Abstract
Case Description—A 6-year-old 680-kg (1,496-lb) German Warmblood gelding was evaluated because of bilateral blepharospasm and head shaking.
Clinical Findings—Moderate blepharospasm was evident bilaterally, and both eyes had hyperemic and edematous conjunctivas and lusterless corneas. For each eye, the Schirmer tear test value was only 7 mm/min. The horse's nasal mucosa was dry. Abnormal behaviors included mild repetitive vertical movement of the head, snorting, and flehmen response (classic signs of head shaking). Touching the horse's nostrils and face revealed paresthesia and dysesthesia with slight nasolabial muscle hypertrophy bilaterally. Cranial nerve examination revealed no other abnormalities. Serum thyroxine concentration was low, and results of thyrotropin-releasing hormone and thyroid-stimulating hormone stimulation tests were negative, indicating that the horse had hypothyroidism. The diagnoses included keratoconjunctivitis sicca and dry nares attributable to parasympathetic facial nerve dysfunction, head-shaking syndrome with paresthesia and dysesthesia of the face attributable to sensory trigeminal nerve disorder, and hypothyroidism. The 2 nerve dysfunctions were considered peripheral neuropathies that were most likely caused by hypothyroidism.
Treatment and Outcome—Treatment of both eyes was initiated with topical applications of cyclosporine, 0.5% sodium hyaluronate, and vitamin A ointment. Levothyroxine (20 Pg/kg [9.1 Pg/lb], PO, q 24 h) was administered. Within 3 weeks to 4 months, serum thyroxine concentration was within reference range, and clinical signs and Schirmer tear test values improved.
Clinical Relevance—Hypothyroidism should be considered as a differential diagnosis in horses with peripheral neuropathy or keratoconjunctivitis sicca. In affected horses, administration of levothyroxine may lead to resolution of neurologic signs.
A 6-year-old German (Saxon) Warmblood gelding was brought to the University of Veterinary Medicine Vienna for an ophthalmologic examination. The horse had a 7-month history of bilateral blepharospasm. At the same time as the blepharospasm developed, the owner noticed that the horse started head shaking during exercise and when at rest; the frequencies with which the horse snorted and displayed flehmen increased, and it was reluctant to be touched or groomed on the face, especially around the nose.
At the time of admission, a physical examination revealed that the horse (a heavy-type Warmblood) was overweight (680 kg [1,496 lb]) and had a marked regional fat deposit over the crest of the neck. A complete ophthalmologic examination including direct and indirect ophthalmoscopy, slit-lamp biomicroscopy, and cranial nerve examination was performed. Findings were considered normal except for moderate blepharospasm of both eyes (the left eye being more affected than the right eye), bilateral hyperemic and edematous conjunctivas, and lusterless corneas (Figure 1). Schirmer tear testsa were performed on both eyes to assess the aqueous component of the tear film. The test value was only 7 mm/min for each eye. Given that Schirmer tear test values ≤ 10 mm/min are indicative of poor production of the aqueous component of the tear film,1,2 tear production in this horse was considered insufficient bilaterally. Examination of the horse's nostrils revealed that the nasal mucosa was dry. After it was placed in a box stall, the horse demonstrated the behavior that the owner had described. It began mild repetitive, vertical movement of the head, snorting, and displaying a flehmen response, which were consistent with classic signs of head shaking.3 Touching the horse's nostrils and face revealed paresthesia and dysesthesia, and there was slight hypertrophy of the nasolabial muscle bilaterally. No other abnormalities were detected during the cranial nerve examination.
Photograph of the left eye of a 6-year-old German Warmblood gelding with KCS attributable to hypothyroidism-associated parasympathetic facial nerve dysfunction. Notice the hyperemic and edematous conjunctiva and lusterless cornea.
