YELLOW-TINTED IOLs IN GLAUCOMA

 

Yellow-tinted intraocular lenses (IOLs) for cataract surgery are being marketed for their ability to block deleterious blue light entering the eye.

Short-wavelength automated perimetry (SWAP) has the ability to detect functional changes in patients with early glaucoma and without visually significant cataracts.

Cataracts have been reported to cause a generalized reduction in sensitivity for standard automated perimetry (SAP) and SWAP tests in normal subjects, and this generalized reduction is more prominent on SWAP testing compared with SAP testing.

SWAP testing uses a blue stimulus of 440 nm on a bright yellow background of 100 candela/m2. (Blue On Yellow= BOY)

Yellow-tinted IOLs contain a yellow chromophore with the ability to absorb the high-energetic visible blue light between 380 and 500 nm.

It is hypothesized that blue-light–filtering IOLs may negatively affect contrast acuity and blue/yellow foveal threshold when compared with UV-only–filtering IOLs in patients without concomitant eye diseases. Just like nuclear sclerotic cataracts, mentioned above, these IOLs may affect the quality of SWAP visual field testing.

The koniocellular pathway which uses the spectrum for blue-yellow light processing has been reported to be damaged in early glaucoma and yellow-tinted IOLs can affect SWAP significantly.

A number of studies have been performed to assess the effect of yellow-tinted IOLs on SWAP testing. Nilofurshan et al., have reported improved MD and FT on SWAP testing in mild-to-moderate glaucoma patients who underwent cataract extraction and implantation of yellow-tinted IOLs. Kara-Júnior et al., compared the effect of clear and yellow-tinted IOLs on SWAP indices in 46 normal subjects (mean age: 68.5 years old) and did not detect any statistically significant differences between these two IOLs in postoperative values. Espindola also reported blue-on-yellow perimetry did not appear to be affected by aspherical or yellow tinted IOLs. Ueda, as well as, Kim have reported no significant influence of yellow-tinted IOLs on FDT perimetry.

However, Jang et al., reported a statistically significant difference in MD and PSD values between yellow-tinted and non-tinted IOLs on SWAP testing.

In view of these studies, it appears that the presence of glaucoma is not a contra-indication for implantation of yellow-tinted IOLs .

REFERENCES:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123272/#:~:text=Conclusions%3A,testing%20than%20visually%20significant%20cataracts.

https://www.scielo.br/j/abo/a/9CGyzBgWSfHtpTLGgknnVpr/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039191/

SOLAR RADIATION & GLAUCOMA

 

There are some reports suggesting that solar radiation, especially ultraviolet (UV) radiation and blue light may play an important role in the causation of glaucoma.

Effect of UV radiation at different ages

The International Commission on Non-Ionizing Radiation Protection (ICNIRP) defines several subgroups of ultraviolet or invisible radiation classified into UVA (315-400 nm), UVB (280-315 nm) and UVC (100-280 nm). Infrared (IR) radiation has also been subdivided into three groups depending on the wavelength: IRA (700-1400 nm), IRB (1400-3000 nm) and IRC (3000-10,000 nm). [1]

Although the exact mechanism of UV-light induced glaucomatous degeneration is not known, yet, there are certain pointers to its probable association.

Osborne et al. have shown that blue light, also called high-energy visible light, which has higher wavelength than UV light (450-490 nm),  adversely affects the mitochondria of retinal ganglion cells (RGCs). Moreover, there is evidence that the mitochondrial electron transport chain-related enzymes flavin and cytochrome-C oxidase are damaged by blue light, resulting in the generation of photochemical effects and reactive oxygen species (ROS). [2]

ROS are normally regulated by antioxidants, but in eyes deformed by ischemia or myopia, blue light leads to excessive production of ROS and mitochondrial DNA damage. Ultimately, this results in the loss of the visual field owing to a cascade of events leading to cell death. When the retina is exposed to blue light under ischemic conditions, it produces relatively low levels of ATP, the RGCs get damaged, and mitochondrial energy metabolism is inhibited. [3]

