Prevalence of Optic Disc Drusen in Young Patients With Nonarteritic Anterior Ischemic Optic Neuropathy: A 10-Year Retrospective Study

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Prevalence of Optic Disc Drusen in Young Patients With Nonarteritic Anterior Ischemic Optic Neuropathy: A 10Year Retrospective Study J. Alexander Fraser, MD, Lea L. Rueløkke, MD, Lasse Malmqvist, MD, PhD, Steffen Hamann, MD, PhD Background: Nonarteritic anterior ischemic optic neuropathy (NAION) in young patients (age #50) accounts for a minority of all cases of NAION and is more highly associated with crowding of the optic nerves and bilateral involvement than NAION in older patients. Optic disc drusen (ODD) are likewise associated with crowded optic nerves and are located in the prelaminar optic nerve head where they could contribute to NAION pathogenesis. The purpose of this study was to determine the prevalence of ODD in the eyes of young NAION patients using modern imaging methods and to compare it to the baseline 1.8%–2.0% prevalence of ODD in the general population. Methods: In this retrospective study, all young NAION patients (ages 18–50 years, inclusive) seen in 2 tertiary care neuro-ophthalmology clinics (in London, Canada and Copenhagen, Denmark) in the ten-year interval between April 1, 2009, and March 31, 2019, were identified and their medical charts reviewed. Patients were included in the study if ODD were diagnosed by any method (including ophthalmoscopy, ultrasound [US], fundus autofluorescence [FAF], computed tomography [CT], or any optical coherence tomography [OCT] method), or if ODD were excluded by enhanced-depth imaging OCT (EDI-OCT) using the ODD Studies (ODDS) Consortium protocol. The presence or absence of ODD was recorded for each eye. Results: There were 37 eligible patients (74 eyes). Mean age of NAION onset was 38.5 ± 10.0 years, and 23 patients (62%) were men. Patients had undergone the following methods of ODD detection: ophthalmoscopy (37 patients), EDI-OCT (36 patients), FAF (31 patients), US (9 patients), Department of Clinical Neurological Sciences (Neurology) (JAF), Western University, London, Canada; Department of Ophthalmology (JAF), Western University, London, Canada; and Department of Ophthalmology (LLR, LM, SH), Rigshospitalet, University of Copenhagen, Glostrup, Denmark. The project was supported in part by The Velux Foundations (Grant number: 00018408). The authors report no conflicts of interest. Address correspondence to J. Alexander Fraser, MD, Room B7-104, London Health Sciences Centre, University Hospital, Department of Clinical Neurological Sciences and Department of Ophthalmology, 339 Windermere Road, London, ON N6A 5A5, Canada; E-mail: Alex. [e-mail] 200 and CT orbits (8 patients). We found a prevalence of ODD of 56.7% in NAION–affected patients and 53.3% in NAION– affected eyes. Only 35.9% of ODD were visible on ophthalmoscopy. Twenty of 21 ODD patients (95.2%) had bilateral ODD. Age of onset and sex did not differ significantly between the ODD-positive group and the ODD-negative group. EDI-OCT outperformed any combination of ophthalmoscopy, US, FAF, and CT at detecting ODD. Conclusion: ODD were found with much higher prevalence in young patients with NAION than in the general population and were usually bilateral and buried. ODD may contribute to NAION pathogenesis by exacerbating an underlying compartment syndrome in the crowded “disc at risk.” EDIOCT may be the best imaging modality for ODD detection in future studies. Journal of Neuro-Ophthalmology 2021;41:200–205 doi: 10.1097/WNO.0000000000000974 © 2020 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy encountered in neuro-ophthalmic practice. It most often occurs in patients older than age 50 and has an annual incidence of 2.3–10.2 per 100,000 (1,2). Recognized vascular risk factors for NAION include hypertension, diabetes, dyslipidemia, and smoking (3); however, structural risk factors also play a role, and one necessary precondition for NAION seems to be a small and crowded “disc at risk” (4). In the leading theory of NAION pathogenesis, optic nerve head crowding sets the stage for a compartment syndrome to take hold within the inflexible confines of the lamina cribrosa and small scleral canal. When an inciting event (ischemic or otherwise) produces localized edema in the prelaminar optic nerve, edematous tissue has no room to expand harmlessly; it instead compresses the adjacent microcirculation, causing further ischemia, and a vicious cycle ensues (3,5,6). The prelaminar optic nerve is also a region that may contain optic disc drusen (ODD)—rigid hyaline deposits Fraser et al: J Neuro-Ophthalmol 2021; 41: 200-205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution comprised mainly of calcium phosphate (7,8). Although ODD are visible ophthalmoscopically in 0.2%–0.3% of the general population (9,10), many more individuals have invisible “buried” ODD, with an overall