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Are We Ready to Replace Cocaine With Apraclonidine in the Pharmacologic Diagnosis of Horner Syndrome?

Kardon, Randy MD, PhD

Journal of Neuro-Ophthalmology: June 2005 - Volume 25 - Issue 2 - p 69-70
doi: 10.1097/01.wno.0000172602.10008.18

Neuro-ophthalmology Division, Department of Ophthalmology and Visual Sciences, University of Iowa and Veterans Administration Hospital, Iowa City, Iowa.

Address correspondence to Randy H. Kardon, MD, PhD, University of Iowa, Department of Neuro-Ophthalmology, 200 Hawkins Drive, Iowa City, IA 52242; E-mail:

In this issue of the Journal of Neuro-Ophthalmology, Freedman and Brown have presented two cases of Horner syndrome, adding to their two previously reported series of six (1) and eight (2) cases in which the diagnosis of oculosympathetic defect was pharmacologically confirmed using topical 0.5% apraclonidine in place of cocaine. Thirty minutes after apraclonidine, the miotic eye with the oculosympathetic defect dilated and the anisocoria reversed in all but one patient.

As a result of these findings, the authors have proposed that apraclonidine be considered a viable alternative to cocaine for pharmacologic confirmation of Horner syndrome. If topical apraclonidine is found to be as sensitive and specific as cocaine in differentiating Horner syndrome from other causes of anisocoria, then it should replace cocaine, which is expensive, not readily available in most doctors' offices, and, as a controlled substance, must be kept under lock and key.

Finally, apraclonidine has an advantage over cocaine in that it will actively dilate the affected eye and not the normal eye, making its action a positive (mydriatic) one in the affected eye rather than a negative one in the affected eye and a positive (mydriatic) one in the unaffected eye, as this is the case with cocaine testing.

As an alpha-2 adrenergic agonist, apraclonidine has been used to lower intraocular pressure after YAG laser treatment. Stimulation of the presynaptic alpha-2 receptor is thought to inhibit release of norepinephrine and reduce aqueous production. In one study (1), apraclonidine 1% had the same pressure-lowering effect in the affected eye of six patients with Horner syndrome as it did in the contralateral eye. During that study, the authors noticed an unexpected mydriatic effect in the eyes with Horner syndrome. This effect is attributed to the drug's weak alpha-1 agonist property, which acts on the denervated, supersensitive iris dilator muscle. Apraclonidine did not appear to cause any significant effect on the pupil of the unaffected eye.

Unlike phenylephrine, whose corneal penetration varies widely among individuals, apraclonidine readily penetrates the cornea and gains access to the iris, so the limiting factor to its mydriatic effect is whether alpha-1 supersensitivity is present in the iris dilator muscle. As early as 1989, the mydriatic effect of topical clonidine in Horner syndrome patients was described in the German literature (3). Apraclonidine has potential advantages over phenylephrine not only in its ease of corneal penetration but also in the fact that it does not need to be diluted. The advantage of apraclonidine over alpha-1 mydriatics, like epinephrine and phenylephrine, used in the past to diagnose Horner syndrome, is that its alpha-1 activity is relatively weak and will not dilate the normal pupil. In a reasonably high concentration (0.5%), apraclonidine will penetrate the cornea and arrive at the alpha-1 receptors of the iris dilator muscle. Strong alpha-1 mydriatics like epinephrine and phenylephrine had to bediluted to the point at which they barely made it through the cornea, and this made them work for some people and not for others.

Should we make the switch from cocaine to apraclonidine? Before doing so, we need more rigorous data to help answer some critical questions. For example, we do not know whether all interruptions of sympathetic outflow cause alpha-1 supersensitivity at the iris dilator muscle, which is required for apraclonidine to have its mydriatic effect, and whether some normal eyes will dilate when exposed to apraclonidine. Also, we do not know how long it takes for significant supersensitivity to develop.

A major concern relates to whether all tumors or carotid dissections will cause supersensitivity at the end organ. And if so, how long does it take for enough supersensitivity to develop to allow apraclonidine to have a significant mydriatic effect? Cocaine will confirm an oculosympathetic defect as long as there is diminished release of catecholamine from any cause at the iris neuromuscular junction in the affected eye. Unlike cocaine, apraclonidine depends on supersensitivity. If supersensitivity does not develop promptly, then theoretically apraclonidine may have a negligible mydriatic effect in the presence of a compressive lesion. In the 2003 case study by the authors (2), one patient out of eight had negligible apraclonidine reversal of anisocoria and had an oculosympathetic defect of unknown cause of 9 years' duration. A second patient had only a small change in anisocoria after apraclonidine. In this patient, Horner syndrome had been present for 4 months. This was the only patient in the series with a compressive lesion (a cervical goiter). In another study quoted by the authors (4), supersensitivity to 1% phenylephrine was found in 10 (71%) of 14 patients with Horner syndrome. Four patients did not show significant mydriasis compared with normal controls.

In Loewenfeld's encyclopedic text on the pupil (5), she indicates two mechanisms by which supersensitivity develops. In the first, there is loss of the ability to terminate the adrenergic response because of degeneration of the postganglionic neuron, which normally provides a presynaptic re-uptake mechanism. This creates an “apparent” supersensitivity caused by the prolonged action of any sympathomimetic agonist. In the second-and more important-mechanism, supersensitivity is caused by receptor upregulation, also called “true” supersensitivity. Loewenfeld provides evidence that disuse or pharmacologic blockade of sympathetic impulses can result in true supersensitivity even without actual pre-ganglionic or post-ganglionic nerve fiber loss. One would thus expect apraclonidine to cause mydriasis in compressive lesions, providing that the decrease in sympathetic firing is severe enough and of long enough duration.

The preliminary results of apraclonidine testing for Horner syndrome appear promising in this context. I recently administered the test to two patients with Horner syndrome caused by compressive lesions and monitored their responses using infrared videography and computerized pupillometry. The reversal of anisocoria was unequivocal, making me cautiously optimistic about the applicability of this agent in the diagnosis of Horner syndrome. We must now perform pharmacologic testing of a larger number of patients with anisocoria caused by Horner syndrome and other causes (including physiologic) in different age groups, using apraclonidine on 1 day and cocaine 1 week later. Such a study would help answer concerns about the sensitivity and specificity of apraclonidine in diagnosing oculosympathetic deficits compared with the previous gold standard of cocaine testing (6).

Freedman and Brown and their colleagues in Lubbock deserve great credit for bringing this potentially useful effect of apraclonidine to the attention of the medical community. Such a study should also include pediatric patients, since apraclonidine has also been recently reported in the diagnosis of childhood Horner syndrome (7).

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© 2005 Lippincott Williams & Wilkins, Inc.