The incorporation of minimally invasive glaucoma surgery (MIGS) devices into the glaucoma management algorithm has been challenging, in part due to an incomplete understanding of aqueous flow dynamics within the episcleral venous system (EVS).
Whereas in previous years the most widely used surgical options, trabeculectomy or tube shunt surgery, bypassed the conventional drainage system, clinicians must now decide whether to enhance or bypass the eye’s natural drainage system and which tools to use. These decisions are presently made in the absence of a quantitative assessment of the episcleral venous system’s capacity to accept additional aqueous, and this may contribute to variable intraocular pressure (IOP) results between patients.1–3 It is our hypothesis that visualization of aqueous flow within the EVS during the perioperative period may provide information to assist with surgical decision-making.
The anatomic pathway of aqueous drainage from the eye is well documented,4–9 but our physiological understanding remains limited. Noninvasive assessment in vivo has been challenging and further work in this area is required to identify the significance of changes within the outflow system in relation to open-angle glaucoma. In this study we used Hemoglobin Video Imaging (HVI) to study aqueous outflow (AO) patterns within the EVS before and after trabecular bypass surgery (TBS) with iStent Inject (Glaukos Corporation, USA) and cataract surgery. Success rates (unmedicated IOP reduction ≥20%) with iStent Inject are ∼76% to 78%.10,11 Our aim is to characterize the perioperative changes in aqueous drainage into the episcleral veins, following interventions that facilitate outflow into Schlemm canal. We expect this information will enhance our existing knowledge of the pathophysiology of glaucoma and the consequences of surgical interventions, leading to improved surgical outcomes.
This study was undertaken in accordance with the Declaration of Helsinki and approved by the Human Research Ethics Committee, Prince of Wales Hospital, South Eastern Sydney Local Health District, Sydney, Australia (LNR 16/224). Written informed consent was obtained from all participants.
HVI was performed on 29 eyes, including 15 with glaucoma and 14 normal controls (Table 1). Fourteen consecutive glaucoma patients went on to have TBS. One glaucoma patient and 2 normal controls underwent cataract surgery with intraocular lens insertion only. All controls were phakic and had IOP <21 mm Hg. Patients undergoing TBS had open-angle glaucoma of varying aetiologies. All patients continued IOP-lowering treatment until the morning of surgery. In addition to the 29 study eyes, HVI was performed on one patient with ocular hypertension (OHT) who was subsequently commenced on brimonidine tartrate 0.15% in both eyes.
The HVI setup has been described previously and images were obtained using the same methods.12,13 In summary, a monochromatic Prosilica GC1380H camera mounted on a Zeiss SL130 slit lamp with a bandpass filter transmitting wavelengths from 540 to 580 nm was used to capture the real-time image series. No drops or dyes were required before HVI. The patient sat upright at the slit lamp in a darkened room and the episcleral venous system was mapped by imaging the entire limbus of each eye. One-minute videos (1800 frames) of the nasal and temporal conjunctival and episcleral microcirculations were recorded. Screening to identify aqueous veins was performed at a nominal magnification of ×12. Areas of AO were identified and examined more closely using ×20 magnification, at which each pixel covers 4 μm2.
Participants underwent preoperative HVI within 3 months of their surgery date. HVI was repeated at each regular follow-up visit during the postoperative period (1 wk, 4 wk, 3 mo, and 6 mo). HVI was also performed 1 day after surgery where possible (n=4). The control group underwent HVI on a single occasion. The values obtained from these patients formed comparative data for preoperative glaucomatous patients. The OHT patient was imaged before, and 6 weeks after, commencement of brimonidine.
In some cases, identification of an aqueous-carrying vein was only possible retrospectively, once flow had been established. This may represent recruitment of a normal vein by aqueous, or reperfusion of a pre-existing aqueous vein after TBS. In such cases there were occasions when the vein had not been the main object of attention in the preoperative angiogram and preoperative images were poorly focused; however, all were adequate for study.
Peribulbar or sub-Tenon block was used to achieve anesthesia. A temporal corneal approach was used in all surgical cases. Nine cases underwent phacoemulsification and insertion of posterior chamber intraocular lens before TBS. In the remaining 5 cases, TBS was an isolated procedure (standalone). 1.4% sodium hyaluronate maintained the anterior chamber and a Volk Transcend Vold Gonio intraoperative gonioscopy lens was used for angle visualization. All patients had TBS with 2 iStents injected into Schlemm canal within the nasal quadrant, between 1 and 2 clock hours apart. Stent positioning was not based on preoperative aqueous vein patterns, because this study was undertaken to demonstrate real-world aqueous flow characteristics associated with TBS. Further studies are planned to address targeted stent insertion.
