Nonarteritic Anterior Ischemic Optic Neuropathy After Cataract Surgery: A Systematic Review and Meta-Analysis

Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported to occur after cataract surgery. It is not clearly established whether cataract surgery increases the risk of NAION over baseline.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD Nonarteritic Anterior Ischemic Optic Neuropathy After Cataract Surgery: A Systematic Review and Meta-Analysis William Shew, MBChB, BOptom (Hons), Michael T. M. Wang, MBChB, Helen V. Danesh-Meyer, MBChB, MD, PhD, FRANZCO Background: Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported to occur after cataract surgery. It is not clearly established whether cataract surgery increases the risk of NAION over baseline. Evidence Acquisition: Medline, PubMed, Embase, and Cochrane Central registers were systematically searched for eligible studies reporting on postcataract surgery NAION (psNAION) within 1 year. All peer-reviewed publications with events n $ 10 were included. Pooled incidence and odds/hazard ratios and 95% confidence intervals (CIs) were extracted and calculated using random effect models for early and delayed psNAION. Time to event data were pooled for temporal analysis of psNAION events within the first year. This systematic review was registered (PROSPERO CRD42021274383). Results: Nine articles met the selection criteria with five studies suitable for meta-analysis. A total of 320 psNAION cases, 1,307 spontaneous NAION (sNAION) cases, 1,587,691 cataract surgeries, and 1,538,897 noncataract surgery controls were included. Pooling of 63,823 cataract surgeries and 161,643 controls showed a hazard ratio of 4.6 (95% CI 2.7–7.8) of psNAION within 1 year of surgery. Pooled unadjusted incidence of psNAION within 2 months was 99.92 (95% CI 38.64–161.19) per 100,000/year, psNAION within 1 year was 32.36 (95% CI 9.38–55.34) per 100,000/year, and sNAION was 8.87 (95% CI 2.12–15.62) per 100,000/ year. psNAION cases were older by a mean of 7.6 years; otherwise, pooled odds ratios for baseline risk factors in psNAION vs. sNAION cases were not statistically significant. psNAION within the first year peaked within 72 hrs and at 6 weeks after the surgery with 73% of cases occurring within 6 months. Conclusion: The risk of NAION after cataract surgery is four times greater within the first year and usually occurs within Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal’s Web site (www.jneuro-ophthalmology.com). Address correspondence to Helen V. Danesh-Meyer, MBChB, MD, PhD, FRANZCO, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; E-mail: [e-mail] Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 6 months. However, the absolute risk remains low at 1 in 1,000–3,100 surgeries and is unlikely to warrant extra mention for consenting. Journal of Neuro-Ophthalmology 2023;43:17–28 doi: 10.1097/WNO.0000000000001625 © 2022 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is one of the leading causes of visual impairment in adults with an estimated annual incidence of 2.3– 10.3 per 100,000 people older than 50 years (1,2). The pathophysiology of NAION remains poorly understood; however, there are a few recognized risk factors such as diabetes, hypertension, obstructive sleep apnea, and smoking (3,4). NAION most commonly occurs in patients who have a specific phenotype of the optic nerve head: a “crowded” nerve with a small cup-to-disc ratio. This “disc at risk” is thought to create a compartment-like syndrome that reinforces further edema, thus creating the NAION complex. The natural history of NAION results in atrophy of the nerve tissue after 4–8 weeks, resulting in potentially devastating visual deficits (5). NAION may be precipitated by sildenafil, amiodarone, anemia, and hypovolemia—in particular following spinal surgery (3,6). There has been debate on whether cataract surgery may trigger of NAION with multiple case series, cohort-based, and population studies in the literature. The objective of this systematic review and meta-analysis was to assess whether cataract surgery increases the risk of subsequent early and delayed types of postcataract surgery NAION (psNAION) compared with spontaneous NAION (sNAION) within the first year and if there are any covariates that predict this risk in the general adult population. METHODS Search methods and reporting were performed in accordance with MOOSE (7) and PRISMA guidelines (8). Initial 17 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review searches of the published literature and in review protocol databases (PROSPERO, DARE and CDSR) showed no existing review protocol. This systematic review was registered in PROSPERO (CRD42021274383). Eligibility Criteria Eligible studies included all retrospective or prospective observational studies that reported NAION incidence as a primary outcome after cataract surgery (inclusive of all other types of combined intraocular surgery e.g., corneal grafting) within 1 year in the general population. NAION criteria was defined by the presence of new-onset optic disc edema, relative afferent pupillary defect (RAPD), a “disc at risk” configuration, a compatible visual field defect, and ruling other possible causes of NAION like presentations. Eligible studies with appropriate controls were selected for metaanalysis. Studies with significant exposures within the last 6 months affecting NAION outcomes (such as prone position surgery) were excluded. Case reports and case series of less than 10 cases with sufficient information to describe surgical risk factors were summarized; however, they not included for the main qualitative or qualitative synthesis due to their inherent biases. Search Methods Medline, PubMed, Embase, and Cochrane database of systematic reviews were searched using Boolean terms [NAION OR NAAION OR “ischemic optic neuropathy” OR “ischaemic optic neuropathy”] AND [cataract]. Applicable medical subject heading (MESH) terms were used if available. Studies from 1960s onward were included (the start of the phacoemulsification era). There were no restrictions on setting, country, or language. Reference lists of retrieved articles were also hand searched to find articles not captured by the database search. Authors were not contacted for further data. Grey literature was also searched for articles fitting the eligibility criteria. The search was completed on June 1, 2021. References were managed by EndNote v20 (Clarivate, Philadelphia, PA). Study Selection Two authors (W.S., M.T.W.) independently screened all electronic abstracts and retrieved full-text articles if studies matched the eligibility criteria. A third author (H.D.M.) was available to arbitrate any conflicts in matching. No differences in study selection occurred between the two authors. Data Collection and Study Quality Assessment Data collection was completed on June 28, and data items (See Supplemental Digital Content, Supplementary Data, http://links.lww.com/WNO/A604) were extracted by two authors (W.S., M.W.). psNAION has been reported in two 18 time periods—within several weeks (9) and several months following NAION (10). For the purpose of this review, we have used the psNAION definition by Mansukhani et al (11) of within 2 months and 1 year of cataract surgery, which we have termed early and delayed psNAION, respectively. Incidence and odds/hazard ratios were extracted and calculated for early delayed and late delayed psNAION. Where hazard ratios were not directly reported, they were extracted from published survival curves (12). Studies with at least 1 year of follow-up and time to event data were extracted for temporal analysis. Studies with summary data of events over a period of more than 2 weeks had individual occurrences transformed to occur evenly across the reported period. Extracted data were managed on Review Manager version 5.4.1 (The Cochrane Collaboration, 2020, Copenhagen). Study quality assessment was independently performed by two authors (W.S. and M.T.W.) using the Newcastle Ottawa Scale (NOS) cohort tool (13). Scores of 0–4; 5 and 6; and 7–9 were defined, respectively, as low, moderate, and high quality (14). Differences in extracted data or NOS scores were resolved through discussion between the two authors. Data Synthesis and Analysis Statistical analysis was performed using R version 4.0.2 (R Foundation, Vienna, Austria). Pooled analysis of incidence rates and hazards/odds ratios were conducted using inverse variance-weighted, DerSimonian and Laird random-effects modeling with Knapp–Hartung adjustments and illustrated using forest plots. I2 statistics were computed to summarize the proportion of variation across studies attributable to heterogeneity rather than random chance, and an I2 value of .50% was considered to indicate moderate to high heterogeneity. All tests were two tailed, and P , 0.05 was considered