Sub-Threshold Laser: The Backstory

The Diabetic Retinopathy Study and the Early Treatment Diabetic Retinopathy Study^1,2 firmly established the benefits of argon laser photocoagulation for the management of diabetic retinopathy, and these studies have dictated the standard of care for decades. While the benefits of destructive thermal therapies are indisputable, the exact mechanism whereby conventional thermal laser therapy results in these improved outcomes remains elusive.

Conventional thinking suggests that the destruction of tissue results in a reduced hypoxic state by lowering the demand for oxygen and decreasing the overall metabolic rate of the retina.^3,4 While destructive laser photocoagulation has beneficial effects, it also causes side effects such as reduced night vision, macular and peripheral scotomas and disruption of the retinal anatomy through scarring.⁵ But, what if we could achieve the benefits of laser therapy without the destruction of tissue?

Changes in Gene Expression

Recent studies have shown that eyes undergoing photocoagulation over-express more than 25 genes.⁶ These genes represent diverse biological functions including photoreceptor metabolism, synaptic function, structural proteins, adhesion-specific proteins and proteins induced by cellular stress and increased thermal conditions known as heat shock proteins (HSPs).

		< Low-duty cycle:  Very little thermal spread can occur during the “on” time and the releatively long “off” time favors the cool-off before the arrival of the next pulse. < Medium-duty cylce: Doubling the “width” of the pulse doubles the energy deposited, increases the heat spread during the “on” time and reduces the cool-off time, but can still avoid cumulative thermal build-up. < High-duty cylce: More energy is deposited with more thermal spread during the “on” time and there is some thermal build-up due to the shorter cool-off time before the next pulse. < CW Pulse (100% duty cycle): The thermal rise and re-equilibration can only be controlled by adjusting the power and the exposure duration of the CW laser emission.
Figure 1. This diagram illustrates the four cycles of micropulse tissue heat control. (Courtesy of Iridex)

HSPs help refold denatured proteins, inhibit protein aggregation and guide proteins to the correct organelles.⁷ They are also involved in protecting against the affects of apoptosis.

Laser photocoagulation also decreases the expression of permeability factors, inducers of vascular endothelial growth factor (VEGF) and the levels of transforming growth factor ßII (TGF-ßII).⁶ Most likely, all these changes in gene expression contribute to the decrease in neovascularization and vascular permeability associated with laser photocoagulation. 

The Sub-Threshold Concept

An ideal laser therapy would retain the beneficial effects of typical laser photocoagulation therapy while minimizing or eliminating its destructive aspects. To achieve this goal, innovators developed the strategy of sub-threshold laser therapy. The term “sub-threshold” refers to photocoagulation that does not produce evidence of retinal damage, either by exam or by standard imaging modalities.⁹  

In the 1990s Thomas Friberg, MD, FACS, developed the MicroPulse laser (Iridex) that divided the laser emission into a “train” of short, repetitive pulses that persisted for 0.1 to 0.5 seconds. The ‘‘on’’ time was the duration of each micropulse and the ‘‘off’’ time the interval between successive micropulses.³ The “off” time allowed for heat dissipation, which decreased collateral damage and confined treatment to the retinal pigment epithelium (RPE) (Figure 1). Usually an “on” time of 5 to 15 percent has been used.

In contrast to conventional continuous wave laser therapy, which delivers the same magnitude of energy throughout the entire exposure time and causes significant collateral damage, micropulse laser is considered to be safer while possibly delivering similar therapeutic benefits with improved overall retinal sensitivity and the ability to treat and retreat in close proximity to the fovea without obvious sequellae.^3,9

An added theoretical benefit of sub-threshold laser is the assumption that its efficacy would improve if more RPE cells were exposed to thermal stress. As a result, most sub-threshold treatment strategies incorporate a higher density of laser spots than conventional macular laser treatments.¹⁰

Micropulse Drawbacks

While a number of studies have reported on the clinical efficacy of micropulse laser for the treatment of central serous chorioretinopathy, diabetic macula edema and vein occlusion,^10-12 a major disadvantage has been the lack of reliable titration protocols to achieve reproducible sub-visible treatments. As a result, reported treatment results have varied.³

For example, if the laser settings are too low, then the treatment will be not only sub-visible but also sub-therapeutic. If the settings are too high, excessive damage to the retina is a risk, especially with the nearly confluent coverage close to the fovea.

In addition, high-density coverage of the macula with relatively small spots and long pulse duration is time- consuming, and because the treatment delivers energy without leaving an observable mark, the surgeon has to keep track of the treated and untreated areas. Otherwise, there’s the likelihood of inadvertent re-treatment to areas during a single session, which could be deleterious.

Addressing the Drawbacks

Dr. Rosenfeld is a professor at Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. He has been the principal investigator and study chair for several clinical trials involving wet and dry AMD. Dr. Schaal is a retina researh fellow at Bascom Palmer.

Some of the drawbacks surrounding micropulse laser therapy have been overcome by the introduction of the PASCAL Endpoint Management (EpM, Topcon Medical Systems) treatment strategy. This sub-threshold laser protocol titrates the laser power and duration based on a retinal thermal model using a laser with a 577-nm wavelength.¹³

As in traditional micropulse laser treatment, the EpM strategy begins retinal treatment with a titration of the laser power to a minimally visible retinal burn. This pulse energy is assigned the 100 percent level on the EpM settings, and the treatment pulse energy is then defined as a percentage of this level. The laser power and pulse duration are paired so that treatment is usually performed at a 30 percent energy level compared with the initial visible burn, a level established as the highest non-damaging setting in animal studies; it should optimize the therapy to induce HSP expression while preventing thermal damage to the RPE.⁷

Because each spot within the high-density laser spot pattern is irradiated with a pulse shorter than  10 ms, a large number of spots can be quickly placed using a predefined pattern and a predefined setting.¹³ During the application, the programmed application of 100 percent energy burns at the corner spots maintains orientation of the treatment pattern so that landmarks are visible (Figure 2).

The EpM software has several advantages over traditional micropulse therapy while apparently achieving similar efficacy. These include a proper titration protocol so that the appropriate energy level is used to stimulate the RPE in every patient, along with shorter pulses and predefined patterns with retinal landmarks that make the treatment faster and more reproducible.¹⁴   RS