Edited by: Michael S. Vaphiades, University of Alabama at Birmingham, United States
Reviewed by: Masoud Aghsaei Fard, Farabi Eye Hospital, Iran; Howard Pomeranz, Northwell Health, United States
This article was submitted to Ophthalmology, a section of the journal Frontiers in Medicine
†These authors have contributed equally to this work
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Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common ischemic optic neuropathy. The incidence rate is 2.5–11.8 per 100,000 cases in men elder than 50 (
The elder men were susceptible to NAION (
The two published meta-analyses reported influences of DM or sleep apnea on NAION, respectively (
We conducted this systematic review and meta-analysis in accordance with the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. The protocol registration number of PROSPERO (
Original literature was searched comprehensively through electronic Pubmed, Medline, Embase, and Cochrane Library databases. The related references were also screened, including gray literature (in the website
The inclusion criteria were listed as follows. First, the clinical studies concerning the comparisons of risk factors between NAION and controls were taken into further consideration. Second, the risk factors should exist before the diagnosis of NAION, which was judged by carefully screening the abstracts and/or full texts. Third, the samples of case and control groups were provided directly, or odds ratios (
Two investigators (B. L. and Y. Y.) did the literature search, study screening, data extraction, and eligible study quality assessment independently. The inconsistency was resolved by a third reviewer or
We collected the following data in a prepared standard form: first author, year of publication, country, ethnicity, study design, study duration, sample size, baseline information of the patient, and the number of patients (
We calculated the pooled unadjusted
We included a total of 49 studies containing more than 10 million patients. The process of verifying the studies was in accordance with a PRISMA flow diagram (
Flow diagram of the meta-analysis.
Baseline information of the included studies.
Chen et al. ( |
Chinese Taipei | Asian | 2007–2013 | Retrospective cohort study | NA | 180 | 77,030 | 48,570/28,640 | 67.4 ± 12.2 | ****** | 13 | ||
Yang et al. ( |
Korea | Asian | 2002–2013 | Retrospective cohort study | Age, sex, systemic risk factors, co-medications-matched | 28 | 10,081 | 8,075/2,034 | NA | ******* | 8 | ||
Yang et al. ( |
Korea | Asian | 2002–2013 | Retrospective cohort study | Age, sex, systemic risk factors, co-medications-matched | 1,097 | 399,877 | 523/574 | 176,163/183,358 | NA | ******** | 13 | |
Lee et al. ( |
Korea | Asian | 2011–2015 | Case-control study | Age, sex, systemic risk factors-matched | 22,498 | 31,475 | 9,175/13,323 | 12,832/ |
58 ± 11 | 58 ± 11 | ******* | 14 |
Sun et al. ( |
Chinese Taipei | Asian | 1996–2013 | Retrospective cohort study | Age, sex-matched | 374 | 42,066 | NA | NA | ******** | 8 | ||
Chen et al. ( |
China | Asian | 2013–2015 | Case-control study | Age, sex-matched | 71 | 142 | 47/24 | 94/48 | 54.86 ± 10.07 | 55.08 ± 10.36 | ******* | 4, 6, 11 |
Zhu et al. ( |
China | Asian | 2011–2016 | Case-control study | Age, sex, laboratory parameters-matched | 48 | 96 | 19/29 | 49/50 | 56.7 ± 11.9 | 57.3 ± 10.9 | ******* | 16 |
Kuhli-Hattenbach et al. ( |
Germany | European | 2010–2015 | Case-control study | Age-matched | 8 | 25 | 5/3 | 11/14 | 45.6 ± 7.2 | 42.9 ± 8.5 | ******* | 2, 12 |