prevalence of ODD in enucleated and cadaveric histopathologic specimens of 1.8%–2.0% (11,12). The ophthalmoscope is therefore an extremely insensitive tool for the detection of ODD. Buried ODD can be detected in vivo by ultrasound (US), fundus autofluorescence (FAF), or computed tomography (CT) of the orbits, but enhanced-depth imaging optical coherence tomography (EDI-OCT) appears to surpass these modalities detecting both visible and buried ODD (13–17). EDI-OCT has exquisite spatial resolution, and its ODD detection rates are on par with published histopathological prevalences (18). NAION does not affect young patients as often as older patients, although previous work has shown that patients younger than 50 years may account for between 7.5% and 23% of cases of NAION (1,5,19). When compared with their older compatriots, young NAION patients seem to have many of the same associated vascular risk factors (5,19), but their NAION is more strongly associated with optic disc crowding (5). Young NAION patients are also more at risk of fellow eye involvement than older NAION patients (5). The aim of this study was to evaluate the prevalence of ODD in young NAION patients (age #50 years) in the modern era of EDI-OCT and to compare it to published prevalences of ODD in the general population, to see whether young NAION patients are disproportionately likely to have ODD in their affected eyes. METHODS A retrospective chart review was conducted of patients seen in the neuro-ophthalmology clinics of 2 tertiary care centers (Western University and the University of Copenhagen), over the 10-year period between April 1, 2009, and March 31, 2019. Patients were included in the study if: (A) they had been diagnosed by a neuro-ophthalmologist with NAION in at least one eye (based on the clinical criteria of monocular acute visual loss, relative afferent pupillary defect (if unilateral), unilateral optic disc edema observed in the affected eye during the acute phase, corresponding nerve fiber bundle pattern of visual field loss, and absence of significant pain or pain with eye movements; in patients diagnosed outside the acute phase, a normal brain MRI with lack of optic nerve enhancement plus the presence of a crowded optic disc in the fellow eye or subsequent development of segmental optic disc pallor (20) were accepted in lieu of optic disc edema); Fraser et al: J Neuro-Ophthalmol 2021; 41: 200-205 (B) were “young” (aged 18–50 years, inclusive) at the time of their event; and (C) satisfied at least one of the following 2 criteria: (i) had a diagnosis of ODD established by ophthalmoscopy, US, FAF, CT, or any OCT method (16,17,21); or (ii) had ODD excluded by EDI-OCT of the optic nerve obtained as per the ODDS Consortium protocol (21). Criterion (i) ensured that any accepted imaging modality for ODD would suffice to diagnose ODD; criterion (ii) ensured that only the most sensitive imaging modality for ODD could be used to rule out ODD (13,14,21). ODD were diagnosed on EDI-OCT by their characteristic morphology, including a hyporeflective core with hyperreflective margins, and a location anterior to the lamina cribrosa according to accepted criteria (21) (example depicted in Fig. 1C). Patients were excluded from the study if they had optic nerve or retinal disease unrelated to NAION (other than ODD) or if an alternative diagnosis to NAION such as optic neuritis or retinal/macular disease was more likely. The following data were collected for each patient included in the study: age at onset of NAION, sex, date of first visit, eye(s) affected by NAION, presence/absence of disc edema acutely, and presence/absence of ODD in each eye on ophthalmoscopy, EDI-OCT, US, FAF, or CT orbits. The primary variable of interest for this study was the presence/absence of ODD in the NAION–affected eye. This study was approved by the Western University Research Ethics Board, the Scientific Ethics Committee of the Capital Region of Denmark, and the Danish Data Protection Agency. Statistical tests were two-tailed, and significance was set at 0.05. The Mann–Whitney U test was used for nonnormal continuous variable comparisons; the Pearson chi-square test with the Fisher exact test was used for categorical variable comparisons. RESULTS In keeping with its relative epidemiologic rarity, the diagnosis of NAION in young patients was not made commonly, but at least one such patient was diagnosed with NAION in most years, with a median of 3 per year (range 0–9 patients per year) across 2 busy neuro-ophthalmology practices. A total of 37 patients met study criteria, and all had undergone detailed ophthalmoscopic examinations with data available for all 74 eyes. The patients had a mean (±SD) age of NAION onset of 38.5 years (±10.0 years). Twenty-three (62%) were men. Thirty-four (91.9%) had optic disc edema observed during the acute phase. Forty-five 201 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Appearance of buried