Effects of brimonidine tartrate 0.2% and 0.15% ophthalmic solution on the static and dynamic pupil characteristics

doi:10.21203/rs.3.rs-2243758/v1

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Effects of brimonidine tartrate 0.2% and 0.15% ophthalmic solution on the static and dynamic pupil characteristics

https://doi.org/10.21203/rs.3.rs-2243758/v1

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Purpose:

To investigate the differences between 0.2% and 0.15% brimonidine tartrate eye drops for anti-mydriatic effects and the optical quality under different light conditions.

Methods

This prospective study involved 50 consecutive high myopia patients undergoing implantation of a V4c ICL. 0.2% brimonidine was administered into the right eye, and 0.15% brimonidine was administered into the left eye of the patients 1 month postoperatively. Visual quality (measured by optical quality analysis system), pupil center, pupil size and refraction under different light conditions were measured before and 0.5h after brimonidine administration. A symptom questionnaire was also evaluated.

Results

There was no statistical difference in the static and dynamic PD and velocity data after LS between the two groups (P>0.05). The 0.2% group had significant changes in pupil center before and after treatment, while there was no obvious movement of the pupil center of the 0.15% group under all illumination condition (P>0.05). The OSI after treatment of the 0.15% group was lower than that of 0.2% group (P=0.012). The PVA9% and PVA100% of the 0.15% group was higher than that of 0.2% group in the dark (P=0.009, P=0.012). The HOA RMS of the 0.15% group was lower than that of 0.2% group (P=0.016). The QIRC score in the 0.15% group was significantly higher than that in the 0.2% group (P=0.043).

Conclusion

0.15% and 0.2% brimonidine tartrate eye drops had similar anti-mydriatic ability, while 0.15% group had better visual quality than 0.2% concentration, and hardly introduced pupil shift. 0.15% brimonidine tartrate eye drops may be more suitable for patients with nocturnal glare symptoms in the early postoperative period after ICL implantation.

Health sciences/Diseases/Eye diseases/Refractive errors

Health sciences/Diseases/Eye diseases/Lens diseases

ICL V4c

High myopia

Brimonidine tartrate

Visual quality

Scotopic pupil

Implantation of phakic intraocular lenses (pIOLs) to correct high myopia or super high myopia can help obtain better vision and visual quality, which is currently a primary surgical method for correcting myopia ^{[1, 2]}. Currently, the widely used phakic posterior chamber implantable collamer lens is implantable collamer lens (ICL), produced by STAAR Surgical ^[3–5]. The current ICL has a 0.36mm aperture in the center which requires no peripheral iridectomy of the patient and allows the circulation of aqueous humor to prevent pupillary block ^[4]. Numerous extensive sample size studies have confirmed that it is a safe and predictable operation method ^[5–8]. In the early stage of ICL surgery, some patients complained dysphotopsia at night, such as ring-shaped ^{[9, 10]}. Recent studies have shown that such visual impairment might be related to pupil dynamics ^[9–12].

Brimonidine is a selective alpha-2 adrenergic receptor agonist that reduces intraocular pressure by reducing aqueous humor production and increasing uveoscleral outflow, and is a commonly used drug for the treatment of glaucoma and ocular hypertension ^[13]. Studies have demonstrated that brimonidine inhibits pupil dilation by stimulating prenodal α2 agonist receptors and reducing synaptic norepinephrine release, and brimonidine tartrate eye drops of 0.2% and 0.15% have been reported to be effective in inhibiting pupil dilation ^{[14, 15]}. It can significantly reduce pupil diameter under scotopic conditions, and can effectively reduce glare and halos after refractive surgery ^{[14, 15]}. Although previous studies have explored the miotic effect of 0.2% and 0.15% brimonidine tartrate eye drops, respectively, in scotopic conditions, no study has compared 0.2% and 0.15% brimonidine tartrate eye drops in scotopic conditions. The differences of effects in anti-mydriatic, on the pupil center, and on the optical quality had not been studied.

1. Study Population

A total of 50 high myopia patients who underwent ICL implantation at the Ophthalmology Department of the First Affiliated Hospital of Zhengzhou University between January 2021 and December 2021 were enrolled in this prospective observational study. Table 1 shows the baseline data for all patients. All patients received a comprehensive eye examination and were informed of the operation-related risks before surgery. In addition, all patients expressed understanding and acceptance and signed a consent form to undergo surgery. The inclusion criteria were: 1) 20–40 years old; 2) myopia ≥ 6.00 D, diopter increase ≤ 0.5 D for two consecutive years; 3) anterior chamber depth (ACD) measured by corneal topography measurements (Sirius; Costruzione Strumenti Oftalmici, Florence, Italy) ≥ 2.80 mm, and corneal endothelial cell count ≥ 2,000/mm²; 4) preoperative intraocular pressure is normal; 5) desire to remove the glasses. The exclusion criteria were: 1) previous corneal refractive surgery, internal eye surgery history, or history of eye trauma; 2) combined cataract, glaucoma history, amblyopia, retinal detachment, uveitis, incomplete eyelid closure, and other eye diseases; 3) systemic organic diseases that affect recovery from surgery; 4) psychological and mental diseases such as severe anxiety and depression. The ethics committee of Zhengzhou University’s First Affiliated Hospital gave its approval to this study, and followed the tenets of the Declaration of Helsinki. Prior to participation in the study, all patients signed a written informed permission form.

