Perspective Chapter: Role of the Vitreoretinal Interface Condition in the Development of Glaucoma

Abstract

Until now, there are no objective criteria to understand the moment of transition of eyes, anatomically predisposed to primary angle-closed glaucoma, from the risk group to the real form of PACG. IOP on the predisposed eyes may remain normal until advanced age without treatment. The aim of this study is to identify factors that can act as a trigger mechanism that starts such transition and the role of vitreous-retinal interface (VRI) condition in this process. A risk group that included 259 eyes (37–88 years old) predisposed to PACG was formed. The criteria for forming the group were gonioscopy, predictive coefficients Lowe and Chirshikov, provocative Hyams test, and ultrasound examination. Monitoring was carried out for up to 4 years. In the risk group, there were eyes in which the state of predisposition was transformed into a real form of PACG during monitoring. Such a transition was accompanied by the occurrence of PVD, which was not detected at the beginning of the monitoring. In eyes with normal IOP predisposed to PACG, PVD appearance leads to destabilization of the vitreous body position inside the vitreous cavity, possibility for iris-lenticular diaphragm displacement forward, appearance of hydrodynamic blocks and undulating IOP increases, and appearance of the real form of PACG.

1. Introduction

Due to the rapid development of vitreoretinal surgery, the vitreoretinal interface (VRI) is the subject of active discussions among ophthalmologists. However, the question of the VRI role in the hydrodynamics of the eye has been studied not enough. One of the subjects of our interest is the influence of VRI condition on the mechanisms of primary angle-closure glaucoma (PACG) development.

The fact is that the development of PACG can occur only in the eyes, in which there is an anatomical predisposition to this disease. This includes a narrow-angle of the anterior chamber of the eye (ACA), which is formed against the background of a disproportionate ratio of the short axial length of the eye and the excessive thickness of the lens. Usually, such eyes have hypermetropic refraction. The primary manifestation of PACG and intraocular pressure (IOP) increases according to the “closed-angle” type occurs on the background of age-related changes. More often these will be undulating IOP increases but in some cases, acute attacks of PACG may develop.

Although in most cases a predisposition to PACG can be identified at an early age, physicians with extensive clinical experience know that IOP in such eyes can remain normal for an indefinitely long time. However, it is difficult to predict the moment when the primary manifestation of PACG in the predisposed eyes will occur.

In cases where we are dealing with eyes at-risk group of PACG to prevent diseases from developing, at some moment it is necessary to make a laser iridectomy. We need an objective criterion in order to decide when to do it, whether laser iridectomy needs to be done urgently, and when the patient can be left for monitoring at the risk group. We assume that the study of the VRI condition can help in solving this issue.

2. Purposes of the research

• To find the relationship between IOP increases in “closed-angle” type and PACG primary manifestation with VRI condition and PVD appearance;

• To find an objective criterion for the moment of laser iridectomy on the eyes with a predisposition to PACG.

3. Reasons to initiate research

The starting point for the research was the observation of one clinical case with a high predisposition to PACG.

The clinical case: The patient S. 55-year-old; high hypermetropia in both eyes; extremely abnormal anatomical parameters (presented in Table 1). The coefficients that determine the predisposition to the development of PACG (see below) in both eyes were extremely unfavorable.

Eye	Vision acuity and refraction	Axial length of the eye (mm)	Anterior chamber depth (mm)	Lens thickness (mm)	Prognostic Lowe coefficient* (N ≥0.2)	Axial Chirshikov coefficient** (N ≤ 10.0)
OD	sph + 7.5D = 0.8	16.0	0.6	5.8	0.06	60
OS	sph + 7.5D = 0.7	16.1	0.6	5.9	0.06	60

Table 1.

Parameters of the patient’ S. eyes. 55years old. High predisposition to PACG.

^*

Lowe coefficient (CLowe) [1]—the coefficient of predisposition to PACG is calculated by the formula:

^**

Axial Chirshikov coefficient (AShC) [2]—the coefficient of predisposition to PACG is calculated by the formula:

$\mathit{\text{CLowe}}=\left(\mathit{ACD}+\frac{1}{2}\mathit{LTh}\right):\mathit{ALE}$

Predisposition to PACG is if CLowe ≤ 0.2.

$\mathit{\text{AShC}}=\left(\mathit{Lth}x100\right):\left(\mathit{ACD}x\mathit{ALE}\right)$

Predisposition to PACG is if AshC ≥ 10.0.

