Panretinal Photocoagulation

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Overview

Laser therapy has been used to treat many pathologies in the eye for decades.  A xenon arc laser was developed in the s by the Carl Zeiss Laboratory and was used clinically in the early days of retinal therapy. The argon laser was discovered in by William Bridges. However, an official study to investigate the effects of laser treatment via PRP was not conducted until the s. This study, the Diabetic Retinopathy Study (DRS) examined the effects of pan-retinal photocoagulation (PRP) through both xenon arc laser and argon laser treatments on patients with proliferative diabetic retinopathy (PDR), to determine whether it was more beneficial than no treatment at all. The study showed that that laser therapy was indeed beneficial to patients with PDR and also showed that argon lasers created less adverse effects for patients than xenon lasers while retaining similar efficacy. This study also set forth the first detailed treatment parameters for PDR. As a result, xenon arc laser therapy is now largely discontinued, in favor of argon laser (or modern equivalent continuous wave millisecond laser systems). The Early Treatment Diabetic Retinopathy Study (ETDRS), conducted shortly after the DRS, examined the effects of PRP on patients with non-proliferative diabetic retinopathy (NPDR), and determined the exact stage in the disease course at which laser therapy should be administered. Currently, more advanced laser delivery systems and other methods of combating diabetic retinopathy are emerging. However PRP remains the mainstay of treatment for PDR.

Laser Physics and Biological Interactions

Light from the laser is absorbed by the retinal pigment epithelium (RPE), and by the underlying choroid. The retinal pigments in the RPE serve to absorb nearly all wavelengths of light. For PRP, typically yellow, green, or red laser light is used. Laser energy is absorbed is converted to thermal energy, raising the tissue temperature approximately 20 or 30 degrees Celsius. Thermal burns denature tissue protein which leads to local retinal cell death and coagulative necrosis. Over time, these areas of thermally damaged tissue eventually scar and become more heavily pigmented, leaving visible laser scars at the level of the RPE. Classically, approximately - micro-burns are made on the retina. By destroying the largely unused, ischemic extramacular retina, PRP reduces the area of ischemic tissue, which in turn reduces total vascular endothelial growth factor (VEGF) production in the eye and thereby reducing the impetus for neovascularization.

Procedure

PRP is typically delivered through either a slit lamp system or laser indirect ophthalmoscope (headlamp/BIO).

Slit lamp:  The laser is attached to the typical ophthalmic slit lamp and the laser energy is delivered in a coaxial fashion. The patient is placed in a seated position, and the chin placed on the chin-rest. A contact lens, which focuses the laser onto the retina, is placed against the cornea with clear coupling agent. Typically a wide angle or mirrored lens is used. The laser goes through the cornea, anterior chamber and lens and focuses on the retina by the contact lens.

Headlamp: The patient may be supine or seated. The doctor wears the typical indirect headlamp with the laser attached coaxially. A hand held lens is used to view the retina and focus the laser on the retina. The doctor's head movements control the aiming beam. In both cases, the doctor or surgeon will place topical anesthesia, usually proparacaine or tetracaine, into both eyes. For infants or patients with compliance problems, stronger anesthesia such as systemic anesthesia or sedative may be administered. Both methods make approximately - typical-sized burns across 1-4 treatment sessions (variable with treatment protocol). According to DRS protocol using a standard argon-type laser PRP, settings include burns that range approximately 200μ to 500μ in size, pulse durations of 100 milliseconds, and 200-250 mW of power. The goal is to produce burns that are grey in color; and avoid dense white burns. Depending on the protocol being used, all settings may be adjusted for the desired effect.

Indications and Evidence

PRP is indicated to treat retinal ischemia and retinal neovascularization, from whatever cause.  However, PRP is most commonly for proliferative diabetic retinopathy.

The DRS, conducted in the s by the National Eye Institute, was a landmark randomized and prospective study examining whether PRP was an effective means of halting the progression of PDR and preventing vision loss, in comparison to no treatment.

The DRS was conducted in fifteen medical centers across the United States, and enrolled over patients. Patients were required to have severe NPDR in both eyes or PDR in at least one eye. Each patient received PRP treatment in one eye, while the other eye served as a control. Patients were randomly assigned to either xenon arc treatment or argon treatment.

The study found that patients who received PRP had significantly better results than those who received no treatment. PRP reduced the risk of severe visual loss (SVL) by more than 50%. Untreated eyes had a vision loss rate of 16.3%, whereas treated eyes only had a vision loss rate of 6.4% over two years. Eyes with high-risk PDR and high-risk characteristics (HRC) received the greatest benefits.