significant. RESULTS Included Study and Participant Characteristics The systematic literature search found 432 results. After exclusion of duplicates, 95 articles were screen for eligibility with 38 full-text articles retrieved. Nine articles met the selection criteria with five studies suitable for meta-analysis. A PRISMA flow diagram for selection study is shown in Figure 1. All studies were retrospective cohorts with two population-based studies (11,15), one survey (16), and the rest were cohort studies of those undergoing cataract surgery. Detailed characteristics of these studies are summarized in Table 1. A total of 320 psNAION cases (125 occurring within 2 months and a further 125 within 1 year of surgery), 1,307 sNAION cases, 1,587,691 cataract surgeries, and 1,538,897 noncataract surgery controls were reported. Denominators for noncataract surgery controls Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review were not included in four studies (10,16–18). Detailed characteristics of cases and controls are summarized in Table 2. A further 19 case series and reports with individual information on operative factors were summarized in the Supplemental Digital Content (See Supplementary Data, http://links.lww.com/WNO/A604) (9,19–37). Risk of Bias and Study Quality Four articles included patients from the same center and risking inclusion of the same cases (17,18,38,39). The single survey study was subject to significant recall, selection, nonresponse, and response inconsistency bias (16). Further methodological issues and NOS assessment scores are detailed in Table 1. Postcataract Surgery Nonarteritic Anterior Ischemic Optic Neuropathy Incidence and Hazard Ratios Raw incidence rates were reported in 5 studies for psNAION and three studies for sNAION. The pooled unadjusted incidence rate for early psNAION was 99.92 (95% confidence interval [CI], 38.64–161.19) per 100,000/year, delayed psNAION was 32.36 (95% CI, 9.38–55.34) per 100,000/year, and sNAION was 8.87 (95% CI, 2.12–15.62) per 100,000/year (Fig. 2). Three studies with an appropriate control group were included for pooling of hazard ratios at 1 year. A total of 63,832 cataract surgery cases and 1,538,589 controls were included with a pooled hazard ratio of 4.60 (95% CI, 2.72– 7.78) (Fig. 3). It is acknowledged that Al-Madani et al (40) did not have a full 1-year follow-up; however, we have included this study for meta-analysis on the basis that psNAION occurs usually within 6 months, and there was adequate control matching by age and cardiovascular risk factors. Baseline Risk Factors for Postcataract Surgery Nonarteritic Anterior Ischemic Optic Neuropathy vs Spontaneous Nonarteritic Anterior Ischemic Optic Neuropathy Cases The pooled mean age of psNAION cases were older by 7.6 years (95% CI 5.09–10.14) compared with sNAION cases. In the series of 11 psNAION cases occurring within 1 month from surgery by McCulley et al (18), the psNAION group had a significantly lower proportion of hypertension and cupto-disc ratios #0.2 compared with sNAION controls. FIG. 1. Selection flow chart. No differences were found in study selection between two independent author searches. *Excluded as case report/series with no control or description of population (n = 24) and editorial/comment with no original data (n = 8). Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Mansukhani et al 2020 (11) Study period Setting Design Population Inclusion criteria 1990–2016 Isolated mixed urban and rural state population, United States Retrospective population cohort Olmsted County, Minnesota Ing et al 2020 (16) 2004–2013 South Korea 2010–2014 Tertiary eye hospital, United States Retrospective survey All certified Canadian Ophthalmological Society Members Retrospective population cohort Random sample of 1,025,340 users of South Korean National Health Insurance Service (97% coverage) Age: $40 years Retrospective cohort Patients in Wilmer eye Network System Cataract surgery, pseudophakia or NAION insurance codes prior to cohort entry Vitrectomy, optic neuritis, central nerve system or demyelinating disease, other systemic connective tissue disease, GCA during study period Insurance-coded cataract surgery Previous presumed or documented NAION Email, online internet discussion boards, cataract conference Residents or fellow Exposure allocation Insurance coded cataract surgery Clear corneal cataract surgery under topical anesthesia. Consultant only cases Control