Authors: Ana Banc (1Department of Ophthalmology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania), George Muntean (2Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA), Valérie Biousse (2Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 3Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA), Mark J. Kupersmith (4Departments of Neurology and Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA), Nancy J. Newman (2Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 3Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; 5Department of Neurological Surgery, Emory University School of Medicine, Atlanta, GA, USA), Beau B. Bruce (2Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; 3Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; 6Department of Epidemiology, Rollins School of Public Health, Emory, Atlanta, GA, USA)
Categories: Article, non-arteritic anterior ischemic optic neuropathy, race, African American or Black, White
Source: American journal of ophthalmology
Authors: Ana Banc, George Muntean, Valérie Biousse, Mark J. Kupersmith, Nancy J. Newman, Beau B. Bruce
Prior studies have shown that non-arteritic anterior ischemic optic neuropathy (NAION) is uncommon in persons of Black race compared to those of White race, but the reasons behind this discrepancy remain unknown. Our goal was to analyze the systemic and ocular features of Black NAION patients compared to White patients.
Retrospective cross-sectional study
Self-reported race was collected from all NAION patients seen between 2014–2022 from a single US neuro-ophthalmology service. All Black NAION patients and a randomly selected sample of White NAION patients were included. We collected information on hypertension, hyperlipidemia, diabetes mellitus, hypothyroidism, obesity, ischemic heart disease, atrial fibrillation, pacemaker insertion, chronic kidney disease, dialysis, anemia, obstructive sleep apnea, deep vein thrombosis, stroke, use of phosphodiesterase inhibitors, and smoking status. We reviewed color fundus photographs and optic nerve OCT images to assess cup-to-disc ratio and document the presence of optic disc drusen. Counterfactual random forest was used to estimate associations for each characteristic of interest by race controlling for the other exposures.
We included 32 Black NAION patients (mean age 57 ± 11 years, 38% men) and 69 of 432 White patients (mean age 57 ± 15 years, 59% men). Time between NAION onset and neuro-ophthalmic examination was significantly longer in Black patients (1.5 to <3 OR 4.07, P = 0.03; 6 to <12 OR 6.05, P = 0.007). Chronic kidney disease (OR 7.53, P = 0.003) and hemodialysis (OR 13.69, P = 0.02) were significantly more frequent in Black patients. No significant differences in cup-to-disc ratio were present (0.15 to <0.25: OR 2.83, P = 0.09; 0.25 to <0.35: OR 0.56, P = 0.46; ≥0.35: OR 0.66, P = 0.44).
Referral delay occurs in Black patients with NAION, likely due to its relative rarity and concern for alternate diagnoses. Black NAION patients were substantially more likely to have chronic kidney disease and be on dialysis than White patients. Despite known racial differences in cup-to-disc ratio, we found no difference between Black and White NAION patients, suggesting that the underlying proposed compartment mechanism is the same between races.
Non-arteritic anterior ischemic optic neuropathy (NAION) is a devastating cause of visual loss with striking racial the vast majority of NAION patients are White, with only approximately 5% or less of patients being African American or Black.^1^ The exact mechanism of NAION is not fully elucidated, but it has been suggested that racial disparities in NAION may be explained by racial differences in optic nerve head (ONH) topography, with Black individuals on average having larger cup-to-disc ratios compared with people of White race.^2–4^ There is a suggestion that Black race individuals have less ONH crowding, example of which is the rare occurrence of optic disc drusen among Black patients.^5^ However, a crowded ONH is not the only suggested risk factor for NAION. Purported systemic risk factors include, but are not limited to, hypertension, hyperlipidemia, diabetes mellitus, and obstructive sleep apnea.^6–8^
Although racial differences in optic disc appearance have been previously described,^2–4^ limited information on systemic and other ophthalmic features exists about individuals of Black race who had NAION. We explored whether the clinical characteristics of Black and White patients with NAION would differ and provide insight as to why there is a low prevalence of NAION in Black relative to White race populations.
We performed a retrospective cross-sectional study in the neuro-ophthalmology services of Emory University Hospitals in Atlanta, GA. The research adhered to the tenets of the Declaration of Helsinki and was approved by Emory’s Institutional Review Board, which waived the need for patient consent due to the retrospective nature of this study.