Furthermore, the DRS examined the efficacy of xenon arc laser treatment versus argon laser treatment. The study showed that argon laser was the better option. Xenon arc laser treatment is now largely discontinued.

While the DRS demonstrated that PRP was more effective at combatting PDR than no treatment, it did not determine when, in the course of the disease, PRP should be administered to receive the greatest benefit. The Early Treatment Diabetic Retinopathy Study (ETDRS) attempted to examine whether early PRP was more effective than deferred PRP treatment. It followed the photocoagulation guidelines set by the previous DRS study.

The DRS study showed that at 2 years, 11% of treated eyes and 26% of control eyes with high-risk retinopathy developed severe visual loss and that at 4 years 20% of treated eyes and 44% of control eyes developed severe visual loss (worse than 5/200). For early proliferative retinopathy- 3% of treated eyes and 7% of untreated eyes developed severe visual loss at 2 years and at 4 years 7% of treated eyes and 21% of untreated eyes developed severe visual loss. The DRS cautioned against treating patients with early-proliferative retinopathy and lesser levels of retinopathy because of the side-effects of laser itself.

As such, the ETDRS study group advised that scatter photocoagulation not be initiated in mild cases of NPDR, in order to balance the potential adverse effects and relative risks of treatment against the minimal benefits gained by treatment at early stages. PRP is to be initiated when NPDR becomes severe or progresses into PDR.

Common PRP Protocols

Long-Duration Typical Treatment (Conventional)

Long-Duration PRP treatment is the oldest and most conventional form of PRP, and was initially investigated by the DRS. The DRS set certain guidelines for its administration; however, some aspects are slightly outdated. Long-duration PRP is associated with the highest levels of patient discomfort, as burns must be delivered individually and the procedure duration is relatively long. Conventional PRP usually consists of pulse durations of 100 milliseconds, large spot size (200-500μ), with 200-250 mW of power applied.

Short Duration Treatment

Typically utilizing pattern Scanning, this protocol delivers a pattern of multiple burns in the same or less amount of time that conventional lasers take to deliver one burn. The speed of delivery allows newer lasers to reduce the pulse duration to 10-30 milliseconds per spot, which is balanced by many more total spots (often -). Short duration laser provides patients with more comfort than the long-duration PRP.  

Navigated Laser Treatment

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Navigated PRP (nPRP) works by tracking retinal eye movements in real time using the assistance of computers. The computer and laser automatically readjust in accordance with the movement of the eyes. Imaging techniques for nPRP include infrared, color, and fluorescence angiographies of the fundus, which minimizes the amount of light that patients are exposed to. Navigated PRP can be either single-spot or pattern-spot arrays that reach all the way to the peripheral retina. It can be short or long duration.

Navigated PRP may have a higher accuracy than conventional PRP techniques, although accuracy is not critical for PRP treatments. The scars that nPRP leaves behind are also more uniform and consistent than those delivered by manually guided lasers. Navigated PRP does not use a contact lens with current machines, due to the various imaging processes involved.

Sub-Threshold Diode Micropulse

Sub-Threshold Diode Micropulse (SDM) laser was originally targeted towards combatting diabetic macular edema (DME). Since diabetic retinopathy affects all parts of the retina in the same way, SDM has recently been hypothesized to also counter PDR. At this point, peripheral SDM instead of PRP is considered experimental.

Adverse Effects

Patients will experience varying levels of discomfort based on the type and duration of PRP received. During the procedure, patients will often experience a small &#;pinching&#; sensation with each burn created in the affected eye. For this reason, PRP may be divided into several sessions.  If the patient cannot tolerate contact lens delivered PRP, laser can be performed using indirect ophthalmoscope. However, for indirect PRP delivery, retrobulbar anesthesia is usually administered and patients are not be able to see for up to three to four hours until the anesthesia wears off.

After the procedure, it is normal for patients to have mild headaches; a tylenol or other such analgesic is appropriate for managing pain. Patients may often experience some permanent decreases in peripheral, color, and night vision. Patients who experience unusual symptoms after PRP, such as an increase in flashes, floaters, pain, redness, a significant decrease in vision, or the sensation that their field of vision is obscured by black curtain, should call their surgeon immediately. Choroidal effusion is a fairly uncommon side effect, which can cause worsening of vision temporarily. Typically, no medications after PRP treatment are indicated. Some doctors may choose to supplement PRP treatment with anti-VEGF intravitreal injections. Patients can resume all normal activity immediately after receiving PRP.

