New insights in the pathogenesis and treatment of normal tension glaucoma

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Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage and reducing IOP improves prognosis. Nevertheless, there is little doubt that other risk factors besides IOP such as unstable ocular perfusion are involved. Blood flow is unstable if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the autoregulation of blood flow disturbed. A common cause for a disturbed OBF autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension glaucoma patients. An unstable blood flow leads to recurrent mild reperfusion injury (chronic oxidative stress) affecting particularly the mitochondria of the optic nerve head. OBF regulation can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase inhibitors.

Graphical abstract

Pathogenetic concept of glaucomatous optic neuropathy (GON) by Flammer J. The upregulation of nitric oxide, in the astrocytes, is part of the activation of these cells either by mechanical or by ischemic/reperfusion cell stress. Reperfusion occurs both in patients with either high IOP or very low blood pressure (BP) exceeding the capacity of autoregulation, as well as in patients with a normal or mildly increased IOP or normal or mildly decreased blood pressure if subjects suffer from disturbed autoregulation. Recurrent mild reperfusion leads to a chronic oxidative stress with the production of free radicals (O2radical dot) inducing injury. Based on: J. Flammer: Glaucoma, third edition, Hogrefe & Huber Publishers (2003).

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Highlights

► One cause of glaucomatous optic neuropathy is an unstable oxygen supply. ► Retinal venous pressure is often increased in glaucoma. ► Primary vascular dysregulation leads to a disturbed autoregulation of blood flow.

Introduction

A number of questions often arise when dealing with normal tension glaucoma (NTG). Some of the common questions asked are: Why does the therapeutic reduction of intraocular pressure (IOP), although on average improving the prognosis of glaucomatous optic neuropathy (GON), not stop progression in all these patients? [1] Why do we see other patients with GON with an IOP in the normal range? [2••] These observations challenge the pathophysiological concept of glaucoma based solely on IOP. Today, we know that other concomitant factors also play an important role. One important factor is a disturbed ocular blood flow.

On average, blood flow is reduced in glaucoma patients in various tissues of the eye [3, 4, 5•]. Blood flow reduction is more pronounced in normal tension glaucoma than in high tension glaucoma and comparatively, more in patients with progressive types of glaucoma than those with stable forms of glaucoma [6, 7]. Blood flow reduction, however, can also be observed in the nailfold capillaries of the fingers [8], indicating that this reduction is not simply due to an increase in IOP or glaucomatous damage. There is a primary component involved. This primary component, as such, is not arteriosclerosis but rather a primary vascular dysregulation [9].

In this review we aim to give insight into some of the factors, besides IOP, which play an important role in the pathogenesis of GON and briefly describe some of the newer treatment modalities.

Section snippets

Risk factors for glaucoma

Factors associated with an increase of IOP are not the same as factors associated with the development of GON. The risk factors leading to an IOP increase and those leading to GON are described below.

Systemic risk factors for increased IOP

All factors known to be risk factors for artherosclerosis are also risk factors for an increase in IOP (age, smoking, dislipidemia, diabetes mellitus, systemic hypertension, male gender, obesity, etc.). The association between IOP increase and these factors is relatively weak but nevertheless significant [10, 11]. Furthemore, treatment of these risk factors (such as physical exercise, weight loss, treatment of dislipidemia, etc.) [12] reduces IOP slightly. It is still a debate why these risk

Systemic risk factors for GON

Elevated IOP is the most commonly identified ocular risk factor in the development of glaucomatous optic neuropathy. It is important to note that not all subjects with elevated intraocular pressure will go on to develop glaucoma (ocular hypertensive subjects) and up to 50% of patients with glaucoma will never have statistically elevated IOP. The correlation between IOP level and progression is very weak [15]. Interestingly, some patients acquire damage before they suffer from an increase in IOP

Ocular blood flow (OBF) in glaucoma

Indeed, it is challenging to measure ocular blood flow (OBF)—several methods are used, but there is no gold standard as yet. Nevertheless, OBF can be measured and different instruments are already in daily use, both for clinical and research purposes [4]. Although these different techniques quantify blood flow or blood-flow velocity in different vessels using different methods, the outcomes are very often well correlated.

On average, OBF is reduced in glaucoma patients in various tissues of the

The role of perfusion pressure

There is still some discussion why OBF is reduced in glaucoma. Some experts focus on perfusion pressure (PP) [25, 26], which is traditionally defined as the difference between the arterial BP and the IOP, in the assumption that IOP is equal to the retinal venous pressure.

There is evidence to suggest that low PP, and in particular a fluctuating PP, is a risk factor for the development of GON [2••]. OBF however is not a simple a function of PP. If this would be the case, patients with systemic

The role of retinal venous pressure

In normal circumstances the retinal venous pressure is approximately equal to the intraocular pressure, explaining the physiological phenomenon of spontaneous venous pulsation. In glaucoma patients, the retinal venous pressure is often increased [32, 33, 34••] and based on our clinical experience it is particularly increased in those patients with a PVD. The fact that the retinal venous pressure is increased in glaucoma patients indicates that the perfusion pressure is lower than one would

Vascular dysregulation syndrome

Subjects with a PVD syndrome have an inborn tendency to respond differently to various stimuli such as cold [35]. Among the most apparent pathological reactions are the vasoconstrictions. But why do these subjects constrict their vessels more than others?

Subjects with a PVD have a normal capacity to produce ATP. Under certain circumstances, however, where these subjects do not use as much ATP, such as when they sit quietly in a cold environment, they are not able to produce as much heat as

The role of oxidative stress

Oxidative stress is induced by an unstable oxygen supply (reperfusion injury) [54, 55]. In POAG, oxygen tension in the tissue often falls temporarily. This drop is very mild but recurrent so that there is a long-term cumulative effect of the small amount of damage caused by these reductions in oxygen tension. To some extent, such a reduction in oxygen tension leads to an adaptation which is called preconditioning. This results in cells becoming resistant to further reductions in oxygen tension.

The pathogenetic concept

There are two main pathogenetic components: first, the activation of the astrocytes and second, damage to the axons (graphical abstract).

Mechanical stress (e.g. by an increase in IOP) activates astrocytes by stimulating the epidermal growth factor receptor (EGFR) [62]. Astrocytes, however, are also activated by Endothelin [63], which is upregulated as a consequence of cell stress as for example due to reperfusion injury (RI) [54].

The activation of the astrocytes alters the local

Therapeutic consequences

It is well known that an IOP reduction improves, on average, the prognosis of all types of glaucoma. It is also known, however, that patients may continue to progress despite achieving their optimal ‘target’ IOP. This insight has lead to the need to develop new therapeutical approaches [69, 70, 71]. Some of these approaches are already in (limited) clinical use, whereas others are still being investigated experimentally. For the purposes of this review, we will focus on treatments that are

Conclusions

Glaucoma is a disease, for which diagnosis and treatment is not solely associated with elevated IOP. Today, the concept of glaucoma implies that this is a multifactorial disease and although elevated IOP still remains an important risk factor, glaucomatous damage results from a combination of elevated IOP and IOP-independent risk factors. Throughout the past century medical, laser and surgical treatments have focused on methods of lowering IOP. However, despite successful lowering of IOP, many

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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    A part of this manuscript has been presented in a lecture by J. Flammer and published in the Internet by Excerpta Media.

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