Lowering threshold of retinal treatments for AMD delivers results with less damage

Retinal photocoagulation can be effective with less collateral damage to healthy tissue, studies are showing.

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Retinal photocoagulation can stop the deterioration of vision in patients with age-related macular degeneration (AMD), but the extensive collateral laser damage pleases neither patients nor physicians. The damage not only destroys healthy retinal tissue, it may also trigger more neovascularization.

In conventional laser photocoagulation, physicians rely on whitish retinal burns as a sign that they have delivered enough energy at the right location on the retina. The Early Treatment of Diabetic Retinopathy Study used a dense white retinal burn as the treatment endpoint.

Now surgeons might be able to deliver less laser energy and achieve the same effect.

According to Martin A. Mainster, MD, PhD, two methods of reducing photocoagulation damage are promising: shortening laser pulses and changing clinical endpoints.

“With very brief laser pulses, there’s less time for heat conduction to spread damage from the retinal pigment epithelium [RPE], where laser light absorption generates heat, to contiguous or overlying neural retina,” Dr. Mainster said. “Unfortunately, for ordinary continuous wave [CW] argon lasers, there’s also less safety margin between retinal burn and retinal hemorrhage.

“Repetitively pulsed lasers work around this problem by delivering each laser pulse as a burst of very brief laser spikes. It turns out that 500 laser spikes have the same effect as a single CW laser pulse with only 20% of the power per spike.” This phenomenon is a result of “the n^-¼th law of laser effects,” Dr. Mainster said. For a given spot size, a reduction in power means a lower RPE temperature rise and therefore less chance of hemorrhage.

Dr. Mainster explained that “the endpoint for standard laser therapy is a white retinal opacity that occurs when heat conduction from the RPE damages the overlying neural retina. Damaged neural retina loses its transparency, and scatters white ophthalmoscopy light back at the surgeon. That’s why a laser ‘burn’ appears white. The more the damage, the whiter the lesion.”

Threshold defined

---SEM X 120 shows marked thermal damage and tissue shrinkage. Energy: 16 mJ; Power: 80 mW; Duration: 200 msec; Spot size: 75 µ; Crater size: 180 µm; Lateral thermal spread: 52.5 µm.
PHOTOGRAPH COURTESY OF DORIS RUSKOVIC, MD, UNIVERSITY OF MUNICH EYE CLINIC.

“A threshold burn is a lesion that’s barely visible ophthalmoscopically at treatment time,” Dr. Mainster said. “Subthreshold protocols use lesions that aren’t ophthalmoscopically visible at treatment time to decrease laser damage.”

Some subthreshold lesions do not appear until several hours after treatment, he continued. Others are never visible upon ophthalmoscopy, although they may be detectable by angiography.

“Some nonvisible lesions aren’t lesions at all,” Dr. Mainster said, “if laser irradiance is insufficient for local chorioretinal melanin density. You might call that ‘the emperor’s new clothes phenomenon.’ It may be possible to develop additional imaging techniques to confirm the presence of subthreshold photocoagulation lesions at treatment time.”

The opportunity to minimize damage is great because the prominent white burns of conventional photocoagulation occur at energies high above the threshold level.

“They cause RPE temperature elevations of 60° to 80°C,” Dr. Mainster explained, “far greater than the 10° to 20°C increases of threshold lesions. Suprathreshold burns expand postoperatively because of scarring from thermal injury and thermal damage contiguous to laser treatment sites that isn’t apparent at treatment time.

“Many clinicians treat with less prominent burns,” Dr. Mainster said. “There’s less damage and scar expansion.”

Researchers now believe that less damaging treatment can achieve the same therapeutic results as conventional, highly suprathreshold protocols.

Suprathreshold treatment

---SEM X 240 shows mild and confined damage Energy: 16 mJ; Power: 80 mW; Duration: 200 msec (100 p, 200 µs, 500 Hz); Spot size: 75 µ; Crater size: 180 µm; Lateral thermal spread: 2.5 µm.
PHOTOGRAPH COURTESY OF DORIS RUSKOVIC, MD, UNIVERSITY OF MUNICH EYE CLINIC

Macular photocoagulation studies have demonstrated efficacy but never found the optimal treatment strategy. Researchers in the 1990s now have started to refine the results.

The National Eye Institute started enrollment in July for its Complications of Age-related Macular Degeneration Prevention Trial (CAPT). Its goal is to assess safety and efficacy of low-intensity laser treatment in patients at risk for severe AMD.

