Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology Studying the Effect of Iris Mechanics on the Pupillary Light Reflex Using Brimonidine-Induced Anisocoria Yanjun Chen,1,2 and Randy H. Kardon1,3 1Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 2Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin 3Department of Veterans Affairs Hospital, Iowa City VA Center for Prevention and Treatment of Visual Loss, Iowa City, Iowa Correspondence: Yanjun Chen, 2828 PURPOSE. To study and correct for the limiting effect of iris mechanics on the amplitude of Marshall Court, Suite 200, Madison, light-evoked pupil contractions in order to derive a more clinically accurate assessment of WI 53705; [email protected]. afferent input to the visual system. Submitted: September 6, 2012 METHODS. Transient pupil responses were recorded to a series of 1-second red Ganzfeld light Accepted: January 2, 2013 stimuli with a stepwise increase in stimulus intensity using a binocular infrared computerized Citation: Chen Y, Kardon RH. Studying pupillometer. One eye of eight healthy subjects was treated with 0.2% brimonidine tartrate the effect of iris mechanics on the ophthalmic solution to induce pupil size reduction. The amount of pupil contraction as a pupillary light reflex using function of stimulus intensity was compared between the brimonidine-treated, miotic eye and brimonidine-induced anisocoria. the untreated eye. Invest Ophthalmol Vis Sci. 2013;54:2951–2958. DOI:10.1167/ RESULTS. Brimonidine treatment produced significant reduction in pupil size in healthy iovs.12-10916 subjects (mean reduction in pupil size: 1.78 6 0.35 mm, P < 0.05). For increasing light intensity, the treated pupil started to show reduced pupil contractions compared with the contralateral untreated pupil when the peak of pupil contraction reached an average pupil size of 3.25 6 0.61 mm (range, 2.38–4.44 mm). When measured by percent pupil contraction (contraction amplitude/baseline pupil diameter), the pupil response as a function of stimulus intensity in the treated, miotic eye did not differ from that in the untreated eye. CONCLUSIONS. Iris mechanics limits the amount of pupil contraction and can act to reduce the assessed neuronal integration of the pupil light reflex. Pupil response assessed by using percent contraction amplitude is least affected by mechanical effects and provides a more accurate approximation of afferent input. Keywords: iris mechanics, pupil contraction, brimonidine he pupillary light reflex (PLR) has a long history of being pupil responses to light, the main factor responsible for any Temployed as a useful clinical test for evaluation of visual reduction in contraction from the more miotic eye is due to iris function.1–11 In addition, there has been increasing evidence mechanics, because the neuronal input to each pupil is suggesting the role of the PLR as a means to evaluate cognitive matched for a given light stimulus. function,12–16 autonomic neuropathy,17–20 and behavior of melanopsin retinal ganglion cells.21–25 Although pupil-based testing has advantages of being objective and easy to perform METHODS by patients, interpretation of pupil contractions recorded can be confounded by the limiting effects of iris mechanics on how Subjects much the pupil can contract. Understanding how iris mechan- ics affect PLR is thus essential to the interpretation of pupil Eight healthy, young subjects (5 males and 3 females) ranging in recording and estimation of afferent input. The mechanical age from 29 to 35 years (mean 6 SD, 32.0 6 4.1) were tested. effect becomes increasingly more important when measuring The exclusion criteria included history of ocular disease, eye pupil response in patients who have smaller pupils, such as in trauma, or ocular surgery; presence of systemic diseases with elderly patients or those using narcotic-derived medications for known ocular involvement; or current use of ophthalmic pain control.26,27 solution or systemic medications that can affect the PLR. An eye Several studies conducted decades ago28–30 investigated the examination, including visual acuity, slit lamp, and undilated impact of mechanical properties of the iris to PLR. It was fundus exam, was performed to rule out any ocular abnormal- suggested that the movement of the pupil is not linear when ities. The procedures conformed to the tenets of the pupil size exceeded a certain range, and the mechanical Declaration of Helsinki. The study was approved by the properties of the iris muscles contributed to this nonlinearity. University of Iowa Institutional Review Board. Written consent In the present study, we used a novel approach to quantify the form was obtained after the details of the test were explained. mechanical limitations of the iris on pupil contraction, by using A 0.2% brimonidine tartrate ophthalmic solution was placed a sympatholytic agent, brimonidine, to induce anisocoria.31–33 in the right eye in three subjects and in the left eye in five By producing anisocoria and simultaneously recording both subjects. All subjects tolerated brimonidine treatment with few Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 2951 Downloaded from iovs.arvojournals.org on 09/28/2021 Iris Mechanics and the Pupillary Light Reflex IOVS j April 2013 j Vol. 54 j No. 4 j 2952 side effects and post-brimonidine pupil recording commenced different stimulus intensities. Holm-adjusted P values less than after waiting for at least 30 minutes after treatment. 