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Questions remain about use of ‘nondamaging’ retinal laser therapies

The use of laser irradiation has changed for the treatment of central serous chorioretinopathy and other retinal conditions.

To see, or not to see, that is the question.

Prince Hamlet in the so-called “nunnery scene” of William Shakespeare’s play Hamlet did not deal with laser irradiation but still can inspire our modern dilemma in ophthalmology: Is “nondamaging” retinal laser therapy, as Wood and colleagues named it, a viable option for treating not only central serous chorioretinopathy but other retinal conditions, or should we still treat our patients with a coagulative and visible effect?

In 2008, we published the first experience of a nonvisible subthreshold micropulse infrared diode laser treatment of central serous chorioretinopathy. We came to similar conclusions as Wood and colleagues, and micropulse laser is our current first-line therapy in cases of central serous chorioretinopathy with identifiable leaking points at fluorescein angiography.

Since our publication, many other reports have appeared in the literature, including some on the treatment of diabetic macular edema by adopting the same philosophy of subthreshold laser irradiation.

Laser photocoagulation is a photothermal process in which heat is produced by the absorption of laser energy by targeted tissues. The purpose of the treatment is to induce thermal therapeutic damage, which causes biological reactions and ultimately beneficial effects. The common traditional endpoint of laser photocoagulation of the chorioretina is an ophthalmoscopically visible retinal whitening. Retinal blanching is the sign that the retina itself has been thermally damaged and results in a number of undesired adverse events. The mechanisms underpinning the efficacy of laser photocoagulation are still poorly understood. However, hypotheses postulate that full-thickness retinal damage may not be needed to obtain beneficial therapeutic effectiveness. Studies with laser photocoagulation on animals demonstrated the ability to create therapeutic lesions confined around the retinal pigment epithelium cells without causing apparent damage to the overlying retina. The laser impacts were not visible by slit lamp biomicroscopy at the time of laser delivery. Recent experiments showed that the beneficial effect of retinal photocoagulation is mediated by factors derived from the retinal pigment epithelium.

Therefore, therapeutic irradiation of the retina may avoid damage to the neural retina and confine the effect around the cells of the retinal pigment epithelium.

As the review article by Wood and colleagues correctly cites, there are currently different methods for obtaining nondamaging retinal therapy. MicroPulse laser photocoagulation (Iridex) has been the first modality commercially available. It is based on a train of repetitive short pulses (usually 0.1 millisecond each) within an envelope of exposure time. Typically, subthreshold treatments are given with duty cycles (the percentage of time the laser is on in one cycle) between 5% and 15%. The other commercially available technology is called EndPoint Management (Topcon), which utilizes continuous wave irradiation to deliver nonvisible spots with an exposure time of 10 to 20 milliseconds. Other proposed modalities are selective retina therapy, which was pioneered by Johann Roider and utilizes microsecond pulses, and retinal regeneration therapy (2RT, Ellex), which delivers nanosecond pulses.

As said, laser photocoagulation has an impact on metabolic activity and gene expression at the level of the retinal pigment epithelium, which results in the production of proteins, enzymes and cytokines involved in angiogenesis and vascular leakage regulation. The idea is then to limit or avoid as much as possible the unnecessary tissue damage in favor of the beneficial cellular response. Therefore, the stimulated area by the subthreshold irradiation has a relevant importance with respect to the subsequent therapeutic effect. This is why many treatment protocols with MicroPulse and EndPoint Management utilize the so-called low-intensity high-density irradiation.

No doubt this is a big change in the way we should use laser irradiation from the earlier days when heavy white burns were placed onto the retina, which resulted in larger and significant chorioretinal atrophies. It is also true that more recently, even with visible treatments and pattern lasers emitting at shorter exposure times, physicians may induce less whitening and spot enlargement over time and therefore less tissue damage.

Many questions still remain partially or totally unsolved.

Firstly, in the era of evidence-based medicine, we need stronger proof that nonvisible, “nondamaging” retinal laser therapies may be considered a consistent option for treating retinal and macular diseases. This is particularly relevant with respect to intravitreal drugs, which are currently considered first-line therapies and have the highest level of evidence.

Secondly, physicians and companies involved in noninvasive laser therapies should put much effort in defining and developing optimized treatment parameters and treatment guidelines.

Finally but still very important, the application of online dosimetry systems for the detection of the nonvisible endpoint alternative to retinal whitening would greatly facilitate the adoption by physicians of “nondamaging” retinal laser therapies. -- by Paolo Lanzetta, MD

References:

Desmettre TJ, et al. Br J Ophthalmol. 2006;doi:10.1136/bjo.2005.086942.

Lanzetta P, et al. Semin Ophthalmol. 2001;16(1):8-11.

Lanzetta P, et al. Eur J Ophthalmol. 2008;18(6):934-940.

Lanzetta P, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2007.08.007.

Lavinsky D, et al. Invest Ophthalmol Vis Sci. 2011;doi:10.1167/iovs.10-6828.

Lavinsky D, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.15-18981.

Mainster MA. Semin Ophthalmol. 1999;14(4):200-209.

Veritti D, et al. Eur J Ophthalmol. 2012;doi:10.5301/ejo.5000078.

Wood EH, et al. Retina. 2017;doi:10.1097/IAE.0000000000001386.

Yu AK, et al. Invest Ophthalmol Vis Sci. 2013;doi:10.1167/iovs.12-11382.

For more information:

Paolo Lanzetta, MD, can be reached at IEMO – Istituto Europeo di Microchirurgia Oculare, Via M.A. Fiducio, 8; 33100 Udine, Italy; email: paolo.lanzetta@iemo.eu.

