JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 4, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2013.0093
Effects of Two Commonly Used Mydriatics on Choroidal Thickness: Direct and Crossover Effects Necip Kara,1 Ali Demircan,2 Gonul Karatas,2 Engin Bilge Ozgurhan,2 Gurkan Tatar,3 Yalcin Karakucuk,2 Abdurrahman Basci,2 and Ahmet Demirok2
Abstract
Purpose: To investigate the effect of 2 commonly used mydriatics on choroidal thickness using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: In this prospective study, 90 healthy subjects were enrolled. The participants were randomly divided into 3 groups based on the application of drops. One eye of each subject received a drop of tropicamide 1% in the tropicamide group (n = 30), a drop of phenylephrine 2.5% in the phenylephrine group (n = 30), and a drop of artificial tear in the control group (n = 30). Drops were given thrice at 5 min intervals. Subfoveal choroidal thickness (SFCT) was measured using EDI-OCT before and at 45 min after drop application in both the dilated eye and nondilated contralateral eye. Results: The SFCT was significantly decreased after drop instillation in both the dilated eye and contralateral eye in the tropicamide group (P < 0.001 and P = 0.001, respectively) and in the phenylephrine group (P < 0.001 and P = 0.001, respectively). However, the SFCT did not significantly differ after drop instillation in either the dropped eye or contralateral eye in the control group (P = 0.108 and P = 0.695, respectively). Conclusion: The findings of the present study revealed that tropicamide and phenylephrine cause a decrease in choroidal thickness. Introduction
T
he choroid is the connective tissue-containing vascular layer between the retina and the sclera. It displays one of the highest rates of blood flow in the body.1 The choroid provides oxygen and nourishment to the retinal pigment epithelium and the retina up to the inner nuclear layer, as well as temperature regulation and waste product removal.2 Thus, a structurally and functionally normal choroidal vasculature is essential for the function of the retina. Abnormal choroidal blood volume or compromised flow or both can result in photoreceptor dysfunction and death.3 The development of new methods to measure choroidal thickness in vivo has enabled new directions in research into normal and pathologic processes in the choroid. Enhanced depth imaging (EDI) is a relatively new technique that enables in vivo examination and quantification of the choroid using particular focusing techniques and a spectral domain optical coherence tomography (SD-OCT) device.4 Choroidal thickness measurements using SD-OCT have been investigated in 1 2 3
many ocular diseases, including degenerative myopia, agerelated macular degeneration, central serous chorioretinopathy, diabetic retinopathy, macular hole, and retinitis pigmentosa.5–9 Previous studies have shown that choroidal thickness is also influenced by several factors, including age, axial length (AL), central corneal thickness (CCT), intraocular pressure (IOP), ocular perfusion pressure, and smoking.10–19 Mydriatic eye drops are regularly used for dilated fundoscopic examination. It has been reported that mydriatic application leads to changes in uveal structures, including iris thickness, angle, and morphology of the iridociliary region.20 The mydriatics most often used are phenylephrine and tropicamide. The aim of the current study was to investigate the influence of 2 commonly used mydriatics on choroidal thickness in healthy subjects using EDI-OCT.
Methods This prospective and observational study was performed at the Beyoglu Eye Research and Education Hospital. The
Department of Ophthalmology, Sehitkamil Government Hospital, Gaziantep, Turkey. Department of Ophthalmology, Beyoglu Eye Education and Research Hospital, Istanbul, Turkey. Department of Ophthalmology, Konya Government Hospital, Konya, Turkey.
366
MYDRIATICS AND CHOROIDAL THICKNESS
367
study followed the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All participants received oral and written information about the study, and each participant provided written informed consent.
Baseline examination protocol and measurements The participants underwent ophthalmologic examinations, including visual acuity and refraction, slit-lamp biomicroscopy, gonioscopy, applanation tonometry, and dilated funduscopy. Study participants underwent CCT and AL measurements using ultrasonic scans, retina nerve fiber layer evaluation using spectral OCT, and visual field test.
Eligibility criteria Inclusion criteria were best-corrected visual acuity of at least 20/20, nonsmoking, no drug and alcohol abuse, no medication, less than 2 diopters of cylindrical and/or 4 diopters of spherical refractive error, and absence of glaucomatous findings such as glaucomatous optic disc changes such as excavation, notching, or focal thinning of the neuroretinal rim, peripapillary hemorrhage, retina nerve fiber layer loss, glaucomatous visual field defects, or IOP readings greater than 22 mmHg. Exclusion criteria included any history of retinal diseases, any systemic abnormalities (e.g., vascular disease, hypertension, or diabetes mellitus), a history of previous intraocular surgery or laser therapy, and poor image quality because of unstable fixation or severe cataract.
Study groups
Control group. The subjects received a drop of artificial tear thrice at 5 min intervals.
EDI-OCT measurement The subfoveal choroidal thickness (SFCT) was measured using SD-OCT (Spectralis, Wave-length: 870 nm; Heidelberg Engineering Co.) with EDI modality. The procedure for EDI-OCT measurement has been previously described.4 SFCT was defined as the vertical distance from the hyperreflective line of Bruch’s membrane to the hyper-reflective line of the inner surface of the sclera. The images were taken by one clinician (G.K.), and the images were assessed by another clinician (A.D.). Both of the clinicians were masked in terms of groups. EDI-OCT measurements were performed before the administration of drops and at 45 min after instillation. All measurements were performed between 9:00 am and 12:00 am.
Data analyses Data analysis was performed using the statistical package Statistical Package for the Social Sciences (SPSS) version 16. For each continuous variable, normality was checked by Kolmogorov–Smirnov test. The choroidal thickness measurements of the groups were compared by independent ttest. A comparison of choroidal thickness values between, before, and after instillation of drops was performed using paired t-tests. The categorical variables between the groups were analyzed using the w2 test. Pearson’s correlation was used to examine the relationships among the measured variables. Values of P < 0.05 were considered statistically significant.