Apoptosis is induced when the apoptosis-inducing factor (AIF), which exists in the spaces between the mitochondrial membranes of retinal epithelial cells, splits into two molecules, gets activated, and enters the nucleus of the cell. In contrast, necroptosis is programmed necrosis within the cell, in which receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) form a complex and perform their functions. In addition to activating AIF in retinal cells, blue light also stimulates RIP1 and RIP3 activation in RGCs. [3]

Osborne et al. demonstrated that while AIF was expressed intact in retinal cells cultured under dark conditions, it was expressed as two fragments under blue light conditions. Furthermore, RGCs exposed to blue light reportedly showed a lower survival rate than those exposed to dark illumination, and the survival rate increased significantly when the expression of RIP1 and RIP3 proteins was inhibited through small interfering RNA (siRNA) technology. It is evident that blue light activates both apoptosis and apoptotic necrosis in retinal cells, which may contribute to the onset or exacerbation of glaucoma. [4]

Pasquale et al., have shown that UV light could also contribute to the development of pseudo-exfoliative glaucoma (PXG). Their study showed that every hour per week spent outdoors during the summer, averaged over a lifetime, was associated with a 4% increased odds of exfoliation syndrome (pooled odds ratio = 1.04; 95% CI: 1.00-1.07; p = .03). For every 1% of average lifetime summer time between 10 a.m. and 4 p.m. that sunglasses were worn, the odds of exfoliation syndrome decreased by 2% (odds ratio = 0.98; 95% CI: 0.97-0.99; p < .001). [5]

After controlling for important environmental covariates, history of work over water or snow was associated with increased odds of exfoliation syndrome (odds ratio = 3.86; 95% CI: 1.36-10.9). There is considerable evidence that climatic factors contribute to the pseudo-exfoliative changes. For example, aboriginal Australians who spend substantial time outdoors have a higher prevalence of pseudo-exfoliative syndrome (PEX).

Dai et al., have shown that both genetic predispositions to using sun/UV protection and having an ease of skin tanning response are associated with a decreased risk of PXG in the European population. According to them, one possible explanation for this association is that UV radiation may influence the expression of nonpigmented ciliary epithelial cells (NPE) in humans through an aryl hydrocarbon receptor (AHR)-associated pathway, thereby contributing to the development of PXG. [6]

Clusterin, produced by NPE, serves as an effective extracellular chaperone, its deficiency in the anterior segment can promote stress-induced aggregation and the stable deposition of pathologic extracellular matrix products—hallmarks of PXG. Zenkel et al. have observed an oxidative milieu in the anterior chamber of PEX eyes, potentially leading to stress-induced protein modifications and misfolding. [7] However, whether oxidation of the UV radiation contributes to this process remains uncertain. TGF-β1, oxidation and UV radiation can induce a significant upregulation in LOXL1 gene expression in human tenon fibroblasts and PEX. UVB has been associated with the increased levels of TGF-beta 1 mRNA, and UVA exposure can induce oxidative damage. Nevertheless, it remains uncertain whether UV radiation affects LOXL1 through direct DNA damage, TGF-β1 mediation, or oxidative stress.

Oxidative stress has also been linked to POAG by increasing flow resistance of aqueous humor through the trabecular meshwork in the presence of high levels of hydrogen peroxide. [1]

TREATMENT OF GLAUCOMA WITH INFRA-RED LIGHT:

Red light increases cytochrome-c oxidase activity in the electron transport system, reducing inflammation and increasing antioxidant reactions to promote cell regeneration. PBM (Photobiomodulation) therapy, which is emerging as a new treatment for glaucoma, induces the inhibition of nitric oxide in the electron transport system and promotes an increase in the activity of cytochrome-C oxidase, reduces oxidative stress and inflammatory reactions in the eye, and increases energy production in the cells. A study by Dr. Galina has shown IOP reduction after 15 minutes of infrared-light exposure to healthy subjects. [7]

SEE POST ON IRL TREATMENT HERE: https://ourgsc.blogspot.com/search?q=Galina

Therefore, the minimization of UV and blue light exposure and the general application of red-light treatment strategies are anticipated to show synergistic effects with existing treatments for glaucoma and should be considered a necessary prospect for the future.

