Influence of Patient Age and Presence of Optic Disc Drusen on Fluctuations in Retinal Nerve Fiber Layer Thickness

Background: It is generally believed that optic disc drusen (ODD) change only over long periods of time. Because, in our experience, this does not apply to younger patients, we investigated the natural course of changes of the peripapillary retinal nerve fiber layer (RNFL) in patients with ODD. Methods: In this retrospective study, 40 eyes with and 40 eyes without ODD were examined, both cohorts were equally subdivided into younger subjects (20 years or younger) and older subjects (21 years or older). Three optical coherence tomography (OCT) scans of the peripapillary RNFL that had an interval of at least 1 month were required for each patient to be included in this study. The largest difference in total RNFL thickness (delta RNFL-t) and in RNFL thickness of the most differing sector (delta RNFL max) measured by OCT was compared. Results: The differences in total RNFL thickness and in the most differing RNFL sector in the group of patients with ODD younger than 21 years were significantly larger than in each of the other 3 groups ( P = 0.0001). The other 3 groups did not differ significantly. Conclusions: Patients with ODD younger than 21 years have distinct variations in peripapillary RNFL thickness without evidence of increased intracranial pressure. In the absence of further pathological findings or neurological symptoms, an observational approach seems adequate in these patients.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Influence of Patient Age and Presence of Optic Disc Drusen on Fluctuations in Retinal Nerve Fiber Layer Thickness Felix Tonagel, MD, Helmut Wilhelm, MD, Lydia Stock, MD, Carina Kelbsch, MD Background: It is generally believed that optic disc drusen (ODD) change only over long periods of time. Because, in our experience, this does not apply to younger patients, we investigated the natural course of changes of the peripapillary retinal nerve fiber layer (RNFL) in patients with ODD. Methods: In this retrospective study, 40 eyes with and 40 eyes without ODD were examined, both cohorts were equally subdivided into younger subjects (20 years or younger) and older subjects (21 years or older). Three optical coherence tomography (OCT) scans of the peripapillary RNFL that had an interval of at least 1 month were required for each patient to be included in this study. The largest difference in total RNFL thickness (delta RNFL-t) and in RNFL thickness of the most differing sector (delta RNFL max) measured by OCT was compared. Results: The differences in total RNFL thickness and in the most differing RNFL sector in the group of patients with ODD younger than 21 years were significantly larger than in each of the other 3 groups (P = 0.0001). The other 3 groups did not differ significantly. Conclusions: Patients with ODD younger than 21 years have distinct variations in peripapillary RNFL thickness without evidence of increased intracranial pressure. In the absence of further pathological findings or neurological symptoms, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany. an observational approach seems adequate in these patients. Journal of Neuro-Ophthalmology 2023;43:348–352 doi: 10.1097/WNO.0000000000001766 © 2022 by North American Neuro-Ophthalmology Society I t is generally believed that optic disc drusen (ODD) change only over long periods of time (1–3). Although numerous publications have described the optical coherence tomography (OCT) characteristics of ODD (4–8), there is little information about possible variations in optic disc prominence. In our neuro-ophthalmologic clinic we came to the impression that in adolescent patients with ODD, the optic disc prominence—and thus also the peripapillary retinal nerve fiber layer (RNFL) thickness—may vary substantially over time. This finding seems important because a pronounced change in optic disc prominence is usually considered as a sign of papilledema because of a pathologic change in intracranial pressure requiring further examinations, some of them being invasive (e.g., lumbar puncture). Therefore, we evaluated data from a total of 80 eyes belonging to 49 patients of different ages, with and without ODD, to investigate whether our clinical impression could be statistically supported. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Compliance with Ethical Standards: Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the local ethics committee of the faculty of medicine of the Eberhard-Karls-University Tuebingen and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The ethics committee of the faculty of medicine of the Eberhard-Karls-University Tuebingen approved this study. Address correspondence to Felix Tonagel, MD, Centre for Ophthalmology, University of Tuebingen, Elfriede-Aulhorn-Str. 7, 72076 Tuebingen, Germany; E-mail: [e-mail] 348 METHODS In this retrospective study, 49 patients were included. When possible, both eyes of the patients were examined. Eyes that had other diseases of the optic nerve or retina except of ODD or patients with symptoms that might have been attributable to raised intracranial pressure were excluded. ODD were detected by ophthalmoscopy in conjunction with positive evidence of ultrasonic examination. ODD were excluded if the funduscopic findings were regular, and the enhanced depth imaging optical coherence tomography examination also showed no evidence of ODD. Tonagel et al: J Neuro-Ophthalmol 2023; 43: 348-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Sex, age, and difference in total RNFL thickness (delta RNFL-t) and RNFL thickness of the most differing sector (delta RNFL-max) in the 4 patient groups. If not stated