Flahavan et al. ( |
UK | European | 2010–2015 | Case-control study | NA | 279 | NA | 279/0 | 61.8 (8.3) | ******* | 15 | ||
Kim et al. ( |
Korea | Asian | 2009–2015 | Case-control study | Age, gender-matched | 45 | 45 | 19/26 | 19/26 | 63.48 ± 15.23 | 62.42 ± 12.51 | ******* | 3, 4, 5, 6, 13 |
Zotz et al. ( |
Germany | European | 1999–2005 | Case-control study | Age, gender-matched | 109 | 109 | 66/43 | 66/43 | 58.1 ± 11.1 | 57.2 ± 10.7 | ******* | 5, 11, 12 |
Yao et al. ( |
China | Asian | 2011–2015 | Case-control study | Age, gender-matched | 42 | 100 | 19/23 | 44/56 | 63.2 ± 3.6 | 63.4 ± 2.3 | ******* | 14 |
Sahin et al. ( |
Turkey | European | 2011–2015 | Case-control study | Age, gender-matched | 46 | 90 | 23/23 | 39/51 | 57.3 ± 9.1 | 55.7 ± 13.2 | ******* | 4, 6, 13, 14 |
Lee et al. ( |
Chinese Taipei | Asian | 2000–2011 | Retrospective cohort study | Age, gender-matched | 414 | 789 | 239/175 | 461/328 | 55.9 ± 18.6 | 55.1 ± 18.4 | ******** | 4, 5, 6, 7, 10 |
Chang et al. ( |
Chinese Taipei | Asian | 2000–2009 | Case-control study | Age, gender-matched | 184 | 187,424 | 98/86 | 92,822/94,602 | NA | ******** | 4, 5, 6, 14 | |
Cestari et al. ( |
USA | Mixed | 2001–2014 | Retrospective cohort study | NA | 977 | 1,380,500 | 529/448 | 557761/ |
64.0 ± 9.2 | 58.4 ± 9.4 | ****** | 1, 2, 5, 6, 7, 8, 13, 14 |
Nathoo et al. ( |
Canada | Mixed | 2000–2011 | Case-control study | Age-matched | 1,109 | 1,237,290 | 1,109/0 | 1,237,290/0 | 69.8 ± 12.6 | 69.8 ± 12.6 | ****** | 5, 6, 7, 9, 10, 15 |
Campbell et al. ( |
Mixed | Mixed | 2008–2012 | Case-control study | Self control | 43 | 43/0 | 61.4 (48–73) | ******* | 15 | |||
Sakai et al. ( |
Japan | Asian | NA | Case-control study | NA | 34 | 102 | 20/14 | 67/36 | 62 (48–91) | 64 (42–88) | ******* | 2, 3, 4, 5, 6, 11 |
Nagy et al. ( |
Hungary | European | 2008–2012 | Case-control study | NA | 21 | 39 | 11/10 | 17/22 | 63.43 ± 10.78 | 73.07 ± 9.58 | ****** | 1, 2, 10, 14 |
Bilgin et al. ( |
Turkey | European | NA | Case-control study | Age, gender, systemic risk factors-matched | 27 | 27 | 15/12 | 15/12 | 64.9 ± 7.86 | 63.7 ± 5.24 | ****** | 8 |
Arda et al. ( |
Turkey | European | 2010–2012 | Case-control study | Age, gender, systemic risk factors-matched | 20 | 20 | 14/6 | 14/6 | 60.90 ± 8.14 | 61.15 ± 7.23 | ****** | 8 |
Stein et al. ( |
USA | Mixed | 2001–2007 | Retrospective cohort study | NA | 3,123 | 2,257,163 | NA | NA | ******* | 8 | ||
Markoula S ( |
Greece | European | 2004–2007 | Case-control study | Age, gender-matched | 47 | 76 | 29/18 | 47/29 | 66.2 | 65.6 | ******** | 4, 5, 6, 11 |
Lee et al. ( |
USA | Mixed | 1991–2007 | Retrospective cohort study | NA | 319 | 50,711 | 20,463/30,567 | NA | ******** | 2, 6 | ||
Felekis et al. ( |
Greece | European | 2003–2008 | Case-control study | Age, gender-matched | 77 | 60 | 50/27 | 32/28 | 63.4 ± 9.3 | 66.3 ± 9.3 | ******** | 4, 5, 6, 11 |
Kuhli-Hattenbach et al. ( |
Germany | European | 2004–2006 | Case-control study | Age, gender-matched | 35 | 70 | 27/8 | 52/18 | 51.5 | 49.8 | ******** | 12 |
Giambene et al. ( |
Italy | European | NA | Case-control study | Age, gender-matched | 85 | 107 | 39/46 | 47/60 | 65 (26–88) | 65 (21–84) | ******* | 3, 4, 5, 6, 11, 12, |
Kesler et al. ( |
Israel | European | NA | Case-control study | Age, gender, smoking, atherothrombotic factors-matched | 33 | 151 | 20/13 | NA | 62.5 ± 0.3 | 61.9 ± 0.1 | ******* | 10 |
Pinna et al. ( |
Italy | European | 1992–2006 | Case-control study | Age, gender-matched | 150 | 280 | 68/72 | NA | 63.6 ± 11.2 | NA | ******* | 4, 5, 6, 7, 9 |