REFERENCES:

1. Ivanov IV, Mappes T, Schaupp P, Lappe C, Wahl S. Ultraviolet radiation oxidative stress affects eye health. J. Biophotonics. 2018; 11:e201700377
2. Osborne N.N., Lascaratos G., Bron A.J., Chidlow G., Wood J.P.M. A Hypothesis to Suggest That Light Is a Risk Factor in Glaucoma and the Mitochondrial Optic Neuropathies. Br. J. Ophthalmol. 2006;90:237–241.
3. Ahn SH, Suh JS, Lim GH, Kim TJ. The Potential Effects of Light Irradiance in Glaucoma and Photobiomodulation Therapy. Bioengineering (Basel). 2023 Feb 7;10(2):223.
4. Osborne N.N., Núñez-Álvarez C., del Olmo-Aguado S., Merrayo-Lloves J. Visual Light Effects on Mitochondria: The Potential Implications in Relation to Glaucoma. Mitochondrion. 2017;36:29–35.
5. Pasquale LR, Jiwani AZ, Zehavi-Dorin T, Majd A, Rhee DJ, Chen T, Turalba A, Shen L, Brauner S, Grosskreutz C, Gardiner M, Chen S, Borboli-Gerogiannis S, Greenstein SH, Chang K, Ritch R, Loomis S, Kang JH, Wiggs JL, Levkovitch-Verbin H. Solar exposure and residential geographic history in relation to exfoliation syndrome in the United States and Israel. JAMA Ophthalmol. 2014 Dec;132(12):1439-45. doi: 10.1001/jamaophthalmol.2014.3326. PMID: 25188364; PMCID: PMC4268013.
6. Jinyue Dai, Lingge Suo, Haocheng Xian, Zhe Pan, Chun Zhang; Investigating the Impact of Sun/UV Protection and Ease of Skin Tanning on the Risk of Pseudoexfoliation Glaucoma: A Mendelian Randomization Study. Invest. Ophthalmol. Vis. Sci. 2023;64(13):4. https://doi.org/10.1167/iovs.64.13.4.
7. Zenkel M, Kruse FE, Jünemann AG, Naumann GO, Schlötzer-Schrehardt U. Clusterin deficiency in eyes with pseudoexfoliation syndrome may be implicated in the aggregation and deposition of pseudoexfoliative material. Invest Ophthalmol Vis Sci. 2006 May;47(5):1982-90. doi: 10.1167/iovs.05-1580. PMID: 16639006.
8. Dimitrova, Galina & Gjorgjioska, Ana & Ilievska, Tatjana & Grkova-Mishkovska, Emilija & Ljubic, Antonela & Purelku, Merjem & Andonovski, Dragan & Stojcev, Sasho. (2019). The effect of infra-red light on intraocular pressure. Arquivos Brasileiros de Oftalmologia. 82. 10.5935/0004-2749.20190017

INTRAOPERATIVE OCT

 

Intra-operative optical coherence tomography (iOCT) has the ability to enhance visualization and depth appreciation during glaucoma surgery, especially with the gaining popularity of Minimally Invasive Glaucoma Surgery (MIGS)—to facilitate targeted device placement and fine surgical maneuvers in the angles, the sub-conjunctival layer and the suprachoroidal space.

The iOCT allows the surgeon during trabeculectomy, to ascertain the depth of the initial scleral incision, as well as to visualize the regularity of the dissection and thickness of the scleral flap. While the current state of technology does not allow precise depth identification, iOCT alters the nature of the procedure from a ‘blind’ approach to a ‘visually guided’ approach. This is particularly important in eyes with high axial myopia, where the thin sclera increases the risk of full-thickness dissection as well as subsequent scarring, contributing to a higher rate of failure. The iOCT also allows more accurate visualization of the sclerostomy and iridectomy during trabeculectomy. iOCT may also be used as a tool for training residents to perform glaucoma filtering surgery.

