Assessment of the Efficacy of Microinvasive Glaucoma Surgery Techniques using an Oculopression Stress Test Nicht invasiver Belastungstest zur Funktionsprüfung von mikroinvasiven Glaukomdrainage-Implantaten und Laserchirurgie

Abstract Background Glaucoma is one of the most common causes of blindness worldwide. The only evidence-based treatment to slow down the progression of glaucoma is the reduction of intraocular pressure (IOP) using local medication or through surgery. During the last years, a large number of microinvasive glaucoma surgery techniques (MIGS) has been developed, in order to reduce the IOP in glaucoma patients safely and effectively. Until now, efficacy of MIGS has been assessed mainly according to the postoperative IOP and the number of medications used. Results from long-term studies are rare or not available in the majority of the cases. In order to better evaluate the functionality of MIGS, a new examination method has been developed with the help of a new oculopressor device. In this study the efficacy of different MIGS techniques will be examined using the new oculopressor. Material/Methods At first, glaucoma patients that had previously received a MIGS surgery (iStent inject, XEN Stent, ELT) were examined with the new oculopression test. Their results were compared with those of non-operated patients and healthy individuals. Overall, 38 healthy subjects (group 1), 10 non-operated patients (group 2), 19 patients after iStent inject implantation (group 3), 14 patients after XEN Stent implantation (group 4) and 5 patients after ELT (group 5) were examined. The new examination measures the IOP-reduction that occurs after oculopression and can be seen as an indirect measurement of the outflow facility of the eye. Results The IOP-reduction after oculopression differed among the study groups. Non-operated patients showed a significantly lower IOP-reduction compared to healthy individuals. Patients after iStent inject and XEN stent implantation showed a larger reduction of IOP after oculopression in relation to non-operated patients and their results approximated those of healthy individuals. These patients needed fewer medications postoperatively in relation to non-operated patients. Patients after ELT showed postoperatively a smaller reduction of IOP after oculopression compared to iStent inject and XEN stent patients. Conclusion MIGS can increase the outflow facility of the eye in patients with glaucoma. Though ELT had the lowest impact on the aqueous outflow among the studied procedures in this study. The new test can help in the evaluation of current and further development of new MIGS in the future. Zusammenfassung Hintergrund Das Glaukom ist eine der häufigsten Erblindungsursachen weltweit. Die einzige evidenzbasierte Behandlungsstrategie, welche die Progression eines Glaukoms aufhalten kann, ist die medikamentöse oder operative Senkung des Intraokulardrucks (IOD). In den letzten Jahren sind zahlreiche mikroinvasive glaukomchirurgische Eingriffe (MIGS) entwickelt worden, um den IOD bei Glaukompatienten zu senken. Bisher werden MIGS ausschließlich nach dem postoperativ erreichten IOD und der Anzahl weiterhin verwendeter Medikamente beurteilt. Langzeitstudien sind in den meisten Fällen nicht verfügbar. Um die Funktionalität der MIGS-Eingriffe standardisiert zu untersuchen, wurde eine neue Untersuchungsmethode mithilfe eines modifizierten Okulopressors entwickelt. In dieser Studie wird die Wirksamkeit verschiedener MIGS mithilfe dieses Okulopressors beurteilt. Material/Methoden Zunächst wurden Glaukompatienten nach einem MIGS-Eingriff (iStent inject, XEN Stent, ELT) mit dem neuen Okulopressionstest untersucht. Ihre Ergebnisse wurden mit denen von gesunden Probanden und nicht operierten Patienten verglichen. Insgesamt wurden 38 gesunde Probanden (Gruppe 1), 10 nicht operierte Patienten (Gruppe 2), 19 Patienten nach iStent-inject-Implantation (Gruppe 3) und 14 Patienten nach XEN-Stent-Implantation (Gruppe 4) sowie 5 Patienten nach ELT (Gruppe 5) untersucht. Der neue Test misst den IOD-Abfall nach Okulopression und kann als eine indirekte Messung der Abflussleichtigkeit des Kammerwassers betrachtet werden. Ergebnisse Der gemessene IOD-Abfall nach Okulopression war unterschiedlich stark in den verschiedenen Gruppen ausgeprägt. Nicht operierte Patienten zeigten einen geringeren IOD-Abfall (− 4,9 ± 1,6 mmHg) im Vergleich zu gesunden Probanden (− 6,6 ± 2,1 mmHg). Bei Patienten nach iStent-inject- und XEN-Stent-Implantation war der IOD-Abfall größer als bei nicht operierten Patienten und ihre Werte näherten sich den Werten der gesunden Probanden an. Zudem verwendeten iStent-inject- und XEN-Stent-Patienten postoperativ signifikant weniger drucksenkende Medikamente im Vergleich zu nicht operierten Patienten. Patienten nach ELT zeigten postoperativ im Vergleich zu iStent-inject- und XEN-Stent-Patienten einen deutlich geringeren IOD-Abfall nach Okulopression. Schlussfolgerung Die MIGS können die Abflussleichtigkeit bei Glaukompatienten steigern, wobei die ELT den geringsten Effekt der analysierten Verfahren bewirkte. Der neue Test kann in der Beurteilung bestehender und Weiterentwicklung neuer MIGS-Operationen behilflich sein.


