Clinical Evaluation of Individualized and Navigated Microsecond Pulsing Laser for Acute Central Serous Chorioretinopathy

Introduction

Central serous chorioretinopathy (CSC) is a pathology of the central zone of the retina occurring predominantly in young/middle-aged males. It is characterized by an idiopathic serous detachment of the neurosensory retina with leakage of fluid through the retinal pigment epithelium (RPE) into the subretinal space, which may be accompanied by detachment of the RPE.¹ Local defects in RPE cells with violation of the blood-retinal barrier and pumping functions play an important role in the development of CSC. Treatment should aim to restore the external blood-retinal barrier without causing excessive damage to adjacent tissues.^2–4 A common approach to treating CSC is focal laser photocoagulation of the retina at the leaking point based on fluorescein angiography (FA) images.^2–10 With the active evolution of laser surgery and the development of the navigated laser system Navilas (OD-OS GmbH, Teltow, Germany), it is possible to control laser focus accurately. Treatment accuracy is complemented by pre-planning of the operation using the data from FA and optical coherence tomography (OCT), compared to a color photograph of the patient’s fundus. This technology enables fast and safe treatment through an advanced tracking system, eliminating the subjective factor and deviation of the laser beam from its pre-planned target.¹¹

First results of navigated focal photocoagulation of the leaking point in CSC illustrate the method’s high efficiency in targeting laser treatment in accordance with the FA-based plan.^12–14 However, although the application of thermal burn by conventional laser can promote the reabsorption of subretinal fluid (SRF), it risks causing central or paracentral scotoma, loss of retinal sensitivity and inadvertent foveal damage.¹⁵

Thermal heating of the neurosensory retina and the underlying choroid can be avoided using microsecond pulsed laser radiation.^16,17 Damage to surrounding tissues is minimized by using microsecond pulse in the selective range of energy parameters, as laser radiation is directed exclusively at the RPE.^16,17 Several case series present this solution, using a yellow laser, as effective for the treatment of CSC without RPE atrophic changes detectable during follow-up.^18–23 This lack of visibility when using a microsecond pulsing laser means it is hard for the operator to follow and track already applied lesions, inhibiting the possibility of achieving true confluency. Again, Navilas in microsecond pulsing mode is an optimal tool to apply and analyze this treatment method. The pre-planning and documentation capabilities prevent this issue, allowing correct definition previously treated areas.^24–29

The use of multimodal diagnostics and treatment done using energy parameters selected for each patient means that treatment can be topographically orientated and pathogenetically validated. Healthy structures in the retina and choroid can be avoided, reducing risk of unnecessary tissue damage. The Navilas 577s navigation system, equipped with a microsecond pulse, allows a new and improved method for personalized laser treatment of patients with CSC with targeted delivery of laser irradiation, minimal energy parameters, and the smallest number of applications to achieve a positive clinical effect.⁴

Data published in this area uses a wide range of parameters, making it difficult to determine which are optimal. They vary from 5% DC to 15% DC, 20 ms to 300 ms and spot sizes between 100 μm and 200 μm (Table 1). Due to this large variance, we pre-analyzed the optimal parameter set based on a computational model.

Table 1: Overview of Parameters Used and Success Rate

The model considers physics of the transmission of laser radiation in the transparent intraocular media, heating processes, and thermal denaturation of proteins, depending on the laser parameters used, such as wavelength, spot size, pulse duration, and duty cycle. Formation and evolution of temperature fields on the basis of a numerical solution of the heat-transfer equation was solved using a specific computer program. The temperature profile was estimated for the cooling of one pulse of various duration and power for various times as well as the temperature dependence in the center of the RPE layer of the cells from the start of the pulse action. After obtaining the temperature fields at various time points, the distribution of the concentration of denatured protein was calculated. To this end, we simulated the processes of irreversible denaturation of proteins of the human eye. To assess the degree of action on the RPE, we employ the concepts of efficiency and selectivity. Efficiency is the ratio of the amount of denatured protein within the RPE layer to the total amount of protein within the RPE layer. Selectivity is the ratio of the amount of denatured protein inside the RPE layer to the total amount of denatured protein.³⁰