allocation Entire county population older than 40 yrs without cataract surgery Nil NAION (outcome) definition Chart review by neuro-ophthalmologist (acute unilateral decrease vision, RAPD, VF loss, optic disc edema, no other etiology One eye chosen at random for bilateral NAION 1–12 years 4/1/3 Acute unilateral decrease vision, RAPD, VF loss, optic disc edema, no other etiology. Diagnosed within 1 year of cataract surgery Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Follow-up Newcastle–Ottawa Scale (out of 9) Study comments No study population baseline characteristics (however, delayed psNAION cases were significantly older) No surgical technique stated Moradi et al 2017 (10) 2018 Canada HICDA, ICD-9, and ICD-10 codes for optic neuropathy Cataract surgery not performed in state Previous optic neuropathy Exclusion criteria Yang et al 2019 (15) 2:1 propensity score-based matching using baseline demographics, comorbidity, comedication, and Charlson index category. Time spent without NAION contributed to control group NAION KCD-6 code ICD-9 NAION diagnosis Computer-coded noncomplex cataract surgeries. Includes combination procedures (e.g., corneal transplant) Nil Confirmed by institute ophthalmologist or neuro-ophthalmologist (acute unilateral decrease vision, RAPD, VF loss, optic disc edema, disc at risk), no other etiology Not stated 1/0/0 10 years 4/2/3 One year from surgery 3/1/3 Recall bias, selection bias, nonresponse and response bias (estimated response rate 18%– 32%), response inconsistency No chart review. No surgical technique stated Restrictive insurance code search. Referral bias. No study population baseline characteristics. No control. May not have returned to same center for NAION episode. No surgical techniques stated State-of-the-Art Review 20 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Summary of study characteristics Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Al-Madani et al 2017 (40) Study period Setting 2015–2016 Tertiary eye hospital, Jordan Design Population Prospective cohort Patients in King Hussein Medical Center Patients undergoing cataract assessment Glaucoma, previous optic neuropathy, general anesthesia, complicated cataract surgery Inclusion criteria Exclusion criteria Exposure allocation Uncomplicated phaco with retrobulbar anesthesia Control allocation Patients with cataract on waitlist .6 months or not willing to have surgery Not defined NAION (outcome) definition Lam et al 2007 (38) 1988–2001 Tertiary eye hospital, United States Retrospective cohort Cases from Bascom Palm Eye Institute Previous NAION in fellow eye Cataract surgery prior to any NAION No confirmed date of previous NAION or cataract surgery Phaco, ECCE, retrobulbar, topical anesthesia No cataract surgery Acute unilateral decrease vision, RAPD, VF loss, optic disc edema or pallor after visual loss ,6 weeks ago, no other etiology McCulley et al 2005 (18) McCulley et al 2003 (39) McCulley et al 2001 (17) 1993–1999 Tertiary eye hospital, United States Retrospective cohort Cases from Bascom Palm Eye Institute NAION within 30 days of surgery Nil 1993–1999 Tertiary eye hospital, United States Retrospective cohort Cases from Bascom Palm Eye Institute NAION within 1 yr of surgery 1993–1997 Tertiary eye hospital, United States Retrospective cohort Cases from Bascom Palm Eye Institute Age: $50 years Nil No follow-up at surgical center, ICCE, ECCE, combined procedures Phaco, ICCE, ECCE, secondary IOL, IOL exchange, complications. Anesthesia not stated 3:1 randomly selected group of spontaneous NAION with similar age and sex Acute unilateral decrease vision, RAPD, VF loss, optic disc edema or pallor after visual loss ,6 weeks ago, no other etiology Phaco, ICCE, ECCE, secondary IOL, IOL exchange, complications. Anesthesia not stated Nil Simple phacoemulsification or phacofracture 6 months 4/1/3 Up to 8 years 4/0/2 30 days from surgery 3/1/2 Acute unilateral decrease vision, RAPD, VF loss, optic disc edema or pallor after visual loss ,6 weeks ago, no other etiology One year from surgery 3/0/3 No detailed population baseline characteristics (summary pooled data stated) Aimed to compare risk of postsurgical NAION in those with previous NAION in fellow eye Referral bias, no control, no study population baseline characteristics No incidence estimate Aimed to compare risk factors on NAION cases Referral bias, no study population baseline characteristics Aimed explore timing of