Frequently Asked Questions About Subthreshold Laser Therapy

The first part of a roundtable discussion about treatment modalities

JAY CHHABLANI, MD • JEFFREY K. LUTTRULL, MD • SOBHA SIVAPRASAD, DM, FRCOphth, FRCS
DANIEL LAVINSKY, MD • SAM E. MANSOUR, MSc, MD, FRCS(C), FACS

With the advent of anti-VEGF therapy and complications associated with conventional laser therapy, laser treatment has taken a backseat in management of macular diseases. However, with recent advances in subthreshold laser therapy, nondamaging retinal laser photocoagulation techniques are taking their position in patient management. There is no level 1 evidence for subthreshold laser therapy as available for anti-VEGF therapy. There are no standard protocols or treatment follow-up for subthreshold therapy. This article presents responses to frequently asked questions by retinal physicians with experience in different subthreshold laser systems.

What kind of subthreshold laser therapy do you use?

Dr. Luttrull: An old Iridex (Mountain View, CA) SLX 810-nm diode laser with micropulse mode.

Dr. Sivaprasad: I use diode micropulse laser (Iridex MicroPulse IQ577).

Dr. Lavinsky: I used micropulse laser during my training at Federal University of Sao Paulo; however, now I am using a pattern scanning laser system with endpoint management (EpM) software for nondamaging retina laser therapy (NRT).

Dr. Chhablani: I use Navilas (OD-OS, Irvine, CA) 577 micropulse.

Dr. Mansour: I use Iridex MicroPulse IQ577.

What is your definition of “subthreshold”?

Dr. Luttrull: “Subthreshold” is an archaic term. As time goes on, words, like everything else, go out of date more and more quickly. Like “nondamaging” — if you ask 10 people to define “subthreshold,” you will get 10 different answers, some as different as night and day. Currently, it means nothing in particular. I prefer “sublethal.” This is unambiguous and everybody understands it. Even better, I like “homeotrophic.” This means that it improves and normalizes retinal function, directly and immediately. That’s what subthreshold diode micropulse (SDM) does. We’ve proved this with electrophysiology and visual function testing.

Dr. Sivaprasad: Subthreshold laser is invisible on slit-lamp biomicroscopy at the time of treatment.

Dr. Lavinsky: I usually don’t use the term “subthreshold” anymore exactly because there is no definition for it. Ideally what we call subthreshold is an invisible treatment fundoscopically and by any imaging exam, such as fluorescein angiography, fundus autofluorescence, and optical coherence tomography. We use the EpM algorithm, which keeps the energy between the range of photothermal stimulation of the retinal pigment epithelium without significant cellular damage.

Dr. Chhablani: The definition is changing, and it may change further with upcoming imaging modalities like adaptive optics. For now, subthreshold means invisible burns without structural damage on available imaging modalities.

Dr. Mansour: Here are my definitions:

Subthreshold laser: photocoagulation endpoint not reached with no lesion visible on clinical exam, color fundus photography, FA, FAF, and OCT.

Subvisible laser: photocoagulation endpoint reached, but lesion not visible on clinical exam/fundus color images; visible on FA, FAF, and OCT.

Threshold laser: photocoagulation endpoint reached with lesion visible on clinical exam, FC, FA, FAF, and OCT.

Suprathreshold laser: photocoagulation endpoint greatly exceeded with lesion visible on clinical exam, FC, FA, FAF, and OCT.

What are the conditions for which you have used subthreshold laser therapy?

