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The earliest studies on 'disability glare' date from the early 20(th) century. The condition was defined as the negative effect on visual function of a bright light located at some distance in the visual field. It was found that for larger angles (>1 degree) the functional effect corresponded precisely to the effect of a light with a luminosity equal to that of the light that is perceived spreading around such a bright source. This perceived spreading of light was called straylight and by international standard disability glare was defined as identical to straylight. The phenomenon was recognized in the ophthalmological community as an important aspect of the quality of vision and attempts were made to design instruments to measure it. This must not be confused with instruments that assess light spreading over small distances (<1 degree), as originating from (higher order) aberrations and defocus. In recent years a new instrument has gained acceptance (C-Quant) for objective and controllable assessment of straylight in the clinical setting. This overview provides a sketch of the historical development of straylight measurement, as well as the results of studies on the origins of straylight (or disability glare) in the normal eye, and on findings on cataract (surgery) and corneal conditions.

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PURPOSE: To assess adding straylight measurements to the indication for cataract surgery. SETTING: Onze Lieve Vrouwe Hospital, Amsterdam, and Zonnestraal Eye Clinic, Hilversum, The Netherlands. DESIGN: Prospective interventional cohort study. METHODS: Before and after cataract extraction, corrected distance visual acuity (CDVA) and straylight were recorded in all patients. Subjective complaints were documented by the 39-item National Eye Institute Visual Function Questionnaire (NEI VFQ-39) and a straylight questionnaire. RESULTS: The population comprised 217 patients with a mean age of 72 years ± 9.12 (SD) (range 29 to 90 years). Preoperatively, the mean straylight was 1.55 ± 0.29 log(s) and the mean CDVA, 0.28 ± 0.21 logMAR. Visual acuity and straylight showed little correlation (R(2) = 0.08). The mean postoperative improvement in CDVA was 0.26 ± 0.20 logMAR (range -0.12 to 1.12 logMAR) and in straylight, 0.31 ± 0.32 log(s) (range -0.50 to 1.27 log[s]). The preoperative breakeven point (50% chance of postoperative improvement) was 0.06 logMAR for CDVA and 1.29 log(s) for straylight. Preoperative and postoperative questionnaires showed straylight had almost the same influence as visual acuity on quality of vision. CONCLUSIONS: Straylight and visual acuity measure different aspects of quality of vision and influenced subjective visual quality almost equally. When straylight was added to preoperative considerations of cataract extraction, postoperative results were more predictable. FINANCIAL DISCLOSURE: The Netherlands Academy of Arts and Sciences has a proprietary interest in the C-Quant Straylight meter. No author has a financial or proprietary interest in any material or method mentioned.

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This study optically determines whether the amount of light scatter due to laser-induced damage to the intraocular lens (IOL) is significant in relation to normal straylight values in the human eye. Two IOLs with laser-induced damage were extracted from two donor eyes. Each IOL had 15 pits and/or cracks. The surface area of each pit was measured using a microscope. For 6 pits per intraocular lens the point spread function (PSF) in terms of straylight was measured and the total straylight for all 15 pits was estimated. The damage in the IOLs was scored as mild/moderate. The total damaged surface areas, for a 3.5 mm pupil, in the two IOLs were 0.13% (0.0127 mm(2)) and 0.66% (0.064 mm(2)), respectively. The angular dependence of the straylight caused by the damage was similar to that of the normal PSF. The total average contribution to straylight was log(s) = -0.82 and -0.42, much less than the straylight value of the normal eye.The straylight due to normal levels of laser induced damage of the IOL is much lower than normal straylight values found clinically for the normal eye and may therefore be considered not significant.

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PURPOSE: To investigate whether light scattering of posterior capsule opacifications (PCOs) changes after fixation with paraformaldehyde (PFA). METHODS: The intraocular lens with the lens capsule were extracted from pseudophakic donor eyes. Images of the extracted sample were acquired pre and post PFA-fixation using a dark field microscope. Light scatter intensity was measured for different regions pre and post fixation. RESULTS: The regression lines between the light intensities measured pre and post fixation for the three color channels showed the same slope of 0.96. Also the correlation coefficients were the same for the three color channels, namely 0.97. CONCLUSIONS: Scattering intensities of PCO tissue pre and post fixation are quantitatively similar. The effects of fixation on the optical properties of PCO can be considered small.