postsurgical NAION Referral bias, no study population baseline characteristics Nil Acute decrease vision, RAPD, RNFL defect associated with VF loss, optic disc edema One year from surgery 3/0/3 Referral bias, no study population baseline characteristics No control, selection bias (less complicated surgeries may be followed up elsewhere) ECCE, extracapsular cataract extraction; GCA, giant cell arteritis; HICDA, Hospital International Classification of Disease Adaptation; ICCE, intracapsular cataract extraction; ICD, International Classification of Disease; IOL, intraocular lens; KCD, Korean Standard Classification of Diseases; NAION, nonarteritic anterior ischemic optic neuropathy; RAPD, relative afferent pupillary defect; RNFL, retinal nerve fiber layer.; VF, visual field. State-of-the-Art Review Follow-up Newcastle–Ottawa Scale (out of 9) Study comments 21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Mansukhani et al 2020A (11) Study Early psNAION (within 8 weeks) Total events 8 week incidence Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Delayed psNAION Total events at 6 months 6 month incidence Total events at 1 yr 1 year incidence Total incidence Total hazard ratio Total NAION cases in cohort (psNAION vs sNAION) Total NAION Comparison of demographics in NAION cases (psNAION vs sNAION) Age (years) Male Comparison of risk factors in NAION cases (psNAION vs sNAION) CD ,0.35 Previous fellow eye sNAION HTN Dyslipidemia DM IHD OSA Stroke/TIA Smoker PDE5 inhibitor Ing et al 2020 (16) Cases (n = 23,169) Controls (n = 1,457,651) 2 NR 8.6 (2.2–34.5) 6.9 (5.7–8.4) Cases (n = 1,499,694) 82 (at 3 weeks) NR Yang et al 2019B (15) Moradi et al 2017C (10) Controls (Nil) Cases (n = 40,356) Controls (n = 80,705) Cases (n = 18,361) Controls (Nil) — 17 NR 1 — — NR NR 5.5 (0.1–30.3) — — — 9 38.9* (20.2–74.7) 86.3* 15.3 (9.4–25.0) — — 93 6.5* (5.3–7.9) 5.6* — — — 107 2.8 (1.6–4.7) — 1.80 (1.46–2.21) — — — — — — 20 NR 31 70 70 (55–86) — NR NR 11 14 27 (25–29) 1 5.5 (0.1–30.3) 2 10.9 (1.3–39.4) — — — 170 — — 20 82 107 — 139 958 18 170 75.3* ± 8.4 56 64.5* ± 10.1 56 NR NR — — 64.5 ± 9.79 15,662 (39) 64.4 ± 9.71 32,787 (41) 71.5* ± 6.9 7* (39) 62.5* ± 12.3 93* (55) NR NR NR NR NR NR NR NR NR NR — — — — — — — — — — NR 0 15,650 (39) 7,507 (19) 9,265 (23) 4,471 (11) NR 1,576 (4) NR NR NR 0 31,387 (39) 14,611 (18) 18,267 (23) 8,748 (11) NR 3,151 (4) NR NR Y NR 10 (56) 7* (39) 3 (17) 2 (11) 3 (17) NR 0* 0 Y NR 100 (59) 98* (58) 44 (26) 24 (15) 32 (19) NR 19* (11) 7 (4) Y 1 (11) 9 (100) 8 (89) 2 (22) 4 (44) 2 (22) 3 (33) 4 (44) 0 (0) 19 66 59 35 28 17 26 40 2 Y (20) (71) (63) (38) (28) (18) (28) (43) (2) State-of-the-Art Review 22 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Baseline participant characteristics of included studies Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Al-Madani et al 2017D (40) Cases (n = 307) Study Cases (n = 17) McCulley et al 2005 (18) Controls (n = 308) McCulley et al 2001 (17) Cases (NA) Cases (NA) Cases (n = 5,787) Controls (NA) 13 (at 4 weeks) — 2 (at 6 weeks) NR — — — 3 51.8 — — — — 3 NR NR — — — 7 (at 1 week) NR NR NR 3 NR 2 NR 11 (at 4 weeks) — 13 NR 1 NR 4 NR 9 NR — — — — — 3.60 (1.7–7.7) 5 NR NR 16 NR NR — — — 13 1 9 59 11 37 3 — NR NR NR NR NR NR NR NR 75 ± 5.25 5 71 ± 9.25 19 79 ± 6.8 0 — — NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 17 (100) NR NR NR NR NR NR NR NR NR 308 (100) NR NR NR NR NR NR NR NR N* 3 (27) 3* (27) 2 (18) 3 (27) NR NR NR 1 (9) NR Y* NR 25* (68) 13 (35) 9 (24) NR NR NR 6 (16) NR NR 2 2 0 1 NR NR NR NR NR — — — — — — — — — — — — — — 9.87 (1.3–74.9) — — 18 State-of-the-Art Review Early psNAION (within 8 weeks) Total events 8 week incidence Delayed psNAION Total events at 6 months 6-month incidence 10.7–151 Total events at 1 year 1 year incidence Total incidence Total hazard ratio Total NAION cases in cohort Total NAION Comparison of demographics in NAION cases Age (years) Male Comparison of risk factors in NAION cases CD ,0.35 Previous fellow eye sNAION HTN Dyslipidemia DM IHD OSA Stroke/TIA Smoker PDE5 inhibitor Controls (n = 233) Lam et al 2007E (38) Data presented as mean ± SD or number (% of participants). Incidence per 100,000/year. *Statistically significant difference; A Characteristics of cases at 1 year reported. B Baseline characteristics are of denominator case/control groups. Hazard ratios reported using propensity matched controls. C Also, no differences for anemia, hypotension, arthritis, amiodarone, intraocular