In all cases, blood was seen to reflux into the anterior chamber during stent insertion. Further 1.4% sodium hyaluronate was injected to tamponade blood reflux if visualization for second stent insertion required improvement. Viscoelastic was removed and the anterior chamber was pressurized with balanced salt solution to reduce the risk of hyphaema during the early postoperative period. Prophylactic intracameral cefazolin 0.5 mg/0.1 mL was injected at the completion of surgery.
All IOP-lowering treatment was stopped in every study eye on the day of surgery. The decision whether to recommence IOP-lowering treatment during the postoperative period was made on an individual basis, depending on the severity of glaucoma and the IOP level. All patients were treated with guttae chloramphenicol 4 times a day for 1 week and a weaning course of guttae dexamethasone 0.1% (Novartis) for 4 weeks. Gonioscopy was performed at every postoperative visit to confirm positioning of each stent.
As blood-filled episcleral veins join those containing aqueous, the stream of aqueous migrates towards the center of the vessel, while blood remains at its periphery: the paraxial zone of low pixel density defines the aqueous stream (Fig. 1C).
In HVI, outside the aqueous stream, pixel density is proportionate to the depth of red cells in the blood column. Transepts of aqueous veins show increasing density from the periphery until the low-density central aqueous column and we have shown that the aqueous column diameter is accurately defined by the separation between the 2 points of maximum pixel density.13 Images of aqueous veins were processed in accordance with this previously described technique, the aqueous column cross-section area (AqCA) being measured to reflect aqueous flow.13 We have already shown this to correlate inversely with IOP immediately after selective laser trabeculoplasty.13
Sometimes aqueous stratifies to one side of the episcleral vessel, giving the appearance of separated layers of aqueous and blood, a phenomenon previously described by Ascher.14 Despite this, HVI can detect the thin stream of erythrocytes that separates aqueous from the vessel wall, and this permits measurement of AqCA (Fig. 2). Aqueous veins may be devoid of blood as they emerge from Schlemm canal; however, all our measurements were made after erythrocytes had entered the vessel.
The number and location of aqueous veins were tallied for each eye and compared between groups. When multiple smaller aqueous veins drained into one larger episcleral vein, this was recorded as a single aqueous vein.
Image J software was used to generate the transept of pixel density (ie, depth of red blood cells) across aqueous veins. The average of 3 measurements was used to represent aqueous column diameter, which was converted to AqCA. Measurements were taken before surgery and at each postoperative follow-up visit. If AqCA was unmeasurable then flow was characterized as visible or unrecordable. This distinction was made to denote a difference between cases where aqueous was visualized (Fig. 1B), but flow appeared slow (AqCA=3, derived from nominal aqueous column diameter of 1), compared with vessels where there was neither blanching nor a defined aqueous column (Fig. 1A) (AqCA=0).
AqCA measurements were recorded from the most prominent aqueous vein (single vein with the greatest AqCA). AqCA was correlated with IOP and medication reduction for intervention eyes. Statistical analysis between preoperative and postoperative AqCA and IOP was undertaken using a 2-tailed, Mann-Whitney test, Wilcoxon signed-rank test and Spearman rank order correlation coefficient (Microsoft Excel version 14.6.7).
Aqueous column diameter measurements were repeatable for each eye. Fluctuations in flow occurred due to the pulsatile and dynamic nature of AO. However, variations at a single timepoint were limited to <40% of the measured column diameter, which is consistent with previous work.13
Distribution of Aqueous Veins
There was no significant difference in the number of aqueous veins visualized in the 2 groups (P=0.30). Glaucomatous eyes were seen to have between 0 and 6; eyes without glaucoma had between 2 and 5.
Nasal fields contained approximately twice as many aqueous veins as did the temporal fields; however, at least 1 temporal aqueous vein was identified in 8 glaucomatous patients before and after surgery, and in 11 controls.
The vein with the largest aqueous column diameter was located within 2 clock hours of the nasal meridian in every glaucomatous and control eye.
Reduction of AqCA in Glaucomatous Eyes
Before surgery, AqCA was significantly reduced in glaucomatous eyes compared with normal controls (P<0.0001) (Fig. 3). AqCA was inversely correlated with preoperative IOP (N=29; rs=−0.6; P<0.001) and number of medications (N=29; rs=−0.8; P<00001).
