**8. Reasons for progressive visual field loss despite controlled glaucoma**

#### **8.1. High IOP fluctuations**

Secondary glaucomas such as pseudoexfoliative and pigmentary glaucomas have high fluctuations of IOP, which varies depending on the dispersion of pseudoexfoliation material or pigment in the anterior chamber angle. The IOP peaks are unpredictable and variable in time and amplitude and may be missed by diurnal curve even if performed every 2 hours. They may occur between the IOP measurements and may be missed. To overcome this, frequent IOP monitoring including at bedtime and at shorter intervals may reveal such patients. Patients with high and large fluctuations that are on full medical treatment may benefit from early glaucoma surgery, either trabeculectomy with mitomycin C or shunt procedure. Still, patients without IOP fluctuations may progress to blindness from other reasons as stated below.

### **8.2. Increased IOP in supine position (at bedtime)**

Other major factors for visual loss are late diagnosis that may occur with all types of chronic glaucomas and slow decision making. Aggressive glaucoma and poor surgical outcomes may

The aim of treatment at present is controlling the IOP to prevent further deterioration in visual fields. The loss of visual field is irreversible. The ideal IOP should be low enough to prevent visual field loss without compromising the functions of the eye. Each patient has a desirable range of IOP—target IOP, which varies between individuals and depends on the aggressiveness of the disease. The aggressiveness of the disease is determined by the IOP, its fluctuations, the type of glaucoma, and the damage to the optic disc and visual field. In normal tension glaucoma, the target IOP is usually less than in other types of glaucoma, because even with normal pressures, the damage continues to progress. The IOP is constantly changing. It depends on the hour (diurnal variations) and seasons. Most but not all subjects have the

To be considered as "controlled glaucoma," the IOP should be within its target during the entire day in a long follow-up with constant use of anti-glaucoma medications or postoperatively. The patients should take their medications properly at a preset times and continuously. Thus, patients intolerant to anti-glaucoma medications or uncompliant are not considered controlled. The IOP may be assessed by diurnal curve every 4 hours, usually between 8 AM

In this chapter, controlled glaucoma was defined as target IOP under diurnal curve of 4 hours in patients, who are dedicated in taking their anti-glaucoma medications or after surgery. It is a philosophic question whether patients who continue to lose their vision are controlled. Perhaps the definition should be patients who do not show further signs of deterioration. However, since the target pressure has been achieved, it is expected that the patients will demonstrate stability of their visual functions (i.e., visual fields), and this may not occur in a subset of these patients.

**8. Reasons for progressive visual field loss despite controlled glaucoma**

Secondary glaucomas such as pseudoexfoliative and pigmentary glaucomas have high fluctuations of IOP, which varies depending on the dispersion of pseudoexfoliation material or pigment in the anterior chamber angle. The IOP peaks are unpredictable and variable in time and amplitude and may be missed by diurnal curve even if performed every 2 hours. They may occur between the IOP measurements and may be missed. To overcome this, frequent IOP monitoring including at bedtime and at shorter intervals may reveal such patients. Patients

contribute to visual loss.

**6. How to define controlled glaucoma?**

28 Causes and Coping with Visual Impairment and Blindness

highest peak in IOP during the early morning.

**7. Matters of definition**

**8.1. High IOP fluctuations**

and 8 PM, because it changes constantly or even every 2 hours.

People spend about one third of the day (6–8 hours) sleeping. The resting time may increase after retirement. The IOP increases at supine position compared with standing or sitting in healthy subjects by 2.47 ± 2.12 mmHg (mean ± standard deviation) (p < 0.001) when measured by non-contact tonometer Keeler, Pulsair EasyEye [2]. In another study, the IOP in sitting position was found to be 13.5 ± 2.0 mmHg in the right eye and 13.2 ± 2.3 mmHg in the left eye in healthy individuals [3]. The IOP increased in supine position to 16.8 ± 2.3 mmHg and 17.0 ± 2.3 mmHg, respectively (p = 0.001). This may result in deterioration of the optic disc and visual fields. Diurnal curve has probably no meaning if the patient is awakened at bedtime, and the pressure is measured while sitting.

The intracranial pressure (ICP) may also influence the progression of glaucoma [4, 5]. The ICP is directed through the subarachnoid space opposite to the IOP through the lamina cribrosa, and the difference between them is the translaminar pressure gradient. Theoretically, if this is low, the progression may be slower than if it is high but this may not be true. A high ICP and IOP with a low gradient may be sufficient to cause increased optic disc damage because of the increased shearing force in the lamina cribrosa and decrease in axonal plasma flow. This may initiate or facilitate axonal apoptosis.

#### **8.3. Increased IOP when sleeping on the affected eye(s)**

Most ophthalmologists do not live with their glaucoma patients and have no idea about their behavior in daily life. The patients may sleep on their affected eye(s), and this causes further increase of the IOP in addition to the increase caused by supine position. When the eye leans against the bed or pillow or when the entire mass of the head is over all or part of the globe, IOP is increased by 33%. Thus, the physician should inquire about the sleeping habits of the glaucoma patients. Actually, increase in IOP measurement can be seen in patients who squeeze their eyes during evaluation with Goldmann tonometer, as well as with some other instruments. It can also be seen if the examiner presses the globe during IOP measurement.