pressure, and optic disc drusen. psNAION cases had overall significantly less cumulative risk factors. D Subgroup analysis of those with and without cardiovascular risk factors (hypertension, diabetes, dyslipidemia) showed that cataract surgery continues to show significantly increased rates of psNAION; E Mean follow-up of 30 months for sNAION. Hazard ratio reported using time-dependent covariates to account for interval between fellow onset NAION and subsequent cataract surgery; this difference was even higher (HR 7.4) after adjusting for age, diabetes, and hypertension. No significant differences between psNAION and sNAION for surgical technique. CD, cup-to-disc ratio (#0.35 defined as disc at risk as per Beck (4)); DM: diabetes mellitus; HTN: hypertension; IHD: ischemic heart disease (includes myocardial infarction and coronary artery disease); OSA: obstructive sleep apnea; TIA: transient ischemic attack; PDE, phosphodiesterase; psNAION, postcataract surgery nonarteritic ischemic optic neuropathy; sNAION, spontaneous nonarteritic ischemic optic neuropathy. 23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) State-of-the-Art Review FIG. 2. Forest plots of unadjusted pooled incidence per 100,000/year of nonarteritic anterior ischemic optic neuropathy occurring (A) within 2 months of cataract surgery, (B) within 1 year post cataract surgery, and (C) spontaneously. Individual studies have reported that psNAION cases have less dyslipidemia (10), hypertension (18), and smoking (10); however, pooled analysis of baseline risk factors in psNAION and sNAION cases showed no significant differences between exposures between the two groups. The odds ratios are summarized in Table 3. For individuals with established sNAION in the fellow eye, pooling was not a valid option with n = 2 studies with significant heterogeneity in surgical technique. In these two studies, the cohort of Lam et al (38) developed 35% of psNAION in the first year and an overall higher rate of psNAION (53%, n = 9 of 17) compared with sNAION controls (19%, n = 59 of 308) across 8 years. Moradi et al (10) reported a lower rate of psNAION (14.3% n = 1 of 7) compared with sNAION (23% n = 31 of 135) within 12 months. Surgical Risk Factors for Postcataract Surgery Nonarteritic Anterior Ischemic Optic Neuropathy Ing et al found that 39% of cases of psNAION in clear corneal cataract extraction was associated with raised FIG. 3. Forest plots of risk ratio of nonarteritic anterior ischemic optic neuropathy occurring within 1 year of cataract surgery vs. spontaneous occurrences. 24 Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 3. Pooled odds ratios for baseline risk factors in postcataract surgery nonarteritic anterior ischemic optic neuropathy compared against spontaneous cases Pooled Odds Ratio (95% CI) Risk Factor Hypertension (10,11,18) Dyslipidemia (10,11,18) Diabetes (10,11,18) Ischemic heart disease (10,11,18) Obstructive sleep apnea (10,11) Stroke/transient ischemic attack (11) Smoker (10,11,18) PDE5 inhibitor (10,11) 0.76 0.76 0.68 1.22 1.00 1.29 0.71 1.02 (0.15–3.88) (0.22–2.66) (0.29–1.57) (0.52–2.86) (0.36–2.78) (0.30–5.54) (0.24–2.09) (0.12–8.54) An odds ratio greater than 1 indicates risk factor more likely to be present in postcataract surgery group. CI, confidence interval. intraocular pressure (IOP) of .28 mm Hg within the first 3 postoperative days. A summary of all reported psNAION cases with perioperative details from large studies and case reports (19–24,26–28,30–34,41) has been included in the Supplemental Digital Content (See Supplementary Data, http://links.lww.com/WNO/A604). Time Course of Postcataract Surgery Nonarteritic Anterior Ischemic Optic Neuropathy Reported mean time to onset of psNAION ranged between 2.2 and 43.8 months (10,11,15,17). Also, 85 psNAION cases were available for time to event analysis; 21% (n = 18) of cases occurred within 3 days postoperatively with a further 18% (n = 15) occurring within 6 weeks. Most (73%) cases will occur within 6 months of surgery. The frequency distribution of events is shown in Figure 4 and suggests two peaks of occurrence: immediately within the first 72 hours and at 6 weeks postcataract surgery. DISCUSSION Optic neuropathy occurring after cataract surgery was first reported in 1946 (42) with later recognition of disc swelling by Townes et al (41) in a series of four cases. Reese and Carroll (9) further described a series of 17 cases whereupon