H. Elsner

Noninvasive optoacoustic online retinal temperature determination during continuous-wave laser irradiation

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 rabbits 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.

Optoacoustic real-time dosimetry for selective retina treatment

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.

[Selective retina therapy: methods, technique, and online dosimetry].

ZusammenfassungDie selektive Retinatherapie (SRT) wird zurzeit als neue, schonende Laserbehandlungsmethode für verschiedene Erkrankungen des Augenhintergrunds evaluiert, die mit einer reduzierten Funktion des retinalen Pigmentepithels (RPE) assoziiert werden. Mit der SRT wird im bestrahlten Areal lediglich das RPE behandelt, ohne die angrenzende neurosensorische Netzhaut mit den Photorezeptoren und die unter dem RPE liegende Aderhaut zu schädigen. Die Therapie führt idealerweise zu einer Regeneration des RPE und einem gesteigerten Metabolismus am chorioretinalen Übergang. Im Gegensatz zur etablierten Laserphotokoagulation, bei der die bestrahlten und umgebenden Areale der Netzhaut komplett verödet werden, bleiben bei der SRT Skotome vollständig aus. Der Artikel gibt eine Übersicht über die Methodik und die Mechanismen zu selektiven RPE-Effekten und resümiert In-vitro- und vorklinische Ergebnisse zur Bandbreite der Selektivität für verschiedene Bestrahlungsparameter. Die Beschreibung einer optoakustischen Methode zur Online-Visualisierung der optisch nicht sichtbaren Effekte und damit zur Dosimetrie ohne angiographische Kontrolle runden die Übersicht ab.AbstractSelective retina therapy (SRT) is currently under evaluation, as a new and very subtle laser method, for the treatment of retinal disorders associated with a degradation of the retinal pigmentary epithelium (RPE). SRT makes it possible to selevtively effect the RPE, sparing the adjacent neural retina with the photoreceptors and also the choroid below the RPE. In the best case, the therapy leads to regeneration of the RPE and a long-term metabolic increase at the chorio-retinal junction. In contrast to conventional laser photocoagulation, which is associated with complete thermal necrosis of and around the treated site, absolutely no scotoma occurs in SRT. This paper reviews the methods and mechanisms behind the selective effects of the RPE. In vitro and preclinical results are used to describe the bandwidth of selective effects with respect to different irradiation settings. An optoacoustic technique is introduced to visualize effects that cannot be seen by ophthalmoscopy and to facilitate dosimetry control without recourse to angiography completes the report.

Topographic angiography and optical coherence tomography: a correlation of imaging characteristics.

Purpose Topographic angiography (TAG) using confocal scanning laser angiography and optical coherence tomography (OCT) are new imaging modalities that have been introduced during recent years. OCT and TAG imaging were compared to specify the characteristics of each imaging modality. Methods TAG using fluorescein angiography (FA) provides a three-dimensional profile of the vascular structures based on the analysis of a set of 32 confocal images over a depth of 4 mm. OCT provides cross-sectional images of the neurosensory retina and the retinal pigment epithelium-choriocapillary complex (RPE-CC). The authors compared and evaluated both modalities in 10 patients with predominantly classic choroidal neovascularization (CNV), 10 patients with serous pigment epithelial detachment (PED), and 10 patients with geographic RPE atrophy, all secondary to age-related macular degeneration (ARMD). Results In patients with classic CNV, TAG detected neovascular structures and delineated their configuration. In PEDs pooling of extravascular fluid is demonstrated, and in geographic RPE atrophy TAG showed reduced choroidal perfusion. Classic CNV was demonstrated by OCT as a hyperreflective band at the level of the RPE-CC, and PED showed a dome-shaped RPE detachment. In geographic RPE atrophy, OCT imaged loss of the RPE band and had an increased depth resolution. Conclusions TAG and OCT are useful imaging modalities in the evaluation of ARMD cases. TAG visualizes the vascular configuration and dynamic perfusion and leakage changes. OCT is able to document intra-, subretinal, and sub-RPE fluid accumulation secondary to CNV. Both modalities may provide further valuable insight into ARMD pathogenesis, enhance diagnostic quality, and improve the assessment of therapeutic effects.

Numerical modelling of conductive and convective heat transfers in retinal laser applications

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.