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The current paper describes the design and population testing of a flicker sensitivity assessment technique corresponding to the psychophysical approach for straylight measurement. The purpose is twofold: to check the subjects' capability to perform the straylight test and as a test for retinal integrity for other purposes. The test was implemented in the Oculus C-Quant straylight meter, using homemade software (MATLAB). The geometry of the visual field lay-out was identical, as was the subjects' 2AFC task. A comparable reliability criterion ("unc") was developed. Outcome measure was logTCS (temporal contrast sensitivity). The population test was performed in science fair settings on about 400 subjects. Moreover, 2 subjects underwent extensive tests to check whether optical defects, mimicked with trial lenses and scatter filters, affected the TCS outcome. Repeated measures standard deviation was 0.11 log units for the reference population. Normal values for logTCS were around 2 (threshold 1%) with some dependence on age (range 6 to 85 years). The test outcome did not change upon a tenfold (optical) deterioration in visual acuity or straylight. The test has adequate precision for checking a subject's capability to perform straylight assessment. The unc reliability criterion ensures sufficient precision, also for assessment of retinal sensitivity loss.

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PURPOSE: Albinism is an inherited disorder that affects the melanin biosynthesis pathway, which results in reduced or absent pigment formation. This may lead to increased light transmission through the iris and more reflected light from the fundus. Both these effects contribute to the occurrence of ocular straylight. One aim of this study is to determine whether and how increased iris transmission and fundus reflection in subjects with albinism contributes to the occurrence of ocular straylight. The other aim is to determine the effect that an iris print-contact lens (CL) could have in terms of reducing the occurrence of ocular straylight. METHODS: Ocular straylight was quantified by means of the straylight parameter s and measured as a function of angle and wavelength in 17 subjects with different types of albinism, none of whom wore an iris print-CL. The measurements were then repeated with the subjects wearing an iris print-CL to reduce the iris transmission component and thus the occurrence of ocular straylight. The contributions of transmission and reflectance components were estimated for each individual. RESULT: Straylight level increase varied from normal (s ≈9) to severe (8x). In 15 cases, the reflectance component contributed s >3 to up to s = 17. In eight cases, the transmission component contributed s >3 to up to s = 101. A significant reduction in straylight was observed using an iris print-CL in six subjects with elevated straylight values. In the other 11 subjects with albinism, the iris print-CL had no significant effect on straylight because of the low values of the transmission component. CONCLUSIONS: This study gives insight into the effects of transmission and reflectance on the total measured straylight occurrence in subjects with albinism. Subjects experiencing increased ocular straylight values may benefit significantly from wearing iris print-CLs because transmission of light through the natural iris may cause a significant increase in straylight.

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A major challenge in biomedical optics is the accurate quantification of in vivo fluorescence images. Fluorescence imaging is often used to determine the pharmacokinetics of photosensitizers used for photodynamic therapy. Often, however, this type of imaging does not take into account differences in and changes to tissue volume and optical properties of the tissue under interrogation. To address this problem, a ratiometric quantification method was developed and applied to monitor photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC) pharmacokinetics in the rat skin-fold observation chamber. The method employs a combination of dual-wavelength excitation and dual-wavelength detection. Excitation and detection wavelengths were selected in the NIR region. One excitation wavelength was chosen to be at the Q band of mTHPC, whereas the second excitation wavelength was close to its absorption minimum. Two fluorescence emission bands were used; one at the secondary fluorescence maximum of mTHPC centered on 720 nm, and one in a region of tissue autofluorescence. The first excitation wavelength was used to excite the mTHPC and autofluorescence and the second to excite only autofluorescence, so that this could be subtracted. Subsequently, the autofluorescence-corrected mTHPC image was divided by the autofluorescence signal to correct for variations in tissue optical properties. This correction algorithm in principle results in a linear relation between the corrected fluorescence and photosensitizer concentration. The limitations of the presented method and comparison with previously published and validated techniques are discussed.

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The objective of this study was to develop an applicator for delivery of light and monitoring of photodynamic therapy (PDT) in the anal cavity for treatment of anal intraepithelial neoplasia grade III (AIN III), which can progress to invasive anal cancer. Forty-eight hours before treatment, patients participating in the study were injected with 0.03 (n=2) or 0.075 (n=2) mg kg(-1) m-THPC. For light delivery and monitoring of PDT, an applicator based on standard anoscopy equipment was developed which facilitates, in addition to a light treatment fiber, fiber optic probes to monitor blood saturation, blood volume, fluorescence and fluence (rate) at two different locations in situ. Patients were given a light dose of 10-17 J cm(-2) at a fluence rate of 45-50 mW cm(-2) based on in situ measured light treatment parameters. We demonstrate that the applicator does not influence the fluence rate profile of the light treatment fiber. Furthermore this study shows the possibility of monitoring blood saturation, blood volume, fluorescence and fluence (rate) during therapeutic illumination without changing the light treatment protocol.

