Countless clinical studies have determined that earlier treatment of age-related macular degeneration (AMD) leads to more favorable outcomes. With this fact in mind, my colleagues and I began examining ways to test patients for choroidal neovascularization (CNV) development at the earliest possible point. We believe the earlier in the course of the disease it is and the smaller the CNV lesion is when treatment begins, the better the patient's visual acuity will remain.
A meta-analysis of control groups of major clinical trials indicated that CNV begins developing in the eye more than 10 months before any visible signs are present.1 We wanted to determine if we could identify these incipient membranes earlier than when they become apparent with routine clinical tests, (eg, fluorescein angiography, optical coherence tomography [OCT]). Development of such a challenge test can allow us to begin treating patients before the CNV membrane grows to a debilitating stage. We hope our observation will help to detect incipient CNV in the transition stages before it progresses into the fovea.
EARLY IDENTIFICATION AND TREATMENT
Currently, our diagnostic methods are not sensitive enough to detect CNV at the subclinical stages of its evolution. We know from histopathology studies, however, that up to 43% of routine autopsies reveal CNV, but fail to give any clinical or angiographic signs.2 Inadequacy of fluorescein angiograms (FA) in detecting the presence and extent of CNV has been witnessed on several occasions. For example, in experimental animal models of CNV correlation of FA with serial histology sections showed there are portions of CNV that never demonstrates fluorescein leakage but contains fenestrated subretinal vessels.3 This discrepancy was also noted during the early days of subfoveal membranectomy when the size of the extracted membranes found to be approximately 1.5 times bigger than their size in FA estimates.4 Considerable differences in the interpretation of angiograms5 and the fact that leakage does not necessarily correlate with net fluid transport has lessened the value of angiograms in detecting CNV.6
Autofluorescence and OCT are two new imaging techniques recently introduced to the clinical arena. They both fall short of detecting early CNV, however. Increased autofluorescence is rarely seen in eyes with CNV,7 and OCT scans did not prove to be much more effective—with retinal thickness scans performing differently depending on the severity of the patient's AMD.8
During the last 4 years in which we have been using intravitreal pharmaceuticals for the treatment of exudative AMD, we observed the fact that fellow AMD eyes are also affected by the intravitreal injection of these drugs, most possibly by systemic absorption.
To better investigate this phenomenon, we initially developed a method for determining the significance of OCT thickness changes. For this reason, we created normograms of diurnal and long-term thickness variations of nine OCT segments of 34 untreated exudative AMD cases. This allowed us to calculate two standard deviations of the variation of each sector. Thus, any change that is more than the threshold value of that sector falls within 4.5% of the normal distribution and is accepted as significant. Multiplying this 1-D value with the sector area gives the significant volume change for that OCT sector, and addition of all these values is expressed as the Standardized Volumetric Change Index. While we were analyzing our data, we noticed five patients who experienced significant decrease in the macular thickness of the fellow eyes without any clinical signs of CNV. These patients subsequently developed exudative AMD, interestingly at the same loci that exhibited thickness decrease. Thus, we believe this observation may be the first recognizable sign of incipient CNV and may establish the basis of a challenge test.
We found five patients (aged 67-81 years) with significant volumetric decreases in one or more OCT zones in their fellow eyes after intravitreal injection of anti-VEGF agents, despite no initial evidence of CNV with clinical exam, OCT, and angiography. Within an average of 8 months (±6 months) all five of these patients had developed clinically detectable subretinal CNV at the corresponding quadrants that had revealed the significant volumetric loss after anti-VEGF treatment.
CASE STUDIES
The first patient is a 77-year-old woman suffering from vision loss in the right eye due to subfoveal CNV. She was treated in this eye with photodynamic therapy (PDT) twice, and her BCVA at presentation was 20/400. Her left eye showed signs of age-related maculopathy with few drusen; however without any clinical, angiographic, or OCT signs of CNV. Her visual acuity in the left eye was 20/20 (Figures 1-3).
We treated the right eye with a combination of PDT and intravitreal triamcinolone acetonide (4 mg) injection. One month after the treatment the fellow eye also revealed decrease in macular thickness. Please note that the observed decrease was mainly located temporal to fovea (Figure 4). Thirty-nine months later the patient developed subretinal CNV at the same location that exhibited a decrease in retinal thickness (Figures 5-6).
