Visual,field,defects,and,retinal,nerve,fiber,layer,damage,in,buried,optic,disc,drusen:,a,new,insight

Brenda Nana Wandji, Artmise Dugauquier, Adle Ehongo

1Faculty of Medicine, Université Libre de Bruxelles, Brussels 1070, Belgium

2Department of Ophthalmology, Erasme Hospital, Brussels 1070, Belgium

Abstract

● KEYWORDS: buried optic disc drusen; visual field;spectral-domain optical coherence tomography; Garway-Heath mapping; retinal nerve fiber layer

Optic disc drusen (ODD) are acellular deposits made of mucopolysaccharides, calcium and nucleic acids located at the prelaminar zone of the optic nerve head (ONH)[1]. Their pathophysiology is not well known but it is commonly admitted that an axonal calcium flow reduction leading to extracellular calcic collections could be the main mechanism[2-3]. ODD have a global prevalence of 0.9%-2.4% and are more common in Caucasians and females[4-5]. There may also be a genetic component, explaining increased intrafamilial occurrence[6].ODD is usually asymptomatic. However, up to 10% of patients may report transient visual obscuration[7]and 88.3% of patients may develop associated visual field defects (VFD)[8-10]. ODD are usually located in the nasal sectors of the papilla[11-12]; they are classified either as visible or buried depending on the fact that they are clearly detected or not by ophthalmoscopy[2].Visible ODD have a typical nodular presentation or appear as polycyclic and blurred distortions of the optic disc margins[10].Buried optic disc drusen (BODD), do not have that typical aspect. They can induce a papillary bulge, often confused with papilledema but the ophthalmoscopic examination can also be strictly normal[2,13]. BODD are therefore insidious because they can be underdiagnosed or confused with pathologies such as normal tension glaucoma (NTG) or papilledema,leading thus to unnecessary investigations[13-14]. BODD are easily detected using the latest optical coherence tomography(OCT) technologies such as swept source-OCT (SS-OCT) and enhanced depth imaging-OCT (EDI-OCT)[15-16]. BODD are more commonly found in children and a transition period is described in adolescence during which BODD exteriorize[2,5].

The alterations caused by BODD on retinal nerve fiber layer (RNFL) and the impact on the visual field (VF) are controversial unlike visible ODD where the association is well known[9,17]. The theory is that BODD are early-stage ODD that have not yet had time enough to exteriorize and cause damages[9].

The relationship between VF patterns and their corresponding regions on the ONH is established[18]. Using this correspondence,we assessed the correlation between the localization of BODD and their impact on the VF in adults. We suggest that drusen may trigger VFD by compressing RNFLand this damage would be more pronounced in adult patients.

Ethical ApprovalWe obtained the approval of the Ethics Committee and that of the institutional board of Erasme Hospital. We have ensured that our study was conducted in accordance with the fundamental principles of medical research as set out in the Declaration of Helsinki. The hospital where our study was conducted is an academic institution that applies the opting-out policy; therefore, all patients admitted give their consent to the hospital for further use of their records for research purpose.

Study DesignWe carried out a retrospective hospital-based cross-sectional descriptive study in the Glaucoma Clinic of the Ophthalmology Department at Erasme Hospital in Brussels,Belgium. Patients aged at least 18 years old diagnosed with BODD, who had complete records and reliable VF were enrolled. We excluded patients with low vision, age-related macular degeneration, retinitis pigmentosa or any other lesion potentially responsible of VFD.

SamplingThe sampling was done with consecutive subjects for whom BODD diagnosis was made over a 3-year period from November 2018 to December 2021.

Study ProcedureData were collected from the files of patients who benefitted from a comprehensive ophthalmic examination including medical history, measurement of their refractive error, best corrected visual acuity (BCVA), intraocular pressure (IOP) using Goldman applanation tonometer fundus examination and pictures with a non-mydriatic retinal camera Visucam 224®(Carl Zeiss Meditec AG, Jena,Germany), automated 24-2 VF using the SITA standard mode of the Humphrey®Field Analyzer 3 (Carl Zeiss Meditec AG, Jena, Germany) and spectral domain OCT (SD-OCT)with Spectralis®OCT model S3300 (Heidelberg Engineering GmbH, Heidelberg, Germany).

