The purpose of this chapter is to discuss the different treatment modalities that were available in clinical practice before the use of anti-vascular endothelial growth factors (anti-VEGF), according to their date of appearance and their clinical significance. At present, many of these techniques have been abandoned, as the reader will conclude, given their efficacy compared to the modern anti-VEGF treatments available. However, we are still far from having an ideal treatment for wet age-related macular degeneration (AMD), and in some circumstances, history has shown that retaking old treatment strategies and combining them with newer modalities, or rethinking previously used principles, can lead science toward new steps in managing these disorders, thus offering novel treatment strategies and improving visual outcomes.

In this chapter, the reader will find a brief review of the different treatment modalities available for AMD previous to the introduction of anti-VEGF in clinical practice. In each treatment option mentioned, we summarized an introduction, the most relevant multicenter studies, their principle and results, and their current use. In those treatments where no randomized, double-blind, placebo-controlled study data were available, we included those obtained from small case series that had significant results and relevance that lead to their application in different disorders.

Between 1979 and 1994, the Macular Photocoagulation Study Group (MPS) conducted three sets of randomized clinical trials (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21). The purpose of these studies was to determine if laser photocoagulation was of benefit in preventing or delaying large losses of visual acuity (VA) in comparison with observation without treatment. The Argon and Krypton studies included patients with choroidal neovascularization (CNV) secondary to AMD, presumed ocular histoplasmosis (POH), and idiopathic choroidal neovascularizations (ICNV). The Argon study studied the effectiveness of photocoagulation with argon blue-green laser in eyes with extrafoveal CNV (200-2,500 µm from the center of the foveal avascular zone [FAZ]). The Krypton study examined CNV lesions with the posterior border 1 to 199 µm from the center of the FAZ, and the Foveal study was carried out in patients with new (never treated) or recurrent (previously treated with laser photocoagulation) subfoveal CNV (CNV with blood or blocked fluorescence within 200 µm of the foveal center).

Although photocoagulation treatment could change the natural history of the disease, it would not restore vision, and unfortunately with the appropriate follow-up, persistent or recurrent CNV would be observed in all kinds of extrafoveal, juxtafoveal, and subfoveal CNVs. Therefore, thermal coagulation produces a scar that goes through all layers of the retina and that manifests itself clinically as a visual field defect.

In light of recent findings on anti-VEGF therapy, it seems like at present photocoagulation for CNV should only be applied for small extrafoveal lesions, which accounts for 5% of all patients. There is no doubt that laser photocoagulation is still useful for peripapillary CNV. However, some ophthalmologists are hesitant to treat peripapillary CNV with photocoagulation, fearing that the procedure may lead to thermal damage of the nerve fiber layer in the papillomacular bundle. Others are hesitant because they believe that the natural course of peripapillary lesions might be more benign than the treatment (21). The MPS reported that in those eyes with peripapillary CNV lesions nasal to the fovea and below the papillomacular bundle, 44% of treated eyes versus 29% of untreated eyes would achieve VA of 20/40 or better at 3-year follow-up. In addition, only 9% of treated eyes compared to 54% of untreated eyes lost six or more lines of VA. The MPS group reported that severe VA loss was noted after treatment only when recurrent CNV extended through the center of the fovea (17,18,19,20,21). This finding suggests that severe visual loss only from nerve fiber layer damage after this treatment approach, in the absence of subfoveal recurrence, must be a rare complication.

In order to avoid thermal necrosis of disc tissue and following the MPS photocoagulation technique, one should consider refraining from treatment within 100 to 200 µm of the optic nerve and consider treatment only when at least 1 ½ clock hours of papillomacular bundle on the temporal side of the disc is uninvolved with CNV so that at least 1 ½ clock hours of papillomacular bundle can be spared of treatment (17).

The Submacular Surgery Trials (SST) was initiated in 1997, prior to the advent of photodynamic therapy (PDT) (25). They were designed to compare the outcome of surgical treatment versus observation in three categories: (a) (SSTN): New subfoveal CNV (without prior laser) secondary to AMD, (b) (SST-H): CNV secondary to POHS or idiopathic etiology, and (c) (SST-B): Thick submacular blood or hematomas associated with AMD. In the three arms, a successful outcome was defined to be either improvement of best-corrected visual acuity or visual acuity no more than 1 line worse at 24-month follow-up. However, none of the three arms showed a benefit over the observation group at the end of the study period (25,26,27,28), according to the following results:

SST-N: Forty-four percent of observed eyes and 41% of eyes assigned to surgery had a successful outcome as defined in the study. Median VA loss at 24 months was 2.1 lines in observed eyes and 2.0 lines in eyes assigned to surgery. Median VA declined from 20/100 to 20/400 at 2 years in both groups (26).

SST-H: Forty-six percent of eyes in the observation arm and 55% of those in the surgery arm had a successful outcome as defined in the study. Median VA at 24 months was 20/250 among eyes in the observation group and 20/160 in the surgery group. A subgroup of eyes with VA worse than 20/100 at baseline had more success with surgery; 76% in the surgery arm versus 50% in the observation arm. However, recurrent CNV developed in 54% of surgically treated eyes at 24 months (27).

SST-B: Forty-one percent of observed eyes and 44% of eyes assigned to surgery achieved a successful outcome as defined in the study (28).

Vitrectomy surgery for removal of subretinal CNV, whether subfoveal or nonsubfoveal, has not been shown to be more beneficial over laser photocoagulation, PDT, or observation in any prospective clinical trial. However, massive subretinal hemorrhage is a medically untreatable entity that will remain in the domain of surgical treatment.

Although an important number of publications were written, several issues remained unsolved regarding the type of CNV that responded best to intravitreal triamcinolone, the dose (from 4 to 25 mg depending on the study), and the frequency of injection (34). The intravitreal administration of steroids alone can no longer be recommended, in view of the results of new VEGF inhibitor treatments and the high rate of complications such as cataract, glaucoma, vitreous hemorrhage, and pseudoendophthalmitis (34). Nowadays, IVTA has been tested as a part of the triple combined treatment (see combined treatment).