PRP and Pharmacologic Therapy of Diabetic Retinopathy

Anti-vascular endothelial growth factor (VEGF) medications are an emerging treatment alternative and supplement to PRP. Anti-VEGF treatments are associated with much decreased peripheral vision, loss and decreased occurrence of central-involving diabetic macular edema. They are thus considered a better treatment than PRP for patients with extensive diabetic macular edema. Currently there are three anti-VEGF agents being used for PDR: bevazicumab, ranibizumab, and aflibercept. All of these agents are believed to be approximately equal in efficacy in DR. Treatment of PDR with monthly anti-VEGF intravitreal injections alone are an emerging treatment. Protocol S was a well-designed randomized clinical trial showing ranibizumab is similar in efficacy to PRP. There are questions, however, about long-term follow up of these patients. Poor visual outcomes can occur in patients who fail to follow up monthly if anti-VEGF are needed for active PDR.

References and Additional Resources

1. Royle P, Mistry H, Auguste P, et al. Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation. Southampton (UK): NIHR Journals Library; Jul. (Health Technology Assessment, No. 19.51.) Chapter 2, The landmark trials: Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study.Available from: https://www.ncbi.nlm.nih.gov/books/NBK/
2. Kozak I, Luttrull JK. Modern retinal laser therapy. Saudi Journal of Ophthalmology. ;29(2):137-146. doi:10./j.sjopt..09.001.
3. Abu El-Asrar AM. Evolving Strategies in the Management of Diabetic Retinopathy. Middle East African Journal of Ophthalmology. ;20(4):273-282. doi:10./-..
4. Evans JR, Michelessi M, Virgili G. Laser photocoagulation for proliferative diabetic retinopathy.Cochrane Database of Systematic Reviews , Issue 11. Art. No.: CD. DOI: 10./.CD.pub2.
5. Saxena S, Jalali S, Meredith T A, Holekamp N M, Kumar D. Management of diabetic retinopathy. Indian Journal of Ophthalmology. | Volume:  48 | Issue Number:  4 | Page: 321-30  
6. Blumenkranz M, Paulus Y. Panretinal Photocoagulation for Treatment of Proliferative Diabetic Retinopathy. October . AAO website
7. http://homepages.abdn.ac.uk/opt065/Lasersideeffects.htm
8. http://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/TreatmentOpts.htm
9. http://www.aao.org/munnerlyn-laser-surgery-center/laser-treatment-of-proliferative-nonproliferative-
10. http://emedicine.medscape.com/article/-overview#showall
11. http://www.retinalphysician.com/articleviewer.aspx?articleID=
12. http://www.bu.edu/eye/evidence-based-medicine/vitreo-retinal-studies/diabetic-retinopathy-study-drs/
13. http://www.ncbi.nlm.nih.gov/books/NBK/
14. http://preview.thenewsmarket.com/Previews/JOUR/DocumentAssets/.pdf
15. http://ophthalmologytimes.modernmedicine.com/ophthalmologytimes/news/drcrnet-protocol-s-results-provide-evidence-retinopathy-advance?page=0,1
16. http://retinatoday.com//10/panretinal-photocoagulation-in-patients-with-dme/
17. http://ophthalmologytimes.modernmedicine.com/ophthalmologytimes/news/navigated-panretinal-photocoagulation-vs-conventional-pattern-laser-pdr?page=0,2
18. http://www.retinaeye.com/common%20diseases/Retinopathy%20of%20Prematurity/Pan-retinal%20Photocoagulation%20handout.pdf

The theory of turning light into a coherent, tight beam goes back to Albert Einstein. In , he proposed stimulated emission of radiation. Light photocoagulation for the retina was first demonstrated in the s by German ophthalmologist Gerd Meyer-Schwickerath, MD, who experimented with focusing natural sunlight into the eye using a heliostat. The invention of photocoagulation represented a major advancement in how retinal pathology could be addressed. Shortly thereafter, Dr. Meyer- Schwickerath began using a carbon arc lamp, and then a xenon photocoagulator.

In , Charles Hard Townes and colleagues from Columbia University in New York developed the stimulated emission of microwave radiation, or maser.