OCT Data CollectionODD were considered visible if they had a typical nodular or polycyclic appearance on ophthalmoscopy[10](Figure 1A) and these eyes were thus non included. Otherwise, they were considered buried. The diagnosis of BODD was made using the glaucoma module of Spectralis®which provides 48 radial sections centred on the papilla. BODD were identified as round hypo reflective lesions with hyper reflective and irregular margins[2](Figure 1B-1D). We were careful not to confuse them with vessels which usually have regular margins and only appear on a single section[19-20].

OCT AnalysisOne radial section out of four was analysed starting from the 12 o’clock position and read clockwise. In case of doubt, the interpretation was refined by reading the neighbouring section on both sides. Then, we made a transition from the hourly to the Garway-Heath distribution[18](Figure 1E).For both the RNFL and the minimal rim width (MRW), we used this all-set distribution provided by the Spectralis®after revision of the Bruch’s membrane position.

To assess the predominantly nasal location of BODD[11-12],we also assessed on the hourly slices, the orientation of the border tissue of Elschnig which is a fibro-astrocytic tissue that separates neural tissue from choroid in the neural canal.It was classified into two categories according to whether it is externally oblique or not from its junction with the sclera to that with Bruch’s membrane: external oblique if its anterior end goes outwards in relation to the center of the optic nerve and non-external oblique otherwise[21](Figure 2A). We then classified the sections at the right eye into two sectors: “nasal”from 12:00 to 6:00 clockwise including the limits (6 and 12)and “temporal” from 6:00 to 12:00 clockwise. To obtain the corresponding mirror sections for the left eye, we made a symmetrical projection around the nasal axis (Figure 2B).“Temporal” data of right and left eyes for the border tissue obliquity were pooled together for each hourly location and the same for the “nasal” part (For example we combined the data from 3:00 of the right eye and 9:00 of the left eye which corresponded to the “nasal 3” sector while the data from 9:00 of the right eye and 3:00 of the left eye corresponding to the“temporal 3” sector).

The topography of BODD using SD-OCT was correlated to that of abnormal sectors for both the MRW and the RNFL.Likewise, the topography of abnormal sectors for MRW was correlated to that of abnormal sectors for the RNFL. A dissociation between the MRW and the RNFL in a sector was defined as normal MRW with damaged RNFL in that same sector or vice-versa.

Visual Field AssessmentVF were considered reliable if they had a rate of false positives, false negatives, and fixation losses ＜20%. Unreliable VFs were excluded. Reliable VFs were then analyzed according to Anderson’s criteria which can be summarized as follows: glaucoma hemifield test (GHT)outside normal limits; or pattern standard deviation (PSD) at aP＜5%; or abnormal cluster. Abnormal cluster is a group of three or more non-edge points along the course of the nerve fiber within the same sector on the pattern deviation plot, all of which are depressed at aP＜5% level with at least one of them depressed at aP＜1% level[22]. Then clusters were listed in Garway-Heath’s zones (Figure 3).

Figure 1 Fundus and OCT aspects of optic disc drusen (A-D) and translocation from hourly sectors to Garway-Heath zones (E) A:Visible optic disc drusen: multinodular aspect on fundoscopy; B: Normal fundoscopy hiding a buried optic disc drusen disclosed by SD-OCT as a round hypo reflective lesion with hyper reflective and irregular margins: the yellow arrow shows a vessel which is round, hypo reflective with hyper reflective regular margins; C: Buried optic disc drusen presenting with a pseudo papilledema aspect on fundoscopy; D: Buried optic disc drusen presenting with peripapillary atrophy on fundoscopy: based on exclusion criteria stated above, this eye was excluded as peripapillary atrophy is a confounding factor for visual field defects[20]; E: Summary of our approach of transposition from hourly sectors on SD-OCT to Garway-Heath areas on a right eye; to obtain a mapping for a left eye, this figure is mirrored by the vertical line crossing the nose. SD-OCT:Spectral-domain optical coherence tomography.