ABSTR AC T
Background Glaucoma is one of the most common causes of blindness worldwide. The only evidence-based treatment to slow down the progression of glaucoma is the reduction of in-traocular pressure (IOP) using local medication or through surgery. During the last years, a large number of microinvasive glaucoma surgery techniques (MIGS) has been developed, in order to reduce the IOP in glaucoma patients safely and effectively. Until now, efficacy of MIGS has been assessed mainly according to the postoperative IOP and the number of medications used. Results from long-term studies are rare or not available in the majority of the cases. In order to better evaluate the functionality of MIGS, a new examination method has been developed with the help of a new oculopressor device. In this study the efficacy of different MIGS techniques will be examined using the new oculopressor.
Material/Methods At first, glaucoma patients that had previously received a MIGS surgery (iStent inject, XEN Stent, ELT) were examined with the new oculopression test. Their results were compared with those of non-operated patients and healthy individuals. Overall, 38 healthy subjects (group 1), 10 non-operated patients (group 2), 19 patients after iStent inject implantation (group 3), 14 patients after XEN Stent implantation (group 4) and 5 patients after ELT (group 5) were examined. The new examination measures the IOP-reduction that occurs after oculopression and can be seen as an indirect measurement of the outflow facility of the eye.

Results
The IOP-reduction after oculopression differed among the study groups. Non-operated patients showed a significantly lower IOP-reduction compared to healthy individuals. Patients after iStent inject and XEN stent implantation showed a larger reduction of IOP after oculopression in relation to non-operated patients and their results approximated those of healthy individuals. These patients needed fewer medications postoperatively in relation to non-operated patients. Patients after ELT showed postoperatively a smaller reduction of IOP after oculopression compared to iStent inject and XEN stent patients.
Conclusion MIGS can increase the outflow facility of the eye in patients with glaucoma. Though ELT had the lowest impact on the aqueous outflow among the studied procedures in this study. The new test can help in the evaluation of current and further development of new MIGS in the future.

Introduction
Glaucoma is one of the commonest causes of blindness worldwide. According to studies, nearly one million people in Germany have glaucoma [1,2]. Although the pathophysiological mechanism that leads to glaucoma has not yet been entirely explained, we know that increased intraocular pressure (IOP) is one of the most important risk factors [3]. In chronic open-angle glaucoma, elevated IOP present for some time leads to progressive damage of the optic nerve with loss of nerve fibres and typical visual field defects [4,5]. The only evidence-based treatment strategy that can halt progression of the disease is reduction of the intraocular pressure (IOP) [6]. Besides the conservative treatment options (pressure-reducing eyedrops) [7,8], a large range of surgical procedures is available to the ophthalmologist to optimise the intraocular pressure of glaucoma patients [9,10]. Filtering glaucoma operations such as trabeculectomy are often performed to treat advanced glaucoma. These methods are very effective but are also associated with an increased risk of complications. Numerous microinvasive glaucoma surgery techniques (MIGS) were therefore developed in the last few years to reduce the intraocular pressure of glaucoma patients to an optimal level safely and in the long term. The desired pressure reduction is achieved in MIGS by use of various implants (e.g. XEN stent, iStent inject) or by changing the physiological outflow in the eye (excimer laser trabeculostomy, ELT) [11,12].

