Abstract
Purpose:
Evaluating bleb morphology is crucial after glaucoma filtering surgery. Advances in anterior segment optical coherence tomography (AS-OCT) allow for objective assessment. While various parameters differentiate functional from failed blebs, limited information exists regarding variations within functional blebs. This study aimed to identify factors influencing morphology of functional blebs following implantation of Preserflo MicroShunt.
Methods:
Eyes with functional blebs after Preserflo were retrospectively included. Age, gender, lens status, preoperative intraocular pressure (pre-IOP) and number of glaucoma medications were documented along with biometric measurements as axial length (AL), white-to-white distance, and anterior chamber depth. Postoperative data included time elapsed since surgery (TaS) and postoperative IOP (post-IOP). Bleb dimensions were measured using AS-OCT including maximal bleb height (MBH), width, length (MBL), bleb wall thickness (BWT), and bleb distance to limbus (DtL) along with dimensions of episcleral lake (maximal height, width [MLW], and length). Linear regression models were applied to correlate these parameters with bleb dimensions.
Results:
Included were 50 eyes from 50 patients. Mean IOP decreased from 25.3 ± 10.0 to 11.9 ± 3.0 mm Hg after 278.5 ± 221.9 days after surgery. MBH correlated negatively with age (unstandardized coefficients [uSC] = −0.012) and TaS (uSC = −0.001, P = 0.008 for both). BWT correlated negatively with age (uSC = −0.013, P = 0.02), MBL with AL (uSC = −0.566, P = 0.01) and MLW with pre-IOP (uSC = −0.073, P = 0.02). DtL exhibited a positive correlation with post-IOP (uCS = 0.136, P = 0.02).
Conclusions:
Morphology of functional blebs might be influenced by multiple factors such as age, TaS, AL, and pre- and post-IOP.
Translational Relevance:
Age, time after surgery, axial length, and preoperative and postoperative IOP could affect the morphology of a functional bleb; hence, these factors should be taken into consideration when making treatment decisions.
This retrospective study included eyes of patients who underwent Preserflo implantation as a treatment for medically noncontrolled glaucoma and developed a functional bleb after surgery. We excluded eyes within the first three months after surgery because of the rapid changes in morphology during the ongoing wound healing process.
14 Additionally, we excluded eyes that had undergone any prior ocular surgeries (such as vitrectomy, pterygium excision, strabismus surgery, or corneal transplantation), any type of glaucoma-filtering surgery (such as trabeculectomy, shunt tubes, deeps sclerectomy, and XEN), or needling/open bleb revision. Eyes undergoing uncomplicated cataract surgery using phacoemulsification were still allowed to be included. A functional bleb was defined as having an IOP ≤ 18 mm Hg without medication at the time of examination, along with a reduction of at least 20% from the time of surgical indication. Only one eye per patient was included, with preference given to the eye that underwent surgery first if both eyes were eligible for inclusion.
We gathered the following preoperative data: age, gender, eye laterality, type of glaucoma, lens status (LS, phakic or pseudophakic), preoperative IOP (pre-IOP) measured in millimeters of mercury using a Goldmann applanation tonometer, and the number of glaucoma medications taken at the time of surgical indication. Additionally, we recorded biometric data that could potentially influence the aqueous drainage pathway, such as axial length (AL), white-to-white distance (WtW), and anterior chamber depth (ACD). Postoperative data included the time elapsed since surgery (TaS) and post-operative intraocular pressure (post-IOP). The reduction in intraocular pressure (red-IOP), calculated as the difference between pre-IOP and post-IOP, was also documented.
During postoperative follow-up visits, we examined bleb morphology using swept-source AS-OCT (Anterion; Heidelberg Engineering GmbH, Heidelberg, Germany). We performed a total of 90 scans for each bleb in two different directions, as previously described,
15 using the imaging module. The qualitative assessment of the blebs was based on the Jenaer bleb grading system,
15 which included evaluating changes in the conjunctiva (C0 = no changes; C1 = intraconjunctival cysts; C2 = subconjunctival spaces), the tenon capsule (T0 = no changes; T1 = hyper-reflective changes; T2 = hyporeflective changes; T3 = cavernous changes), and the episcleral space (ES0 = no visible episcleral lake; ES1 = visible episcleral lake). In addition, we measured eight geometrical parameters of the bleb and its contents as follows: maximal bleb height (MBH), width (MBW), length (MBL), as well as bleb wall thickness (BWT) and distance to the limbus (DtL). In addition to that, we measured the episcleral lake, whenever visible, including maximal height (MLH), width (MLW), and length (MLL). The measurements were conducted by a single experienced examiner (S.M.H.), who maintained a blind status regarding the clinical data. Qualitative classification was carried out by comparison to published standard images, as outlined in the reference article.
