Cataract surgery and the risk of progression of macular degeneration

Abstract

Purpose of review

Cataract surgery improves vision loss due to cataracts in eyes with co-existing age-related macular degeneration (AMD), but whether surgery itself pose an increased risk for the progression of AMD has been of concern to both physicians and their patients. This review describes evidence on cataract surgery and its impact on the progression of AMD.

Recent findings

Recent evidence suggests that cataract surgery does not increase the risk for progression of AMD.

Summary

Cataract surgery should be discussed in patients with both AMD and visually significant cataract. Patients should be reassured that the cataract surgery will not increase the risk of AMD progression. In patients with AMD, especially those with the more severe intermediate stage and those with advanced AMD in the fellow eye, the natural course of progression to late AMD is high. The importance of vigilant follow-up needs to be emphasized for the detection of natural progression of the disease and early initiation of treatment should signs of neovascularization develop.

Introduction

Vision impairment from cataracts and AMD is expected to increase with the global rise in the aging population.(1) Cataract often co-exists in eyes with age-related macular degeneration (AMD) as both share common risk factors.(2, 3) Cataract surgery improves vision loss due to lens opacities in eyes with co-existent AMD. The surgical procedure, however, can cause intraocular inflammation which could theoretically contribute to AMD progression.(4) The risk of AMD progression after cataract surgery, if any, is of concern to both patients and their physicians. This review analyzes current evidence that will help counsel patients with AMD for potential cataract surgery often seen in day-to-day clinical practice.

Evidence from epidemiological studies

Evidence on the risk of AMD progression after cataract surgery stems from the earlier population-based longitudinal studies.(5–10) The Beaver Dam Eye Study (BDES) and the Blue Mountains Eye Study (BMES) found that eyes with a history of cataract surgery at baseline had an increased risk of late AMD, Odd’s ratio (OR) of 5.5 (95% Confidence Interval [CI]: 2.4 – 13.6), relative to their phakic cohort.(6) The risk of late AMD in eyes that had cataract surgery before the baseline visit persisted at 10 years with a risk ratio of 3.81 (95% CI: 1.89 – 7.69) for BDES and 3.3 (1.1 – 9.9) for BMES (Table 1).(5, 8) The risk of late AMD was not increased in the BMES cohort when cataract surgery occurred within five years after the baseline visit (OR of 0.82, 95%CI: 0.26 – 2.59).(8) The BDES, however, found that of the 39% of their original cohort assessed at 20 years, eyes that received cataract surgery after the baseline visit had an increased risk of late AMD (OR of 1.93, 95%CI: 1.28 – 2.90, Table 1) and the OR was higher ≥ 5 years after the surgery than < 5 years.(11) The Rotterdam Eye Study reported an association of incident subtype of late AMD, geographic atrophy, in eyes that had a history of cataract surgery (OR of 3.43, 95%CI: 1.82 – 6.49, Table 1).(9)

Table 1.