Figure 2 Representation of border tissue and right-left equivalent hourly sectors A: Border tissue orientation; A1: external oblique: anterior end goes outwards in relation to the center of the optic nerve and non-external oblique otherwise; A2 and A3: non external oblique (respectively non-oblique and internal oblique); B: Hourly sectors on right and left eyes.

The topography of BODD using SD-OCT was correlated to VFD distribution according to Garway-Heath correspondence.All data including VF were analyzed by two independents researchers (Dugauquier A and Ehongo A) and a third one(Nana Wandji B) independently validated their findings. In case of agreement, data were saved in an Excel sheet and in case of disagreement, they were reviewed collegially. If a doubt persisted, the data were excluded.

Statistical AnalysisStatistical analysis was performed using Microsoft Office Excel and STATA SE 17 (64 bit) software.The qualitative variables were expressed in terms of frequencies,while the quantitative variables were expressed as median,interquartile range (IQR) and range. The Fisher’s exact test was used to verify the associations between the different variables of interest because most expected counts were ＜5.We also used the Phi correlation coefficient for categorical variables to rate the strength of our correlation. We performed an exact logistic regression adjusting for elevated IOP(＞21 mm Hg) which influences VFD[23-24]. The tests were considered significant for aP-value ＜0.05.

General CharacteristicsTwenty eyes of 15 patients, aged 19 to 76y (median±IQR: 63±43y), of which 9/15 (60%)females, were included. Patients’ distribution according to the age is shown in Figure 4A. The optic disc aspect was strictly normal in 19 out of 20 eyes (95%); We had one case of pseudo papilledema. One eye with peripapillary atrophy and BODD was excluded as the former may be related to VFD[20]. BODD were found in 12 left eyes (60%) and in 8 right eyes (40%);They were bilateral in 6 (40 %) patients. Circumstances of diagnosis were usually related to glaucoma (Figure 4B). The other general characteristics are summarized in Table 1.

SD-OCT AnalysisBODD were mostly found in areas A, E and F, corresponding to the nasal region (Figure 5A). RNFL was predominantly damaged in the D, E, and F zones (Figure 5B). MRW was slightly impaired (Figure 5C).

The border tissue obliquity was predominantly external in the temporal sectors while it was non external in the nasal sectors (Figure 6A). Figure 6B shows the association between BODD location and the orientation of the border tissue. There is less BODD in the temporal areas, where the border tissue is predominantly external oblique. This association was not statistically significant.

RNFL damage was significantly associated with BODD location in C, D and E areas; There was no statistically significant association between BODD location and MRW impairment (Table 2).

Table 1 General characteristics of the sample

After adjusting for high IOP, the association between the presence of BODD and RNFL damage was still significant in D (P=0.03) and E (P=0.025; Table 3). Moreover, BODD located in E were significantly associated with damaged RNFL in neighboring sectors D (P=0.012) and F (P=0.02; Table 3).A statistically significant MRW/RNFL dissociation was noticed on the A, E and F Garway-Heath areas with a damaged RNFL meanwhile MRW was still normal (Table 4). Figure 7 shows the distribution of MRW-RNFL dissociation by Garway-Heath areas (Figure 7A-7B). A case of dissociation is also illustrated(Figure 7C1-7C4).

Visual Field AnalysisWe excluded one VF because it did not meet the reliability criteria. The overall positive rate for Anderson criteria was 63% (12/19; Figure 8A). Clusters were mostly located in the B (31.6%), D (21%), and E (26.3%)Garway-Heath’s areas (Figure 8B).

There was a statistically significant association between the location of BODD and the location of clusters only in zone D. This association remained significant after adjustment for high IOP (P=0.009; Table 5). Figure 9 illustrates one case of structure-function correspondence.

The further away from the F-zone, the less BODD are present.The RNFL damage also follows this pattern but with a more spread-out distribution. When it comes to VFD, the areas with the most defects are those adjacent to the areas with the most BODD: areas B and E with the most VFDs are adjacent to areas A and F with the most BODD (Figure 10).

The median age at diagnosis in our study sample was 63y, which indicates a delay in diagnosis since BODD are asymptomatic.BODD are usually found in a younger population[5,25], but our study did not include any patients under 18 years old. There was a slight female predominance, which is consistent with the literature[9]. The mean visual acuity of our patients was nearly normal like the one in the study of Malmqvistet al[9]. This could also play a role in the delayed diagnosis.