15 Detailed definitions of these measurements are listed in
Table 1 and shown in
Figure 1. We measured biometric data, including AL, WtW, and ACD, using the same AS-OCT machine (Anterion) with the cataract module.
Table 1. Definition of Measured Bleb Parameters Using Anterior Segment OCT
Table 1. Definition of Measured Bleb Parameters Using Anterior Segment OCT
To prepare for the surgery, all glaucoma medications are discontinued four weeks prior to the procedure. Patients are prescribed dexamethasone eye drops (Dexapos COMOD 1.0 mg/ml eye drops, Ursapharm, Saarbrücken, Germany) to be used three times daily and oral Acetazolamide 250 mg (Glaupax 250 mg tablets, Omni-Vision, Puchheim, Germany), the dosage of which is adjusted based on IOP measurements.
After disinfection, a fixation suture (7-0 Vicryl; Ethicon, Somerville, NJ, USA) is placed in the cornea at the 12 o'clock position, and the surgical field is exposed. A peritomy is performed superiorly over a span of two hours, with two radial cuts made in the conjunctiva. The Tenon layer is then dissected extensively from the sclera in a horizontal and posterior direction, and caution is exercised while cauterizing the episcleral vessels. Two Lasik cornea shields soaked in MMC solution (0.2 mg/mL) are placed under the Tenon layer side by side and as posteriorly as possible for a duration of three minutes. Subsequently, the surgical field is irrigated with 20 mL of balanced salt solution. The sclera is marked 3 mm posterior to the limbus, and a knife is used to create a scleral tunnel measuring approximately 2 mm in length. The 25-gauge needle is inserted into the anterior chamber through the tunnel, ensuring the appropriate distance from the cornea and iris. The Preserflo-MicroShunt is then inserted into the anterior chamber via the tunnel. After confirming proper drainage, the Tenon layer is approximated to the limbus and secured to the sclera using two interrupted sutures (10-0 Vicryl), followed by closure of the conjunctiva with two to four interrupted sutures (10-0 Vicryl).
Patients are prescribed Ofloxacin eye drops (Floxal 3 mg/mL eye drops; Bausch & Lomb, Rochester, NY, USA) to be administered five times daily for a duration of one month. In addition, dexamethasone eyedrops (Dexapos Comod 1.0 mg/mL eye drops; Ursapharm, Saarbrücken, Germany) are initially administered every two hours during the first week and then reduced to five times daily starting from day 8. The dosage of dexamethasone is gradually reduced by one drop per day every four weeks. As per this schedule, patients receive dexamethasone eye drops for a total of five months after surgery. Postoperative injection of antimetabolites (5-fluorouracil) was considered according to the conjunctival appearance and vascularization.
The collected data underwent normality testing using the Shapiro-Wilk test. Bivariate correlations were performed between the independent variables (age, pre-IOP, TaS, post-IOP, and red-IOP), as well as the biometrical parameters (AL, WtW, ACD) using either the Pearson or Spearman correlation coefficient. Each of these variables was correlated with the dependent variables (MBH, MBW, MBL, BWT, DtL, MLH, MLW, and MLL).
Differences in the outcome parameters based on binary variables (sex or LS) were assessed using the Mann-Whitney U test. Variables that showed a correlation with an outcome at a significance level of P ≤ 0.05, or binary variables that demonstrated differences in the outcome at a significance level of P ≤ 0.05, were included in the multivariate linear regression models. Separate regression models were created for each of the outcome variables.
Informed consent was obtained from subjects included. The study was conducted in compliance with the tenets of the Declaration of Helsinki and approved by the local ethical committee of the Jena university hospital (Reg-Nr.: 2023-3018-Daten).
Successful healing and minimal scarring play crucial roles in achieving long-term surgical success after filtering surgery.
