MRI IN GLAUCOMA (PART 4)

Magnetization Transfer Imaging (MTI) MRI scan is a specialized MRI technique that enhances visualization of tissue microstructure, especially myelin in the brain, by detecting subtle changes missed by a standard MRI scan.

It has been highly useful in assessing Multiple Sclerosis (MS) lesions, quantifying disease burden, and monitoring treatment effects on white matter damage and brain atrophy, revealing microscopic damage even in seemingly normal areas. 

MTI uses radiofrequency pulses to excite water protons in macromolecules like myelin, revealing the integrity and content of myelin sheaths, crucial for nerve signal transmission.

The MTI method is a selective tissue signal suppression technique in MRI. It is based on the magnetization transfer effect and provides quantitative measures like the Magnetization Transfer Ratio (MTR). The MTR reflects the protons bound to macromolecules in different tissues, which reveals the degree of proton exchange between free water and macromolecules. It primarily measures the degree of myelination, axon integrity, and macromolecules on the cell membrane of the central nervous system and provides pathological information such as overall disease burden, lesion severity, and brain tissue loss (atrophy).

The magnetization transfer (MT) effect of the brain arises from biological macromolecules in the neuronal cell membrane and organelle membranes, such as cholesterol, galactose cerebroside, and phospholipid in a myelin sheath. With MTR, the ability of these macromolecules to exchange magnetization with surrounding water molecules in the brain is measured.

MTR can be measured in different segments of the entire optic nerve, which provides useful information on the progressive nature of demyelination and remyelination over time. The decrease of MTR occurs due to axonal injury caused by demyelination and Waller degeneration, and the increase of MTR may indicate remyelination.

Kitsos et al. evaluated the brain and optic nerve pathways of 26 patients with POAG and found that the MTR of the optic chiasm, geniculocalcarine, and the visual cortex decreased significantly compared with the control group. Zhang et al. studied the geniculocalcarine and striatal region of patients with primary glaucoma by using the region of interest (ROI) analysis of MTR. They found that the MTR of bilateral geniculocalcarine and striatal region in patients with glaucoma decreased, suggesting that there is geniculocalcarine demyelination and degeneration of striatal region in primary glaucoma. 

Ho et al., found that the MTR of the sclera, cornea, optic nerve, and the lens cortex in the glaucoma group was higher than that of the anterior chamber and the vitreous body.

However, MTI has a few limitations. It cannot identify the different types and stages of glaucoma, which may affect the results of the examination. A larger sample size of homogeneous samples should be carried out, and the clinical indicators of glaucoma, such as IOP and VF defect, should be associated with the changes of MTR to draw more convincing conclusions from studies using MTI.

MRI IN GLAUCOMA (PART 3)

Diffusion Kurtosis Imaging (DKI):

It is an advanced MRI technique that goes beyond standard diffusion imaging (DWI/DTI) by analyzing non-Gaussian water movement, revealing more complex tissue microstructure details in the brain and body, helping differentiate tissues, assess stroke severity, and detect subtle changes in conditions like Parkinson's or cancers, by measuring "kurtosis" which quantifies deviations from normal water diffusion due to cellular obstacles. Kurtosis (K) is a key parameter that quantifies this deviation, indicating tissue complexity and restriction.

Unlike DTI (Diffusion Tensor Imaging) which assumes simple, linear water movement, DKI captures how water diffusion deviates from a straight line (non-Gaussian) in complex tissues like the brain. DKI also provides additional advanced metrics like Mean Kurtosis (MK), Axial Kurtosis (AK), and Radial Kurtosis (RK), offering richer data than just diffusivity (MD, FA) provided by DTI. The RK reflects the complexity of fiber orientation and vertical orientation.

The DKI method is based on the principle that water diffusion in vivo moves in intercellular space and cells, and it does not have free motion. Therefore, the motion displacement of diffusion of real water molecules follows a non-Gaussian distribution. The greater that the diffusion of water molecules is limited by the surrounding environment, the more mixed the tissue components are in voxels, and the more significant the non-Gaussian nature of diffusion. 

Jensen et al. proposed the DKI model in 2005, which can be used to quantify the integrity of microstructure and tissue complexity even in the presence of cross fibers. 

Studies using DKI have shown that MK decreases along the brain visual pathway in patients with glaucoma. Xu et al. used 3T DKI to evaluate the damage to the microstructure of the visual pathway in patients with primary glaucoma. They found that glaucoma is a complex nervous system disease that affects the whole visual pathway. The RK of optic tract in glaucoma patients was significantly lower than that in healthy controls. This indicates that water diffusion perpendicular to the axon axis is less limited, which is consistent with the high RD in DTI.

Sun et al. found that in addition to the damage of axon integrity, glial cells were involved in glaucoma.