EARLY LASER SYSTEMS
Theodore Maiman, PhD, at the Hughes Research Laboratory in Malibu, CA built the first working laser (Light Amplification by the Stimulated Emission of Radiation) in . Dr. Maiman wrapped a high-powered flash lamp around a ruby rod lined with silver flashing on each end of the rod to stimulate the emission of coherent light. The lamp pulsed light into the rod, which then reflected back and forth and became more and more coherent. Because the flashing on one end of the rod was less than on the other, eventually the light was emitted through that end as a coherent beam of light. Leon Goldman, MD, then pioneered the study of lasers on biologic systems and performed the first studies of the effects of laser on human tissue. In , he developed a CO2 laser that emitted light at 10,600 nm and that successfully coagulated tissue. It was applied in ENT and gynecologic surgery. That same year, both the Neodymium:Ytrium Aluminum Garnet (Nd:YAG) laser and the continuous wave 488 nm bluegreen argon lasers were developed.

The Nd:YAG laser is commonly used to make an opening in the posterior capsule for treatment of opacification following cataract surgery. The argon laser produces a light frequency that penetrates the tissues appropriately for retina procedures.

The earlier lasers were large, bulky, difficult to use, and required a water-cooling mechanism. During the s, however, innovation in laser technology continued and dye lasers, which became available in , allowed for a variable wavelength.

VALIDATION OF LASERS FOR RETINAL APPLICATIONS
In , the excimer laser was introduced and opened up the field of refractive eye surgery, and by a new generation of smaller, yet more powerful, lasers became available. In particular, the diode laser,which was used in retinal surgery, was portable enough so that it could be carried to the hospital or office setting to treat patients. First developed in by Steve Charles, MD, the introduction of endophotocoagulation was a significant advance in vitreoretinal surgery.1 In his original system, Dr. Charles used a fiber optic probe attached to a portable xenon arc photocoagulator. Several years later, Gholam Peyman, MD, developed an argon laser probe that enabled more rapid firing, had a more comfortable and safe working distance, and didn't generate as much heat.2 The argon green and diode lasers were then used most frequently. Carmen Puliafito, MD, utilized semiconductor based laser technology to decrease instrument size, increase portability and improve stability.

Since then, there have been many lasers developed for use in the retinal OR. In vitreoretinal surgery, lasers are most commonly used to treat retinal detachments, retinal tears, or neovascularization.

The findings of the landmark Diabetic Retinopathy Vitrectomy Study (DRVS), which was performed in the and 80s, were the first to indicate that lasers were effective in retinal applications. The visual acuity results were mixed in DRVS,3-5 but it was concluded that this was partly due to the fact that in the early phases of this study, lasers were not used in the OR during vitrectomy. After panretinal photocoagulation was used during vitrectomy, the results began improving and subsequent data showed more stability.6,7

Alcon Laboratories, Inc. (Fort Worth, TX) first entered the laser market with the EYELITE 532 nm Photocoagulator. Long-term experience using the EYELITE laser is that it is stable and holds up well with heavy use. Alcon, however, has developed a new laser photocoagulation system, the PUREPOINT Laser, which represents an improvement in multiple areas and offers other clinical advantages and efficiencies.

TECHNOLOGICAL ADVANCES IN LASER PHOTOCOAGULATION
The PUREPOINT Laser is a 532 nm, green, frequencydoubled Nd:Crystal laser. Like the EYELITE Photocoagulator, the PUREPOINT (Figure 1) Laser can be used with an endolaser probe during a vitrectomy procedure and also has a laser indirect ophthalmoscope (LIO) attachment. The firing rate of the PUREPOINT Laser is 25 Hz, vs 9 Hz on the EYELITE&#; a significant improvement in speed that allows completion of laser treatment much more rapidly. Additionally, the maximum power on the PUREPOINT Laser is higher than on the EYELITE Photocoagulator. This is helpful in situations such as where there is a significant amount of haze, hemorrhage or edema that requires extra power. The engine on the PUREPOINT is designed to be reliable and the unit is smaller and lighter than the EYELITE.

Multifunction foot pedal. The PUREPOINT Laser addresses time and efficiency with a multifunction foot pedal (Figure 2) that allows the surgeon to have more control over the laser. The surgeon can control standby-to-ready and power settings and can also customize side switches on the pedal to suit surgical technique. The OR staff benefits from this technology in that they are free to perform other duties, improving productivity.