CAPT will enroll 1,000 patients in 23 clinical centers for 18 months. Patients will undergo unilateral treatment and then undergo 5 years of follow-up. Patients must be more than 50 years old and have large drusen bilaterally, 20/40 bilateral vision and no previous laser treatments.

According to Frederick L. Ferris, MD, director of the National Eye Institute’s Division of Biometry and Epidemiology, CAPT will determine whether placing a few mild laser burns would slow the progression or prevent the complications of AMD.

Patients enrolled in the study will have large drusen in both eyes. One eye will be randomly assigned to receive small laser burns and the other eye will be an untreated control. According to Dr. Ferris, previous studies have shown that in many eyes, the laser burns can cause the drusen to become markedly reduced or to disappear entirely. Some patients with large drusen near the center of the fovea have noticed improvement in visual acuity after treatment. However, the laser burns might increase the risk of neovascularization. This trial will allow for a comparison of the risks and the benefits of treatment.

Applications for drusen

Drusen, deposits between Bruch’s membrane and the RPE, result from debris that accumulates over decades between the RPE cells and their own basement membranes.

The eye does not have a good way of getting rid of debris because the RPE basement membrane forms a barrier between the RPE and the choroidal blood supply.

The eye’s only other blood supply, the retinal vasculature, has tight junctions that restrict the deposit of material into the bloodstream. Any debris that accumulates in the eye has a hard time getting out.

Meanwhile, ultraviolet light and chemical reactions that produce free radicals can create compounds that the RPE cells cannot digest, Dr. Ferris said. So the eye packages these up into little “trash bags” within the cell. This occurs from infancy, and this material can build up considerably over the decades.

When the RPE cell extrudes this material, it can be seen as the white spots called drusen. They can be small and discrete and have no visual significance, or they can be larger and have less distinct borders. Pigment clumping may be present, which is a sign of RPE cell disease or death.

“Those eyes that have large drusen and large pigment clumping are at much higher risk of developing abnormal blood vessels,” Dr. Ferris said. “The jump in faith is that the debris is the reason these abnormal blood vessels are developing. The debris being deposited between the RPE and its blood supply, the choriocapillaris, could make the transport of nutrients and oxygen more difficult, which may be why the blood vessels try to grow in there.”

Lasers applied

The next question is how to use as little laser energy as possible to make drusen disappear.

In an attempt to reduce irradiance, researchers have found another way to deliver less energy to the retina. Instead of reducing power, spot size or duration, they pulse the beam. The same amount of energy is delivered, but interruptions in its delivery allow the adjacent retinal tissues to conduct energy away and prevent heat build-up and burning.

Surgeons evaluated the Iris Medical OcuLight SLx MicroPulse 810 nm diode laser (Iridex, Mountain View, Calif.), a solid-state laser that allows both conventional continuous wave (CW) and MicroPulse operating modes. Re searchers have already used the system to treat macular edema secondary to branch retinal vein occlusion (BRVO) and proliferative diabetic retinopathy.

The proprietary MicroPulse technology aims to limit damage to the RPE to the minimum level required to trigger the therapeutic benefit (to inhibit future proliferation) and still preserve the neurosensory retina.

David G. Wagner, MD, in practice in Washington, D.C., has used the MicroPulse mode as a minimalist treatment — using just enough power to achieve the desired effect.

“Whenever we do laser photocoagulation for these diseases, we have a tradeoff,” he said. “We’re damaging retina but in exchange we’re creating less edema. Patients see better, but there is collateral damage. Here is a technology that has similar efficacy but a lot less collateral damage.”

The MicroPulse technology changes the physics of the laser-tissue interaction, according to Dr. Wagner.

Invisible lesions

Standard retinal photocoagulation burns create spherical thermal lesions that affect the RPE and other tissues. The MicroPulse mode allows the tissue to cool between bursts. This causes a flat burn only on the RPE, more of a pancake shape than a sphere, Dr. Wagner said.

The MicroPulse effect is possible because the OcuLight system uses diode lasers that can be electronically turned on and off quickly enough to achieve the desired effect (see illustrations). Gas lasers are associated with “thermal inertia” and cannot achieve this effect. Dr. Wagner compared gas lasers with an incandescent light bulb, which remains hot even when it is switched on and off.

Gas lasers can be pulsed with a shutter known as an acousto-optical modulator, but these systems are more expensive. The solid-state laser is less expensive and can last 100,000 hours.

In another study, grid macular photocoagulation using an infrared diode laser in patients with nonexudative age-related macular degeneration can significantly reduce drusen and improve visual acuity, said R. Joseph Olk, MD, of St. Louis.