Note
The only evidence-based treatment strategy that can halt progression of the disease is reduction of intraocular pressure.
Hitherto, the effectiveness of these procedures has been judged exclusively by the postoperative IOP and the number of pressurelowering medications that continue to be used. Long-term results and the results of stand-alone operations are not available for most MIGS. In the past, aqueous drainage and facility of flow were measured by tonography and oculopression tonometry. Both methods are no longer used routinely today, however, because they are invasive for the patient and time-consuming for the examiner [13 -16]. A standardised method that can measure changes in aqueous fluid dynamics and aqueous drainage would therefore be of great significance for evaluating and developing MIGS procedures. This study presents the first results of a new test method that uses a newly developed oculopressor and IOP measurements to permit conclusions about the aqueous drainage system and thus assess the effectiveness of MIGS operations.
Schlussfolgerung Die MIGS können die Abflussleichtigkeit bei Glaukompatienten steigern, wobei die ELT den geringsten Effekt der analysierten Verfahren bewirkte. Der neue Test kann in der Beurteilung bestehender und Weiterentwicklung neuer MIGS-Operationen behilflich sein. point directly over him with the other eye so that both eyes are in primary position during the oculopression. This raises the intraocular pressure artificially to about 43 mmHg during oculopression [17]. It is known from earlier studies of tonography [13,14] and oculopression tonometry [15,16] that aqueous fluid drains increasingly through the eyeʼs physiological pathways during the compressive stress. After the oculopressor is removed, the intraocular pressure is reduced to a lower level. Equilibrium between production and drainage of aqueous fluid is then restored in the recovery phase after oculopression.
In the study protocol, the baseline IOP was first measured with an iCare tonometer with the patient seated (TA01, Icare, Vantaa, Finland). This was followed by oculopression of the study eye for 4 minutes with the patient supine. The intraocular pressure was then measured directly after removal of the oculopressor and again after a recovery phase of a further 4 minutes (▶ Fig. 1). The measured IOPs and especially the resulting pressure drop after oculopression can be regarded as an indirect measurement of aqueous fluid outflow.
An advantage of the new test method compared with older methods is that there is no contact with the cornea during oculopression so corneal anaesthesia is not necessary.
To investigate the changes in aqueous fluid dynamics and the pressure-reducing potential of MIGS operations, glaucoma patients who had undergone a MIGS operation in Rostock University Eye Clinic between 2015 and 2018 were tested according to the protocol described above. The operations were performed either as stand-alone procedures or combined with a cataract operation. Exclusion criteria were corneal diseases and corneal surgery in the study eye, which could affect accurate IOP measurement using the iCare tonometer [18], argon laser trabeculoplasty (ALT), selective laser trabeculoplasty (SLT) or filtering glaucoma operations that alter the eyeʼs physiological outflow system as well as advanced glaucoma with major vision loss. A further group of nonoperated glaucoma patients and a group of healthy subjects were also examined for purposes of comparison. All patients and sub-jects received a detailed ophthalmological examination with slit lamp, measurement of the intraocular pressure with the iCare tonometer and oculopression of the study eye.
All results were then analysed statistically using SPSS Software. Descriptive statistics were first used to calculate the mean, standard deviation, range (minimum, maximum) and median. The data were further analysed using the Kolmogorov Smirnov test and Kruskal-Wallis test to examine the test distribution and Spearmanʼs correlation to examine the correlation coefficients.