Characteristics of the studies included in the review

Study/Author	Published year	Participants cases/controls	Adjusted/matched factors	AMD classification	Follow-up	OR/RR/HR	95% CI	Remarks
Population-based studies
BDES/Klein R, et al.,(2)	1998	3684	Age, smoking, alcohol consumption, pulse pressure, hypertension and vitamin use	Late AMD	5 years	OR – 2.80	1.03 – 7.63
BDES/Klein R, et al.,(5)	2002	2764	Age, gender, smoking, alcohol consumption, systolic blood pressure, vitamin use	Late AMD	10 years	RR – 3.81	1.89 – 7.69
BDES/Klein R, et al.,(11)	2012	1913	Age, gender, education, smoking, alcohol consumption, cardiovascular disease, diabetes and diastolic pressure	Late AMD	20 years	OR – 1.93	1.28 – 2.90
BMES/Cugati S, et al.,(8)	2006	1952	Age, gender, smoking and presence of early age-related maculopathy lesions	Late AMD	10 years	OR – 3.31	1.11 – 9.87
RES/ Ho, L et al.,(9)	2008	6032	Age, gender, follow-up duration and co-relation between eyes	Late AMD - GA	5.7 years	OR – 3.43	1.82 – 6.49
Clinic-based studies
BEI/Xu L, et al.,(13)	2011	3826	-	Early AMD Late AMD	-	P = 0.99 P = 0.99
KNHNES/ Park SJ, et al.,(12)	2016	34863	Age, gender, smoking status, gross income, education, occupation, diabetes, dyslipidemia, body mass index, hepatitis B surface antigens and anemia	Both early and Late AMD	-	OR – 1.02	0.87 – 1.21
Armbrecht AM, et al.,(14)	2003	40/43	-	Late AMD	1 year	RR – 0.58α	0.06 – 6.17α
Sutter FKP, et al.,(16)	2007	499	-	Late AMD	-	OR – 1.04	0.77 – 1.39
Baatz H, et al.,(15)	2008	696	Age, baseline visual acuity	Late AMD	1 year	OR – 1.30	0.52 – 3.24
CSAMD/ Wang JJ, et al.,(17, 18)	2012 2016	1760	-	Late AMD	3 years 5 years	0.74 0.70	0.23 – 2.36 0.40 – 1.20
Age-Related Eye Disease Study
AREDS/Chew E, et al.,(20)	2009	4577	Age, AMD status, gender, smoking,	nAMD	10 years	HR – 1.20/1.07 (Right/left eyes)	0.82 – 1.75 / 0.61 – 1.06
				GA		HR – 0.80/0.94 (Right/left eyes)	0.61 – 1.06 / 0.71 – 1.25
				CGA		HR – 0.87/0.86 (Right/left eyes)	0.64 – 1.18 / 0.64 – 1.49
			Age, AMD status, gender, smoking, AMD status of the fellow eye, AREDS treatment, duration of follow-up after surgery	nAMD GA CGA		OR – 0.76 OR – 0.55 OR – 0.68	0.44 – 1.30 0.31 – 0.99 0.33 – 1.41	Matched-pair analysis
			Age, gender, AMD status, duration of follow-up after surgery	nAMD GA CGA		OR – 1.49 OR – 0.58 OR – 0.90	1.07 – 2.10 0.42 – 0.80 0.62 – 1.29	Logistic regression model
AREDS2/Bhandari S, et al.,(21)	2022	2754	Age, AMD severity score, smoking gender, education	Late AMD	9 years range(1 – 12)	HR – 1.1/0.96 (Right/left eyes)	0.89 – 1.25 / 0.81 – 1.13
		1061/1061	Age, AMD score, duration of follow-up, gender, education, AREDS2 treatment group, smoking, diabetes, aspirin and statin use	Late AMD	6 years	OR – 0.92	0.77 – 1.10	Matched-pair analysis
		1702	Age, AMD severity score, smoking gender, education	Late AMD	9 years range(1 – 12)	OR – 0.92	0.56 – 1.49	Logistic regression model

BDES – Beaver Dam Eye Study; BMES – Blue Mountain Eye Study; RES – Rotterdam Eye Study; BEI – Beijing Eye Study; KNHES – Korean National Health and Nutrition Examination Survey; CSAMD – Cataract Surgery and Age-Related Macular Degeneration Study; AREDS – Age-Related Eye Disease Study; AREDS2 – Age-Related Eye Disease Study 2; AMD – Age-related macular degeneration, nAMD – Neovascular Age-related macular degeneration; GA – Geographic atrophy, CGA – Central geographic atrophy; OR – Odd’s ratio; RR – Relative risk; HR – Hazards ratio

^α- Estimated

Recent epidemiological studies, in contrast, did not find AMD progression following cataract surgery. The Korean National Health and Nutrition Examination Survey found that there was no association between cataract surgery and late AMD (OR of 1.42, 95%CI: 0.88 – 2.29, Table 1).(12) The Beijing Study found that neither cataract nor cataract surgery was associated with early or late AMD (p = 0.99).(13)

Evidence from Clinic-based studies

Clinic-based studies have consistently found that eyes with early or moderate AMD that received cataract surgery did not have an accelerated progression to late AMD in the 12 months following the surgery (Table 1).(14, 15). A study found that there was no difference in the lens status in eyes with late AMD and their fellow eyes without advanced AMD (OR of 1.42, 95%CI: 0.88 – 2.29).(16) The Australian Cataract Surgery and Age-Related Macular Degeneration Study that prospectively evaluated the rates of late AMD at 5 years in eyes receiving cataract surgery with their fellow phakic eyes provides compelling data on the risk of AMD progression after cataract surgery. This study found that there were no statistically significant differences in the rate of late AMD between the pseudophakic eyes and their fellow eyes at 3 and 5 years of follow-up (Table 1).(17, 18)