otherwise, the median and the range are given With Drusen Female patients % (n) Age, yr (min–max) Delta RNFL-t (mm) Delta RNFL-max (mm) Most frequent max sector (%) Without Drusen Age # 20 Age .20 Age # 20 Age .20 60 (12) 10 (5–17) 10 (0–29) 34 (8–109) Superior (47) 70 (14) 46 (25–75) 2 (0–11) 9 (1–36) Nasal inferior (40) 50 (10) 16 (3–18) 1 (0–4) 8 (3–26) Nasal superior (36) 65 (13) 53 (61–80) 2 (0–7) 10.5 (4–28) Nasal inferior (33) RNFL, retinal nerve fiber layer. This study consecutively assigned patients who had been seen at the eye hospital as outpatients and who had at least 3 OCT examinations of the RNFL with an interval of at least 1 month. The 2 scans with the largest difference in RNFL thickness within 1 year were used for this study. In both groups, half of the eyes belonged to patients aged up to 20 years and half to patients 21 years and older. The RNFL was measured by spectral domain optical coherence tomography (SD-OCT, Heidelberg Engineering glaucoma module Heidelberg Engineering, Heidelberg, Baden-Wuerttemberg, Germany) using a circular peripapillary measurement with 3.5-mm diameter. The differences of the total thickness of the RNFL (delta RNFL-t) and the RNFL thickness of the sector that showed the greatest change within 1 year (delta RNFL-max) were evaluated. Each OCT finding was selected by experienced neuroophthalmologists. Special care was taken to ensure that no technical errors were present, such as a decentered ring scan, faulty segmentation, or generally reduced signal quality because of cloudy optical media. All analyses were performed using JMP 15.2.0 statistical software (SAS Institute, Cary, NC). Continuous data were summarized with the median and range; categorical data are reported as numbers and percentages. To compare continuous unpaired data between groups, the 2-sided 2-sample t test was used. Categorical data were tested using the chisquare test. A P value of less than 0.025 was considered statistically significant. FIG. 1. Change of total RNFL thickness (delta RNFL-t) of the 4 patient groups with indication of the number of eyes and patients examined. The boxplot displays the first quartile, median, and third quartile, the whiskers the variability outside the upper and lower quartiles. Delta RNFL-t is significantly greater for the group of patients with ODD younger than 21 years than for all other groups. Accordingly, significant fluctuations in the total thickness of the RNFL occur only in this group. ODD, optic disc drusen; RNFL, retinal nerve fiber layer. Tonagel et al: J Neuro-Ophthalmol 2023; 43: 348-352 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution RESULTS DISCUSSION Sixty-one percent of the patients were female. Table 1 presents the demographical data of the individual groups. All patients with ODD younger 21 years had funduscopically buried drusen, in patients with ODD older than 20 years, and buried drusen were present in 7 of 20 eyes. The median delta RNFL-t for the group of patients younger than 21 years was 10 mm (range 0–29) and 1 mm (0–4) with and without ODD, respectively (Fig. 1). Patients older 20 years showed a median delta RNFL-t of 2 mm (0–11) and 2 mm (0–7) with and without ODD, respectively. Delta RNFL-max in the group younger than 21 years resulted in 34 mm (8–109) with and 8 mm (3–26) without ODD (Fig. 2). Patients older than 20 years showed a delta RNFL-max of 9 mm (1–36) and 10.5 mm (4–28) with and without ODD. Delta RNFL-t and delta RNFL-max in the group of patients with ODD younger than 21 years differed significantly from the other 3 groups (P = 0.0001). Delta RNFL-max affected the superior sector in 47% of patients younger than 21 years with ODD and in 36% of the nasal superior sector in patients younger than 21 years without ODD. Delta RNFL-max affected the nasal inferior sector in all patients 21 years or older (patients with ODD 40%, without ODD 33%). Figure 3 shows exemplary fundus photographs and OCT images at 2 different time points of 4 patients with ODD younger than 21 years in whom significant variations in RNFL thickness were noted (see Supplemental Digital Content, Supplemental Data File, http://links.lww.com/WNO/A655). ODD are not a rare disease. They may be as frequent as 2.4% in our population (5). Even if the diagnosis of ODD is clearly established (e.g., by ultrasound or typical OCT appearance), it cannot be excluded that those patients may suffer from papilledema in addition. Unfortunately, it is not trivial to distinguish papilledema from pseudopapilledema because of buried ODD or a combination of both (9). Lee et al (10) demonstrated that in papilledema, the peripapillary RNFL was significantly thicker in all sections than in ODD. However, this is of limited usefulness in the assessment of an individual patient, as no exact RNFL thickness range can be defined allowing a clear differentiation. Fard et al able to demonstrate that a total RNFL thickness greater than 127 mm was indicative of papilledema, but the sensitivity and specificity of 73% do not allow reliable differentiation in individual cases, and only adults were included in this study (11). In addition, RNFL thickness seems to be thicker in buried drusen than in superficial drusen, further complicating the distinction (4). Our study showed a considerable fluctuation of peripapillary RNFL thickness over time in the group of patients younger than 21 years with ODD. Owing to the careful selection and control of each OCT scan by experienced neuro-ophthalmologists, it can be excluded that the variations in RNFL thickness are caused by artifacts or incorrectly performed OCT scans. An influence of the results by device-related test–retest variability is very FIG. 2. Change of RNFL thickness of the most differing sector (delta RNFL-max) of the 4 patient groups with indication of the number of eyes and patients examined. The boxplot displays the first quartile, median, and third quartile, the whiskers the variability outside the upper and lower quartiles. Delta RNFL-max is significantly greater for the group of patients with ODD younger than 21 years than for all other groups. Accordingly, significant fluctuations in the total thickness of the RNFL occur only in this group. ODD, optic disc drusen; RNFL, retinal nerve fiber layer. 