Note
The new method is a dynamic measurement of intraocular pressure. The reduction in IOP after oculopression can be regarded as an indirect measurement of the eyeʼs aqueous fluid outflow.
8 patients in the second group were diagnosed with primary chronic open-angle glaucoma, one patient had secondary openangle glaucoma due to pseudoexfoliation syndrome and another patient had melanin dispersion glaucoma.
The healthy subjects had a mean baseline IOP of 16.2 ± 3.6 mmHg. Non-operated glaucoma patients had a baseline IOP of 15.2 ± 5.8 mmHg and used an average 2.5 ± 1.3 different pressure-lowering medications. Patients after iStent inject implantation had a baseline IOP of 15.2 ± 4.3 mmHg and used 0.8 ± 1.4 different medications on average. Patients after XEN stent implantation had the lowest baseline IOP at 12.6 ± 2.9 mmHg and used only 0.4 ± 0.9 different medications. The baseline IOP in patients after ELT was 16.8 ± 6.5 mmHg and these patients used an aver-▶ Fig. 1 Oculopression technique using the new modified oculopressor (a, c) and an iCare tonometer (b). age of 1.6 ± 0.9 pressure-lowering medications. The interval between operation and oculopression was 7.3 ± 5.9 months in group 3, 10.5 ± 11 months in group 4 and 4.8 ± 5.3 months in group 5. The medications still required after operation are shown in ▶ Fig. 2.
The measured IOP levels followed the same trend in most cases and showed a drop in IOP initially after oculopression (PR0 -P0). The intraocular pressure then rose again during the recovery phase and approached the baseline levels (▶ Figs. 3 and 4).
After statistical analysis of the results, a positive correlation was seen between baseline IOP and IOP reduction. In general, it can be said that the higher the baseline IOP, the greater the IOP decrease after oculopression (PR0 -P0). To examine the pressure-lowering effect of the respective MIGS procedure or the oculopressor effect independent of the baseline IOP, the pressure reduction compared with the baseline IOP was calculated with the following formula: In the first part of the oculopression test, the IOP varied greatly between the different groups. In group 2 (non-operated glaucoma patients) the IOP decrease after oculopression (PR0 -P0) was significantly lower (p = 0.021) compared with group 1 (healthy subjects). As regards the IOP decrease after oculopression, however, there was no significant difference between healthy subjects (group 1) and patients after iStent inject (group 3) or XEN stent (group 4) implantation (p = 0.142 and p = 0.058). Compared with the baseline IOP, patients after XEN stent implantation showed the greatest IOP decrease (− 42.8 ± 10.2 %) and patients after ELT showed the lowest IOP decrease (− 25.7 ± 13.9 %) in all groups. Because of the type of implant and the use of a subconjunctival stent drainage space, a relatively large proportion of the patients who had XEN stent implantation required postoperative revision surgery or bleb needling. Bleb needling had to be performed in 5 of the 14 patients in this study group, and one of these patients had already had bleb needling three times up to the time of the study.
Similarly complex postoperative management is not necessary in patients who have had implantation of an iStent inject or ELT.

Discussion
This study presents a new method of testing functionality after microinvasive glaucoma surgery. The new test was performed in routine clinical practice successfully and with minimal patient stress. The test found differences in the decrease in IOP after oculopression (PR0 -P0) in the different groups. As expected, nonoperated glaucoma patients had a smaller drop in IOP after oculopression compared with healthy subjects. This correlates very well with earlier studies of tonography and oculopression tonometry, which showed that aqueous outflow is much lower in glaucoma patients compared with healthy subjects [13 -16]. In this study, the results in glaucoma patients after iStent inject and XEN stent implantation approached the levels of healthy subjects. This shows that these procedures produced a positive effect on aqueous outflow. Moreover, patients after iStent inject and XEN stent implantation had to use significantly less pressure-lowering medications compared with non-operated patients. Patients after XEN stent implantation needed the least pressure-lowering eye drops postoperatively, had the lowest baseline IOP (12.6 ± 2.9 mmHg) and showed the greatest IOP decrease compared with the baseline IOP (− 42.8 ± 10.2 %). On the other hand, these patients often needed revision or bleb needling to ensure continued aqueous drainage. Patients after iStent inject implantation and ELT usually needed less intensive aftercare. They had higher baseline IOP levels, however, and showed a smaller IOP decrease after oculopres-▶ Table 1 Definition of the groups and number of investigated patients and subjects.

