Diagnostic Ophthalmology

History and clinical signs

A 9-year-old neutered male, Shetland sheepdog was referred to the ophthalmology service at the Western College of Veterinary Medicine with left enophthalmos, miosis, ptosis, and third eyelid prolapse, and anisocoria (Figure 1). The referring veterinarian had tentatively diagnosed anterior uveitis. The menace responses, and the direct and consensual pupillary light reflexes, palpebral, and oculocephalic reflexes were present in both eyes. The left pupil was smaller than the right and the anisocoria was substantially worse in scotopic conditions. Schirmer tear tests (Schirmer Tear Test Strips; Alcon Canada, Mississauga, Ontario) were 27 and 25 mm/min in the right and left eyes, respectively. The intraocular pressures were estimated with a rebound tonometer (Tonovet; Tiolat Oy, Helsinki, Finland), and were 13 and 8 mmHg in the right and left eyes, respectively. Topical ophthalmic tropicamide (Mydriacyl; Alcon Canada, Mississauga, Ontario) was applied to both corneas and the right pupil dilated completely within 20 min. The left pupil dilated minimally (1 to 2 mm) and remained at mid-sized at 30 min. Biomicroscopic (Osram 64222; Carl Zeiss Canada, Don Mills, Ontario) and indirect ophthalmoscopic (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) examinations were completed. Abnormalities were limited to incipient nuclear cataracts and the anisocoria. Fluorescein stain (Fluorets; Bausch & Lomb Canada, Markham, Ontario) was applied and rinsed from the corneal surfaces and the eyes were examined under cobalt filtered light; staining was not evident.

Figure 1.

This 9-year-old male Shetland sheepdog with left eye enophthalmos, third eyelid prolapse, ptosis, and anisocoria. The dog is actively tilting its head during the photo, there was no neurological head tilt.

What are your clinical diagnoses, diagnostic and therapeutic plans, and prognosis?

Discussion

Our tentative clinical diagnoses were left Horner’s syndrome and bilateral incipient nuclear cataracts. The latter are common incidental findings in many dog breeds. The cataracts do not progress and the prognosis for retention of vision is excellent. Horner’s syndrome should be considered in all animals with an anisocoria in which both pupils constrict after light stimulation, and the anisocoria worsens in scotopic conditions. However, ptosis, enophthalmos, and third eyelid prolapse are common non-specific accompanying signs that are also found when uveitis and keratitis are present.

To confirm the diagnosis of left Horner’s syndrome additional diagnostic tests are required. The gold standard test for diagnosing Horner’s syndrome in humans is lack of dilatation of the affected pupil in response to topical cocaine (1), with dilatation of the normal pupil. Cocaine blocks the norepinephrine reuptake at the neuromuscular junctions of the iris dilator muscle. With Horner’s syndrome norepinephrine is not released from the pre-synapse and therefore does not accumulate in the neuromuscular junction and does not stimulate mydriasis of the iris dilator muscle. In contrast, the normal pupil will dilate and the anisocoria worsens which confirms the diagnosis of Horner’s syndrome. Topical ophthalmic cocaine was not available at the time of presentation of this case and is seldom used in veterinary ophthalmology. Aproclonidine (weak α-₁ agonist) will stimulate the iris dilator muscle in the Horner-affected eye that is adrenergic hypersensitive and it will reverse the anisocoria and also confirm some cases of Horner’s syndrome (2,3). Aproclonidine was not available at the time of examination of this dog so additional diagnostic testing was not completed.

The subtle dilation of the left pupil with tropicamide was considered typical of Horner’s syndrome based on our experience. This parasympatholytic agent blocks the parasympathetic portion of the oculomotor nerve and in Horner’s cases the pupil will dilate slightly as the parasympathetic tone is removed (pupillary escape) and the anisocoria lessens, which in this case was approximately 1 to 2 mm. The slight dilatation also facilitates the important biomicroscopic and indirect ophthlamoscopic examinations. The lack of biomicroscopic and indirect ophthalmoscopic evidence of uveitis, or keratitis in this dog, further supported the tentative clinical diagnosis of Horner’s syndrome. We scheduled the dog for an adrenergic response test to confirm and localize the lesion responsible for Horner’s syndrome (4,5).

