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Selective retina therapy (SRT) targets the retinal pigment epithelium (RPE) with pulsed laser irradiation by inducing microbubble formation (MBF) at the intracellular melanin granula, which leads to selective cell disruption. The following wound healing process rejuvenates the chorio-retinal junction. Pulse energy thresholds for selective RPE effects vary intra- and interindividually. We present the evaluation of an algorithm that processes backscattered treatment light to detect MBF as an indicator of RPE cell damage since these RPE lesions are invisible during treatment. Eleven patients with central serous chorioretinopathy and four with diabetic macula edema were treated with a SRT system, which uses a wavelength of 527 nm, a repetition rate of 100 Hz, and a pulse duration of 1.7 μs. Fifteen laser pulses with stepwise increasing pulse energy were applied per treatment spot. Overall, 4626 pulses were used for algorithm parameter optimization and testing. Sensitivity and specificity were the metrics maximized through an automatic optimization process. Data were verified by fluorescein angiography. A sensitivity of 1 and a specificity of 0.93 were achieved. The method introduced in this paper can be used for guidance or automatization of microbubble-related treatments like SRT or selective laser trabeculoplasty., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

Aberration-corrected imaging of human photoreceptor cells, whether hardware or software based, presently requires a complex and expensive setup. Here we use a simple and inexpensive off-axis full-field time-domain optical coherence tomography (OCT) approach to acquire volumetric data of an in vivo human retina. Full volumetric data are recorded in 1.3 s. After computationally correcting for aberrations, single photoreceptor cells were visualized. In addition, the numerical correction of ametropia is demonstrated. Our implementation of full-field optical coherence tomography combines a low technical complexity with the possibility for computational image correction.

With a simple setup, mainly composed of a low coherence light source and a camera, full-field optical coherence tomography (FF-OCT) allows volumetric tissue imaging. However, fringe washout constrains its use in retinal imaging. Here, we present a novel motion-insensitive approach to FF-OCT, which introduces path-length differences between the reference and the sample light in neighboring pixels using an off-axis reference beam. The temporal carrier frequency in scanned time-domain OCT is replaced by a spatial carrier frequency. Volumetric in-vivo FF-OCT measurements of the human retina were acquired in only 1.3 s, comparable to the acquisition times of current clinically used OCT devices.

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.

Laser coagulation is a treatment method for many retinal diseases. Due to variations in fundus pigmentation and light scattering inside the eye globe, different lesion strengths are often achieved. The aim of this work is to realize an automatic feedback algorithm to generate desired lesion strengths by controlling the retinal temperature increase with the irradiation time. Optoacoustics afford non-invasive retinal temperature monitoring during laser treatment. A 75 ns/523 nm Q-switched Nd:YLF laser was used to excite the temperature-dependent pressure amplitudes, which were detected at the cornea by an ultrasonic transducer embedded in a contact lens. A 532 nm continuous wave Nd:YAG laser served for photocoagulation. The ED50 temperatures, for which the probability of ophthalmoscopically visible lesions after one hour in vivo in rabbits was 50%, varied from 63°C for 20 ms to 49°C for 400 ms. Arrhenius parameters were extracted as ΔE=273 J mol(-1) and A=3 x 10(44) s(-1). Control algorithms for mild and strong lesions were developed, which led to average lesion diameters of 162 ± 34 μm and 189 ± 34 μm, respectively. It could be demonstrated that the sizes of the automatically controlled lesions were widely independent of the treatment laser power and the retinal pigmentation.

The induced thermal damage in retinal photocoagulation depends on the temperature increase and the time of irradiation. The temperature rise is unknown due to intraocular variations in light transmission, scattering and grade of absorption in the retinal pigment epithelium (RPE) and the choroid. Thus, in clinical practice, often stronger and deeper coagulations are applied than therapeutically needed, which can lead to extended neuroretinal damage and strong pain perception. This work focuses on an optoacoustic (OA) method to determine the temperature rise in real-time during photocoagulation by repetitively exciting thermoelastic pressure transients with nanosecond probe laser pulses, which are simultaneously applied to the treatment radiation. The temperature-dependent pressure amplitudes are non-invasively detected at the cornea with an ultrasonic transducer embedded in the contact lens. During clinical treatment, temperature courses as predicted by heat diffusion theory are observed in most cases. For laser spot diameters of 100 and 300 μm, and irradiation times of 100 and 200 ms, respectively, peak temperatures range between 70°C and 85°C for mild coagulations. The obtained data look very promising for the realization of a feedback-controlled treatment, which automatically generates preselected and reproducible coagulation strengths, unburdens the ophthalmologist from manual laser dosage, and minimizes adverse effects and pain for the patient.