ODD in the right eye of a 26-year-old woman following NAION: (A) Fundus photograph showing a crowded and cupless optic disc with subtle inferior/nasal segmental pallor and no visible ODD; (B) FAF showing a brightly fluorescing buried ODD in the nasal optic disc (arrow); (C) EDI-OCT at the level of the cross-section shown in Panels A and B (lines) showing a deeply buried ODD (arrow) below the Bruch’s membrane opening. The ODD appears on EDI-OCT as a mass with a hyporeflective signal-poor core, hyperreflective margins, and adjacent horizontal hyperreflective bands along the posterior margins (13,17,21). ODD, optic disc drusen; NAION, nonarteritic anterior ischemic optic neuropathy; FAF, fundus autofluorescence; EDI-OCT, enhanced-depth imaging optical coherence tomography. of the 74 eyes included in this study had NAION. Bilateral sequential NAION had occurred in 8 (22%) patients. Among the 29 patients with unilateral NAION, the left eye was affected by NAION in 13 (45%) and the right eye was affected in 16 (55%). reasoned that this ODD was unlikely to have contributed in a direct pathophysiological way to the development of NAION in the opposite eye, and therefore, this patient was counted as an ODD-negative patient for the purposes of this study. Imaging Modalities Detection Rates of ODD by Various Modalities The imaging modalities that were undertaken for each patient depended on practice patterns at the time of diagnosis or during their follow-up, and not all patients had undergone all possible imaging modalities; however, 36 patients had, at some point, undergone imaging with EDIOCT. Thirty-one patients had also undergone FAF. Nine patients had undergone an US. Eight patients had undergone a CT orbits. Only one patient, with definite bilateral superficial ODD evident on ophthalmoscopy, had not undergone EDI-OCT (or other ocular imaging) to characterize the ODD further. ODD were detected by different modalities at different rates, as shown in Table 2. The modalities, in descending order of ability to detect ODD in the eye of a young NAION patient, were EDI-OCT, CT orbits, US, FAF, and ophthalmoscopy (few patients underwent US or CT, however). EDI-OCT detected more ODD than were detected by any combination of ophthalmoscopy, FAF, US, and CT. Conversely, EDI-OCT missed only one ODD detected by these modalities (instead detecting horizontal hyperreflective bands, a possible ODD precursor (18)). The sensitivity and specificity of each modality, when compared with EDI-OCT as the reference standard, are shown in Table 3. Prevalence of ODD The diagnosis of ODD was established by ophthalmoscopic examination or by one or more imaging modalities in 24 of 45 NAION–affected eyes (and in 21 of 37 NAION– affected patients), giving an ODD prevalence of 53.3% in NAION–affected eyes (and 56.7% in NAION–affected patients). There were no statistically significant differences in the percentage of men or in the mean age of NAION onset between the group of patients with ODD and the group without (Table 1). Laterality of ODD Out of all 21 patients with ODD, only 1 patient (4.8%) had unilateral ODD (in the NAION–affected eye). Twenty patients (95.2%) had bilateral ODD, of whom 4 patients (20.0%) also had bilateral NAION. One study patient had a single, small, deeply buried ODD detected on EDI-OCT in the eye contralateral to the NAION–affected eye. It was 202 Prevalence of Optic Disc Edema During Testing Seven of the 37 patients in this study (19%) were investigated for ODD during the acute phase of NAION, before acute optic disc edema had subsided. Despite the presence of optic disc edema, a theoretical confounder of optical imaging, EDI-OCT detected, or excluded ODD in excellent concordance with the other imaging modalities in these patients (with agreement in 13 of 14 eyes). Four of these 7 patients had bilateral ODD on EDI-OCT, all confirmed by at least one additional modality; 2 of these 7 patients had no ODD on EDI-OCT in either eye, confirmed by at least one additional modality. The one exception was a patient who had a unilateral buried ODD on EDI-OCT, but bilateral ODD on CT orbits. This patient, also discussed in the paragraph above, underwent EDI-OCT 24 days after symptom onset, when the disc Fraser et al: J Neuro-Ophthalmol 2021; 41: 200-205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Characteristics of young NAION patients with and without ODD Patients With ODD (N = 21) Patients Without ODD (N = 16) P 11 (52%) 36.2 12 (75%) 41.4 0.167 0.114 Male sex, number (%) Mean age at onset, years NAION, nonarteritic anterior ischemic optic neuropathy; ODD, optic disc drusen. edema had almost completely resolved; therefore, it is unlikely that confounding optical effects of optic disc edema played a significant role in EDI-OCT’s nondetection of a corresponding ODD. DISCUSSION The prevalence of ODD in young NAION patients in our study was 56.7%—considerably higher than the 1.8%– 2.2% prevalence