Correlations between AqCA and postoperative IOP did not reach significance and are difficult to interpret due to recommencement of IOP-lowering treatment in some patients.
Effectiveness of TBS
In the glaucoma group, of the 14 patients that underwent TBS, at the 6 months postoperative follow-up period (n=9), 6 patients achieved ≥20% reduction in IOP without medication. Median preoperative IOP was 20.5 mm Hg on 3 medications, including 3 patients requiring oral acetazolamide. Postoperative IOP (Fig. 4) measured at 1 day was 13 mm Hg (N=14), 1 week 19 mm Hg (N=14), 4 weeks 19.5 mm Hg (N=14), 3 months 13 mm Hg (N=10), and 6 months 14 mm Hg (N=9). Significant reductions in IOP and number of medications were seen at 3 (N=10; P<0.05) and 6 months (N=9; P<0.05).
It was necessary to recommence IOP-lowering medication during the postoperative period in 4 cases: 3 following standalone TBS and 1 after combined phacoemulsification/TBS. Despite measurable AqCA before surgery, the latter was the only patient who did not demonstrate an improvement in AqCA at any point during the study. Micropulse cyclodiode laser was required after 6 months of follow-up, which enabled cessation of oral acetazolamide. This was the only patient who required an additional IOP-lowering procedure postoperatively.
The aqueous column was measurable at the end of each patient’s observation period, with the exception of one case. This patient had refused traditional glaucoma drainage surgery and before TBS had IOP of 30 mm Hg on 4 IOP-lowering agents (including oral acetazolamide) with no visualized AO. Despite establishment of AO with isolated TBS, he required recommencement of brimonidine and fixed-combination brinzolamide/timolol after 1 month. He stopped all treatment after 5 months and, at his 6-month review, his IOP measured 45 mm Hg and AO could not be visualized. Recommencement of topical treatment controlled his IOP (14 mm Hg 1 mo later) and AO was re-established.
No intraoperative complications occurred in any patient. All stents appeared well-positioned at each follow-up, and with no visible obstruction. Comparison between combined phacoemulsification/TBS and standalone TBS was limited in this study due to small sample size. Detailed comparison is planned for a future study.
Re-establishment of AO
Preoperative AO was unrecordable in 3 patients. All episcleral veins appeared full of blood and IOP was uncontrolled on maximal tolerated medical therapy, including oral acetazolamide in 2 patients. The decision to avoid bleb-forming surgeries in these cases was based on patient preference, despite patients being given advice to undergo traditional drainage surgery. All 3 patients developed measurable laminar flow at 1 month following TBS, indicating a return of aqueous to blood-filled aqueous veins (Figs. 1, 5, 6).
Patterns of Aqueous Flow After TBS
After TBS, visible AO always remained most prominent in the nasal quadrant; however, AqCA of the largest temporal vein increased significantly in 5 patients (all after combined phacoemulsification/TBS), 4 weeks after surgery (P<0.03). The remaining patients did not demonstrate temporal AqCA improvement. Standalone TBS was not associated with improved temporal AqCA in any case.
Mean nasal AqCA was similar between combined (N=9) and standalone cases (N=5) preoperatively (126 and 94 μm2; P=0.42) and at 1 month (349 and 404 μm2; P=0.69), respectively. Direct comparison between the groups beyond 1 month was not possible due to small sample size in the standalone TBS group.
HVI was performed in 3 cases on the first postoperative day. It was not possible in the remainder of the cases due to subconjunctival hemorrhage or patient preference. In all 3 cases there was dilation and tortuosity of episcleral vasculature, which is a characteristic feature of inflammation.15 AO was not detectable, but all 3 cases had IOP ≤14 mm Hg and laminar flow recovered within 1 week (Fig. 7).
Laminar flow was also confirmed 1 week after TBS in all patients who had visible preoperative AO anywhere in the nasal quadrant. In some patients, a second episcleral vessel, devoid of aqueous before surgery, demonstrated laminar flow at 1 week (Fig. 8).
The recovery of AO in the 3 patients with no preoperative evidence of aqueous veins was particularly interesting. One case recovered laminar aqueous flow by 1 week postoperatively, but 2 passed through a phase in which episcleral vessels became blanched (week 1 postoperative), and had developed laminar aqueous flow by week 4 (Figs. 1, 6).