Optoacoustic temperature determination at the fundus of the eye during transpupillary thermotherapy

Transpupillary Thermotherapy (TTT) is a retinal laser treatment targeting on occult neovascular membranes. However, the induced temperature increase during irradiation is not exactly known. Model calculations show that differences in pigmentation and vascular perfusion should lead to a different temperature rise under same treatment parameters. In order to evaluate the temperature profiles during TTT, we developed a non-invasive optoacoustic method. The experiments were carried out on enucleated porcine eyes (ex-vivo) and rabbits (in-vivo). Simultaneously to the irradiation with a TTT-laser (λ=810nm, P≤3W) through a slit lamp, pulses from a pulsed dye laser (λ=500nm, τ=3ns, E=5μJ) were applied onto the irradiated area. This probe irradiation induces an ultrasonic pressure wave, its amplitude depends on the temperature of the absorbing media. We measured this pressure wave by an ultrasonic transducer integrated into a contact lens. The induced pressure maximum for porcine RPE samples was found to raise by 14.6% between 37°C and 50°C. Using this relation we determined optoacoustically the temperature increase during TTT. A comparison of the acoustic data with simultaneous temperature measurements by a thermo couple positioned in the choroid showed accordance within ±1.2°C. Differences in pigmentation led to a 1.8 fold induced temperature increase between weak and heavy pigmented eyes. First results in the in-vivo animal study showed an average temperature increase of (2.45 ±0.16)°C for an irradiation of 1W/cm2. In conclusion the developed optoacoustic method seems adequate for real-time temperature determination during retinal laser treatments and might serve as a dosimetry control for TTT.© (2005) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Optoacoustic online dosimetry during selective RPE treatment

Introduction: The selective RPE treatment (SRT) is a new method, which targets retinal diseases associated with disorders in the retinal pigment epithelium (RPE). By applying a train of μs laser pulses, it is possible to selectively damage RPE cells while sparing the adjacent photoreceptors and the neural retina. Due to the ophthalmoscopic invisibility of the RPE effects we investigated an optoacoustic (OA) on-line dosimetry system to monitor RPE damage non-invasively. Material and Methods: For in vitro experiments porcine RPE was irradiated with a Nd:YLF laser pulse train (527nm, 1.7μs, 5-40μJ, 30 pulses, 100 Hz). Pressure waves (optoacoustic transients) generated at the RPE were measured with a piezoelectric transducer. The RPE cell damage was visualised by fluorescence microscopy by means of the vitality stain CalceinAM. During 27 patient treatments (527nm, 1.7μs, 50-150μJ, 30 pulses, 100 Hz) the optoacoustic signals were measured with an ultrasonic transducer embedded in the contact lens. The RPE leakage was visualized by fluorescein and ICG angiography. Results: In vitro: Below the RPE cell damage threshold, the optoacoustic transients from each single pulse are almost similar. With RPE damage, fluctuations of the individual transients are observed during the pulse train. These fluctuations can be explained by statistical irregular microbubble formation around the strong light absorbing melanosomes inside the RPE cells, which occur after the temperature exceeds the vaporization threshold. The transient microbubbles probably lead to RPE cell disruption. An optoacoustic value (OA-value) calculated from the fluctuations was defined in order to assess RPE damage. Patient treatment: If optoacoustic pulse-to-pulse fluctuations were measured, RPE leakage was observed in fluorescein and ICG angiography. In 96% of the irradiated areas, RPE-leakage in fluorescein angiography and OA-value correlated. The stronger the optoacoustic pulse-to-pulse fluctuations, thus the higher the OA-value, the more intense angiographic leakage was observed in ICG-angiography. Conclusion: A non-invasive optoacoustic on-line dosimetry control to monitor RPE damage during SRT was developed. In order to avoid invasive angiography, it is currently evaluated in a multicenter clinical SRT study.

Non-invasive optoacoustic temperature determination during retinal cw-laser treatments

In almost all retinal laser treatments the therapeutic effect is initiated by a transient temperature increase. Due to differences in tissue properties and physiology like pigmentation and vascular blood flow an individually different temperature increase might occur with crucial effects on the therapeutic benefit of the treatment. In order to determine the individual retinal temperature increase during cw-laser irradiation in real-time we developed a non-invasive method based on optoacoustics. Simultaneously to the cw-laser irradiation (λ = 810 nm, P < 3 W, t = 60 s) pulses from a dye laser (λ = 500 nm, τ = 3.5 ns, Ε ≈ 5 μJ) are applied concentrically to the cw-laser spot on the eyeground. The absorption of the pulses lead to a consequent heating and thermoelastic expansion of the tissue. This causes the emission of an ultrasonic pressure wave, which amplitude was found to be temperature dependent following in good approximation a 2nd order polynomial. The pressure wave was measured by an ultrasonic transducer embedded in a contact lens placed on the cornea. The experiments were performed in-vivo on rabbits. Simultaneous measurements with a miniaturized thermocouple showed a similar slope with a maximum local deviation of 0.4 °C for a temperature increase of 5.5 °C. On two rabbits measurements pre and post mortem at the same location were performed. The temperature increase after 60 s was found to raise by 12.0 % and 66.7 % post mortem, respectively. These data were used to calculate the influence of heat convection by blood circulation using a numerical model based on two absorbing layers and assuming a constant perfusion rate for the choriocapillaris and the choroid. Overall the presented optoacoustic method seems feasible for a non-invasive real-time determination of cw-laser induced retinal temperature increases and might serve as a temperature based dosimetry control during retinal laser treatments.