16,17 Various strategies exist to modulate wound healing during the postoperative phase
18 including the use of anti-inflammatory agents, factors that affect fibroblast proliferation, and angiogenesis inhibitors. The decision of when and how to intervene in the post-operative phase largely depends on the functionality of the bleb and thus on the assessment of its morphology.
1,4 The introduction of AS-OCT and its increasing use in evaluating bleb morphology has led to the development of new classification systems that also offer prognostic value.
7,19,20 Several tomographic parameters measured using AS-OCT have shown significant differences between functional and nonfunctional blebs after trabeculectomy where functional blebs were correlated with increased MBH, MLH, and BWT compared to nonfunctional ones.
9,21 Additionally, there is a wide spectrum of surgical technical variations in trabeculectomy, resulting in morphological diversity of blebs.
13,22 Therefore these variations should be taken into consideration when evaluating blebs. Studying blebs after implantation of Preserflo theoretically reduces many of the surgery-related variations observed after trabeculectomy, as the surgical technique for Preserflo is generally more straightforward and less modifiable. However, in clinical practice, we still observe a wide range of variations in bleb morphology after Preserflo, even among functional blebs. This diversity makes the evaluation of blebs more challenging and increases the risk of misinterpretation, leading to inappropriate interventions.
One of the interesting results of this study was that we observed tenon changes in all examined eyes. The most common forms were the hyporeflective changes (T2) followed by the hyper-reflective (T1) and cavernous (T3) changes. This is a result of the inclusion criteria where only functional blebs were analyzed. Blebs not showing any tenon changes are usually flat nonfunctional blebs, although nonfunctional blebs may also show other forms with different tenon changes.
Our understanding of the factors that potentially impact the morphology of functional blebs remains limited. Existing data primarily focus on comparing functional and nonfunctional blebs. Although this comparison is valuable in a clinical context, it is equally important to investigate the variations observed within functional blebs. Failure to accurately interpret these variations as signs of normal function can lead to negative consequences for patients. Therefore it is crucial to thoroughly examine and comprehend the range of variations within functional blebs to avoid misinterpretation and its potential detrimental effects on patient care.
Our study encompassed a comprehensive range of preoperative and postoperative parameters that could potentially influence bleb morphology. We investigated their correlation with measured dimensions and ultrastructure of the bleb. Interestingly, we observed that older patients with a longer duration since surgery tended to have lower bleb height. Similarly, there was a negative correlation between age and bleb wall thickness, indicating that older patients tended to exhibit thinner bleb walls. In a clinical context, IOP is regarded as a primary indicator of bleb function. However, it's crucial to also consider bleb morphology as another significant determinant. In the case of two patients with borderline IOP levels, the observation of a lower bleb height in an older patient several months after surgery is a typical presentation and should be interpreted within this context. Conversely, if a young patient exhibits a similar morphology a few weeks after surgery, it should raise concerns about potential bleb failure. This situation warrants closer follow-up and repeated IOP measurements. Age-related negative correlations with bleb height have been documented in earlier studies involving both successful and failed blebs after trabeculectomy and EX-PRESS shunt procedures.
23,24 This correlation was interpreted as a result in reduced success rates in younger patients. Confirming the negative correlation of age even within functional blebs should therefore be taken into consideration when evaluating bleb height or the thickness of its wall, as shallower blebs and those showing thinner walls might be a normal variation of functional bleb in older patients. The reason of this correlation remains unclear. One potential explanation could be the age-related increase in tissue laxity and reduction in tenon thickness.
25,26 These changes decrease tissue resistance and lead to increased aqueous diffusion over a larger bleb area resulting in reduced bleb height and wall thickness. Another possible explanation may involve age-related alterations in the vascular and lymphatic systems of the conjunctiva, which are responsible for the absorption of drained aqueous humor.
27 Although a study by Kawana et al.,
28 which included both functional and nonfunctional blebs, reported a negative correlation between postoperative IOP and bleb height and wall thickness, in our study we did not observe such correlations of height or wall thickness with other factors, such as pre- or post-IOP or biometric parameters.
The bleb height in our study, however, also correlated negatively with the time elapsed since surgery. Previous studies in a cohort of functional and nonfunctional blebs have shown that the height and wall thickness of blebs after trabeculectomy experience rapid increases during the initial three months after surgery, followed by stabilization.