ACD, anterior chamber depth; LTh, lens thickness; ALE, axial length of the eye.

However, despite the very narrow ACA (Figures 1 and 2), IOP in both eyes remained stable at normal values for long time. The primary manifestation of PACG on OS with undulating IOP increases up to 29 mm Hg was detected only 4 months before the visit to the clinic. At the same time, there were never detected increases of IOP on OD before.

Figure 1.

The anterior chamber angle of the left eye. Patient S., 55 years old, high predisposition to PACG. Extremely narrow anterior chamber angle (Pentacam, author’ photo).

Figure 2.

Patient S., 55 years old. Hypermetropia +7.5 D. Internal dimensions of OD (the OS parameters are the same) (US B-scan, author’ photo). There is a combination of the short axial length of the eye with a disproportionately lens thickness, narrow anterior chamber angle.

OD: The optic nerve head and visual field are consistent with the norm; OS: The optic nerve head and visual field are consistent with the early stage of glaucoma.

When analyzing this clinical case, the following questions arose:

• How, with such extremely unfavorable anatomical parameters of the eyes, IOP was normal until the age of 55 years old?

• Why did in fellow eyes with identical anatomical parameters the IOP increases were detected on the left eye only, while no hydrodynamic disturbances were detected in the right eye?

When comparing the ultrasound picture of the fellow eyes of patient S., we paid attention to the fact that on OD (IOP was always normal), the vitreous was in close contact with the retina. Unlike this, on the OS, a plane posterior vitreous detachment (PVD) and retrohyaloid space were found (Figure 3a and b).

Figure 3.

(a, b) Fellow eyes of patient S., 55 years old (US B-scan, author’ photos). (a) OD: the eye is at risk group for the development of PACG, the diagnosis of PACG was not confirmed. IOP is stable within the normal range. PVD is absent. Choroid is thickened. (b) OS: the IOP increases up to 29 mm Hg firstly was detected 4 months ago. Plane PVD. Choroid is thickened. The diagnosis of PACG is confirmed.

We assumed that the reason for PACG primary manifestation on the OS could be the violation of VRI and the appearance of PVD. The presence of retrohyaloid space could be a reason for the destabilization of vitreous body position in the vitreous cavity. This makes it possible for the vitreous body micro-displacement in the sagittal direction. This, in turn, could be a cause for changes in the position of the iris-lens diaphragm (ILD) and its displacement toward the anterior chamber of the eye. As a result of this, there was a narrowing of the ACA, the development of hydrodynamic blocks for the intraocular fluid movement, and IOP increases.

4. Vitreous-retinal interface

The vitreous body is externally bounded by the cortical (hyaloid) membrane, which is a layer 100–200 μm thick, in which the concentration of hyaluronic substances and the density of the fibrillary layer are higher in comparison to other parts of the vitreous [3].

We can talk about two different clinical and anatomical conditions of the posterior hyaloid membrane (PHM)—before and after the development of PVD. Before the PVD appears, PHM is not visible either histologically or clinically, however, after the PVD it can be observed ophthalmoscopically as well as using OCT and ultrasound methods of research [4].

VRI (the contact zone between the retina and PHM) condition is important for the physiology of the eye. The power of the contact of the vitreous with the retina is different: the strongest one is in the area where the optic nerve enters the eyeball (“posterior basis of the vitreous”), in the zone of premacular bursa and in the zone of contact between the vitreous body and retinal vessels [5, 6]. At young age, VRI is most durable but with the age and with some metabolic disorders in vitreous substances, as well as with a progressive increase in the axial size of the eye, the strength of the VRI weakens, which leads to the appearance of PVD.

The functional significance of VRI for the eye is more often considered from the point of view of the retina condition. In our work, we will consider the issue of the VRI role from the point of view of the hydrodynamics of the eye. The subject of the research was the study of VRI in eyes with an anatomical predisposition to the development of PACG.

5. The hydrodynamic blocks in the eye and the reasons for IOP increases on “angle-closed” type

A special feature of the clinical manifestations of PACG (except the acute attack of glaucoma) is an alternation of IOP increases with periods of IOP normalization (in contrast to primary open-angle glaucoma, in which IOP steadily increases due to outflow ways degradation). In PACG cases, IOP increases occur as a result of the development of hydrodynamic blocks that impede intraocular fluid movement from the zone of secretion in the posterior chamber of the eye to the zone of outflow in the ACA.

