Perimetric early diagnosis of primary open angle glaucoma

Primary open angle glaucoma (POAG) is no longer considered an isolated optic neuropathy, but a systemic neurodegeneration.^1,2 In addition to the glaucoma-typical changes, which involve the entire visual system (corpus geniculatum laterale, radiatio optica, visual cortex), there are also generalised cerebral impairments with synaptic connection disorders^3,4, which involve both the central autonomic network and the peripheral autonomic nervous system.^3,4,5 The visual system is a complex structure that is interconnected via 4 neurons, which link the retina to the visual cortex. It starts at the photoreceptors (1st neuron) and the bipolar cells (2nd neuron), and then continues via the retinal ganglion cells (3rd neuron) to the corpus geniculatum laterale (4th neuron), a neuronal relay station in which the input from the eye is connected to the brain and processed and vice versa. From there, it goes via the radiatio optica to the visual cortex in the V1 region (occipital lobe).³⁵ The retinal ganglion cells are roughly divided into 3 large groups⁶:

1.  The magnocellular ganglion cell system (approx. 10%), which has a low spatial and a high temporal resolution. It is primarily responsible for motion, depth and contrast perception.
2. The parvocellular ganglion cell system (approx. 80%) with a high spatial but low temporal resolution. It is responsible for visual acuity and red/green colour vision.
3. The koniocellular ganglion cell system (about 10%), which represents a direct connection to the blue cone bipolar cells and is responsible for blue-yellow colour vision.

It is important to note, however, that the visual system does not end in the V1 region. Starting from the V1 region, there exists a dorsal path through the parietal lobe (V2, V5, medial superior temporal area (MST)), which is responsible for the control of actions or the perception of movement and position and goes through the magnocellular ganglion cell system. In addition, there is a ventral path through the temporal lobe, which is responsible for the recognition of objects and for the perception of colour, pattern and shape and is located in the parvocellular ganglion cell system.^7,8,9 The importance of the visual system is evidenced by the large proportion of the cerebral cortex that is involved in the act of vision. In addition to the primary visual cortex (V1), which accounts for about 15% of the total cerebral cortex, more than 30 different visual areas have been described so far. Overall, about 60% of the cerebral cortex is involved in the perception, interpretation and response to visual stimuli.¹⁰ Regarding glaucoma, cerebrospinal fluid circulation disorders with reduced cerebrospinal fluid pressure occur in the brain in patients with normal tension glaucoma (NTG) as well as in patients with POAG compared to control groups of a similar age.¹² In this context, the literature also discusses the involvement of the glymphatic system in POAG.¹¹

The question of how this systemic glaucomatous neurodegeneration occurs has not yet been clarified. On the one hand, there is the hypothesis that cerebral changes in POAG are a consequence of anterograde transsynaptic diffusion of cell death signals caused by the degeneration of the retinal ganglion cells themselves.¹³ On the other hand, it is also discussed in the literature that the above-mentioned  disturbances in the visual system may represent a consequence of a retrograde transsynaptic degeneration.^14,15 This would mean that the cerebral changes in POAG occur very early on and appear earlier than or simultaneously with glaucomatous optic neuropathy. This pathophysiological concept is supported by the observation that POAG exhibits a primary mitochondriopathy^16,17 that does not selectively affect the optic nerve. Increased triggering of oxidative stress causes neuroinflammation¹⁷, which has a far-reaching influence on the CNS. Regardless of the underlying process, or probably rather due to the interplay of both processes, glaucomatous optic neuropathy also involves long-term decline of retinal ganglion cells (RGC) with a loss of their axons. From a neurophysiological point of view¹⁸, when the natural cellular compensation mechanisms are exhausted, RGC struggle to survive. The first functional failures appear when the harmful stimuli act chronically on the RGC. However, these damages can be reversed if the general conditions for the RGC improve again, for example by reducing the intraocular pressure significantly, improving ocular perfusion, optimization of present systemic diseases and/or avoiding unnecessary harmful factors, such as smoking.

