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. 2021 Feb 18;16(2):e0247126. doi: 10.1371/journal.pone.0247126

Risk factors and visual outcome of Non-Arteritic Ischemic Optic Neuropathy (NAION): Experience of a tertiary center in Kuwait

Raed Behbehani 1,*, Abdullah Ali 1, Ashref Al-Moosa 1
Editor: Yoshiaki Taniyama2
PMCID: PMC7891726  PMID: 33600480

Abstract

Background

Non-arteritic ischemic optic neuropathy (NAION) is the most common acute optic neuropathy over the age of 50 years. NAION is commonly associated with systemic vascular risk factors (diabetes, hypertension, hyperlipidemia) and small cup-to-disc-ratio. We have assessed the prevalence risk factors of NAION and the visual outcome in patients referred to a tertiary ophthalmology center in Kuwait.

Materials and methods

A retrospective review of new cases of NAION presenting within 2 weeks of onset were included and baseline clinical and demographics characteristic were determined. The prevalence of risk factors and the visual outcome (change in logMAR visual acuity, mean deviation of visual field) was compared between young NAION patients (below 50 years of age) and older NAION patients (over 50 years of age). The odds ratio of a final favorable visual outcome (visual acuity 20/40 or better) by age category was determined.

Results

Seventy-eight eyes of 78 patients with recent onset NAION were included in the study. The most prevalent risk factors for NAION in our subjects were diabetes (64.1%), small cup-to-disc ratio (61.5%), hyperlipidemia (51.3%) and hypertension (38.5%). Young NAION patients had better final logMAR visual acuity (0.55 +- 0.57) then older NAION patients (0.9 +- 0.73), (p = 0.03). Furthermore, young NAION patients were 2.8 times more likely to have a final visual acuity of 20/40 or better than older NAION patients, odds ratio (OR), 2.87; 95% confidence interval (CI), 1.12–7.40, Chi-square p-value = 0.03).

Conclusion

There is a high prevalence of systemic vascular risk factors and small cup-to-disc ratio in NAION patients referred to our center across different age groups (below and above 50 years). Patients below the age of 50 years with NAION are more likely to have a final visual acuity of 20/40 or better than NAION patients above the age of 50 years.

Introduction

Non-arteritic ischemic optic neuropathy (NAION) is the second most common optic neuropathy following glaucoma in patients over the age of 50 years and is the most common cause of optic nerve-related acute vision loss [1]. It is associated with systemic risk factors such as diabetes, hypertension, hyperlipemia and anatomical risk factors mainly crowded anomalous optic disc (disc at risk) or small cup-to-disc ratio [2,3]. The exact mechanism of NAION is not fully understood but it is thought to result from hypo-perfusion of the optic nerve head resulting in optic nerve head ischemia and swelling. Since predisposed individual frequently have a small cup-to-disc ratio, this can lead to a secondary compartment syndrome and further ischemia [4]. There are few studies that examined the natural history and the visual outcome of NAION [1,5,6]. There is increasing awareness that NAION can also occur in younger patients and is occasionally misdiagnosed as optic neuritis or papillitis, which can lead to inappropriate work-up and management [7,8]. In this study we have investigated the clinical characteristics and the visual outcome of patients with NAION, who were referred to a tertiary ophthalmology center. Moreover, we have assessed the visual outcome of NAION patients below 50 years of age in comparison to NAION patients above the age of 50 years.

Methods

We have retrospectively reviewed the records of patients presenting with a diagnosis of NAION between the period of 2006–2019. All patients were assessed by two neuro-ophthalmologists (RB, AM) and only new NAION cases which presented within 2 weeks of symptom onset were included. The diagnosis was based on the typical clinical presentation of sudden painless visual loss with a relative afferent pupillary defect and a swollen optic disc with or without disc hemorrhages. Additional supportive findings included the presence of a crowded disc or a small cup-to-disc ratio in the same eye or the contralateral eye, and the presence of the classical systemic risk factors (diabetes, hypertension, and hyperlipidemia). Patients with previous NAION in the contralateral eye, perioperative ischemic optic neuropathy (ocular or systemic surgery), shock-induced ischemic optic neuropathy and patients with severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or diabetic macular edema, were excluded. Medical records were reviewed to obtain clinical date including systemic risk factors identified either by direct history from the patient or laboratory testing. Snellen visual acuity was obtained at presentation and at the final follow up and was converted into logarithm of the minimum angle of resolution (logMAR) visual acuity to aid statistical analysis. A change in visual acuity of at least 0.3 logMAR unit change was set as a criterion for either improvement or worsening and a change in visual field mean deviation (MD), whether improvement or worsening, was defined as a change of at least 3 decibels.

Vertical cup-to-disc ratio was obtained using either time-domain optical coherence tomography for patients seen between 2006–2008 (TD-OCT, Stratus OCT, Carl Zeiss Meditec, USA), and with spectral domain optical coherence tomography (Topcon SD-OCT 3000) for patients seen from 2008 onwards. The visual field MD was obtained from Humphrey automated perimetry (24–2 FAST SITA strategy) at both baseline and the last follow up. The study was approved by the research ethics committee of Al-Bahar Ophthalmology Center.

Statistical analysis

Descriptive statistics were applied for demographic clinical variable and Chi-square test was used to study the association between categorical variables. To compare the visual outcome of NAION in patients below and above 50 years of age, Mann–Whitney U test was used for the change in logMAR visual acuity and MD of visual fields from baseline to the last recorded visit.

Multivariable binary logistic regression was used to determine if there was any independent effect of the NAION risk factors on the visual outcome. Statistical analysis was done using SPSS (IBM Corp. IBM SPSS, Version 23.0).

Results

Clinical characteristics of NAION patients

Seventy-eight eyes of 78 patients with newly diagnosed NAION were included in the study. The baseline characteristics of the patients are shown in Table 1.

Table 1. Baseline clinical characteristics of study subjects.