Flow within the conjunctival and episcleral vasculature altered in every patient following TBS. In 1 case, a previously invisible or closed aqueous vein demonstrated laminar flow 1 week after surgery (Fig. 9). There was additional improvement in flow through 2 other aqueous veins that had been evident preoperatively. The patient had IOP of 16 mm Hg on 3 IOP-lowering agents before TBS, and this fell to 11 mm Hg, where it remained without any treatment throughout the postoperative period.
Time Course of Change
AqCA increased significantly during the study period (Fig. 10) with improvement at 4 weeks (N=14; P=0.002), 3 months (N=10; P<0.05), and 6 months (N=9; P<0.05). AqCA did not increase suddenly after TBS, but improved gradually over months (Fig. 11). The time-course of this varied between cases.
Patterns of Aqueous Flow After Cataract Surgery and Brimonidine
An increase of AqCA in nasal and temporal vessels was seen in all 3 cases (1 with glaucoma, 2 without) who had isolated cataract surgery. In the glaucomatous patient, AqCA improved from visible only (AqCA=3 μm2) in each vessel to 547 μm2 in the nasal aqueous vein and 1168 μm2 in the temporal aqueous vein after 4 weeks. IOP was 16 mm Hg on 3 IOP-lowering agents before surgery, and 22 mm Hg unmedicated at 4 weeks after surgery. Similarly, both patients without glaucoma who had cataract surgery demonstrated an improvement in AqCA after 4 weeks; patient 1 improved from 1427 μm2 in both vessels to 1712 μm2 in the nasal vessel and 2188 μm2 in the temporal vessel, although in patient 2 the nasal vessel improved from 1010 to 1202 μm2, and the temporal vessel from 324 to 392 μm2. Longer-term follow-up and a larger cohort are planned to compare AO in patients having cataract surgery or TBS.
In a single patient with OHT, the effect of brimonidine commencement on AqCA of the largest aqueous vein was examined in both eyes. IOP reduced from 23 mm Hg right eye and 22 mm Hg left eye before treatment to 17 mm Hg in both eyes after 6 weeks of brimonidine. AqCA increased >2.5 times in both vessels studied; from 232 to 634 μm2 in the right eye and 324 to 835 μm2 in the left eye.
We used HVI, a noninvasive outpatient technique, to visualize aqueous drainage within the EVS before and after TBS. Angiographic AO patterns have been shown to improve following TBS,6 but real-time analysis of AO in physiological conditions has only recently been introduced.12,13 Our study suggests AO improves in eyes with established preoperative flow, and is restored in eyes without recordable flow preoperatively.
This study compared aqueous flow patterns in normal and glaucomatous eyes, and then observed a cohort of glaucomatous patients for up to 6 months after TBS. A very broad range of glaucoma severity was included. The sample size was modest, but our results were consistent. For the purpose of this study, we used the cross-section area of the aqueous column to quantify AO. This approach is here validated by the significant difference in AqCA between control and glaucomatous eyes.
We were unable to include a medication washout period for any patient, and so the possibility remains that some changes depicted in the EVS may have been influenced by cessation or recommencement of topical IOP-lowering therapies. Cessation of brimonidine at the time of surgery could relax episcleral vasoconstriction and assist AO, and it is conceivable that this explains reperfusion of the previously invisible aqueous vein in Figure 9. Nevertheless, both eyes from our OHT patient showed an increase in AqCA, 6 weeks after brimonidine commencement, suggesting an improvement in AO. Johnstone et al16 also demonstrated an acute increase in aqueous discharge into the episcleral venous system 2 hours after instillation of brimonidine in 8 normal subjects. The longer-term effect of its use has not been reported to our knowledge. Angiographic responses to different topical treatments have not yet been studied methodically. No patient was using local AO-promoting therapies such as latanoprostene bunod or Rho-kinase inhibitors (these are not yet available in Australia).
Cataract surgery appeared to improve aqueous drainage into nasal and temporal episcleral veins, whereas standalone TBS was associated with only nasal AqCA improvement. This suggests that cataract surgery may augment AO when combined with TBS; AqCA of 5 combined phacoemulsification/TBS cases improved in nasal and temporal aqueous veins. We acknowledge that further studies are required to separate this effect from iStent insertion in combined cases.