French et al. ( |
USA | Mixed | 2004–2005 | Retrospective cohort study | Age, smoking, systemic risk factors-matched | 3,702,474 | 3,702,474/0 | 67 | ******* | 15 | |||
3,775,840 | 3,775,840/0 | 68 | |||||||||||
Li et al. ( |
USA | Mixed | 2000–2004 | Case-control study | Age, gender-matched | 73 | 73 | 38/35 | 38/35 | 63.5 ± 11.0 | 63.5 ± 11.1 | ******** | 3, 5, 6, 7, 8, 9, 13, 14 |
Margo and French ( |
USA | Mixed | 2004–2005 | Retrospective cohort study | NA | 4,157,357 | 4,157,357/0 | 64 | ******* | 15 | |||
Palombi et al. ( |
France | European | NA | Case-control study | Age, gender-matched | 27 | 5,615 | 18/9 | 2,648/2,967 | 65 | 63.5 | ******* | 8 |
Nagy et al. ( |
Hungary | European | 1997–2004 | Case-control study | Age, gender-matched | 36 | 81 | 23/13 | 53/28 | 65.9 ± 11.6 | 61.6 ± 12.6 | ******* | 3, 4, 5, 6, 7, 11, 12 |
Salomon ( |
Israel | European | 1984–2000 | Case-control study | NA | 92 | 145 | 66/26 | 85/60 | 61.8 ± 11.7 | 57.3 ± 18.4 | ****** | 1, 2, 14 |
Glueck et al. ( |
USA | European | 1999–2003 | Case-control study | Age, gender, race-matched | 12 | 36 | 4/8 | 12/24 | 62 ± 15 | 63 ± 15 | ******* | 11 |
Deramo et al. ( |
USA | European | 1995–1998 | Case-control study | Age, gender-matched | 37 | 74 | 25/12 | 50/24 | 43.2 | 43 | ******* | 3, 4, 5, 6, 14 |
Weger et al. ( |
Austria | European | 1996–2000 | Case-control study | Age, gender-matched | 71 | 71 | 30/41 | 30/41 | 68.1 ± 8.7 | 68.3 ± 9.4 | ******* | 3, 4, 6, 7, 9, 14 |
Mojon et al. ( |
USA & Switherland | Mixed | 9 months | Case-control study | Age, gender-matched | 17 | 17 | 15/2 | 15/2 | 64.6 ± 11.7 | 63.3 ± 11.0 | ******* | 3, 5, 6, 7, 8 |
Salomon et al. ( |
Israel | European | 1984–1999 | Case-control study | NA | 74 | 71 | 54/20 | 43/28 | 64.5 (41–89) | 66 | ****** | 2, 11 |
Pianka et al. ( |
Israel | European | 1998–1999 | Case-control study | Age, gender-matched | 40 | 81 | NA | 66.3 ± 1.96 | 66 ± 2 | ******* | 12 | |
Salomon et al. ( |
Israel | European | 1984–1997 | Case-control study | Age, gender-matched | 61 | 90 | 45/16 | 53/37 | 62 (34–85) | 66 (31–85) | ******* | 3, 4, 5, 6, 7, 11, |
Jacobson et al. ( |
USA | Mixed | 1987–1995 | Case-control study | Age, gender-matched | 51 | NA | 30/21 | NA | 68 (48–86) | NA | ******** | 3, 5, 6, 7, 14 |
Johnson et al. ( |
USA | European | 1993–1996 | Case-control study | Race, cup-disc ratio matched | 43 | 30 | 27/16 | 14/16 | 70.7 | 77.9 | ******* | 2, 3, 4, 6, 9, 14 |
Talks et al. ( |
UK | European | 1986–1992 | Case-control study | Age, gender-matched | 41 | 41 | 27/14 | 27/14 | 66.7 | 66.9 | ******* | 3, 4, 5, 6, 12, 14 |
Fry et al. ( |
USA | Mixed | 1987–1990 | Case-control study | Age, sex-matched | 15 | 30 | 7/8 | NA | 61 | 61 | ******* | 16 |
Kalenak et al. ( |
USA | Mixed | NA | Case-control study | Age, gender, race-matched | 45 | 45 | 21/24 | 21/24 | 66.7 ± 9.1 | 66.6 ± 9.7 | ******* | 5, 6, 7, 13, 14 |
Meta-analysis of the association of nonarteritic anterior ischemic optic neuropathy (NAION) with age
Twelve studies (
Hypertension was studied in the 16 original articles (
Meta-analysis of the association of NAION with hypertension
We extracted and pooled data from the 19 original studies (
Twenty-three studies (
Meta-analysis of the association of NAION with diabetes mellitus (DM)
The data from 11 original studies (
Nine studies (
Cerebrovascular disease was investigated in a total of five studies (
Meta-analysis of the association of NAION with cerebrovascular diseases.