Patients (n = 78) Mean ± standard deviation
Age in years, mean± SD 50.60 (± 9.6)
Age category Below 50 years (n,%) 32 (41.0%)
Above 50 years (n,%) 46 (59.0%)
Gender Male (n,%) 53 (67.9%)
Female (n,%) 25(32.1%)
Ethnicity Arab (n,%) 58 (75%)
Indian (n,%) 15 (19%)
Asian (n,%) 5 (6%)
Cup-to-disc ratio ≤ 0.3 (n,%) 48 (61.5%)
Diabetes Mellitus (n,%) 50 (64.1%)
Hyperlipidemia (n,%) 40 (51.3%)
Hypertension (n, %) 30 (38.5%)
Smoking (n,%) 25 (32.1%)
Ischemic heart disease (n,%) 16 (20.5%)
Stroke (n,%) 12 (15.4%)
Obstructive Sleep Apnea (n,%) 9 (11.5%)
Cup-to-disc ratio, mean ± SD 0.32 ± 0.15
Baseline logMAR visual acuity, mean ± SD 0.8 ± 0.70
Follow-up logMAR visual acuity, mean ± SD 0.76 ± 0.70
Baseline visual field MD (decibels), mean ± SD -15.3 ± 9.0
Follow-up visual field MD (decibels), mean ± SD -13.5 ± 8.6
Follow-up duration (days), mean ± SD 111 ± 44.8
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Mean ± standard deviation.

MD = Mean Deviation.

Our subjects were of various ethnic backgrounds but were predominantly Middle-Eastern Arabs (75%) followed by Indian (19%) and Asian (6%) backgrounds. The most prevalent risk factors for NAION were diabetes, cup-to-disc ratio equal to or below 0.3, hyperlipidemia and hypertension. A significant proportion of our study subjects (41%) were below the age of 50, and a cup-to-disc ratio (≤ 0.3) was found in 68.75% of young NAION patients and 56,6% of older NAION patients. Sixty-four percent of our subjects had at least 3-month follow up while the rest (31%) had at least 2-month follow up and only four patients (5%) had 1-month follow up.

NAION subjects below 50 years of age were composed mainly of males (84.4%) while in NAION over 50 years of age, gender distribution was more equal with 56.6% males and 43.5% females. Older NAION patients had significant higher prevalence of diabetes, hypertension, ischemic heart disease and stroke, (p <0.05). (Table 2).

Table 2. Non-arteritic anterior ischemic optic neuropathy risk factor prevalence by age category (above and below 50 years of age).

Age Category Younger than 50 (N = 32,41%) Older than 50 (N = 46,59%) P-value
Gender Male (n,%) 27 (84.4%) 26 (56.6%) 0.01 *
Female (n,%) 5 (15.6%) 20 (43.5%)
Diabetes mellitus (n,%) 14 (43.8%) 36 (78.3%) 0.04 *
Smoking (n,%) 14 (43.8%) 11 (23.9%) 0.08
Hyperlipidemia (n,%) 14 (35%) 25 (65%) 0.36
Hypertension (n,%) 7 (21.9%) 23 (76.7%) 0.02 *
Ischemic heart disease (n,%) 2 (6.3%) 14 (30.4%) 0.01 *
Stroke (n,%) 0 12 (26.1%) 0.01 *
Obstructive sleep apnea (n,%) 2 (6.3%) 7 (15.2%) 0.3
Cup-to-disc ratio ≤ 0.3 (n,%) 22 (68.75%) 26 (56.5%) 0.3
Final visual acuity equals or better than 20/40 (logMAR ≤ 0.3) (n,%) 17 (53.1%) 13 (28.3%) 0.03*
Improvement of ≥ 0.3 logMAR from baseline to follow up, (n,%) 11 (34%) 12 (26%) 0.4
Improvement of ≥ 3 decibels in MD of visual field from baseline to follow up (n,%) 13 (40%) 12 (26%) 0.4
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• P-value ≤0.05 is statistically significant.

However, there was a trend for higher prevalence of smoking in young NAION patients compared to older NAION patients, (p = 0.08).

Visual outcome in young vs older NAION patients

In young patients with NAION, logMAR visual acuity improved by at least 0.3 in 11 patients (34%), remained stable in 17 patients (53.2%), and worsened in 4 patients (12.5%). Whereas in older patients with NAION, the logMAR visual acuity improved in 12 (26%), remained stable in 25 (54.3%) and worsened in 8 (19.3%). The visual field MD improved in 13 (40.6%), remained stable in 15 (46.9%) and worsened in 4 (12.5%) in the young NAION patients, whereas in older NAION patients, the MD improved in 12 (26.3%), remained stable in 28 (60.9%) and worsened 6 (13%). There was no significant difference in the mean baseline logMAR visual acuity between young patients with NAION (0.69 +- 0.66) and older patients with NAION (0.87+- 0.72). Young NAION patients had significantly better final mean logMAR visual acuity (0.55 +- 0.57) than older NAION patients (0.9 +- 0.73), (p = 0.03). (Table 3, Fig 1).

Table 3. Mean values of visual function at baseline and follow up based on age category (below and above age 50 years).

Age Below 50 Over 50 P-value
Baseline logMAR Visual Acuity 0.69 ± 0.66 0.87 ± 0.72 0.17
Follow up logMAR Visual Acuity 0.55 ± 0.57 0.90 ± 0.73 0.03 *
Baseline Visual Field MD -14.13 ± 8.7 -16 ± 9.26 0.35
Follow up Visual Field MD -11.52 ± 6.50 -14.85 ± 6.70 0.10
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• P-value ≤0.05 is statistically significant.

± standard deviation.

MD = Mean deviation.

Fig 1.

Fig 1

Open in a new tab

Box plot showing the comparison between baseline (A) and final (B) logMAR visual acuity between young (below 50) and older NAION (over 50). The horizontal line in the box plot represents the mean. NS = not statistically significant (p > 0.05). SS = statistically significant (p ≤0.05).

There was no significant difference in the mean MD of the visual fields between young and older NAION patients at baseline and there was a trend only towards a better mean visual field MD at follow up in young NAION patients (p = 0.1). (Table 3) Young NAION patients were 2.8 times more likely to have a final visual acuity of 20/40 or better than older NAION, odds ratio (OR), 2.87; 95% confidence interval (CI), 1.12–7.40, Chi-square p-value = 0.03).

