Should All Patients With Nonarteritic Anterior Ischemic Optic Neuropathy Receive a Sleep Study?

Numerous studies have demonstrated an association between nonarteritic anterior ischemic optic neuropathy (NAION) and obstructive sleep apnea (OSA), but it is unclear whether OSA is causative or coincidental. It also remains uncertain whether a sleep study should be performed routinely in patients with NAION. Two experts debate this topic.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Should All Patients With Nonarteritic Anterior Ischemic Optic Neuropathy Receive a Sleep Study? Clare L. Fraser, MD, Thomas R. Hedges, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Numerous studies have demonstrated an association between nonarteritic anterior ischemic optic neuropathy (NAION) and obstructive sleep apnea (OSA), but it is unclear whether OSA is causative or coincidental. It also remains uncertain whether a sleep study should be performed routinely in patients with NAION. Two experts debate this topic. Pro: Thomas R. Hedges, MD A possible association between NAION and OSA was brought to my attention in 2001 by a nephrologist. He had been referred because of bilateral NAION and told me that he believed it was due to OSA. My fellow at the time, Emily Karam, and I started asking patients if they snored. The patients tended to deny it, but their spouses confirmed it. We asked if they stopped breathing, and again, it was denied and then confirmed by spouses. We presented our results at the International Neuro-ophthalmology Society meeting in Dublin in 1999. At the meeting, Daniel Mojon, MD, told me that he also was looking into this possible association. Dan and I published the results of sleep tests in our patients with NAION in the Archives of Ophthalmology in 2002. We found that 12 of the 17 patients with NAION had OSA, whereas 3 of the 17 control subjects had OSA (1). The possible effects of OSA on the eye had been previously described, including an article by Purvin et al on possible papilledema and OSA (2). This was commented on by Lee in a letter to the editor (3). Indeed, Dr. Mojon himself had written about a possible association of OSA with glaucoma (4). This received little attention from neuroophthalmologists, except for a report that suggested that there was no association (5) until 2006, when Palombi et al published a study showing that OSA was more prevalent in their subject group than known risk factors of hypertension, diabetes, hyperlipidemia, and carotid atheromatous disease (6). Li et al subsequently showed that a group of patients Medicine and Health (CLF), University of Sydney, Sydney, Australia; Department of Ophthalmology (TRH), Tufts University, Boston, Massachusetts; Blanton Eye Institute (AGL), Houston, Texas; and Department of Ophthalmology of Visual Sciences (GPVS), Washington University in St. Louis, St. Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, John Hardesty Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110; E-mail: [e-mail] 542 with NAION were 2.62 times more likely to have OSA (7), compared with controls. Stein et al showed that if patients having OSA were not treated with continuous positive airway pressure (CPAP), there was a 16% increase in hazard of experiencing NAION (8). In 2013, Arda et al reported a higher prevalence of OSA in patients with NAION vs controls with similar risk factors (9), and Bilgin et al found OSA in 15 of the 27 patients with NAION vs 6 of the 27 in controls (10). This evidence was reviewed by Archer et al in 2013 (11). In 2015, Bandi et al found OSA in 18 of the 19 patients with NAION vs 13 of the 31 controls (12), whereas Aptel et al found that patients with OSA who were noncompliant with CPAP had an increased risk of second eye involvement (13), and Huon et al reported an association between OSA, glaucoma, AION, retinal vein occlusion, central serous retinopathy, and floppy eye lids (14). Wu et al showed that subjects with OSA had a more than 6-fold risk of NAION (15). In 2019, Sun et al and Yang et al showed a strong association between NAION and OSA (16,17). In addition, other researchers have shown that the risk of stroke, hypertension, and atrial fibrillation is greater in individuals with OSA (18). Furthermore, CPAP use can reduce a risk of cardiovascular disease (19). However, so far, there has been no compelling evidence that treatment of OSA with CPAP or surgery reduces the risk of NAION. There may be an increased risk of second eye involvement in patients with NAION who are nonadherent to CPAP treatment (13), but treatment of OSA has not yet been shown to reduce the 15% risk of second eye involvement in NAION (20). Nonetheless, because there is the possibility that treating OSA might be beneficial, I advise all of my patients with NAION to be tested for OSA. It is easy and relatively inexpensive. If one has OSA and is treated, especially with CPAP, they feel better, their partners sleep better, and they are much less likely to fall asleep while operating a motor vehicle (21). Fraser et al: J Neuro-Ophthalmol 2021; 41: 542-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Con: Clare L. Fraser, MD OSA is a breathing disorder that occurs during