29 Blebs during the first three months were, however, excluded in our study, which explains the difference to our study. According to our results, it appears that a "mature" functional bleb tends to flatten as time progresses. Because our study only included functional blebs, it is unlikely that this flattening is indicative of reduced bleb function. Instead, it could be explained by a late remodeling process of the conjunctiva and tenon tissues. The cause of this remodeling is not known, but one of the possible explanations might be the movement of the superior eyelid over a higher bleb during blinking.
During the design of this study, one of the key questions that emerged was the relationship between the dimensions of a functional bleb and the axial length. Theoretically, longer eyes may be associated with longer blebs. However, it is worth noting that myopic eyes exhibit higher concentrations of specific inflammatory cytokines such as angiopoietin-1, insulin-like growth factor-binding protein 2, interleukin-17B and the matrix metalloproteinase-2,
30 which could potentially have a negative impact on bleb dimensions. Our study revealed a negative correlation between axial length and bleb length. Although myopia itself did not show a correlation with increased failures after trabeculectomy,
31 the higher concentrations of inflammatory cytokines in myopic eyes
30 may contribute to the reduction in bleb length as axial length increases. Additionally, a positive correlation was found between axial length and the aqueous concentration of transforming growth factor beta-2, an important factor in the regulation of the extracellular matrix that is highly regulated in patients with primary open-angle glaucoma.
32,33 The elevated levels of these cytokines may have influenced the length of a functional bleb.
When studying the dimensions of the episcleral lake, we found a negative correlation of the pre-IOP to the lake width but not the height or length. Studies following trabeculectomy with combined cohorts (functional and nonfunctional blebs) showed a negative correlation of the post-IOP to the episcleral lake,
28 and this was considered a sign of reduced bleb function. The relationship of the pre-IOP to the bleb morphology is scarcely mentioned in the literature; however, higher pre-IOP was found to be a predictive factor of trabeculectomy failure.
34,35 The episcleral lake is a well-documented sign of functional bleb after ab-externo stent surgeries
36 and the negative correlation of pre-IOP can be interpreted in this context, because functional blebs with higher pre-IOP tend to show smaller episcleral lakes than those with lower pre-IOP.
During our examination of bleb position, we observed a positive correlation between postoperative intraocular pressure (post-IOP) and the distance of the bleb from the limbus. Specifically, higher post-IOP values were associated with blebs located more posteriorly. This correlation could be explained anatomically by the fact that the outer opening of the Preserflo is situated approximately 6 mm posterior to the limbus and always points posteriorly. Consequently, increased pressure (post-IOP) may result in greater outflow in the posterior direction, leading to the formation of a more posteriorly positioned bleb. Another plausible explanation could be the thickening of the tenon tissue as we move posteriorly, a thicker tenon might also correspond to higher post-IOP values in posterior blebs, as some studies have previously demonstrated,
23 so it's not really clear whether the increased post-IOP results in more posteriorly located bleb or if the posterior bleb results in higher post-IOP.
Our study has certain limitations that should be acknowledged. First, the retrospective design and the relatively small number of eyes included necessitate future studies with a prospective design and a larger patient population to validate our findings. Additionally, since our study only focused on blebs following Preserflo surgery, the results may not be applicable to other types of bleb surgeries, such as trabeculectomy, XEN-Gel-Stent, or Ex-PRESS procedures.
Furthermore, although we considered numerous potential parameters that could affect bleb morphology, there are likely other factors that may have played a role but were not available for analysis in this study. For example, the concentrations of cytokines (among others, interleukin 6, interleukin 8, monocyte chemoattractant protein 1, platelet-derived growth factor AA, transforming growth factor beta-2, and vascular endothelial growth factor) could also impact bleb morphology and should be considered in future studies. Although we examined 90 scans for each bleb and chose the measured parameters carefully according to a clearly predefined schema, variations of measurements between observers might affect the results because these are done manually. Our cohort included only Caucasian patients, so the results may not apply to other ethnicities.
Nonetheless, our study is the first, to the best of our knowledge, to exclusively include functioning blebs after Preserflo surgery and investigate potential factors influencing bleb morphology in this specific group of eyes. The findings of the study are supporting the use of AS-OCT to assist in determining the need for intervention in the postoperative phase.