Citation: Journal of the American Veterinary Medical Association 233, 11; 10.2460/javma.233.11.1761
At this time, the diagnoses were bilateral KCS and dry nasal mucous membranes, head-shaking syndrome with snorting and flehmen responses, and paresthesia and dysesthesia of the face. Possible causes were considered. Keratoconjunctivitis sicca develops because of tear film deficiency or desiccation of the cornea.1,2 Diseases that result in reduced or absent eyelid closure lead to evaporative dry eye syndrome; possible causes of eyelid dysfunction include ptosis caused by facial nerve paralysis, loss of corneal sensation, or other ocular surface diseases.1,2 Tear production can be reduced because of disease of or damage to the lacrimal gland or neurogenic dysfunction of the parasympathetic fibers of the facial nerve. Diseases of the lacrimal gland can be inflammatory (eg, granulomatous dacryoadenitis associated with habronemiasis or Thelazia lacrimalis infection)2,4,5 or neoplastic (eg, squamous cell carcinoma)2,4 or may result from direct trauma to the lacrimal gland.4 Other possible causes include exposure to toxins (eg, locoweed poisoning) or chemicals, which can damage the lacrimal glands directly.2,6,7 However, immune-mediated lacrimal gland adenitis, drug-induced decreased tear production, and congenital lacrimal gland hypoplasia in horses apparently have not been reported.2,6
Facial nerve dysfunction that induces KCS can be caused by diseases of the facial nerve or adjacent structures; these include intracranial disease (eg, equine protozoal meningoencephalitis), inner or middle ear disease, disease of the auditory tube diverticula (guttural pouches), parotid gland disease, periorbital myositis or cellulitis, dental abscess, and peripheral nerve trauma (eg, postanesthetic complications associated with positioning or head collar–associated damage).2,8 The main etiology of KCS in horses appears to be trauma that causes damage to the facial nerve, in particular fracture of the mandible, basilar bone (ie, the basisphenoid and basioccipital bones), petrous temporal bone, or stylohyoid bone.4,9–11 In horses with these types of fracture, facial paralysis with drooping of the ear and upper eyelid is typically described9–11; 1 horse with KCS that had no signs of facial paralysis had a history suggestive of a basilar skull fracture.11 Temporohyoid osteoarthropathy, which often leads to fusion of the temporohyoid joint and predisposes horses to fractures of petrous temporal or stylohyoid bone, is reported to cause facial nerve paralysis.12
Given the numerous possible causes of the horse's clinical signs, further investigations were undertaken. Trauma and the effects of toxins (especially toxic plants) and chemicals were excluded on the basis of information obtained from the owner. Ophthalmologic examination findings ruled out evaporative eye syndrome and diseases of the lacrimal gland. A lack of other clinical findings excluded a basilar skull fracture, vestibular disease (inner and middle ear disease), mandibular fracture, and petrous temporal bone fracture. Radiography of the head (lateral, dorsoventral, and oblique views) and endoscopy of the upper airways (including the guttural pouches) revealed no abnormalities; therefore, fractures as well as temporohyoid osteoarthropathy and guttural pouch diseases that might cause damage to the facial nerve were excluded from consideration. Endoscopy of the lower portions of the respiratory tract airway revealed only a subclinical recurrent airway obstruction. Results of clinicopathologic analyses were within reference range values (serum concentrations of triglycerides and cholesterol were not assessed).
