Horner syndrome (HS) (1-3) is classically described as a triad of clinical signs arising from disruption of sympathetic innervation to the eye and ipsilateral face that causes miosis, upper lid ptosis, mild elevation of the lower lid, and anhidrosis of the facial skin. Confirmation of a suspected clinical diagnosis of HS is made by pharmacologic testing of the pupils with cocaine, which will fail to dilate the pupil of an affected eye.
Cocaine is an indirect sympathomimetic agent that binds to monoamine NE transport proteins (4) on the sympathetic nerve endings in the iris, causing decreased re-uptake of NE from the synaptic junctions. Norepinephrine stimulates α1 receptors on the iris dilator muscle, causing contraction and an increase in pupil diameter. With complete sympathetic disruption, no dilation occurs because there is no tonic release of NE.
A plausible alternative to cocaine in the diagnosis of HS is apraclonidine (Iopidine; Alcon, Fort Worth, TX), a direct α-receptor agonist with strong α2 and weak α1 activity (5). In normal eyes, the α2 activity tends to down-regulate the production and release of NE. Patients with chronic reduction or elimination of NE in the synaptic junctions have denervation supersensitivity of the α1 receptors (6). When apraclonidine is applied to the eye, the up-regulated smooth muscle α1 receptors are directly activated by the medication, causing pupil dilation. The α2 receptors are also activated, but because there is little NE production and release, further inhibition does not decrease the pupil diameter.
We have reported the use of apraclonidine 1% (7) and 0.5% (8) to confirm the diagnosis of HS. In these studies, pupil diameters were first measured in bright and dim illumination to the nearest 0.5 mm using a pocket pupil card. Then apraclonidine was instilled, and the measurements were repeated 30 minutes later. Reversal of anisocoria occurred, that is, the HS pupil became larger than the normal pupil.
Here we report two additional HS cases confirmed with topical apraclonidine to show its practical applicability and to promote the development of a larger clinical trial.
A 37-year-old man underwent a cervical diskectomy for a C6-C7 disk herniation. He noted left upper lid ptosis beginning 2 weeks after surgery. The patient was examined by one of us (KAF) 5 months later. The left upper lid had 2 mm of ptosis. Under ordinary indoor illumination, the right pupil measured 4.0 mm and the left pupil 3.0 mm; in dim light the right pupil measured 6.0 mm and the left pupil 4.0 mm with obvious dilation lag (Fig. 1A). Apraclonidine 0.5% was instilled into both eyes. Approximately 30 minutes later, reversal of anisocoria occurred with the right pupil measuring 3.5 mm and the left pupil 5.0 mm (Fig. 1B). This test result confirmed the neurosurgeon's clinical diagnosis of HS.
A 5-year-old boy was noted at birth to have unequal pupil size with the left pupil smaller and an obvious difference in iris color. There was no history of birth trauma or difficulty moving the left arm in infancy. All findings were stable and the child's growth and development were normal. History regarding decreased sweating of the left forehead was unclear. The patient was referred to one of us (SMB) for a second opinion. Classic findings of congenital HS were present, including marked iris anisochromia (dark brown OD; light blue OS), anisocoria with the left pupil smaller (Fig. 2A), dilation lag of the left pupil, and increased anisocoria with reduced room illumination, left upper lid ptosis, and left lower lid elevation. After instillation of apraclonidine 0.5% into both eyes, the anisocoria reversed and the ptosis partially resolved (Fig. 2B).
Apraclonidine testing for HS is easily performed because this compound is a commercially available medication. The endpoint of testing is unequivocal and can be detected with the naked eye. Other clinical signs of denervation supersensitivity, such as resolution of ptosis, serve to increase the clinician's confidence in the result.
We have previously reported the effect of apraclonidine in HS patients (7,8) using both the 1% (N = 6) and 0.5% (N = 8) concentrations. Eleven cases were pharmacologically confirmed with cocaine (N = 4) or hydroxyamphetamine (N = 7); of these, 10 showed reversal of anisocoria in response to apraclonidine, yielding a sensitivity of 0.91 for the apraclonidine test against these two customary agents.
The disadvantages of cocaine as a test agent for HS are many. Cocaine is a weak dilator of the pupil. In many instances, the normal (control) pupil will not dilate at all (9), raising doubts about the potency of the solution. Cocaine cannot diagnose a partial HS in which NE release is reduced but not eliminated; blocking reuptake may still cause pupil dilation. The drops sting when instilled. Because of its use as an illegal recreational drug, patients are often understandably wary of receiving cocaine in any form; urine metabolites are detectable after systemic absorption of ophthalmic solutions. Because it is a controlled substance, cocaine is difficult to obtain, and because of its short shelf-life, the solution must be compounded for each individual patient.
If apraclonidine does not cause reversal of anisocoria in a patient with strong clinical attributes of HS, the clinician may proceed to cocaine testing despite the practical difficulties. Because the apraclonidine test is primarily based on denervation supersensitivity, a false-negative result may occur in a very recently acquired HS because the α1 receptors have not yet up-regulated. Presumably in an acute complete HS, the cocaine test would more likely be positive.
The relatively low frequency of HS in the general population makes a more extensive study of the sensitivity and specificity of the apraclonidine test difficult. However, the increasing cost and difficulty associated with obtaining cocaine and hydroxyamphetamine might make a multicenter study worthwhile.
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