Dr. Luttrull: I have used SDM exclusively since 2000 for all the usual things: diabetic macular edema, proliferative diabetic retinopathy, central serous chorioretinopathy (CSR), and branch retinal vein occlusion, as well as for less common things like pseudophakic and uveitic cystoid macular edema, macular telangiectasia (MT), macular edema associated with epiretinal membranes (to avoid surgery, and to improve visual acuity after membrane peeling), etc. In the last few years we’ve figured out how retinal laser works (the “reset to default” theory).¹ The “reset theory” suggested SDM should improve virtually anything. And so it does. So now I use it every day to reverse drug tolerance in wet AMD, to reduce the injection burden in wet age-related macular degeneration, to improve retinal and visual function in dry AMD and inherited retinopathies like RP, for neuroprotection and visual field improvement in glaucoma, and to reduce the risk of choroidal neovascular membrane in dry AMD. Some of these have been published; the rest are on the way. The crazier it sounds, the more progress it represents. Sublethal laser sounded crazy to everyone 16 years ago. I know, because they told me (Figures 1 and 2).

Figure 1. Subthreshold diode micropulse laser (SDM) retinal protective therapy (RPT) in a 70-year-old man with retinitis pigmentosa (RP). A) Pattern electroretinogram (PERG) prior to SDM RPT (both eyes) shows poor waveforms. B) PERG performed four months after SDM RPT for RP (both eyes). Note the improved waveforms. Steady-state PERG can be useful in evaluating patients with advanced RP. While electroretinograms in the disease may be extinguished, the PERGs are recordable, and they improve with treatment.

Figure 2. Omnifield resolution perimetry of the right eye of the same patient in Figure 1 before (A) and one month after (B) subthreshold diode micropulse laser (SDM) RPT for RP. Similar improvement was documented in the left eye. Snellen visual acuites prior to treatment were 20/60 (right eye) and 20/40 (left eye). VAs improved to 20/40 in both eyes after treatment.

Dr. Sivaprasad: The most common indication is CSR.² A less common indication is DME.³

Dr. Lavinsky: I usually use NRT to treat chronic CSR, DME, macular edema secondary to BRVO, and more recently, MT type 2.^4,5

Dr. Chhablani: I have been using micropulse laser for naïve or chronic DME, acute or chronic CSR, and a few cases of polypoidal choroidal vasculopathy. I recently started using it for nonresponding wet AMD and nonproliferative MT as well.

Dr. Mansour: I use it for common indications, such as DME, RVOs, and CSR. However, I have some experience in using subthreshold laser for MT as well.

In your opinion, which line of treatment is subthreshold laser for treatment in DME: primary, combination, or for recalcitrant cases?

Dr. Luttrull: Both. Since SDM has no adverse treatment effects, I can treat very early. This makes SDM the ideal first-line treatment for most indications. Because laser works fundamentally differently than drugs, it can also work when drugs don’t. My approach is simple: if the VA is 20/40 or better, I use SDM alone. Treating this early, I virtually never have to use drugs for DME. If the VA is worse, I start with a drug to improve the VA and then go to SDM. So even when I use injections, it is usually only one or two injections, tops.

Dr. Sivaprasad: In the UK, the National Institute for Health and Care Excellence has recommended anti-VEGF agents for eyes with central subfield thickness of 400 μm or more. So micropulse laser has a place as primary therapy in eyes with CST less than 400 μm.

Dr. Lavinsky: In Brazil, we don’t have easily available anti-VEGF drugs by the health system, so for a significant amount of patients, we use NRT as a primary treatment, always combining with injections when possible.

Dr. Chhablani: I use micropulse laser as addition to anti-VEGF therapy after reducing the edema to less than 350 μm of central subfoveal macular thickness (CMT). For non–center-involving edema, I use micropulse laser as primary therapy.

Dr. Mansour: I use micropulse laser as primary therapy in macular edema less than 400 μm on OCT. If the edema is more, I usually start with anti-VEGF injections and then add micropulse laser in all DMEs.

Do you think subthreshold laser is dependent on retinal thickness?

Dr. Luttrull: No. Worse disease is simply less responsive to any treatment and takes longer to improve. SDM uses 810, so retinal thickness and hemorrhage don’t matter. VA is what is important to my patients. So I treat based on VA, not retinal thickness.

Dr. Sivaprasad: As in standard laser, micropulse laser is less effective in eyes with significant DME.

