Methods aim to decrease laser damage in treatment of retinal, choroidal conditions

Subthreshold laser photocoagulation has been investigated.

Issue: October 2011

ByDaniele Veritti, MD

ByPaolo Lanzetta, MD

ByValentina Sarao, MD

Daniele Veritti

For more than 40 years, retinal laser photocoagulation has been considered the first-line therapy for a series of retinal and choroidal conditions.

Laser treatment causes thermal damage, particularly at the level of the retinal pigment epithelium (RPE). Concurrent harm to the adjacent choriocapillaris and retinal layers, such as the photoreceptors, usually occurs as a consequence of heat transmission.

The clinical endpoint for conventional retinal photocoagulation is an ophthalmoscopically visible retinal whitening associated with collateral iatrogenic retinal consequences, such as visual acuity impairment, reductions in night, color and contrast sensitivity, visual field defects and progressive enlargement of laser scars. Other factors include subretinal fibrosis, subretinal neovascular membrane and epiretinal membrane formation.

Previous studies have reported a less invasive treatment strategy to reduce the laser energy applied and to avoid or minimize thermal injury to the overlying neural retina while maintaining the laser’s efficacy. Thereby, with new developments in laser technologies, tissue-sparing laser protocols may become a field of interest worldwide for many retinal physicians. With the aim of decreasing laser damage, several protocols have been investigated for detecting the appropriate amount of laser energy required for subthreshold lesions.

Micropulse irradiation

One of these is micropulse irradiation, which is arranged so that a pulse envelope is delivered in a succession of constant short laser pulses (pulse train). Each micropulse envelope is characterized by a distinctive frequency (Hz) and a certain duty cycle (a fraction of time in which the laser is on). During subthreshold micropulse laser photocoagulation, every micropulse impact produces a brief thermal increase that remains confined to the RPE cells, saving the contiguous retinal layers. Thus, the thermal gradient in adjacent structures remains below the threshold to obtain visible damage. Subthreshold laser treatment does not produce any tissue response or retinal color change, and so it is not ophthalmoscopically visible.

Several clinical trials have reported that subthreshold micropulse diode laser photocoagulation appears to be as effective as conventional green laser in the treatment of numerous human eye conditions, such as diabetic macular edema, central serous chorioretinopathy, proliferative diabetic retinopathy and macular edema due to branch retinal vein occlusion.

However, it must be noted that micropulse laser irradiation still lacks a large randomized multicenter clinical trial, similar to the Early Treatment Diabetic Retinopathy Study, that validates its results.

Subthreshold laser photocoagulation

Subthreshold laser photocoagulation may be obtained by modifying laser parameters used for conventional photocoagulation, such as lowering the energy used in continuous wave irradiation or shortening the laser exposure time. Subthreshold laser photocoagulation may become a valid substitute to conventional laser to achieve good therapeutic effects. However, the absence of the feedback of an ophthalmoscopically visible endpoint makes it difficult to know when the therapeutic amount of energy has been delivered to the RPE. For that reason, there is much interest in exploring a method for real-time detection of subclinical therapeutic laser lesions during retinal laser photocoagulation.

How to visualize subthreshold lesions

Subthreshold treatment cannot be seen ophthalmoscopically or on color fundus photographs. Fluorescein angiography, performed immediately after treatment, does not normally reveal subthreshold laser lesions. Several studies have suggested that subthreshold laser impacts can be detected postoperatively using a scanning laser ophthalmoscope equipped for indocyanine green angiography and/or fundus autofluorescence imaging. Some investigators have reported that patients who received indocyanine green infusion and were treated with near-infrared subthreshold laser irradiation after 20 minutes to 30 minutes presented a so-called “subthreshold infrared footprinting.” Also referred to as postoperative hypofluorescent spots corresponding to the irradiated areas, they reveal non-visible laser spots and help in monitoring the need for additional treatment. Furthermore, recent research has shown that hypofluorescent spots immediately detectable by autofluorescence imaging may facilitate supervision of the efficacy of the controlled laser treatment and help to titrate the therapeutic amount of energy laser delivered.

Recently, some studies have proposed a noninvasive optoacoustic real-time dosimetry system, based on the detection of a thermoelastic wave that provides an estimation of the temperature increase. This technique can identify in vivo and in real time the temperature rise within the retinal tissue. Optical coherence tomography studies have shown that the human retina has a definite and typical pattern of reflectivity that may change in ocular diseases or after laser photocoagulation. Clinical studies have reported that spectral domain OCT permits us to identify early variations in the retinal reflectivity profile during conventional and subthreshold non-visible laser exposure. For that reason, a laser-integrated OCT prototype has been studied recently at our department of ophthalmology. This combined platform consists of a slit lamp, a digital camera and a slit lamp-equipped OCT aligned to a 532 nm wavelength laser photocoagulator. In this work, presented at the 2011 Association for Research in Vision and Ophthalmology annual meeting, we have demonstrated that real-time OCT scanning allows us to detect the subclinical laser photocoagulation lesions in artificial and biological samples.

