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Clinical science
Vessel density and retinal nerve fibre layer thickness following acute primary angle closure
  1. Sasan Moghimi1,
  2. Mona SafiZadeh2,
  3. Benjamin Y Xu3,
  4. Masoud Aghsaei Fard2,
  5. Nassim Khatibi2,
  6. Harsha Laxmana Rao4,
  7. Robert N Weinreb1
  1. 1 The Viterbi Family Department of Ophthalmology/Shiley Eye Institute, University of California San Diego, La Jolla, California, USA
  2. 2 Department of Ophthalmology, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
  3. 3 Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
  4. 4 Glaucoma, Narayana Nethralaya, Bangalore, India
  1. Correspondence to Dr Robert N Weinreb, The Viterbi Family Department of Ophthalmology/Shiley Eye Institute, University of California San Diego, La Jolla, California, USA; rweinreb{at}ucsd.edu

Abstract

Background To evaluate changes in circumpapillary vessel density (cpVD) and retinal nerve fibre layer (cpRNFL) thickness after a successfully treated episode of acute primary angle closure (APAC) and to identify factors associated with glaucoma progression in these eyes.

Methods Twenty-six patients successfully treated for a unilateral episode of APAC were included in this prospective study. Optical coherence tomography (OCT) cpRNFL thickness and OCT angiography (OCTA) cpVD were compared between 2 and 8 months after treatment. Multiple logistic regression analysis was conducted to identify factors that influenced cpRNFL outcome.

Results cpRNFL thicknesses was thinner in the affected eye (94.0 µm (95% CI: 87.3 to 100.8)) than in the unaffected fellow eye (103.1 µm (99.3 to 106.9)) at 2 months (p=0.039). The cpRNFL thickness of the affected eye decreased 8 months after remission (89.5 µm (84 to 95)), but was unchanged in the unaffected eye. Although cpVD was significantly lower (p=0.001) in APAC eyes 2 months after treatment (56.7% (53.8 to 59.7)) compared with fellow eyes (62.9% (61.4 to 64.4)), there was no significant change in cpVD of the affected eye between 2 and 8 months. In the multivariable analysis, the only factor that was associated with cpRNFL progression was lower cpVD at 2 months after APAC remission (OR=1.79, p=0.036).

Conclusion Early reductions of the vessel density and long-term decrease in cpRNFL thickness were observed during the first 8 months after an APAC attack. A lower vessel density at 2 months was the best predictor of conversion to an abnormal cpRNFL thickness. Glaucomatous progression should be suspected in eyes with lower vessel density even after remission of an episode of APAC.

  • optical coherence tomography angiography
  • glaucoma
  • acute primary angle closure
  • vessel density
  • retinal nerve fiber layer

https://doi.org/10.1136/bjophthalmol-2019-314789

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    Introduction

    Although acute primary angle closure (APAC) generally does not result in significant visual morbidity if it is effectively treated promptly, delayed optic nerve damage still can occur even after the remission of the acute episode.1–5 However, the mechanism(s) underlying the development of permanent optic nerve damage, even after the resolution of the acute episode, and the initiating or influencing factors have yet to be established. The interplay between optic disc perfusion and damage to retinal ganglion cell (RGC) axons has been hypothesised as key for understanding the mechanism of glaucomatous optic neuropathy in APAC.1 4

    Several studies of longitudinal changes in circumpapillary retinal nerve fibre layer (cpRNFL) thickness in APAC demonstrated that cpRNFL thickness initially is increased within 2 weeks of a single APAC episode, followed by a decrease.6–8 Another study showed that lamina cribrosa depth reduced until 2~3 months and then remained stable.9

    Optical coherence tomography angiography (OCTA) enables images of the retinal microcirculation to be acquired and provides reproducible qualitative and quantitative evaluations of the vasculature in the optic nerve head (ONH) and peripapillary regions.10 OCTA has been used to assess glaucoma severity and progression.11 Studies using OCTA have shown a reduction of vessel density within the ONH, the peripapillary retina and the macula in primary open angle glaucoma (POAG) eyes.12–14 Several reports have suggested that impaired perfusion of the ONH could have a primary role in the progression of glaucomatous optic neuropathy.15–17 However, most of these studies have focused on POAG,13 17–20 and there only have been a few that have investigated eyes with primary angle closure glaucoma (PACG).21 22