The control of the temperature increase is an important issue in retinal laser treatments. Within the fundus of the eye heat, generated by absorption of light, is transmitted by diffusion in the retinal pigment epithelium and in the choroid and lost by convection due to the choroidal blood flow. The temperature can be spatially and temporally determined by solving the heat equation. In a former analytical model this was achieved by assuming uniform convection for the whole fundus of the eye. A numerical method avoiding this unrealistic assumption by considering convective heat transfer only in the choroid is used here to solve the heat equation. Numerical results are compared with experimental results obtained by using a novel method of noninvasive optoacoustic retinal temperature measurements in rabbits. Assuming global convection the perfusion coefficient was evaluated to 0.07 s(-1), whereas a value of 0.32 s(-1)--much closer to values found in the literature (between 0.28 and 0.30 s(-1))--was obtained when choroidal convection was assumed, showing the advantage of the numerical method. The modelling of retinal laser treatment is thus improved and could be considered in the future to optimize treatments by calculating retinal temperature increases under various tissues and laser properties.

Introduction: New diagnostic tools such as the retinal thickness analyzer (RTA), optical coherence tomography (OCT), and topographic angiography (TAG) were introduced into clinical ophthalmology during the last years giving the examiner new insights into anatomical and functional aspects of macular disease. In this study, advantages and disadvantages of the new imaging methods have been evaluated in patients with serous (sPED) and fibrovascular pigment epithelial detachments (fPED) secondary to age-related macular degeneration (AMD)., Methods: TAG, using fluorescein angiography (FA), provides a three-dimensional profile of the fluorescein pattern based on the analysis of a set of 32 confocal images over a depth of 4 mm. RTA and OCT provide cross-sectional images of the neurosensory retina and the retinal pigment epithelium-choriocapillary complex as well as retinal thickness data encoded in a false color map. We compared and evaluated these modalities in 15 patients with fPED and 15 patients with sPED secondary to AMD., Results: In patients with classic fPED, TAG detected neovascular structures and delineated their configuration. In sPEDs, pooling of extravascular fluid was detected in a dome-shaped configuration. OCT provided detailed information on the neurosensory retina's structures but failed to detect the neovascular membrane in fPED. Mapping the retinal thickness, RTA and OCT both failed to detect the PED and showed typical algorithm error-based patterns., Conclusion: TAG OCT and RTA are useful imaging modalities in the evaluation of AMD cases. TAG visualizes the vascular configuration, dynamic perfusion, and leakage changes. OCT and RTA are able to complementarily document intra-, subretinal, and sub-RPE fluid accumulation secondary to CNV. However, OCT seems to be more efficient in imaging AMD-related pathologies than RTA, as this modality is often compromised by intra- or subretinal structural abnormalities. Nevertheless, all modalities may provide further valuable insight into AMD pathogenesis, enhance diagnostic quality, and improve the assessment of therapeutic effects.

The therapeutic effect of most retinal laser treatments is initiated by a transient temperature increase. Although crucial to the effectiveness of the treatment, the temperature course is not exactly known due to individually different tissue properties. We develop an optoacoustic method to determine the retinal temperature increase in real time during continuous-wave (cw) laser irradiation, and perform temperature calculations to interpret the results exemplary for transpupillary thermotherapy (TTT). Porcine globes ex vivo and rabbit eyes in vivo are irradiated with a diode laser (lambda=810 nm, P< or =3 W, phi=2 mm) for 60 s. Simultaneously, pulses from a N2-laser pumped dye laser (lambda=500 nm, tau=3.5 ns, E approximately 5 microJ) are applied on the retina. Following its absorption, an ultrasonic pressure wave is emitted, which is detected by a transducer embedded in a contact lens. Using the previously measured temperature-dependent Gruneisen coefficient of chorioretinal tissue, a temperature raise in porcine eyes of 5.8 degrees C(Wcm2) after 60 s is observed and confirmed by simultaneous measurements with an inserted thermocouple. In a rabbit, we find 1.4 degrees C(Wcm2) with, and 2.2 degrees C(Wcm2) without perfusion at the same location. Coagulation of the rabbit's retina occurs at DeltaT=21 degrees C after 40 s. In conclusion, this optoacoustic method seems feasible for an in vivo real-time determination of temperature, opening the possibility for feedback control retinal laser treatments.