After baseline examination, selected subjects were invited the next day for EDI-OCT measurements. The participants were randomly divided into 3 groups based on the application of drops as follows:
Results
Tropicamide group. The subjects received a drop of 1% tropicamide thrice at 5 min intervals.
Demographic profile and baseline clinical characteristic
Phenylephrine group. The subjects received a drop of 2.5% phenylephrine thrice at 5 min intervals.
The study included 90 eyes of 90 subjects: 30 subjects in the tropicamide group, 30 subjects in the phenylephrine
Table 1.
No. of subjects Gender F/M Age, years Mean – SD Range Sphere, D Mean – SD Range AL, mm Mean – SD Range CCT, mm Mean – SD Range IOP, mmHg Mean – SD Range
Demographic and Clinical Characteristics of Three Groups Pa
Tropicamide
Phenylephrine
Control
30
30
30
16/14
19/11
17/13
0.727
33 – 10 23 to 57
39 – 12 20 to 59
32 – 7 19 to 48
0.061
0.06 – 0.85 - 1.50 to 3.25
0.11 – 0.36 0.00 to 1.50
- 0.1 – 1.11 - 2.00 to 2.00
0.707
23.38 – 1.23 21.95 to 28.05
23.47 – 1.05 21.77 to 25.54
22.85 – 1.08 21 to 25
0.112
565 – 33 506 to 641
575 – 44 511 to 698
559 – 10 537 to 576
0.313
16.95 – 3.56 11 to 21
16.5 – 2.94 12 to 21
16.5 – 2.66 11 to 20
0.868
a One-way ANOVA test. SD, standard deviation; F, female; M, male; AL, axial length; CCT, central corneal thickness, IOP, intraocular pressure.
368
Table 2.
KARA ET AL.
Subfoveal Choroidal Thickness Changes Before and After Eye Drop Instillation in Three Groups Dilated eye
Groups Tropicamide Mean – SD Range Phenylephrine Mean – SD Range Control Mean – SD Range
Contralateral eye (nondilated) a
Before
After
Difference
Pa
Before
After
Difference
P
348 – 89 230 to 527
326 – 83 214 to 507
- 22 – 14 - 62 to - 2.0
< 0.001
349 – 89 160 to 511
335 – 87 160 to 527
- 14 – 16 - 64 to - 16
0.001
294 – 90 142 to 480
276 – 85 142 to 447
- 17 – 9 - 33 to 0.0
< 0.001
291 – 96 178 to 534
283 – 95 160 to 511
- 7.9 – 9.0 - 30 to 3.0
0.001
342 – 81 212 to 506
348 – 82 209 to 506
5.3 – 3.5 - 3.0 to 6.0
0.108
354 – 110 173 to 527
354 – 109 176 to 524
0.3 – 3.3 - 7.0 to 7.0
0.695
Boldface indicates that a p-value of less than 0.05 was considered significant. a Paired t-test.
group, and 30 subjects in the control group. The demographic and baseline clinical features of the 3 groups of subjects are shown in Table 1. No statistically significant differences were observed among the groups in terms of age, gender distribution, spherical refraction, AL, CCT, or IOP (P > 0.05 for all).
Discussion
The changes in SFCT are documented in Table 2. In the tropicamide and phenylephrine groups, the SFCT was significantly decreased after drop instillation in both the dilated eye and contralateral eye (P < 0.001 and P = 0.001 for both groups) (Figs. 1 and 2). In the control group, the SFCT did not significantly differ after drop instillation in either the dropped eye or contralateral eye (P = 0.108 and P = 0.695). A pairwise comparison of groups for changes in SFCT is shown in Table 3. SFCT changes after drop instillation were significantly higher in the tropicamide group than in the control group in the dilated eye (P = 0.008 and P = 0.003, respectively), and significantly higher in the phenylephrine group than in the control group in the dilated eye (P = 0.032). The change in SFCT was also significantly greater in the tropicamide group than in the control group in the contralateral eye (P = 0.003).
This observational study showed that tropicamide and phenylephrine caused a significant decrease in SFCT in both the dilated and nondilated contralateral eyes. In addition, the changes in SFCT did not significantly differ between the tropicamide and phenylephrine groups in either the dilated or contralateral eyes. Mydriatics are regularly used to dilate pupils in patients presenting to ophthalmology clinics for assessment and in follow up for a wide variety of ophthalmic conditions. Commonly used mydriatics include phenylephrine and tropicamide. Phenylephrine is a sympathetic agonist that exerts its mydriatic effect by activating sympathetic receptors on the iris dilator muscle. Tropicamide, on the other hand, is an anticholinergic agent that enhances pupil dilation by inhibiting iris sphincter muscle action. Phenylephrine has no cycloplegic effect, but tropicamide has a cycloplegic effect. Mydriatics lead to changes in iris thickness, angle, and the morphology of the iridociliary region.20 As a part of the uveal structure, the choroid can also be affected by the contraction and relaxation of ciliary muscles induced by the instillation of mydriatics. Choroidal thickness changes after instillation of mydriatics may be explained by several possible mechanisms. Due to the previously suggested
FIG. 1. Subfoveal choroidal thickness (SFCT) values before and after eye drop instillation in 3 groups in the dropped eye.
FIG. 2. SFCT values before and after eye drop instillation in 3 groups in the contralateral eye.
Choroidal thickness changes
MYDRIATICS AND CHOROIDAL THICKNESS
Table 3.
