Static And Dynamic Pupillometric Changes With Silodosin; Selective α1 Adrenoceptor Blocker

Backround: Intraoperative oopy iris syndrome is a variant of the small pupil syndrome that has been observed during cataract surgery in some patients currently or previously treated with the α1 adrenergic blockers. It is important for cataract surgeons to predict the probable complications, preoperatively. The aim of our study is to evaluate the static and dynamic pupil characteristics of patients treated with silodosin –a selective α1 adrenergic blocker- for Benign Prostate Hypertrophy (BPH) and to compare these values with healthy subjects using an automatic quantitative pupillometry system. Methods: A total of 74 BPH patients treated with silodosin for six months (group 1) and 30 healthy subjects (group 2) were enrolled in this prospective multidisciplinary cross-sectional study. Static and dynamic pupillometric measurements were obtained under optimized conditions and the results were compared between the two groups. Results: Seventy four male patients with a mean age of 63,35±7,21 (46-77) years with BPH treated with silodosin and 30 normal male subjects with a mean age of 63,07±4,73 (52-71) years were analyzed. There were statistically signicant differences between the groups with regard to scotopic pupil diameter (PD), high photopic PD, and low photopic PD (p<0.001, for each one). Patient group has statistically signicant higher values of amplitude and velocity of pupil contraction and lower values of duration of pupil contraction and latency, duration and velocity of pupil dilation. Conclusion: Static and dynamic pupil characteristics of subjects treated with silodosin for BPH is different from healthy eyes. In addition, our results may have shed light on understanding the risk for IFIS before cataract surgery and thus surgeons can be on the alert and take precautions. Backround: and redilation of patients treated with silodosin. Our results indicated that patients show statistically signicantly higher differences with regard to amplitude of pupil contraction, and velocity of pupil contraction. Duration of pupil contraction, and duration, velocity and latency of pupil dilatation values was statistically signicantly lower when compared with healthy eyes. Pupillary dynamics (amplitude and velocity of constriction and dilatation) are a function of the balance between sympathetic and parasympathetic tone in which increased sympathetic balance decreases the constriction velocity, whereas increased parasympathetic balance increases it. (20) These results may suggest that silodosin alters the pupillary kinetics and could be responsible from IFIS as a side effect.

study was to evaluate the static and dynamic pupil characteristics of patients treated with silodosin for LUTS/BPH and to compare these values with healthy subjects using an automatic quantitative pupillometry system.