Figure 3 Transition of visual field data from the results sheet to the Garway-Heath mapping A: VF results sheet; B: Pattern deviation; C:Garway-Heath areas; the defects correspond to D, E, and F areas.

Figure 4 General characteristics A: Age distribution (n=15); B: Circumstances of diagnosis (n=21).

Figure 5 Distribution by Garway-Heath area A: BODD location; B: RNFL damage; C: MRW damage. The results presented here are those for right and left eyes combined by Garway-Heath sector. The mapping for a right eye is just used for simplification. BODD: Buried optic disc drusen location; RNFL: Retinal nerve fiber layer; MRW: Minimal rim width.

Table 2 Correspondence between BODD location, RNFL, and MRW damage

Figure 6 Border tissue orientation analysis A: Distribution of border tissue orientation; B: Association between external obliquity of border tissue and BODD location. EO: External oblique; NEO: Non external oblique; BODD: Buried optic disc drusen location.

Figure 7 MRW/RNFL dissociation A: Summary of overall MRW/RNFL dissociation according to Garway-Heath areas. The dissociation is more prevalent in sectors D, E, and F. B: Distribution of the part of MRW/RNFL dissociation related to damaged RNFL. The cases of nasal dissociation are mainly due to damage of RNFL. C: Illustration of a case of dissociation in a right eye. This 76-year-old patient has bilateral BODD discovered in the context of shallow anterior chamber work up, maximum IOP 10 mm Hg. C1: Hourly sectors with the cursor at 2 o’clock;C2: BODD seen on SD-OCT; C3: Normal MRW; C4: Damaged RNFL in D, E and F Garway-Heath areas. BODD: Buried optic disc drusen location; RNFL: Retinal nerve fiber layer; MRW: Minimal rim width; IOP: Intraocular pressure.

Figure 8 Visual field deficits A: Rate of Anderson criteria fulfilled (n=19). Clusters were found in 58% (11/19) of eyes, the PSD was ＜5% in 53% (10/19) of eyes and 63% of the eyes (12/19) had an abnormal GHT. B: Clusters proportion by Garway-Heath zone. PSD: Pattern standard deviation; GHT: Glaucoma hemifield test.

Figure 9 Right eye correspondence between BODD located in the D, E, and F Garway-Heath areas with clusters in D, E, and F on visual field In each line, the infrared image with OCT radial sections in the left shows the location and orientation of the slice disclosing the drusen.A-C: SD-OCT with BODD respectively at 11, 1, and 2 o’clock; D: Transposition from corresponding hourly sections to D, E, F Garway-Heath areas; E: Visual field of the same patient with defects on the D, E and F areas. The same patient illustrated in Figure 7. BODD: Buried optic disc drusen location.

Figure 10 Overview of BODD, RNFL damage, and clusters distribution A: BODD, RNFL damage, and VFD distribution; B: Garway-Heath mapping. BODD: Buried optic disc drusen location; RNFL: Retinal nerve fiber layer; VFD: Visual field defects.

We found a bilateral BODD rate of 40%. We found no studies describing only the rate of bilaterality of BODD only. The papilla appeared normal in 95% of our sample, with the typical presentation of pseudo papilledema[19]being found only in one case. This suggests that BODD are underdiagnosed, thus their true prevalence is underestimated. Nearly 60% of BODD included in our study were discovered during investigative assessment for pathologies related to glaucoma (narrow angle glaucoma work-up, 2ndopinion for glaucoma)[26]. Therefore,BODD are a diagnosis to keep in mind when dealing with glaucoma[14,27].

BODD were predominantly located in Garway-Heath sectors A, E and F, corresponding to the lower, upper, and middle nasal regions which is in accordance with those found by Satoet al[11]and Teixeiraet al[12]. The orientation of the border tissue was mostly external oblique in the temporal region, where very few BODD were found. Although this association was not statistically significant, we suggest that this may explain why BODD are more often found in the nasal area. This phenomenon has already been described in myopic eyes with external obliquity of the border tissue on the temporal side; The prelaminar optic nerve then tends to slide nasally, freeing the temporal part[21]. Since the pathogenesis of BODD results from an alteration of axonal metabolism[2], a more frequent number of BODD in the nasal area would then be related to the greater number of nerve fibers in this area due to the orientation of the border tissue. So far, no study has provided a hypothesis on the predominantly nasal localization of BODD.