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BACKGROUND AND OBJECTIVE: In order to understand the mechanisms of photodynamic therapy (PDT) it is important to monitor parameters during illumination that yield information on deposited PDT dose. The aim of this study is to investigate the possibility of monitoring implicit parameters, such as photobleaching, in addition to monitoring explicit parameters (fluence (rate), oxygenation, photosensitizer concentration) directly or indirectly. These parameters are monitored during PDT without interrupting the therapeutic illumination. MATERIALS AND METHODS: Rats were injected with 0.3 mg kg(-1) m-THPC. Sixteen hours after administration the abdominal muscle in rats was irradiated for 1,500 seconds using clinically relevant fluence rates of 50, 100, and 250 mW cm(-1) of diffuser length at 652 nm. In addition to the linear diffuser for delivering treatment light, isotropic fiber-optic probes and fiber-optic probes for differential path-length spectroscopy (DPS) were placed on both sides of the muscle to monitor tissue physiological parameters, fluence rate, and fluorescence. RESULTS: The m-THPC treatment groups show a decrease in fluence rate throughout PDT of 16%, 19%, and 27% for the 50, 100, and 250 mW cm(-1) groups, respectively. Both during and post-PDT differences in vascular response between treatment groups and animals within the same treatment group are observed. Furthermore we show fluence rate dependent bleaching of m-THPC up to a measured fluence rate of 100 mW cm(-1). CONCLUSION: The data presented in this study show the possibility of simultaneously monitoring fluence (rate), fluorescence, hemoglobin oxygen saturation, and blood volume during PDT without interruptions to the therapeutic illumination. Differences in saturation profiles between animals and treatment groups indicate differences in vascular response during illumination. Furthermore, the relationship between fluence rate and m-THPC fluorescence photobleaching is complex in an interstitial environment.

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We present an optical method based on fluorescence spectroscopy for measuring chromophore concentrations in vivo. Fluorescence differential path length spectroscopy (FPDS) determines chromophore concentration based on the fluorescence intensity corrected for absorption. The concentration of the photosensitizer m-THPC (Foscan) was studied in vivo in normal rat liver, which is highly vascularized and therefore highly absorbing. Concentration estimates of m-THPC measured by FDPS on the liver are compared with chemical extraction. Twenty-five rats were injected with 0.3 mg kg m-THPC. In vivo optical concentration measurements were performed on tissue 3, 24, 48, and 96 h after m-THPC administration to yield a 10-fold variation in tissue concentration. After the optical measurements, the liver was harvested for chemical extraction. FDPS showed good correlation with chemical extraction. FDPS also showed a correlation between m-THPC fluorescence and blood volume fraction at the two shortest drug-light intervals. This suggests different compartmental localization of m-THPC for different drug-light intervals that can be resolved using fluorescence spectroscopy. Differences in measured m-THPC concentration between FDPS and chemical extraction are related to the interrogation volume of each technique; approximately 0.2 mm(3) and approximately 10(2) mm(3), respectively. This indicates intra-animal variation in m-THPC distribution in the liver on the scale of the FDPS sampling volume.

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We have developed a new technique, fluorescence differential path length spectroscopy (FDPS), that enables the quantitative investigation of fluorophores in turbid media. FDPS measurements are made with the same probe geometry as differential path length spectroscopy (DPS) measurements. Phantom measurements are performed for two fiber diameters (400 microm and 800 microm) and for a wide range of optical properties (mu(s)': 0 to 10 mm(-1); mu(a): 0 to 2 mm(-1)) to investigate the influence of the optical properties on the measured differential fluorescence signal. The differential fluorescence signal varies by a factor of 1.4 and 2.2 over the biologically relevant scattering range (0.5 to 5 mm(-1)) for a given fluorophore concentration for 400 microm and 800 microm fibers, respectively. The differential fluorescence signal is attenuated due to absorption at the excitation wavelength following Lambert-Beer's law with a path length equal to the differential path length.

