Monte Carlo simulation of latanoprost induced iris darkening

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Abstract

The aim of this study was to provide numerical evidence that latanoprost induced iris darkening (LIID) can be caused by changes to the melanin granule size distribution in the anterior segment of the iris. Iridectomies from two patients were used, where both had undergone unilateral treatment with latanoprost and had exhibited LIID. The untreated eye provided the comparative control. Micrographs from the iris samples were analysed to determine the number and size of the mature melanin granules. Monte Carlo (MC) simulation of light propagation in the iris was performed to examine the changes in reflectance and absorption with varying particle size and density. The reflected intensity of light was obtained as a function of wavelength. CIE colour theory was employed in order to estimate a perceived colour from the reflectance data.

MC simulations showed that the reflectance was reduced for the LIID irises compared to the control irises for both subjects and for all wavelengths of light. The MC simulated colours were in good agreement with the in vivo photography of the eye colour. Hence, we have demonstrated that increases in melanin granule size causes iris darkening, and can explain LIID.

Introduction

Glaucoma affects between 70 and 90 million people worldwide [1], [2] and it is one of the leading causes of blindness in the western world. It is disease of the eye in which the optic nerve is damaged, and vision is impaired. The major cause of this damage is an increase in the intraocular pressure (IOP). Over the last decade, a group of drugs know as prostaglandins have been found to be effective at controlling the IOP by causing an increase in the outflow of aqueous humour from the anterior chamber of the eye. The main prostaglandin drug that is commonly used is the F analogue latanoprost (Xalatan®) [3]. An unusual side effect has been observed with all of the topically applied prostaglandin drugs, namely, a darkening of the iris in susceptible individuals. As this side effect was first seen with latanoprost it has come to be known as latanoprost induced iris darkening (LIID). It has been reported that LIID is seen in 22.9% of patients in the UK that received latanoprost [4] and that irises of a mixed colouration (i.e. blue/brown, hazel and golden browns) have a greater tendency to darken.

Although latanoprost induced iris darkening does not affect directly the health of the patient (as far as we are aware), it can affect the quality of life of the patient drastically. This is because of the potentially large and certainly unwanted change in iris appearance that is central to ones self-awareness and identity. We believe that this effect is very important therefore, and that it warrants further study.

Much work has been carried out experimentally in order to understand this darkening effect. Previous experimental studies [5], [6], [7], [8], [9], [10] strongly indicate that latanoprost does not stimulate cell proliferation. A study (denoted as MainzIIb [9] henceforth) provided the first morphological evidence of the changes that are occurring in LIID cases. This study considered two cases of LIID, and demonstrated that populations of melanocyte cells in LIID cases were stable. However, a detailed analysis of the melanin granules contained in the melanocytes found that there was no increase in the number of melanin granules. The only detectable change that was found was a small, but significant, increase in the sizes of the melanin granules. It has been postulated that this increase in granule size is responsible for the darkening in LIID. However there has been a residual question as to whether such a small change could be totally responsible for bringing about the, sometimes dramatic, observable change of eye colouration that is seen in LIID cases. The purpose of this work is to test this hypothesis theoretically.

As far as we are aware theoretical analysis of the effect of changes to melanocytes, and/or their melanin granules, with respect to iris colour has ever been carried out. Monte Carlo (MC) methods are a standard approach of numerical simulation. The basic methodology of MC methods in simulating scattering of light with human tissues is, by now, strongly established. Thus, much research focussing on the application of MC techniques to specific medical or biologically inspired problems [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Typical recent examples range from of the spectral response of the skin [17] and ocular fundus [23], [24] to that of cancerous tissues [11], [15]. In such MC light scattering simulations, this approach employs a ‘stochastic’ computer simulation technique that involves tracing the flight path of a ‘wave packet’ of light as it undergoes scattering and absorption in the tissues. The path length and scattering angles are sampled randomly. Overall observable quantities of the tissue, such as the total light reflectance and absorption, are calculated by taking the average over all such wave packets. The objective of this work reported in this article, was to ascertain whether iris darkening can indeed occur because of increased granule size, by using Monte Carlo (MC) simulation.

Section snippets

Experimental subjects data collection

The Mainz II study group [6] consisted of 17 patients, all of whom required bilateral surgical intervention (known as a trabeculectomy) to control their elevated IOP. The increased IOP was caused by primary open angle glaucoma (POAG). During the trabeculectomy procedure a small piece of tissue is removed from the trabecular meshwork and the peripheral iris (this is known as an iridectomy) (Fig. 1). At the start of the study the patients had a trabeculectomy on the first eye. The fellow eye was

Results

Stereological analysis of the two-dimensional sectioned data enabled a reconstruction of the original three-dimensional melanin granule sphere population. The diameter (D) range of melanin granules seen in the iris melanocyte was found to be 0.131.09 μm. The size distribution profiles for each of the four cases are shown in Fig. 6, and these are expressed as the numerical frequency of granules of a given size per unit volume of tissue. Following LIID there was a 17% and 38% increase in the mean

Discussion

The MC simulations carried out here demonstrated that the small changes in the melanin granule size can lead to an observable darkening of the iris colour.

In the original clinical study, iris darkening was assessed by the treating consultant, and recorded photographically. It is important to note that the photography was performed under suboptimal conditions and is therefore not standardised: the photographs were taken at different times on different photographic films and processed separately.

Conclusions

We have demonstrated that MC techniques may be employed in order to simulate iris colouration for hazel- and brown-coloured irises. Qualitatively similar results were obtained for the predicted colour of the iris using MC simulation and CIE theory compared to in vivo photography. These MC results support the supposition that increased melanin granule size after topical administration of latanoprost can be responsible for darkening and colour-change of the iris.

Acknowledgment

We would like to thank Pfizer Global Pharmaceuticals for their supported of all of our studies on LIID.

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