Table 1

Demographic data of the study population pre-/ post- V4c ICL implantation
Parameter
Number of patients (eyes)		50 (100)
Sex (male: female)		17: 33
Age (years)		25.35 ± 4.59
WTW (mm)		11.54 ± 0.35
ACD (mm)		3.15 ± 0.24
CCT (µm)		517.92 ± 27.41
ICL Size (mm)		12.69 ± 0.39
	Preoperative		Postoperative	P Value
UDVA (logMAR)	1.42 ± 0.42		0 ± 0.11	< 0.003
CDVA (logMAR)	0.07 ± 0.11		-0.08 ± 0.12	< 0.001
Spherical (D)	-9.07 ± 3.17		0.26 ± 0.49	< 0.001
Cylindrical (D)	-1.64 ± 1.06		-0.38 ± 0.37	< 0.006
Spherical equivalent (D)	-9.92 ± 3.38		0.10 ± 0.45	< 0.001
Axial length (mm)	27.25 ± 1.26		27.24 ± 1.30	0.638
ECD (cells/mm²)	2899.19 ± 216.93		2735.32 ± 201.47	0.199
IOP (mmHg)	16.36 ± 2.41		15.48 ± 1.71	0.989

2. Surgical methods

ICL V4c implantation procedures were performed by one experienced surgeon (WW). 1/2 hour before the operation, the assistant applied the compound tropicamide eye drops to the surgical eye to dilate the pupil. The patient was placed in the supine position, and after disinfection and draping, 0.4% oxybuprocaine surface anesthesia was performed. A 3.0mm clear corneal incision was made about 1.0mm away from the temporal corneal limbus and pushed the ICL lens into the anterior chamber using a particular injection device. After the lens naturally expanded, the viscoelastic was injected, and the loop was implanted into the ciliary sulcus behind the iris through the adjusting hook. After adjusting the lens's position, the viscoelastic surgical agent was removed using the compound sodium chloride. Postoperative medications included antibiotics eye drops, non-steroidal anti-inflammatory eye drops, steroidal eye drops, and artificial tears.

3. Measurements

Each eye underwent comprehensive preoperative evaluations. The anterior chamber depth (ACD), anterior chamber angle (ACA), central corneal thickness (CCT), and horizontal white-to-white diameter (hWTW) were assessed using Sirius topography (CSO, Florence, Italy). Performed the following measurements and procedures: uncorrected distance visual acuity, corrected distance visual acuity, manifest refraction spherical equivalent (MRSE), intraocular pressure measurement (IOP), endothelial cell density (ECD), and axial length (AL). ICL V4c was calculated based on the vertex formula of the software (https://evo-ocos.staarag.ch). The following parameters were collected one month postoperatively: manifest refraction, logMAR UDVA, logMAR CDVA, and IOP.

4. Pupillometry

Pupillometry was performed by a single physician under the same environmental conditions 2 weeks postoperatively. To minimize the effect of circadian variation on PD and pupil motility, all measurements were performed at the same time of day (between 9:00 AM and 11:00 AM). Pupillography module of Sirius topography (CSO, Florence, Italy) was used, the measurement shooting page and data display page of pupillography module are shown in Supplementary File S1 and Supplementary File S2. For patients at 2 weeks postoperatively, 0.2% brimonidine was administered into randomly into one eye, 0.15% brimonidine was dropped into the contralateral eye. Both the patients and the examiner were masked to the ophthalmic solution. All parameters were measured before and 30 minutes after eye drops administration. Static pupillometry was conducted for the PD (mm) under 3 standardized illumination conditions: scotopic (0.4 lux), mesopic (4 lux), and photopic (40 lux) light conditions. At least three consecutive measurements of PD were taken at each illumination level, and the average values were selected for analysis. After 15 minutes of dark adaptation, dynamic pupillometry was measured. The capture is begun with the disk rings fully illuminated (500 lux ca.), it is switched off at the moment capture begins. In this manner, it is possible to monitor pupil dilation in conditions from photopic to scotopic conditions and analyze pupil size and pupil offset instant by instant. After at least three valid responses were recorded, the average pupil dynamics were automatically quantified, including the initial PD, smallest PD after light stimulation, velocity of pupil dilation within 1 second, within 2 seconds, and between 1 second and 2 second.

5. Optical quality measurement

The modulation transfer function (MTF) cutoff frequency, Strehl ratio, objective scattering index (OSI), and predicted visual acuities (PVAs, 100, 20, and 9%) under scotopic and photopic lighting conditions were measured using the Optical Quality Analysis System™ (OQAS; Visiometrics, Terrassa, Spain) preoperatively and at one month after surgery. First, scotopic measurements were performed in a dark room, with the addition of black covers on the instrument to rule out any influence of light from the computer screen. Second, photopic measurements were performed after turning on the room light source, and a light reflex was induced by shining a penlight (250 lm) into the contralateral eye. All of the above measurements were performed under the corresponding pupil diameter. All the manifest refractive errors were fully corrected during these measurements. All measurements were performed three times, and the mean value was calculated and recorded. According to the measuring principle of OQAS, participants with lower OSI, higher MTF cutoff, higher Strehl ratio and higher PVAs tend to have better optical quality, and the determination of the fundamentals and definitions of the parameters have been described previously ^[16].

6. Corneal aberrations measurement

The total corneal aberrations in a 6-mm zone were obtained from corneal tomography. Parameters of corneal aberrations included total RMS, LOA RMS (referring to the Zernike coefficients of order 2), and HOA RMS (referring to the Zernike coefficients of order greater than 2). In general, participates with lower RMS tend to have better optical quality.

7. Quality of Life Impact of Refractive Correction

Quality of Life Impact of Refractive Correction (QIRC) questionnaire was developed and validated for assessing the quality of life of people with refraction corrections, including those who accept refractive surgery. QIRC was developed by Pesudovs et al ^[17], and adapted for use in Chinese by Xu et al ^[18]. A total of 20 items are included in this scale under the following four modules: postoperative symptoms, visual and physical functions, social activities, and mental health. Postoperative changes in physical, physiological, psychological, and social health of patients are comprehensively evaluated. Clinically, its Chinese edition is highly reliable and valid and can be used to evaluate the quality of life of refractive surgery patients. In general, higher scores represent subjects with higher visual quality for life.

