Laser Resensitizes Eyes to Anti-VEGF Treatment in AMD

Pam Harrison

July 15, 2015

A type of laser known as subthreshold diode micropulse laser (SDM) therapy restores sensitivity to inhibitors of vascular endothelial growth factor (VEGF) for treatment in patients with neovascular age-related macular degeneration (AMD) whose eyes no longer respond to treatment, new research shows.

"SDM is simple and exceedingly safe. It has no known side effects or adverse treatment effects, provided it is done correctly, and anyone can do it with appropriate existing equipment," lead author Jeffrey K. Luttrull, MD, from Diseases and Surgery of the Macula, Retina, and Vitreous, Retina Diagnostic Laboratory of Ventura County, Ventura, California, told Medscape Medical News.

"And the discovery that SDM works without laser-induced retinal damage gives us important new insights into retinal physiology and will create new opportunities for therapeutic and preventative treatments."

The study was published in the June issue of Retina.

Researchers performed SDM laser treatment in a total of 13 eyes in 12 patients between 73 and 97 years of age (average age, 84 years).

Patients had developed drug tolerance to anti-VEGF treatment, including at least three consecutive ineffective aflibercept injections, after receiving an average of 34 anti-VEGF injections (range, 16 - 67 injections), typically given on a near-monthly basis.

Once diagnosed with drug intolerance, patients were treated with a single session of SDM administered 1 month after the final clinically ineffective aflibercept injection. Aflibercept was resumed 1 month later.

After SDM treatment and resumption of aflibercept, 92% (12 of 13) of eyes improved, with complete resolution of macular exudation in 69% (9 of 13 eyes), Dr Luttrull and colleagues report.

"Even eyes that did not completely respond had only trace amounts of residual exudation, as is normally observed in drug-sensitive patients," Dr Luttrull observed.

The one eye that did not respond at all to the SDM session had retinal pigment epithelium (RPE) atrophy. As Dr Luttrull explained, in this eye, there was nothing to absorb the laser, and if there is no absorption target, the laser can have no effect.

"Drug tolerance may recur in some patients, generally about 6 to 9 months after initial reversal," Dr Luttrull said. "But these eyes can be retreated with SDM, and drug sensitivity restored again as needed."

Reverse Drug Tolerance

Asked to explain how SDM works to reverse drug tolerance, Dr Luttrull noted that SDM targets the RPE and improves RPE function. "This means that RPE cytokine expression is normalized, as well as retinal autoregulation," he added, primarily by activating heat-shock proteins.

Because SDM triggers heat-shock protein activation far below the threshold for RPE cell death, "SDM can reliably and safely [treat] various retinal diseases," Dr Luttrull noted.

The clinical implications of these effects could potentially be wide-ranging. For example, patients with diabetes or retinitis pigmentosa usually have normal vision for decades before developing retinopathy, which is when visual loss begins. This process is actually caused by secondary defects that occur both up- and downstream from the primary defect of diabetes or retinitis pigmentosa.

"At some point, the accumulation of these secondary abnormalities kills the cell, and vision loss ensues," Dr Luttrull said.

By triggering heat-shock protein-mediated retinal repair, SDM could repair these secondary defects.

"This has the effect of 'turning back the clock' on the disease," Dr Luttrull added. "So, SDM can slow or reverse progression of virtually any chronic progressive retinal disease."

He added, "And we expect that by treating [patients with] AMD, diabetics, and others early on and not waiting for retinopathy to develop...we can significantly reduce long-term visual loss and disability."

Extremely Useful

Daniel Lavinsky, MD, professor of ophthalmology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil, who himself uses laser to treat different retinal diseases, is convinced that lasers can be extremely useful for the treatment of not just AMD but also other diseases of the retina.

"We believe that this kind of laser photostimulation of the RP cells can treat not only AMD but other diseases such as diabetic macular edema and macular telangiectasia," Dr Lavinsky told Medscape Medical News.

"Lasers stimulate the RP cells," he added, "and the RP cells express proteins such as heat-shock proteins that are able to protect RP cells as well as photoreceptors," he said. "So SDM elicits a neuroprotective effect, which is probably how it works."

Dr Lavinsky confirmed that in his experience, laser therapy such as used by himself and Dr Luttrell is completely safe, and there is no cumulative damage if patients require more than one treatment.

"The important thing is to apply the right amount of energy to stimulate the RP cells, but not enough to damage cells," Dr Lavinsky said.

In his own practice in Porto Alegre, Brazil, Dr Lavinsky and colleagues have treated many patients with both diabetic macular edema and central serous chorioretinopathy, using photothermal stimulation guided by an algorithm.

Patients with diabetic macular edema are common in his area of practice, but because many of them cannot afford anti-VEGF drugs, Dr Lavinsky and colleagues often treat them with laser therapy instead.

The authors have disclosed no relevant financial relationships. Dr Lavinsky is a consultant to Topcon Medical Laser Systems.

Retina. 2015;35:1184-1194. Abstract

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