a subset of these cases had a period of good vision followed by unilateral disc swelling, RAPD, and visual field defects. In retrospect, the clinical descriptions are consistent with psNAION. Since these initial cases, there have been several publications providing both evidence for and against an association of cataract surgery and NAION. Our meta-analysis indicates that there is a 4.6 increased risk of NAION from cataract surgery within the first year and no baseline factor except for higher age (mean difference 7.6 years) that was associated with psNAION. The absolute risk of psNAION is estimated to be 1 in 1,000–3,100 surgeries. Specifically, we identified a higher raw incidence of psNAION of 99.92 per 100,000/year within the first 2 months and 32.36 per 100,000/year within the first year. The peak of events occurred within 72 hours and at 6 weeks postsurgery. Pooled baseline risk factors associated with psNAION that did not reach statistical significance included the following: hypertension, dyslipidemia, diabetes, ischemic heart disease, obstructive sleep apnea, previous stroke or transient ischemic attack, smoking, and use of PDE5 inhibitors. Individual studies have shown that NAION is still associated with cataract surgery despite a significantly lower proportion of cases with dyslipidemia (10), hypertension (18), and cup-to-disc ratios of #0.2 (18) compared with sNAION controls. It has been suggested that patients needing cataract surgery with sNAION in the fellow need special consideration (45) based on a single study by Lam demonstrating that cataract surgery increased the risk of NAION by 3.6 times with half of the eyes eventually developing NAION in the next 8 years following surgery (38). A more recent study by Moradi et al (10) did not show an increased risk. Pooled event analysis was FIG. 4. Frequency distribution of postcataract surgery nonarteritic ischemic optic neuropathy cases in studies with at least 1 year of follow-up and time to event data. A. (n = 85) raw distribution. B. (n = 67) exclusion of immediate events within 3 days of surgery. Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 25 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review not a valid approach due to differences between the psNAION characteristics of Lam et al and Moradi et al. The cohort of Lam et al had an even mix of ECCE and phacoemulsification procedures with the majority (82%) receiving a retrobulbar block. The cohort of psNAION cases of Moradi et al were all performed with phacoemulsification with the majority (67%) under topical anesthesia. They also had small numbers (1 of 7 with psNAION), and use of restrictive inclusion criteria for psNAION cases may have resulted in underreporting and compounded by the rarity of psNAION. Data of Moradi et al would suggest that modern cataract surgery carries a negligible risk of psNAION in a susceptible eye. Estimates of sNAION in range from 2.3 (1) to 10.2 (2) per 100,000/year in the general US population (and up to 82 per 100,000/year in the elderly diabetic US population (43)). Internationally, estimates of sNAION in Koreans older than 40 years has been reported at 11.4 per 100,000/year (44). Control cohort groups in this review were in keeping with these figures, suggesting that the study sample was representative of the general population. There was significant heterogeneity in reported rates of psNAION reflecting the significant methodological differences in studies. Therefore, the true incidence of psNAION is difficult to determine. Our analysis identified that 21% of psNAION cases occurred within 72 hrs of surgery and a second peak of events at 6 weeks (11.7%). Several mechanisms are thought to contribute to the timeline of psNAION. psNAION occurring within the first 3 days without a period of good vision is most closely linked to high IOP, regional anesthesia, and intraoperative hypotension (32). Early psNAION outside of the first 72 hours is thought to be triggered by postoperative inflammation resulting in vasogenic disc edema (15,18,45) in a similar fashion to postcataract surgery cystoid macular edema (46). This is characterized by a period of good postoperative vision with subsequent deterioration due to NAION. Although we had found that the majority of events occurred within the first 6 months, individual studies continued to demonstrate higher rates of psNAION compared with controls after this period. The mechanisms