8. Statistical analysis

All statistical analyses were performed using SPSS version 24.0 (SPSS Inc., IBM, USA). The results are expressed as the mean ± SD. Use a paired t-test on data that fits a normal distribution. Comparison of data between multiple groups using analysis of variance (ANOVA) with Bonferroni. A P value less than 0.05 was considered statistically significant.

The study comprised 50 patients. No intraoperative or short-term postoperative events were observed in any of the eyes. At 2 weeks postoperatively, the mean logMAR UDVA and CDVA were − 0.01 ± 0.12 and − 0.08 ± 0.12, respectively. The mean values of the efficacy indexes of all 100 eyes were 1.18 ± 0.19 (Fig. 1A), all the eyes had postoperative UDVA ≥ 20/33, and 82% of the eyes achieved better than 20/20. None of the eyes lost 1 or more lines of CDVA, 16% remained unchanged, 78% gained 1 line, and 4% gained 2, and 2% gained more than 2 lines (Fig. 1B). The mean values of the safety indexes of all 100 eyes were 1.23 ± 0.21. In 56% of the eyes (Fig. 1C), the preoperative CDVA was maintained, in 32%, it increased by one line, in 8%, it increased by two lines, in 4% it by more than two lines, and no CDVA declined. A scatterplot and the best linear fit line (r = 0.9776) of the attempted versus the achieved SE correction are shown in Fig. 1D Of all the eyes, 94% were within ± 1.00 D (Fig. 1D, green lines) and 100% were within ± 2.00 D of the desired SE refraction (Fig. 1D, purple lines).

1. Pupillary Characteristics

As shown in Table 2, 0.2% and 0.15% groups had no significant difference in the static and dynamic pupillary parameters before instillation(P > 0.05). Pupil diameter prior to installation was 6.58 ± 0.75 mm (photopic PD), 5.04 ± 0.94 mm (mesopic PD) and 4.08 ± 0.77 mm (photopic PD) for the 0.2% group and 6.47 ± 0.76 mm (photopic PD), 4.96 ± 0.77 mm (mesopic PD) and 4.20 ± 0.54 mm (photopic PD) for the 0.15% group, with no significant differences (P > 0.05). After instillation, the scotopic PD, mesopic PD and photopic PD of the 0.2% post and the 0.15% post were both significantly smaller than pre-PD. The pupil dilation velocities within 1S, 2S, and 1S-2S after LS of both groups were significantly slower than those before instillation. While there was no statistical difference in the static and dynamic PD and velocity data after LS between the two groups.

Table 2

Pupil size and pupil dynamics in brimonidine-treated eyes before, and at 1/2 h after instillation
	0.2% Pre	0.15% Pre	0.2% Post	0.15% Post	P ^a Value	P ^b Value	P ^c Value	P ^d Value
Scotopic PD (mm)	6.58 ± 0.75	6.47 ± 0.76	5.16 ± 1.15	4.88 ± 1.09	0.859	0.209	< 0.001	0.008
Mesopic PD (mm)	5.04 ± 0.94	4.96 ± 0.77	4.06 ± 0.89	3.95 ± 0.63	0.653	0.384	0.001	0.001
Photopic PD (mm)	4.08 ± 0.77	4.20 ± 0.54	3.48 ± 0.47	3.35 ± 0.62	0.398	0.083	0.002	< 0.001
Initial PD (mm)	4.07 ± 0.64	4.11 ± 0.69	3.17 ± 0.42	3.08 ± 0.37	0.305	0.406	0.008	0.003
Minimum PD after LS (mm)	3.73 ± 0.64	3.53 ± 0.48	3.23 ± 0.50	3.18 ± 0.53	0.166	0.503	0.006	0.027
V_0 − 1s after LS (mm/s)	0.73 ± 0.15	0.76 ± 0.21	0.41 ± 0.13	0.50 ± 0.20	0.582	0.059	< 0.001	< 0.001
V_0 − 2s after LS (mm/s)	0.58 ± 0.11	0.64 ± 0.16	0.29 ± 0.10	0.33 ± 0.14	0.221	0.340	< 0.001	0.001
V_1 − 2s after LS (mm/s)	0.43 ± 0.11	0.51 ± 0.15	0.17 ± 0.12	0.16 ± 0.13	0.171	0.859	< 0.001	< 0.001
Pre = before instillation of brimonidine, Post = 30 minutes after instillation of brimonidine.
P ^a Values for the analysis of t tests performed between 0.2% Pre and 0.15% Pre.
P ^b Values for the analysis of t tests performed between 0.2% Post and 0.15% Post.
P ^c Values for the analysis of t tests performed between 0.2% Pre and 0.2% Post.
P ^d Values for the analysis of t tests performed between 0.15% Pre and 0.15% Post.

2. Pupil Center

Pupil center coordinates prior to installation were scotopic (-0.08 ± 0.14, 0.04 ± 0.12), mesopic (0 ± 0.14, 0.06 ± 0.11) and photopic (0 ± 0.16, 0.04 ± 0.12) for the 0.2% group and scotopic (-0.05 ± 0.12, 0.02 ± 0.13), mesopic (-0.03 ± 0.12, 0.01 ± 0.10) and photopic (-0.06 ± 0.14, 0.03 ± 0.13) for the 0.15% group, with no significant differences (Table 3, P > 0.05). 0.2% group had significant changes in pupil center before and after treatment. Among them, the X-axis coordinates of the scotopic pupil center in the 0.2% group moved from − 0.08 ± 0.14mm to 0.03 ± 0.17mm (P = 0.006), showing that the pupil center moved to the nasal side (Fig. 2A). The Y-axis coordinate of the mesopic pupil center in the 0.2% group moved from 0.06 ± 0.11mm to -0.03 ± 0.50mm (P = 0.046), showing the pupil center moved downward (Fig. 2B). While in the photopic environment, the X-axis and Y-axis of the pupil centers did not change significantly. There was no obvious movement of the pupil center of the 0.15% group compared with that before administration under all illumination condition (P > 0.05).

