dystrophy

A 5-month-old Pony of the Americas colt presented to Oklahoma State University's Boren Veterinary Medical Teaching Hospital with a history of neurologic signs present since birth. The foal's condition had deteriorated to a point where rising from recumbency required the owner's assistance. The colt was born full term to a multiparous mare. The dam's previous foals were normal, and none shared the same sire as this colt. The birth was unattended, but was known to have occurred within a 1-hour period of time. The foal was found recumbent but with normal mentation. It was unable to stand and nurse within an appropriate timeframe, so the owner bottle-fed colostrum from the dam.

The local veterinarian examined the foal and presumed birth asphyxia as a cause of the developmental delay. The owner continued supportive care at home, and the foal improved, standing with assistance on day 2, and walking without help on day 3. Despite this progress, the foal was never able to obtain proper head position to nurse. The owner continued bottle feedings, initially with mare's milk, then with a combination of goat's milk and a commercial mare's milk replacer. The foal showed persistent neurologic signs over the next few months, including stumbling and abnormal head carriage. The owner also described behavior she considered atypical for a foal, including a lack of fear or “flight response” when confronted with loud, moving objects such as farm equipment that caused other foals to flee.

On presentation, the foal was in good flesh with a body condition score of 5/9. Vital parameters were within normal limits. A small amount of mucopurulent, bilateral nasal discharge was noted. Neurologic examination showed grade 3–4/5 ataxia and dysmetria affecting all 4 limbs. The pelvic limbs appeared more severely affected, and hoof placement was consistently wide based. The foal's head carriage was abnormal, consistently tilted to either side. Frequent changes of head position from one side to the other involved wide, swinging movements as well as more subtle tremors as the head crossed the midline of the foal's body. Pendular nystagmus was also observed.

Numerous causes of neurologic disease in foals have been documented. This foal's clinical presentation was consistent with cerebellar abiotrophy or hypoplasia, but this condition typically is seen in Arabians. Occipital-atlanto-axial malformation and equine degenerative myeloencephalopathy (EDM) commonly present in foals of this age but do not characteristically include signs of cerebellar dysfunction. Hepatoencephalopathy may be seen in foals with portosystemic shunts but onset often is around the time of weaning, and abnormal neurologic signs may be cyclical rather than persistent. Other possible causes for this foal's signs included unobserved trauma, toxins ingested by the mare during pregnancy, intracranial abscessation, and parasitic migration to the central nervous system.

A CBC and serum biochemistry were unremarkable, making a metabolic cause less likely. Computed tomography of the brain and skull were within normal limits, ruling out an underlying structural anomaly, space-occupying lesion, or gross traumatic injury. The dam had grazed from the same pasture with previous pregnancies, as had other mares. The congenital nature of the foal's condition and the lack of an apparent structural or metabolic cause suggested primary central nervous system disease and likely a poor prognosis. The foal was euthanized at that time because of ongoing clinical deterioration. Vitamin E and selenium concentrations and thyroid hormone concentration were not evaluated.

Gross examination was unremarkable. Microscopic examination identified neuroaxonal dystrophy (NAD) in the brainstem gray matter, characterized by spheroids in the reticular formation, lateral cuneate nucleus, chief sensory nucleus of the trigeminal nerve in the dorsal pons, and the spinal trigeminal ganglia more caudal in the brainstem and medulla (Fig 1a and b). A prominent external granular cell layer was noted in the cerebellum (Fig 2a and b). The presence of both NAD and clinical signs of cerebellar dysfunction in this foal was unique among reported cases of equine neurologic disease. The clinical relevance of the prominent external granular cell layer initially was uncertain.


Figure 1.  (a) Histopathology of the foal's brainstem showing multiple axonal spheroids. H&E stain. Scale bar = 200 μm. 789 × 682 mm (96 × 96 DPI). (b) High power photomicrograph of axonal spheroids shown in (a). H&E stain. Scale bar = 100 μm. 177 × 133 mm (432 × 432 DPI).

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Figure 2.  (a) Prominent external granular cell layer evident in the foal's cerebellum. H&E stain. Scale bar = 500 μm. 177 × 123 mm (432 × 432 DPI). (b) High power photomicrograph showing the prominent external granular cell layer evident in the foal's cerebellum. H&E stain. Scale bar = 100 μm. 177 × 147 mm (432 × 432 DPI).

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NADs are a diverse group of diseases that present with variable clinical signs and pathologic lesions in many species. The defining characteristic is the histopathologic presence of “axonal spheroids” representing areas of localized axonal swelling, along with distal axonal atrophy and secondary alterations in myelin.1,2 NADs have been reported in humans,2 companion animals,3,4 domestic large animals,5,6 and wildlife species.7,8 Autosomal recessive heredity is reported in humans with some forms of NAD,2 but although familial tendencies are observed in animal species, a distinct pattern of simple inheritance has not been found.4,9,10

A single, definitive etiology of the NAD remains elusive. A genetic mutation in humans has been associated with at least 3 childhood NADs. The resultant enzyme defect is thought to cause dysregulation of phosphatidylcholine concentrations in cell membranes, subsequent structural and functional abnormalities, and possibly dysregulation of apoptosis.11 An association with low concentrations of α-tocopherol has been made both in clinical12–14 and research settings.15 Diverse metabolic, structural, or functional abnormalities may manifest themselves as a common pathologic lesion.