According to the computer simulation’s results, a selective yet effective microsecond pulse is achieved within a narrow window of parameters, in relation to the transparent optical media, varying intensity of the ocular fundus’ pigmentation, and technical characteristics of the Navilas 577s laser system (577 nm wavelength). The computer simulation was conducted, and parameters were determined from the range available on Navilas taking into account its technical characteristics and found the conditions under which the maximum effect on the RPE (thermal damage) is achieved. Based on this model, the parameter set to achieve an optimal selectivity efficaciously is obtained with the following parameters: a spot diameter of 100 μm, a pulse duration of 50 μs, a pulse interval of 2,000 μs, duty cycle of 2.4%, a time duration is 10 ms (5 pulses in the envelope), power of 0.4 W to 1.9 W. The power must be selected individually, depending on the degree of pigmentation and transparency of the optical media.³¹ The computer simulation demonstrates the high variability of a person’s individual characteristics. To achieve the most selective and effective action and to determine the threshold for a particular patient, it is necessary to evaluate the thermal damage to the RPE using advanced, highly sensitive diagnostic methods, such as short-wave autofluorescence. Short-wave autofluorescence (488 nm) is the most sensitive diagnostic method for detecting the effect on the RPE of the selective micro-impulse regime.³² This model has been assessed for safety, based on a titration spots placed in a case series. However, the clinical effectiveness of the modeled parameter set is not yet demonstrated and shall be analyzed herein with a case series.

Patients and Methods

All patients signed informed consent and the case series was conducted in accordance with the ethical standards stated in the 1964 Declaration of Helsinki.

Twelve patients were initially examined using standard procedures and diagnosed with acute CSC (duration of 3 to 6 months). Inclusion criteria included presence of SRF involving the fovea for a period of 3 to 6 months in optical coherence tomography (OCT) images and presence of CSC-induced leakage on fundus FA. Patients with concomitant ocular diseases, severe general pathology, previous treatment for CSC (preliminary laser treatment, angiogenesis inhibitor administration, photodynamic therapy), or severe media opacities were excluded. In our study, none of the patients in the main group received topical dorzolamide (Trusopt; Merck, Kenilworth, NJ) or oral mineralocorticoids blockers.

The results of the treatment group were compared to a control group (12 eyes of 12 patients with CSC), who were matched with the treatment group. All patients in the control group received topical dorzolamide as eye drops two times a day.

Best-corrected visual acuity (BCVA), OCT with the Cirrus HD-OCT 5000 device (Zeiss, Jena, Germany), and retinal sensitivity using MAIA (CenterVue, Padova, Italy) were obtained at baseline, prior to Navilas microsecond pulse laser treatment. FA images were processed with Spectralis HRA (Heidelberg Engineering, Heidelberg, Germany) to evaluate the leaking point and define the treatment area before the actual treatment, as well. OCT, BCVA, FA and retinal sensitivities were performed at 1- and 3-month follow-up.

Each patient underwent OCT and FA at baseline and was diagnosed with defects and RPE detachments, corresponding to the leaking points with accurate topographic localization, relating to retinal vasculature. A color photograph of the ocular fundus was then acquired with the Navilas 577s laser device and the digital FA images were superimposed using the embedded software. Based on the data obtained, localization of the RPE defects and detachments corresponding to the points of leakage relating to the vasculature on a color photograph of the fundus were determined and a treatment plan created accordingly. To this end, we selected a free-form confluent pattern using 100 μm spot size and positioned the spots to fully cover the defects and detachments of the RPE corresponding to the leaking points. In addition, two safety zones, established in areas of the ocular fundus, were not exposed to laser irradiation.

Computer simulation demonstrated high variability in each patient’s individual characteristics. A series of titration spots were performed with the Navilas, without a contact lens, before treating the leakage. Titration spots were applied using 100 μm pulse duration of 50 μs, pulse interval of 2000 μs, duty cycle of 2.4%, envelope pulse duration of 10 ms, and power range from 0.4 W to 1.9 W. An individual test plan (Figure 1) was created for each patient, taking into account the varying degree of fundus pigmentation and transparency of optical media. Laser irradiation was then performed using the Navilas 577s. Because CSC almost always occurs in young patients, optical media are usually transparent. Slight opacities of the lens are, however, initially observed in some cases. Therefore, testing began at a power of 0.4 W to 1.2 W for transparent optical media and high-intensity pigmentation, from 0.8 W to 1.7 W for medium-intensity pigmentation, and from 1.0 W to 1.9 W for a low-intensity pigmentation. Testing started from 0.8 W to 1.9 W in the event of low-intensity opacities of the optical media.

Figure 1. Navilas 577s individualized plans (A) for the titration phase and (B) as the actual treatment plan.

To achieve the most selective and effective influence and to determine the threshold for a particular patient, it is necessary to evaluate the thermal damage of RPE using autofluorescence (488 nm). The parameters of laser treatment were selected individually by titration, based on the use of the minimum power at which laser spots were visualized using short wavelength autofluorescence (488 nm).

After an appropriate power level is defined for treatment of the lesion, the laser applications were applied according to the preset plan without the use of a contact lens.

