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Purpose: New lasers with a continuous wave power exceeding 15 W are currently investigated for retinal therapies, promising highly localized effects at and close to the Retinal Pigment Epithelium (RPE). The goal of this work is to evaluate mechanisms and thresholds for RPE cell damage by means of pulse durations up to 50 µs., Methods: A diode laser with a wavelength of 514 nm, a power of 15 W, and adjustable pulse durations between 2 µs and 50 µs was used. Porcine RPE-choroidal explants (ex vivo) and chinchilla bastard rabbits (in vivo) were irradiated to determine threshold radiant exposures for RPE damage \({\bar H&#95;{Cell}}\) by calcein vitality staining and fluorescence angiography, respectively. Thresholds for microbubble formation (MBF) \({\bar H&#95;{MBF}}\) were evaluated by time-resolved optoacoustics. Exemplary histologies support the findings., Results: \({\bar H&#95;{{{MBF}}}}\) is significantly higher than \({\bar H&#95;{Cell}}\) at pulse durations ≥ 5 µs (P < 0.05) ex vivo, while at 2 µs, no statistically significant difference was found. The ratios between \({\bar H&#95;{{{MBF}}}}\) and \({\bar H&#95;{Cell}}\) increase with pulse duration from 1.07 to 1.48 ex vivo and 1.1 to 1.6 in vivo, for 5.2 and 50 µs., Conclusions: Cellular damage with and without MBF related disintegration are both present and very likely to play a role for pulse durations ≥ 5 µs. With the lower µs pulses, selective RPE disruption might be possible, while higher values allow achieving spatially limited thermal effects without MBF. However, both modi require a very accurate real-time dosing control in order to avoid extended retinal disintegration in this power range.

We conducted a study to correlate the retinal temperature rise during photocoagulation to the afterward detected tissue effect in optical coherence tomography (OCT). 504 photocoagulation lesions were examined in 20 patients. The retinal temperature increase was determined in real-time during treatment based on thermoelastic tissue expansion which was probed by repetitively applied ns laser pulses. The tissue effect was examined on fundus images and OCT images of individualized lesions. We discerned seven characteristic morphological OCT lesion classes. Their validity was confirmed by increasing visibility and diameters. Mean peak temperatures at the end of irradiation ranged from approx. 60 °C to beyond 100 °C, depending on burn intensity., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Retinal laser photocoagulation carries the risk of overtreatment due to effect variation of identically applied lesions. The degree of coagulation depends on the induced temperature increase and on exposure time. We introduce temperature controlled photocoagulation (TCP), which uses optoacoustics to determine individually exposure times necessary to create reproducible lesions., Methods: Optoacoustic temperature measurement relies on pressure waves that are excited in the retinal tissue by repetitive low-energy laser pulses. Signal amplitudes correlate with tissue temperature and are detected by a transducer in the laser contact lens. We used a continuous wave (CW) photocoagulator for treatment irradiation and superimposed probe laser pulses for simultaneous temperature measurement. Optoacoustic data of 1500 lesions (rabbit) were evaluated to develop an algorithm that controls exposure times automatically in TCP. Lesion diameters of 156 TCP lesions were compared to 156 non-controlled lesions. Histology was performed after 1 hour, and 1 and 4 weeks., Results: TCP resulted in exposure times from 4 to 800 ms depending on laser power chosen. Ophthalmoscopic and histologic lesion diameters were independent of power between 14 and 200 mW. TCP lesions barely were visible with a mean diameter equal to the treatment beam (130 μm). In contrast, standard lesion diameters increased linearly and statistically significantly with power. Histology confirmed sparing of the ganglion and nerve fiber layers in TCP., Conclusions: TCP facilitates uniform retinal lesions over a wide power range. In a clinical setting, it should generate soft and reproducible lesions independently of local tissue variation and improve safety, particularly at short exposure times.