Effect of systemic risk factors on visual outcome

There was no significant difference in the final visual outcome between smokers vs non-smokers (p = 0.84), diabetics vs non-diabetics (p = 0.12), patients with cup-to-disc ratio ≤0.3 vs cup-to-disc ratio >0.3 (p = 0.23) in the univariate analysis. Furthermore, multivariable binary logistic regression showed that neither diabetes mellitus, smoking, ischemic heart disease, hypertension, hyperlipidemia or cup-to-disc ratio ≤0.3, had had any significant effect on attaining a final Snellen visual acuity of 20/40 or better (0.3 logMAR).

Discussion

The most common risk factors in NAION subjects in our study was cup-to-disc ratio equal to or less than 0.3 followed by diabetes mellitus, hyperlipidemia and hypertension. (Table 1) The mean age for NAION patients in our study was 50.4 years and the subset of patients younger than 50 years comprised 41% of subjects in our study with a mean age of 41 years (range 29–48). (Table 2) This is in contrast to most large reported studies with less prevalence of NAION below the age of 50 years (10–12.5%) and the age for NAION was relatively older (around 60 years) [2,5,6,9,10]. Thirty-nine percent of young NAION patients in our study had at least one vascular risk factor associated with NAION, which reflects higher prevalence of diabetes and cardiovascular disease even among younger individuals in our region [11]. While older NAION subjects had significantly higher prevalence of diabetes, hypertension and ischemic heart disease compared to younger NAION subjects, there was a trend in the latter group towards higher prevalence of tobacco smoking. (Table 2) It has been also previously reported that smokers have an earlier age of onset of NAION, compared to former smokers and non-smokers [12].

The final mean logMAR visual acuity in young NAION patients was significantly better than older NAION patients and younger patients were significantly more likely to attain a final Snellen visual acuity of 20/40 or better. (Tables 2 and 3). There was also a trend (p = 0.1) for a better final visual field MD in younger NAION patients compared to older NAION patients. There was also a trend (p = 0.17) for better mean baseline logMAR visual acuity in young NAION patients (0.69 +- 0.66) compared to older NAION patients (0.87 +- 0.72) (Table 3). More young NAION patients than older NAION patients had at least 0.3 logMAR unit improvement in visual acuity (34% vs 26%), and 40% of young NAION patients had at least 3 decibels improvement in the visual fields MD compared to 40% of older NAION patients, but both of these changes were not statistically significant (p = 0.4). However, significantly more of young NAION patients had a final visual acuity of 20/40 or better compared to older NAION patients (53% vs 28.3%, p = 0.03) (Table 2). Preechwat et al have found also a favorable visual outcome in NAION patients younger than 50 years with 73% having a final visual acuity equal or better than 20/64 and only 13% have had a final visual acuity of less than 20/200 [8]. Sun et al., however, did not find a difference in the visual outcome in NAION between patients younger and older than 55 years [13]. It is possible that in our subjects, young NAION patients have better final visual outcome because they tend to have a better presenting visual acuity than older NAION patients and they are also more likely to improve over the course of NAION. More studies with larger sample size are needed to investigate this further.

The most common reported systemic risk factors associated with NAION are diabetes, and hypertension [2]. Other systemic associations include hyperlipidemia, stroke, ischemic heart disease, tobacco use, systemic atherosclerosis, and obstructive sleep apnea [3,7,14]. Crowded disc (disc at risk) or small cup-to-disc ratio is another important anatomical risk factor in NAION, especially in younger patients with no systemic risk factors [15,16]. In our study, a cup-to-disc ratio ≤0.3 was seen in 61.5% overall and in 68.75% of young NAION patients and 56.5% of older NAION patients.

We could not find an independent effect of any of the systemic risk factors (diabetes, hypertension, hyperlipidemia) or optic disc configuration on the final visual outcome. Although there are several risk factors associated with NAION, the pathophysiology and the extent to which these risk factors are directly implicated in NAION is not fully understood. Current concepts about the pathophysiology of NAION is thought to involve “microvascular insufficiency” leading to edema of the optic nerve head and subsequently a compartment syndrome causing further microvascular ischemia [17]. Therefore, it is likely that it is the cumulative and inter-dependent effects of these systemic vascular risk factors which lead to optic nerve ischemia rather than any single independent effect. Sharma et al have evaluated the visual outcome in diabetic NAION versus non-diabetic patients and have shown that ischemic heart disease and greater age was associated with worse visual outcome [6]. In non-diabetic patients, the most prevalent risk factor for NAION was hyperlipidemia, while for diabetic patients, the most common risk factors were hypertension, hyperlipidemia, and small cup-to-disc ratio [6].

There are several limitations of our study including selection bias of referral to a tertiary center, the relatively small sample size, and the retrospective nature which may have led to underestimation the systemic risk factors in the study subjects. The heterogeneity of the follow up period led to variability in recording and timing the final visual outcome. However, the visual outcome (visual acuity and visual field) following NAION stabilizes quite early usually in 2–3 months and even in the so called “progressive ischemic optic neuropathy”, worsening occurs in the first 2–4 weeks following NAION onset and then visual function stabilizes [18].There is an emerging interest in the role of disc drusen in NAION especially in younger patients, and while in our study there was no patients with visible disc drusen, we did not routinely perform ocular ultrasound to rule this out. In addition, since this study spanned a long time period, newer sensitive OCT technology to detect drusen such as Enhanced-depth imaging OCT was not readily available [19].

In summary, we have found a high prevalence of systemic vascular (diabetes, hypertension, hyperlipidemia, smoking) and anatomical risk factors (cup-to-disc ratio < = 0.3) in patients with NAION. In our study subjects, NAION was fairly common patients under the age of 50 years and many of those patients had systemic vascular risk factors or small cup-to-disc ratio. Finally, NAION in patients below the age of 50 years tended to have a better visual outcome and were more like to have a final visual acuity of 20/40 or better than NAION patients over 50 years of age. This may be important when counseling patients with NAION about their prognosis.