 Sensitive perimetric methods are required to be able to detect these early functional signs. Conventional achromatic perimetry is not adequate in this regard, since it only detects functional disorders after about 30% of the RGC have been lost.¹⁹ For this reason, numerous new perimetric techniques have come onto the market in the last 20 years in order to be able to detect functional damage earlier, especially in the case of early initial damage and the onset of the progression. One of the first developments in this direction was blue-yellow perimetry, which is an inexpensive early perimetry method, especially in younger glaucoma patients (< 55 years), since it can often be obtained by a software update of the classic perimeter. The introduction of quick strategies also in blue-yellow perimetry has eliminated the problem of a longer examination time. However, the main disadvantage of blue-yellow perimetry is its age-related restriction of use, because the yellow coloration of the lens and the loss of blue cones lead to less reliable results from the age of 55. Newer perimetric procedures with a movement stimulus are age-independent and can be used easily both in children and in older patients. Currently, the following methods are commercially available: frequency doubling perimetry (Matrix, Zeiss Meditec), pulsar perimetry (Octopus 600-Pulsar, Haag-Streit) and flicker perimetry (Heidelberg Edge Perimeter, Heidelberg Engineering). What all three of these perimetric techniques have in common is that they use a moving stimulus rather than a static one, as in static achromatic perimetry (SAP), in which the stimulus can only be distinguished from its background by means of the difference in luminance. In addition to the parvocellular ganglion cells, the movement stimulus primarily addresses the magnocellular ganglion cells, which are responsible for perceiving motion. Since the proportion of magnocellular ganglion cells constitutes only about 10% of all RGC, early cell subsidence of these RGC can be noticed more quickly, since they cannot be compensated sufficiently well by the other magnocellular RGC (hypothesis of reduced redundancy). Most of the experience with these perimetry techniques is with frequency doubling perimetry (FDP). Already 20 years ago it could be shown that FDP can detect perimetric damage earlier than SAP²⁰, which was then extensively confirmed by subsequent studies.^{21,22,23,39,40} Furthermore, it was shown that, with FDP, perimetric progression can be detected earlier than with SAP.^24,25,38 In addition, FDP is more sensitive in the detection of glaucoma than multifocal VEP.²⁶

However, FDP also has its limits. Due to its high sensitivity, it does not have enough capacity reserve for the visual field examination of an advanced glaucoma. Therefore, this perimetry method cannot replace achromatic perimetry as the gold standard, but it is a helpful addition in early diagnostics. In addition, as with all functional and structural examination techniques, systemic diseases can also lead to abnormalities in FDP results and overlap with glaucoma-related anomalies. Such interferences have been described, for example, for diabetes mellitus^27,28 and Alzheimer's disease^29,30. Furthermore, FDP can not be replaced by imaging diagnostics, since, in their currently available form, they are mainly used in the detection of dead RGC with loss of the retinal nerve fibre layer, which neurobiologically represents the end of an RGC and has nothing to do with early diagnosis. Recent developments in Optical Coherence Tomography (OCT) may provide an insight into the functional state of RGC (for example, with Polarization OCT³¹ or Adaptive Optics OCT³²), but these techniques are not yet clinically available. There is a synergy to explore in the combined application of FDP and OCT. A new algorithm, for example, has improved significantly the specificity of glaucoma detection.³³ In summary, these "newer" perimetric methods, representative of which is frequency doubling perimetry, allow for an earlier detection of scotomas in glaucoma in the initial diagnosis and progression assessment when compared with SAP. This is likely to include not only disorders in the optic nerve itself, but also cerebral neurodegenerative disorders within the framework of POAG³⁴, which affect a large proportion of the brain.  As a result of the time gained thanks to the earlier detection of the scotomas, an antiglaucomatous therapy can be initiated earlier and thus the progression can be prevented or at least slowed down. However, specific cost-effectiveness studies are not available. FDP is considered the most useful of perimetric procedures in a study on the quality and cost effectiveness of screening procedures for the detection of primary open-angle glaucomas.³⁶ Even the American Academy of Ophthalmology recommends FDP and blue-yellow perimetry for early diagnosis: "Frequency doubling technology and short-wavelength automated perimetry (SWAP) are two alternative testing methods shown to be helpful in screening for early visual field damage, especially when SAP is normal".³⁷

Perimetric methods have been available for over 20 years, but they are still hardly used in the everyday diagnosis of glaucoma. They should therefore be applied more frequently in the future, since every year gained in the diagnosis means a longer life with fewer functional disorders for glaucoma patients, which has a positive influence on their quality of life. Thus, frequency doubling perimetry in particular has an important place in perimetric diagnostics both in early diagnosis and in progression evaluation.