#### **8.4. Antihypertensive drugs at bedtime**

Glaucoma patients are usually older and have many associated aging and pathologic conditions, including atherosclerosis and systemic hypertension. Other ischemic diseases such as diabetes mellitus may also be encountered. Taking antihypertensive drugs before sleeping increases the risk for anterior ischemic optic neuropathy (AION) [6]. Antihypertensive medications decrease the perfusion into the optic disc, and this may join atherosclerotic changes in the blood vessels. AION may be difficult to diagnose in patients with advanced glaucoma. In advanced glaucoma, the cup may be large (cup/disc ratio of 0.8 or more), and the rim is thin enough not to distinguish pallor of the rim following additional AION. In addition, AION field defects may be superimposed on the glaucoma visual field defects. In advanced glaucoma, the visual field scotomata may be large enough (e.g., tubular vision) to prevent detection of the additional scotomata caused by AION. According to the vascular theory, damage to the optic nerve may be caused also from ischemia if the optic disc does not receive enough oxygen even without AION. This damage is added to the damage caused by the mechanical effect of optic disc compression.

occur in the cytoplasm, endoplasmic reticulum, and mitochondria that lead signals to the nucleus to degenerate. The end result is shrinkage of the nucleus, fragmentation of the deoxyribonucleic acid (DNA), and death of the cell. It is possible that some additional mechanisms and pathways exist that involve adjacent cells such as astrocytes, oligodendrocytes, and even vascular endothelial cells. Despite controlled IOP, the apoptosis may continue once started causing additional ganglion cell death. Ganglion cells in different stages of apoptosis may "signal" adjacent normal cells to commence with apoptosis cascade, leading to further loss

Why Do Patients with Controlled Glaucoma Continue to Lose Their Vision?

http://dx.doi.org/10.5772/intechopen.79764

31

**9. Recommendations to prevent further visual loss in patients with** 

bedtime. It is the physician role to make these recommendations.

glaucoma as well as other fields to prevent cellular few or no by apoptosis.

Patients with high IOP fluctuations are not controlled and may benefit from early surgery such as trabeculectomy with mitomycin C or shunt procedures. These patients can be traced because they usually have secondary glaucoma mainly pseudoexfoliative and pigmentary. It is worthwhile to ask the patients to sleep at 20–30° head-up position. The IOP decreases when the bed head is tilted up in 30° and is 14.2 ± 2.3 mmHg OD and 14.1 ± 1.9 OS and not when the patient is sleeping on multiple pillows (16.3 ± 2.4 OD and 16.5 ± 2.6 OS) [3]. In another study, the IOP decreased from 16.02 ± 1.65 to 14.5 ± 1.36 mmHg [10]. The IOP may decrease by 9.33% in glaucoma patients, and this effect is found in 82% of them. Patients should avoid sleeping on their affected eye(s). Sleeping over the back or even on the side as long as the orbital rim is lying against the pillow is the best option for these patients. Antihypertensive medications should be taken when the patient is awake and active, usually in the morning and not at

Additional efforts should be made to discover drugs that can abolish or slow down the apoptosis. Antibodies against PD-L1, FasL, growth factors, or their receptors may be helpful. Forty chemical compounds have inhibitory effects on different steps of apoptosis but may be toxic to normal cells. Phenoxodiol, an isoflavone that targets a regulator of sphingosine kinase depriving the cell of XIAP and FLIP was evaluated for ovarian cancer but was disappointing. Thus, it is essential to discover biologic agents such as antibodies against one or more of the extracellular mediators with better effects and with few or no side effects that will be approved for clinical use to arrest axonal apoptosis at the optic nerve. So far, none has been discovered, and research efforts are mandatory because such molecules may be used in

Department of Ophthalmology, Galilee Medical Center, Nahariya and Faculty of Medicine,

of neuronal cells.

**Author details**

Shimon Rumelt\* and Schachar Schreiber

Bar Ilan University, Zefat, Israel

\*Address all correspondence to: shimonr@gmc.gov.il

**controlled glaucoma**

#### **8.5. Continuation of the neuronal apoptosis**

Patients with glaucoma suffer loss of axons of the ganglion cells as they pass the optic disc. Two theories explain the axonal loss. The first one is mechanical. According to this theory, the force caused by the IOP impedes axonal transport (flow) (micro-strangulation) and this may trigger axonal apoptosis [7]. The second theory is vascular. This means that the IOP impedes vascular supply to the optic disc. This causes a relative ischemia to the optic disc and triggers apoptosis. It is probable that both mechanisms coexist and the mechanical force may have a greater influence. Nonetheless, apoptosis, and not degeneration/necrosis, is the mechanism of axonal death in glaucoma. Apoptosis is programmed cell death, while necrosis is a different process involving extracellular components of inflammation. It consists of several pathways initiated be certain extracellular ligands such as programmed death ligand 1 (PD-L1), Fas ligand (FasL), tumor necrosis factor (TNF), nerve growth factor (NGF), growth factors, and others (**Figure 4**) [8, 9]. These molecules attach to receptors on the cell wall such as tropomyosin kinase receptor (TRK), tyrosine kinase receptor (RTK), receptor of apoptosis signal factor (Fas), and tissue necrosis factor receptor (TNFR) that trigger intracellular cascades that involve multiple pathways and molecules including the caspase cascade. These processes

**Figure 4.** The pathways of apoptosis. Interference with any of these steps may prevent the apoptosis cascade.

occur in the cytoplasm, endoplasmic reticulum, and mitochondria that lead signals to the nucleus to degenerate. The end result is shrinkage of the nucleus, fragmentation of the deoxyribonucleic acid (DNA), and death of the cell. It is possible that some additional mechanisms and pathways exist that involve adjacent cells such as astrocytes, oligodendrocytes, and even vascular endothelial cells. Despite controlled IOP, the apoptosis may continue once started causing additional ganglion cell death. Ganglion cells in different stages of apoptosis may "signal" adjacent normal cells to commence with apoptosis cascade, leading to further loss of neuronal cells.