There are several blocks, typical for PACG:

• Iris-lenticular block, in which movement of fluid through the space between the anterior surface of the lens and the posterior surface of the iris toward the pupil is disturbed;

• Pupillary block, in which the pupil is obturated by the anterior surface of the lens and fluid movement from posterior chamber into anterior chamber of the eye is disturbed;

• Angular block, in which a critical narrowing of the ACA occurs and the access of fluid to trabecula and uveal-scleral outflow zone is impaired [7, 8].

In eyes with axial myopia weakening of VRI and PVD development occurs at a young age. However, in such eyes, the occurrence of PACG is extremely rare. Even the lens thickness in such eyes is big, there is no anatomical predisposition to the development of hydrodynamic blocks of the “angle-closure” type.

Physicians with extensive clinical experience know that IOP can remain normal indefinitely despite the anatomical predisposition to PACG and the presence of a narrow ACA. However, against the background of age-related changes, once a primary manifestation of PACG is occurring. It is difficult to predict the moment when the primary manifestation of PACG will start. This is very important for tactics of managing patients in risk groups for PACG development. An objective criterion is needed to understand whether it is safe to continue to observe a patient at risk group or whether a laser iridectomy should be performed.

IOP undulated increases are possible only in those cases when there is a fluctuation of ACA width. The reason for such fluctuation may be the appearance of factors leading to the periodic displacement of iris-lenticular diaphragm (ILD) toward the anterior chamber. Normally, ILD is in a stable position, which guarantees a constant width of ACA and normal access of intraocular fluid to the drainage zone of the eye. For this reason, even in situations with very narrow ACA (as it was described in the clinical case), its width remains stable and IOP can remain at a normal level until old age.

There is an opinion that the main factor that leads to displacement of ILD forward and as a result—the PACG development is the involutional increase of lens thickness. However, this cannot fully explain the pathogenesis of the undulating nature of IOP increases, which is so typical for chronic form of PACG. If the development of hydrodynamic blocks occurs only due to the thickening of lens, then IOP increases would have a constant stable lasting nature. In practice, chronic forms of PACG are more common when periods of IOP increase alternate with periods of its normalization.

There is another opinion, that the cause of displacement of ILD forward is increase in the volume (edema) of the vitreous body. The basis for this point of view is that some organs in different functional states can significantly change their volume due to changes in blood supply or functional edema. For the vitreous, the situation associated with edema of its substance is unlikely. Hyaluronic substances, which form a vitreous body, have very high hydrophilicity. In normal situations, the hyaluronic substances bind interstitial water in the intercellular spaces (according to various sources, in a ratio of up to 1: 4000), while forming very viscous solutions. This is necessary for the stable maintenance of the volume of the vitreous body inside the vitreous cavity throughout life (Figure 4).

Figure 4.

(a, b) Cadaver’s eye vitreous body specimens. Vitreous body can keep its shape and volume for some time after the specimen preparation due to resilience of vitreous (specimens preparation and photos of the author). (a) Specimen of vitreous body with retina after sclera and choroid elimination. There is the opening in the place of optic nerve entrance. (b) Specimen of vitreous body after retina elimination.

It is known that the universal response of vitreous to a violation of its chemical composition is a decrease in its volume (vitreosyneresis). The edema of the vitreous body and its increase in volume are highly unlikely. For this reason, a vitreous substance in normal condition is in a state of maximum hydration and cannot additionally increase its volume [9]. (If edema of vitreous can be possible, any situation associated with a functional increase in ocular blood flow could be accompanied by an increase of vitreous volume, and as a result, in anatomically predisposed eyes, this would be accompanied by obligate IOP increase, which does not happen in reality.)

Thus, there is a need to find other reasons for the development of hydrodynamic blocks in addition to increase in thickness of the lens and hypothetical vitreous edema.

One of the diagnostic methods that allow you to accurately say whether anatomically predisposed eyes have a real form of PACG (and active treatment is needed) or while the eyes are still at risk group (and you can limit the tactic by monitoring only), is the Hyams stress test [10].

