Laser Treatment of Choroidal Neovascularization
Marc J. Spirn
Carl Regillo
The word “laser” is an acronym that stands for “light amplification by stimulated emission of radiation.” Lasers concentrate high amounts of energy into a narrow beam of monochromatic electromagnetic radiation. In doing so, lasers play an important diagnostic and therapeutic role in present day ophthalmology, enabling ophthalmologists to lower intraocular pressure, remove lesions of the skin, and even perform refractive surgery. Vitreoretinal specialists rely heavily on lasers to treat a number of neovascular problems.
Choroidal neovascularization (CNV) underlies a number of visually debilitating eye conditions, including age-related macular degeneration (AMD), ocular histoplasmosis syndrome, pathologic myopic, and posttraumatic choroidal rupture, among others. The untreated natural history of CNV typically involves fibrosis, and if the lesion involves the fovea, concomitant vision loss occurs.
The Macular Photocoagulation Study (MPS) was initiated in 1979 to determine the effect of laser photocoagulation on CNV secondary to AMD, ocular histoplasmosis syndrome, and idiopathic lesions. The MPS was a series of randomized controlled clinical trials sponsored by the National Eye Institute. Between 1979 and 1994, the MPS evaluated extrafoveal, juxtafoveal, and subfoveal lesions, comparing laser photocoagulation to observation.
LESION CLASSIFICATION
Historically, CNV has been classified by its location relative to the foveal avascular zone (FAZ), as determined by fluorescein angiogram. Extrafoveal lesions, which are located between 200 and 2500 microns from the FAZ, cause the least visual disturbance. Juxtafoveal lesions, which are 1 to 199 microns from the FAZ, and subfoveal lesions, which involve the FAZ, cause more profound visual complaints.
EXTRAFOVEAL LESIONS
Senile Macular Degeneration Study
In patients over the age of 55, AMD is the leading cause of legal blindness in the developed world. While only approximately 10% of AMD patients have exudative AMD, i.e., which is associated with CNV, 90% of vision loss in AMD patients occurs secondary to CNV. The first MPS study was the Senile Macular Degeneration Study (SMDS). This study was designed to answer the question “Is argon laser photocoagulation useful in preventing severe vision loss in eyes with evidence of senile macular degeneration and a choroidal neovascular membrane outside the fovea?” (1). To be eligible for this study, patients had to exhibit extrafoveal AMD-related CNV and visual acuity of 20/100 or better. Extrafoveal lesions were defined as being 200 to 2500 microns from the center of the FAZ.
At 18 months, 60% of untreated eyes versus 25% of treated eyes experienced severe vision loss, defined as a loss of six or more lines of visual acuity. Because of this marked discrepancy between treatment and observation, recruitment was terminated after 18 months. The initial cohort was, however, followed over time. By 5 years of follow up, 46% of treated eyes and 64% of untreated eyes had lost six or more lines of visual acuity (2, 3 and 4), suggesting a significant advantage to undergoing laser photocoagulation for extrafoveal lesions. After 5 years, however, 54% of laser treated eyes developed recurrent neovascularization either contiguous to or independent from the original lesion. Despite this high recurrence rate, the SMDS showed that laser treatment to AMD-related CNV at least 200 microns from the center of the FAZ reduced the risk of severe visual loss.
Ocular Histoplasmosis Study
In ocular histoplasmosis syndrome, CNV may emanate from previous areas of chorioretinal atrophy. When CNV encroaches on the foveal center, vision loss may occur. The ocular histoplasmosis study (OHS) was initiated to evaluate whether argon laser photocoagulation prevents vision loss in patients with extrafoveal CNV from ocular histoplasmosis syndrome. At 5 years, 10% of treated eyes lost six or more lines of visual acuity compared to 41% of untreated eyes (4). At 5 years, the rate of recurrence was 26%. This rate of recurrence was lower than that in treated patients with AMD and with idiopathic causes. As with AMD patients, laser photocoagulation of ocular histoplasmosis-related extrafoveal lesion was shown to decrease the risk of vision loss.
Idiopathic Neovascularization Study
The idiopathic neovascularization study (INVS) was a separate arm of the MPS study that evaluated the effect of argon laser photocoagulation in eyes with extrafoveal CNV secondary to an unknown disease process (i.e., idiopathic). Like the SMDS and OHS, the INVS evaluated whether argon photocoagulation prevented severe vision loss compared to observation in eyes with idiopathic lesions (3). The small number of patients in the INVS precluded subgroup analysis. Despite a small patient population, however, the results suggested a treatment benefit from laser compared to observation. At one year, 40% of untreated patients compared to 18% of treated patients had experienced a loss of six lines of vision. As with the AMD and ocular histoplasmosis subgroups, recurrence was common. By 5 years, 34% of patients had recurrence.