Background and Objectives: To explore the potential of Er:YAG-laser irradiation for precise and tractionless retinal tissue and inner limiting membrane ablation., Materials and Methods: We used free-running Er:YAG-laser irradiation (lambda = 2.94 microm) transmitted either through a 10 cm long low-OH-quartz fiber or a 2 m long sapphire fiber that produced a more homogenous light distribution at the fiber tip. Retinal ablation in porcine retinal explants was performed under air or perfluorodecaline (PFD). Ablation depth was evaluated by optical coherence tomography (OCT) and from histologic sections., Results: A radiant exposure of 5.0 J/cm(2) delivered through a low-OH-quartz fiber and PFD caused a complete transsection of the neurosensory retina. Radiant exposures between 3.5 and 2.0 J/cm(2) resulted in marked variations of ablation depth and adjacent thermal damage. By contrast, laser pulses of 4.0 and 3.0 J/cm(2) transmitted through the sapphire fiber produced more homogenous defect patterns and less thermal damage. Close to the ablation threshold, with 1.0-2.0 J/cm(2), ablation was limited to a 10-20 microm thin layer of the neural retina., Conclusions: We achieved in vitro ablation of inner retinal layers, but could not produce selective and reproducible ILM removal.

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.

We investigate the relationship between the laser beam at the retina (spot size) and the extent of retinal injury from single ultrashort laser pulses. From previous studies it is believed that the retinal effect of single 3-ps laser pulses should vary in extent and location, depending on the occurrence of laser-induced breakdown (LIB) at the site of laser delivery. Single 3-ps pulses of 580-nm laser energy are delivered over a range of spot sizes to the retina of Macaca mulatta. The retinal response is captured sequentially with optical coherence tomography (OCT). The in vivo OCT images and the extent of pathology on final microscopic sections of the laser site are compared. With delivery of a laser pulse with peak irradiance greater than that required for LIB, OCT and light micrographs demonstrate inner retinal injury with many intraretinal and/or vitreous hemorrhages. In contrast, broad outer retinal injury with minimal to no choriocapillaris effect is seen after delivery of laser pulses to a larger retinal area (60 to 300 microm diam) when peak irradiance is less than that required for LIB. The broader lesions extend into the inner retina when higher energy delivery produces intraretinal injury. Microscopic examination of stained fixed tissues provide better resolution of retinal morphology than OCT. OCT provides less resolution but could be guided over an in vivo, visible retinal lesion for repeated sampling over time during the evolution of the lesion formation. For 3-ps visible wavelength laser pulses, varying the spot size and laser energy directly affects the extent of retinal injury. This again is believed to be partly due to the onset of LIB, as seen in previous studies. Spot-size dependence should be considered when comparing studies of retinal effects or when pursuing a specific retinal effect from ultrashort laser pulses., (Copyright 2004 Society of Photo-Optical Instrumentation Engineers.)

Background: To investigate the potential of an Er:YAG laser for precise and traction-free removal of retinal layers in vitro., Material and Methods: Retinal ablation in porcine retinal explants was performed using a free running Er:YAG laser focused either into a low-OH quartz fiber or a sapphire fiber. The explants were treated under air or perfluorodecaline (PFD). The ablation depth was evaluated by optical coherence tomography (OCT) and histology sections., Results: A radiant exposure of 5.0 J/cm(2) under air and PFD resulted in complete transsection of the neurosensory retina. Between 3.5 and 2.0 J/cm(2) the ablation depth and the defect patterns varied markedly and adjacent thermal zones areas were seen. Below 2.0 J/cm(2) no defects could be created in air, whereas under PFD the ablation extended into the ganglion cell layer. Ablations using a sapphire fiber and 2.0 J/cm(2) showed a significantly higher reproducibility of ablation depth, and homogeneous defect patterns limited to the nerve fiber layer could be produced without thermal damage., Conclusions: The Er:YAG laser system with a low-OH quartz fiber allowed ablation of inner retinal layers in vitro, but revealed a variable ablation depth and low reproducibility.However, a sapphire fiber showed markedly improved results. Therefore its use during vitreoretinal surgery seems possible not only as a cutting device but also as a tool for the ablation of fine retinal structures.