All consecutive adult NAION patients (age at onset > 18 years) examined between July 2014 and May 2022 were identified using electronic medical records database search engines and ICD-10 diagnosis codes, all of which were assigned by experienced neuro-ophthalmologists. We collected self-reported race at the time of neuro-ophthalmologic evaluation and included all patients who self-identified as African American or Black and a randomly selected sample of patients who self-identified as White. White patients were selected from those available by generating a reordered list of available patients using the sample function in R 4.3.0 without replacement. Medical records were reviewed to confirm NAION based on history of acute visual loss secondary to an anterior optic neuropathy with documented disc edema at presentation; clinical characteristics and outcomes consistent with NAION; and no evidence of another neurologic or ocular disorder that could explain optic disc edema and visual loss. Patients with non-ischemic etiologies of optic neuropathy, with arteritic anterior ischemic optic neuropathy, or with other causes of visual loss were excluded.
For each patient, we collected basic demographic information, neuro-ophthalmic examination findings at initial visit (including best corrected visual acuity, mean deviation of standard automated perimetry visual field testing, optic disc appearance, presence of optic disc drusen, and cup-to-disc ratio assessed on color fundus photographs and ONH and peripapillary optical coherence tomography images, other ophthalmic comorbidities), data on systemic cardiovascular risk factors (obesity, hypertension, hyperlipidemia, diabetes mellitus, anemia, ischemic heart disease, atrial fibrillation, pacemaker insertion, chronic kidney disease, dialysis, anemia, obstructive sleep apnea, deep vein thrombosis, stroke, tobacco smoking status), chronic obstructive pulmonary disease, cancer, thyroid status, and use of phosphodiesterase-5 inhibitors.
Statistical analysis was performed in R 4.3.0 (R Foundation). Single stochastic random forest imputation was used for missing data. Counterfactual random forest was used to calculate associations for each characteristic of interest by race controlling for the other exposures.^9,10^
We identified 35 Black NAION patients among 481 NAION patients. Three patients were excluded for concurrent glaucoma in at least one eye. Table 1 comprises the demographic and systemic features of each of the 32 Black NAION patients included in the present study. Three patients (9.4%) did not have any systemic risk factors or disorders requiring medication. The most frequently found systemic comorbidities were hypertension (75%), obesity (56%), and hyperlipidemia (53%). In Table 2 we present the ocular features of Black NAION patients. For the 9 Black patients with bilateral sequential disease, the interval between the first and second eye involvement was 5 weeks to 15 years, median 1.75 years (interquartile range 3.25 years); 7 patients (21.8%) had NAION in the fellow eye within 5 years of the first eye onset. Mean cup-to-disc ratio in non-affected eyes was 0.13 ± 0.1, while only one patient had optic disc drusen in both the affected and non-affected eyes.
We randomly selected 70 (from available 432) White NAION patients; one was excluded for coexisting glaucoma. Compared to White NAION patients, Black patients were less frequently men (38% vs. 59%, P = 0.07) in our sample (Table 3). For the 26 White patients with bilateral sequential disease, the interval between the first and second eye involvement was 4 days to 25 years, median 1 year (interquartile range 7.87 years); 11 patients (15.9%) developed NAION in the fellow eye within 5 years of the first eye onset. Mean cup-to-disc ratio in non-affected eyes was 0.18 ± 0.16 (three eyes had optic disc drusen).
We performed the comparison between the two groups first by considering only the non-affected eyes of all patients and second by including exclusively the eyes with history of NAION (Table 4).
Black patients had a longer time between their NAION onset and the neuro-ophthalmic evaluation (median 7 months, interquartile range 15.25 months; P = 0.03; Table 4). The re-assessment of their electronic medical records showed a referral delay to neuro-ophthalmology as a result of incorrect diagnoses as eye care providers considered alternate diagnoses (e.g., “diabetic retinopathy”, “neuroretinitis”, “possible central retinal artery occlusion”, or “papilledema”).
In general, Black and White NAION patients had similar prevalence of systemic clinical features, but Black patients had non-significant higher frequency of cardiovascular risk features such as obesity, hypertension, non-insulin-dependent diabetes mellitus, and ischemic heart disease than White patients. White patients had non-significant higher frequency in anemia, obstructive sleep apnea, and stroke. However, chronic kidney disease (P = 0.003) and hemodialysis (P = 0.02) were significantly more prevalent in Black patients, whereas hypothyroidism (P = 0.02) was more frequent in White patients. There were no differences in ocular features between Black and White NAION patients (Table 4).