369
Pairwise Comparison of Subfoveal Choroidal Thickness Changes Between the Groups Dilated eye
Contralateral eye (nondilated) 95% confidence interval
Groups T T P
P C C
95% confidence interval
Mean difference
SE
Pa
Lower bound
Upper bound
Mean difference
SE
Pa
Lower bound
Upper bound
- 4.15 - 27.40b - 23.25b
8.28 8.28 8.28
0.959 0.008 0.032
- 25.92 - 49.17 - 45.02
17.62 - 5.62 - 1.47
- 6.20 - 14.40b - 8.20
3.95 3.95 3.95
0.404 0.003 0.172
- 16.60 - 24.80 - 18.60
4.20 - 3.99 2.20
Boldface indicates a p-value of less than 0.05 was considered significant. a Tukey’s post hoc test. b The mean difference is significant at the 0.05 level. T, tropicamide group; P, penylephrine group; C, control group; SE, standard error.
connection between nonvascular smooth muscle cells beneath the fovea and ciliary muscle fibers,1 mydriatics may alter choroidal thickness. Furthermore, the choroid contains nonvascular smooth muscle that is innervated by both sympathetic and parasympathetic inputs.21–23 Therefore, topical mydriatic administration may induce the contraction of nonvascular smooth muscle in the choroid. Contraction of these smooth muscles might result in the efflux of fluid out of the choroid, which results in a thinning of the choroid.1 Moreover, since both sympathomimetics and anticholinergics have vasoconstricting effects, tropicamide and phenylephrine may lead to vasoconstriction of the choroidal vascular bed, which results in choroidal thinning. In contrast to our study, 2 previous studies have reported that mydriatics did not influence choroidal thickness measurement.24,25 Kim et al. investigated the influence of MydrinP (tropicamide 5 mg/mL and phenylephrine 5 mg/mL; Santen Pharmaceuticals) on choroidal thickness measurement in healthy subjects using EDI-OCT.24 Their study demonstrated that a phenylephrine and tropicamide combination had no significant influence on choroidal thickness measurement at the subfoveal region and at 0.5 mm intervals (up to 3.0 mm) from the fovea at nasal, temporal, superior, and inferior locations. In another study, Mwanza et al. compared choroidal thickness measurements obtained before and after pupil dilation with tropicamide 1% in healthy individuals and glaucoma patients using SD-OCT.25 They reported that pupil dilation with tropicamide 1% did not have an effect on choroidal thickness in either healthy subjects or glaucomatous patients. While our results differ from the findings of 2 previous studies, we also investigated the crossover effects of mydriatics on choroidal thickness, which is a strength of our study compared with the 2 previous studies. We found that a significant decrease in SFCT after tropicamide or phenylephrine instillation was observed in undilated contralateral eyes. Systemic absorption of topical ocular drugs occurs by the nasal mucosa or after absorption through the cornea and conjunctiva. The drug accumulates in the aqueous humor and may be distributed via systemic circulation through the trabecular meshwork pathway.26 In this manner, topical application of ophthalmic drops either may cause changes in the contralateral eye or may cause systemic side-effects.27–29 Choroidal thickness measurements may be influenced by several factors that should be considered when choroidal thickness is evaluated. Aging is one factor that affects choroidal thickness, and older patients have thinner choroids.5,10,13,15 High myopia and AL have been found to be
associated with a significantly thinner choroid.5,10,13,15,17,30 Sızmaz et al. currently reported that smoking 1 cigarette induced a significant decrease in choroidal thickness, which continued to last for at least 3 h.19 To the best of our knowledge, our study contributes a new finding to the literature, which is that the application of mydriatics affects SFCT measurements in the dropped eye and the un-dropped contralateral eye, which should be considered when choroidal thickness is measured. However, our study has some limitations. The manual measurement of SFCT is one of the principal drawbacks of this study. Current OCT equipment does not provide software for the automated measurement of choroidal thickness. Moreover, the reproducibility of choroidal thickness measurements using OCT is still debatable. However, some studies found high interobserver correlation, high repeatability, and high intersystem, interexaminer, and intervisit reproducibility in choroidal thickness measurements.4,30,31 The study investigated the effect of 1% tropicamide and 2.5% phenylephrine on choroidal thickness. Hence, the current findings cannot be directly extrapolated to other mydriatics that contain different tropicamide or phenylephrine concentrations. In addition, the baseline SFCT thickness was lower in the phenylephrine group than in tropicamide and control groups. This may be related with many factors such as age and AL, which were higher in the phenylephrine group. However, the main purpose of this study was not to compare the baseline and follow-up SFCT values. We investigated the changes in SFCT after mydriatics. In conclusion, the study showed that pupil dilatation with tropicamide or phenylephrine leads to a decrease in SFCT. This result should be taken into consideration when choroidal thickness is evaluated in chorioretinal disease or clinical research.
Author Disclosure Statement No author has a financial or proprietary interest in any material or method mentioned.
References 1. Nickla, D.L., and Wallman, J. The multifunctional choroid. Prog. Retin. Eye Res. 29:144–168, 2010. 2. Parver, L.M. Temperature modulating action of choroidal blood flow. Eye (Lond). 5:181–185, 1991. 3. Cao, J., McLeod, S., Merges, C.A., and Lutty, G.A. Choriocapillaris degeneration and related pathologic changes in
370
4. 5.
6. 7.
8.
9. 10.
11.
12.
13. 14.
15. 16.
17. 18. 19.