The iOCT allows the surgeon to perform goniosynechiolysis without the use of intra-operative gonioscopy. Post-synechiolysis, the iOCT may enable the surgeon to more objectively assess the adequacy of synechiolysis and the effectiveness of the procedure in opening the angle. However, in eyes with hazy corneas, the iOCT may be of limited advantage, given that it shares similar limitations as a table-top SDOCT in these scenarios.

The iOCT may be useful in bleb needling by allowing the visualization of deeper tissue and structures within the bleb, demonstrating the extent and location of adhesions and loculations, thereby allowing targeted release of these areas of fibrosis. The iOCT further allows objective assessment of surgical success, by identifying multiple cystic spaces within a rising bleb. The iOCT also allows visualization of the often concomitantly performed flap lift, which could be obscured by significant encapsulation and tenon’s proliferation.

Swaminathan et al. described the use of iOCT in guiding the GDD tube into the eye during surgery, demonstrating its particular usefulness in the sulcus-placement of tubes. The direct visualization of the tunnelling needle into the anterior chamber (AC) provides the surgeon certainty of its entry into the AC. Conversely, the anterior movement of the iris over the needle on iOCT indicates the entrance of the needle into the sulcus. iOCT visualization may aid in reducing the risk of tube erosion after GDD implantation by ensuring adequate coverage of conjunctiva and partial-thickness sclera or donor tissue over the tube.

Siebelmann et al. reported the use of iOCT as an adjunct to ab-externo canaloplasty surgery. The iOCT allows the visualization of intra-operative structures, facilitating precise microcatheter passage through the Schlemm’s canal. The iOCT may also allow direct visualization of the suture tightening against the Schlemm’s canal—altering the shape of the AC, from a concave, to an M-shape. The appreciation of the degree between the AC and Schlemm’s canal upon suture tightening may allow the surgeon to titrate the tension of the suture. Furthermore, the iOCT may help the surgeon minimize the risk of complications from this procedure by reducing the risk of complete penetration during dissection and minimizing the incidence of DM detachments.

Trabecular aspiration is an angle-based MIGS which acts by clearing the inter-trabecular spaces of extracellular debris, thereby improving aqueous drainage through the angle. iOCT-use would theoretically facilitate more accurate siting of the aspiration cannula. However, Heindl et al. has reported the limitations of the iOCT in its application here—given the 840-nm wavelength of the iOCT, visibility of the angle remains limited. In addition, the iOCT scans only vertically or horizontally and may not allow precise imaging of the aspirator tip in relation to the TM. OCT-guided trabecular aspiration using 1310 nm wavelengths has also been attempted in porcine eyes.

The ab-interno trabectome is another angle-based MIGS device which may benefit from adjunct iOCT use, involving the removal of trabecular tissue to increase aqueous outflow. The concurrent use of a gonioprism or Swan–Jacobs gonioscopy lens and the iOCT has been shown to aid the surgeon in visualizing the angle and in identifying the opening of the inner wall of Schlemm’s canal. Tilting the microscope and the iOCT from the regular 60° to a more horizontal position may provide better visualization for the surgeon.

The iOCT may be useful during XEN45 implantation as it may help determine the final placement of the implant during surgery. The use of iOCT may decrease intra-operative risks and optimize placement of the implant. The iOCT may also be useful in visualizing the XEN45 implant in the event of sub-conjunctival hemorrhage, which obscures the surgical field and hinders accurate placement of the implant, at times requiring the surgeon to abort the procedure entirely.

Limitations of iOCT:

Firstly, as both stand-alone iOCTs and microscope-integrated iOCT systems are expensive, therefore, cost and accessibility remain a limitation in the use of this technology.

Secondly, adopting iOCT in one’s surgical practice may involve a steep initial learning curve. The microscope-integrated iOCT platforms require simultaneous viewing of both the surgical field and the OCT image during surgery, through both oculars of the microscope.

Thirdly, the scanning raster of current iOCT platforms has a restricted scanning area and this may require the surgeon to constantly move the scanning zone during surgery to visualize the instrument tip or area of interest.