Dr. Olk and colleagues conducted a pilot study to collect data on the effectiveness and safety of treating AMD patients with the 810 nm OcuLight SLx diode laser.

The pilot study compared two treatment strategies — visible burns versus subthreshold, invisible lesions — to untreated controls.

Researchers studied 229 eyes of 152 patients. Surgeons applied either visible burns or subthreshold treatment and compared results to the control eyes. One year postoperatively, 70% of eyes treated with visible burns showed reduced drusen. The same percentage of eyes treated with subthreshold lesions reached this point by 18 months. According to Iridex, this suggests that less damaging laser treatment can eventually deliver the same therapeutic value as conventional — and more damaging — treatment in which a visible burn is the endpoint.

Visual acuity improved in treated eyes from both groups, and formation of CNV was similar in all groups through 2 years follow-up.

“It appears that the 810 nm diode laser is the ideal wavelength in the treatment of this disease,” Dr. Olk said.

Researchers at Moorfields Eye Hospital wrote in the journal Eye that they examined 52 eyes of 33 consecutive patients receiving MicroPulse laser treatment in a 6-month period.

In this group, 13 eyes had proliferative diabetic retinopathy and 39 had edema secondary to BRVO or diabetic maculopathy. Surgeons applied subthreshold (not clinically visible) panretinal and grid-pattern laser treatments in the MicroPulse mode.

Patients tolerated MicropPulse treatments well, with no sensation or light flashes reported intraoperatively. From the study, 10 eyes (77%) with proliferative disease showed regression of new vessel growth. Of the patients with macular edema, the condition resolved in 22 eyes (57%). Of all eyes, 27 (69%) maintained visual acuity and 11 eyes (28%) improved.

One drawback of the MicroPulse treatment is that the lesions created by the laser are not visible and thus harder to work with. This required that surgeons plan treatment patterns in advance. The potential advantage, according to Iridex, is that the absence of pain may improve patient cooperation, and the substantial reduction in postoperative inflammation could make it possible to complete panretinal treatment in a single session.

Searching for balance

“In most subjects, knowledge is related inversely to publication number,” Dr. Mainster said. “There’s still a huge amount written about AMD, but comparatively few publications on diabetic retinopathy. Retinal photocoagulation certainly has a role in treating AMD, but results aren’t nearly as good as those for treating macular edema in diabetic retinopathy and retinal vascular occlusion.”

Dr. Mainster believes that surgical approaches to AMD such as macular translocation surgery are promising, but that the future of AMD treatment lies in photodynamic, antiangiogenic and gene therapies.

“The best way to treat AMD is to prevent it,” he suggested.

In the near term, retinal photocoagulation and retinal surgery may help patients who have immediate problems that might not be treatable later.

“The efficacy of suprathreshold laser protocols has been established in large prospective, controlled studies, and vision could be lost attempting less aggressive and destructive therapy,” Dr. Mainster said. “On the other hand, subthreshold protocols do decrease chorioretinal damage and preliminary results are very promising.

“You can’t perform retinal photocoagulation and above all do no harm. The challenge facing us is to determine how to help patients with laser therapy — and above all do as little harm as possible.”

For Your Information:

• Martin A. Mainster, MD, PhD, can be reached at Kansas University Medical Center, Ophthalmology, 39th and Rainbow Blvd., Kansas City, KS 66160-7379; (913) 588-6600; fax: (913) 588-6615. Dr. Mainster has no direct financial interest in any products nor is he a paid consultant to any companies mentioned in this article.
• Frederick L. Ferris, MD, is director of the Division of Biometry and Epidemiology of the National Eye Institute, 31 Center Drive, MSC 2510, Bldg. 31, Room 6A52, Bethesda, MD 20892; (301) 496-6583; fax: (301) 496-2297. Dr. Ferris has no direct financial interest in any products nor is he a paid consultant for any companies mentioned in this article.
• David G. Wagner, MD, practices at 3800 Reservoir Road NW, PHC 7th Floor GUMC, Washington, DC 20007-2197; (202) 687-7395; fax: (202) 687-4978. Ocular Surgery News was not able to confirm quotes with Dr. Wagner or obtain a disclosure of any financial interest.
• R. Joseph Olk, MD, practices at The Retina Center of St. Louis County, 11710 Old Ballas Road, Ste. 102, St. Louis, MO 63141; (314) 569-2020; fax: (314) 569-1596. Dr. Olk has no direct financial interest in any products mentioned in this article. He is a paid consultant for Iridex Corporation.

• Iridex Corporation can be reached at 1212 Terra Bella Ave., Mountain View, CA 94043; (650) 962-8100; fax: (650) 962-0486.