Data Availability

All relevant data are within the manuscript.

Funding Statement

I have received no funding for this work and I have no financial interests to disclose.

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Decision Letter 0

Yoshiaki Taniyama

4 Dec 2020

PONE-D-20-30757

Risk Factors and Visual Outcome of Non-Arteritic Ischemic Optic Neuropathy (NAION): Experience of A Tertiary Center in Kuwait .

PLOS ONE

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Reviewer #1: The authors present characteristics of a group that has not been previously studied for NAION in the past. Thus, there is some relevance to the field.

The paper needs to be reproofed for writing, as there are typos and verbiage mistakes (‘Yong’ for young, ‘visual outcome NAION patients’, instead of ‘the visual outcome of NAION patients’), even in the abstract.

The introduction needs to be tightened and probably shortened, since they use a number of lax definitions. For example, while the ultimate lesion in NAION ultimately is an ischemic infarct, and in fact a few cases may be directly caused by ‘an infarct’, NAION is probably more commonly caused by a compartment syndrome resulting in capillary compression and ultimate ischemia, rather than a simple clot (Tesser et al). That is the reason a ‘disk at risk’ is so strongly correlated with NAION: that it predisposes to a compartment syndrome. Similarly, the studies using aspirin, IVT anti-VEGF have not shown effect, but that is not the reason treatment is directed at controlling systemic vascular risk factors. The reason treatment is directed at systemic vascular risk factors is that these have been shown to be associated with NAION. The idea that so many young individuals get NAION is quite new, and I would delve deeper into this in the introduction.

Methods:

A question comes up as to whether the younger individuals are actually experiencing NAION, and how they know this is not due to other causes such as mitochondropathy (LHON). The strongest association with diabetes is particularly interesting, since NAION is usually associated with HTN, suggesting there may be some genetic factor involved in this population. Additionally, 111 days is quite short (< 4 months), and this is a very short time to evaluate final vision in an ischemic optic nerve lesion.

Results: Table 1 shows 41% of individuals>50 years, while Table 2 shows 41% of individuals <50 years. Which is the real number?

The value of the report is based on two things: 1) the reporting from a specific regional group that has not been previously reported on. 2) the evaluation of responses and recovery in younger and older populations. The last is particularly interesting, since 59% of individuals developed NAION below 50 years of age: typically NAION is associated with individuals above the age of 50. What is the mean age of the below 50 group, and what is the youngest? This begs the question as to whether the younger individuals are actually experiencing NAION, and how they know this is not due to other causes such as mitochondropathy (LHON). They have few other associations, less crowded disks and they are male, as well as with many fewer vascular comorbidities, but strong association with smoking. The lack of visual field improvement is consistent with other studies.

The discussion needs to be rewritten, and focused on the data they have. They bring in a lot of possible associations, but little actual analysis, for the simple reason, as they point out, ‘…several limitations of our study including selection bias, etc;). The reasons for the younger individuals and their lack of correlation with classical NAION comorbidities makes me suspicious. I would really focus on a better analysis of the data that they have, evaluating the two groups better (young and old), and bring into the discussion the possibility of other (mitochondrial) disorders masquerading as NAION, particularly in the younger individuals, as well as performing a secondary analysis on these younger individuals, with possible mitochondrial screening if available (it may not be). The reason for this caution is that the authors are potentially bringing into the literature a report that people will quote about ‘NAION affects more young people than people over 50’, and this is going to be very confusing, and possibly wrong. In this case, I do not think it excessive caution.

Reviewer #2: Comments:

This is a retrospective study which determined systemic vascular risk factors and disc configurations in NAION patients. The authors also compared visual function outcome between young and older subgroups.

1.“a crowded disc or small cup-to-disc ratio (=<0.3) was found in 31% of young and 43.3% of older NAION.” Do you include either crowded disc or small cup-to-disc ratio? I didn’t find the definition of crowded disc, small C/D, or disc at risk in methods? Is “Small C/D ratio” equal to or smaller than 0.3? This should be defined in methods about how you recruited the patients. But 0.3 is usually considered as normal ratio. “Disc at risk” is usually appreciated in the unaffected eye, because the affected optic nerve head is swollen. A “Disc at Risk” commonly has a cup to Disc Ratio less than 0.3 (usually 0.1). “Crowded disc” is usually used to describe small optic nerve head. The definition you use for the analysis should be clarified. It would be better to cite references.

2. Introduction Line 4: “Although NAION is thought to be infarction of the optic nerve head”. Based on multiple papers, NAION is thought to be associated with “hypoperfusion of optic nerve head” rather than infarction.

3. “Only one eye of each new NAION case was included” Is this for bilateral NAION? The number of unilateral AION and bilateral AION should be clarified.

4. “patients with severe diabetic retinopathy” Please define the “severe DR”. Is it defined by international clinical classification system for DR and DME? Does this mean the study excluded the DR that is worse than or equal to “severe NPDR”?

5. Visual field MD should be spelled out when first appeared in the text.

6. “Visual acuity change was defined as 0.1 logMAR unit change was considered either improvement or worsening.” Any references to support this definition? There is a paper recommended using at least 0.2 logMAR or greater to distinguish acuity changes from no change. (Daniel A. Rosser. How Sensitive to Clinical Change are ETDRS logMAR Visual Acuity Measurements? IOVS. 2003; 44(8): 3278-3281.) In Dr. Hayreh’s paper (reference 9), they used 0.3 logMAR.

7. Results: Seventy right eyes should be “ Seventy-eight”?

8. Table 1 should have headers for each column on the top. (e.g. Variables)

9. I recommend ranking the variables in table 1 and 2 in reasonable order, e.g. from the most common to the least common risk factors (diabetes, hyperlipidemia, hypertension, smoking…). You can still separate the systemic factors from ocular configurations and visual functions as it is now.

10. I’m curious about how many patients had finished 3 months and 6 months follow-up. Two months follow up is relatively short term.

11. Recently some papers discussed about young NAION and optic disc drusen. Did you have any chance to rule out optic disc drusen in young NAION in this study?