Fourthly, optimal iOCT images may be difficult to obtain. Current iOCT platforms do not respond well to movements of the eye during surgery—motion artefacts are generated, and there is a noticeable time lag in between real-time movement and the displaying of images. A dry corneal surface, incorrect magnification and improper focus may also compromise image quality.

Fifthly, structures posterior to metallic instruments may not be visualized due to impedance of OCT light source wavelength.

https://www.nature.com/articles/s41433-019-0689-3 

SION GONIOTOMY DEVICE

 

Sight Sciences Inc., is a US-based company involved in eye care technology. The company has announced the development of a blade-less device for goniotomy. The procedure can be performed as a stand-alone or in combination with cataract surgery.

The device consists of an upper foot which helps guide the trabecular meshwork into the trap and tissue collection window. The lower foot guides the device along the Schlemm’s canal. The toe gently punctures the trabecular meshwork and facilitates access into the Schlemm’s canal. The device has a trap in which excised trabecular meshwork tissue is grasped and accumulates during the goniotomy procedure. A tissue collection window permits visualization of the trabecular meshwork collected in the trap.

Trabecular meshwork tissue is excised over several clock hours to permit aqueous flow through the Schlemm’s canal.

WEBSITE LINK: https://sionsurgical.com/

BETA-AMYLOID TEST FOR GLAUCOMA

 

Amydis Inc., is a company devoted to the development of ocular biomarkers for the detection of diseases of the eye, heart and brain. In the end of last year, the company announced the launch of its Phase 2 clinical program for the study of a novel retinal tracer, AMDX-2011P, which can detect amyloid-beta in glaucoma patients. This biomarker can detect molecular changes in the retina, which can add to the structural-functional changes seen in glaucoma patients.

There are reports suggesting amyloid-beta is a key factor in the pathogenesis of glaucoma. Amyloid beta is also associated with the development of Alzheimer’s disease, suggesting glaucoma is an “ocular Alzheimer’s disease”.

The patented retinal tracer, AMDX-2011P, is a small molecule which can be used to detect and quantify amyloid beta deposits in the retina using currently available imaging devices. Therefore, the procedure claims to increase the capture rate of glaucoma and improving clinical management. This is achieved through earlier intervention and potentially, facilitate amyloid beta targeted neuroprotective therapies.

In collaboration with the University of California-San Diego (UCSD), Amydis completed proof-of-concept studies demonstrating the Amydis tracers detect amyloid beta in post-mortem human eyes of glaucoma patients, but not healthy subjects. The results have been submitted for publication.

Dr. Stella Sarraf, Amydis founder and chief executive officer was quoted, “We are thrilled to launch a new clinical program for an eye disease. Enabling micron-level in-vivo tracking of retinal amyloid beta formation in glaucoma patients will add a gain-of-function test to current loss-of-function testing, empowering doctors to deliver better patient care,” “Our goal is to also facilitate the development of neuroprotective agents to help provide more therapeutics for patients.”

“If successful, the creation of a molecular endpoint with the Amydis technology has the potential to enhance standard of care for glaucoma patients by enabling improved diagnostic and prognostic evaluation, as well as being used as an endpoint to develop neuroprotective therapies,” said Dr. Robert N. Weinreb, Chair of the Amydis Scientific Advisory Board, Chair and Distinguished Professor of Ophthalmology at UCSD and Director of Shiley Eye Institute.

Amydis has launched a phase 2 open label, blinded endpoint assessment study of AMDX-2011P as a retinal tracer in subjects with primary open angle glaucoma. This trial is being conducted at three sites in Southern California to collect multi-modal retinal imaging data on 40 subjects. This multi-modal data will include optical coherence tomography (OCT) and OCT Angiography (OCT-A), enabling Amydis to map retinal amyloid beta, retinal structure (OCT), and retinal vascular (OCT-A) signatures and monitor their relative changes to better understand the pathophysiology of glaucoma.

Much like DARC technology, this technique also relies on intravenous injection of the tracer. That is an impractical technique for most patients visiting OPD clinics. Such diagnostic methods need to develop drops or use other routes for the tracer to reach the retina.