sleep, characterized by repetitive episodes of partial or complete collapse of the pharynx. The intermittent airway obstruction results in concurrent hypoxia, sympathetic activation, and arterial hypertension (22). It is these changes that are believed to underlie the comorbidities associated with OSA. American cohort studies, using a definition of OSA as being more than 5 apnea–hypopnea events per hour, estimated the prevalence to be between 17% and 31% for men and 6.5%–9% for women (23,24). These increasing prevalence numbers may be related to the increased sensitivity of newer recording equipment and increasing obesity, but even so, these numbers suggest a worrying public health issue (25). It is therefore important to consider how this condition might affect our roles as neuro-ophthalmologists when assessing patients. What is the evidence against a link between nonarteritic anterior ischemic optic neuropathy and obstructive sleep apnea? Although the data are convincing about the link between severe OSA and some causes of mortality and morbidity, there has been some inconsistency, particularly for those with mild-to-moderate OSA. A case–control study of 20 patients with diagnosed NAION were matched to 20 control subjects using age, sex, body mass index (BMI), smoking, alcohol consumption, diabetes, and hypertension (9). All patients and controls underwent formal overnight diagnostic polysomnography (dPSG), with an apnea–hypopnea index (AHI) .5 used as the cut-off to diagnose OSA. Of those with NAION, 85% were diagnosed with OSA, compared with 65% of the control group (P = 0.144). The authors concluded that OSA is not a risk factor for NAION in itself. In a large review of patients in an American-managed care network, again OSA was not identified as an independent risk factor for NAION (26). In this study, beneficiaries aged between 45 and 75 years who had monitoring for over 2 years between 2001 and 2014 were assessed to identify those with newly diagnosed NAION. The diagnosis was based on International Classification of Diseases, ninth revision (ICD-9); all were under ophthalmic surveillance and had more than one confirmatory ICD-9 code for NAION in follow-up. Of nearly 1.4 million people, 977 (0.1%) developed NAION. Systemic diseases associated with NAION included hypertension (HR = 1.62), hypercoagulable states (HR = 2.46), and diabetic patients with end-organ damage (HR = 1.27). Risk was also seen to increase with each additional year of age (HR = 1.02) but Fraser et al: J Neuro-Ophthalmol 2021; 41: 542-546 decreased with female sex (HR = 0.64) and African ancestry (HR = 0.91). OSA was diagnosed in 12.9% of patients without NAION and 19.4% of those who did develop NAION. This difference was significant (P , 0.001); however, once multivariable cox regression modeling was used to generate the hazard ratios, this statistical significance did not remain. A review of a Taiwanese database between 1996 and 2013 matched 8,488 patients with newly diagnosed OSA to 33,952 non-OSA controls (16). The patients’ data were followed until death or the last day of the study and assessed for a new diagnosis of NAION. In the age ranges 40–69 years, there was no increased hazard of developing NAION in patients with OSA, P . 0.5 in all decade brackets (40– 49, 50–59, and 60–69). This trend did not change with either multivariate or univariate regression analysis. The authors concede that in the years 40–69, which accounted for a large portion of the patients with NAION, that there was no difference in the rates and risk of NAION between the OSA group and the control group. How much do overnight sleep studies actually cost? The gold-standard measure of the AHI to diagnose OSA is made with an overnight dPSG. The health care burden of administering such sleep studies is substantial. The tests require a dedicated facility for overnight stays with one sleep technician per 2 patients (on average) and dedicated sleep physicians to interpret the results. In 2014, 845,569 sleep studies were completed for Medicare beneficiaries for a total of $189 million USD (26). This implies a cost of $223 per sleep study. However, Clear Health Costs reviewed the costs to the patient or insurer for dPSG and found a basic study costs $600–900 for a self-pay patient in some areas, but costs could range up to $6,177 per study, with interpretation and doctors’ fees being an additional charge (27). Based on various estimates the incidence of NAION is 2.3 to 10.2 per 10,000 in a population older than 50 years in the United States (28). Thirty-four percent of the US population (total 331 million in 2020) is aged 50 and older that equates to somewhere between 2,590 and 11,500 new NAION cases in that age group per year. Using these numbers and the costs listed above, it would cost up to $70.8 million USD per year to test all new patients with NAION. This figure does not even include those younger than 50 years. Are there any alternative diagnostic tools? Questionnaires including STOP-Bang (SBQ), the Epworth Sleepiness Scale (ESS), and the Berlin Questionnaire (BQ) are 543 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point used for OSA screening. A recent study