    Changes in the vessel density after APAC are not well described. The pathophysiology of optic nerve damage might be different in APAC23–25 as optic nerve damage can occur after the sudden rise in intraocular pressure (IOP) associated with an APAC episode. While it is generally accepted that mechanical compression of the optic disc is the main mechanism of damage in angle closure disease, especially APAC,23–25 vascular factors also may have a role in the pathogenesis of angle closure glaucoma. Wang et al 26 found that even when IOP was normalised after an acute episode, APAC eyes had a lower peripapillary retinal vessel density compared with fellow eyes. However, the time sequence for the development of peripapillary microcirculation abnormalities or other glaucomatous changes, such as cpRNFL thinning, was not characterised. In a more recent study,27 it was shown that peripapillary vessel density is decreased at 1 week after a treated APAC episode and continues to decrease for ~2 months. In contrast, these eyes had an initial increase in cpRNFL thickness at 1 week that was followed by a subsequent decrease after weeks.

    The current study evaluated changes in ONH vessel density and cpRNFL at 2 and 8 months after a treated APAC episode and evaluated the factors that influence glaucoma progression after APAC remission.

    Patients and method

    All of the included subjects were enrolled in the ongoing prospective Farabi Angle Closure Study (FACS) being conducted at the Farabi Eye Hospital, Tehran, Iran. Each of them provided written informed consent. The protocol for this prospective, case-control study was approved by the institutional review board of Tehran University of Medical Sciences.

    An APAC episode was diagnosed based on the following criteria: (1) at least two of the symptoms of an acute episode of IOP rise (nausea and/or vomiting, decreased vision, ocular pain or headache and rainbow-coloured halos around lights); (2) IOP at presentation of 30 mm Hg or more by Goldmann applanation tonometry; (3) signs such as corneal epithelial oedema, conjunctival injection, shallow anterior chamber and a fixed mid-dilated pupil; (4) narrow angles in at least three quadrants on gonioscopic examination (defined as invisible posterior trabecular meshwork in at least 270 degrees with gonioscopy) and (5) a narrow angle in the fellow eye.

    Patients were included when there was (1) unilateral APAC; (2) remission after medical treatment and laser peripheral iridotomy (LPI) and (3) a follow-up of least 8 months after the remission. Exclusion criteria were (1) preexisting glaucoma or history of previous APAC; (2) secondary angle closure, such as lens induced glaucoma, neovascular glaucoma or uveitic glaucoma or (3) history of laser (eg, LPI) or intraocular surgery in either the affected or contralateral eyes, (4) poor-quality OCTA or OCT scans of the optic disc (ie, signal strength index <48, motion artefact, poor segmentation, poor clarity).

    Participants received medical treatment followed by LPI within 12 hours of the documented APAC. LPI was also performed for the fellow eyes at the same visit. The participants were followed up at 1 week, 2 months and at 2-month intervals, thereafter. All subjects underwent a complete ophthalmic examination, which included a review of their medical history, slit-lamp biomicroscopy, IOP measurement (Goldmann applanation tonometry) and gonioscopy during follow-up visits. Axial length was measured by partial coherence interferometry using an IOLMaster (Carl Zeiss Meditec, Germany) at 2-month follow-up.

    Visual field testing (Humphrey Field Analyzer II 750; 24-2 Swedish interactive threshold algorithm; Carl-Zeiss Meditec, Dublin, California, USA), spectral domain optical coherence tomography (SDOCT; Optovue, Fremont, California, USA, software V.5.6.3.0) and OCTA (Optovue, software V.5.6.3.0) examinations were performed for all patients at the 2-month and 8-month visits. Only reliable visual fields (defined as false-positive error rate of less than 15%, false-negative error rate of less than 25% or fixation loss of less than 33%) were included in the analysis.

    Optical coherence tomography angiography

    The ONH vessel density was evaluated at baseline using the OCT AngioVue system.19 Each volume in this system contains 304×304 A-scans with two consecutive B-scans captured at each fixed position. The split-spectrum amplitude-decorrelation angiography (SSADA) method was used to capture the dynamic motion of the red blood cells and provides a high-resolution 3D visualisation of perfused retinal vasculature. Vessel density was automatically calculated as the proportion of measured area occupied by flowing blood vessels defined as pixels having decorrelation values acquired by the SSADA algorithm above the threshold level. Circumpapillary vessel density (cpVD) was calculated in the region defined as a 750 μm wide elliptical annulus extending from the optic disc boundary.