Table 3

Mean mean pupil barycentre configurations in brimonidine-treated eyes before, and at 1/2 h after instillation
		0.2% Pre	0.15% Pre	0.2% Post	0.15% Post	P ^a Value	P ^b Value	P ^c Value	P ^d Value
Scotopic	Xc (mm)	-0.08 ± 0.14	-0.05 ± .12	0.03 ± 0.17	-0.03 ± 0.17	0.630	0.478	0.006	0.218
Scotopic	Yc (mm)	0.04 ± 0.12	0.02 ± 0.13	0.03 ± 0.46	-0.01 ± 0.55	0.246	0.848	0.813	0.754
Mesopic	Xc (mm)	0.00 ± 0.14	-0.03 ± 0.12	0.02 ± 0.18	-0.04 ± 0.14	0.604	0.515	0.946	0.933
Mesopic	Yc (mm)	0.06 ± 0.11	0.01 ± 0.10	-0.03 ± 0.50	-0.06 ± 0.52	0.229	0.913	0.046	0.584
Photopic	Xc (mm)	0.00 ± 0.16	-0.06 ± 0.14	0.03 ± 0.17	-0.08 ± 0.11	0.249	0.140	0.811	0.952
Photopic	Yc (mm)	0.04 ± 0.12	0.03 ± 0.13	0.10 ± 0.11	0.09 ± 0.10	0.618	0.830	0.071	0.076
Pre = before instillation of brimonidine, Post = 30 minutes after instillation of brimonidine.
P ^a Values for the analysis of t tests performed between 0.2% Pre and 0.15% Pre.
P ^b Values for the analysis of t tests performed between 0.2% Post and 0.15% Post.
P ^c Values for the analysis of t tests performed between 0.2% Pre and 0.2% Post.
P ^d Values for the analysis of t tests performed between 0.15% Pre and 0.15% Post.

3. Visual Quality

Table 4 shows the pre-instillation and post-instillation optical quality. Both in the 0.2% and 0.15% groups, all optical quality parameters were significantly improved after treatment with brimonidine eye drops. To further analyze the optical quality data, we measured the change in each optical quality parameter at various time points (30 min after therapy and pre-therapy, shown as OSI, MTF, SR, PVA_100%, PVA_20%, and PVA_9%).

Table 4

Optical quality parameters in brimonidine-treated eyes before and at 1/2 h after instillation under different lighting conditions
		0.2% Pre	0.15% Pre	0.2% Post	0.15% Post	P ^a Value	P ^b Value	P ^c Value	P ^d Value
Bright	OSI	1.09 ± 0.53	1.10 ± 0.50	0.86 ± 0.56	0.82 ± 0.55	0.928	0.375	0.034	0.036
	MTF	35.44 ± 0.55	36.05 ± 0.53	41.01 ± 0.56	44.07 ± 0.54	0.915	0.004	0.028	0.017
	SR	0.21 ± 0.07	0.21 ± 0.69	0.23 ± 0.12	0.23 ± 0.16	0.695	0.116	0.031	0.003
	PVA100%	1.13 ± 0.07	1.14 ± 0.09	1.32 ± 0.08	1.33 ± 0.09	0.778	0.229	0.019	0.038
	PVA20%	0.87 ± 0.03	0.86 ± 0.04	0.99 ± 0.07	1.00 ± 0.06	0.375	0.441	0.021	0.037
	PVA9%	0.53 ± 0.04	0.54 ± 0.02	0.58 ± 0.02	0.61 ± 0.03	0.562	0.117	0.047	0.039
Dark	OSI	1.05 ± 0.35	1.03 ± 0.41	0.89 ± 0.49	0.78 ± 0.40	0.834	0.012	0.032	0.018
	MTF	26.95 ± 0.49	27.01 ± 0.51	31.56 ± 0.48	34.71 ± 0.58	0.732	0.142	0.021	0.002
	SR	0.15 ± 0.03	0.16 ± 0.02	0.18 ± 0.03	0.19 ± 0.03	0.683	0.384	0.003	0.032
	PVA100%	0.90 ± 0.06	0.89 ± 0.07	1.10 ± 0.06	1.13 ± 0.07	0.372	0.102	0.006	0.023
	PVA20%	0.62 ± 0.05	0.60 ± 0.04	0.79 ± 0.03	0.80 ± 0.04	0.424	0.310	0.003	0.002
	PVA9%	0.37 ± 0.04	0.38 ± 0.03	0.44 ± 0.04	0.48 ± 0.03	0.243	0.090	0.027	0.041
Pre = before instillation of brimonidine, Post = 30 minutes after instillation of brimonidine.
P ^a Values for the analysis of t tests performed between 0.2% Pre and 0.15% Pre.
P ^b Values for the analysis of t tests performed between 0.2% Post and 0.15% Post.
P ^c Values for the analysis of t tests performed between 0.2% Pre and 0.2% Post.
P ^d Values for the analysis of t tests performed between 0.15% Pre and 0.15% Post.

The MTF of the 0.2% and 0.15% groups were both significantly higher than that of pre-treatment. In the bright environment, the MTF of the 0.2% group was increased from 35.44 ± 0.55 to 41.01 ± 0.56 (P = 0.028), and the MTF of the 0.15% group was increased from 36.05 ± 0.53 to 44.07 ± 0.54 (P = 0.017), the MTF after treatment of the 0.15% group was higher than that of 0.2% group (P = 0.004). And in the dark environment, the OSI of the 0.2% group was decreased from 1.05 ± 0.35 to 0.89 ± 0.49 (P = 0.032), and the OSI of the 0.15% group was decreased from 1.03 ± 0.41 to 0.78 ± 0.40 (P = 0.018), the OSI after treatment of the 0.15% group was lower than that of 0.2% group (P = 0.012).