Group
Definition Number Age (means and standard deviation in years)  Fig. 2 Number of patients who needed further medication to reduce IOP postoperatively (orange) and medication-free patients (blue).
sion (− 36.5 ± 14 % after iStent inject implantation and − 25.7 ± 13.9 % after ELT) compared with patients after XEN stent implantation. Patients who had ELT showed a smaller IOP decrease after oculopression compared with iStent inject and XEN stent patients. It must be considered, however, that it is difficult to draw conclusions about the ELT group because of the small number of patients.
The range of the IOP decrease after oculopression (PR0 -P0) was much greater in the iStent inject group than in all other ▶ Fig. 3 Course of intraocular pressure during the oculopression tests in groups 1 to 5. Group 1 (healthy subjects), group 2 (non-operated glaucoma patients), group 3 (glaucoma patients after iStent inject implantation), group 4 (glaucoma patients after XEN stent implantation), group 5 (glaucoma patients after ELT). The pressure was measured at 3 different times: P0 (baseline), PR0 (IOP directly after oculopression), PR4 (IOP after a 4-minute recovery phase). groups. Since the groups were relatively small and non-homogeneous, it is difficult to draw clear conclusions. However, the range could be associated with the way the trabecular procedure functions in this group. Insertion of the iStent bridges over the trabecular meshwork and the resistance to aqueous outflow through this barrier is largely abolished. From the pathophysiological aspect, increased outflow resistance in the trabecular meshwork is the cause of the raised intraocular pressure in most cases of glaucoma. All interindividual differences in aqueous physiology and outflow in Schlemmʼs canal and adjacent aqueous channels persist postoperatively, however, which can contribute to a greater range. In addition, the location of the iStents in the chamber angle can be a further factor in the postoperative differences in measurements between the individual patients as aqueous drainage is greater in the nasal than in the temporal area [19]. Nevertheless, the physiological drainage pathway of the aqueous fluid through the trabecular meshwork barrier is modified and usually "improved" by iStent inject implantation. By comparison, subconjunctival filtration operations such as XEN stent implantation create another, non-physiological outflow pathway for the aqueous, which additionally bypasses Schlemmʼs canal and aqueous channels. It might therefore be supposed that these procedures deliver more uniform results as the interindividual differences are compensated by the standardised drainage implant and have less effect.
Note iStent inject and XEN Stent had a positive effect on outflow in operated patients. However, this effect could not be confirmed in patients after ELT.
Based on the results of this study, it can be said that the XEN gel stent and probably other procedures also, which enable subconjunctival filtration of aqueous fluid, can be very effective. This also applies in part for MIGS that alter the trabecular drainage system (e.g. iStent inject). Other procedures appear less successful (ELT). In future, however, measurements should be made in larger groups of patients to detect more detailed differences between the different MIGS techniques.
In addition, preoperative and postoperative measurements in the same patients before and after a MIGS procedure could allow better assessment of the pressure-reducing effect of the different operative procedures. Another advantage of repeated postoperative measurements after MIGS procedures in glaucoma patients would be a kind of follow-up or review of the functionality of the drainage implants. It is known that nearly all subconjunctival draining procedures often tend to postoperative scarring in the area of the stent or bleb. The new test could help the ophthalmologist to promptly identify a reduction in drainage capacity caused by these scarring reactions and thus the optimal timing of any necessary intervention (e.g. needling).
Although the new test method provides valuable insights into aqueous fluid dynamics in patients who have had MIGS, it is also associated with a few limitations. The test enables conclusions to be drawn about aqueous outflow but it cannot measure this directly, as tonography does. Moreover, our study protocol involves a change in the patientʼs position from sitting to supine and back to sitting. This can induce changes in the episcleral venous pressure as well as IOP changes, which are probably more pronounced in glaucoma patients compared with healthy subjects [20,21]. To minimise these IOP changes as far as possible, the patientʼs inclination during oculopression was kept to less than 90°with the aid of a pillow. It was shown in earlier studies that the rise in IOP in the horizontal position is between 0.3 ± 1.8 and 5.6 ± 1.7 mmHg in healthy subjects [20]. These changes are very small compared with the IOP levels that are achieved during oculopression (c. 43 mmHg). In addition, according to studies, the positional changes in episcleral venous pressure are more pronounced in older persons than in younger persons [21]. Our study did not find any statistically significant correlation between age and IOP decrease after oculopression (PR0 -P0), however. This suggests that the change in the patientʼs position from sitting to supine during the test does not cause any significant errors.

Conclusion
A new test to assess functionality after MIGS procedures using dynamic measurement of intraocular pressure after oculopression was used successfully and with minimal patient stress in a clinical study. The results show that there are differences in pressures between healthy subjects and glaucoma patients. In glaucoma patients who have had XEN stent and iStent inject implantation, hardly any differences are found postoperatively compared with healthy subjects. MIGS thus produced a positive effect on aqueous outflow in these patients in the observed postoperative period.
The new test could play a part in the future development of MIGS procedures when the "performance" and "pressure-reducing potential" of the most varied stents or microinvasive techniques are to be investigated.