Ocular Effects of Apraclonidine in Horner Syndrome

CLINICAL SCIENCES Ocular Effects of Apraclonidine in Horner Syndrome

Jose Morales, MD; Sandra M. Brown, MD; Aziz S. Abdul-Rahim, MD; Craig E. Crosson, PhD

Objective: To determine the location of action of apra- this difference was not statistically significant. The av- clonidine, an ␣-adrenergic receptor agonist that re- erage baseline PDs for affected and normal eyes were 3.2 duces aqueous production and lowers intraocular pres- mm and 4.2 mm, respectively. Instillation of apracloni- sure (IOP). dine into affected eyes produced mydriasis of 1.0 to 4.5 mm; baseline anisocoria reversed in all patients. There Methods: The study cohort consisted of 6 patients with was no significant change in the PD of normal eyes after Horner syndrome (decreased or absent sympathetic in- ipsilateral instillation of apraclonidine. nervation of 1 eye). We instilled 1% apraclonidine into the affected eye, and the changes in IOP and pupil di- Conclusions: Apraclonidine’s major site of pharmaco- ameter (PD) of both eyes were measured over 4 hours. logic action for reduction of aqueous production is on In a separate session, apraclonidine was instilled into the postjunctional ␣2 receptors in the ciliary body. The up- normal eye and the measurements were repeated. regulation of ␣ receptors that occurs with sympathetic denervation unmasks apraclonidine’s ␣1 effect, which clini- Results: The average baseline IOP was 16.3 mm Hg cally causes pupil dilation. Apraclonidine may be a useful for affected eyes and 16.7 mm Hg for normal eyes. The medication for the diagnosis of Horner syndrome. average maximum ipsilateral reduction in IOP was 5.8 mm Hg in affected eyes and 5.2 mm Hg in normal eyes; Arch Ophthalmol. 2000;118:951-954

PRACLONIDINE (Iopidine; also provide an opportunity for the evalu- Alcon, Fort Worth, Tex) is ation of the ␣1 effect, without the influ- an adrenergic receptor ence of normal sympathetic tone. Our agonist that is approved for study examines the change in IOP and pu- the treatment of elevated pil diameter (PD) after instillation of 1% intraocular pressure (IOP) following ar- apraclonidine in the affected and normal A 1 gon laser trabeculoplasty. It lowers IOP eyes of patients with HS. primarily by reducing aqueous produc- 2 tion through its effect on ␣2 receptors. RESULTS Apraclonidine’s ␣1 activity does not affect aqueous production, but it causes the The baseline IOPs for affected and nor- conjunctival vasoconstriction often noted mal eyes were 16.3 ± 1.5 and 16.7 ± 1.0 with its use. Although several ␣2 agonists mm Hg, respectively. Figure 1 shows the are used clinically as ocular hypotensive IOP response to unilateral apraclonidine agents, their site(s) of action is not com- administration. Apraclonidine produced pletely understood. Animal studies have a significant reduction in ipsilateral IOP provided evidence that ␣2 agonists can in both affected and normal eyes. The lower IOP by acting on prejunctional and maximum reductions for affected and postjunctional receptors in the eye as well normal eyes were 5.8 ± 1.0 and 5.2 ± 0.8 From the Department of as on ␣2 receptors in the central nervous mm Hg, respectively. In contrast, a sig- Ophthalmology and Visual system.3-5 nificant contralateral reduction in IOP was Sciences, Texas Tech University Patients with Horner syndrome (HS) observed only in normal eyes. Health Sciences Center, Lubbock. Dr Crosson is (disruption of sympathetic innervation to The average baseline PDs for af- currently affiliated with the the eye and adnexa) provide a unique op- fected and normal eyes with room lights Medical University of South portunity to study the relative contribu- on were 3.2 mm and 4.2 mm, respec- Carolina, Storm Eye Institute, tions of the peripheral and central ac- tively. Figure 2 shows the PD response Charleston. tions of ␣2 agonists in lowering IOP. They following apraclonidine administration. In

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16 Eleven patients with unilateral HS were identified from the records of the study facility between 1989 and