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.

Objective: To investigate whether photocoagulation of the retinal pigment epithelium is possible with sparing of the photoreceptors., Methods: Mild laser effects of a neodymium:yttrium-lithium-fluoride (Nd:YLF) laser (527 nm) were applied to 17 patients. To establish the necessary energy, test exposures were performed to the lower macula (laser variables: 1.7 microseconds, 100 and 500 pulses applied in a train at 500 Hz, 20-130 microJ, 160 microm). Of 179 test lesions, 73 were followed up at various time intervals up to 1 year by performing microperimetry directly on top of the laser lesions., Results: All of the test lesions were at the threshold of retinal pigment epithelial disruption, and none of the laser effects were visible by ophthalmoscopy during photocoagulation; they were detectable only by fluorescein angiography. After exposure with 500 pulses, retinal defects were detected in up to 73% of the patients (100 microJ) after the first day. Most of these defects were no longer detectable after 3 months. After exposure with 100 pulses, no defects could be detected with 70 and 100 microJ after 1 day. The absence of microscotomas in the follow-up period suggests that retinal damage was minimal or, if it occurred, was functionally repaired., Conclusion: By choosing proper energy and number of pulses, it is possible to produce retinal pigment epithelial effects with no subsequent retinal damage detectable by microperimetry.

Background and Objective: Retinal laser photocoagulation is generally performed by laser pulses of a few hundred milliseconds. The tissue interaction mechanism is a pure thermal interaction mechanism. As pulse duration gets shorter, different, non-thermal interaction mechanisms start to appear. The time domain for a change of tissue interaction mechanism seems to be in the ns and micros range. The goal of this study was to characterize the tissue interaction mechanism with 200-ns laser pulses, which approximate the thermal relaxation time of single melanin granules., Materials and Methods: The retinas of 19 eyes of 10 rabbits were irradiated by 10 and 500 repetitive laser pulses (wavelength, 532 nm; repetition rate, 500 Hz; pulse duration, 200 ns; per pulse energy, 0-120 microJ; retinal spot size, 100 microm). The effects were evaluated by fluorescein angiography, ophthalmoscopy and by theoretical thermal calculations. Light microscopy and transmission electron microscopy were additionally performed on lesions irradiated by 500 pulses., Results: Single pulse threshold energies for angiographic visibility were 3.5 microJ (10 pulses) and 2.1 microJ (500 pulses), for ophthalmoscopic visibility 9.0 microJ (10 pulses) vs. 8.6 microJ (500 pulses). At energy levels above ophthalmoscopic visibility macroscopically visible bubble formation inside the retina could be observed. This occurred at energy levels of 35 microJ (10 pulses) vs. 17 microJ (500 pulses). Microscopic evaluation of lesions irradiated with 500 pulses and energies at the angiographic threshold showed a damage primarily to the RPE. Additional outer segment damage of the photoreceptors could be found. A gap between damaged RPE cells and the outer segments could be repeatedly found as well as damaged RPE cells, which were detached from intact Bruch's membrane. Temperature calculation shows that temperatures above 100 degrees C may exist around single melanin granules., Conclusion: The studies suggest that RPE damage may occur by bubble formation around single melanin granules.

Objective: To compare the cross-sectional images of primate retinal morphology obtained by optical coherence tomography (OCT) with light microscopy to determine the retinal components represented in OCT images., Methods: Laser pulses were delivered to the retina to create small marker lesions in a Macaca mulatta. These lesions were used to align in vivo OCT scans and ex vivum histologic cross sections for image comparison., Results: The OCT images demonstrated reproducible patterns of retinal morphology that corresponded to the location of retinal layers seen on light microscopic overlays. Layers of relative high reflectivity corresponded to horizontally aligned retinal components such as the nerve fiber layer and plexiform layers, as well as to the retinal pigment epithelium and choroid. In contrast, the nuclear layers and the photoreceptor inner and outer segments demonstrated relative low reflectivity by OCT., Conclusions: Retinal morphology and macular OCT imaging correlate well, with alignment of areas of high and low reflectivity to specific retinal and choroidal elements. Resolution of retinal structures by OCT depends on the contrast in relative reflectivity of adjacent structures. Use of this tool will enable expanded study of retinal morphology, both normal and pathologic, as it evolves in vivo.