4. Corneal Aberrations

Table 5 shows the pre-instillation and post-instillation scotopic corneal aberrations. Both in the 0.2% and 0.15% groups, all corneal aberrations parameters were significantly improved after treatment with brimonidine eye drops (shown as LOA RMS, HOA RMS, RMS and SR). The RMS of the 0.2% and 0.15% groups were both significantly lower than that of pre-treatment. The RMS of the 0.2% group was reduced from 1.09 ± 0.53 to 1.06 ± 0.56 (P = 0.034), and the RMS of the 0.15% group was reduced from 1.10 ± 0.56 to 1.02 ± 0.55 (P = 0.036), while there was no statistical difference in RMS between the 0.2% and 0.15% groups (P = 0.375). The HOA RMS of the 0.15% group decreased from 0.27 ± 0.69 to 0.21 ± 0.16 (P = 0.003), while the HOA RMS of the 0.2% group had no significant differences before and after treatment.

Table 5

Scotopic corneal aberrations in brimonidine-treated eyes before, and at 1/2 h after instillation
	0.2% Pre	0.15% Pre	0.2% Post	0.15% Post	P ^a Value	P ^b Value	P ^c Value	P ^d Value
RMS	1.09 ± 0.53	1.10 ± 0.50	1.06 ± 0.56	1.02 ± 0.55	0.928	0.375	0.034	0.036
LOA RMS	1.04 ± 0.55	1.05 ± 0.53	1.01 ± 0.56	1.07 ± 0.54	0.915	0.004	0.028	0.710
HOA RMS	0.27 ± 0.07	0.27 ± 0.69	0.28 ± 0.12	0.21 ± 0.16	0.695	0.016	0.531	0.003
QIRC score	43.89 ± 5.17	44.10 ± 4.98	46.63 ± 6.03	47.33 ± 4.83	0.703	0.043	0.017	0.012
Pre = before instillation of brimonidine, Post = 30 minutes after instillation of brimonidine.
P ^a Values for the analysis of t tests performed between 0.2% Pre and 0.15% Pre.
P ^b Values for the analysis of t tests performed between 0.2% Post and 0.15% Post.
P ^c Values for the analysis of t tests performed between 0.2% Pre and 0.2% Post.
P ^d Values for the analysis of t tests performed between 0.15% Pre and 0.15% Post.

5. Qirc Score

The QIRC score of the 0.2% and 0.15% groups was significantly higher than that of the point before treatment, which were shown in Table 5. The QIRC score of the 0.2% group increased from 43.89 ± 5.17 to 46.63 ± 6.03 (P = 0.017), and the 0.15% group increased The QIRC score increased from 44.10 ± 4.98 to 47.33 ± 4.83 (P = 0.012), and the QIRC score in the 0.15% group after treatment was significantly higher than that in the 0.2% group (P = 0.043).

6. Manifest Refraction And Iop

The spherical refraction of 0.2% and 0.15% group were 0.39 ± 0.41D and 0.21 ± 0.47D before installation, and the spherical refraction of 0.2% and 0.15% group were 0.40 ± 0.55D and 0.37 ± 0.64D after the treatment, with no significant differences (P > 0.05). The pre-/post-installation cylindrical refraction of 0.2% group (-0.50 ± 0.35 and − 0.51 ± 0.23) and 0.15% group (-0.25 ± 0.36 and − 0.35 ± 0.60) didn’t have significant changes (P > 0.05). And the equivalent spherical of 0.2% and 0.15% group didn’t have significant changes before and after eye drops administration (Table 6, P > 0.05). The IOP before the treatment were 15.67 ± 1.28mmHg and 14.65 ± 2.04mmHg for 0.2% and 0.15% groups, and the IOP after administration were 12.38 ± 1.88mmHg and 11.12 ± 2.11mmHg for 0.2% and 0.15% groups, both 0.2% and 0.15% post showed a significant IOP decreases (P = 0.015, P = 0.034), while there was no statistically significant difference between 0.2% post and 0.15% post (P > 0.05).

Table 6

Refraction parameters and IOP in brimonidine-treated eyes before, and at 1/2 h after instillation
	0.2% Pre	0.15% Pre	0.2% Post	0.15% Post	P ^a Value	P ^b Value	P ^c Value	P ^d Value
Spherical refraction (D)	0.39 ± 0.41	0.21 ± 0.47	0.40 ± 0.55	0.37 ± 0.64	0.156	0.832	0.855	0.617
Cylindrical refraction (D)	-0.50 ± 0.35	-0.25 ± 0.36	-0.51 ± 0.23	-0.35 ± 0.60	0.229	0.426	0.812	0.645
Spherical equivalent (D)	0.13 ± 0.41	0.10 ± 0.50	0.20 ± 0.51	0.19 ± 0.74	0.974	0.961	0.581	0.802
IOP (mmHg)	15.67 ± 1.28	14.65 ± 2.04	12.38 ± 1.88	11.12 ± 2.11	0.282	0.704	0.015	0.034
Pre = before instillation of brimonidine, Post = 30 minutes after instillation of brimonidine.
P ^a Values for the analysis of t tests performed between 0.2% Pre and 0.15% Pre.
P ^b Values for the analysis of t tests performed between 0.2% Post and 0.15% Post.
P ^c Values for the analysis of t tests performed between 0.2% Pre and 0.2% Post.
P ^d Values for the analysis of t tests performed between 0.15% Pre and 0.15% Post.

Clinically, a few patients complain of apparent ring-shaped dysphotopsia in the early postoperative period after ICL V4c implantation ^[11]. Brimonidine tartrate 0.2% and 0.15% ophthalmic solution has been shown to improve the symptoms of ring-shaped dysphotopsia in postoperative ICL patients via pharmacologic miosis ^{[14, 15]}. But no literature exists reporting the differences in the anti-mydriatic effects of the two concentrations. Therefore, this study is the first to compare the anti-mydriatic effect, visual quality, and effect on the pupil center of brimonidine 0.2% and 0.15% in different brightness environments.