Evidence from Age-Related Eye Disease Study (AREDS) and AREDS2

The association between cataract surgery and progression to late AMD has been of considerable interest to the investigators of the Age-Related Eye Disease Study (AREDS) and Age-Related Eye Disease Study 2 (AREDS2) research groups. AREDS was a randomized placebo-controlled clinical trial in participants 55 – 59 years that assessed the role of vitamins and mineral supplementation on the development of late AMD and cataract.(19) An analysis from AREDS evaluated the risk of developing late AMD after incident cataract surgery in 8050 eyes (4557 participants) without cataract and late AMD at baseline.(20) The Cox proportional hazards model showed a hazards ratio for neovascular AMD of 1.20 (95%CI: 0.82 – 1.75) for right and 1.07 (95%CI: 0.72 – 1.58) for left eyes, for geographic atrophy of 0.80 (95%CI: 0.61 – 1.06) for right and 0.94 (95%CI: 0.71 – 1.25) for left eyes and for central geographic atrophy of 0.87 (95%CI: 0.64 – 1.18) for right and 0.86 (95%CI: 0.63 – 1.19) for left eyes. The two other models used for data analyses, logistic regression and matched-pair analysis, did not suggest an increased risk for late AMD progression following cataract surgery either (Table 1). The AREDS results showed no increased risk of late AMD over a median follow-up of 10 years after cataract surgery (Table 2).

A recent study from AREDS2 prospectively evaluated the incidence of late AMD following cataract surgery.(21) The AREDS 2 enrolled 4203 participants 50 – 85 years with bilateral large drusen or unilateral AMD in a randomized controlled clinical trial between 2006 – 2008 to evaluate the potential benefits of a modified nutritional supplement on the development of late AMD and were followed until 2012.(22) An additional follow-up of 5 years (2013 – 2018) was conducted on the surviving AREDS2 participants after the end of the clinical trial in 2012. Telephone interviews at 6-monthly intervals collected data on adverse events, AMD treatment and cataract surgery between the study visits for this cohort during the clinical trial.

In the final 5 years of follow-up, only telephone interviews were conducted to obtain information regarding cataract surgery. A subset of the AREDS2 participants (n=709) underwent a comprehensive eye exam, and stereoscopic fundus and red reflex lens photographs at the year 10 study visit. Late AMD was defined as the presence of neovascularization or the presence of geographic atrophy on color fundus photos and/or a history of nAMD treatment during the clinical trial period supplemented by telephone calls and medical records at follow-up. Of the 2754 participants (4553 eyes) available for analysis in the Cox proportional hazards model, 1767 eyes (1195 participants) had cataract surgery while 1981 eyes (1524 participants) developed late AMD. The hazard ratio for the development of late AMD after cataract surgery was not statistically significant, 0.96 (95% CI: 0.81 – 1.13) for right eyes and 1.05 (95%CI: 0.89 – 1.25) for left eyes. Neither the logistic regression model (OR of 0.92, 95% CI: 0.56 – 1.49) nor the matched-pair analysis (OR of 0.92, 95% I: 0.77 – 1.10) showed an increased risk of AMD progression among AREDS2 participants with up to 10 years of follow-up (Table 1). This study from AREDS2 is consistent with the results of the AREDS study and provides further evidence that cataract surgery does not increase the risk of developing late AMD.

Reasons for the differences in the results

One of the reasons for the differing results between the Age-Related Eye Disease studies and the prior population-based longitudinal studies that reported an increased risk of AMD progression after cataract surgery may be the difference in the study participants. The AREDS and AREDS 2 clinical trials enrolled a highly selective group of healthy volunteers who are more health conscious and may have healthier lifestyles than the general population with the disease. The volunteers selected in the previous epidemiological studies were at higher risk of developing late AMD. More than two-fifths of their cohort had high-risk characteristics for late AMD such as at least one large drusen, extensive intermediate drusen, or geographic atrophy not involving the center of the macula. The inclusion of a higher proportion of participants who had a demonstrable propensity for AMD progression in these studies might have reduced the likelihood of detecting additional risk factors, such as the impact of cataract surgery.