KARA ET AL.
human diabetic eyes. Arch. Ophthalmol. 116:589–597, 1998. Spaide, R.F., Koizumi, H., and Pozzoni, M.C. Enhanced depth imaging spectral-domain optical coherence tomography. Am. J. Ophthalmol. 146:496–500, 2008. Fujiwara, T., Imamura, Y., Margolis, R., Slakter, J.S., and Spaide, R.F. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am. J. Ophthalmol. 148:445–450, 2009. Zeng, J., Li, J., Liu, R., et al. Choroidal thickness in both eyes of patients with unilateral idiopathic macular hole. Ophthalmology. 119:2328–2333, 2012. Dhoot, D.S., Huo, S., Yuan, A., et al. Evaluation of choroidal thickness in retinitis pigmentosa using enhanced depth imaging optical coherence tomography. Br. J. Ophthalmol. 97:66–69, 2013. Kim, S.W., Oh, J., Kwon, S.S., Yoo, J., and Huh, K. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina. 31:1904–1911, 2011. Nagaoka, T., Kitaya, N., Sugawara, R., et al. Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br. J. Ophthalmol. 88:1060–1063, 2004. Agawa, T., Miura, M., Ikuno, Y., et al. Choroidal thickness mea-surement in healthy Japanese subjects by threedimensional high-penetration optical coherence tomography. Graefes Arch. Clin. Exp. Ophthalmol. 249:1485–1492, 2011. Manjunath, V., Taha, M., Fujimoto, J.G., and Duker, J.S. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am. J. Ophthalmol. 150:325–329, 2010. Hirata, M., Tsujikawa, A., Matsumoto, A., et al. Macular choroidal thickness and volume in normal subjects measured by swept-source optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:4971–4978, 2011. Ikuno, Y., Kawaguchi, K., Nouchi, T., and Yasuno, Y. Choroidal thickness in healthy Japanese subjects. Invest. Ophthalmol. Vis. Sci. 51:2173–2176, 2010. Maul, E.A., Friedman, D.S., Chang, D.S., et al. Choroidal thickness measured by spectral domain optical coherence tomogra-phy. Factors affecting thickness in glaucoma patients. Ophthalmology. 118:1571–1579, 2011. Margolis, R., and Spaide, R.F. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am. J. Ophthalmol. 147:811–815, 2009. Mwanza, J.C., Hochberg, J.T., Banitt, M.R., Feuer, W.J., and Budenz, D.L. Lack of association between glaucoma and macular choroidal thickness measured with enhanced depth-imaging optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:3430–3435, 2011. Brown, J.S., Flitcroft, D.I., Ying, G.S., et al. In vivo human choroidal thickness measurements: evidence for diurnal fluctuations. Invest. Ophthalmol. Vis. Sci. 50:5–12, 2009. Francis, B.A., Wang, M., Lei, H., et al. Changes in axial length following trabeculectomy and glaucoma drainage device surgery. Br. J. Ophthalmol. 89:17–20, 2005. Sızmaz, S., Kucukerdonmez, C., Pınarcı, E.Y., Karalezli, A., Canan, H., and Yılmaz, G. The effect of smoking on choroidal thickness measured by optical coherence tomography. Br. J. Ophthalmol. 97:601–604, 2013.
20. Marchini, G., Babighian, S., Tosi, R., Perfetti, S., and Bonomi, L. Comparative study of the effects of 2% ibopamine, 10% phenylephrine, and 1% tropicamide on the anterior segment. Invest. Ophthalmol. Vis. Sci. 44:281–289, 2003. 21. Schrodl, F., De Laet, A., Tassignon, M.J., et al. Intrinsic choroidal neurons in the human eye: projections, targets, and basic electrophysiological data. Invest. Ophthalmol. Vis. Sci. 44:3705–3712, 2003. 22. Schrodl, F., Tines, R., Brehmer, A., and Neuhuber, W.L. Intrinsic choroidal neurons in the duck eye receive sympathetic input: anatomical evi-dence for adrenergicmodulation of nitrergic functions in the choroid. Cell Tissue Res. 304:175–184, 2001. 23. May, C.A., Neuhuber, W., and Lutjen-Drecoll, E. Immunohistochemical classification and functional morphology of human choroidal gan-glion cells. Invest. Ophthalmol. Vis. Sci. 45:361–367, 2004. 24. Kim, M., Kwon, H.J., and Lee, S.C. Influence of mydriatics on choroidal thickness measurement using enhanced depth imaging-OCT. Optom. Vis. Sci. 89:1150–1155, 2012. 25. Mwanza, J.C., Sayyad, F.E., Banitt, M.R., and Budenz, D.L. Effect of pupil dilation on macular choroidal thickness measured with spectral domain optical coherence tomography in normal and glaucomatous eyes. Int. Ophthalmol. 33:335–341, 2013. 26. Chien, D.S., Homsy, J.J., Gluchowski, C., and Tang-Liu, D.D. Corneal and conjunctival/scleral penetration of p-aminoclonidine, AGN 190342, and clonidine in rabbit eyes. Curr. Eye Res. 9:1051–1059, 1990. 27. Alpay, A., Ermis, B., Ugurbas, S.C., Battal, F., and Sagdik, H.M. The local vasoconstriction of infant’s skin following instillation of mydriatic eye drops. Eur. J. Clin. Pharmacol. 66:1161–1164, 2010. 28. Gray, C. Systemic toxicity with topical ophthalmic medications in children. Paediatr. Perinat. Drug Ther. 7:23–29, 2006. 29. Ogut, M.S., Bozkurt, N., Ozek, E., Birgen, H., Kazokoglu, H., and Ogut, M. Effects and side effects of mydriatic eyedrops in neonates. Eur. J. Ophthalmol. 6:192–196, 1996. 30. Rahman, W., Chen, F.K., Yeoh, J., Patel, P., Tufail, A., and Da Cruz, L. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:2267–2271, 2011. 31. Ikuno, Y., Maruko, I., Yasuno, Y., et al. Reproducibility of retinal and choroidal thickness measurements in enhanced depth imaging and high-penetration optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:5536–5540, 2011.