Voice confirmation technology. Voice confirmation is important because many surgeons are set up without direct visual access to the laser and would have to physically turn to check that the power setting is correct. The PUREPOINT Laser's voice recognition feature, however, states what settings have been activated. The surgeon does not have to take his eyes away from the operating microscope and again, has a higher level of control over the laser. Voice confirmation occurs for parameter changes, verification of laser accessories, and insertions including endoprobes, LIO, slit lamp, and protection filters.

Radiofrequency identification technology (RFID). The PUREPOINT laser is equipped with ENGAUGE RFID technology (Alcon Laboratories, Inc.; Figure 3), which automatically recognizes Alcon devices equipped with this technology when connected to the laser. The laser settings can be preset and automatically loaded as the type of delivery device is detected and inserted into the laser. For example, if a surgeon connects an Alcon RFID equipped probe into the laser, the machine identifies the device and adjusts the settings appropriately. The manufacturer presets some of this information, but the surgeon can program his own settings. Each programmed set is color coded and easily recognizable for both the surgeon and the staff. Dual laser attachment ports. The PUREPOINT Laser has dual laser attachment ports (Figure 4). This is a convenient and efficient feature because it takes away the step of unplugging and replugging the endolaser probe when switching to a laser indirect ophthalmoscope (LIO). Every time an endolaser probe is unplugged, it is flexed and there is an increased risk of breaking it. Additionally, it takes time to switch back and forth. The PUREPOINT has dual ports and with the touch of a button, the surgeon can switch from endoprobe to LIO.

SUMMARY
The PUREPOINT Laser is a newly designed next generation laser for use in the operating room and the office with advanced technology that increases surgeon control. The coherence and power of the laser beam on this system is excellent and enables an effective, efficient procedure. The repeat rate is fast and speeds up placement of the laser pattern. The improvements to the PUREPOINT Laser result in a laser photocoagulation system that provides increased surgeon control and increased efficiencies while reducing dependence on OR staff during the laser procedure. &#;

Roger Novack, MD, PhD, FACS, is a Partner in the Retina Vitreous Associates Medical Group, Los Angeles, California and Assistant Clinical Professor at the Jules Stein Eye Institute Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Dr. Novack is a paid consultant of Alcon Laboratories and Optos Corporation. Dr. Novack can be reached at +1 213 483 ; fax: +1 213 481 ; or via : .
1. Charles S. Endophotocoagulation. Retina. ;1:117-120.
2. Peyman GA, Grisolano JM, Palacio MN. Intraocular photocoagulation with the argon krypton laser. Arch Ophthalmol. ;98:-.
3. Diabetic Retinopathy Vitrectomy Study Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) report #1. Ophthalmology. ;92(4):492-502.
4. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. The Diabetic Retinopathy Vitrectomy Study Research Group. Arch Ophthalmol. ;103(11):-.
5. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial&#;Diabetic Retinopathy Vitrectomy Study Report 3. The Diabetic Retinopathy Vitrectomy Study Research Group. Ophthalmology. ;95(10):-.
7. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Clinical application of results of a randomized trial&#;Diabetic Retinopathy Vitrectomy Study Report 5. The Diabetic Retinopathy Vitrectomy Study Research Group. Ophthalmology. ;95(10):-.
7. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol. ;108(7):958-964.

Roger Novack, MD, PhD, FACS, is a Partner in the Retina Vitreous Associates Medical Group, Los Angeles, California and Assistant Clinical Professor at the Jules Stein Eye Institute Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Dr. Novack is a paid consultant of Alcon Laboratories and Optos Corporation. Dr. Novack can be reached at +1 213 483 ; fax: +1 213 481 ; or via : .1. Charles S. Endophotocoagulation. Retina. ;1:117-120.2. Peyman GA, Grisolano JM, Palacio MN. Intraocular photocoagulation with the argon krypton laser. Arch Ophthalmol. ;98:-.3. Diabetic Retinopathy Vitrectomy Study Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) report #1. Ophthalmology. ;92(4):492-502.4. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. The Diabetic Retinopathy Vitrectomy Study Research Group. Arch Ophthalmol. ;103(11):-.5. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial&#;Diabetic Retinopathy Vitrectomy Study Report 3. The Diabetic Retinopathy Vitrectomy Study Research Group. Ophthalmology. ;95(10):-.7. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Clinical application of results of a randomized trial&#;Diabetic Retinopathy Vitrectomy Study Report 5. The Diabetic Retinopathy Vitrectomy Study Research Group. Ophthalmology. ;95(10):-.7. Diabetic Retinopathy Vitrectomy Study Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol. ;108(7):958-964.

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