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 a-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 a2 receptors in the ciliary body. The up- normal eye and the measurements were repeated. regulation of a receptors that occurs with sympathetic de- nervation unmasks apraclonidine’s a1 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 a1 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 a2 receptors. RESULTS Apraclonidine’s a1 activity does not af- fect 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 a2 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 a2 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 a2 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 a2 agonists in lowering IOP. They following apraclonidine administration. In (REPRINTED) ARCH OPHTHALMOL / VOL 118, JULY 2000 WWW.ARCHOPHTHALMOL.COM 951 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A Normal Eyes HS Eyes 18 MATERIALS AND METHODS 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 post- ganglionic 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 re- corded 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. P#.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. P#.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 a receptors in the eye and ocular adnexa. 7 the HS eyes, the administration of apraclonidine pro- Ocular a2 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, a2 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 a2 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 a2 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 a1 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- (REPRINTED) ARCH OPHTHALMOL / VOL 118, JULY 2000 WWW.ARCHOPHTHALMOL.COM 952 ©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 a2 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.