of ODD in the general population (1,10,18). The prevalence of ODD in NAION–affected eyes in young patients was 53.3%. Our prevalences suggest a strong association between ODD and NAION in young patients, and increase the likelihood that ODD contribute to the pathogenesis of NAION, at least in patients #50 years of age. The majority of ODD detected in our study (64.1% of ODD eyes) were buried (Fig. 1), an observation meriting 2 comments. First, the relative ophthalmoscopic invisibility of these ODD may explain why a strong association between NAION and ODD has gone unrecognized for so long. A tentative association between NAION and ODD had been surmised based on several published case reports of their coexistence (22–25), and in one study of young NAION patients, the observed prevalence of ophthalmoscopydetected ODD was significantly higher than in the general population—but still only 6% (19). Only in the era of EDIOCT, with its ability to generate detailed images of the deep optic nerve head in vivo, can buried ODD (i.e., the majority of all ODD) be detected and accurately characterized. Second, the buried nature of most ODD may be relevant pathophysiologically, as deeply situated ODD are well-positioned to aggravate the vicious cycle of ischemiaedema-ischemia that is believed to underlie NAION pathogenesis (3,20,22,26–28). ODD are situated in the region of the optic nerve where the ischemia and edema occur in NAION—anterior to the lamina cribrosa—and also tend to be found in crowded optic discs with small scleral canals, the very eyes most vulnerable to NAION (29–31). Indeed, one recent study found that vascular comorbidities were rare among young NAION patients with ODD, suggesting that ODD may be an independent risk factor for NAION (32). Deep ODD increase the crowding of axons near the lamina cribrosa by themselves occupying space, exacerbating any incipient compartment syndrome that takes hold. Theoretically, ODD could even provoke NAION by compressing the densely packed adjacent neurons or microvasculature, triggering inflammatory edema or infarction, and initiating the ischemic cascade. Such compression could occur as a result of the ODD growing in size over time (18), migrating relative to the surrounding tissue (e.g., as overlying optic nerve fibers atrophy), or through the repetitive microtrauma of prelaminar vessels or nerve fibers bending over a rigid ODD with normal eye movements (28). In our study of young NAION patients with ODD, we found that 95.2% had ODD bilaterally. This finding has precedent: in previous studies of NAION patients (of all ages), 54%–80% of patients with ODD were found to have bilateral ODD (20,27). Compared with those reports, our higher figure for bilateral ODD likely reflects the more sensitive imaging modalities we used to detect ODD, including EDI-OCT (14). Most of our patients (80%) with bilateral ODD still only had their NAION in one eye, raising the question: what relevance could ODD in an TABLE 2. Detection rate of ODD in young NAION patients, by modality Modality # Eyes With ODD Detected # Eyes Assessed % Eyes With ODD Detected # Patients With ODD Detected # Patients Assessed % Patients With ODD Detected EDI-OCT CT orbits US FAF Ophth. 39 8 8 24 16 72 16 18 62 74 54.2 50 44.4 38.7 21.6 21 4 4 15 10 36 8 9 31 37 58.3 50 44.4 48.3 27.0 CT, computed tomography; EDI-OCT, enhanced-depth imaging optical coherence tomography; FAF, fundus autofluorescence; NAION, nonarteritic anterior ischemic optic neuropathy; ODD, optic disc drusen; Ophth., ophthalmoscopy; US, ultrasound. Fraser et al: J Neuro-Ophthalmol 2021; 41: 200-205 203 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Sensitivity and specificity of each modality for the detection of ODD, using EDI-OCT as the reference standard Detection in Eyes With ODD Modality FAF US CT Ophth. Detection in Patients With ODD Sensitivity Specificity # ODD Eyes Used in Calculation Sensitivity Specificity # ODD Patients Used in Calculation 71% 53% 100% 36% 100% 100% 89% 100% 62 17 16 72 83% 50% 100% 43% 100% 100% 80% 100% 31 9 8 36 CT, computed tomography; EDI-OCT, enhanced-depth imaging optical coherence tomography; FAF, fundus autofluorescence; ODD, optic disc drusen; Ophth., ophthalmoscopy; US, ultrasound. unaffected contralateral fellow eye have to ipsilateral NAION pathogenesis? We suspect the bilateral presence of ODD instead serves as a general marker of increased ODD burden in each eye, including the affected eye. For example, a patient with bilateral ODD could be more likely to have larger or faster-growing ODD in each eye, which consequently increase the risk of triggering or exacerbating the pathogenic NAION cascade in one eye. We did not characterize the size, location, or morphology of ODD in our study, so further work is needed to address this possibility. Consistent with many other studies (13–15), we found that EDI-OCT outperformed the other imaging modalities at detecting