Traditionally, equine neuroaxonal dystrophy (END) has been diagnosed in cases in which spheroid lesions are primarily limited to the brainstem, most commonly the cuneate nuclei.6 The condition has been reported in several breeds, including Quarter Horses,16 Morgans,9 and Haflingers,12 with familial tendencies observed in the latter 2 breeds.

EDM is a related disorder currently defined as NAD with the additional presence of clinically relevant lesions in the spinal cord. The condition was first described in 8 related zebra foals.17 Subsequent reports described similar findings in 5 horses (2 of which were related) and 1 zebra,18 and in 5 young Quarter Horses.19 Familial occurrence was prominent in other reports involving Appaloosas,14 Standardbreds, and Paso Finos.10

Efforts to determine a common underlying cause of EDM have been unrewarding and at times conflicting. Copper deficiency as occurs in similar neurodegenerative diseases in other species was not found in 25 horses with EDM,20 nor was deficiency of serum vitamin E or blood glutathione peroxidase concentrations in 40 horses with histologically confirmed EDM.21 Risk factors associated with EDM as determined by 1 client survey included insecticide use on foals, exposure of foals to wood preservatives, time on dirt lots, and a previous EDM foal from the dam. Time on grass pasture was protective.22 Other studies have shown coexistence of a familial tendency toward disease and vitamin E deficiency suggestive of a hereditary disorder of vitamin E metabolism that is not malabsorptive in etiology.10,14,23 Abnormal expression of synaptic proteins in dystrophic axons in 2 Arabians suggested dysregulation of axonal transport as a possible etiology.24

Our patient differs from those previously described with equine NAD and EDM because of the presence of clinical signs consistent with cerebellar disease, most notably head tremor. In all reports of NAD and EDM cited above, neurologic signs consisted of pelvic limb and sometimes thoracic limb ataxia, with histopathologic lesions limited to the brainstem and spinal cord. Cerebellar signs frequently occur in humans with infantile NAD, and also in affected cats and dogs, with cerebellar lesions that typically are reported to be atrophic or dystrophic in nature.3,4,25

Pendular nystagmus was also a prominent clinical feature in our case. Pendular nystagmus is frequently present in children with infantile NAD, and is reported to be the 1st indication of disease in a subset of this group.25 The foal's apparent lack of responsiveness to auditory stimuli raises the possibility of auditory involvement, variably reported in humans and cats.3 Brainstem auditory evoked response testing would have helped to confirm or refute this suspicion, but unfortunately this diagnostic tool was not available at the time.

The clinical relevance of the prominent external granular layer in this foal is difficult to interpret because of lack of published research on the age of completion for external granular cell migration in the horse.

Migration disorders (MDs) are another multifaceted, complex group of diseases resulting from failure of embryologic neuronal cells to migrate properly to their final location. Genetic mutations have been identified as a cause of human MDs, along with external factors including early maternal hypothyroxinemia and cocaine use.26 Ethanol has been shown to affect external granular cell migration, and is a component of fetal alcohol syndrome in children.27 A murine model of neonatal cytomegalovirus infection, a cause of central nervous system disease in children, produced delayed external granular cell migration,28 and disruption of external granular cell migration is a feature of in utero parvovirus infection in cats.29 Disorders of matrix metalloproteinases are also being investigated as a cause of disrupted migration.30

Existing literature suggests that cerebellar development of precocious neonates is more advanced at birth than in those who do not walk for a longer period of time. In 1 study, the external granular layer of a foal at birth was only 2–3 cells thick.31 A postmortem study showed a single cell layer similar to the external granular layer in horses up to 8 years old.32 A dissertation study demonstrated a nearly absent external granular layer in the cerebellar cortex of prenatal (14 days before calculated due date) foal fetuses.33 To attempt further clarification, we examined cerebella from 5 age-matched controls that were necropsied for clinical complaints not involving the central nervous system. Although 2 foals had no visible evidence of an external granular layer, and 2 exhibited multifocal remnants, 1 foal had a conspicuous layer similar to the foal in this report. Thus, migration of external granular cells is highly variable relative to age in the horse, and a correlation between cerebellar dysfunction and a prominent external granular layer in this foal cannot be made. Notably, MDs as a specific cause of cerebellar signs have not been documented in foals; reported cerebellar disease includes abiotrophy, characterized by Purkinje cell degeneration.34

The presence of spheroids in the granular layer has been reported in companion animals with NAD and clinical signs of cerebellar disease,4 and some forms of human NAD frequently involve cerebellar lesions, commonly atrophy.2 An early, functional lesion may have existed in this foal's cerebellum but may not have progressed to an extent that would result in the histopathologic presence of characteristic spheroids. A similar theory has been proposed to explain the presence of pelvic limb ataxia in horses with lesions limited to the lateral cuneate nucleus, which typically is associated with proprioception of the neck.6

The coexistence of NAD and clinical signs of cerebellar disease is a unique finding in this foal. ENDs rarely encompass a broader spectrum of clinical findings as is the case with human and companion animal NADs. NADs or other developmental brain diseases therefore should be included in the differential diagnosis of foals or young horses presenting with signs of cerebellar disease.


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