0.05 were considered statistically significant. Apparatus RESULTS The details of the apparatus set up are described elsewhere.34 Briefly, a dual-channel binocular eye frame pupillometer Brimonidine treatment resulted in absolute pupil size reduc- (Arrington Research, Scottsdale, AZ) was used to record tion of 1.47 to 2.60 mm (mean 6 SD, 1.77 6 0.35 mm), and pupilresponse(Fig.1).Themaximalhorizontalpupil percentage pupil size reduction of 22% to 35% (mean 6 SD, diameter was recorded in real time. The pupil of the 29% 6 6%) across all subjects (P < 0.05). brimonidine-treated, miotic eye was stimulated; the fellow Figure 2 shows an example of a pupil tracing to one eye was occluded by an eye patch made of a near infrared stimulus intensity in one subject before and after brimonidine passing 780-nm filter. The pupil responses from both eyes treatment. The right eye was treated and marked black, the left were recorded simultaneously. The 780-nm filter blocks the eye was untreated and marked red. Before brimonidine visual stimulus of lesser wavelengths of light to enter retina treatment (left, pre-brimonidine), a small anisocoria was in the occluded eye; however, it still enables recording of present between the two eyes in this subject (separation of pupil responses by the infrared camera. Pupil recording the red and black tracings of approximately 0.50 mm along the began 5 seconds before the first stimulus and continued y-axis). The pupil contraction was similar between the two throughout the stimulus paradigm, including 30 seconds of eyes (length of red and black dotted arrows approximately the poststimulus dark period. equal); better demonstrated after the right eye recording (black) is shifted vertically (gray). After brimonidine treatment (right, postbrimonidine), the pupil constricted from 7.31 mm Stimulus to 3.50 mm (contraction amplitude 3.61 mm) in the untreated Details of the stimulus set up are described elsewhere.35 left eye (red), whereas the pupil constricted from 4.42 mm to Briefly, a diffuse, wide-field stimulus was produced using a 2.31 mm (contraction amplitude 2.11 mm) in the treated right light-emitting diode Color Dome Ganzfeld electroretinogram eye (black); the waveform shape of the pupil light reflex was apparatus (Diagnosys, Lowell, MA) (Fig. 1). At a distance of 75 not significantly altered by brimonidine, as evidenced by rescaling the right pupil tracing to equal the same contraction mm from the front of the eye to the opening of the bowl, the amplitude as the left pupil (superimposed gray tracing). horizontal radius of the viewing angle was 458. Light stimuli When pupil contraction (in mm) was plotted against with a spectral band of 640 6 10 nm (red light) were chosen stimulus intensity (Fig. 3, middle), the contraction amplitude to elicit PLR. Before the pupil recording was started, subjects was similar (left inset) in the treated (black filled circle) and were dark adapted for 10 minutes. A trial consisted of a series untreated eye (red filled circle) at lower stimulus intensities of 1-second duration red stimuli, each followed by a period of (À4.0 to À2.5 log cd/m2). At medium stimulus intensities, the darkness. The stimulus intensity ranged from À4.0 to 2.6 log pupil contraction amplitude in the treated eye started to cd/m2 (0.0001–450 cd/m2), with stepwise increment of 0.5 log become less compared to the untreated eye (the middle inset). cd/m2. The difference in contraction amplitude became most notice- able at high stimulus intensities (right inset). When contraction Analysis of Pupil Records amplitude is replotted in percentage (top), the pupil response intensity curve is similar for the treated right versus untreated Analysis of the pupil recording was performed by a custom- left eye. designed software program using IgorPro 6.1 (WaveMetrics, The pupil size at which iris mechanics started to limit Inc., Lake Oswego, OR) and Excel (Microsoft Corp., Redmond, pupil contraction was derived by identifying the pupil size at WA). Baseline pupil diameter for each eye was calculated as the the peak of contraction (Fig. 3, bottom,) at which the pupil average pupil diameter over a 1-second period prior to stimulus contraction amplitude in the treated eye started to fall below onset.