Purpose: To test selective retina therapy (SRT) as a treatment of clinically significant diabetic macular edema (DME)., Methods: Prospective two-center interventional uncontrolled phase II pilot study. Thirty-nine eyes of 39 patients with previously untreated non-ischemic DME were treated with focal laser treatment using a Q-switched frequency doubled Nd:YLF laser which selectively affects the retinal pigment epithelium while sparing the photoreceptor layer. Optoacoustic measurements, fundus fluorescein angiography (FFA), and funduscopy were used to determine the individual threshold of RPE damage of each patient. The pulse energy was adjusted to apply angiographically visible but funduscopically invisible effects. Optoacoustic measurements were correlated with funduscopy and FFA. Follow-up examinations at 3 and 6 months post-treatment included best-corrected ETDRS visual acuity (BCVA), FFA, fundus photography, and retinal thickness measured by optical coherence tomography. The primary outcome measure was change of BCVA. Other outcome measures were change of retinal thickness, presence of hard exudates, leakage in FFA, accuracy of optoacoustic measurements, and correlation of BCVA with change of anatomical and systemic parameters., Results: Mean BCVA improved from 43.7 letters (standard deviation, SD=9.1) at baseline to 46.1 letters (SD=10.5) at the 6-month follow-up (p=0.02). BCVA improved (>5 letters) or remained stable (+/-5 letters) in 84% of eyes. Thirteen percent of eyes improved by > or =10 letters, while 16% of eyes lost more than 5 letters. There was no severe loss of vision (> or =15 letters). Overall, retinal thickness, hard exudates, and leakage in FFA did not change significantly (p> 0.05), while improvement of BCVA correlated with a reduction of hard exudates (p=0.01) and central retinal thickness (p=0.01). Specificity and sensitivity of detecting the angiographic visible threshold of RPE damage by optoacoustic measurements were 86% and 70% respectively. No adverse effects or pain were noted during or after treatment. Conclusions Functional and anatomical improvement or stabilization was observed in most patients. SRT appears to be safe. Optoacoustic measurements accurately detect the individual threshold of RPE damage. A randomized trial is required to further test efficacy and safety of SRT as a treatment of clinically significant diabetic macular edema (DME).

Background: For geographic atrophy (GA) due to age-related macular degeneration (AMD) there is so far no approved treatment option. Usually, increased autofluorescence (AF) levels of different patterns adjacent to the atrophic area indicate lipofuscin-laden retinal pigment epithelium (RPE) cells at a high risk for apoptosis. Herein, SRT was used to selectively treat these cells to stimulate RPE proliferation, in order to reduce or ideally stop further growth of the atrophic area., Material and Methods: Six eyes of six patients with bilateral equally pronounced GA were treated by SRT, while the fellow eye served as control. Irradiation was performed using a prototype SRT laser (Medical Laser Center Lübeck, Nd:YLF laser; 527 nm; 200 ns/1.7 micros pulse duration; 30 repetitive pulses at 100 Hz). Test lesions with increasing energies were applied at the lower vessel arcade to determine the individual angiographic and ophthalmoscopic threshold radiant exposures. Treatment was then performed in the area of increased AF adjacent to the GA using energies between both thresholds. The GA progression rates of treated and fellow eyes were evaluated., Results: After a 1-year follow-up, a progression of the atrophic area was observed in the treated eyes (0.7-8.0 mm(2)/yr, mean 3.0 mm(2)/yr; 46%/yr) whereas the progression rates of the fellow eyes were insignificantly lower (0.46-4.04 mm(2)/yr, mean 1.9 mm(2)/yr; 30%/yr; p = 0.134). The progression rate in the treated eyes of two patients increased significantly, while in the other four patients, the progression rates were nearly the same between both eyes. Moreover, one of these two eyes showed an unexpected RPE reaction after treatment, since all laser lesions led to RPE atrophy and thus an accelerated enlargement of the GA occurred., Conclusion: SRT in the hyperautofluorescent areas of GA was not able to stop or slow down the progression of GA. However, modified treatment strategies might be more promising, e.g. placing the spots outside the hyperautofluorescent areas where RPE apoptosis is postulated. Moreover, SRT studies on GA might be more successfully performed on specific subgroups of GA, based on autofluorescence and other findings.