We found an association in the location of BODD and RNFL damage (upper nasal and upper temporal) in Garway-Heath zones D and E, suggesting that BODD are not that harmless.This finding is quite innovative since in the literature, BODD seem not to cause RNFL alterations compared to ODD[9,17]. It has been hypothesized that BODD are early-staged drusen, not present long enough to damage nerve fibers[9]and also, that the outer walls of BODD are less calcified than those of ODD,making the former less harmful[28].Interesting, we found that the lesions caused by BODD on the RNFL are not only restricted in the area where the drusen is located but also afar. This could be explained by a possible mass effect away on the nerve fibers rather than at the epicenter of the drusen. A similar process occurs in case of intracranial expansive pathology that causes deficits in the ipsilateral and contralateral cerebral hemisphere also[29].

Table 3 Correspondence between BODD location and RNFL damage adjusted for high IOP (exact logistic regression)

Table 4 RNFL damage in MRW/RNFL dissociation

Table 5 Correspondence between clusters’ location and drusen’s location

The MRW was hardly damaged in most of our patients. This was also highlighted by Poliet al[30]. Moreover, we had a significant RNFL/MRW dissociation with damaged RNFL. As suggested by Poliet al[30], we suggest that the contribution of the MRW as indicator of fiber nerve damage is quite limited in case of morphological papillary abnormality such as BODD.The measurement between the internal limiting membrane and Bruch’s membrane is overestimated by the space taken by BODD[27,30].

This is a major difference with early glaucomatous lesions where alterations are first flagged by MRW[31]. The 63% of our patients had an abnormal VF. This is slightly higher than the rate found by Malmqvistet al[9]in patients with BODD which was 54.6% but this was remarkably high compared to the result found by Katzet al[17], who had a rate of 5% of VFD in patients with BODD. This can be explained by the higher average age of our population which was 63y. Katzet al[17]and Malmvisqtet al[9]in their studies had a mean age of patients with BODD of 35 and 35.4y respectively. In our subjects, this would have given BODD more time to damage nerve fibers.

The defects were predominantly found in areas B, D and E;contrary to what was found by Malmqvistet al[9]and Novalet al[25]which had a predominance of nasal defects. However,Katzet al[17]found that BODD caused inferior arciform scotomas. This corresponds to Garway-Heath areas D and E which was also predominant in our study. The presence of defects in B could be explained by the possibility of a mass effect as for RNFL damages. BODD being less calcified[9]would be more damaging by mass effect and therefore remotely whereas visible ODD would alter the fibres locally because of their calcifications.

Moreover, we observed a correspondence between the location of BODD and the presence of clusters in sector D (superior temporal). This correspondence was known in visible ODD but not in BODD[5,9].

The sample size was small. Our study was monocentric, and retrospective and we did not have a control group. Since our participants were recruited at the Glaucoma Clinic, this is a potential selection bias. However, we focused on BODD, which are neglected in most studies and considered benign. We showed that VFD are also present in BODD. We did the study with a more specific distribution according to the Garway-Heath areas.We can conclude that BODD do not affect only young patients and can be more harmful than usually expected, as VFD are present in 63% of cases. There is a correspondence between BODD location, RNFL damage, and VFD. When dealing with BODD, RNFL status is a better indicator of ganglion fiber damage compared to MRW unlike glaucoma. We suggest there is a possible remote nerve fiber damage, and the border tissue orientation would be a hypothesis explaining the preferential nasal location of the BODDs. Those assumptions could be the subject of further studies.

ACKNOWLEDGEMENTS

The authors would like to thank Mr. Bouziotis Jason,Biomedical Research Department, Erasme Hospital, for his advice in biostatistics.

Conflicts of Interest: Nana Wandji B,None;Dugauquier A,None;Ehongo A,None.