1994. Six agreed to participate in the investigation, 14 which was approved by the institutional review board. ∗ The diagnosis of HS was made on clinical grounds mm Hg IOP, alone if the patient had ptosis of no more than 2 mm, ∗ ∗ ∗ ipsilateral miosis, and ipsilateral dilation lag to sud- 12 ∗ den darkness.6 Horner sydrome was confirmed in pa- ∗ ∗ tient 6, who had more than 2 mm of ptosis, when the ipsilateral miotic pupil failed to dilate after instilla- 10 tion of 1 drop of 10% cocaine. Instillation of 1% hy- droxyamphetamine was used to localize HS as ei- 18 B ther preganglionic or postganglionic in 5 of the 6 patients. In patient 3, localization was presumed to be postganglionic because of intact facial sweating and 16 an established diagnosis of cluster headaches. Two patients had preganglionic lesions and 4 had postganglionic lesions. 14 Testing with apraclonidine was divided into 2 sessions. In session 1, baseline pupil diameter mea- mm Hg IOP, ∗ sured in normal room illumination and with room ∗ 12 lights off and IOP by Goldmann applanation were recorded for each eye. Pupil diameter was determined to the nearest 0.5 mm using the pupil gauge on the 10 Rosenbaum pocket vision screener. One drop of 1% 01 234 apraclonidine was applied to the eye with HS. Pupil- Time, h lary and IOP measurements were repeated at 1, 2, 3, and 4 hours after instillation. During session 2 on a Figure 1. Intraocular pressure (IOP) response vs time after instillation of 1 drop of 1% apraclonidine into 1 eye. A, Ipsilateral IOP response. separate day, the same data were recorded; how- B, Contralateral IOP response. HS indicates Horner syndrome; asterisk, ever, apraclonidine was instilled into the normal eye. PՅ.05. The 2 sessions were separated by 4 to 11 days. For analysis of IOP and PD data, eyes with both preganglionic and postganglionic HS lesions were flow is greatly reduced with preganglionic lesions, there grouped as “affected eyes,” owing to the low num- is still a small, tonic release of norepinephrine from the ber of patients with preganglionic HS lesions iden- intact postganglionic nerve terminals into the junc- tified. Values were expressed as means and SEs. Data tional spaces of the ciliary epithelium. In contrast, le- from affected eyes were compared with those from sions that affect the postganglionic efferent neurons from normal eyes by means of the paired t test. PՅ.05 was the superior cervical ganglion cause total depletion of nor- considered significant. epinephrine at the target tissues. Associated with the reduced or absent sympathetic drive is an up-regulation of postjunctional ␣ receptors in the eye and ocular adnexa. 7 the HS eyes, the administration of apraclonidine pro- Ocular ␣2 receptors exist prejunctionally on the duced a rapid increase in ipsilateral PD of 1.0 to 4.5 mm sympathetic nerve terminals and postjunctionally7 on the (Table). This increase in PD was maintained through- ciliary epithelium and the trabecular meshwork cells.8 In out the 4-hour study period, and a reversal of the base- addition, ␣2 receptors are present on nerve fibers of the line anisocoria was observed in all subjects. In contrast, sympathetic chain in the central nervous system.5 In post- the administration of apraclonidine to the normal eyes ganglionic HS, prejunctional ␣2 receptors are absent. Be- did not significantly alter ipsilateral PD at any time point. cause 1% apraclonidine caused an equal decrease in IOP No significant contralateral response was observed for in normal eyes and in eyes with postganglionic HS, the either eye. A representative patient is shown in Figure 3. activation of postjunctional ␣2 receptors is sufficient to account for apraclonidine’s affect on IOP. The small con- COMMENT tralateral response measured in normal eyes but not in affected eyes suggests that the activation of prejunc- Horner syndrome is caused by interruption of the serial tional or central receptors can also lower IOP to a small 3-neuron sympathetic outflow path to the eye and ad- extent. nexa. Lesions that affect the neurons that travel from the Apraclonidine can also stimulate ␣1 adrenergic re- brainstem to the spine, or from the spine to the superior ceptors. The most pronounced clinical effect in normal cervical ganglion, are termed preganglionic. Lesions that patients is conjunctival vasoconstriction. A finding of this affect efferent fibers from the superior cervical ganglion study was that 1 drop of 1% apraclonidine dilated the ab- are termed postganglionic. Although sympathetic out- normal miotic pupil of the patients with HS, often dra-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 matically. This response was seen in eyes with pregan- in normally innervated eyes, 1% apraclonidine pro- glionic or postganglionic lesions. In control eyes, mydriasis duces little or no pupil dilation. Paradoxically, Jampel of 0.5 mm was noted in only 1 patient at 1 time point. et al11 noted miosis in response to 0.25% apraclonidine. Others have investigated the effects of apraclonidine on This may be due to selective activation of prejunctional the pupils of patients with ocular hypertension and of ␣2 receptors at lower concentrations, leading to de- normal volunteers. In some reports, dilation of approxi- creased release of norepinephrine; this effect would be mately 0.5 mm was observed in a small proportion of the more pronounced in individuals with greater resting sym- subjects1,9-12 while in other studies13,14 no significant di- pathetic tone and absent in patients with HS. We postu- lation was observed. Our results confirm the finding that late that the mydriatic response we observed in eyes with HS was due to denervation supersensitivity of the ␣1 receptors on the iris dilator muscle, as has been demon- Normal Eyes HS Eyes 7 A strated with epinephrine bitartrate and phenylephrine hydrochloride.15,16 ∗ Observation of the pupils in our small series of pa- 6 ∗ ∗ ∗ tients leads us to propose that reversal of anisocoria after simultaneous instillation of 1 drop of 1% apracloni- 5 A