The Hyams stress test is carried out as follows: IOP is measured with the patient in recumbent position (e.g., with a Schiotz or a Maklakov ophthalmic tonometer [11]. After that, the patient is asked to turn over and lie in the “face down” position for 1 hour. After this time, the patient is again asked to turn over on his back and IOP is measured again. If during this time IOP has increased by 5 mm Hg or more, the test is considered positive, and the diagnosis of PACG is confirmed. If IOP remains unchanged or increases by less than 5 mm Hg, then the test is considered negative.

The Hyams test makes it possible to divide eyes with an anatomical predisposition to PACG into two groups. In a group with negative results, the eyes can be left in the risk group without any treatment, with monitoring only. In a group with positive results, the real form of PACG is confirmed. In such cases, the patients need to receive active treatment (laser iridectomy act).

In the issue of PACG pathogenesis, there is no clear opinion in which cases the ILD has ability to displace forward and create conditions for hydrodynamic blocks, and in which cases ILD remains stable in its normal position.

From our point of view the mechanism of IOP increases on “angle-closured” type in eyes with an anatomical predisposition to PACG largely depends on the VRI condition. In eyes that have full-fledged VRI, the vitreous body is tightly fixed in its place in the vitreous cavity and does not have a compressive effect on the ILD under the influence of gravitational load in “face down” position (Figure 5a and b). Due to this, hydrodynamic blocks do not occur, IOP remains normal, and the results of the Hyams test are NEGATIVE.

Figure 5.

Cross section of the eye at the beginning of the Hyams test or in the case of negative result (Scheme). 1. Vitreoretinal interface is normal. The posterior hyaloid membrane is in close contact with the retina. 2. Vitreous body (fixed to the retina). 3. Lens. 4. Free intraocular fluid movement. 5. Pupil. 6. Anterior chamber angle. Good vitreoretinal interface gives fixation of vitreous body inside vitreous cavity. There is no pressure of vitreous on the iris-lenticular diaphragm and it is not displaced. Hydrodynamic blocks are absent. Intraocular fluid can freely pass from posterior chamber through the pupil into anterior chamber to drainage zone direction.

If VRI condition is unsatisfactory, there are PVD and retrohyaloid space, which gives the opportunity for vitreous body micro-displacement in the vitreous cavity in sagittal direction. In the “face down” position, under the influence of a gravitational load, vitreous begins to press on the ILD. In eyes with an unfavorable anatomical predisposition to PACG, it can be a cause of hydrodynamic blocks described above, and the results of Hyams test are POSITIVE (Figure 6a and b). When the patient returns to the vertical position, the gravitational load vector changes and this allows ILD to return to its normal position. The hydrodynamic blocks are eliminated and IOP is reduced.

Figure 6.

Cross section of the eye at the Hyams test with a positive result (Scheme). 1. Vitreoretinal interface is violated. Posterior hyaloid membrane is detached. 2. Vitreous body. (Fixation vitreous to retina is disrupted). 3. Lens. 4. Hydrodynamic blocks for the intraocular fluid movement. 5. Pupil is blocked. 6. Narrowing and blocking of anterior chamber angle. 7. Retro-hyaloid space. 8. Anterior hyaloid membrane is pressing on the iris-lenticular diaphragm. 9. Gravity load vector. Due to violation of vitreoretinal interface, posterior vitreous detachment occurred and retrohyaloid space appeared. The vitreous body fixation at the posterior pole of the eye is disturbed, which makes it possible for its micro-displacement in sagittal direction. When the patient is positioned “face down” during the Hyams test, the vitreous body (which has lost its fixation with the retina at the posterior pole of the eye) under the influence of a gravitational load, begins to put pressure on the iris-lenticular diaphragm. As a result, the iris-lenticular diaphragm is displaced forward. This leads to the formation of irido-lenticular, pupillary and angular hydrodynamic blocks. As a result there is IOP increases.

6. Clinical research

To confirm this concept, we conducted a clinical study, the results of which were partly published earlier [12]. For 4 years we supervised a group of patients (135 people—259 eyes, aged 37 up to 88 years, of which 87 women and 48 men) in whose eyes there was an anatomical predisposition to PACG (narrow ACA and an unfavorable ratio between the size of the axial length of the eye, the depth of the anterior chamber of the eye and the thickness of the lens). In all eyes, the Lowe and Chirshikov predictive coefficients were calculated in order to objectively confirm the anatomical predisposition to PACG. In 91.0% of the examined eyes, there was hypermetropic refraction (from +0.5 to +16.0D).