Purpose: To assess the in vivo evolution of argon laser retinal lesions by correlating the cross-sectional structure from sequential optical coherence tomography with histopathologic sectioning., Methods: Argon laser lesions were created in the retinas of Macaca mulatta and evaluated by cross-section optical coherence tomography, which was compared at selected time points with corresponding histopathology., Results: Argon laser lesions induced an optical coherence tomography pattern of early outer retinal relative high reflectivity with subsequent surrounding relative low reflectivity that correlated well with histopathologic findings. The in vivo optical coherence tomography images of macular laser lesions clearly demonstrated differences in pathologic response by retinal layer over time., Conclusion: The novel sequential imaging of rapidly evolving macular lesions with optical coherence tomography provides new insight into the patterns of acute tissue response by cross-sectional layer. This sequential imaging technique will aid in our understanding of the rapid evolution of retinal pathology and response to treatment in the research and clinical setting.

The small difference in wavelength between an argon laser (514 nm) and a frequency-doubled Nd:YAG laser (532 nm), together with the advantage of the solid-state technology, makes the Nd:YAG laser likely to play a major role in retinal photocoagulation in the near future. For technical reasons all frequency-doubled Nd:YAG lasers work in a quasi-continuous mode, emitting a burst of highly repetitive short laser pulses during the exposure time desired. We investigated the side effects due to high peak irradiances of those short laser pulse trains (Crystal Focus Nd:YAG laser, Emerald; pulse duration 1-10 microseconds, repetition rate 13 KHz) in rabbits in comparison with a standard argon laser system (Zeiss, Visulas, Argon II). The energy necessary for blanching the retina was similar in both cases. As opposed to the argon laser system, subretinal bubbles were regularly visible ophthalmoscopically with the Nd:YAG system, when average powers as high as 200 mW were used. The ED50 power for bubble formation is about 2-3 times above the ED50 power for blanching. Thermal calculations show that this bubble formation effect is likely to be related to the peak power of the short pulses. The hemorrhage threshold is similar in both systems. However, light microscopically there is no difference between the two laser systems. Panretinal photocoagulation (300-500 microns, 100-200 ms) in patients with proliferative diabetic retinopathy produced such bubbles about once per 1000 lesions.

Purpose: Nd:YAG laser photodisruption with nanosecond (ns) pulses in the millijoule range is an established tool for intraocular surgery. This study investigates tissue effects in cornea, lens, and retina to assess whether picosecond (ps) pulses with energies in the microjoule range can increase the surgical precision, reduce collateral damage, and allow applications requiring more localized tissue effects than can be achieved with ns pulses., Methods: Both ps and ns Nd:YAG laser effects on Descemet's membrane, in the corneal stroma, in the lens, and at the retina were investigated in vitro in bovine and sheep eyes and in cataractous human lens nuclei. For each tissue, the optical breakdown threshold was determined. The morphology of the tissue effects and the damage range of the laser pulses were examined by light and scanning electron microscopy. The cavitation bubble dynamics during the formation of corneal intrastromal laser effects were documented by time-resolved photography., Results: The optical breakdown threshold for ps pulses in clear cornea, lens, and vitreous is, on average, 12 times lower than that for ns pulses. In cataractous lens nuclei, it is lower by a factor of 7. Using ps pulses, Descemet's membrane could be dissected with fewer disruptive side effects than with ns pulses, whereby the damage range decreased by a factor of 3. The range for retinal damage was only 0.5 mm when 200 microJ ps pulses were focused into the vitreous. Picosecond pulses could be used for corneal intrastromal tissue evaporation without damaging the corneal epithelium or endothelium, when the pulses were applied in the anterior part of the stroma. The range for endothelial damage was 150 microns at 80 microJ pulse energy. Intrastromal corneal refractive surgery is compromised by the laser-induced cavitation effects. Tissue displacement during bubble expansion is more pronounced than tissue evaporation, and irregular bubble formation creates difficulties in producing predictable refractive changes., Conclusions: The use of ps pulses improves the precision of intraocular Nd:YAG laser surgery and diminishes unwanted disruptive side effects, thereby widening the field of potential applications. Promising fields for further studies are intrastromal corneal refractive surgery, cataract fragmentation, membrane cutting, and vitreolysis close to the retina.