12. I don’t really understand this sentence. “except four patients who had 1 month of follow up and excluding those patients those patients had no effect on the final visual outcome analysis.” Who (how many) are included and who (how many) are excluded? If you didn’t include all subjects for follow-up analysis, I recommend mentioning it in table 1 as a footnote. I assume all the data in table 1 should be collected from 78 patients (eyes).

13. I recommend separating the results into several paragraphs with headlines. E.g. Basic characteristics of NAION patients (This should include follow-up), The risk factors in NAION patients, The risk factors in young NAION vs. older NAION, The visual function outcome in young NAION vs. older NAION…

14. I also recommend having diabetic or nondiabetic patients as subgroups to further analysis (risk factors and visual function).

15. “There was no statistically significant difference in the MD of the visual fields between young and older NAION patients neither at baseline nor follow up. ” Do you mean “no significant difference …either at baseline or follow-up”?

16. In the first and the second paragraphs of discussion, the “ischemic optic decompression trial” is the same as “In the optic nerve sheath decompression trial (IONDT) ”. This should be consistent with “IONDT”.

17. The heterogeneity of the follow up period meant the method of recording the final visual outcome was not standardized. In my opinion, the “methods of recording visual outcome” are visual field and acuity test but not follow up period.

18. In figure 1(A), ns should be followed by p value even if p > 0.05.

19. For table 2, I recommend calculating the p value for comparison of gender (male vs. female).

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 18;16(2):e0247126. doi: 10.1371/journal.pone.0247126.r002

Author response to Decision Letter 0

14 Dec 2020

Answers to Reviewer's Comments

Reviewer #1: The authors present characteristics of a group that has not been previously studied for NAION in the past. Thus, there is some relevance to the field.

The paper needs to be reproofed for writing, as there are typos and verbiage mistakes ('Yong' for young, 'visual outcome NAION patients', instead of 'the visual outcome of NAION patients'), even in the abstract.

The introduction needs to be tightened and probably shortened, since they use a number of lax definitions. For example, while the ultimate lesion in NAION ultimately is an ischemic infarct, and in fact a few cases may be directly caused by 'an infarct', NAION is probably more commonly caused by a compartment syndrome resulting in capillary compression and ultimate ischemia, rather than a simple clot (Tesser et al). That is the reason a 'disk at risk' is so strongly correlated with NAION: that it predisposes to a compartment syndrome. Similarly, the studies using aspirin, IVT anti-VEGF have not shown effect, but that is not the reason treatment is directed at controlling systemic vascular risk factors. The reason treatment is directed at systemic vascular risk factors is that these have been shown to be associated with NAION. The idea that so many young individuals get NAION is quite new, and I would delve deeper into this in the introduction.

Answer: The introduction was shortened and some sentences were removed, notably the sentence stating that the etiology is "infarction of the optic nerve". We did not mean to imply that the etiology was due to an embolus and we have elaborated a bit, as suggested by the reviewer, that the current understanding of NAION is "hypo-perfusion" of the optic nerve head with secondary swelling and a "compartment syndrome". We agree that that some of the treatments stated (IVA, steroids) are of limited success and that sentence was removed. Furthermore, we have added the reference suggested by the reviewer (Tesser et al. The morphology of infarct in NAION) in the introduction.

Methods:

A question comes up as to whether the younger individuals are actually experiencing NAION, and how they know this is not due to other causes such as mitochondropathy (LHON). The strongest association with diabetes is particularly interesting, since NAION is usually associated with HTN, suggesting there may be some genetic factor involved in this population. Additionally, 111 days is quite short (< 4 months), and this is a very short time to evaluate final vision in an ischemic optic nerve lesion.

Answer: It is widely-accepted that NAION is a clinical diagnosis made based on the clinical history and examination findings and is associated with a characteristic clinical features natural history. While other optic nerve disorders such LHON can mimic NAION, it is virtually impossible to rule out LHON in every patient unless the genetic testing in every single case. The high prevalence of diabetes of NAION can be explained by the high prevalence of diabetes in the general population in Kuwait, even among younger patients. Finally, we think that the follow up period (111 days) is relatively short but still adequate to assess the final visual outcome in NAION patients since vision (visual acuity, visual field) does not change significantly following 2-3 months, but the disc changes (optic disc swelling and subsequent atrophy) does lag behind and may take longer to finally stabilize. (N R Miller, A C Arnold. Current concepts in the diagnosis, pathogenesis and management of Non-arteritic anterior ischemic optic neuropathy. Eye. 2015)

Results: Table 1 shows 41% of individuals>50 years, while Table 2 shows 41% of individuals <50 years. Which is the real number?

Answer: Patients younger than 50 composed 41% and this was corrected in table 1.

The value of the report is based on two things: 1) the reporting from a specific regional group that has not been previously reported on. 2) the evaluation of responses and recovery in younger and older populations. The last is particularly interesting, since 59% of individuals developed NAION below 50 years of age: typically NAION is associated with individuals above the age of 50. What is the mean age of the below 50 group, and what is the youngest? This begs the question as to whether the younger individuals are actually experiencing NAION, and how they know this is not due to other causes such as mitochondropathy (LHON). They have few other associations, less crowded disks and they are male, as well as with many fewer vascular comorbidities, but strong association with smoking. The lack of visual field improvement is consistent with other studies.

Answer: We thank the reviewer for this comment. Patients younger than 50 years comprised 41% of all NAION patients in the study as stated above. The mean age of patients below 50 years was 41 years and the minimum age was 29 and the maximum was 48. We agree that the is a strong trend in our study in young NAION patients with Tobacco consumption, and although it did not reach statistical significance this may have been due to relatively low sample size. The association between tobacco use and an earlier age of onset of NAION has already been reported (Hayreh et al. Nonarteritic anterior ischemic optic neuropathy and tobacco smoking. Ophthalmology , 2007) and we have added this reference in the manuscript.