Various concentrations of brimonidine (0.1%, 0.15%, and 0.2%) demonstrated their anti-mydriatic effect, which can be used to reduce night vision problems such as halos and glare after laser refractive surgery ^{[14, 15, 19, 20]}. The anti-mydriatic effect of brimonidine on pupil diameter results from brimonidine's a2 agonist activity, which reduces the production, storage and release of norepinephrine into synapses, and thus inhibiting iris dilation ^{[13,14,15,19−21]}. Although the anti-mydriatic effect of brimonidine has been shown in scotopic, mesopic, and photopic conditions, previous research suggested that the anti-mydriatic effect was more prominent in scotopic states because norepinephrine is the primary mediator of nocturnal pupil dilation, brimonidine inhibits the amount of pupil dilation at night by reducing the release of norepinephrine ^[19–21]. In addition, since brimonidine does not induce a miotic effect, the amount of reduction in pupil size is limited ^{[15, 19]}.

Similar to the previous study, we found that pupil size was significantly decreased under scotopic, mesopic and photopic conditions 30 minutes after brimonidine tartrate 0.15% and 0.2% instillation. scotopic PD reduced from 6.58 ± 0.75mm to 5.16 ± 1.15mm after brimonidine tartrate 0.2%, while scotopic PD after brimonidine tartrate 0.15% decreased from 6.47 ± 0.76mm to 4.88 ± 1.09mm. Thorsen et al. reported that under scotopic conditions, 100% and 60% of healthy eyes had a reduction in pupil size of ≥ 1.0 mm at 30 minutes and 6 hours, respectively ^[22]. The results of previous studies showed that the scotopic PD minimized from 7.2 ± 0.4mm to 5.5 ± 0.8mm after 0.2% brimonidine instillation ^[15]; the mean pupil size reduced from 6.09 ± 1.03mm to 4.45 ± 1.04mm after 0.15% brimonidine instillation ^[14]; the photopic and scotopic PD before 0.15% brimonidine instillation was 4.8 ± 1.2 mm and 5.8 ± 1.2 mm, respectively, and 30 minutes after instillation, the photopic and scotopic PD decreased to 4.3 ± 1.1 mm and 5.3 ± 1.0 mm, respectively ^[23]. The present study showed that brimonidine 0.15% and 0.2% had the same anti-mydriatic effect under scotopic, mesopic, and photopic conditions, as well as initial PD and Minimum PD after LS is basically consistent with previous research data trends.

The speed of pupil dilation after light stimulation of 0.2% and 0.15% post-instillation was significantly slower than pre-instillation, and there was no statistical difference between the 0.2% and 0.15% groups. Particularly, velocity within 1 second after LS decelerated from 0.73 ± 0.15mm/s to 0.41 ± 0.13 mm/s after brimonidine tartrate 0.2%, In 0.15% group, velocity within 1 second after LS decreased from 0.76 ± 0.21 mm/s to 0.50 ± 0.20 mm/s. Recent studies had the similar trend, compared with pre-instillation measurements, 0.15% brimonidine treated eyes had significantly lower pupil dilation velocity in all studied seconds, within 1 second, the average speed reduced from 0.79mm/s to 0.37 mm/s ^[23].

The pupil center plays a central role in the optical system of the eye. Retinal image quality is significantly affected by the center of the pupil and the center of the lens. In general, the pupil center is located on the nasal side, slightly above the geometric corneal center. Studies have found a correlation between pupillary excursion (the distance from the center of the pupil to the center of the cornea) and dark pupil diameter, which increases pupillary excursion when pupil diameter is increased by changing lighting conditions from photopic to mesopic, the displacement increased with the pupil diameter of the subjects ^{[24, 25]}. In the present study, the pupil center tended to be closer to the corneal center (the geographic center of the radar map) after treatment with 2 concentrations of brimonidine eye drops. Especially in scotopic and medium scotopic vision, the data of the 0.15% group is more statistically significant. Whereas the visual axis is the line connecting the fovea and the fixation point through the node, the visual axis does not pass through the center of the entrance pupil because the eye is not a rotationally symmetric optical system.

The spherical refraction, cylindrical refraction and spherical equivalent before and after instillation had no significant changes in both groups. The reduction of intraocular pressure had no statistical differences between two groups, which is consistent with the results of previous studies. Previous studies have indicated that brimonidine tartrate reduces intraocular pressure by reducing aqueous humor production and increasing uveoscleral output, and has demonstrated the efficacy and safety of brimonidine in reducing intraocular pressure ^[26]. Numerous studies suggest that preservatives may cause severe ocular toxicity or reduced tolerance, especially after prolonged chronic use and/or frequent dosing, and are often associated with increased OSD frequency. As mentioned earlier, topical antiglaucoma treatments may cause local side effects due to their active ingredients, preservatives, or excipients. Previous studies have shown significant negative changes in tear parameters after 4 weeks of use with preservative brimonidine eye drops. To eliminate this toxicity, attempts have been made to design new eye drop dispensing devices to provide preservative-free formulations. The previous study also compared the efficacy and safety of brimonidine 0.15% twice daily with brimonidine 0.2% twice daily in POAG or OHT patients and concluded that in POAG or OHT patients, brimonidine Nitidine 0.15% provided comparable IOP reduction to brimonidine 0.2%. The advantage of reducing side effects (eg allergic conjunctivitis) is increased patient satisfaction ^[27].