In 36 eyes the diagnosis of PACG had already been confirmed before and treatment was prescribed earlier. The remaining 223 eyes without confirmed PACG where IOP increases had not been detected yet were taken for the research group.

In 88 patients, both paired eyes (176 eyes) were examined. In 47 patients only one eye was examined (because in the fellow eye, the diagnosis of PACG had already been confirmed or it was unsuitable for our research or the eye was absent).

The aim of the research was to study the influence of VRI condition on the development of PACG in anatomically predisposed eyes. Hyams test, OCT, and ultrasound examination were performed on all examined eyes. Depending on the results of the Hyams test, the examined eyes were divided into two groups: with a positive and negative results of the test. It is important to note that in some cases fellow eyes of one patient were attributed to different groups.

PVD and a well-visualized retrohyaloid space were found in all eyes with a positive Hyams test. In the group with negative Hyams test, the plane and very low PVD were detected in four cases. In other eyes from the group with negative results, the PVD was not detected.

In the next stage of the research, we focused attention and took dynamic monitoring of the eyes from the group where despite predisposition to PACG the Hyams test was negative. These eyes were taken for monitoring (4 years). Every 6 months a planned examination was carried out, which included the repeats of the Hyams test, as well as ultrasound examination and OCT for targeted detection of signs of PVD.

During the monitoring process, it was discovered that in 27 eyes from this group the Hyams test transformed from negative to positive over time. We considered such transformation as a non-alternative sign of the eye’s transitions from the risk group to the group with real, confirmed PACG. In 23 eyes from this group, where initially PVD could not be detected, PVD appeared during the monitoring process (Figure 7a and b). In 4 eyes with low-plane PVD (described above), we observed an increase in them to a clinically significant size.

Figure 7.

(a, b) The eye of patient K. (68 years old) with anatomical predisposition to PACG there was a transition from risk group to the real PACG form. Dynamic monitoring. US B-scan (author’photos). (a) The eye of the patient K. at the first examination. Hyams test is negative, PVD is absent. The risk group. (b) The same eye of the Patient K. after 1.5 years. Transformation of the Hyams test result from negative to positive. The plane PVD was detected. A diagnosis of PACG was confirmed. The patient was sent for laser iridectomy.

The result of the research has shown that PVD is an obligate feature for the manifested PACG. At the same time, we tried to understand the role of the lens thickness increase factor in the development of PACG. In 9 eyes out of 27 (from the group where the Hyams test was transformed from negative to positive), during monitoring, the lens thickness increased by 0.1–0.15 mm was noted, in the other 18 eyes, the lens thickness remained unchanged. In 16 eyes, in which the Hyams test remained negative, in five cases the thickness of the lens increase by 0.1–0.15 mm was also noted, however, in these eyes, IOP remained within the normal range.

7. Conclusion

VRI condition is important factor in determining the vitreous body fixation inside the vitreous cavity. PVD (and as a result—retrohyaloid space appearance) in the eyes, and anatomically predisposition to PACG are factors that can be a reason for vitreous body and iris-lenticular membrane displacement to the anterior chamber direction in unfavorable situations (e.g., as a result of Hyams probe). Such displacement can provoke the occurrence of iris-lenticular, pupillary, and angular hydrodynamic blocks and IOP increase on “angle-closed” type.

VRI in the eyes with normal or short size (in cases of absence of another problem), for many years, provides good fixation of the vitreous body inside the vitreous cavity. Age-related syneresis processes in the vitreous body are factors determining the VRI violation and as a result the transition of eyes predisposed to PACG from a risk group to a group with a really confirmed form of PACG.

The age-related increase of the lens thickness, of cause, also contributes to the destabilization of ILD location and hydrodynamic processes in the eyes predisposed to PACG, but this should be considered only as one of the factors leading to the development of PACG.

An important and repeating question when we are talking about eyes with narrow ACA and predisposition to PACG is the question—at what moment it is necessary to make a laser iridectomy. Do we have to do it now or we can wait and only monitor the patient?

Based on the foregoing, it is possible to give a recommendation for this issue solution: the detection of PVD is a signal for the transition from passive monitoring to the start of active treatment (laser iridectomy, etc.). And if VRI continues to reliably fix the position of the vitreous body inside the vitreous cavity and the examination does not detect signs of PVD, we can leave the patient under monitoring.

Note

The text is based on data obtained during the work of the author at the Research Institute of Eye Diseases of the Russian Academy of Sciences from 2008 to 2018.