Navilas system is the unique retinal laser, which allows for navigated topographically oriented treatment without a contact lens (noncontact procedure). The system supports digital pre-planning and computer-assisted delivery of laser spots due to its integrated eye tracking technology.

The laser applications were placed close to one another, covering the entire area of defects and RPE detachment, according to the OCT and the leaking points revealed by FA.

Results

We observed 12 patients (three women and nine men) aged 36 to 63 years (mean age: 46.75 years ± 2.43 years) with acute CSC. The results are summarized in Table 2.

Table 2: Summarized Results, Treatment Group

The symptom duration was 3 to 6 months. The baseline BCVA was 0.86 ± 0.03. According to OCT, detachment of the neurosensory retina with accumulation of SRF in the macula was determined in all patients and the maximum central retinal thickness (CRT) was 452.58 μm ± 24.53 μm. In three cases of neurosensory retinal detachment (NSD), detachment of the pigment epithelium, corresponding to the point of the leakage, was determined. In one case, detachment of the pigment epithelium was slight, at a level of 67 μm; in two cases at a level of 319 μm and 281 μm. According to FA, eight cases of a single leaking point were detected; in three patients, two leaking points were diagnosed, and in one patient, three leaking points. Retinal sensitivity of the central zone was studied with a MAIA microperimeter and averaged 24.1 dB ± 1.09 dB.

In all cases, testing and treatment with the Navilas 577s navigation laser system did not require use of corneal contact lens and it was comfortable, painless, and almost unnoticeable for patients. In all cases of using laser applications for examination of the ocular fundus, there were no visible changes both immediately after exposure and 2 hours after exposure. Lack of RPE changes in the treatment area are shown in Figure 2.

Figure 2. Retinal pigment epithelium (RPE) alterations as seen in autofluorescence. (A) Lesions from testing phase as visualized 1 hour post-treatment with short wave autofluorescence. (B) No detectable RPE changes at 3 months, neither in the testing area nor in the treatment site.

One month after treatment, positive dynamics were observed in all patients. Visual acuity increased, on average, to 0.92 ± 0.02. According to OCT data, the maximum thickness of the retina in the macula decreased to 344.75 μm ± 17.73 μm. Complete RPE attachment was observed in two patients. In one case, the height of detachment of the pigment epithelium decreased to 71 μm. According to the microperimetry data, on average, retinal sensitivity increased to 27.6 dB ± 0.32 dB.

After 3 months, the mean BCVA increased to 0.97 ± 0.01. According to OCT, the thickness of the retina in the macula was 249.25 μm ± 2.92 μm. Detachment of the pigment epithelium was resolved. All patients showed complete resorption of the SRF and attachment of the neurosensory retina. Retinal sensitivity increased, on average, to 28.98 dB ± 0.23 dB. Areas with reduced retinal sensitivity in the laser treatment zones were not revealed. Fixation location was central and stable in all eyes in the main group after treatment was demonstrated by microperimetry. Fixation location in the control group was predominantly central in all eyes. In the control group, fixation was stable in 10 (83%) and relatively unstable in two (17%).

Areas exposed to laser in the treatment and testing area were not visualized by biomicroscopy, digital imaging in reflected infrared light, autofluorescence images or fluorescein angiograms. Figure 3 shows results of an exemplar case and demonstrates the lack of side effects from laser treatment as well as a significant effect onto retinal sensitivity and anatomy.

Figure 3. Clinical example. Line 1: Navilas plans. (A) Test plan for Navilas 577s. (B) Autofluorescence demonstrating titration effects. (C) Treatment protocol with the Navilas 577s. Laser applications are placed close to each other, completely covering the point of leakage and retinal pigment epithelium (RPE) defect with minimum power (1.3 W), whereby there are visible signs of RPE damage revealed in the autofluorescence. Line 2: Baseline. (D) Fluorescein angiography (FA). The leaking point in the foveal avascular zone is observed. (E) Computerized microperimetry. Retinal sensitivity: 24.2 dB. A decrease in central macular sensitivity can be observed. (F) Optical coherence tomography. Subretinal fluid (SRF) in the macula. Line 3: 3 months. (G) FA. There are no visible changes in areas of laser treatment and testing. (H) Microperimetry. Retinal sensitivity: 27.9 dB. (I) Optical coherence tomography. SRF is completely resorbed.

The results of the control group are summarized in Table 3. After 6 months of follow-up in the control group, CSC episodes were resolved in eight patients (66.7%) and persisted in four patients (33.3%). One case was resolved after 1 month (8.3%), three cases (25.0%) after 2 months, and two cases (16.6%) after 3 months.