The data of this study showed that with 0.15% and 0.2% concentration of brimonidine eye drops after half an hour of treatment, the visual quality in both bright and dark environments had significantly improved compared with that before the treatment. Among them, in the dark environment, the 0.15% group had significantly higher visual quality than the 0.2% group, manifested in higher OSI, PVA100%, and PVA9%. In bright environments, the 0.15% group also had higher MTF values than the 0.2% group. There could be three explanations for these results. First, 0.15% brimonidine has a better corneal microenvironment after instillation because it is free of preservatives ^[27]. Second, Recent research has proven the halo size correlated independently with OSI ^[28–31]. The objective scatter index (OSI) is an objective parameter to estimate intraocular scattering. The OSI is calculated as the ratio of the amount of light in the peripheral zone (an annular area of 12 and 20 min) to the central zone (central peak of 1 min of arc) of the retinal image ^[32–34]. Third, the 0.15% group had minor HOA RMS in the dark environment than the 0.2% group, which is consistent with the recent research. The corneal higher-order aberrations dependent on corneal microvilli correlated significantly with haloes and optical quality ^[35]。

There are two limitations of this study, the first is that each subject's eyes were studied, this could potentially double our statistical power. This was addressed by reanalyzing the data with each participant's randomly selected eye, which revealed the same statistically significant trends. A randomized placebo-controlled or contralateral eye-controlled trial would be the best option to confirm the authenticity of the results. The second is the relatively small sample size, more healthy subjects are needed to confirm our initial findings.

In conclusion, both 0.15% and 0.2% concentrations of brimonidine tartrate eye drops have been shown to be effective postoperative treatment options for improving night vision quality after ICL V4c implantation. This study showed that 0.15% and 0.2% brimonidine tartrate eye drops had similar anti-mydriatic ability, while 0.15% group had better visual quality than 0.2% concentration, and hardly introduced pupil shift. In conclusion, 0.15% brimonidine tartrate eye drops may be more suitable for patients with nocturnal glare symptoms in the early postoperative period after ICL implantation.