Disclosure: Lanzetta reports no relevant financial disclosures.

To see, or not to see, that is the question.

Prince Hamlet in the so-called “nunnery scene” of William Shakespeare’s play Hamlet did not deal with laser irradiation but still can inspire our modern dilemma in ophthalmology: Is “nondamaging” retinal laser therapy, as Wood and colleagues named it, a viable option for treating not only central serous chorioretinopathy but other retinal conditions, or should we still treat our patients with a coagulative and visible effect?

In 2008, we published the first experience of a nonvisible subthreshold micropulse infrared diode laser treatment of central serous chorioretinopathy. We came to similar conclusions as Wood and colleagues, and micropulse laser is our current first-line therapy in cases of central serous chorioretinopathy with identifiable leaking points at fluorescein angiography.

Since our publication, many other reports have appeared in the literature, including some on the treatment of diabetic macular edema by adopting the same philosophy of subthreshold laser irradiation.

Laser photocoagulation is a photothermal process in which heat is produced by the absorption of laser energy by targeted tissues. The purpose of the treatment is to induce thermal therapeutic damage, which causes biological reactions and ultimately beneficial effects. The common traditional endpoint of laser photocoagulation of the chorioretina is an ophthalmoscopically visible retinal whitening. Retinal blanching is the sign that the retina itself has been thermally damaged and results in a number of undesired adverse events. The mechanisms underpinning the efficacy of laser photocoagulation are still poorly understood. However, hypotheses postulate that full-thickness retinal damage may not be needed to obtain beneficial therapeutic effectiveness. Studies with laser photocoagulation on animals demonstrated the ability to create therapeutic lesions confined around the retinal pigment epithelium cells without causing apparent damage to the overlying retina. The laser impacts were not visible by slit lamp biomicroscopy at the time of laser delivery. Recent experiments showed that the beneficial effect of retinal photocoagulation is mediated by factors derived from the retinal pigment epithelium.

Therefore, therapeutic irradiation of the retina may avoid damage to the neural retina and confine the effect around the cells of the retinal pigment epithelium.

As the review article by Wood and colleagues correctly cites, there are currently different methods for obtaining nondamaging retinal therapy. MicroPulse laser photocoagulation (Iridex) has been the first modality commercially available. It is based on a train of repetitive short pulses (usually 0.1 millisecond each) within an envelope of exposure time. Typically, subthreshold treatments are given with duty cycles (the percentage of time the laser is on in one cycle) between 5% and 15%. The other commercially available technology is called EndPoint Management (Topcon), which utilizes continuous wave irradiation to deliver nonvisible spots with an exposure time of 10 to 20 milliseconds. Other proposed modalities are selective retina therapy, which was pioneered by Johann Roider and utilizes microsecond pulses, and retinal regeneration therapy (2RT, Ellex), which delivers nanosecond pulses.

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As said, laser photocoagulation has an impact on metabolic activity and gene expression at the level of the retinal pigment epithelium, which results in the production of proteins, enzymes and cytokines involved in angiogenesis and vascular leakage regulation. The idea is then to limit or avoid as much as possible the unnecessary tissue damage in favor of the beneficial cellular response. Therefore, the stimulated area by the subthreshold irradiation has a relevant importance with respect to the subsequent therapeutic effect. This is why many treatment protocols with MicroPulse and EndPoint Management utilize the so-called low-intensity high-density irradiation.

No doubt this is a big change in the way we should use laser irradiation from the earlier days when heavy white burns were placed onto the retina, which resulted in larger and significant chorioretinal atrophies. It is also true that more recently, even with visible treatments and pattern lasers emitting at shorter exposure times, physicians may induce less whitening and spot enlargement over time and therefore less tissue damage.

Many questions still remain partially or totally unsolved.

Firstly, in the era of evidence-based medicine, we need stronger proof that nonvisible, “nondamaging” retinal laser therapies may be considered a consistent option for treating retinal and macular diseases. This is particularly relevant with respect to intravitreal drugs, which are currently considered first-line therapies and have the highest level of evidence.

Secondly, physicians and companies involved in noninvasive laser therapies should put much effort in defining and developing optimized treatment parameters and treatment guidelines.

Finally but still very important, the application of online dosimetry systems for the detection of the nonvisible endpoint alternative to retinal whitening would greatly facilitate the adoption by physicians of “nondamaging” retinal laser therapies. -- by Paolo Lanzetta, MD

References:

Desmettre TJ, et al. Br J Ophthalmol. 2006;doi:10.1136/bjo.2005.086942.

Lanzetta P, et al. Semin Ophthalmol. 2001;16(1):8-11.

Lanzetta P, et al. Eur J Ophthalmol. 2008;18(6):934-940.

Lanzetta P, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2007.08.007.

Lavinsky D, et al. Invest Ophthalmol Vis Sci. 2011;doi:10.1167/iovs.10-6828.

Lavinsky D, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.15-18981.

Mainster MA. Semin Ophthalmol. 1999;14(4):200-209.

Veritti D, et al. Eur J Ophthalmol. 2012;doi:10.5301/ejo.5000078.

Wood EH, et al. Retina. 2017;doi:10.1097/IAE.0000000000001386.

Yu AK, et al. Invest Ophthalmol Vis Sci. 2013;doi:10.1167/iovs.12-11382.

For more information:

Paolo Lanzetta, MD, can be reached at IEMO – Istituto Europeo di Microchirurgia Oculare, Via M.A. Fiducio, 8; 33100 Udine, Italy; email: paolo.lanzetta@iemo.eu.

Disclosure: Lanzetta reports no relevant financial disclosures.