Monitoring Conversion from Non-neovascular to Neovascular AMD and Identifying Patients at Risk

Catching those patients early who will convert from dry to wet AMD may spare vision

Monitoring Conversion from Non-neovascular to Neovascular AMD and Identifying Patients at Risk

Catching those patients early who will convert from dry to wet AMD may spare vision.


Conversion from non-neovascular (non-NV) to neovascular (NV) age-related macular degeneration is hard to predict. We know that only about 15% of all AMD patients progress to the advanced form of the disease, but obviously this form accounts for the more severe visual impairment.1 So, is it possible to identify these specific patients who are prone for conversion? And are there any measures for early detection of conversion, aside from the Amsler grid, which has low sensitivity and specificity?

The introduction of anti-VEGF therapy made early detection of conversion to neovascular AMD dramatically relevant. A subgroup analysis of the MARINA and ANCHOR studies demonstrated that treatment benefit is greater if initial visual acuity is better and if the size of a choroidal neovascular lesion is smaller.2,3 Unfortunately, many patients are diagnosed only after they experience visual symptoms, when visual function is already impaired and potential treatment benefit is likely to be reduced.

In order to identify the patients who are prone for conversion, a high index of suspicion in high-risk groups, along with early detection tests, may allow for earlier treatment and better visual outcomes.


Genetic Factors Affecting AMD Conversion

The complement factor H (CFH) Y402H and LOC387115 A69S polymorphisms were each found independently related to progression from early or intermediate stages to advanced stages of AMD with odds ratios of 2.6 and 4.1, respectively, for the homozygous risk genotypes.4 A recently published study suggests that a combined influence of the CC (Y402H) genotype of CFH gene and C-reactive protein (CRP) levels resulted in a superadditive risk for prevalent late AMD (odds ratio of 19.3) and AMD progression (odds ratio of 6.8).5 Higher levels of the systemic inflammatory markers CRP and interleukin (IL)-6 were also found independently associated with progression of AMD.6 Other factors, such as ethnic origin (eg, Anglo-Saxon ethnicity) and light iris color, were also associated with greater progression of AMD.7 Therefore, genetic factors probably play a role, not only in disease prevalence but also in disease progression.

Clinical Clues During Ocular Examination

The recently published report of the Submacular Surgery Trial identified characteristics predictive of progression to advanced AMD in fellow eyes. The study authors found three baseline eye ocular features that were significantly related to progression to AMD: drusen size, focal hyperpigmentation and nonfoveal geographic atrophy.8 An eye with soft drusen is also more likely to progress to atrophy or CNV than an eye with hard drusen only. These signs can be helpful in identifying suspects for progression and probably suggest a closer follow-up regimen.

Imaging Modalities

Lower choroidal perfusion (assessed with laser Doppler flowmetry and laser interferometry) was found to be a risk factor for developing CNV in the fellow eye of patients with unilateral CNV.9 Drusenoid PED larger than two disc diameters, demonstrated by clinical examination and imaging modalities such as fluorescein angiography, indocyanine green angiography and optical coherence tomography, were also associated with disease progression. Over 10 years, geographic atrophy and CNV occurred in 75% and 25% of these patients respectively, with a poor visual outcome.10 Hence, closer follow-up may be beneficial in these patients.


The rate of a fellow-eye CNV is fairly high: the AREDS study team reported a 35% rate of fellow eye CNV with a median follow-up of 6.3 years.11 In the MARINA and ANCHOR studies, after 24 months, a new CNV developed in the fellow eye in 38.0% and in 35.1% of the two ranibizumab 0.5-mg groups, respectively. Differences in conversion rates between ranibizumab and control groups were not statistically significant, suggesting that monthly ranibizumab injections do not reduce the rate of CNV development in untreated fellow eyes.12


Although several previously published reports found an association between cataract surgery and AMD progression, more current studies did not find such an association after controlling for relevant confounders. One hypothesis suggested that many cases of presumed progression may have been present prior to cataract surgery, but not recognized owing to lens opacity.13 However, the results of different studies are contradictory, and it may be prudent to monitor patients undergoing cataract surgery more closely.


The NEI recommends dry AMD patients use the Amsler grid daily, consume the AREDS formulation (if required) and undergo a dilated exam at least once a year.15 However,in everyday practice, patients are often monitored more closely (eg, every three to four months) to identify early signs of progression, such as subtle subretinal or intraretinal fluids, PEDs or retinal hemorrhages. In these cases, FA and OCT are usually performed promptly. Some physicians use OCT to monitor dry AMD as a part of the routine followup, but no clear guidelines exist regarding this measure.