 

MicroMT GLAUCOMA IMPLANT

 

The MicroMT is a novel membrane-tube (MT) type glaucoma shunt device developed by Ahn and colleagues in Korea.

The MicroMT consists of an expanded polytetrafluoroethylene (e-PTFE) membrane and a silicone tube with an intraluminal stent, which allows aqueous drainage from the anterior chamber through a lamellar scleral flap in a similar fashion as conventional trabeculectomy surgery. The intraluminal stent prevents excessive aqueous drainage and allows additional IOP reduction through retraction or removal of the stent.

The MicroMT consists of (1) a 2 × 2-mm area, 0.2 mm thick e-PTFE membrane, by which the tube is anchored to the scleral flap bed using a suture, and (2) a silicone microtube with an external diameter of 200 μm and an internal diameter of 100 μm, which is attached to the membrane using silicone adhesive. The tube is 6 mm long, and is trimmed during the operation.

The silicone tube has an intraluminal stent, which is a 7-0 nylon suture. The more the stent (suture) is pulled out of the silicone tube, the more is the aqueous outflow.

 

SURGICAL TECHNIQUE:

A fornix-based conjunctival incision is made, Tenon’s capsule is dissected, a partial-thickness lamellar scleral flap is formed, eyes are treated using either 0.02% or 0.04% mitomycin-C for 2–4 min, and a sclerostomy is performed into the anterior chamber using a 30-gauge needle.

The tube’s length is adjusted, and is placed in the anterior chamber; aqueous drainage is confirmed when droplets appeared at the end of the microtube. The MicroMT membrane is anchored to the scleral flap bed using a 10-0 nylon suture. The scleral flap is sufficiently closed to prevent exposure of the MicroMT, and the post-luminal part of the stent is fixed with a suture to restrict its movement. After the conjunctival incision is closed, the distal end of the stent is placed on the conjunctival surface and fixed using a 10-0 nylon suture.

During the early postoperative period (<4 weeks), if the amount of aqueous drainage through the tube needs to be increased, the post-luminal part of the stent, which is located on the conjunctival surface, is retracted using forceps under a slit-lamp biomicroscope in an outpatient clinic. To further reduce IOP in a stepwise fashion, all intraluminal stents are completely removed 4 weeks after surgery.

CLINICAL STUDY:

In a study reported by Ahn and colleagues, the MicroMT was implanted in 43 eyes of 43 subjects (11 female and 32 male).

The mean (SD) follow-up period after the surgery was 27.9 (13.7) months (range, 7–47 months). The mean (SD) IOP before the operation was 22.5 (6.9) mmHg. After the surgery, the mean IOP decreased to 14.8 (9.0) mmHg, 12.6 (4.8) mmHg, and 11.1 (3.6) mmHg at 1, 2 and 3 years, respectively, after the operation (34.2%, 44.0%, and 50.7% reduction, respectively, from baseline; P<0.01).

Complete removal of the stent 4 weeks after the operation reduced mean IOP from 17.9 (6.3) to 12.2 (4.9) mmHg (an additional 40.2% reduction, P<0.01).

The mean (SD) number of IOP-lowering medications decreased from a preoperative value of 2.6 (0.6) to 0.5 (0.9), 0.5 (0.8) and 0.4 (0.8) at 1, 2 and 3 years, respectively, after the operation (P0.05; Table 2). The cumulative survival rate (standard error) was 89.5% (5%) 3 years after the surgery (Fig. 4). Failure was observed in four eyes at 7, 9, 10, and 20 months after the operation.

When visual acuity was compared between before and after the surgery, no significant change was observed at any of the postoperative visits (P>0.05).

The only observed complication was conjunctival wound leakage, which was found in one (2.3%) eye with avascular bleb 7 months after the operation; this was successfully resolved by conjunctival suturing.

WEBLINK: https://onlinelibrary.wiley.com/doi/10.1111/ceo.12772

 

Structural and Functional Brain Changes beyond Visual System in Patients with Advanced Glaucoma

 

A major characteristic of glaucomatous degeneration is the loss of RGCs and their axons, which leads to progressive blindness. However, some MRI studies show that neural abnormalities in glaucoma are not limited to the RGCs and are more extensive, extending to the entire visual pathway.