Although intravitreal therapy has become a standard measure to treat retinal conditions, laser therapy maintains a key position in the treatment of several retinal and choroidal diseases. A growing body of evidence reinforces the need for evaluating the efficacy and the safety of controlled laser exposure systems and for supporting the development of real-time detection of subclinical laser technologies in order to obtain the maximum laser therapeutic effect with minimized iatrogenic unnecessary tissue damage.

References:

Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol. 1976;81(4):383-396.

Dorin G. Subthreshold and micropulse diode laser photocoagulation. Semin Ophthalmol. 2003;18(3):147-153.

Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology. 1991;98(5 Suppl):S766-S785.

Figueira J, Khan J, Nune S, et al. Prospective randomized controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant macular oedema. Br J Ophthalmol. 2009;93(10):1341-1344.

Framme C, Schüle G, Brinkmann R, Birngruber R, Roider J. Online autofluorescence measurements during selective RPE laser treatment. Graefe’s Arch Clin Exp Ophthalmol. 2004;242(10):863-869.

Guyer DR, D’Amico DJ, Smith CW. Subretinal fibrosis after laser photocoagulation for diabetic macular edema. Am J Ophthalmol. 1992;113(6):652-666.

Koinzer S, Bever M, Schlott K, et al. Real time temperature measurement during laser photocoagulation of human retina. Presented at: Association for Research in Vision and Ophthalmology meeting; May 2011; Fort Lauderdale, Fla.

Lanzetta P, Dorin G, Pirracchio A, Bandello F. Theoretical bases of non ophthalmoscopically visible endpoint photocoagulation. Semin Ophthalmol. 2001;16(1):8-11.

Lanzetta P, Furlan F, Morgante L, Veritti D, Bandello F. Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy. A pilot study. Eur J Ophthalmol. 2008;18(6):934-940.

Lanzetta P, Polito A, Veritti D. Subthreshold laser. Ophthalmology. 2008;115(1):216.

Laursen ML, Moeller F, Sander B, Sjoelie AK. Subthreshold micropulse diode laser treatment in diabetic macular oedema. Br J Ophthalmol. 2004;88(9):1173-1179.

Lövestam-Adrian M, Svendenius N, Agardh E. Contrast sensitivity and visual recovery time in diabetic patients treated with panretinal photocoagulation. Acta Ophthalmol Scand. 2000;78(6):672-676.

Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol. 2005;89(1):74-80.

Mojana F, Brar M, Cheng L, Bartsch DU, Freeman WR. Long-term SD-OCT/SLO imaging of neuroretina and retinal pigment epithelium after subthreshold infrared laser treatment of drusen. Retina. 2011;31(2):235-242.

Ohkoshi K. Subthreshold micropulse diode laser photocoagulation for diabetic macular edema. J Jpn Soc Laser Surg Med. 2007;28:183-188.

Parodi MB, Spasse S, Iacono P, Di Stefano G, Canziani T, Ravalico G. Subthreshold grid laser treatment of macular edema secondary to branch retinal vein occlusion with micropulse infrared (810 nanometer) diode laser. Ophthalmology. 2006;113(12):2237-2242.

Prskavec FH, Fulmek R, Klemen C, Stelzer N. Changes in the visual field and dark adaptation following panretinal photocoagulation in diabetic retinopathy. Klin Monatsbl Augenheilkd. 1986;189(5):385-387.

Roider J. Laser treatment of retinal diseases by subthreshold laser effects. Semin Ophthalmol. 1999;14(1):19-26.

Rutledge BK, Wallow IH, Poulsen GL. Sub-pigment epithelial membranes after photocoagulation for diabetic macular edema. Arch Ophthalmol. 1993;111(5):608-613.

Sarao V, Veritti D, Lanzetta P. Real-time OCT scanning during sub-threshold laser irradiation. Presented at: Association for Research in Vision and Ophthalmology meeting; May 2011; Fort Lauderdale, Fla.

Salvetti P, Rosen JM, Reichel E. Subthreshold infrared footprinting with indocyanine green for localizing low-intensity infrared photocoagulation. Ophthalmic Surg Laser Imaging. 2003;34(1):44-48.

Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol. 1991;109(11):1549-1551.

Schuele G, Huttmann G, Framme C, Roider J, Brinkmann R. Noninvasive optoacoustic temperature determination at the fundus of the eye during laser irradiation. J Biomed Opt. 2004;9(1):173-179.

Sivaprasad S, Sandhu R, Tandon A, Sayed-Ahmed K, McHugh DA. Subthreshold micropulse diode laser photocoagulation for clinically significant diabetic macular oedema: a three-year follow up. Clin Experiment Ophthalmol. 2007;35(7):640-644.

Varley MP, Frank E, Purnell EW. Subretinal neovascularization after focal argon laser for diabetic macular edema. Ophthalmology. 1988;95(5):567-573.

Daniele Veritti, MD, can be reached at Department of Ophthalmology, University of Udine, p.le S. Maria della Misericordia, 33100 Udine, Italy 33100; +39-0432-559907; email: verittidaniele@gmail.com.

Disclosures: Dr. Veritti and Dr. Sarao have no relevant financial disclosures. Dr. Lanzetta has a patent with Iridex and has received honoraria or travel reimbursement from OptiMedica.