Received: May 4, 2013 Accepted: December 2, 2013 Address correspondence to: Dr. Necip Kara Department of Ophthalmology Sehitkamil Government Hospital Pancarli Mh., 15 nolu Sk No. 9, Sehitkamil Gaziantep 27060 Turkey E-mail: [email protected]
Effects of Two Commonly Used Mydriatics on Choroidal Thickness: Direct and Crossover Effects Necip Kara,1 Ali Demircan,2 Gonul Karatas,2 Engin Bilge Ozgurhan,2 Gurkan Tatar,3 Yalcin Karakucuk,2 Abdurrahman Basci,2 and Ahmet Demirok2
Abstract
Purpose: To investigate the effect of 2 commonly used mydriatics on choroidal thickness using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods: In this prospective study, 90 healthy subjects were enrolled. The participants were randomly divided into 3 groups based on the application of drops. One eye of each subject received a drop of tropicamide 1% in the tropicamide group (n = 30), a drop of phenylephrine 2.5% in the phenylephrine group (n = 30), and a drop of artificial tear in the control group (n = 30). Drops were given thrice at 5 min intervals. Subfoveal choroidal thickness (SFCT) was measured using EDI-OCT before and at 45 min after drop application in both the dilated eye and nondilated contralateral eye. Results: The SFCT was significantly decreased after drop instillation in both the dilated eye and contralateral eye in the tropicamide group (P < 0.001 and P = 0.001, respectively) and in the phenylephrine group (P < 0.001 and P = 0.001, respectively). However, the SFCT did not significantly differ after drop instillation in either the dropped eye or contralateral eye in the control group (P = 0.108 and P = 0.695, respectively). Conclusion: The findings of the present study revealed that tropicamide and phenylephrine cause a decrease in choroidal thickness. Introduction
T
he choroid is the connective tissue-containing vascular layer between the retina and the sclera. It displays one of the highest rates of blood flow in the body.1 The choroid provides oxygen and nourishment to the retinal pigment epithelium and the retina up to the inner nuclear layer, as well as temperature regulation and waste product removal.2 Thus, a structurally and functionally normal choroidal vasculature is essential for the function of the retina. Abnormal choroidal blood volume or compromised flow or both can result in photoreceptor dysfunction and death.3 The development of new methods to measure choroidal thickness in vivo has enabled new directions in research into normal and pathologic processes in the choroid. Enhanced depth imaging (EDI) is a relatively new technique that enables in vivo examination and quantification of the choroid using particular focusing techniques and a spectral domain optical coherence tomography (SD-OCT) device.4 Choroidal thickness measurements using SD-OCT have been investigated in 1 2 3
many ocular diseases, including degenerative myopia, agerelated macular degeneration, central serous chorioretinopathy, diabetic retinopathy, macular hole, and retinitis pigmentosa.5–9 Previous studies have shown that choroidal thickness is also influenced by several factors, including age, axial length (AL), central corneal thickness (CCT), intraocular pressure (IOP), ocular perfusion pressure, and smoking.10–19 Mydriatic eye drops are regularly used for dilated fundoscopic examination. It has been reported that mydriatic application leads to changes in uveal structures, including iris thickness, angle, and morphology of the iridociliary region.20 The mydriatics most often used are phenylephrine and tropicamide. The aim of the current study was to investigate the influence of 2 commonly used mydriatics on choroidal thickness in healthy subjects using EDI-OCT.
Methods This prospective and observational study was performed at the Beyoglu Eye Research and Education Hospital. The
Department of Ophthalmology, Sehitkamil Government Hospital, Gaziantep, Turkey. Department of Ophthalmology, Beyoglu Eye Education and Research Hospital, Istanbul, Turkey. Department of Ophthalmology, Konya Government Hospital, Konya, Turkey.
366
MYDRIATICS AND CHOROIDAL THICKNESS
367
study followed the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All participants received oral and written information about the study, and each participant provided written informed consent.
Baseline examination protocol and measurements The participants underwent ophthalmologic examinations, including visual acuity and refraction, slit-lamp biomicroscopy, gonioscopy, applanation tonometry, and dilated funduscopy. Study participants underwent CCT and AL measurements using ultrasonic scans, retina nerve fiber layer evaluation using spectral OCT, and visual field test.
Eligibility criteria Inclusion criteria were best-corrected visual acuity of at least 20/20, nonsmoking, no drug and alcohol abuse, no medication, less than 2 diopters of cylindrical and/or 4 diopters of spherical refractive error, and absence of glaucomatous findings such as glaucomatous optic disc changes such as excavation, notching, or focal thinning of the neuroretinal rim, peripapillary hemorrhage, retina nerve fiber layer loss, glaucomatous visual field defects, or IOP readings greater than 22 mmHg. Exclusion criteria included any history of retinal diseases, any systemic abnormalities (e.g., vascular disease, hypertension, or diabetes mellitus), a history of previous intraocular surgery or laser therapy, and poor image quality because of unstable fixation or severe cataract.
Study groups
Control group. The subjects received a drop of artificial tear thrice at 5 min intervals.
EDI-OCT measurement The subfoveal choroidal thickness (SFCT) was measured using SD-OCT (Spectralis, Wave-length: 870 nm; Heidelberg Engineering Co.) with EDI modality. The procedure for EDI-OCT measurement has been previously described.4 SFCT was defined as the vertical distance from the hyperreflective line of Bruch’s membrane to the hyper-reflective line of the inner surface of the sclera. The images were taken by one clinician (G.K.), and the images were assessed by another clinician (A.D.). Both of the clinicians were masked in terms of groups. EDI-OCT measurements were performed before the administration of drops and at 45 min after instillation. All measurements were performed between 9:00 am and 12:00 am.
Data analyses Data analysis was performed using the statistical package Statistical Package for the Social Sciences (SPSS) version 16. For each continuous variable, normality was checked by Kolmogorov–Smirnov test. The choroidal thickness measurements of the groups were compared by independent ttest. A comparison of choroidal thickness values between, before, and after instillation of drops was performed using paired t-tests. The categorical variables between the groups were analyzed using the w2 test. Pearson’s correlation was used to examine the relationships among the measured variables. Values of P < 0.05 were considered statistically significant.