The laboratory biochemical markers measuring coagulative status were examined and studied (
Meta-analysis results of the association of hypercoagulation, cardiovascular drugs, and ocular risk factors with non-arteritic anterior ischemic optic neuropathy (NAION).
Increased fibrinogen | 3 | 186 | 231 | 1.78 (1.26–2.52) | 0.001 | |
Hyperhomocysteinemia | 4 | 269 | 367 | 3.14 (1.99–4.93) | <0.00001 | |
Increased lipoprotein(a) | 3 | 229 | 286 | 1.36 (1.09–1.71) | 0.007 | |
Elevated VIII factor | 3 | 180 | 260 | 1.91 (0.79–4.63) | 0.15 | |
Antithrombotics | 3 | 468 | 979 | 2.30 (1.86–2.84) | <0.00001 | |
Statins | 3 | 1,556 | 1,238,230 | 1.32 (1.18–1.48) | <0.00001 | |
β-blockers | 2 | 447 | 940 | 1.48 (1.05–2.08) | 0.02 | |
Microaneurysm/retinal hemorrhage | 1 | 45 | 45 | 5.37 (1.09–26.49) | 0.04 | |
Small cup | 1 | 45 | 45 | 35.20 (4.45–278.25) | 0.007 | |
Small cup to disc ratio | 1 | 40 | 120 | NA | <0.00001 | |
IOP | 1 | 46 | 90 | 1.27 (1.08–1.48) | 0.003 | |
AMD | 1 | 977 | 1,380,500 | 3.29 (2.85–3.80) | <0.00001 | |
RVO | 1 | 977 | 1,380,500 | 9.72 (7.95–11.89) | <0.00001 | |
Number of anti-VEGF injections | 1 | 180 | 77,030 | <10 vs. 10–15 times | 1.91 (1.32–2.76) | 0.0006 |
<10 vs. >15 times | 2.20 (1.42–3.43) | 0.0004 | ||||
Post-cataract surgery | 1 | 1,097 | 399,877 | 1.80 (1.46–2.21) | <0.00001 | |
Glaucoma | 3 | 1,095 | 1,380,618 | 0.74 (0.11–5.00) | 0.76 |
Data of cardiovascular drugs history were collected and pooled. Three studies (
We analyzed the six genotypes and gained pooled results from the nine included studies (
Six trials from the five studies were analyzed for the impact of 1-month use of PDE5-Is on NAION (
Meta-analysis of the association of NAION with the use of phosphodiesterase type-5 inhibitors (PDE5-Is) within 1-month.
Apart from the systematic diseases, ocular factors were also studied and recorded comprehensively in the published literature; however, they were mentioned in less than the three articles. In three studies (
Meta-analysis results of the association of rare factors with NAION.