Two days later the anisocoria was present and the reexamination without topical tropicamide was similar to that noted on the initial examination. A topical 0.1% solution of phenylephrine was prepared and 1 drop was placed on the right and left pupils and the time was noted. Within 20 min (Figure 2) the signs within the left eye (enophthalmos, third eyelid prolapse, and miosis) dissipated. The right pupil did not react to this dilute adrenergic and remained responsive to light and mobile, while the left pupil hyper-responded and dilated indicating a post-ganglionic or third order Horner’s lesion. The hyper-response develops approximately 1 mo after lesion development due to denervation hypersensitivity in the postsynaptic neuromuscular junction, which occurs as a compensatory change.

Figure 2.

The same dog as noted in Figure 1, 18 min after 0.1% phenylephrine had been applied to both eyes. The left pupil is dilated and only a mild left ptosis remains.

Post-ganglionic lesions are the most common form of Horner’s syndrome in dogs that we diagnose (6), and the prognosis is excellent (7–10). The clinical signs of Horner’s syndrome (miosis, ptosis, and enophthalmos) will usually resolve spontaneously within a few months; further diagnostic evaluations are not required for third order Horner’s syndrome.

Horner’s syndrome is the most common neuro-ophthalmologic condition diagnosed in animals in our practice. Horner’s syndrome was first reported by John Reid at Saint Andrews in 1839 approximately 3 decades before Johann Friedrich Horner reported the condition which bears his name (11). This neurologic syndrome develops secondary to a lack of sympathetic innervation to the eye (10). Inflammatory, traumatic, or neoplastic lesions can occur at any point in the long pathway from the hypothalamus through the cervical and thoracic spinal cord (first order neuron) to the spinal cord segments T1–T3 (12), through the mediastinum cranially with the vagus nerve up the ventral cervical area (second order neuron) where it separates and synapses with the cranial cervical ganglion near the tympanic bulla (8,13). Then the post-ganglionic fibers course on towards the globe (third order neuron) and lesions here induce the signs of post-ganglionic Horner’s syndrome (6,14).

Although topical ocular cocaine is the topical diagnostic test of choice to confirm Horner’s syndrome it is rarely reported or completed in domestic animals related to the availability, control, and regulations surrounding storage and use of this potent medication. We photograph the eyes and pupils of dogs with a tentative diagnosis of Horner’s syndrome pre- and post-dilatation and during lesion localization. We recommend a thorough biomicroscopic and indirect ophthalmoscopic examination after attempted pupillary dilatation with topical tropicamide to exclude keratitis and uveitis as differential diagnoses. Finally, we recommend lesion localization and additional diagnostic tests a few days later. Horner localization should begin with a very dilute topical application of 0.1% phenylephrine to the affected and control eye. The dilute adrenergic will have no effect on the pupil of the normal eye and a peak effect on post-ganglionic Horner’s of at least 3-weeks duration will be pupillary dilatation and loss of enophthalmos and third eyelid prolapse within 20 min. This response confirms post-ganglionic Horner’s (third order) related to a denervation hypersensitivity in the post-synaptic neuromuscular junction. Post-ganglionic Horner’s syndrome in dogs is often idiopathic and is hypothesized to develop secondary to inflammation in the region of the tympanic bullae (otitis media), while second order Horner’s syndrome develops most commonly due to cervical trauma (needle sticks during jugular sampling or other cervical traumas or thoracic/mediastinal neoplasia or inflammatory conditions). Second order Horner cases are localized by topical application of 10% phenylephrine and a response within 40 min will confirm this lesion. Rarely in our experience do we see first order Horner’s syndrome which is associated with cervical and cranial neoplasms and inflammatory conditions (8,12). These lesions require sectional imaging and additional diagnostic evaluations to confirm and prognosticate.

Post-ganglionic Horner’s syndrome usually requires no additional diagnostic tests and signs usually resolve within weeks; quite often only a mild residual ptosis will remain. In contrast, pre-ganglionic and central forms of Horner’s syndrome require further diagnostic testing to establish the etiology and appropriate surgical or medical therapy. The prognosis varies greatly depending on the etiology.