Methods:
Study was designed as a prospective multidisciplinary cross-sectional study and carried out from July 2015 to July 2017 at ophthalmology and urology clinics of a tertiary hospital The study protocol was approved by the Gulhane Education and Research Hospital Clinical Research Ethics Committee and the study was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from the each individual participant.
A total of 74 BPH patients treated with silodosin for six months (group 1) and 30 healthy subjects (group 2) were enrolled in the study. BPH patients were examined by Urology Department. The inclusion criteria were as follows; male patients ≥ 45 years with symptomatic BPH, a peak ow rate (Qmax) of < 15 ml/s, International Prostate Symptom Score (IPSS) of ≥ 8, quality of life score (QLS) of ≥ 3, and a peak ow rate (Qmax) of < 15 ml/s. The patients with severe hepatic or renal insu ciency, urinary tract infections, urethral stricture, neurogenic bladder, history of urethral or prostatic surgery and history of various alfa blocker were excluded from the study.
All the subjects underwent a comprehensive ophthalmic examination, including the measurement of the uncorrected and best corrected visual acuity, slit-lamp biomicroscopy. Individuals with a history of systemic vasculopathies, ocular in ammation, anisocoria, head/orbital trauma or ocular surgery/laser treatment were excluded. İris and/or pupil abnormalities such as coloboma, anterior -posterior synechia, pseudoexfoliation syndrome; glaucoma, medications that may affect iris mechanics such as tropicamide, cyclopentolate, pilocarpine and narcotic-derived medications; neurological disease or other diseases of the visual pathways; and those who were not cooperative enough to undergo pupillometry examinations were also excluded.
A technician blind to study performed pupillometry measurements using the same automatic quantitative pupillometry system (MonPack One, Vision Monitor System, Metrovision, Pérenchies, France) Average values were selected after three consecutive measurements for each participant using the automaticrelease mode of the device. (Fig. 1) All measurements were performed at the same time period in a day (12:00 am -01:00 pm) The following parameters were recorded; latency and duration of contraction and dilatation (ms); initial, minimum, maximum and mean pupil diameter (PD) (mm); amplitude of contraction (mm); and contraction and dilatation speed (velocity) of the pupil (mm/s). Static pupillometry measurements were obtained under several illumination levels to measure pupil size in scotopic (0.1 cd/m2), mesopic (1 cd/m2), low photopic (10 cd/m2), and high photopic (100 cd/m2) vision conditions. Scotopic PD, mesopic PD, low photopic PD and high photopic PD values were recorded. In darkness, after ve minutes of darkness adaptation, dynamic pupillometry measurements were obtained for a duration of 90 seconds. (Fig. 2) Statistical Analysis: Statistical Package for Social Sciences (SPSS) version 20.0 for Windows (IBM, New York, USA) was used for data analysis. The statistical signi cance was set at p < 0.05. Descriptive statistics were presented as mean ± standard deviations, frequency distributions and percentages. The normal distribution of the variables was tested using analytical methods (Kolmogorov-Smirnov/ Shapiro-Wilk tests). Independent sample t-test was used to compare quantitative data.
There were no signi cant differences between the groups with regard to age (p = 0.57). Table 1 shows static pupillometry measurements of Group 1 (patient) and Group 2 (control). There were statistically signi cant differences between the groups with regard to scotopic PD, high photopic PD, and low photopic PD (p < 0.001, for each one). Mesopic PD was not statistically signi cant despite the powerful difference. (p = 0.007) Dynamic pupillometric measurements of the groups are shown in Table 2. Patient group has statistically signi cant higher values of amplitude and velocity of pupil contraction and lower values of duration of pupil contraction and latency, duration and velocity of pupil dilation. On the other hand resting diameter values was not statistically signi cant but there were a powerful difference between groups.(p = 0.007).There were no signi cant differences between the groups with regard to latency of pupil contraction (p = 0.895) Discussion: In this study, we used an automatic system for static and dynamic pupillometry measurements on the cases with BPH treated with silodosin -a selective α-blocker -and healthy subjects to determine the differences in static and dynamic pupil characteristics. To the best of our knowledge, this is the rst study to evaluate the static and dynamic pupil characteristics in subjects treated with silodosin using an automatic quantitative pupillometry system (Vision Monitor System, Metrovision).
Pupillary examination including pupil size, shape, symmetry, response to light,and response to near re ex is important before planning intraocular surgery. However, subjective examination of pupillas can be affected by several factors such as illumination and the examiner's experience. (9) Pupillary response to light can be measured by using an automatic pupillometry system with controlling lightening conditions and can be obtained multiple, quantitative measurements. This improves the repeatability of the measurements, solves the problem of examiner-dependent errors and reduces false negative responses. (10,11) IFIS is a variant of the small pupil syndrome and was rst described by Chang et al. in 2005. (6) Previous studies have shown that tamsulosin and other ABs inhibit phenylephrine-induced mydriasis, causing myosis in almost equal extent and duration with regardless of dose. (12) An important mechanism of IFIS is drug-melanin interaction causing dilator muscle atrophy (13) Silodosin is a novel, more selective alpha-blocker, which is speci c to the lower urinary tract and may have fewer side effects than the other alpha-blockers. (14,15) Although this selectivity, Ipekci and Chatterjee reported silodosin-associated IFIS in their cases similar to other AB's. (16,17) Clinically poor dilated and oppy iris during surgery may shrink the visualisation of the surgical eld and complicate the surgery. (18) This clinically observed pupillary changes did not ever been observed with quantitative pupillometric analysis before.
The following parameters were measured with automatic pupillometry system: pupil diameter before and after light stimulus; latency, duration, velocity and amplitude of pupillary constriction; velocity, latency and duration of pupillary dilatation. Amplitude and maximum constriction velocity re ect the active parasympathetic part of the light re ex, whereas the dilatation velocity re ects the active sympathetic part (4) In this study, all static PDs including the scotopic, mesopic low and high photopic PDs were smaller in patient group. Furthermore, the present study found that patients had higher resting PDs than healthy group. Since the pupillary resting diameter re ects the balance between sympathetic and parasympathetic autonomic systems, it can be said as a result of this study that, silodosin disrupts the balance between autonomic systems in the direction of the parasympathetic system. Dogan et al. This study investigated the pupil dynamics including latency, duration, and velocity of pupil constriction and redilation of patients treated with silodosin. Our results indicated that patients show statistically signi cantly higher differences with regard to amplitude of pupil contraction, and velocity of pupil contraction. Duration of pupil contraction, and duration, velocity and latency of pupil dilatation values was statistically signi cantly lower when compared with healthy eyes. Pupillary dynamics (amplitude and velocity of constriction and dilatation) are a function of the balance between sympathetic and parasympathetic tone in which increased sympathetic balance decreases the constriction velocity, whereas increased parasympathetic balance increases it. (20) These results may suggest that silodosin alters the pupillary kinetics and could be responsible from IFIS as a side effect.
This study had a number of limitations. The relatively small number of patients in the control group could affect the validity and importance of the comparisons. The fact that the pupillometry system used in the study requires full compliance of the patients, may affect the results. It is important to have an experienced technician so that this situation does not affect the work. Another disadvantage of the study is that PD differences such as physiological anisocoria can be seen even in completely healthy subjects.
In conclusion, this study revealed that static and dynamic pupil characteristics of subjects treated with silodosin for BPH differs from healthy eyes. .In addition, our results may have shed light on understanding the risk for IFIS before cataract surgery and thus surgeons can be on the alert and take precautions. There have been limited studies about comparison of effects of silodosin in the literature so that further longterm studies are required to clarify the effects of silodosin on static and dynamic pupillary functions.

Declarations:
Ethics approval and consent to participate The procedures in this manuscript were conducted ethically in accordance with the tenets of the Declaration of Helsinki. The study protocol was approved by the Gulhane Education and Research Hospital Clinical Research Ethics Committee (29.06.2015/71). Written informed consent was obtained from the each individual participant.

Consent for publication
All subjects gave consent to publish this manuscript.

Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Unfortunately, the data is not publicly available due to local data protection laws. Tables: Table-   Static and Dynamic Pupillometric Results.