4 Pupil Diameter, mm Pupil Diameter,

2 B 7 B

5 C

4 Pupil Diameter, mm Pupil Diameter,

Figure 3. All photographs were taken with room lights on. A, The patient 2 01 234at baseline, showing left ptosis and miosis; note the incidental elevated Time, h left upper eyelid fold consistent with levator aponeurosis dehiscence. B, Forty-five minutes after instillation of 10% cocaine to each eye. Failure of Figure 2. Pupil diameter (PD) response vs time after instillation of 1 drop of the left pupil to dilate indicates Horner syndrome. C, Several weeks later, 1% apraclonidine into 1 eye. A, Ipsilateral PD response. B, Contralateral PD appearance 1 hour after instillation of 1 drop of 1% apraclonidine to the left response. HS indicates Horner syndrome; asterisk, PՅ.05. eye. Note reversal of baseline anisocoria.

Pupil Size at Baseline and 1 Hour After Instillation of 1% Apraclonidine to the Affected Eye of Patients With HS

Pupil size, mm

Baseline After Apraclonidine Ambient Patient Laterality Location Illumination RLRL 1 L Postganglionic Dk 6.0 5.0 6.0 8.0 Lt 4.0 3.0 4.0 6.0 2 R Preganglionic Dk 5.0 5.0 6.0 5.0 Lt 3.5 4.0 5.0 4.0 3 R Postganglionic Dk 3.0 4.5 5.5 4.5 Lt 3.0 4.0 5.0 4.0 4 L Postganglionic Dk 6.0 5.0 5.0 8.0 Lt 3.5 2.5 3.0 7.0 5 L Preganglionic Dk 5.5 8.0 9.0 7.5 Lt 4.0 6.5 7.5 4.5 6 L Postganglionic Dk 5.5 4.0 4.5 8.0 Lt 3.5 3.0 3.0 6.5

*HS indicates Horner syndrome; R, right eye; L, left eye; Dk, room lights off; and Lt, room lights on.