Histological evidence of neurodegeneration of the visual system in experimental glaucoma supports in-vivo MRI data and suggests that MRI-derived findings could reflect the extent of neuroaxonal damage along the entire visual system.

Frezzotti et al., have performed MRI studies and assessed across the whole brain: i) changes in microstructural integrity of white matter (WM) tracts by tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) measures, ii) structural changes in grey matter (GM) volume by VBM-style analysis, iii) functional connectivity (FC) changes of brain networks by resting-fMRI, and iv) how brain changes could be related to visual impairment. The study found changes such as reduced microstructural integrity of the optic radiations, decreased volume of the visual cortex, and altered FC of the visual network.

TBSS analysis of DTI diffusivities confirmed the presence of an altered integrity of the WM tracts in POAG patients with respect to normal controls (NC). Such abnormalities were present along the visual pathway, but also beyond the visual pathway, namely in the middle cerebellar peduncle, posterior limb of the internal capsule mapping on the corticospinal tract, anterior thalamic radiation on the right, and superior longitudinal fascicle (SLF).

In several distinct brain regions GM volume was lower in POAG patients than in NC. Patients also showed GM volume decrease in the cerebellum on the left, temporal lobe (hippocampus bilaterally), frontal lobe (fronto-orbital cortex, subcallosal cortex and frontal pole on the left) and parietal lobe (superior parietal lobule on the right, postcentral gyrus on the left).

POAG patients had lower FC in an extrastriate region of the visual network (lingual gyrus on the right) in the working memory network (superior frontal gyrus on the left supramarginal gyrus and LOC on the right) and in the dorsal attention network (LOC bilaterally, pre- and postcentral gyrus on the left).

POAG patients had higher FC than NC in the visual network (LOC bilaterally and temporo-occipital fusiform cortex on the left) and in the medial part of the executive network (superior frontal gyrus, parancigulate gyrus and anterior cingulate).

GM atrophy was found in the most anterior and medial parts of the visual cortex (anterior lingual gyrus), and also in the most posterior and lateral regions (LOC). Another recent study has found reduced cortical thickness in primary and secondary visual cortex in a heterogeneous group of POAG patients.

Other WM tracts and cortical GM regions that are not part of the typical visual pathway, such as the anterior thalamic radiation, corticospinal tract and middle cerebellar peduncle were also found altered in POAG patients in Frezzotti’s study.

POAG patients showed GM atrophy in regions involved in cognitive processing such as the hippocampus (memory), fronto-orbital cortex (decision-making) and superior parietal lobule (spatial orientation).

In addition to brain structural abnormalities, POAG patients also had functional connectivity changes in different resting state networks (RSNs). In patients with severe impairment of visual field, decreased FC in visual and working memory networks could be interpreted as due to maladaptation, thus contributing to clinical deficits.

The findings of widespread brain abnormalities observed in the present study delineate POAG as a more complex disorder than classically thought, capable of involving, at least in advanced stages, unanticipated brain structures and functions.

Therefore, glaucoma could be interpreted as the expression of a complex neurodegenerative process at cerebral level. The diffuse involvement of different distinct structures and functions could be an expression of the spread of neurodegeneration, similarly to what is found in typical neurodegenerative conditions such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease.

There is evidence indicating a close link between glaucoma and neurodegenerative conditions on the basis of the similarities in the loss of selective neuron populations, in the trans-synaptic disease spreading from injured neurons to connected and distant neurons, and in the common mechanisms of apoptosis, including oxidative injury, glutamate excitotoxicity and abnormal protein accumulation.

The prevalence of glaucoma was found to be much higher in different cohorts of patients with Alzheimer disease than in NC and this was independent from the IOP values.

By using a multimodal MRI approach, this exploratory study demonstrates that patients with advanced POAG have structural and functional changes that go well beyond the visual system, suggesting that POAG can be considered a vision disorder falling within the group of neurodegenerative disorders and, as such, spreading throughout the brain.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105931