compared their use and concluded that compared with the BQ and ESS, the SBQ is a more accurate tool for detecting mild, moderate, and severe OSA (29,30). The STOP-Bang questionnaire is an 8-item selfreport questionnaire designed to screen for OSA and was originally validated in preoperative surgical patients. The STOP items are snoring, daytime tiredness, observed apnea, and high blood pressure. The BANG items are BMI .35 kg/m2, age .50 years, neck circumference .40 cm, and male sex. In a large meta-analysis of sleep questionnaires, 17 studies, involving 9,000 patients, were analyzed (30). The sensitivity of SBQ was 90%, 94%, and 96% to detect mild, moderate, and severe OSA, confirming the high performance of SBQ in sleep clinic and surgical populations. Several portable devices exist to perform “home polysomnography” with reduced monetary costs (31). Studies show agreement between portable monitors and dPSG when AHI .5 is used to define OSA, with a sensitivity of 95%, a specificity of 69%, and a positive predictive value of 89% (32). The American Association of Sleep Medicine guidelines state that home sleep apnea testing (HSAT) is an acceptable approach in otherwise “healthy patients” with a high pretest probability of moderate-tosevere OSA (33). However, HSAT should not be used for general screening of asymptomatic populations. Guidelines for the use of HSAT in practice are available (34). Unfortunately, the accuracy of smartphone applications within a clinical population is low and are not recommended (35). Does continuous positive airway pressure treatment alter outcomes? Interestingly, a review of obesity, OSA, and cardiovascular events (36) found that although the gold-standard treatment for moderate-to-severe OSA is CPAP, significant reductions in major cardiovascular events were not observed in clinical trials. However, they did show that weight control was essential to decrease the risk of cardiovascular events and mortality. Furthermore, in a randomized controlled trial of CPAP alone vs CPAP plus 6-month intensive Mediterranean diet and lifestyle intervention, it was found that AHI decreased by 0.8 events/hour in the CPAP group compared with 24 events/hour in the CPAP + lifestyle intervention group (37). So, should all patients with nonarteritic anterior ischemic optic neuropathy receive a sleep study? Certainly, an argument can be made for why not all patients with NAION should undergo a formal overnight dPSG. First, there are a few studies that suggest the link between OSA and NAION is more a consequence of associated increased age, weight, hypertension, and other risk factors, particularly in the 40–69 age range. Second, the monetary cost of formal sleep studies is not insignificant, and therefore cheaper alternatives or screening tools could be considered before ordering the expensive “gold-standard” test. Finally, perhaps we should just be getting our patients to lose weight rather than treating them with CPAP, and if that is true, we do not need to even assess them for OSA. Rebuttal: Thomas R. Hedges, MD I appreciate Dr. C. L. Fraser’s comments. I myself have had a sleep study, and I found it relatively convenient. An informal poll of my patients indicates to me that CPAP can make a very significant difference in many patient’s lives. Rebuttal: Clare L. Fraser, MD Dr. T. R. Hedges highlights the increasingly convincing evidence for a link between OSA and NAION, as well as many other causes of morbidity and mortality (including falling asleep at the wheel of a car!). I agree that this evidence outweighs the studies I mentioned for the CON side of this discussion. It seems that we both agree that all patients with NAION should have a thorough sleep history taken, not just from the patient but also from the spouse. I disagree that overnight sleep studies are “easy and relatively inexpensive.” Patients need to attend a dedicated sleep center early in the evening, be hooked up to a plethora of wires, and then try to fall asleep 544 on a strange bed with cameras pointed at them. Often, the patient is woken up at 2 AM for a trial of CPAP and then woken again, unhooked, and sent home before 8 AM. As I have discussed, the cost break-down is not insubstantial either. With the increasing use of telehealth, perhaps there is a middle ground. Alternative screening processes with the STOP-Bang, ESS, or BQ, along with portable “home polysomnography” may be a good option, with formal dPSG reserved for those cases where the result is still uncertain. We need to work closely with our sleep physician colleagues to create a sensible referral pathway. Fraser et al: J Neuro-Ophthalmol 2021; 41: 542-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Conclusions: Andrew G. Lee, MD and Gregory P. Van Stavern, MD Although there is still debate about whether a sleep study is indicated for all patients with NAION, it is reasonable to recommend that all patients presenting with NAION should be screened for common symptoms of OSA. The decision to proceed with a sleep study should be based on the patient’s associated risk factors, body habitus, and the previous probability of the disease. 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