350 Tonagel et al: J Neuro-Ophthalmol 2023; 43: 348-352 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Fundus photographs and OCT images at 2 different time points from 4 patients with ODD younger than 21 years in whom significant variations in RNFL thickness were noted. OCT imaging shows a decrease in RNFL thickness in patients #1, #3, and #18 and an increase in patient #3. On closer inspection, a difference in optic disc prominence and optic disc margin blur is even visible on the fundus photographs in these patients. OCT, optical coherence tomography; ODD, optic disc drusen; RNFL, retinal nerve fiber layer. unlikely. Instrument variations would have influenced all groups in the same way, and the variability of the Heidelberg Engineering SD-OCT in follow-up mode seems to be very low. Ghasia et al (12) found that the total peripapillary RNFL thickness for 4 different groups of subjects differed only within 1 micrometer by 3 measurements on the same day. Hong et al (13) demonstrated an average test–retest variability of RNFL thickness of 4.5 mm. Therefore, not every RNFL fluctuation in younger individuals requires a complete neurological assessment including MRI and lumbar puncture. Instead, an observational approach seems reasonable in particular cases, provided that no other findings show additional abnormalities and no new visual loss and no classic symptoms of elevated cerebral pressure are present. In case of doubt, fluorescein angiography may be an additional diagnostic option because fluorescein leakage of the optic nerve head (ONH) could be indicative of papilledema (9). It should be kept in mind that the number of patients allows a clear evaluation but is still limited. A minor drawback of this study can be attributed to its retrospective nature: Patients with normal-appearing ONH did not Tonagel et al: J Neuro-Ophthalmol 2023; 43: 348-352 receive ultrasonic examination of the ONH. However, this does not seem like a strong disadvantage because positive ultrasonic detection is almost impossible in funduscopically completely normal-appearing ONH according to our experience. We therefore consider the chance of having overlooked ODD because of the lack of ultrasonic examination to be very small. In the conception of this study, we made a conscious decision to use a peripapillary ring scan of the RNFL instead of volume scans of the ONH. The reason for this was that, in our experience, in case of clearly prominent papillae, the OCT software very often leads to segmentation errors, impairing the accuracy of the measurement, and the comparability of the data even if corrected manually. Therefore, we used the standard RNFL ring scan with 3.5-mm diameter. A possible disadvantage of this procedure is that it cannot be ruled out that minor differences in the configuration of the papillae could not be detected because they may have not reached the scanned area 1.75 mm from the center of the optic disc. The pathomechanism of RNFL fluctuations in younger patients with optic disc drusen remains unclear. It seems 351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution plausible that short-term RNFL fluctuations cannot be due to structural changes in the retina or optic nerve but must be caused by mild RNFL edema. Because the cause of drusen is still not fully understood, we can only speculate about the reason for a fluctuating edema of the RNFL in young patients with ODD. One hypothesis for the occurrence of ODD is that a narrow sclera canal obstructs axoplasmic flow (14). Another hypothesis attributes ODD to congenitally dysplasia of the optic disc and its blood supply (15). If one of these hypotheses were true, either the compression of the optic nerve would have to be subject to fluctuations or the axoplasmic flow would have to change in quantity or composition to cause RNFL edema. However, the assumption of a narrow sclera canal is contradicted by the findings of Floyd et al, who demonstrated by OCT measurements that sclera canals of drusen papillae are not narrower than in control eyes (16). Beyond that the close relationship of dysplasia with fluctuating findings seems unusual from a general point of view. Another hypothesis for the occurrence of ODD is that abnormal axonal metabolism is responsible through axon rupture and in the extracellular space extruded mitochondria loaded with calcium (3,17). Under this assumption, a possible explanation would be that the disturbance of axonal metabolism in younger patients with ODD does not proceed uniformly but intensifies at times leading to a temporary compression of the nerve fibers and the formation of RNFL edema. Why this would occur only in adolescent patients would remain unclear. In summary, we demonstrated that patients with ODD younger than 21 years have distinct variations in peripapillary RNFL thickness without evidence of increased intracranial pressure. In the absence of further pathological findings or neurological symptoms, an observational approach seems adequate in these patients. STATEMENT OF AUTHORSHIP Conception and design: F. Tonagel, H. Wilhelm, L. Stock, C. Kelbsch; Acquisition of data: F. Tonagel, C. 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