A number of studies on cadaveric eyes have clearly demonstrated the anatomy of the conventional AO pathway, dating back to Ascher and Ashton early work.4,5,14 More recently, intraoperative aqueous angiography, using fluorescein and indocyanine green at the time of TBS,6 has shown detailed outflow pathways predominantly in the nasal quadrant, consistent with previous in vivo7–9,17,18 and ex vivo19,20 distal outflow work. Our study confirms segmental AO with a higher incidence of aqueous veins in the nasal episcleral vasculature in patients with and without glaucoma.
Our studies of aqueous veins in 15 glaucomatous participants showed widely variable preoperative AO patterns, ranging from no visible flow to healthy laminar flow. This was significantly different from the 14 control subjects, who all demonstrated good AO. AqCA was significantly reduced in glaucomatous eyes compared with controls, an observation that will be studied in more detail in future work. AO is dynamic and likely to undergo diurnal variation, which also needs to be considered.
Most of the TBS cohort required large numbers of IOP-lowering agents before surgery, despite which some patients still had very high preoperative IOPs. TBS is commonly advocated in mild to moderate glaucoma.21,22 We have demonstrated that TBS can re-establish AO in a range of glaucoma patients, but this study cohort is not a true representation of real-world case selection. Three patients from the TBS cohort were initially advised to have glaucoma drainage surgery. None of these patients would agree to bleb-forming surgery, but were willing to undergo TBS. This provided a unique opportunity to assess the IOP and HVI responses in eyes with poor IOP control.
Proof of aqueous vein reperfusion has been elegantly demonstrated by Huang et al,6 but in nonphysiological states. Our study showed re-establishment of aqueous flow after TBS in all 3 patients who had lacked aqueous veins preoperatively. TBS also increased AqCA regardless of the state of preoperative aqueous drainage. However, aqueous flow did not suddenly increase as intraoperative angiography might predict.6 Aqueous vein congestion, seen in all 4 patients imaged on the day after surgery, was presumed to be related to postoperative inflammation. IOP was low in these cases, but aqueous was not visible. By 1 week, there was recovery of AO and normalization of the episcleral vasculature in most patients. Gradual improvement in AO occurred over weeks to months, and in some cases fluctuation in flow occurred.
The speed and quality of aqueous vein revitalization following TBS differed between patients and likely depended on the functionality of Schlemm canal and the EVS. In some patients, laminar aqueous flow only became apparent after 4 weeks, possibly indicating gradual reperfusion of collector channels and/or Schlemm canal, or may reflect attempts by the eye to establish a new homeostatic balance of aqueous flow. Generalized blanching of vessels, seen in some patients, may reflect low aqueous flow velocity, with failure of discrete aqueous and erythrocyte columns to form; alternatively, aqueous channels that have not yet joined the episcleral venous circulation. Aqueous flow accelerates during the postoperative period and flow laminae develop within episcleral vessels. This variability in flow may explain IOP variations in the early postoperative period.
The postoperative variation in IOP results and flow dynamics suggests that multiple mechanisms may contribute to IOP dysregulation, other than TM dysfunction. These may include disorganized control of episcleral venous pressure and aqueous production, as well as effects from the use of postoperative topical steroid and the cessation of IOP-lowering drops. It is clear that the eye may take time to recover from the shock of a sudden change in fluid dynamics caused by TBS. We hypothesize that the EVS may participate in the detection and control of IOP.
The patency and resilience of Schlemm canal almost certainly plays a significant role in aqueous drainage.23–25 Evolving techniques to image the trabecular meshwork and Schlemm canal, such as phase-sensitive OCT,21 may complement HVI.
Many interventions to control IOP affect AO and, using HVI, we have been able to characterize some of these changes. In this study of patients undergoing TBS, we have observed an increase in aqueous column diameter, and the restoration of laminar aqueous flow where it had not been visible preoperatively. Furthermore, this is the first report of a noninvasive examination of aqueous veins in which evolution of surgically induced changes in AO can be monitored and compared with characteristics recorded preoperatively. In this way, HVI can be applied to other techniques that manipulate AO; and subsequent findings may contribute to a greater physiological understanding of IOP homeostasis. Further work is required to identify specific HVI features that are predictive of surgical success or failure. HVI is also a promising technique for comparing different MIGS devices and for investigating the targeting of TBS according to preoperative AO.
Using HVI, we have demonstrated impaired episcleral aqueous flow in glaucoma, and the manner of its restoration by TBS. This clinical technique enables the physiology of AO to be studied and quantified to establish normal drainage, define pathology and monitor therapeutic interventions.
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