Background: It has been shown that selective retina treatment (SRT) using a train of 1.7 microseconds laser pulses allows selective damage of the retinal pigment epithelium (RPE) while sparing the adjacent photoreceptors and thus avoiding laser scotoma. It was the purpose of this work to investigate SRT laser effects with Q-switched pulses of only 8 nanoseconds in duration by evaluating the angiographic and ophthalmoscopic damage thresholds and the damage range by histology in a rabbit model., Materials and Methods: A flash lamp pumped frequency doubled (532 nm) Nd:YAG laser with 8 nanoseconds pulse duration was used. In total 210 laser lesions, each calculated to be 102 microm in diameter on retina, were applied through a slit lamp onto the fundus of six eyes of Chinchilla Bastard rabbits. The rabbits were irradiated with increasing energies with single pulses and a train of 10 laser pulses at 10 Hz. After treatment fundus photography and angiography were performed to determine the damage thresholds (ED(50)-probability of RPE cell damage and neurosensory retinal damage) as well as the safety range between both thresholds (ratio of angiographic ED(86) vs. ophthalmoscopic ED(14)). Selected histology was taken for single and repetitive pulse lesions after treatment., Results: Angiographic and ophthalmoscopic ED(50)-thresholds decreased with increasing number of pulses. For single pulse application ophthalmoscopic and angiographic ED(50) were determined to 365 and 144 mJ/cm(2), respectively. Regarding 10 pulses 266 and 72 mJ/cm(2) were found. No retinal hemorrhages or disruptions were observed for both sets of parameters. The therapeutic window between angiographic and ophthalmoscopic threshold revealed a factor of 3.1 for single pulses and 2.3 for repetitive pulse irradiation. The safety range respectively had a factor of 0.8 (single pulses) and 1.7 (10 pulses). Histologic examination of laser lesions with single and repetitive pulses at radiant exposures within the therapeutic window-292 and 213 mJ/cm(2) respectively-revealed damaged RPE, intact Bruch's membrane and choriocapillaries. Photoreceptors were partly spared but also damaged to various extents., Conclusions: Short laser pulses of 8 nanoseconds pulse duration can damage the RPE without retinal hemorrhage or disruption. Selective damage of the RPE without affecting the photoreceptors can only rarely be achieved due to the small safety range. Thus, so far microsecond laser pulses for SRT seems favorable compared to nanosecond pulses in order to prevent unintentional photoreceptor damage.

The selective retina treatment (SRT) targets retinal diseases associated with disorders in the retinal pigment epithelium (RPE). Due to the ophthalmoscopic invisibility of the laser-induced RPE effects, we investigate a noninvasive optoacoustic real-time dosimetry system. In vitro porcine RPE is irradiated with a Nd:YLF laser (527 nm, 1.7-micros pulse duration, 5 to 40 microJ, 30 pulses, 100-Hz repetition rate). Generated acoustic transients are measured with a piezoelectric transducer. During 27 patient treatments, the acoustic transients are measured with a transducer embedded in an ophthalmic contact lens. After treatment, RPE damage is visualized by fluorescein angiographic leakage. Below the RPE damage threshold, the optoacoustic transients show no pulse-to-pulse fluctuations within a laser pulse train. Above threshold, fluctuations of the individual transients among each other are observed. If optoacoustic pulse-to-pulse fluctuations are present, RPE leakage is observed in fluorescein angiography. In 96% of the irradiated areas, RPE leakage correlated with the optoacoustic defined threshold value. A noninvasive optoacoustic real-time dosimetry for SRT is developed and proved in vitro and during patient treatment. It detects the ophthalmoscopically invisible laser-induced damage of RPE cells and overcomes practical limitations of SRT for use in private practice.

Background: Fundus autofluorescence (AF) is derived from the lipofuscin contained by the retinal pigment epithelial cells. Using a scanning laser ophthalmoscope, two-dimensional AF measurements of the ocular fundus can be achieved. Directly after conventional photocoagulation and also after selective RPE laser treatment (SRT) with ophthalmoscopically non-visible laser lesions, irradiated areas reveal reduced AF, indicating RPE damage. Since the green treatment laser beam could also be used for AF excitation, the aim of this study was to evaluate whether absolute measurements of AF can be performed, and also possible changes in AF detected, online during SRT., Methods: SRT was carried out by use of a frequency-doubled Nd:YLF laser (wavelength 527 nm, pulse duration 1.7 micros, repetition rate 500 and 100 Hz, number of pulses 100 and 30, single pulse energy 50-130 microJ) in vitro (porcine RPE; retinal spot size 160 microm) and during patient treatment (retinal spot size 176 microm). During irradiation, fluorescence light from the RPE was decoupled from the laser light inside the slit lamp and detected by a photomultiplier or photodiode at wavelengths above 550 nm. Additionally, temperature-dependent fluorescence intensity measurements of A2-E, the main fluorescent component of lipofuscin, were performed in a different in-vitro setup., Results: The intensity of AF decreased over the number of applied pulses during laser irradiation, and this trend was more pronounced in porcine RPE samples than during human treatment. In vitro, the AF intensity decreased by about 22%; however, only a weak signal was detected. When treating patients, the AF intensity was strong and the rate of decay of fluorescence intensity with number of pulses was greater when irradiating at 500 Hz than at the 100 Hz repetition rate. However, for both repetition rates the AF decay was merely up to 6-8% over the number of pulses per laser spot. Fluorescence intensity of A2-E decreased linearly with increasing temperature at about 1% per 1 degrees C and was completely reversible., Conclusions: Online measurements of AF during selective RPE laser treatment are possible and reveal a decay in AF as a function of the number of laser pulses applied to the RPE. If A2-E results can be transferred to RPE fluorescence, the AF decay could be related to the temperature increase within the tissue during treatment. Further clinical studies-in SRT as well as in conventional laser photocoagulation-might be able to show online AF changes on different areas of the retina and on different pathologies. Due to the temperature dependence of the fluorescence, on-line AF measurements during laser treatments such as photocoagulation or TTT may be able to be used as a real-time method for temperature monitoring.