To assess the horse's thyroid gland function, the serum concentration of T4 was measured by use of a competitive ELISA.b The serum T4 concentration was < 12.9 nmol/L (reference range, 17 to 53 nmol/L). Measurements were repeated at various time points throughout the day, but values never exceeded 12.9 nmol/L. To determine whether the horse had hypothyroidism, a TRH stimulation test was performed, as previously described.13 Blood samples were obtained via jugular venipuncture immediately before (baseline) and 2 and 4 hours after IV administration of 1 mg of TRH.c The baseline serum T4 concentration as well as the values measured 2 and 4 hours after TRH administration were < 12.9 nmol/L. To substantiate the diagnosis of hypothyroidism, a TSH stimulation test was performed, as previously described.14 Five units of bovine TSHd were administered IV; blood samples were collected 1 minute before and 2, 4, and 6 hours after TSH administration. At all time points, serum T4 concentration was less than the lower limit of the reference range and remained < 12.9 nmol/L. Results of the TSH-stimulation test confirmed the inability of the thyroid gland to react to hormonal stimulation. To rule out other endocrinologic problems, ACTH activity and cortisol concentration in serum were measured. Serum ACTH activity was measured by use of a validated competitive ELISAb and was < 10 pg/mL (reference range, 20 to 50 pg/mL). Serum cortisol concentration was quantified by use of a competitive ELISAb 6 times over successive days and at different times of day; the value was consistently < 1.00 μg/dL (reference range, 2.00 to 8.50 μg/dL). Ultrasonographic evaluation of the thyroid gland by use of 7.5-MHz linear and 5-MHz curvilinear transducers revealed a large thyroid gland lobe (1.6 × 2.1 × 3.3 cm) on the right side and a slightly smaller lobe on the left side of the proximal portion of the trachea. Compared with the ultrasonographic appearance of the thyroid gland of a clinically normal horse, the thyroid gland parenchyma in the affected horse appeared hypoechoic, and the lobulation seemed reduced; those findings also supported the diagnosis of hypothyroidism. An ECG was performed, and the findings were unremarkable.
To determine whether the hypothyroidism was autoimmune in origin, serum was analyzed for antithyroglobulin, anti-triiodothyronine, and anti-T4 autoantibodies. A serum sample from the horse underwent western blot analysis with equine thyroglobulin and thyrocyte-lysate, but no reaction indicative of autoantibodies against thyroid hormones was detected.
On the basis of the clinical findings, the diagnoses included KCS and dry nares attributable to parasympathetic facial nerve dysfunction, head-shaking syndrome with paresthesia and dysesthesia of the face attributable to sensory trigeminal nerve disorder, and hypothyroidism. The 2 nerve dysfunctions were considered as peripheral neuropathies that were most likely caused by hypothyroidism.
Eye treatment was initiated with topical application of cyclosporine ointmente (5-mm-long strip in lower eyelid, q 12 h) to reduce conjunctival inflammation and any secondary inflammation of the lacrimal gland. Because the underlying cause was not adenitis, the value of this treatment was questionable. Sodium hyaluronate ophthalmic dropsf (1 drop, q 4 h) and vitamin A ointmentg (5-mm-long strip in lower eyelid, q 12 h) were used as lubricants and protectants for the cornea. Levothyroxine sodiumh (a synthetic thyroid hormone; 20 μg/kg [9.1 μg/lb]) was administered orally once daily.14 Because of the long duration of clinical signs, a guarded prognosis was given regarding the resolution of neurologic signs.
The horse was referred back to the local veterinarian, who consented to seek advice when other drugs should be needed; it was also recommended that NSAIDs or glucocorticoids should not be administered at the same time as L-T4. The owner was advised to administer the thyroid hormone medication to the horse in the morning approximately 30 minutes before it ate its grain meal because humans take thyroid hormone medication immediately after awakening and 30 minutes prior to eating. Also, it is known that fiber and bran products as well as calcium-containing antacids can inhibit intestinal absorption.15
In horses treated with L-T4, it is recommend that serum T4 concentrations are maintained close to or within reference range values.15 Therefore, serum T4 concentration was measured after the horse had been treated with L-T4 for 3 weeks. The value was 38.5 nmol/L. Not only was the serum T4 concentration within the reference range (17 to 53 nmol/L), but also it was considered in the therapeutic range because the value was in the upper half of the reference range. Measurement of serum TSH concentration was not advised because the value decreases with administration of L-T4 and also varies widely among horses and among sample collection times.15
After 3 weeks of treatment with L-T4, the owner reported that the horse had undergone weight reduction and a change in behavior. At an examination performed by the local veterinarian 4 months after the referral evaluation, Schirmer tear test values were 13 mm/min in the left eye and 16 mm/min in the right eye. The episodes of snorting and flehmen display ceased later. The blepharospasm resolved after 5 months of L-T4 administration, although the owner noticed intermittent serous nasal discharge. During a telephone conversation with the owner 6 months after diagnosis, it was reported that the supply of ophthalmologic drugs had been exhausted, after which only gentamycin eye ointment was occasionally topically applied as antimicrobial agent if ocular mucopurulent discharge was apparent. Twelve months after starting the L-T4 treatment, the horse had none of the clinical signs for which it was initially evaluated.