    Statistical analysis

    Distributions of the numerical values were explored with histograms. Non-parametric tests were used for all statistical analyses. The vessel density and RNFL thickness parameters were compared between APAC and fellow eyes at each time-point using the Mann-Whitney U test. Comparison of parameter values at initial visit and final follow-up was performed using the Wilcoxon signed-rank test. Univariate regression analysis was performed to determine the factors that were associated with final visual field mean deviation (VF MD) in APAC eyes. The potential predictors with p<0.10 and variance inflation factor less than 3 were selected for the final multivariate model, with age and sex included in the model.

    Conversion to an abnormal cpRNFL thickness was defined as any of the six sectors in the circular diagram showing conversion of the cpRNFL thickness from within the normal or borderline range of the normative database (green or yellow colour) to beyond the lower 99% confidence limit (red colour), and where the cpRNFL loss was evident in the corresponding area of the circumpapillary B-scan image9 (figure 1). Logistic regression analysis was performed to investigate the factors associated with the conversion to abnormal cpRNFL at 8 months after the resolution of an APAC episode. All statistical analyses were performed with commercial software (Stata V.14.0; StataCorp). A p value of less than 0.05 was considered statistically significant.

    Figure 1
    Figure 1

    Representative images of a study eye after acute primary angle closure episode. Retinal nerve fibre thickness (RNFL) was reduced during follow-up (A1 and A2) and new abnormal sectors appeared at 8-month visit (A2). Ganglion cell complex (GCC) thickness was also reduced during follow-up (B1 and B2). C1 and C2 demonstrate the optical coherence tomography angiography (OCTA) image at 2-month and 8-month visit. In the fellow eye, the RNFL was 103 µm and 101 µm and circumpapillary vessel density (cpVD) was 62.6% and 63.1% at 2-month and 8-month visit, respectively.

    Results

    After excluding nine cases due to loss of follow-up (four cases) or poor-quality OCTA images (five cases), 26 patients with broken APAC attacks were included for analysis. The mean age of the patients was 57.7 years (95% CI: 54 to 61.5). There were 18 women and 8 men. Mean IOP in the affected eye was 40.7 (32.1 to 49.3) mm Hg and 16.6 (15.1 to 18.1) mm Hg at presentation and 2-month follow-up, respectively. Patient demographics and other ocular findings in the affected and fellow unaffected eyes are shown in table 1.

    View this table:
    Table 1

    Comparison of clinical and ocular characteristics of eyes with APAC and their fellow eyes

    IOP increased to >21 mm Hg within 2 months after remission of the attack in six patients. However, IOP decreased to less than 21 mm Hg following cataract surgery or IOP-lowering medications. Thirteen of the 26 APAC eyes (6 eyes before 2 months after the APAC attack and 7 eyes between 2 months and 8 months after the attack) received cataract surgery during the follow-up period according to the patients’ preference, after being informed about the effects of lens extraction on the anterior chamber angle anatomy and IOP in eyes with primary angle closure. Two APAC eyes required treatment with medications at the 8-month follow-up.

    Table 2 shows the ONH cup to disc area and cpRNFL thicknesses at each follow-up. The cup to disc area of the affected eyes was comparable to fellow eyes at 2 months (p=0.423). However, it significantly increased at 8 months after remission in APAC eyes (p=0.003). The global and sectoral cpRNFL thicknesses were thinner in the affected eyes than in the fellow eyes at 2 months (94.0 (87.3 to 100.8) µm vs 103.1 (99.3 to 106.9) µm, respectively, for global cpRNFL (p=0.039) and decreased to 89.5 (84 to 95) µm at 8 months after remission (p=0.049.) Moderate to strong relationship was found globally and sectorally between RNFL thickness and cpVD at 8-month follow-up in APAC eyes (r between 0.47 and 0.76, p≤0.18 for all, online supplementary table 1).

    View this table:
    Table 2

    Comparison of optic nerve head parameters between month 2 and month 8 in APAC eyes and fellow eyes

    Although cpVD and sectoral vessel density were significantly lower in APAC eyes at 2 months after remission compared with the fellow eyes (56.7% (53.8 to 59.7) vs 62.9% (61.4 to 64.4) for cpVD, respectively, p=001)), no significant change in vessel density parameters of affected eye occurred between 2 and 8 months after remission (p=0.879) (table 3). Eleven eyes had good-quality OCTA images within a week following the APAC episode. In these eyes, cpVD decreased at month 2 (54.8%±8.3%) relative to the initial visit (57.0%±5.6%).