VNTR B allele | 1 | 92 | 145 | 4.25 (1.67–10.82) | 0.002 |
P-selectin | 1 | NA | 4.12 (1.22–13.91) | 0.02 | |
Flow-mediated dilation | 1 | NA | 1.79 (1.67–2.01) | <0.00001 | |
Anemia | 1 | 977 | 1,380,500 | 2.13 (1.83–2.47) | <0.00001 |
Depression | 1 | 977 | 1,380,500 | 0.87 (0.72–1.06) | 0.17 |
Peripheral vascular occlusive disease | 2 | 1,022 | 1,380,545 | 1.99 (1.52–2.59) | <0.00001 |
Recurrent herpes labialis | 1 | 43 | 30 | 3.11 (1.18–8.19) | 0.02 |
Mean platelet volume | 1 | 46 | 90 | 1.61 (1.13–2.28) | 0.008 |
IgG titer to Chlamydia pneumoniae | 1 | 71 | 61 | 3.48 (1.26–9.61) | 0.02 |
COPD | 3 | 73 | 73 | 0.80 (0.34–1.85) | 0.6 |
Hypothyroidism | 2 | 78 | 115 | 2.68 (0.61–11.72) | 0.19 |
End-stage renal disease | 1 | 184 | 187,424 | 2.60 (1.88–3.59) | <0.00001 |
Ischemic kidney injury | 1 | 22,498 | 31,475 | 1.53 (0.67–3.46) | 0.31 |
Carotid stenosis | 2 | 63 | 126 | 39.70 (0.02, 99269.34) | 0.36 |
In our systematic review and meta-analysis, we included articles studying a variety of risk factors: age, gender, ethnicity, systematic diseases, ocular factors, genotypes, cardiovascular drugs, and so on. We finally concluded the following risk factors to be significantly associated with NAION: male gender, hypertension, hyperlipidemia, DM, CHD, sleep apnea, medication history of cardiovascular drugs, and factor V Leiden heterozygous. Some other systematic and ocular diseases were researched in <3 studies and did not seem to be significant risk factors. In the subgroup analyses based on ethnicities, we found that the influences of gender in Asians and CHD and sleep apnea in Europeans were not significant. Therefore, we should take notice when applying our results to different populations.
In our meta-analysis, the cardiovascular factors were highly associated with NAION and studied in most literature, including hypertension, hyperlipidemia, and DM. NAION probably results from topical and/or systematic hypoperfusion (
Although the above major factors were reported to induce NAION, we summarized and reconfirmed these conclusions. In addition, we included the hypercoagulative biomarkers and possible risky genetic polymorphisms from the published literature. We first performed the meta-analyses on these factors, demonstrating that increased homocysteinemia, fibrinogen, lipoprotein(a), and factor V Leiden heterozygous were risk factors of NAION. Several diseases and biomarkers were identified in <3 studies, which are listed in
Diabetes and sleep apnea were proved to be important risk factors in the previously published meta-analyses (
We found no apparent association between the occurrence of NAION and 1-month use of PDE5-Is, which was published by us in 2018 (
A crowded optic disc was often observed in NAION because hypoperfusion or ischemia of the optic nerve head is apparent in a tight optic disc structure (
Some other factors were researched in <3 studies. Johnson and colleagues (
Although our meta-analysis was conducted comprehensively and included multiple potential risk factors of NAION, it still has several limitations. First, all the included original articles were case-control or retrospective cohort studies. No RCTs or prospective cohort studies have been published yet. Recalled data might be incomplete and inaccurate, bringing biases to these studies. Second, most NAION possible factors have similar mechanisms and act as confounders. Independence of these factors may probably be examined by RCTs; however, no RCTs can be conducted on studying the risk factors. Third, the time span of the included studies lasts from 1991 to 2019, during which the changes in lifestyles and medical techniques influence the type of risk factors. Finally, some risk factors were examined in <3 studies and it was hard to confirm their association with NAION. The above limitations reduced the quality of our meta-analysis partly and restricted our results to be applied.
Consequently, our study concluded that the following risk factors were associated with NAION: male gender, hypertension, hyperlipidemia, DM, CHD, sleep apnea, medication history of cardiovascular drugs, and factor V Leiden heterozygous. Better understanding of these risk factors in NAION can direct future research and therapeutic approaches.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
BL, TD, and DX: conceptualization and project administration. BL and YY: literature search and screening, formal analysis, data curation, and writing—original draft preparation. BL and TD: methodology and software. BL, YY, and TD: validation. WL, TD, and DX: writing—review and editing. TD and DX: supervision. All authors contributed to the article and approved the submitted version.
This study was supported by a grant from the Natural Science Foundation of Guangdong Province, China (No. 2020A1515110113) and the Science and Technology Planning Project of Guangzhou, China (No. 202102020113).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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