Discussion
In horses, as in other animals, the ophthalmic branch of the trigeminal nerve provides the sensory supply to the eye and lacrimal gland.1 The lacrimal gland, which releases serous secretion, is innervated by sympathetic and parasympathetic nerve fibers from the lacrimal branch of the facial nerve.16 Keratoconjunctivitis sicca with neurogenic etiology is the most common cause of reduced tear production in horses.1,4,6,9–11 In 2 case reports9,10 of horses with KCS attributable to neurogenic dysfunction of the facial nerve caused by trauma, the patients also had motor dysfunction. In one of these cases, no Schirmer tear test was performed.10 In another horse with KCS, there were no apparent clinical signs of facial paralysis, but the horse had a history of falling over backward followed by bilateral epistaxis, which suggested the presence of a basilar skull fracture; however, radiography was not performed to confirm this theory.11
In the horse of this report, facial nerve motor function was not affected, and the horse was able to close its eyelids and did not have any other signs of facial paralysis. Because the horse had bilateral KCS and no signs of facial paralysis or head tilt, all disorders resulting from lesions to the preganglionic parasympathetic fibers proximal to the geniculate ganglion (eg, otitis media or interna) that result in vestibular disease17 were ruled out. Also lesions affecting the pterygopalatine ganglion itself (eg, periorbital myositis, cellulitis, salivary gland disease, and dental abscess16) were ruled out on the basis of physical examination findings. Other abnormalities (temporohyoid osteoarthropathy or inner and middle ear inflammation) and fractures (mandible, stylohyoid bone, petrous temporal bone, or basilar skull) as well as guttural pouch disease were ruled out not only because of the lack of other clinical signs but also because of findings of the endoscopic and radiographic examinations of the horse's head. Equine protozoal meningoencephalitis, polyneuritis equi, or intracranial diseases were considered unlikely on the basis of the absence of associated clinical signs and the fact that the horse had never been outside Austria and Germany. In this horse, the neuropathy had to be located within the autonomic system (ie, the parasympathetic branch of the facial nerve) and—taking the head shaking into account—the sensory trigeminal nerve.
In general, causes of peripheral neuropathy are inflammatory, infectious, immune-mediated, degenerative, neoplastic, inherited, traumatic, and metabolic or toxic disorders. With regard to horses, little is known about the causes of peripheral neuropathy other than trauma. An endocrinopathy involving thyroid gland function was believed to be a possible cause of disease in the horse of this report.
In humans and dogs, peripheral neuropathy caused by hypothyroidism is a relatively rare but well-documented disorder.18–23 In dogs, cranial neuropathy, including facial paralysis, peripheral vestibular disease, trigeminal dysfunction, and laryngeal paralysis, has been reported.18,20,22,24,25 Keratoconjunctivitis sicca in association with hypothyroidism and facial neuropathy has been identified in at least 1 dog.26 In a report25 of the prevalence of hypothyroidism in dogs with KCS, it is suggested that as many as 20% of KCS-affected dogs may have hypothyroidism. Results of another study27 indicated that tear production in 12 dogs with hypothyroidism was significantly decreased, compared with findings in 100 unaffected control dogs. In a report24 of a study of 66 dogs with hypothyroidism, facial neuropathy and KCS are described as common clinical signs. To the authors' knowledge, KCS caused by hypothyroidism-induced peripheral neuropathy of parasympathetic nerve fibers of the facial nerve and hypothyroidism-induced neuropathy of the sensory trigeminal nerve in horses has not been reported.