    View this table:
    Table 3

    Comparison of vessel density parameters between month 2 and month 8 in APAC eyes and fellow eyes

    Ten APAC eyes (35.7%) showed a conversion to an abnormal cpRNFL thickness at the 8-month follow-up. Logistic regression analysis showed that cpRNFL progression was significantly associated with a thinner global cpRNFL at 2 months (OR=1.1 (1.02 to 1.19), p=0.010), lower cpVD at 2 months (OR=1.57 (1.14 to 2.14), p=0.005) and IOP re-elevation after breaking the attack (OR=5 (0.94 to 26.53), p=0.059) in the univariable analysis (table 4). In the multivariable analysis, the only factor that was associated with cpRNFL progression was lower cpVD at 2 months (OR=1.79 (1.04 to 3.08), p=0.036).

    View this table:
    Table 4

    Factors influencing RNFL progression in APAC eyes: univariate and multivariate logistic regression

    Reliable visual fields were found in 10 and 21 patients at 2 months and 8 months follow-up, respectively. The age-adjusted model showed that greater cpVD at 2 months was a significant predictor of better VF MD after 8 months (B=0.92 (95% CI: 0.43 to 1.41), p=0.001). However, there was no association between RNFL thickness and VF MD 8 months after the acute attack (B=0.18 (95% CI: −0.12 to 0.47), p=0.218). Similarly, greater cpVD (B=−0.38 (95% CI: −0.61 to 0.15), p=0.001) at 2 months and not RNFL (−0.04 (95% CI: −0.16 to 0.07), p=0.400) was associated with lower VF pattern standard deviation (PSD) after 8 months in age-adjusted linear model.

    Discussion

    The current study showed that following a treated episode of APAC, there was significant thinning of the cpRNFL. While significant microvascular dropout was observed in affected eyes after 2 months, no change in vessel density parameters occurred between 2 and 8 months after remission. Vessel density at month 2 was a better predictor of glaucoma progression compared with cpRNFL at month 2. These data demonstrated that vessel density decreased soon after an attack of APAC and that OCTA measurements at month 2 may be useful for identifying patients with a higher risk of future glaucoma progression in APAC eyes.

    Studies using OCTA have shown that there is reduced perfusion in the ONH and the central retina with glaucoma.12 13 17–21 26 28 Decreased vessel density has been described as significantly associated with severity of VF damage independent of cpRNFL damage.12 29 30 However, most of these studies focused on retinal vessel density in eyes with POAG.

    Our results showed that vessel density dropout is evident in APAC eyes at 2 and 8 months after remission compared with fellow eyes. Loss of vessel density in APAC eyes reflects the loss of capillaries and may be a measure of reduced perfusion after a sudden rise in IOP. In an earlier study, OCTA showed a significant reduction in peripapillary vessel density 2 to 120 days after the episode in APAC eyes, even when structural measurements were not significantly changed.26 More recently, microvascular dropout was found in APAC eyes even at 1 week after the attack and vessel density continued to decrease for 6 weeks.

    A lower prevalence of choroidal microvascular dropout in PACG compared with POAG has been reported, and it was suggested that this might be due to the pathogenesis of these glaucoma subtypes being different. In particular, it was suggested that non-IOP-related (vascular) factors have less of a role in the pathogenesis of PACG.22 The findings might differ from APAC eyes as retinal perfusion can be markedly reduced by elevated IOP in the 40 to 50 mm Hg range during the acute episode.31 Moreover, the pattern of glaucomatous damage has been reported to be different after an acute IOP rise compared with a chronic IOP rise.23–25

    The current study demonstrated significant cpRNFL thinning between 2 and 8 months in the affected APAC eye. Previous studies have shown a progressive decrease in cpRNFL after a short period of thickening.6–8 In a longitudinal study,6 cpRNFL thickness was found to decrease significantly from 2 to 16 weeks after APAC, with the greatest change occurring in the inferior quadrant. Another study reported a significant decrease in cpRNFL thickness by 6 months or later relative to the previous visit.9 Interestingly, decreased visual field sensitivity also has been shown to progress after an episode of APAC.2

    The progressive thinning of the cpRNFL in the weeks after the initial insult may be attributed to secondary degeneration in the propagation of damage after APAC.32 33 Brubaker34 reported a series of patients in whom the glaucoma continued to progress after therapeutic normalisation of IOP. He suggested that one possible mechanism might be that RGCs become hypersensitive to IOP due to the irreversible damaging effects of previously elevated IOP. In APAC, the abrupt IOP elevation compresses the vessels in the prelaminar region.35 Low perfusion pressure interferes with nutrition and the normal physiology of axons in the area of lamina cribosa.36 We hypothesise that the change in microcirculation after an APAC episode has a role in the secondary degeneration of the RGCs. However, one cannot exclude the possibility that reduction of the vessel density can be detected first due to RGC swelling.