The discussion needs to be rewritten, and focused on the data they have. They bring in a lot of possible associations, but little actual analysis, for the simple reason, as they point out, '…several limitations of our study including selection bias, etc;). The reasons for the younger individuals and their lack of correlation with classical NAION comorbidities makes me suspicious. I would really focus on a better analysis of the data that they have, evaluating the two groups better (young and old), and bring into the discussion the possibility of other (mitochondrial) disorders masquerading as NAION, particularly in the younger individuals, as well as performing a secondary analysis on these younger individuals, with possible mitochondrial screening if available (it may not be). The reason for this caution is that the authors are potentially bringing into the literature a report that people will quote about 'NAION affects more young people than people over 50', and this is going to be very confusing, and possibly wrong. In this case, I do not think it excessive caution.

Answer: As suggested by the reviewer, the discussion was shortened to focus on the data analysis and we have removed parts of the discussion which may not be relevant to our study. We have discussed the possible association between NAION and tobacco use in younger patients. Unfortunately, since this is a retrospective study, mitochondrial screening for younger NAION is not feasible and would be out of the scope of the study. Although LHON although occurs more frequently in young patients, it can present at any age even in older patients and the presence and thus this would require another study possibly perhaps looking at the association between NAION and LHON mutations. Finally, many of the mitochondrial mutations if detected can be due to genetic heterogeneity and polymorphism and not necessarily causing LHON. We believe that NAION is a clinical diagnosis and is being diagnosed more in younger patients. The strong trend for tobacco use in our younger patients with NAION in our study may also explain the relatively high prevalence of NAION.

Reviewer #2: Comments:

This is a retrospective study which determined systemic vascular risk factors and disc configurations in NAION patients. The authors also compared visual function outcome between young and older subgroups.

1."a crowded disc or small cup-to-disc ratio (=<0.3) was found in 31% of young and 43.3% of older NAION." Do you include either crowded disc or small cup-to-disc ratio? I didn't find the definition of crowded disc, small C/D, or disc at risk in methods? Is "Small C/D ratio" equal to or smaller than 0.3? This should be defined in methods about how you recruited the patients. But 0.3 is usually considered as normal ratio. "Disc at risk" is usually appreciated in the unaffected eye, because the affected optic nerve head is swollen. A "Disc at Risk" commonly has a cup to Disc Ratio less than 0.3 (usually 0.1). "Crowded disc" is usually used to describe small optic nerve head. The definition you use for the analysis should be clarified. It would be better to cite references.

Answer: To avoid confusion, we have removed the terms "crowded disc" or "disc at risk" and we have replaced that with "cup-to-disc ratio <=0.3" to be all encompassing since as the reviewer has pointed out that a disc-at-risk or crowded disc have much smaller cup-to-disc ratio and the sometimes the cup is totally absent. Some textbooks would cite 0.4 to 0.5 as "normal" and below that would be "low" although and in the AAO manual for glaucoma it is stated that "C/D ratio between 0.1-0.4 can be normal" while most clinicians would perhaps 0.1 as low. Finally, we have obtained vertical C/D ratio by OCT and it is understandable that there may be discordance as C/D ratio can be under-estimated with ophthalmoscopy alone.

2. Introduction Line 4: "Although NAION is thought to be infarction of the optic nerve head". Based on multiple papers, NAION is thought to be associated with "hypoperfusion of optic nerve head" rather than infarction.

Answer: This has been addressed and the introduction was changed.

3. "Only one eye of each new NAION case was included" Is this for bilateral NAION? The number of unilateral AION and bilateral AION should be clarified.

Answer: This sentence was removed to avoid confusion. We have included only unilateral NAION and patient with prior NAION in the contralateral eye were excluded.

4. "patients with severe diabetic retinopathy" Please define the "severe DR". Is it defined by international clinical classification system for DR and DME? Does this mean the study excluded the DR that is worse than or equal to "severe NPDR"?

Answer: Yes. We have excluded patents severe non-proliferative diabetic retinopathy/proliferative DR and macular edema. This was corrected and clarifies in the text.

5. Visual field MD should be spelled out when first appeared in the text.

Answer: This was corrected.

6. "Visual acuity change was defined as 0.1 logMAR unit change was considered either improvement or worsening." Any references to support this definition? There is a paper recommended using at least 0.2 logMAR or greater to distinguish acuity changes from no change. (Daniel A. Rosser. How Sensitive to Clinical Change are ETDRS logMAR Visual Acuity Measurements? IOVS. 2003; 44(8): 3278-3281.) In Dr. Hayreh's paper (reference 9), they used 0.3 logMAR.

Answer: We have corrected this typo error and indeed we have used 0.3 logmar change as the minimum for change for either improvement or worsening as in the study by Hayreh et al. Nonarteritic Anterior Ischemic Optic Neuropathy: Natural History of Visual Outcome. Ophthalmology 2008.

7. Results: Seventy right eyes should be " Seventy-eight"?

Answer: corrected.

8. Table 1 should have headers for each column on the top. (e.g. Variables)

Answer: This was added.

9. I recommend ranking the variables in table 1 and 2 in reasonable order, e.g. from the most common to the least common risk factors (diabetes, hyperlipidemia, hypertension, smoking…). You can still separate the systemic factors from ocular configurations and visual functions as it is now.

Answer: This was done.

10. I'm curious about how many patients had finished 3 months and 6 months follow-up. Two months follow up is relatively short term.

Answer: Fifty out of the 75 patients (67%) in of our study had at least 3-month follow up while the rest (33%) had at least had at least 2-month follow up. Only four patients had 1month follow up and when excluded from the in the data analysis as a trial there was no effect on the results so we have included then in the final analysis. We believe that 2-3 months follow up period is adequate for NAION since the final visual outcome tends to stabilize relatively early in NAION (2-3 months) as opposed to other optic neuropathies (N R Miller, A C Arnold. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye. 2015), but in the discussion we did acknowledge this as one of the study limitations.

11. Recently some papers discussed about young NAION and optic disc drusen. Did you have any chance to rule out optic disc drusen in young NAION in this study?

Answer: That would be an interesting point and although none of the patients in our study had visible drusen, we did not look for buried drusen by Ultrasound. Furthermore, the study spanned a long period of time, at which perhaps new technology such as EDI-OCT, which are very sensitive and reliable to rule out disc drusen was not available. We have mentioned this also as one of study limitations in the discussion.