for delayed psNAION are unclear. Possibly the loss of the crystalline lens eliminates a biological protective barrier for the posterior pole (47); however, this has not been seen in AMD progression after cataract surgery (48). It is possible that confounders and the severity of covariates (e.g., mild vs severe hypertension) have a significant role in determining rates of psNAION many years after surgery. There were insufficient studies to adequately perform subgroup analysis and no single study controlled for all known NAION covariates. Therefore, we cannot definitively conclude whether cataract surgery itself continues to raise the risk of NAION months to years afterward. Several interventions have been suggested to reduce the risk of psNAION during the perioperative period. These include avoiding surgery until warranted, use of topical anesthesia, clear corneal incision phacoemulsification, ensuring good IOP 26 control intraoperatively, thorough clearance of viscoelastic, and avoid breaching the posterior capsule (45). Control of IOP during perioperative period with acetazolamide and topical aqueous suppressants postoperatively can also be considered (32). Higher levels of VEGF and cytokines have been found in anterior chambers of active NAION eyes, and intravitreal VEGF or corticosteroid has been proposed as an adjunct (49). Although intravitreal injections can increase IOP (3), performing this at the time of cataract surgery would presumably equalize the IOP and is usual practice for diabetic macular edema. Another option is to use prophylactic topical NSAIDs in the postoperative period to reduce posterior pole edema, which is probably the least harmful intervention. No studies have assessed the effect of these interventions due to the infrequent nature of psNAION. This review has several strengths and limitations. There was significant heterogeneity between studies such as defining NAION by insurance coding (10,15), inclusion of complex cataract surgery (11), selection bias (17), referral bias (10), and no matching of major NAION risk factors (15). Some studies had a significantly younger control comparison group. This review included cases from 1990 onward when phacoemulsification was the major surgical technique; however, refinements over the past three decades (e.g., a preference for topical (30%) and sub-Tenon block (46.9%) based on 2008 United Kingdom audit (50)) have made cataract surgery less traumatic and thus likely to reduce the rate of immediate psNAION significantly. The predominance of historical cases contained in this review limits the ability to draw definitive conclusions about the risk of psNAION with modern day clear corneal cataract surgery under topical anesthesia; however, the absolute risk per cataract surgery found in this review is low. Prospective studies of psNAION are time and cost prohibitive, and despite issues with confounding, a major strength of this study is the pooling of available data with temporal analysis. This review represents the most comprehensive review to date and will assist the practicing ophthalmologist when consenting for cataract surgery and determining monitoring requirements post surgery. CONCLUSIONS Cataract surgery increases the risk of NAION within the first year by 4.6 times and usually peaks within 72 hours and at 6 weeks. Most cases occur within 6 months. The absolute risk remains low at 1 in 1,000–3,100 surgeries and is unlikely to warrant extra mention for consenting. Older age was associated with psNAION; however, no other pooled baseline risk factor reached statistical significance, including cases with previous sNAION in the fellow eye. This was attributed to study heterogeneity and low event numbers resulting in wide CIs of pooled estimates. Multiple perioperative optimizations have been suggested; however, no studies have reported outcomes of these interventions. More recent surgical techniques may reduce this risk; Shew et al: J Neuro-Ophthalmol 2023; 43: 17-28 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review however, the data are not definitive. Whether psNAION continues to remain a problem in modern day cataract surgery under topical anesthesia remains unanswered and may be a possible future avenue for study. STATEMENT OF AUTHORSHIP Conception and design: W. Shew; acquisition of data: W. Shew, M. T. M. Wang; analysis and interpretation of data: W. 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