Dr. Lavinsky: I usually don’t wait for decreased thickness to treat with laser. Since we are focusing on the RPE and don’t expect to have any photoreceptors bleach, there isn’t sufficient loss by scattering of energy by the thickened retina to justify postponing treatment.

Dr. Chhablani: Yes, I do reduce the thickening to less than 350 µm before micropulse laser.

Dr. Mansour: Definitely. I like to reduce the CMT to <400 μm using pharmacotherapy before applying subthreshold laser.

Do you perform subthreshold laser for acute CSR? Are there any specific indications such as in subfoveal leakage?

Dr. Luttrull: Yes. The key with CSR, like anything else you treat with SDM, is to maximize coverage with enough spots and area⁶ — the more the better. You should cover everything and then some. In my study published in March, an average of 772 spots per eye were performed in a single session for CSR, with no treatment failures. As for subfoveal laser, I have treated transfoveally for every macular indication for several years.⁷ I usually wait four to six weeks for spontaneous improvement in CSR before I treat. But because of the safety, I can treat any time and in the fovea.

Dr. Sivaprasad: I perform subthreshold laser in acute CSR if it is persistent after four months of observation, and the CSR is due to a focal extramacular leak. I haven’t used micropulse for subfoveal leaks.

Dr. Lavinsky: Yes, I usually treat all chronic CSR with NRT with EpM, especially those with subfoveal or juxtafoveal leakage.

Dr. Chhablani: Yes, I have used micropulse laser for CSR and even for subfoveal leaks. We did a study in which we found excellent resolution of subretinal fluid for persistent subfoveal leaks in CSR [paper under review]. Micropulse laser can be considered a cheap alternative to photodynamic therapy for subfoveal leaks.

Dr. Mansour: I use micropulse laser following a three- to four-week pretreatment with topical NSAIDs (eg, ketorolac 0.5% bid) if there is still any fluid. My application of subthreshold laser is to the entire area of subretinal fluid and not just the leakage site.

Do you perform subthreshold laser for chronic CSR as first-line treatment, with combination, or only in recalcitrant cases?

Dr. Luttrull: Yes, all cases.

Dr. Sivaprasad: I perform micropulse laser in chronic CSR only if a focal leak can be identified.

Dr. Lavinsky: Yes, as first-line therapy.

Dr. Chhablani: Yes, as first-line therapy and also for recurrence after PDT or oral medication.

Dr. Mansour: I use subthreshold laser in combination with topical NSAIDs. If no or minimal response (less than 10% decrease in CMT in comparison to baseline), I then will switch to consider systemic oral therapy (eg, acetazolamide, rifampin, mifepristone, etc.). I then repeat subthreshold laser at three months

What are your parameters for subthreshold laser?

Dr. Luttrull: Currently, 200-μm spot, 1.40-W power, 5% duty cycle (DC), and 0.15-second duration. At this point, I have only two treatment regimens: panmacular (covering the entire area between the arcades) and panretinal (covering the entire area outside the arcades). The only thing I treat “locally” is BRVO. Regarding the settings, it is very different depending on the wavelength you’re using. Whatever wavelength you use, you should never exceed a 5% DC in the macula if you want to avoid burns.

Dr. Sivaprasad: Two hundred microns, 200 msec, and power usually between 400 and 600 mW.

Dr. Lavinsky: We treat with 200-μm spots, and we titrate outside the arcades for a barely visible burn after 3 seconds using 15-msec duration and an average of 100 to 180 mW. Then, we treat the macula region with 30% of this energy using the EpM software.

Dr. Chhablani: I usually use 15% DC for DME and 5% DC for CSR. I titrate outside the arcade with the aforementioned DC then apply 30% of threshold power. Spot size is 100 μm, 200 msec duration. I usually perform confluent burns with no spacing.

Dr. Mansour: 400 mW; 5% DC; 200-msec duration; 200-μm spot; 0.25 spot spacing within grid.