The clinical signs in the horse of this report were indicative of mild KCS. Severe signs such as excessive mucopurulent ocular discharge, nonspecific vascular keratitis, and corneal edema and ulceration were absent. The horse was treated on the basis of the signs of KCS, and applications of mucolytic agents (eg, acetylcysteine) and antimicrobial agents that are usually recommended for treatment of corneal ulcers6 were not necessary. Because the KCS improved within a few months after initiation of L-T4 administration, there was no need for additional treatments such as occlusion of the nasolacrimal puncta, temporary or permanent tarsorrhaphy, or parotid duct transposition that have been used in horses with more chronic or persistent KCS.4,28
Hypothyroidism in adult horses is a rare condition, and the prevalence of the condition is unknown.13,29 In a study30 of 125 horses in New Zealand, low serum T4 concentrations were detected in 35 horses; however, results of TRH stimulation tests did not support a diagnosis of hypothyroidism in any of those horses. The clinical signs of thyroidectomized horses are lethargy, low exercise tolerance, and poor coat quality.14,29 The affected horse in this report was overweight and had a cresty neck. These signs could be attributed to the type of horse and may not necessarily be associated with hypothyroidism. A poor coat quality was not evident at the initial examination. It is reported that clinical signs in horses with naturally occurring hypothyroidism are more subtle and vague than those in experimentally thyroidectomized horses.14,29 Horses in which hypothyroidism is induced through administration of propylthiouracil are reported to develop no clinical signs.29 Clinical examination, ECG, and clinicopathologic analyses revealed that the horse of this report did not have low basal heart rate, respiratory rate, rectal temperature, and PCV (ie, anemia) as are detected in horses from which the thyroid glands have been surgically removed.14,29 To the authors' knowledge, there are no reports of thyroidectomized or propylthiouraciltreated horses with ocular or neurologic signs.
Because hypothyroidism alters lipid metabolism and because increased serum concentrations of triglycerides and cholesterol are detected in horses after thyroidectomy, it would have been interesting to have assessed these values in the horse of this report; however, these variables were not assessed at the time of admission.
The release of TSH from the pituitary gland is pulsatile, and a circadian rhythm has been detected.14 There is diurnal variation in plasma thyroxine concentration in horses,14,31 and single measurements of serum T4 concentration are difficult to interpret, especially because thyroid hormone metabolism and transport can be affected by a variety of causes.32 Therefore, in the horse of this report, the serum T4 measurements were repeated at several time points throughout the day. Multiple extrathyroidal factors (eg, drugs such as antimicrobials, furosemide, heparin, phenobarbitone, and steroidal and nonsteroidal antiphlogistics) can cause decreases in circulating concentrations of thyroid hormones,31,33 but these were ruled out. Nonthyroidal illness syndrome (sick euthyroidism) has been described in humans and dogs34,35 and also may develop in horses.13,30 In systemic illnesses, serum thyroid hormone concentrations are thought to decrease as a result of hypothalamic-pituitary gland dysregulation.14 A systemic disease was not evident in the affected horse of this report. Other causes of decreased thyroid gland function (eg, short-term food deprivation, alterations in diet, and dietary imbalances) were not relevant in this case. Assessments of thyroid hormone responses to administration of TRH or TSH generally are considered to be the most reliable diagnostic tests currently available for use in horses.32 The diagnosis of hypothyroidism in the horse of this report was substantiated by the lack of increases in serum T4 concentration following challenge with TRH and TSH.