After baseline examination, selected subjects were invited the next day for EDI-OCT measurements. The participants were randomly divided into 3 groups based on the application of drops as follows:
Results
Tropicamide group. The subjects received a drop of 1% tropicamide thrice at 5 min intervals.
Demographic profile and baseline clinical characteristic
Phenylephrine group. The subjects received a drop of 2.5% phenylephrine thrice at 5 min intervals.
The study included 90 eyes of 90 subjects: 30 subjects in the tropicamide group, 30 subjects in the phenylephrine
Table 1.
No. of subjects Gender F/M Age, years Mean – SD Range Sphere, D Mean – SD Range AL, mm Mean – SD Range CCT, mm Mean – SD Range IOP, mmHg Mean – SD Range
Demographic and Clinical Characteristics of Three Groups Pa
Tropicamide
Phenylephrine
Control
30
30
30
16/14
19/11
17/13
0.727
33 – 10 23 to 57
39 – 12 20 to 59
32 – 7 19 to 48
0.061
0.06 – 0.85 - 1.50 to 3.25
0.11 – 0.36 0.00 to 1.50
- 0.1 – 1.11 - 2.00 to 2.00
0.707
23.38 – 1.23 21.95 to 28.05
23.47 – 1.05 21.77 to 25.54
22.85 – 1.08 21 to 25
0.112
565 – 33 506 to 641
575 – 44 511 to 698
559 – 10 537 to 576
0.313
16.95 – 3.56 11 to 21
16.5 – 2.94 12 to 21
16.5 – 2.66 11 to 20
0.868
a One-way ANOVA test. SD, standard deviation; F, female; M, male; AL, axial length; CCT, central corneal thickness, IOP, intraocular pressure.
368
Table 2.
KARA ET AL.
Subfoveal Choroidal Thickness Changes Before and After Eye Drop Instillation in Three Groups Dilated eye
Groups Tropicamide Mean – SD Range Phenylephrine Mean – SD Range Control Mean – SD Range
Contralateral eye (nondilated) a
Before
After
Difference
Pa
Before
After
Difference
P
348 – 89 230 to 527
326 – 83 214 to 507
- 22 – 14 - 62 to - 2.0
< 0.001
349 – 89 160 to 511
335 – 87 160 to 527
- 14 – 16 - 64 to - 16
0.001
294 – 90 142 to 480
276 – 85 142 to 447
- 17 – 9 - 33 to 0.0
< 0.001
291 – 96 178 to 534
283 – 95 160 to 511
- 7.9 – 9.0 - 30 to 3.0
0.001
342 – 81 212 to 506
348 – 82 209 to 506
5.3 – 3.5 - 3.0 to 6.0
0.108
354 – 110 173 to 527
354 – 109 176 to 524
0.3 – 3.3 - 7.0 to 7.0
0.695
Boldface indicates that a p-value of less than 0.05 was considered significant. a Paired t-test.
group, and 30 subjects in the control group. The demographic and baseline clinical features of the 3 groups of subjects are shown in Table 1. No statistically significant differences were observed among the groups in terms of age, gender distribution, spherical refraction, AL, CCT, or IOP (P > 0.05 for all).
Discussion
The changes in SFCT are documented in Table 2. In the tropicamide and phenylephrine groups, the SFCT was significantly decreased after drop instillation in both the dilated eye and contralateral eye (P < 0.001 and P = 0.001 for both groups) (Figs. 1 and 2). In the control group, the SFCT did not significantly differ after drop instillation in either the dropped eye or contralateral eye (P = 0.108 and P = 0.695). A pairwise comparison of groups for changes in SFCT is shown in Table 3. SFCT changes after drop instillation were significantly higher in the tropicamide group than in the control group in the dilated eye (P = 0.008 and P = 0.003, respectively), and significantly higher in the phenylephrine group than in the control group in the dilated eye (P = 0.032). The change in SFCT was also significantly greater in the tropicamide group than in the control group in the contralateral eye (P = 0.003).
This observational study showed that tropicamide and phenylephrine caused a significant decrease in SFCT in both the dilated and nondilated contralateral eyes. In addition, the changes in SFCT did not significantly differ between the tropicamide and phenylephrine groups in either the dilated or contralateral eyes. Mydriatics are regularly used to dilate pupils in patients presenting to ophthalmology clinics for assessment and in follow up for a wide variety of ophthalmic conditions. Commonly used mydriatics include phenylephrine and tropicamide. Phenylephrine is a sympathetic agonist that exerts its mydriatic effect by activating sympathetic receptors on the iris dilator muscle. Tropicamide, on the other hand, is an anticholinergic agent that enhances pupil dilation by inhibiting iris sphincter muscle action. Phenylephrine has no cycloplegic effect, but tropicamide has a cycloplegic effect. Mydriatics lead to changes in iris thickness, angle, and the morphology of the iridociliary region.20 As a part of the uveal structure, the choroid can also be affected by the contraction and relaxation of ciliary muscles induced by the instillation of mydriatics. Choroidal thickness changes after instillation of mydriatics may be explained by several possible mechanisms. Due to the previously suggested
FIG. 1. Subfoveal choroidal thickness (SFCT) values before and after eye drop instillation in 3 groups in the dropped eye.
FIG. 2. SFCT values before and after eye drop instillation in 3 groups in the contralateral eye.
Choroidal thickness changes
MYDRIATICS AND CHOROIDAL THICKNESS
Table 3.