Psychophysical changes may precede anatomical changes, and therefore psychophysical tests have the potential for early detection of conversion. Several detection tests have been proposed; some are under investigation or theoretical, and others may be used in clinical practice. These tests are based on several mechanisms:

► detection of deterioration of visual acuity (eg, reading tests)
► reduction of contrast sensitivity (eg, low contrast visual acuity tests)
► detection of scotoma (eg, Amsler grid, a macular mapping test in which letters are projected at various locations of the macular visual field; microperimetry with scanning laser ophthalmoscope assessing correlation of macular pathology with visual function; entopic perimetry based on enhancement of a scotoma during gaze at random noises flickering at high frequency)
► detection of metamorphopsia (eg, Preferential Hyperacuity Perimeter [PHP], a perimeter that employs stimuli to detect and quantify metamorphopsia)
► detection of color deficits (eg, short wavelength automated perimeter projecting blue targets on yellow background; color matching tests)
► impaired adaptation mechanism (eg, dark adaptation; glare recovery testing recovery of visual functions following intense illumination; flicker sensitivity, measured by finding the contrast threshold at which an alternating stimulus is no longer visible)
► electrophysiology testing (eg, multifocal ERG).14

Preferential Hyperacuity Perimetry

The low reliability of the Amsler grid encouraged the development of the ForeseePHP (Notal Vision, Israel), an FDA-approved medical device that was shown to have higher sensitivity and specificity in detection of a new CNV. The device repeatedly presents brief visual stimuli on a touch screen positioned in front of the tested patient. Each stimulus is presented as a line consisting of dots; most of the dots are arranged along a linear axis, but several units are misaligned, thus forming a small artificial “bump.”

The patient is asked to mark the area of distortion on the touch screen. The short time of stimulus presentation ascertains the patient's reaction only after the stimulus has already disappeared. A CNV area may cause the patient to perceive a distortion in addition to the bump. If this pathological distortion is more prominent than the artificial bump, the patient's attention may be attracted to it, rather than to the artificial bump.

The data from a series of stimuli are compared to a normative database comprising tests done by intermediate AMD and newly diagnosed CNV patients. This comparison is used to compute a probability that the test belongs to a patient with CNV. This device was designed for clinical settings and under supervision of a technician.

A newer home version, ForeseeHome (Notal Vision), was recently introduced and allows self-monitoring. The home version is designed as a closed hood that enables testing each eye separately. The patient responds by using a mouse-controlled pointing device, rather than directly pointing on a touch screen. The accuracy of the device (average of sensitivity and specificity) was found to be high — between 84% and 85% — comparable with that of the larger touch screen device designed for clinic settings.


Earlier detection and treatment of a CNV may result in better visual outcomes for patients with AMD. Identifying patients at risk for conversion may be based on a combination of genetic factors, ocular examination, imaging modalities, and awareness of patients with a fellow eye CNV or those who have undergone cataract surgery. Evolving monitoring tests may be beneficial in early detection of conversion to neovascular AMD and enhance visual outcomes following treatment. RP


1. Haddad S, Chen CA, Santangelo SL, Seddon JM. The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol. 2006;51:316-363.
2. Boyer DS, Antoszyk AN, Awh CC, Bhisitkul RB, Shapiro H, Acharya NR. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007;114:246-252.
3. Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol. 2007;144:850-857.
4. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA. 2007;297:1793-1800.
5. Robman L, Baird PN, Dimitrov PN, et al. C-Reactive protein levels and complement factor H polymorphism interaction in age-related macular degeneration and its progression. Ophthalmology. 2010 Jun 2. [Epub ahead of print]
6. Seddon JM, George S, Rosner B, Rifai N. Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol. 2005;123:774-782.
7. Nicolas CM, Robman LD, Tikellis G, et al. Iris colour, ethnic origin and progressionof age-related macular degeneration. Clin Exp Ophthalmol. 2003;31:465-469.
8. Solomon SD, Jefferys JL, Hawkins BS, Bressler NM, Bressler SB. Risk factors for second eye progression to advanced age-related macular degeneration: SST report No. 21 Submacular Surgery Trials Research Group. Retina. 2009;29:1080-1090.
9. Boltz A, Luksch A, Wimpissinger B, et al. Choroidal blood flow and progression of age-related macular degeneration in the fellow eye in patients with unilateral choroidal neovascularization. Invest Ophthalmol Vis Sci. 2010;51:4220-4225.
10. Roquet W, Roudot-Thoraval F, Coscas G, Soubrane G. Clinical features of drusenoid pigment epithelial detachment in age related macular degeneration. Br J Ophthalmol. 2004;88:638-642.
11. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL 3rd. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology. 2005;112:533- 539.
12. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB. Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol. 2010;149:939-946.e1.
13. Dong LM, Stark WJ, Jefferys JL, et al. Progression of age-related macular degeneration after cataract surgery. Arch Ophthalmol. 2009;127:1412-1419.
14. Waisbourd M, Manor Y, Loewenstein A. Early detection and diagnosis of age-related macular degeneration: from slit lamp examination to advanced imaging techniques and psychophysical tests. In: Catlin RB, ed. Retinal Degeneration: Causes, Diagnosis and Treatment. Hauppauge, NY; NOVA Publishers; 2009:155-190.
15. Facts about age-related macular degeneration. National Eye Institute Website. Accessed September 22, 2010.

Michael Waisbourd, MD, is on the faculty of the Department of Ophthalmology at the Tel-Aviv Sourasky Medical Center in Israel and is on the Sackler Faculty of Medicine at Tel-Aviv University. Anat Loewenstein, MD, is the head of the Department of Ophthalmology at the Tel-Aviv Sourasky Medical Center and vice dean of the Sackler Faculty of Medicine at Tel-Aviv University. Dr. Waisbourd reports no financial interest in the products or companies discussed in this article. Dr. Loewenstein reports moderate financial interest in Notal Vision, Israel. Dr. Waisbourd can be reached via e-mail at