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 dine in both eyes of a patient with possible HS may be a REFERENCES sensitive and specific test for this disorder. Topical 5% or 10% cocaine has been the standard medication for the 1. Robin AL. Short-term effects of unilateral 1% apraclonidine therapy. Arch Oph- 16-18 pharmacologic diagnosis of HS for decades. Co- thalmol. 1988;106:912-915. caine, a narcotic, is a controlled substance that must be 2. Maus TL, Nau C, Brubaker RF. Comparison of the early effects of brimonidine and apraclonidine as topical ocular hypotensive agents. Arch Ophthalmol. 1999; prepared by individual pharmacies for local use. Topi- 117:586-591. cal apraclonidine has an advantage in that it is readily 3. Burke J, Crosson C, Potter D. Can UK-14, 304-18 lower IOP in rabbits by a pe- available and widely used, most commonly for the pre- ripheral mechanism? Curr Eye Res. 1989;8:547-552. 4. Potter DE, Crosson CE, Heath AR, Ogidigben MJ. Review: alpha 2 and DA2 ago- vention of IOP elevation after laser capsulotomy. Addi- nists as antiglaucoma agents: comparative pharmacology and clinical potential. tional studies comparing the sensitivity and specificity J Ocul Pharmacol. 1990;6:251-257. 5. Campbell WR, Potter DE. Centrally mediated ocular hypotension: potential role of these 2 drugs in diagnosing HS will be necessary to of imidazoline receptors. Ann N Y Acad Sci. 1995;763:463-485. definitively demonstrate the diagnostic utility of apra- 6. Thompson H, Miller N. Disorders of pupillary function, accommodation, and lac- clonidine. rimation. In: Miller N, Newman N, eds. Walsh and Hoyt’s Clinical Neuro- Ophthalmology. Baltimore, Md: Williams & Wilkins; 1998:961-1040. In summary, our study provides evidence that the 7. Crosson CE, Heath AR, DeVries GW, Potter DE. Pharmacological evidence for activation of ocular postjunctional ␣2 receptors is suffi- heterogeneity of ocular alpha 2 adrenoceptors. Curr Eye Res. 1992;11:963-970. cient to lower IOP in humans. Therefore, efforts to re- 8. Wiederholt M, Schafer R, Wagner U, Lepple-Wienhues A. Contractile response of the isolated trabecular meshwork and ciliary muscle to cholinergic and ad- duce the systemic absorption of topical adrenergic ago- renergic agents. Ger J Ophthalmol. 1996;5:146-153. nist medications, such as closing the eyes and placing 9. Lin SL, Liang SS. Evaluation of adverse reactions of aponidine hydrochloride oph- thalmic solution. J Ocul Pharmacol Ther. 1995;11:267-278. pressure over the lacrimal sacs, should reduce adverse 10. Yuksel N, Guler C, Caglar Y, Elibol O. Apraclonidine and clonidine: a comparison effects without sacrificing the ocular hypotensive activ- of efficacy and side effects in normal and ocular hypertensive volunteers. Int Oph- ity. The mydriatic effect of apraclonidine in eyes with HS thalmol. 1992;16:337-342. 11. Jampel HD, Robin AL, Quigley HA, Pollack IP. Apraclonidine: a one-week dose- supports the idea that ␣1 receptors are up-regulated in response study. Arch Ophthalmol. 1988;106:1069-1073. the uveal tissue of these eyes. Because 1% apraclonidine 12. Gharagozloo NZ, Relf SJ, Brubaker RF. Aqueous flow is reduced by the alpha- is easy to obtain, can be used as formulated by the manu- adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology. 1988; 95:1217-1220. facturer, and has no excessive regulatory controls, it rep- 13. Stewart WC, Laibovitz R, Horwitz B, Stewart RH, Ritch R, Kottler M. A 90-day resents an attractive alternative to other agents in the study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol: Apraclonidine Primary Therapy Study Group. Arch Ophthalmol. 1996; diagnosis of HS. 114:938-942. 14. Abrams DA, Robin AL, Pollack IP, deFaller JM, DeSantis L. The safety and efficacy of topical 1% ALO 2145 (p-aminoclonidine hydrochloride) in normal vol- Accepted for publication January 4, 2000. unteers. Arch Ophthalmol. 1987;105:1205-1207. 15. Langham ME, Weinstein GW. Horner’s syndrome: ocular supersensitivity to ad- This research was supported in part by grant EYO9741 renergic amines. Arch Ophthalmol. 1967;78:462-469. from the National Institutes of Health, Bethesda, Md (Dr 16. Thompson HS, Mensher JH. Adrenergic mydriasis in Horner’s syndrome: hy- droxyamphetamine test for diagnosis of postganglionic defects. Am J Ophthal- Crosson). mol. 1971;72:472-480. Reprints: Sandra M. Brown, MD, Department of Oph- 17. Wilhelm H, Ochsner H, Kopycziok E, Trauzettel-Klosinski S, Schiefer U, Zrenner thalmology and Visual Sciences, Texas Tech University E. Horner’s syndrome: a retrospective analysis of 90 cases and recommenda- tions for clinical handling. Ger J Ophthalmol. 1992;1:96-102. Health Sciences Center, Sixth and Flint, Lubbock, TX 79430 18. Thompson BM, Corbett JJ, Kline LB, Thompson HS. Pseudo-Horner’s syn- (e-mail: [email protected]). drome. Arch Neurol. 1982;39:108-111.

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