Availability of Data and Materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Jonker SMR, Berendschot TTJM, Saelens IEY, Bauer NJC, Nuijts RMMA. Phakic intraocular lenses: An overview. Indian J Ophthalmol. 2020;68(12):2779-2796. doi:10.4103/ijo.IJO_2995_20
Kohnen T. Phakic intraocular lenses: Where are we now?. J Cataract Refract Surg. 2018;44(2):121-123. doi:10.1016/j.jcrs.2018.03.005
Kaur M, Titiyal JS, Falera R, Sinha R, Sharma N. Indications for explant of implantable collamer lens. Eye (Lond). 2018;32(4):838-840. doi:10.1038/eye.2017.307
Montés-Micó R, Ruiz-Mesa R, Rodríguez-Prats JL, Tañá-Rivero P. Posterior-chamber phakic implantable collamer lenses with a central port: a review. Acta Ophthalmol. 2021;99(3):e288-e301. doi:10.1111/aos.14599
Yang W, Zhao J, Zhao J, et al. Changes in anterior lens density after Implantable Collamer Lens V4c implantation: a 4-year prospective observational study. Acta Ophthalmol. 2021;99(3):326-333. doi:10.1111/aos.14584
Ye Y, Zhao J, Niu L, Shi W, Wang X, Zhou X. Long-term evaluation of anterior lens density after implantable collamer lens V4c implantation in patients with myopia over 40 years old [published online ahead of print, 2021 Jun 28]. Br J Ophthalmol. 2021;bjophthalmol-2021-319205. doi:10.1136/bjophthalmol-2021-319205
Zhao J, Yang W, Zhao J, et al. A four-year observation of corneal densitometry after implantable collamer lens V4c implantation. Ann Transl Med. 2021;9(7):536. doi:10.21037/atm-20-6628
Martínez-Plaza E, López-Miguel A, López-de la Rosa A, McAlinden C, Fernández I, Maldonado MJ. Effect of the EVO+ Visian Phakic Implantable Collamer Lens on Visual Performance and Quality of Vision and Life. Am J Ophthalmol. 2021;226:117-125. doi:10.1016/j.ajo.2021.02.005
Martínez-Plaza E, López-Miguel A, Fernández I, Blázquez-Arauzo F, Maldonado MJ. Effect of central hole location in phakic intraocular lenses on visual function under progressive headlight glare sources. J Cataract Refract Surg. 2019;45(11):1591-1596. doi:10.1016/j.jcrs.2019.06.022
He T, Zhu Y, Zhou J. Optical quality after posterior chamber Phakic implantation of an intraocular Lens with a central hole (V4c implantable Collamer Lens) under different lighting conditions. BMC Ophthalmol. 2020;20(1):82. Published 2020 Mar 4. doi:10.1186/s12886-020-01340-0
Eom Y, Kim DW, Ryu D, et al. Ring-shaped dysphotopsia associated with posterior chamber phakic implantable collamer lenses with a central hole. Acta Ophthalmol. 2017;95(3):e170-e178. doi:10.1111/aos.13248
Totsuka K, Ishikawa H, Kamiya K, Shoji N, Shimizu K. Pupil Dynamics Induced by Light Reflex After Posterior Chamber Phakic Intraocular Lens Implantation. J Refract Surg. 2017;33(10):704-707. doi:10.3928/1081597X-20170721-06
Oh DJ, Chen JL, Vajaranant TS, Dikopf MS. Brimonidine tartrate for the treatment of glaucoma. Expert Opin Pharmacother. 2019;20(1):115-122. doi:10.1080/14656566.2018.1544241
Tuncer I, Bilgin S, Zengin MÖ, et al. Effect of brimonidine tartrate 0.15% on scotopic pupil size and upper eyelid position: controlled trial. Eye (Lond). 2021;35(2):672-675. doi:10.1038/s41433-020-1007-9
Chen X, Wang X, Naidu RK, Qian Y, Miao H, Zhou X. Effect of brimonidine tartrate 0.2% ophthalmic solution on visual quality after implantable collamer lens implantation with a central hole. Int Ophthalmol. 2021;41(1):293-301. doi:10.1007/s10792-020-01581-4
Kamiya K, Shimizu K, Saito A, et al. Comparison of optical quality and intraocular scattering after posterior chamber Phakic intraocular Lens with and without a central hole (hole ICL and conventional ICL) implantation using the double-pass instrument. PLoS One. 2014;8:e66846.
Pesudovs K, Garamendi E, Elliott DB. The quality of life impact of refractive correction (QIRC) questionnaire: development and validation. Optom Vis Sci. 2004;81:769–777.
Xu Y, Yang X, Yu Y, Wang Q, Lü F. Application and evaluation of a quality of life scale for Chinese people with refractive correction. Chin Ophthalmic Res. 2011;28:623–626.
Kato COS, Shimizu K, Kamiya K, Ishikawa H, Igarashi A. Effects of brimonidine tartrate 0.1% ophthalmic solution on the pupil, refraction, and light reflex. Sci Rep. 2018;8(1):9003. Published 2018 Jun 13. doi:10.1038/s41598-018-27436-8
Cankurtaran V, Tekin K. Effects of a Single Dose of Topical Brimonidine 0.15% on Anterior Segment Morphology, Pupil Characteristics, and Choroidal Thickness in Healthy Subjects. Eye Contact Lens. 2021;47(6):323-329. doi:10.1097/ICL.0000000000000708
Nejad M, Lin SR, Hwang LH, Landig M, Al-Hashimi S, Bartlett JD. Effect of over-the-counter brimonidine tartrate 0.025% ophthalmic solution on pupil size in healthy adults. Graefes Arch Clin Exp Ophthalmol. 2021;259(11):3333-3338. doi:10.1007/s00417-021-05297-8
Thordsen JE, Bower KS, Warren BB, Stutzman R. Miotic effect of brimonidine tartrate 0.15% ophthalmic solution in normal eyes. J Cataract Refract Surg. 2004;30(8):1702-1706. doi:10.1016/j.jcrs.2003.12.037
Cate S, Bektas C, Turgut B. Comparative Analysis of Pupil Diameters in Light and Dark Conditions After Instillation of 0.15% Brimonidine Drops in Eyes With and Without Pseudoexfoliation Syndrome. Beyoglu Eye J. 2020;5(3):209-213. Published 2020 Dec 28. doi:10.14744/bej.2020.52244
Mabed IS, Saad A, Guilbert E, Gatinel D. Measurement of pupil center shift in refractive surgery candidates with caucasian eyes using infrared pupillometry. J Refract Surg. 2014;30(10):694-700. doi:10.3928/1081597X-20140903-07
Akıncı N, Bakan N, Karaören G, et al. Comparison of Clinical Effects of Dexketoprofen and Paracetamol Used for Analgesia in Endoscopic Retrograde Cholangiopancreatography. Turk J Anaesthesiol Reanim. 2016;44(1):13-20. doi:10.5152/TJAR.2016.09483
Duru Z, Ozsaygili C. Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy, safety, and potential advantages. Cutan Ocul Toxicol. 2020;39(1):21-24. doi:10.1080/15569527.2019.1680685
Kim CY, Hong S, Seong GJ. Brimonidine 0.2% versus brimonidine Purite 0.15% in Asian ocular hypertension. J Ocul Pharmacol Ther. 2007;23(5):481-486. doi:10.1089/jop.2007.0042
Schallhorn SC, Kaupp SE, Tanzer DJ, Tidwell J, Laurent J, Bourque LB. Pupil size and quality of vision after LASIK. Ophthalmology. 2003;110(8):1606-1614. doi:10.1016/S0161-6420(03)00494-9
Kobashi H, Kamiya K, Yanome K, Igarashi A, Shimizu K. Effect of pupil size on optical quality parameters in astigmatic eyes using a double-pass instrument. Biomed Res Int. 2013;2013:124327. doi:10.1155/2013/124327
Rio D, Woog K, Legras R. Effect of age, decentration, aberrations and pupil size on subjective image quality with concentric bifocal optics. Ophthalmic Physiol Opt. 2016;36(4):411-420. doi:10.1111/opo.12300
Yao L, Xu Y, Han T, Qi L, Shi J, Zou Z, Zhou X. Relationships Between Haloes and Objective Visual Quality in Healthy Eyes. Transl Vis Sci Technol. 2020 Sep 11;9(10):13. doi: 10.1167/tvst.9.10.13. PMID: 32974085; PMCID: PMC7488622.
Martínez-Roda JA, Vilaseca M, Ondategui JC, Giner A, Burgos FJ, Cardona G, Pujol J. Optical quality and intraocular scattering in a healthy young population. Clin Exp Optom. 2011 Mar;94(2):223-9. doi: 10.1111/j.1444-0938.2010.00535.x. Epub 2010 Nov 17. PMID: 21083759.
Kamiya K, Umeda K, Kobashi H, Shimizu K, Kawamorita T, Uozato H. Effect of aging on optical quality and intraocular scattering using the double-pass instrument. Curr Eye Res. 2012 Oct;37(10):884-8. doi: 10.3109/02713683.2012.688164. Epub 2012 May 15. PMID: 22587340.
Artal P, Benito A, Pérez GM, Alcón E, De Casas A, Pujol J, Marín JM. An objective scatter index based on double-pass retinal images of a point source to classify cataracts. PLoS One. 2011 Feb 4;6(2):e16823. doi: 10.1371/journal.pone.0016823. PMID: 21326868; PMCID: PMC3033912.
Cennamo G, Montorio D, Del Prete S, Del Prete A, Cennamo G. Anterior-Segment Optical Coherence Tomography and Scanning Electron Microscopy to Evaluate Corneal Epithelial Changes in Patients Undergoing Glaucoma Therapy. Cornea. 2018;37(12):1522-1526. doi:10.1097/ICO.0000000000001752.

No competing interests reported.

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Effects of brimonidine tartrate 0.2% and 0.15% ophthalmic solution on the static and dynamic pupil characteristics

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Abstract

Figures

Introduction

Materials And Methods

1. Study Population

2. Surgical methods

3. Measurements

4. Pupillometry

5. Optical quality measurement

6. Corneal aberrations measurement

7. Quality of Life Impact of Refractive Correction

8. Statistical analysis

Results

1. Pupillary Characteristics

2. Pupil Center

3. Visual Quality

4. Corneal Aberrations

5. Qirc Score

6. Manifest Refraction And Iop

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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