Our primary findings were that there was no difference in systemic risk factors and the cup-to-disc ratios in the non-affected eyes of Black and White NAION patients.
The lack of difference in the cup-to-disc ratios contrasts with the known racial differences in cup-to-disc ratios between people of Black and White race reported in studies of the general population.^2–4^ The mean vertical cup-to-disc ratio reported in normal eyes of Black individuals was 0.33 ± 0.22, and 0.27 ± 0.23 in normal eyes of White persons, P = 0.23.^3^ Our results suggest that the pathogenesis of NAION is similar among the two races, with a crowded disc responsible for a potential compartment syndrome that results in NAION. This suggests the low prevalence of NAION among Black persons is most likely explained by their low prevalence of small cup-to-disc ratios.
There was, however, a referral delay to neuro-ophthalmology among Black NAION patients, due to misdiagnoses rather than reduced access to care of these patients. Our previous paper showed that all patients had expedited care regardless of race.^1^ Misdiagnoses could also result in lack of referral to neuro-ophthalmology, potentially leading to an underestimation of the true prevalence of NAION among persons of Black race.
White and Black race NAION patients had different trends for most cardiovascular risk factors. The high prevalence of chronic kidney disease and hemodialysis in our Black NAION patients likely reflects racial differences in chronic kidney disease. According to the National Institute of Diabetes and Digestive and Kidney Diseases, chronic kidney disease is more prevalent in people of Black race, and Black people are nearly 4 times more likely to develop end-stage kidney disease compared to White people.^11^
Similarly, our results regarding the prevalence of hypothyroidism among the two groups likely mirror the racial distribution of the disease. A population-based study conducted in the US,^12^ as well as other subsequent studies,^13^ found the prevalence of hypothyroidism is significantly lower in Black persons compared to White persons.
Given the relatively high number of patients with bilateral NAION, we performed an additional analysis based on NAION eyes instead of at the patient level. Although cup-to-disc ratio can be highly influenced by time since NAION onset -- with loss of cup in the acute edematous phase and progressively larger cup in the chronic phase as atrophy occurs, our analysis of ocular features was controlled for the remaining features, including time between NAION onset and neuro-ophthalmic examination. Nevertheless, no visual acuity or visual field mean deviation differences between Black and White NAION patients were observed, suggesting that the disease course is similar between the two groups. However, due to the retrospective cross-sectional nature of this study, conclusions on the course of the disease are necessarily limited.
Our results are in overall agreement with the recently published clinical features of patients with NAION enrolled in the Quark 207 Treatment Trial, which showed that a small cup-to-disc ratio is the dominant feature associated with NAION, and the prevalence of cardiovascular risk factors in NAION patients does not appear to be greater than in the general population.^14^ Although the Quark 207 Treatment Trial included a large cohort of participants (729 patients with acute unilateral NAION), a comparison between Black and White NAION patients was not feasible due to the enrollment of only one Black patient.^14^ As all participants entered the trial within 14 days of symptom onset,^14^ the delay in NAION diagnosis in Black patients that was identified in our study could explain the underrepresentation of Black patients in the Quark 207 Treatment Trial and in the Ischemic Optic Neuropathy Decompression Trial. Should a treatment become available for NAION, the enrollment in clinical trials of representative sample sizes of patients of all races is essential for the understanding of a drug’s efficacy. Therefore, a timely diagnosis of NAION is of paramount importance.
The limitations of the present study result from the unavailability of certain data due to its retrospective nature. One of the limitations of our research is using clinical ophthalmoscopy and non-stereo pairs of fundus photos to assess the cup-to-disc ratio. To improve our understanding of the racial differences in NAION patients, future studies should more completely evaluate the ONH size and structural features of affected and unaffected eyes in each patient. Another limitation is the insufficient availability of the data on the referral diagnoses of White patients. Future research should compare the rate of misdiagnoses between Black and White NAION patients and estimate its impact on the prevalence of the disease.
In summary, although the Black race population typically has a larger cup-to-disc ratio than the White race population, the majority of Black NAION patients had the expected smaller cup-to-disc ratio, similar to White NAION patients. Referral delay occurs in Black patients with NAION, possibly in part due to its relative rarity leading to alternate diagnoses.