In retinal laser photocoagulation, constant exposure parameters do not result in identical lesions. This lack of reproducibility increases the rate of complications from over- or undertreatment and inhibits determination of the optimal treatment endpoints for different retinal disorders. To this end, a feedback-controlled photocoagulator could make retinal photocoagulation a safer, more reproducible, and faster procedure. A dynamic confocal reflectometer was integrated into a slit lamp laser delivery system. Real-time reflectance changes on the retinas of pigmented rabbits were obtained by monitoring the increasing back-scattered light of the coagulating beam during argon laser photocoagulation. Reproducible temporal reflectance patterns were measured that correlated with ophthalmoscopically assessed lesion intensity independent of the exposure parameters, the transparency of the optical media, and the focusing conditions. As a step toward the development of a feedback-controlled photocoagulator, the confocal reflectometer has been proven in animal trials closely resembling clinical practice.

Repetitive exposure to short laser pulses is shown to cause selective damage to absorbing structures (cells, organelles, or enzymes) with pulse energies below the threshold energy for single-pulse damage. Directly adjacent structures are spared in vivo. Additivity of (presumably nonphotochemical) subthreshold effects is demonstrated. Selective damage to the retinal pigment epithelium with sparing of the neural retina is shown (514 nm, 5 microseconds, 1-500 pulses at 500 Hz, 2- to 10-microJ pulse energy). A melanin granule model has been developed and applied to the experimental situation. Histological results as well as the basic mechanism for these effects are discussed.

Laser indirect ophthalmoscope (LIO) photocoagulation and transscleral photocoagulation through the conjunctiva and subconjunctiva were performed in the fundus of chinchilla gray rabbits using various exposure times and powers, and the thresholds for retinal blanching and choroidal hemorrhage were determined. The therapeutic range was described for both applications as the ratio between energy values to produce grayish white lesions and hemorrhage at 50% probability. The therapeutic range appeared to remain almost constant with different exposure times. The mean ratio with LIO was 3.2 +/- 0.28, similar to that with slit-lamp delivery reported in our previous study. The mean ratio with transscleral photocoagulation through the conjunctiva and subconjunctiva were 2.48 +/- 0.28 and 2.38 +/- 0.26, respectively. The variability of LIO appeared to be a little lower than with transscleral photocoagulation. There was no significant difference between the variability with transscleral photocoagulation through the conjunctiva and subconjunctiva.

Mild continuous wave (CW) irradiation (100 ms, 20 mW, 514 nm) and irradiation with 100 repetitive 5 microseconds laser pulses (3 or 6 microJ, 514 nm) at a repetition rate of 500 Hz was performed to the regio macularis of chinchilla rabbits. The angiographically visible lesions were histologically followed up to 4 weeks. With both irradiation modalities the original retinal pigment epithelium (RPE) was replaced by a monolayer of new RPE cells. Only minimal immediate and no subsequent damage to the photoreceptors was found after selective RPE photocoagulation. Only minimal inflammatory response was found after selective RPE photocoagulation in contrast to CW photocoagulation where macrophages, RPE cells and lymphocytes regularly appear in the damaged photoreceptor layer.

A thermal damage model including heat conduction for retinal lesions is described to explain thermal threshold damage and compare it to experimental values in the regime of 1 ms to 300 ms. With the aid of these model calculations unspecific thermal damage (denaturation of proteins) could be separated from thermally induced damage to the photoreceptors. Furthermore, the thermal model allows an extrapolation to hazards to the fundus from intense light irradiation that have not been investigated experimentally.

Different kinds of damage can be produced by intense light irradiation of the retina. These types of damage can be separated into changes which are induced by photochemical or thermal effects in the tissue. Photochemical damage occurs mainly with intense irradiation of a few seconds or longer whereas thermal effects appear to prevail at irradiation times in the 1 ms to 1000 ms-range. Distinction between photochemical and thermal damage is very difficult because both types of injury appear as disorders in the retinal pigment epithelium and the outer segments of the photoreceptors. A thermal model has therefore been developed which takes into account the light absorption in the different layers of RPE and choroid and allows the calculation of the temporal development of temperature at each site and depth of the fundus. Model calculations are used to correlate exposure parameters (wavelength, irradiance, exposure time etc.) with the resulting temperature profiles. This correlation leads to a better distinction between exposure limits for thermal and photochemical damage of the retina.