In humans, measurement of serum TSH concentration is a highly sensitive and accurate means of diagnosing hypothyroidism. Through assessment of the hypothalamic-pituitary-thyroid axis, it is possible to differentiate between hypothyroid and euthyroid sick syndrome, and to provide data on which to base an accurate diagnosis. In 18% to 38% of dogs with hypothyroidism, serum TSH measurements are within reference range, and as many as 14% of euthyroid dogs have increased serum TSH concentrations.36 In healthy horses, baseline serum concentrations of TSH vary greatly, but assessments of this variable may be useful in the diagnosis of hypothyroidism once reference values become available.15,32 Ultrasonographically, the thyroid gland lobes of hypothyroid dogs are typically reduced in size and volume and the thyroid parenchyma has decreased echogenicity, compared with findings in clinically normal dogs.37,38 Similar abnormal features were detected in the horse of this report; however, we are not aware of any reports describing the ultrasonographic appearance of the thyroid gland in horses with hypothyroidism.
To further evaluate the horse of this report, scintigraphic examination and biopsy of the thyroid gland would have been useful diagnostic procedures. Scintigraphy could not be performed and a biopsy specimen of the thyroid gland was not obtained because the lobes of the gland were small and were located directly adjacent to the carotid artery.
The possibility that the horse's hypothyroidism had an autoimmune-mediated cause was considered. However, results of western blot analysis of serum from this horse provided no evidence for the role of autoimmune antibodies against the thyroid hormones. Pars intermedia dysfunction was ruled out on the basis of the horse's low serum ACTH activity. Serum cortisol concentration in the affected horse was low, but a dexamethasone-suppression test was not performed. Therefore, polyglandular failure involving the thyroid and adrenal glands may have been ongoing in this horse. In humans and dogs, such a type 2 polyendocrinopathy (Schmidt syndrome) is thought to be an autoimmune disease.39,40 Because the horse was negative for thyroid hormonespecific autoantibodies, polyglandular failure is not a likely diagnosis. No further diagnostic evaluations were performed to rule out equine metabolic syndrome because, other than the apparent cresty neck, the horse had no clinical signs suggestive of this syndrome.
The signs of peripheral neuropathy in this horse with hypothyroidism were similar to those detected in humans and dogs with hypothyroidism. The pathogenesis of peripheral metabolic mono- or polyneuropathy associated with hypothyroidism is not completely understood. One theory is that reduced mitochondrial activity results in a lack of ATP, thereby causing a decrease in Na+-K+ pump activity with a subsequent reduction in axonal transport velocity.41,42 A second possible cause is thought to be myxedema formation in peripheral nerves followed by secondary compression.43 In humans, deposition of mucopolysaccharide-protein complexes within the endoneurium and perineurium as well as dystrophic and degenerative changes in axons and marked reduction of myelin has been reported.44 In dogs with hypothyroidism and neurologic dysfunction, hyperlipemia with concurrent atherosclerosis and thromboembolic events is also thought to play a role.45 In dogs, administration of thyroid hormone medication results in resolution of neurologic abnormalities.18,20,22
In the horse of this report, there was no evidence of another disease condition that could account for the clinical signs. Because the neurologic signs resolved 5 months after the start of treatment with L-T4, we believe that this horse had peripheral neuropathy attributable to hypothyroidism.
ABBREVIATIONS
| KCS | Keratoconjunctivitis sicca |
| L-T4 | Levothyroxine |
| STT | Schirmer tear test |
| T4 | Thyroxine |
| TRH | Thyrotropin-releasing hormone |
| TSH | Thyroid-stimulating hormone |
STT, Essex Pharma GmbH, Munich, Germany.
Immulite, DPC Bühlmann, Salzburg, Austria.
Protirelin (Relefact), Aventis Pharma, Vienna, Austria.
Thyrotropic hormone, Sigma Aldrich, St Louis, Mo.
Optimmune, Essex Pharma GmbH, Munich, Germany.
Na-hyaluronate 0.5%, Croma Pharma GmbH, Korneuburg, Austria.
Vit-A-POS, Ursapharm GmbH, Saarbrücken, Germany.
Levothyroxine, Sandoz, Kundl, Austria.
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