Background and Objectives: The therapeutic effect of laser treatment for macular diseases is related to the damage to the retinal pigment epithelium (RPE) and the subsequent restoration of the defect due to RPE proliferation. In contrast to conventional laser treatment, it is possible to damage the RPE selectively and to spare the photoreceptors by using repetitive microsecond laser pulses. It was the aim of the study to investigate the influence of pulse duration and number of pulses on angiographically and ophthalmoscopically visible retinal damage thresholds in order to optimize treatment modalities., Study Design/materials and Methods: In total, 625 laser lesions with various parameters were applied to the retina in 11 eyes of 6 Chinchilla breed rabbits using an experimental laser system (Nd:YLF at 527 nm). Pulse duration (1.7 microseconds and 200 nanoseconds) and number of pulses (100, 10, and 1 pulses) were varied at a constant repetition rate of 100 Hz. Damage thresholds were determined in terms of ophthalmoscopic and fluorescein angiographic visibility, and the therapeutic window (TW; angiographic ED(50) vs. ophthalmoscopic ED(50)) as well as the safety range (SR; angiographic ED(84) vs. ophthalmoscopic ED(16)) between both thresholds were calculated. Selected laser lesions were evaluated by histology., Results: Generally, the ED(50) radiant exposure for angiographic visibility decreases for shorter laser pulses and with an increase in the number of pulses. The TW for both pulse durations (1.7 microseconds and 200 nanoseconds) was wider with 100 pulses than with single pulses. The widest TW was found for 100 pulses at 200 nanoseconds pulse duration (5.9-fold above the angiographic threshold), and the smallest TW with a factor of 1.6 was found for 1.7 microseconds single pulses. In terms of SR, only irradiation with 100 pulses at 200 nanoseconds pulse duration was associated with a ratio >2. Independently of pulse duration, histological examination of laser sites 1 hour after irradiation revealed widely intact photoreceptors, while the underlying RPE was damaged., Conclusions: Pulse duration and number of pulses have a significant influence on RPE damage thresholds and consecutively on TW and SR. Because fundus pigmentation in humans may vary intra- and interindividually by a factor of 2, a large TW and ideally also a large SR should be ensured in a clinical treatment context. In rabbits, the safety range with 200 nanoseconds pulses is higher than with the pulse duration of 1.7 microseconds currently in clinical use. These findings suggest the need for clinical pilot studies to prove whether these results can be transposed to the situation in humans., (Copyright 2004 Wiley-Liss, Inc.)

Background and Objectives: Selective treatment of the retinal pigment epithelium (RPE) by repetitively applying green micros-laser pulses is a new method for retinal diseases associated with a degradation of the RPE, which spares the neural retina. We investigated an alternative approach to realize repetitive micros-laser exposure by rapidly scanning a continuous wave (CW)-laser beam across the RPE., Study Design/materials and Methods: An Ar(+) laser beam (514 nm) with a diameter of 18.75 microm was repetitively scanned across porcine RPE samples in vitro providing an irradiation time of 1.6 micros per point on the central scan axis. RPE cell damage was investigated by means of the fluorescence viability assay Calcein-AM., Results: The ED(50) cell damage is 305 mJ/cm(2) when applying 10 scans with a repetition rate of 500 Hz. The threshold decreases with the number of scans, a saturation was found at 135 mJ/cm(2) with more than 500 exposures applied. The depth of focus in beam direction is 350 microm, defined by an increase of the threshold radiant exposure by 20%., Conclusions: Targeting of pigmented cells with high local resolution has been proved with a laser-scanning device. Looking ahead selective RPE-treatment, the adaptation of a laser-scanning device on a slit-lamp or into a modified retina angiograph seems to be an attractive alternative to the pulsed micros laser device., (Copyright 2003 Wiley-Liss, Inc.)