369
Pairwise Comparison of Subfoveal Choroidal Thickness Changes Between the Groups Dilated eye
Contralateral eye (nondilated) 95% confidence interval
Groups T T P
P C C
95% confidence interval
Mean difference
SE
Pa
Lower bound
Upper bound
Mean difference
SE
Pa
Lower bound
Upper bound
- 4.15 - 27.40b - 23.25b
8.28 8.28 8.28
0.959 0.008 0.032
- 25.92 - 49.17 - 45.02
17.62 - 5.62 - 1.47
- 6.20 - 14.40b - 8.20
3.95 3.95 3.95
0.404 0.003 0.172
- 16.60 - 24.80 - 18.60
4.20 - 3.99 2.20
Boldface indicates a p-value of less than 0.05 was considered significant. a Tukey’s post hoc test. b The mean difference is significant at the 0.05 level. T, tropicamide group; P, penylephrine group; C, control group; SE, standard error.
connection between nonvascular smooth muscle cells beneath the fovea and ciliary muscle fibers,1 mydriatics may alter choroidal thickness. Furthermore, the choroid contains nonvascular smooth muscle that is innervated by both sympathetic and parasympathetic inputs.21–23 Therefore, topical mydriatic administration may induce the contraction of nonvascular smooth muscle in the choroid. Contraction of these smooth muscles might result in the efflux of fluid out of the choroid, which results in a thinning of the choroid.1 Moreover, since both sympathomimetics and anticholinergics have vasoconstricting effects, tropicamide and phenylephrine may lead to vasoconstriction of the choroidal vascular bed, which results in choroidal thinning. In contrast to our study, 2 previous studies have reported that mydriatics did not influence choroidal thickness measurement.24,25 Kim et al. investigated the influence of MydrinP (tropicamide 5 mg/mL and phenylephrine 5 mg/mL; Santen Pharmaceuticals) on choroidal thickness measurement in healthy subjects using EDI-OCT.24 Their study demonstrated that a phenylephrine and tropicamide combination had no significant influence on choroidal thickness measurement at the subfoveal region and at 0.5 mm intervals (up to 3.0 mm) from the fovea at nasal, temporal, superior, and inferior locations. In another study, Mwanza et al. compared choroidal thickness measurements obtained before and after pupil dilation with tropicamide 1% in healthy individuals and glaucoma patients using SD-OCT.25 They reported that pupil dilation with tropicamide 1% did not have an effect on choroidal thickness in either healthy subjects or glaucomatous patients. While our results differ from the findings of 2 previous studies, we also investigated the crossover effects of mydriatics on choroidal thickness, which is a strength of our study compared with the 2 previous studies. We found that a significant decrease in SFCT after tropicamide or phenylephrine instillation was observed in undilated contralateral eyes. Systemic absorption of topical ocular drugs occurs by the nasal mucosa or after absorption through the cornea and conjunctiva. The drug accumulates in the aqueous humor and may be distributed via systemic circulation through the trabecular meshwork pathway.26 In this manner, topical application of ophthalmic drops either may cause changes in the contralateral eye or may cause systemic side-effects.27–29 Choroidal thickness measurements may be influenced by several factors that should be considered when choroidal thickness is evaluated. Aging is one factor that affects choroidal thickness, and older patients have thinner choroids.5,10,13,15 High myopia and AL have been found to be
associated with a significantly thinner choroid.5,10,13,15,17,30 Sızmaz et al. currently reported that smoking 1 cigarette induced a significant decrease in choroidal thickness, which continued to last for at least 3 h.19 To the best of our knowledge, our study contributes a new finding to the literature, which is that the application of mydriatics affects SFCT measurements in the dropped eye and the un-dropped contralateral eye, which should be considered when choroidal thickness is measured. However, our study has some limitations. The manual measurement of SFCT is one of the principal drawbacks of this study. Current OCT equipment does not provide software for the automated measurement of choroidal thickness. Moreover, the reproducibility of choroidal thickness measurements using OCT is still debatable. However, some studies found high interobserver correlation, high repeatability, and high intersystem, interexaminer, and intervisit reproducibility in choroidal thickness measurements.4,30,31 The study investigated the effect of 1% tropicamide and 2.5% phenylephrine on choroidal thickness. Hence, the current findings cannot be directly extrapolated to other mydriatics that contain different tropicamide or phenylephrine concentrations. In addition, the baseline SFCT thickness was lower in the phenylephrine group than in tropicamide and control groups. This may be related with many factors such as age and AL, which were higher in the phenylephrine group. However, the main purpose of this study was not to compare the baseline and follow-up SFCT values. We investigated the changes in SFCT after mydriatics. In conclusion, the study showed that pupil dilatation with tropicamide or phenylephrine leads to a decrease in SFCT. This result should be taken into consideration when choroidal thickness is evaluated in chorioretinal disease or clinical research.
Author Disclosure Statement No author has a financial or proprietary interest in any material or method mentioned.
References 1. Nickla, D.L., and Wallman, J. The multifunctional choroid. Prog. Retin. Eye Res. 29:144–168, 2010. 2. Parver, L.M. Temperature modulating action of choroidal blood flow. Eye (Lond). 5:181–185, 1991. 3. Cao, J., McLeod, S., Merges, C.A., and Lutty, G.A. Choriocapillaris degeneration and related pathologic changes in
370
4. 5.
6. 7.
8.
9. 10.
11.
12.
13. 14.
15. 16.
17. 18. 19.