12. I don't really understand this sentence. "except four patients who had 1 month of follow up and excluding those patients those patients had no effect on the final visual outcome analysis." Who (how many) are included and who (how many) are excluded? If you didn't include all subjects for follow-up analysis, I recommend mentioning it in table 1 as a footnote. I assume all the data in table 1 should be collected from 78 patients (eyes).

Answer: This sentence was removed to avoid confusion. We have included all patients in the table and follow up analysis. When we excluded the 4 patients from as trial in the data analysis, there was no change in the statistical significance of the results so we decided to include them since there was no benefit of excluding them.

13. I recommend separating the results into several paragraphs with headlines. E.g. Basic characteristics of NAION patients (This should include follow-up), The risk factors in NAION patients, The risk factors in young NAION vs. older NAION, The visual function outcome in young NAION vs. older NAION…

Answer: This was done as suggested by the reviewer.

14. I also recommend having diabetic or nondiabetic patients as subgroups to further analysis (risk factors and visual function).

Answer: We have performed both uni-variable and multivariable logistic regression analysis to determine if ant of the prevalent systemic risk factors (smoking, diabetes, hyperlipidemia) or ocular (small cup-to-disc ratio) had any effect on the final visual outcome and we could not see any. This was mentioned in the last paragraph in the results section but we have elaborated on it more in the revision.

15. "There was no statistically significant difference in the MD of the visual fields between young and older NAION patients neither at baseline nor follow up. " Do you mean "no significant difference …either at baseline or follow-up"?

Answer: Yes. The difference did not reach statistical significance. The sentence was reworded as suggested to avoid confusion.

16. In the first and the second paragraphs of discussion, the "ischemic optic decompression trial" is the same as "In the optic nerve sheath decompression trial (IONDT) ". This should be consistent with "IONDT".

Answer: We have corrected this as suggested and this study was abbreviated as IONDT later throughout the text.

17. The heterogeneity of the follow up period meant the method of recording the final visual outcome was not standardized. In my opinion, the "methods of recording visual outcome" are visual field and acuity test but not follow up period.

Answer: This was changed to "timing of recording the final visual outcome was not standardized".

18. In figure 1(A), ns should be followed by p value even if p > 0.05.

Answer: We have added this as suggested.

19. For table 2, I recommend calculating the p value for comparison of gender (male vs. female).

Answer: This was done and added as suggested.

Decision Letter 1

Yoshiaki Taniyama

19 Jan 2021

PONE-D-20-30757R1

Risk Factors and Visual Outcome of Non-Arteritic Ischemic Optic Neuropathy (NAION): Experience of A Tertiary Center in Kuwait .

PLOS ONE

Dear Dr. Behbehani,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

One of the reviewer wants the authors to correct the manuscript by a native speaker.

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper has bad spelling, grammar, to the point that it is painful to read and it was not reviewed by a native English speaker. The authors must understand that this is being read by a non-specialist audience who will not stop to struggle through their syntax, in addition to the errors they made in their arguments. I STRONGLY recommend that the manuscript should be reviewed by someone whose primary language is English before this is resubmitted! There are some important data here but it is overshadowed by non-scientific issues! There are also problems with both understanding of facts and logic! Please see my other comments in the attached review

Reviewer #2: Thanks for the rapid response and the authors had addressed all the questions.

Only some minor comments:

1. Table 1: The heading on the right column should be" Patients (n=78)". Second row, Age (years, mean± SD). Third row, "Below 50 years (n, %)". Please correct all the others in this table.

2. "+_"should be"±". "<=" should be "≤".

3. Results part 2, revise the subheading: Visual Outcome in Young NAION Versus Older NAION

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

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PLoS One. 2021 Feb 18;16(2):e0247126. doi: 10.1371/journal.pone.0247126.r004

Author response to Decision Letter 1

21 Jan 2021

Answers to reviewer Comments

Reviewer 1:

1) The paper has bad spelling, grammar, to the point that it is painful to read. I STRONGLY recommend that the manuscript should be reviewed by someone whose primary language is English before this is resubmitted!

Answer: The paper was revised extensively again for syntax, grammar and spelling errors and the errors pointed out by the reviewer and other errors found in the text were corrected.

2) Glaucoma is the most common optic neuropathy (it affects 60,000,000 people in the world, vs ~10,000,000 max for NAION, assuming an incidence of 10.2/100,000 for NAION). NAION is the second most common optic neuropathy and the most common cause for sudden optic nerve-related vision loss.

Answer: Agree. We have added the sentence suggested by the reviewer.

3) Put the reference numbers (1); ((2,3) before the period at the end of the sentence.

Answer: This was changed throughout the text.

4) Results: The paragraph describing visual outcome in young vs old NAION is confusing and should be revised (and this should be written: young patients (or individuals) vs old patients (or individuals) with NAION). The last sentence in this paragraph is describing the MEAN final logmar visual acuity for Young individuals with NAION and MEAN final logmar visual acuity for old individuals with NAION.

Answer: This was changed and corrected as suggested by the reviewer.

5) The authors need to clarify their discussion of the effect of improved mean acuity in the young individuals with NAION (paragraph 2). The reason for this is the difference between the number of younger individuals who improve their acuity, vs the MEAN final acuity. There is already a trend for better acuity in young individuals with NAION vs older individuals with NAION (Baseline mean logMAR visual acuity; p value=0.17). Young NAION patients: Old NAION patients:

Visual acuity improved in 21.9% (n=7), Visual acuity improved in 39% (n=18)

Stable in 56.3% (n=18) Stable in 33.6% (n=15)

Worsened in 21.9% (n=7) Worsened in 28.3% (n=13)

That the ULTIMATE MEAN visual acuity in the younger age group is better does not mean that the outcome for any younger individual is more favorable, since fewer younger individuals have improvements in their visual acuity. The authors are clearly trying to puzzle this out with their second paragraph, with their inclusion of Sun, Hayreh and IONDT data.