The penetration depth of laser light into the fundus is dependent on the wavelength. Thereby, the profile of damage depends on the absorption and on the temperature profile. It has been demonstrated earlier that wavelength-dependent differences in penetration depth are hard to detect ophthalmoscopically or histologically in severe lesions in Chinchilla gray rabbits. Therefore in this study, the wavelength-dependent exposure powers necessary for (1) similar retinal effects and (2) similar choroidal effects were compared. The resulting wavelength-dependent differences were smaller than expected-due to at least three reasons: (1) predominance of the temperature profile over the absorption profile for clinically useful exposure times; (2) light scatter in the retina in relationship to the exposure time (and wavelength?): (3) changes in the choroidal geometry in relationship to the exposure time and wavelength. Nevertheless, it appears to be possible to spare the retina somewhat by using longer wavelengths. In order to evaluate the clinical situation experimentally despite the fact that the human choroid is about three times thicker than the rabbit choroid, a geometrical model has been developed. The results indicate that the retina is less damaged using Nd:YAG lasers than using argon lasers when similar choroidal effects are produced.

A method is described for monitoring the light reflected from exposed areas during and after argon laser photocoagulation of rabbit eyes. The light serves as a measure of the retinal blanching and thus of the tissue reaction. It is shown, that the reflected light changes its time-dependent behavior qualitatively if hemorrhages occur. The energy necessary for a therapeutic coagulation is shown to decrease with decreasing exposure time as does the therapeutic band width for clinical coagulations. A relationship between exposure time and therapeutic band width was found and is discussed.

The effects of intense light produced by an argon laser, a helium-neon laser and a xenon are photocoagulator in the retinas of gray chinchilla rabbits, cynomolgus monkeys, and rhesus monkeys were studied clinically and histopathologically including electron microscopy. An improved experimental set-up was used allowing a very good consistency of the inflicted lesions. Threshold lesions were produced in chinchilla rabbits and cynomolgus monkeys by an argon laser and a helium-neon laser. The lesions were evaluated ophthalmoscopically and histograms were drawn indicating ophthalmoscopic ED50 values. For the two lasers examined these values were 12 and 17 mW, respectively, for exposure durations in the range of the blink reflex (125-150 msec). Histopathologically, ophthalmoscopic threshold lesions of both laser types showed evidence of thermal damage of the outer retinal half. This damage was principally identical in both species involving the retinal pigment epithelium and the full extension of the photoreceptor cells up to their synapses within the outer plexiform layer. The ophthalmoscopic threshold value was associated, therefore, with an irreversible loss of visual function within the retinal area concerned. No evidence for primary sites of significant energy absorption within the neural retina was found. The width of ophthalmoscopic threshold lesions was determined by measuring within the histologic sections with a microscope and a calibrated graticule the extension of damage at the level of the retinal pigment epithelium and at the level of the outer nuclear layer. In the cynomolgus monkey for ophthalmoscopic argon laser threshold lesions the extension at the level of the RPE was 70-80 mum in diameter and at the level of the outer nuclear layer it was 40-50 mum in diameter. Laser lesions that had a diameter of 60 mum at the level of the RPE and of 30 mum at the level of the outer nuclear layer were ophthalmoscopically subvisible. It is concluded that probably also in man such laser lesions, as well as various other pathologic changes of this size or smaller, cannot be evaluated by clinical ophthalmoscopy. The ophthalmoscopic threshold was correlated with a histopathologic threshold as defined by minimal histopathologic damage. Very likely, such damage lies within the range of functional recovery, and the histopathologic threshold demarcates at the same time the decisive functional threshold. The conversion ratio between histopathologic-functional and ophthalmoscopic threshold for argon lesions in cynomolgus monkeys was somewhat greater than 3, e.i. the ophthalmoscopic threshold was more than 3 times higher than the histopathologic-functional threshold. Using this data together with additional biologic and optical considerations, a safety threshold for man for cw-lasers within the visible spectrum was estimated to be 1-2 mW.

In damage tests conducted on rabbit and monkey eyes, the threshold values for retinal damage resulting from different laser radiation were determined. The reproduction of the "worst-case" situation was ensured by the test apparatus. All physical parameters, such as power/energy, exposure time, and retinal spot, were carefully controlled. Probit analysis showed a very precise determination of the threshold values based on ophthalmoscopical visibility. The attempt of a simple physical interpretation of the thresholds leads to contradictions in major points, so a detailed calculation of damage functions and thermal model calculations are necessary.

Purpose: Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. Material and methods: This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). Results: Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. Conclusion: Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending. [ABSTRACT FROM AUTHOR]