KARA ET AL.
human diabetic eyes. Arch. Ophthalmol. 116:589–597, 1998. Spaide, R.F., Koizumi, H., and Pozzoni, M.C. Enhanced depth imaging spectral-domain optical coherence tomography. Am. J. Ophthalmol. 146:496–500, 2008. Fujiwara, T., Imamura, Y., Margolis, R., Slakter, J.S., and Spaide, R.F. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am. J. Ophthalmol. 148:445–450, 2009. Zeng, J., Li, J., Liu, R., et al. Choroidal thickness in both eyes of patients with unilateral idiopathic macular hole. Ophthalmology. 119:2328–2333, 2012. Dhoot, D.S., Huo, S., Yuan, A., et al. Evaluation of choroidal thickness in retinitis pigmentosa using enhanced depth imaging optical coherence tomography. Br. J. Ophthalmol. 97:66–69, 2013. Kim, S.W., Oh, J., Kwon, S.S., Yoo, J., and Huh, K. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina. 31:1904–1911, 2011. Nagaoka, T., Kitaya, N., Sugawara, R., et al. Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br. J. Ophthalmol. 88:1060–1063, 2004. Agawa, T., Miura, M., Ikuno, Y., et al. Choroidal thickness mea-surement in healthy Japanese subjects by threedimensional high-penetration optical coherence tomography. Graefes Arch. Clin. Exp. Ophthalmol. 249:1485–1492, 2011. Manjunath, V., Taha, M., Fujimoto, J.G., and Duker, J.S. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am. J. Ophthalmol. 150:325–329, 2010. Hirata, M., Tsujikawa, A., Matsumoto, A., et al. Macular choroidal thickness and volume in normal subjects measured by swept-source optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:4971–4978, 2011. Ikuno, Y., Kawaguchi, K., Nouchi, T., and Yasuno, Y. Choroidal thickness in healthy Japanese subjects. Invest. Ophthalmol. Vis. Sci. 51:2173–2176, 2010. Maul, E.A., Friedman, D.S., Chang, D.S., et al. Choroidal thickness measured by spectral domain optical coherence tomogra-phy. Factors affecting thickness in glaucoma patients. Ophthalmology. 118:1571–1579, 2011. Margolis, R., and Spaide, R.F. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am. J. Ophthalmol. 147:811–815, 2009. Mwanza, J.C., Hochberg, J.T., Banitt, M.R., Feuer, W.J., and Budenz, D.L. Lack of association between glaucoma and macular choroidal thickness measured with enhanced depth-imaging optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:3430–3435, 2011. Brown, J.S., Flitcroft, D.I., Ying, G.S., et al. In vivo human choroidal thickness measurements: evidence for diurnal fluctuations. Invest. Ophthalmol. Vis. Sci. 50:5–12, 2009. Francis, B.A., Wang, M., Lei, H., et al. Changes in axial length following trabeculectomy and glaucoma drainage device surgery. Br. J. Ophthalmol. 89:17–20, 2005. Sızmaz, S., Kucukerdonmez, C., Pınarcı, E.Y., Karalezli, A., Canan, H., and Yılmaz, G. The effect of smoking on choroidal thickness measured by optical coherence tomography. Br. J. Ophthalmol. 97:601–604, 2013.
20. Marchini, G., Babighian, S., Tosi, R., Perfetti, S., and Bonomi, L. Comparative study of the effects of 2% ibopamine, 10% phenylephrine, and 1% tropicamide on the anterior segment. Invest. Ophthalmol. Vis. Sci. 44:281–289, 2003. 21. Schrodl, F., De Laet, A., Tassignon, M.J., et al. Intrinsic choroidal neurons in the human eye: projections, targets, and basic electrophysiological data. Invest. Ophthalmol. Vis. Sci. 44:3705–3712, 2003. 22. Schrodl, F., Tines, R., Brehmer, A., and Neuhuber, W.L. Intrinsic choroidal neurons in the duck eye receive sympathetic input: anatomical evi-dence for adrenergicmodulation of nitrergic functions in the choroid. Cell Tissue Res. 304:175–184, 2001. 23. May, C.A., Neuhuber, W., and Lutjen-Drecoll, E. Immunohistochemical classification and functional morphology of human choroidal gan-glion cells. Invest. Ophthalmol. Vis. Sci. 45:361–367, 2004. 24. Kim, M., Kwon, H.J., and Lee, S.C. Influence of mydriatics on choroidal thickness measurement using enhanced depth imaging-OCT. Optom. Vis. Sci. 89:1150–1155, 2012. 25. Mwanza, J.C., Sayyad, F.E., Banitt, M.R., and Budenz, D.L. Effect of pupil dilation on macular choroidal thickness measured with spectral domain optical coherence tomography in normal and glaucomatous eyes. Int. Ophthalmol. 33:335–341, 2013. 26. Chien, D.S., Homsy, J.J., Gluchowski, C., and Tang-Liu, D.D. Corneal and conjunctival/scleral penetration of p-aminoclonidine, AGN 190342, and clonidine in rabbit eyes. Curr. Eye Res. 9:1051–1059, 1990. 27. Alpay, A., Ermis, B., Ugurbas, S.C., Battal, F., and Sagdik, H.M. The local vasoconstriction of infant’s skin following instillation of mydriatic eye drops. Eur. J. Clin. Pharmacol. 66:1161–1164, 2010. 28. Gray, C. Systemic toxicity with topical ophthalmic medications in children. Paediatr. Perinat. Drug Ther. 7:23–29, 2006. 29. Ogut, M.S., Bozkurt, N., Ozek, E., Birgen, H., Kazokoglu, H., and Ogut, M. Effects and side effects of mydriatic eyedrops in neonates. Eur. J. Ophthalmol. 6:192–196, 1996. 30. Rahman, W., Chen, F.K., Yeoh, J., Patel, P., Tufail, A., and Da Cruz, L. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:2267–2271, 2011. 31. Ikuno, Y., Maruko, I., Yasuno, Y., et al. Reproducibility of retinal and choroidal thickness measurements in enhanced depth imaging and high-penetration optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 52:5536–5540, 2011.
Received: May 4, 2013 Accepted: December 2, 2013 Address correspondence to: Dr. Necip Kara Department of Ophthalmology Sehitkamil Government Hospital Pancarli Mh., 15 nolu Sk No. 9, Sehitkamil Gaziantep 27060 Turkey E-mail: [email protected]