What is your preferred spot spacing: one burn, two burns, or confluent? Please specify if it varies with disease.

Dr. Luttrull: Confluent contiguous spots and absolutely no burns. Panmacular for everything; add panretinal for DR/PDR.

Dr. Sivaprasad: Confluent laser burns in the area of focal leakage in CSR and in the edematous retina in DME.

Dr. Lavinsky: I usually start with 0.25 diameter spacing, but in severe cases or retreatment, I may treat confluently.

Dr. Chhablani: I use confluent burns while using 5% DC, one burn width apart while using 15% DC.

Dr. Mansour: 0.25 spot spacing.

How do you change your laser parameters for subfoveal laser?

Dr. Luttrull: I use the above laser parameters for every patient and all treatment indications. I don’t change them for anything — race, media opacity, or retinal thickness. The safe parameters have been worked out in more than 16 years of clinical experience and confirmed by physics. If you look at the literature, titration virtually guarantees burns. Since I treat the fovea in virtually every patient, I can’t afford that risk.

Dr. Sivaprasad: I test in micropulse mode with Quantel laser (Bozeman, MT) starting at 1,000 mW in normal retina adjacent to the edematous area to be treated, and then I reduce it to 50%.

Dr. Lavinsky: When properly titrated, 30% energy using EpM software seems to be safe for subfoveal treatment; however, it is always prudent to check outside the foveal area if your treatment is at least clinically nondamaging.

Dr. Chhablani: I use 5% DC with confluent burns and 30% of threshold power, as explained before.

Dr. Mansour: First, I perform a continuous-wave (CW) test spot for all cases with a spot size (adapter) of 200 µm using Mainster focal grid/equivalent (magnification ≤1.1x), pulse duration of 200 msec, and power of 50 mW. For test post, in the nonedematous macula more than 2 disc diameters from the foveal center, I titrate power upward in 10-mW increments (moving to a new area each time) until a barely visible tissue reaction is seen. If a reaction is evident with 50 mW, I do not increase the power. Note the threshold power.

To perform micropulse laser therapy, I switch to 5% DC and adjust the power to four times the test-spot threshold. The rest of the settings, including spot size, lens, and duration, remain the same as in test spot.

If using the multispot TxCell (Iridex) Scanning Delivery System, ensure that there is confluent treatment using 0.00 spot or 0.25 spacing within the patterned grid. If using single-spot delivery, ensure high-density delivery.

I tend to minimize treatment overlap and treat all edematous areas within the vascular arcades, avoiding the foveal center (500-µm radius from the anatomical foveola, estimated on OCT).

How do you define “therapeutic range” when applied to your treatment approach?

Dr. Luttrull: For SDM, the therapeutic range is from the threshold of a biologic effect, up to thermally induced cell death. By that definition, CW lasers have a therapeutic range of about 10 mW. Nanosecond lasers have a therapeutic range of zero because they explode or implode the RPE. SDM has a therapeutic range up to 3.0 W. That is a huge safety margin. Anything within that range is clinically effective. Therefore, with SDM, we use the same parameters on all patients, routinely treat the fovea, and don’t need to titrate. It is very low anxiety.

Dr. Sivaprasad: Nearly all patients can be treated in the parameters I have mentioned above. However, the therapeutic range is unclear.

Dr. Lavinsky: Based on our experimental data, our therapeutic range in terms of energy is between 25% and 40%; however, we defined the best parameter to use 30% of the energy that produced a barely visible burn after three seconds.

Dr. Chhablani: We still have no clarity about the exact mechanism of subthreshold lasers; therefore, we really cannot comment. However, I believe the therapeutic range is based on threshold burns.

Dr. Mansour: Based on clinical efficacy as assessed by VA and OCT and no display of photocoagulative damage.

COMING NEXT

In the second part of this roundtable discussion, coming in the next issue, the physicians discuss follow-up, retreatment, and complications, and they offer pearls for readers. RP

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