PROGNOSIS
Based on the results of the SMDS, OHS, and INVS studies, it appeared that patients with ocular histoplasmosis syndromerelated extrafoveal CNV responded better to laser than patients with idiopathic or AMD related lesions. Patients with ocular histoplasmosis had lower rates of severe visual loss and lower rates of recurrence compared to patients with idiopathic CNV and AMD patients. Although the sample size was small for idiopathic lesions, these patients seemed to have an intermediate prognosis between ocular histoplasmosis-related and AMD-related extrafoveal lesions. While AMD patients seemed to do the worst among these three subgroups, they still did
significantly better with laser photocoagulation than with observation alone.
significantly better with laser photocoagulation than with observation alone.
TREATMENT PROTOCOL FOR EXTRAFOVEAL LESIONS
In patients who met eligibility criteria, treatment was carried out as soon as possible after the initial diagnosis. Two essential elements of the treatment protocols in SMDS, OHS, and INVS included a fluorescein angiogram within 72 hours of treatment and retrobulbar anesthesia to ensure akinesia of the globe and to facilitate treatment. Using argon blue green laser, the goal of treatment was to treat and obliterate the neovascular complex in its entirety. Treatment consisted of uniform white overlapping laser burns. The parameters were set such that each burn was 200 microns in size and 0.5 seconds in duration. The burns extended 100 to 125 microns beyond the CNV on all sides. If the CNV was within 350 microns of the FAZ, burn size and duration were reduced to 100 microns and 0.2 seconds to reduce the probability of treating the FAZ. When blood, pigmentation, or blocked fluorescence was present, photocoagulation was extended 100 to 125 microns beyond these areas. In treated patients, follow up was arranged between 3 and 9 weeks after photocoagulation, followed by visits at 3 months, 6 months, and then every 6 months if treatment effect persisted. A fluorescein angiogram was performed at each follow up, and any sign of recurrence was promptly retreated with laser photocoagulation.
JUXTAFOVEAL LESIONS
Age-Related Macular Degeneration Study-Krypton Laser, Ocular Histoplasmosis Study-Krypton Laser, and Idiopathic Neovascularization Study-Krypton Laser
After the initial success of treating extrafoveal lesions with laser photocoagulation, the MPS turned its attention to treating juxtafoveal lesions, which were located between 1 and 199 microns from the FAZ. As with extrafoveal lesions, juxtafoveal lesions were divided into AMD-related, ocular histoplasmosisrelated, and idiopathic. Patients deemed eligible underwent krypton laser photocoagulation with the hope of obliterating the CNV and preventing vision loss.
As with extrafoveal lesions, laser photocoagulation decreased the risk of severe vision loss when applied to juxtafoveal lesions. The results, however, were tempered by higher rates of severe vision loss and higher rates of recurrence. At the five follow-up point, 61% of untreated eyes versus 52% of treated eyes lost six or more lines of visual acuity in patients with AMD. In patients with ocular histoplasmosis at five years, 28% of untreated eyes lost six lines of visual acuity compared to 10% of treated eyes. Similarly, among idiopathic lesions, 28% of untreated lesions versus 20% of treated lesions sustained severe vision loss at five years.
Initially, there was hesitancy to treat juxtafoveal lesions because of their close proximity to the fovea and the fear of inducing vision loss. These factors may have contributed to the high rates of persistence in juxtafoveal lesions. For example in the Age-Related Macular Degeneration Study-Krypton Laser (AMDS-K) study, 32% of patients had persistent neovascularization and 47% had recurrence over 5 years. This is compared to 10% persistence and 47% recurrence of extrafoveal lesions at 5 years. Thus, most of the difference between juxtafoveal and extrafoveal lesions was with persistence rather than recurrence, suggesting a possibility of inadequate initial treatment.
As with the other MPS related studies, patients enrolled in the AMDS-K, Ocular Histoplasmosis Study-Krypton Laser (OHS-K), and Idiopathic Neovascularization Study-Krypton Laser (INVS-K) were questioned about their medical history. During subgroup analysis it was determined that for juxtafoveal lesions in patients with AMD, normotensive patients experienced a greater benefit from laser treatment than did patients with a history of hypertension. In fact, AMD patients with hypertension and juxtafoveal lesions did not appear to gain a significant benefit from treatment.
As mentioned previously, the recurrence rate for extrafoveal lesions was high. Given the location of juxtafoveal lesions closer to the FAZ, one might expect the recurrence and persistence rates to be higher on the foveal side, since treatment may be impeded by the FAZ. In fact, this was the case. At five years, 78% of AMD patients had recurrence or persistence of the lesion, and 33% of ocular histoplasmosis patients had recurrence or persistence. Because the sample size for the idiopathic group was small, recurrence rates could not be reliably reported. As with extrafoveal lesions, therefore, patients with ocular histoplasmosis did best, with the lowest rates of recurrence, persistence and visual loss.
TREATMENT PROTOCOL FOR JUXTAFOVEAL LESIONS
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