Background and Objective: In both clinical and animal studies, it has been shown that repetitive short laser pulses can cause selective retinal pigment epithelium damage (RPE) with sparing of photoreceptors. Our purpose was to determine the ophthalmoscopic and angiographic damage thresholds as a function of pulse durations by using different pulsed laser systems to optimize treatment modalities., Materials and Methods: Chinchilla-breed rabbits were narcotized and placed in a special holding system. Laser lesions were applied using a commercial laser slit lamp, contact lens, and irradiation with a frequency-doubled Nd:YLF laser (wave-length: 527 nm; repetition rate: 500 Hz; number of pulses: 100; pulse duration: 5 micros, 1.7 micros, 200 ns) and an argon-ion laser (514 nm, 500 Hz, 100 pulses, 5 micros and 200 ms). In all eyes, spots with different energies were placed into the regio macularis with a diameter of 102 microm (tophat profile). After treatment, fundus photography and fluorescein angiography were performed and radiant exposure for ED50 damage determined. Speckle measurements at the fiber tips were performed to determine intensity peaks in the beam profile., Results: Using the Nd:YLF laser system, the ophthalmoscopic ED50 threshold energies were 25.4 microJ (5 micros), 32 microJ (1.7 micros), and 30 microJ (200 ns). The angiographic ED50 thresholds were 13.4 microJ (5 micros), 9.2 microJ (1.7 micros), and 6.7 microJ (200 ns). With the argon laser, the angiographic threshold for 5 micros pulses was 5.5 microJ. The ophthalmoscopic threshold could not be determined because of a lack of power; however, it was > 12 microJ. For 200 ms, the ED50 radiant exposures were 20.4 mW ophthalmoscopically and 19.2 mW angiographically. Speckle factors were found to be 1.225 for the Nd:YLF and 3.180 for the argon laser. Thus, the maximal ED50 -threshold radiant exposures for the Nd:YLF were calculated to be 362 mJ/cM2 (5 micros), 478 mJ/cm2 (1.7 micros), and 438 mJ/cm2 (200 ns) ophthalmoscopically. Angiographically, the thresholds were 189 mJ/cm2 (5 micros), 143 mJ/cm2 (1.7 micros), and 97 mJ/cm2 (200 ns). For the argon laser, the maximal ED50 radiant exposure threshold was 170 mJ/cm2 angiographically., Conclusion: The gap between the angiographic and the ophthalmoscopic thresholds for the 200 ns regime (4.5 times above angiographic ED50) was wider than for the 1.7 micros regime (3.3 times above the angiographic ED50). This would suggest the appropriate treatment would be 200 ns pulses. However, histologies have yet to prove that nonvisible mechanical effects increase with shorter pulse durations and could reduce the "therapeutic window." When comparing the thresholds with 5 micros pulses from the argon and Nd:YLF laser, it demonstrates that intensity modulations in the beam profile must be considered.

Laser photocoagulation is an established treatment for a variety of retinal diseases. However, when using the same irradiation parameter, the size and strength of the lesions are unpredictable due to unknown inter- and intraindividual optical properties of the fundus layers. The aim of this work is to investigate a feedback system to generate desired lesions of preselectable strengths by automatically controlling the irradiation time. Optoacoustics were used for retinal temperature monitoring. A 532-nm continuous wave Nd:YAG laser was used for photocoagulation. A 75-ns∕523-nm Q-switched Nd:YLF laser simultaneously excited temperature-dependent pressure transients, which were detected at the cornea by an ultrasonic transducer embedded in a contact lens. The temperature data were analyzed during the irradiation by a LabVIEW routine. The treatment laser was switched off automatically when the required lesion strength was achieved. Five different feedback control algorithms for different lesion sizes were developed and tested on rabbits in vivo. With a laser spot diameter of 133 μm, five different lesion types with ophthalmoscopically visible diameters ranging mostly between 100 and 200 μm, and different appearances were achieved by automatic exposure time control. The automatically controlled lesions were widely independent of the treatment laser power and the retinal pigmentation. [ABSTRACT FROM AUTHOR]