Patient two. An 82-year-old male with bilateral geographic atrophy presented with cystoid macular edema in the left eye that had undergone a successful retinal detachment repair 14 years ago. His vision in the left eye was 20/40. His fellow eye had no signs of CNV. The vision in the right eye was 20/25 (Figures 7-9). The patient received intravitreal triamcinolone acetonide (4 mg) in the left eye and exhibited significant decrease in both eyes (Figure 10). Three months later he presented with decreased vision in the right eye (20/60) accompanied by subretinal hemorrhage and fluid. After three subsequent intravitreal triamcinolone acetonide injections his vision was stabilized at 20/40 level (Figure 11).
Patient three. An 81-year-old man with subfoveal CNV in the right eye presented with a BCVA of 20/400. He had previously been treated with PDT. His left eye had geographic atrophy without any clinical or angiographic signs of CNV. BCVA in the left eye was 20/50. Note that patient is fixating just above the superior border of the geographic atrophy in the left eye (Figure 12).
A combined treatment of PDT and intravitreal triamcinolone acetonide (4.0 mg) was applied to the right eye. Two months after the treatment a significant decrease in thickening was observed not only in the right eye but also in the fellow eye, mainly at the point of fixation and above. Seventeen months later the patient presented with a decrease in vision of the left eye down to 20/160. Clinical exam, OCT, and FA revealed the presence of active subretinal CNV along the superior border of the geographic atrophy (Figure 13).
Patient four. A 79-year-old female with subfoveal CNV in the right eye presented with counting fingers vision. Her BCVA in the left eye was 20/20. She had geographic atrophy in the left eye but did not have clinical or angiographic signs of CNV. Indocyanine green (ICG) and OCT also failed to show any signs of CNV in the left eye. Her right eye was treated with a combination of PDT and intravitreal triamcinolone acetonide (4.0 mg). An OCT 2 months after the intravitreal injection revealed significant decrease in the fellow macula (Figure 14). Twenty-nine months later the patient presented with CNV in the fellow eye which had manifested with hemorrhagic pigment epithelial detachment. Her visual acuity decreased to 20/640.
Patient five. An 80-year-old female presented with a history of bilateral exudative AMD. She had been treated with bilateral PDT. Her visual acuity in the right eye was 20/125 and 20/20 in the left eye. She had mild subretinal fluid in the right eye which was confirmed with OCT. The left eye did not show any evidence of active CNV. The patient received a combination of intravitreal bevacizumab (1.25 mg) and triamcinolone acetonide (2.0 mg) in the right eye.
Six-weeks after the injection, the fellow eye (left) revealed significant decrease in macular thickness (Figure 15). Two months later her visual acuity decreased to 20/40 in the left eye with appearance of subretinal blood. A fundus fluorescein angiogram revealed the presence of a recurrent CNV (Figure 16).
From animal models and human histopathology studies we know that CNV is uncommon. Most of these vascular membranes remain dormant either within layers of Bruch's membrane or underneath the retinal pigment epithelium (RPE) without any clinical signs. Diagnostic tools we use in the clinic, such as FA, ICG, OCT, and autofluorescence often fail to detect these incipient vascular membranes. Once a fraction of these membranes start to invade the sub-RPE or subretinal space they create an anatomical space above them and become detectable by routine clinical means. At this stage, however, they rapidly grow toward the fovea, resulting in disruption of the subfoveal architecture and causing loss of central vision. Thus, there is a need to recognize these incipient membranes as early as possible.
The cases we presented herein demonstrate that subclinical membranes leak earlier than they develop typical clinical signs. Leaking fluid may be pumped back by MŸller cells and RPE, keeping the retinal thickness within normal limits. Temporary shutting of the leak with pharmaceuticals may result in returning of the retinal thickness to normal. This can manifest itself as a significant decrease in the macular thickness. We believe our observation will establish the basis of a clinical challenge test for an earlier diagnosis of subretinal neovascularization. In the mean time, we would like to caution our colleagues to watch the fellow eyes closely for any significant decrease in macular thickness which may be the earliest sign of an incipient CNV.
Tongalp H. Tezel, MD, is Associate Professor, Departments of Ophthalmology & Visual Science and Anatomical Science and Neurobiology, at the University of Louisville, Kentucky. Dr. Tezel states that he has no financial interest in the products or companies mentioned. He may be reached at tongalp.tezel@louisville.edu; or phone: 502-852-5466.
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