Table 3: Summarized Results, Control Group

Discussion

In most cases, the first episode of acute CSC resolves spontaneously and does not require any treatment. However, it has been established that chronic manifestation of the disease (persistence of the SRF) is associated with risk of incomplete recovery of central visual functions. Degenerative alterations to the RPE and dystrophic changes in the retinal structure with progressive thinning of the photoreceptor layer are associated with recurrence of CSC or its transition to a chronic form, leading to an irreversible reduction in visual function.³³ Switching to active therapeutic techniques is therefore recommended if SRF persists for more than 3 months.¹⁵

As CSC is usually found in young, working-age patients, it is important to use the most careful (function-sparing) and tissue-preserving laser treatment techniques. The main target of laser application is the RPE, based on the pathogenesis of the disease.^15,18 RPE cells proliferate, migrate, and completely cover the defect in the laser action zone. Laser treatment restores their barrier function, which leads to resorption of SRF and reattachment of the neurosensory retina.¹⁹ Thermal damage to adjacent structures (the retina and choroid) is undesirable and a negative side effect of treatment.¹⁹ Microsecond pulsed laser radiation allows targeted action on the RPE with minimization of damage on adjacent structures. This approach is recognized as the most promising in the treatment of CSC.^{18,20–23,34,35}

Our previously published paper determined a parameter set using a computational model based on the characteristics of the laser and temperature fields. This parameter set differed from that suggested in previously published literature. Specifically, the use of 2.4% DC at relatively high powers of up to 1.9 W combined with low envelope times has not been used before. No tissue destruction was observed in any case, regardless of treatment location (subfoveal or extrafoveal) or size. The computation model pointed to a strong coagulation threshold variability between individuals. The titration procedure was therefore included to determine the optimal energy setting, sufficient to trigger the healing process while reliably avoiding tissue defects.

The requirement for varied energy settings was clear throughout this study (Figure 4), where a larger difference in power values between patients of varying pigmentation or media opacity occurred.

Figure 4. Lesion visibility in patients of different age and media opacity. (A) Female patient age: 39 years. Transparent optical media. Most of the test applications are visualized. (B) Male patient age: 57 years. A slight decrease in the transparency of optical media can be observed. Only laser applications applied with high power are visualized.

Using these parameters and varying power values based on the patient showed consistently positive results, with an improvement in BCVA, increase in retinal sensitivity, and a reduction in central retinal thickness.

Although research to date demonstrates a positive effect on tissue thickness and retinal sensitivity, this usually takes several months to manifest and is generally modest within the first 3 months. In published literature, resolution of SRF varied between 36% to 80% at 12 months, including re-treatment with microsecond pulsing laser. Our results demonstrate a much faster (detectable at 1 month) and more effective reaction, with 100% resolution rate at 3 months following laser treatment.^24–29 This difference can likely be attributed to two aspects that were optimized in this case series; firstly, the selection of parameters, which provide the highest efficacy and selectivity. All referenced publications use parameter sets with much longer pulse duration, lower power, and more bursts, which reduces the optimal measure of efficacy and selectivity and appears to be less successful than our approach. Secondly, the use of the Navilas 577s navigation laser system has several advantages compared to standard technology. Navilas targets the retina based on a clearly defined topographic plan created using multimodal diagnostic data, primarily from FA. This allows an optimal definition of the treatment area, even though our study only includes a small number of patients. Additionally, the built-in high-speed eye-tracking system eliminates random exposure of the laser beam in neighboring, intact areas.^4,12 When working with a standard laser device and examining the ocular fundus in clinical practice, it is often nearly impossible to visualize the RPE defect corresponding to a leakage. It is also difficult to determine location of laser action during the procedure. Therefore, anatomical landmarks are used to determine location of the leakage, relative to the vasculature, visually comparing it to the patient’s FA. It is, therefore, practically impossible with standard laser systems to perform targeted treatment without affecting the tissues adjacent to the point of leakage.

Another difficulty includes working with a microsecond pulse, given that traces of the laser action on the retina are not visible. Repeated exposure of the pulse on the same site cannot be eliminated, and the lack of correct confluency of the microsecond pulse applications further reduces effectiveness. Use of navigation technology in laser treatment completely solves the above problems through the accurate use of laser applications clearly in the designated area, in compliance with a set interval, in accordance with a plan and based on a precise topographical map of the laser action.

Personalized laser treatment of CSC using a microsecond pulse mode with individual selection of parameters based on the computer model (50 μs 2.4% DC, 100 μm, 10 ms) on Navilas laser system 577s showed efficacy and safety especially if the RPE leak is located close to the fovea. Additional research should verify these results using a control group and larger study population.