    A recent study17 on eyes with POAG found that reduced vessel density is associated with faster rate of glaucoma progression. This phenomenon might be exaggerated in APAC eyes compared with PACG and POAG eyes with a chronic and modest increase in IOP. Moreover, it was observed that cpRNFL thinning that occurred after IOP was controlled after APAC, while cpRNFL thickness did not progressively decrease in PACG eyes after IOP was lowered.37 In the current study, vessel density did not change between 2 and 8 months after remission in APAC eyes and the vessel density was lower in the APAC eyes compared with fellow eyes at 2 months. In the 11 eyes where good-quality OCTA images were available after the APAC episode, cpVD decreased at month 2 relative to the initial visit. In a previous investigation, we showed progressive decrease of vessel density for 6 weeks after an APAC episode. These results suggest that most of the changes in the vessel density happen earlier after the attack.

    In the current study, vessel density at 2 months was the best predictor of glaucoma progression in the affected eye. The oedema of retina after the acute episode might be one reason for a weaker association between cpRNFL thickness at 2 months and glaucoma progression. This is in agreement with a recent study showing that peripapillary vessel density is significantly correlated with visual field loss in glaucomatous eyes with a history of APAC.21 In another cross-sectional study in APAC eyes, peripapillary vessel density was more strongly linked to PSD than to any other variable.26 While previous results have been equivocal and variable, a longer duration of symptoms,25 greater IOP increase,38 larger CD ratio at baseline,39 worse initial visual field38 and lamina cribrosa depth reduction have been suggested as potential risk factors for glaucoma progression after APAC. Eyes with sustained severe episodes of APAC are thought to be particularly at risk. Perimetric examination during acute episodes is difficult and usually unreliable, and OCT measurement of RNFL thickness is influenced by optic disc oedema in the first few weeks after attack.6 8 The present data showed that OCTA measurements at 2 months might be a more sensitive method for detecting patients with higher risk of future glaucoma progression in APAC eyes.

    The present study had some limitations. First, the ideal study would perform imaging investigations at the time of the onset of APAC, but this was not possible due to the presence of corneal oedema. Good-quality OCTA images were only available for 11 cases during the first week following the remission. As with prior studies of APAC, baseline thickness and vessel density parameters were not available, and parameters from the fellow eyes were used as surrogates for baseline values. Second, some APAC eyes underwent lens extraction, but most unaffected eyes did not. This might have influenced the quality of SDOCT and OCTA images and their measurements.40 However, most of the eyes had a mild degree of cataract, and any effects on the results would have been minimal. Third, we excluded cases in which the attack was not effectively treated, which might introduce bias if those eyes sustained more severe ocular damages during APAC. Fourth, reliable visual fields were available in only 21 eyes at 8 months, and our sample is too small to meaningfully explore regional structure-function relationship or detect factors that had small effects on glaucoma progression. Moreover, OCT imaging was performed only once at 8 months in the present study, and the reproducibility of the measurement was not assessed. Finally, information regarding the onset of APAC symptoms is self-reported, which might not be reliable.

    In conclusion, early reductions of the vessel density and long-term decrease in the cpRNFL were observed during the first 8 months after an APAC attack. A lower vessel density at 2 months was the only parameter associated with conversion to an abnormal cpRNFL thickness. Therefore, glaucomatous progression should be suspected in eyes with lower vessel density after effective treatment of an episode of APAC and needs attentive follow-up for glaucoma. Future studies with more frequent thickness and vessel density measurements after acute attack might provide more information about the trend and factors related to glaucoma progression.

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    Footnotes

    • Correction notice This article has been corrected since it was published Online First. Minor formatting has been corrected.

    • Contributors SM and RNW conceived and designed the trial. SM and RNW were the chief investigators and oversaw the trial throughout. Data were provided by SM, MS and MAF. SM, MS and MAF monitored the data and SM, HLR and BYX performed analyses. All authors contributed to the interpretation of data, drafting of the report and decided on its content. All authors approved the final version.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests RNW: Aerie Pharmaceuticals (C), Alcon (C), Allergan (C), Bausch & Lomb (C), Eyenovia (C), Unity (C), Heidelberg Engineering (F), Carl Zeiss Meditec (F), Genentech (F), Konan (F), OptoVue (F), Topcon (F), Optos (F), Centervue (F). HLR: Santen (C), Carl Zeiss Meditec (C), Allergan (C).

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon request.