The Pathophysiological Relevance of the Posttrabecular Drainage Pathway for Minimally Invasive Trabecular Glaucoma Surgery Using Stents in Primary Open-Angle Glaucoma

Over the past 20 years, trabecular minimally invasive glaucoma surgery (MIGS) using the iStent inject® (Glaukos Corporation, USA) or the Hydrus® (Alcon, USA) has gained increasing importance in glaucoma surgery. It is considered easy to learn and simple to perform, has relatively few side effects and complications [1], and requires minimal follow-up care. However, these advantages are offset by low pressure-lowering efficacy. Meta-analyses show that, as stand-alone procedures, they do not result in additional pressure reduction compared to cataract surgery [2], and when performed in conjunction with phacoemulsification, the additional pressure reduction is only 1.49 mmHg, whereas incisional trabecular surgery using, for example, the Kahook Dual Blade® (New World Medical, USA)-which features a larger opening zone-was significantly more effective, with an additional pressure reduction of 3.4 mmHg [3]. In a comparative study between the iStent Inject® and the Kahook Dual Blade®, no improvement in trabecular outflow was achieved with the iStent Inject® in patients with predominantly primary open-angle glaucoma (POAG) [4]. The cause lies primarily in the post-trabecular outflow system, whose significance for MIGS will be briefly outlined here.

In the eye, intraocular pressure is determined by the balance between aqueous humor production in the ciliary body and aqueous humor outflow. The three known outflow systems are the conventional pathway, consisting of the trabecular meshwork- Schlemm’s canal-collector channels – the intrascleral venous plexus and episcleral veins as a functional unit [5]; uveoscleral outflow via the ciliary muscle and the orbital venous and lymphatic systems; and drainage via the retina and the posterior lymphatic system [6,7]. The trabecular drainage complex accounts for the largest share, at 60–70%. This system exhibits two main drainage barriers: The inner or proximal first drainage barrier is the juxtacanalicular trabecular meshwork [8], which is connected via direct contact with the endothelium of Schlemm’s canal. Due to the tightly sealed endothelium of Schlemm’s canal [9], aqueous humor enters Schlemm’s canal primarily via the transcellular route through intracellular pores containing giant vacuoles [10]. Via this venous ring sinus, the aqueous humor flows through the collector channels into the intrascleral venous plexus, which constitutes the outer or distal second drainage barrier [8]. From there, the aqueous humor flows through the episcleral veins into the venous circulatory system.

The structure of the intrascleral venous plexus in connection with the episcleral veins has not yet been extensively studied, particularly in the context of POAG. However, it is known that this complex is regulated by neuronal, humoral, and-above allneurocrine mechanisms via numerous neurotransmitters, such as the vasoactive intestinal peptide, substance P, and neuropeptide Y [11]. The pressure resulting from this distal outflow resistance is referred to in the literature as episcleral venous pressure (EVP), which ranges between 8 and 10 mmHg under healthy conditions [12,13,14]. For every 1 mmHg increase in EVP, it is assumed that mean intraocular pressure rises proportionally by approximately 1 mmHg [12]. As defined by the Goldmann equation (and modified versions), EVP is always additive to intraocular pressure [12]. To date, however, there are clinically no consistent and accurate methods for measuring IOP available [15]. What is known so far is that it does not change with age and does not exhibit a daynight rhythm [6]. In addition, two corroborating experimental studies have shown that in normal human eyes, even after a 360° trabeculotomy or complete removal of the trabecular meshwork, approximately 30–60% of the outflow resistance remains [16,17], underscoring the importance of this distal outflow resistance system.

In POAG, significant changes occur in the three outflow systems as the disease progresses. Since POAG is associated with a primary mitochondriopathy [18,19], the resulting increase in free radicals and the loss of antioxidant defense systems lead to oxidative stress [20], which can be detected both systemically in serum and, most notably, in the aqueous humor [21]. Consequently, POAG leads to widespread inflammation that affects not only the retinal ganglion cells, microglia, and the lamina cribrosa, but also the anterior segment of the eye [15,18]. As a result of this inflammation, there is a significant increase in endothelin-1 [23]-the most potent endogenous vasoconstrictor-in the aqueous humor, as well as elevated levels of the transforming growth factor TGF-β [24], tumor necrosis factor TNF-α [25], and interleukin IL-6 [26]. The associated inflammation of the trabecular meshwork [27] leads to significant biochemical changes and structural remodeling [28,29,30]. In addition, the elevated endothelin-1 levels in the aqueous humor in POAG cause a contraction of the smooth vascular muscle of the downstream collector channels [31,32]. This means that the proportion of functioning collector channels involved in aqueous humor drainage decreases, and its outflow into the episcleral venous system is impeded [33]. Since the system comprising the trabecular meshwork, Schlemm’s canal, collector channels, intrascleral venous plexus, and episcleral veins is regarded as a continuum [5], the inflammatory remodeling processes described above in POAG mean that the entire conventional outflow system is affected. This is particularly important because it means that the juxtacanalicular trabecular meshwork-as the internal resistanceis affected just as much as the intrascleral venous plexus-as the external resistance.

Ultimately, distal resistance in the conventional outflow system is still poorly understood and has rarely been studied under conditions of POAG. For example, most animal studies were conducted on healthy animals, so the results cannot be directly applied to the intraocular inflammatory conditions seen in POAG. Furthermore, the processes described here make it clear that trabecular MIGS using various stents can have only a very limited pressure-lowering effect. Much more research will be needed in the future to achieve scientifically evidence-based, positive results.

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