Answer: We thank the reviewer for this comment. I think we were responsible for this confusion since the we have the percentages above was part of overview descriptive statistics and ANY change in visual acuity even single Snellen line or 0.1 logMAR unit was calculated as improvement in visual acuity. This has to led to over-estimation of improvement or worsening in visual acuity and was reflected by having seemingly more improvement in visual acuity in older NAION patients. However, when we re-calculated this based on the criteria of for visual acuity improvement presented in the methods section (improvement of visual acuity of at least 0.3 logMAR unit), we have found that slightly more of young NAION patients actually had improved visual acuity and the majority of patients in both young and older NAION patients was stable. The revised calculation is the following:

LogMAR acuity change Young NAION patients Older NAION patients

Better 11 (34%) 12 (26%)

Stable 17 (53.2%) 25 (54.3%)

Worse 4 (12.5%) 8 (19.3%)

Similarly, when have calculated a change of MD visual field as at least 3 decibel change to qualify for either improvement or worsening in MD, we found the following:

MD visual field change Young NAION patients Older NAION patients

Better 13 (40.6%) 12 (26.3%)

Stable 15 (46.9%) 28 (60.0%)

Worse 4 (12.5%) 6 (13%)

Therefore, despite having a trend for younger NAION patients for a better presenting visual acuity compared to older NAION patients, more of the young NAION patients had an improvement of logMAR visual acuity than older NAION patients from baseline to follow up (34% vs 26%) but this was not statistically significant. Similarly, more of the young NAION patients had improvement of the visual field MD than older NAION patients from baseline to follow up (40.6% vs 26.3%) but this was also not statistically significant. Only when we used a final visual acuity of 20/40 or better as an outcome, young NAION patients reached this outcome significantly more than older NAION patients. Finally, there was a trend towards young NAION patients having a better visual field MD at follow up than older NAION patients (-11.52 vs 14.85, p=0.1).

Therefore, in trying to answer the question posed by the reviewer as to whether young NAION patients have a better final visual acuity because there was a trend towards in them having a better presenting visual acuity, this certainly may one valid hypothesis. However, at least by numbers, young NAION patients also they also were more likely to improve in visual acuity (34% vs 26%) and visual field MD (40.6% vs 26.3%) from baseline to follow up. Therefore, it is quite possible that they there is an element both factors (better presenting visual acuity and higher likelihood of improvement over the course of NAION in younger patients) but our study was not powered enough for this to reach statistical significance. We have added this clarification in the discussion and we have acknowledged this as a limitation of our study. We have updated table 2 to include these comparisons. Finally, we have removed the sentences in the discussion citing the paper Hayreh and the IODNT which we felt they were strictly non-relevant to our findings.

6) Importantly, the authors have made a crucial error in their third paragraph. A cup to disk ratio <0.3 cannot be seen in 61.5% of patients overall when you have 31% of young individual with a c:d <0.3 and 43% of older individuals with a c:d<0.3. The total number of individuals was 78; the total number of individuals with C:D< 0.3 is 30; the percentage of total with C:D<0.3 is 38.4% (30/78).

Answer: We thank the reviewer for this comment. This has unfortunately stemmed from an inadvertent error in Table 2 which we have corrected since the total number of patients in the with c:d ratio <0.3 is 48 as presented in table 1 and numbers table 2 before correction was 10 in young NAION patients and 20 in older NAION patients (total 30). The true number of young NAION patients with c:d <0.3 is 22 of total 32 patients (68.75%) and in older NAION patients it is 26 of total 46 patients (56.5%) . So the total number of patients with c:d <0.3 is (22+26=48) and is 61.5% (48/78) of the total subjects.

Reviewer 2

1. Table 1: The heading on the right column should be" Patients (n=78)". Second row, Age (years, mean± SD). Third row, "Below 50 years (n, %)". Please correct all the others in this table.

Answer: All table headings were revised and corrected as suggested.

2. "+_"should be"±". "<=" should be "≤".

Answer: This was changed as suggested throughout the text.

3. Results part 2, revise the subheading: Visual Outcome in Young NAION Versus Older NAION

Answer: This was changed to "Visual Outcome in Young vs Older NAION Patients".

Attachment

Submitted filename: Answers to reviewer Comments-R2.docx

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Decision Letter 2

Yoshiaki Taniyama

2 Feb 2021

Risk Factors and Visual Outcome of Non-Arteritic Ischemic Optic Neuropathy (NAION): Experience of A Tertiary Center in Kuwait .

PONE-D-20-30757R2

Dear Dr. Behbehani,

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Reviewer #1: Page 19 of the compiled PDF: add the words to 'therefore it is likely that IT IS the cumulative and inter-dependent effects.....

Reviewer #2: Thanks for the authors addressing all the comments. There are still some errors that need to be revised. I hope the whole paper can be polished before accepted.

1. “Non-arteritic ischemic optic neuropathy (NAION) is the second most common optic neuropathy following glaucoma in patients over the age of 50 years most common cause for sudden optic nerve-related vision loss.” This is not a sentence. Please revise it. “Optic neuropathy presenting with sudden vision loss” or “ optic nerve-related acute vision loss” is better than “sudden optic nerve-related vision loss”.

2. In results, “predominantly Middle-Eastern Arabs followed by Indian and Asian backgrounds.” I would recommend giving the exact numbers if it is available.

3. There are still some grammatical errors and the errors of putting space before or after the punctuation. e.g. It is associated with systemic risk factors such as diabetes , hypertension , hyperlipemia and anatomical risk factors mainly crowded anomalous optic disc (disc at risk) or small cup-to-disc ratio (2, 3). Please delete the space after diabetes.

4. Please check “+-” throughout the whole paper.

5. In table 1, “Cup-to-disc ratio , mean± SD”，Space should be added before “±”.

6. “<=” should be “≤”.

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Reviewer #1: No

Reviewer #2: No

Acceptance letter

Yoshiaki Taniyama

3 Feb 2021

PONE-D-20-30757R2

Risk Factors and Visual Outcome of Non-Arteritic Ischemic Optic Neuropathy (NAION): Experience of A Tertiary Center in Kuwait. 

Dear Dr. Behbehani:

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