ODD. Although the detection (or exclusion) of ODD on one modality could conceivably influence the interpretation of an equivocal finding on a subsequent modality, and thereby introduce an element of confirmation bias among the various modalities, the effect of any such bias would be toward a homogeneity of test interpretations, in which case the superior diagnostic performance of EDIOCT was detected despite this possible confounding effect. EDI-OCT detected more ODD than were detected by any combination of ophthalmoscopy, FAF, US, and CT; furthermore, EDI-OCT only missed one ODD that was detected by these modalities. In that patient, EDI-OCT instead detected isolated horizontal hyperreflective bands (believed to be an ODD precursor) in one eye of a patient with ODD on CT orbits, while the other eye showed ODD on both modalities. We recommend that EDI-OCT be used for ODD detection in future work, especially work in young NAION patient populations. Seven of our 37 patients were evaluated during the acute phase of NAION, but we do not believe this was a significant confounding factor in the interpretation of their ocular imaging. Although optic disc edema in the acute phase of NAION could theoretically decrease the rate of EDI-OCT detection of ODD by thickening and opacifying tissues between the light source and an ODD, confirmatory comparisons with other imaging modalities did not show this to be the case in our study; furthermore, if anything, this effect would have underestimated our 204 detected 56.7% prevalence of ODD in young patients with NAION. Conversely, it is doubtful that acute optic disc edema could have somehow falsely increased the detection rate of ODD in our study, as ODD have a very characteristic morphology on EDI-OCT (Fig. 1C) (21), and we took special pains to distinguish between PHOMS (peripapillary hyperreflective ovoid mass-like structures, a mimic of ODD common in patients with optic disc edema) and true ODD (17,21). Moreover, in our study, all ODD that were detected on EDI-OCT in the setting of acute optic disc edema were confirmed by another imaging modality. Our study has several limitations. Because our study was retrospective in design, we were limited to data that had been obtained during routine clinical care, and this was not always obtained systematically, particularly over the long, ten-year, timeframe of our study. For example, not every patient underwent US, FAF, and CT. Fortunately, all ODD-negative patients and almost all ODD-positive patients had EDI-OCT, which seems to be emerging as the new gold standard for diagnosing ODD (13–15). It is therefore unlikely that we would have missed ODD in patients who did not undergo the full battery of tests. Although the diagnosis of NAION was established in each patient by an experienced neuro-ophthalmologist, it was done so for the purposes of clinical care and without anticipating future retrospective research. Therefore, strict standardized research criteria for NAION were not used at the time of diagnosis. For example, 3 patients (8.1%) did not have optic disc edema observed during the acute phase, but were nevertheless diagnosed with NAION based on the alternative features described in our inclusion criterion (A). This approach was sufficient, on a pragmatic level, to exclude the main mimics (e.g., optic neuritis) and to ensure confidence in our diagnosis of NAION. Inflammatory markers (ESR and CRP) were not routinely obtained in all patients, but the likelihood of giant cell arteritis in this population of patients aged #50 years is negligibly small. The patients in our study were drawn from only 2 centers, and therefore, our study could be subject to biases Fraser et al: J Neuro-Ophthalmol 2021; 41: 200-205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution in referral bases, practice patterns, and patient populations. For example, the prevalence of ODD is known to vary by race (30). An international multicenter study, undertaken over a shorter time interval (thereby entailing a more standardized “routine clinical practice”) and including a broader demographic base, may be the best way to confirm our preliminary results and improve generalizability. In summary, our results show a much higher prevalence of ODD, especially buried ODD, in young NAION patients than previously reported. Whether patients over age 50 with NAION—so-called “garden-variety NAION” (27)—also have an increased prevalence of ODD remains unknown. If confirmed by larger studies, ideally ones using EDI-OCT as the standard to detect/exclude ODD, our results suggest that ODD may be a major risk factor for NAION in the young, may play a role in its pathogenesis, and may increase the odds of bilateral disease. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. A. Fraser, L. L. Rueløkke, L. Malmqvist, and S. Hamann; b. Acquisition of data: J. A. Fraser, L. L. Rueløkke, L. 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