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The presence of phased protoporphyrin IX (PpIX) bleach kinetics has been shown to correlate with esophageal response to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) in animal models. Here we confirm the existence of phased PpIX photobleaching by increasing the temporal resolution of the fluorescence measurements using the therapeutic illumination and long wavelength fluorescence detection. Furthermore fluorescence differential pathlength spectroscopy (FDPS) was incorporated to provide information on the effects of PpIX and tissue oxygenation distribution on the PpIX bleach kinetics during illumination. ALA at a dose of 200 mg kg(-1) was orally administered to 15 rats, five rats served as control animals. PDT was performed at an in situ measured fluence rate of 75 mW cm(-2) using a total fluence of 54 J cm(-2). Forty-eight hours after PDT the esophagus was excised and histologically examined for PDT-induced damage. Fluence rate and PpIX photobleaching at 705 nm were monitored during therapeutic illumination with the same isotropic probe. A new method, FDPS, was used for superficial measurement on saturation, blood volume, scattering characteristics and PpIX fluorescence. Results showed two-phased PpIX photobleaching that was not related to a (systematic) change in esophageal oxygenation but was associated with an increase in average blood volume. PpIX fluorescence photobleaching measured using FDPS, in which fluorescence signals are only acquired from the superficial layers of the esophagus, showed lower rates of photobleaching and no distinct phases. No clear correlation between two-phased photobleaching and histologic tissue response was found. This study demonstrates the feasibility of measuring fluence rate, PpIX fluorescence and FDPS during PDT in the esophagus. We conclude that the spatial distribution of PpIX significantly influences the kinetics of photobleaching and that there is a complex interrelationship between the distribution of PpIX and the supply of oxygen to the illuminated tissue volume.

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A method for the quantification of the concentration of the photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC) in tissue samples is presented. The technique is an extension of a previously published method based on alkaline hydrolysis of tissue, using Solvable as a tissue solubilizer. mTHPC quantification was achieved by subsequent fluorescence spectroscopy. Since the original extraction method involved multiple steps in which water dilution of the sample was implemented, we studied the spectral characteristics of mTHPC in different Solvable/water mixtures. Using UV-VIS absorption and fluorescence spectroscopy, it was demonstrated that the spectral characteristics of mTHPC vary for different Solvable concentrations. In the range of 20-100% Solvable, the fluorescence intensity of mTHPC did not change, while dramatic changes in the mTHPC fluorescence intensity were observed for lower Solvable concentrations (< 20%) due to increasing hydrophilicity of the environment, combined with pH alterations. We also demonstrated that the absorption and fluorescence spectra of the dissolved tissue were time-dependent. Longer incubation of the samples resulted in a significant increase of the native tissue chromophore fluorescence. This implies that for the correct quantification of photosensitizer concentrations, the fluorescence of native tissue chromophores must be accounted for.

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Protoporphyrin IX (PpIX) fluorescence that is bleached during aminolevulinic acid (ALA) mediated photodynamic therapy (PDT) increases again in time after treatment. In the present study we investigated if this increase in PpIX fluorescence after illumination is the result of local re-synthesis or of systemic redistribution of PpIX. We studied the spatial distribution of PpIX after PDT with and without cooling using the skin-fold observation chamber model. We were unable to show a correlation between the local PpIX fluorescence increase and the distance from a blood vessel. The spatial distribution of PpIX fluorescence within normal tissue or tumour is not changed in response to the illumination. These observations suggest that there is no diffusion of PpIX into the treated tissue. Cooling the tissue to 12 degrees C, a temperature at which PpIX synthesis is inhibited, inhibited the PpIX fluorescence increase normally observed after illumination. We also found a strong correlation between local PpIX photobleaching during illumination and the fluorescence intensity 1 h after illumination similar to what we have observed in patients treated with ALA-PDT. Therefore we conclude that the increase in PpIX fluorescence after illumination is due to local cellular re-synthesis.

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Photodynamic therapy (PDT) of superficial basal cell carcinoma (sBCC) using topical 5-aminolevulinic acid (ALA) and a light fluence of 75-100 J cm(-2) yields unsatisfactory long-term results. In several animal models, illumination with two light fractions 2 hours apart was considerably more effective than single illumination. Response is further enhanced if the fluence of the first light fraction is reduced, although the cumulative fluence is maintained. We compared the response of sBCC to a single illumination and 2-fold illumination scheme in which two light fractions of 20 and 80 J cm(-2) are performed 4 and 6 hours after the application of a single dose of 20% ALA. We randomly assigned 154 patients with a total of 505 primary sBCC into two treatment groups. Two hundred and forty-three lesions were treated using a single illumination of 75 J cm(-2) at a fluence rate of 50 mW cm(-2). Fractionated PDT, at the same fluence rate, was performed on 262 lesions. The complete response (CR) following a 2-fold illumination scheme is significantly greater than that following a single light fraction (P=0.002, log-rank test). Twelve months after therapy, CR rate to a 2-fold illumination is 97%, whereas the CR to a single illumination is 89%.

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