The other reason for the contradicting risks on AMD progression following cataract surgery could have resulted from unadjusted confounding. Cataract and AMD share common risk factors and aging is an important risk factor for both.(2, 3) Eyes that had cataract at baseline in the previous population-based studies had signs of early AMD.(3, 7) These eyes were more susceptible to developing late AMD.(5) In contrast, eyes that had incident cataract surgery and those that did not in AREDS and AREDS2 studies had an equal propensity for developing late AMD.

The presence of unrecognized, subtle maculopathy before cataract surgery in the previous population-based studies could have led to the discrepancy in the results from those of the recent epidemiological studies, clinic-based studies, and AREDS and AREDS2.(2, 7–9) Cataract surgery could have facilitated better visualization of the fundus and identification of the maculopathy persisting before the surgery. Both cataract and AMD decrease visual acuity making it difficult to predict whether a decreased vision requiring cataract surgery in the earlier epidemiological studies had contributions from one or the other.(2, 3) Eyes that had cataract and early AMD at baseline in the earlier population-based studies were more likely to receive cataract surgery than those with cataract in the absence of early AMD at baseline.(5) Moreover, the decision for cataract surgery in the clinic-based studies and the AREDS studies were highly adjudicated by physicians who had examined the participants at regular intervals, thus participants in these studies were less likely to receive the surgery for subtle macular changes.

The earlier epidemiological studies that found an increased risk of AMD progression following cataract surgery date to the mid- or late 1990s.(3, 7, 23) Significant advances have occurred in surgical techniques and diagnostic tools since then. The cataract surgical technique evolved from extracapsular/intracapsular during these studies to less traumatic phacoemulsification cataract surgery - the standard of care in the later epidemiological studies, clinic-based studies, and AREDS and AREDS2 studies. The increased use of ultraviolet blocking or blue filtering intraocular lenses might have addressed the potential macular toxicity and eventual degeneration after cataract surgery. Evaluation of the retina using optical coherence tomography provides a better assessment of the macula before contemplating cataract surgery.

Visual acuity and quality of life after cataract surgery

The AREDS and AREDS2 studies reported significant visual gains after cataract surgery in all the subgroups that were stratified by pre-operative AMD severity.(24, 25) A significant proportion of eyes achieved a visual acuity (VA) ≥ 20/40 after the surgery. A post-hoc analysis of landmark clinical trials of anti-vascular endothelial growth factor (VEGF) antibody for the treatment of neovascular AMD (Minimally Classic/Occult Trial of the anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD [MARINA] and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD [ANCHOR]) reported an improvement in VA by 2 lines in eyes that received cataract surgery.(26) Functional vision improvement, however, is dependent on the pre-operative VA.(27) The improvement in eyes with pre-operative VA ≥ 20/40 is similar to those without retinal pathology while for those ≤ 20/40, improvement is significantly less and is decreased with a decreasing pre-operative VA.(27) Cataract surgery may not reliably improve VA in fovea-involving geographic atrophy. However, it improves other critical aspects of visual function such as contrast sensitivity, color vision, peripheral vision, glare and also the quality of life indices.(28)

Conclusion

Recent evidence suggests that cataract surgery does not increase the risk of AMD progression. Patient with AMD who have visually significant cataracts should be counseled that cataract surgery improves vision and quality of life without imposing a significant risk for disease progression. The patient should also be made aware about the natural progression of the disease irrespective of cataract surgery. Patient should be encouraged to vigilant follow-up visits for the detection of signs of neovascular changes for which early initiation of treatment leads to good outcomes.

Key points.

• A recent prospective study that evaluated the association of cataract surgery with incident late age-related macular degeneration (AMD) found that the risk of AMD progression was not increased after cataract surgery.

• Data from the Age-Related Eye Disease Studies, clinic-based studies, and recent epidemiological studies show that cataract surgery does not worsen AMD.

• Emphasis on follow-up visits should be made after cataract surgery in patients with AMD for the detection of the natural progression of AMD and early initiation of treatment should there be signs of neovascular AMD.