Studies have shown that NTG leads to the reorganization of information flow between the visual cortex and other brain regions, which is consistent with damage to the brain’s microstructure.

Magnetic Resonance Spectroscopy (MRS): 

The MRS is a non-invasive technology, which can detect, identify, and quantify biochemical compounds or metabolites in brain tissue. Due to the chemical heterogeneity of the human brain, there are various concentrations of important metabolites in normal brain structural areas, which provide different physiological and chemical information. Metabolites that can be measured using MRS include n-acetylaspartic acid (NAA), choline (Cho), creatine (Cr), lactate, glutamine, glutamate, lipids, and macromolecules. 

MRS creates detailed anatomical images (pictures) of the brain using water protons. MRS focuses on the chemical signals (frequencies) from specific brain chemicals within a defined spot (voxel). It generates a spectrum (graph) showing the relative amounts of different metabolites, indicating cellular activity and disease presence. While MRI shows where problems are, MRS shows what they're made of, revealing biochemical changes. 

Barbosa found that molecular biomarkers can help diagnose glaucoma and may lead to new targeted therapy.

MRS has revealed neurodegeneration of the LGB and the visual cortex in patients with glaucoma. These findings suggest that mapping the metabolic changes of the whole visual pathway by MRS will guide the treatment and follow-up plans of glaucoma patients.

There are some limitations to MRS: Quantification of a single metabolite is usually not feasible due to the presence of a large number of detectable metabolites. Therefore, although they have high diagnostic value, these methods make it more difficult to connect the obtained data with potential metabolic pathways.

MRI IN GLAUCOMA (PART 2)

Diffusion-weighted imaging (DWI):

The DWI method is a non-invasive functional imaging analysis of the internal structure and tissue components of lesions at the molecular motion level by detecting the diffusion movement of water molecules in vivo.It can detect the cerebrospinal fluid flow in the subarachnoid space of the optic nerve in a non-invasive manner.

It has been found that the flow range ratio of NTG patients was significantly lower than that of healthy control participants. This finding suggests that impaired cerebrospinal fluid dynamics may play a role in the pathophysiology of NTG.

Cio et al. found that there were global differences in structural connectivity and local graph theoretical measures in glaucoma patients, and these changes far exceeded the main visual pathways. The results support the hypothesis that whole brain structural reorganization occurs in patients with glaucoma, which is specific to structural connections. 

This finding means that glaucoma can be categorized in the recently defined category of a brain disconnection syndrome.

The results provide indirect evidence that unknown factors may limit the reorganization of white matter after visual loss in glaucoma patients.

There are several limitations to DWI. First, DWI delineates that random Brownian motion of water in normal and pathological neural tissue environments changes. Reduced water diffusion has been shown to be sensitive to many diseases in the brain but is not specific to glaucoma. Therefore, the detection results of DWI may be affected by other factors and cannot be used as a biomarker of glaucoma neurodegeneration. Second, according to the partial volume effect and image slice direction, the diffusion limitation of the optic nerve may be ignored due to the small size of the optic nerve. Therefore, in the case of insufficient spatial sampling, the incidence of limited diffusion in the optic nerve may be underestimated. Thin slices (e.g., 3 mm) arranged parallel to the optic nerve should improve the sensitivity of optic nerve diffusion limitation. Third, although the sensitivity and accuracy of rs-EPI and rFOV-EPI are similar, their image quality in the orbital segment is significantly higher, and there are still artifacts in the optic canal segment and the intracranial segment.

Diffusion tensor imaging (DTI):

Based on conventional DWI, the new neuroimaging technology of DTI is an MRI method that goes by the assumption that water molecules diffuse with a Gaussian distribution to measure and obtain the anisotropy information of different tissues. 

The dislocation of water molecules in nerve fibers and axons can be detected by the diffusion of water molecules along axons without a gadolinium contrast agent. Doing so can reveal abnormalities of the white matter structure and brain connection. 

The DTI technology is the most commonly used method in MRI, and it can quantitatively measure the integrity of microstructure and tissue in vivo. It has been widely used to study the differences of white matter bundles in the visual pathway in glaucoma patients. Microstructural differences of white matter structures have been found in the optic nerve, optic tract, optic chiasm, optic radiation, and the occipital lobe of glaucoma patients. 

It is believed that DTI may reveal early axonal injury with more sensitivity than a conventional MRI can.

Some researchers argue that DTI can be used to distinguish different glaucoma subtypes. 

Compared to the established ophthalmic diagnostic methods, these new imaging techniques seems to enable earlier diagnosis of NTG.

Studies by Schreiber et al. further support the hypothesis that glaucoma can be considered a pan-neurodegenerative disease. The mechanism of brain injury outside the visual pathway in POAG patients is not the direct extension of visual pathway degeneration, but the primary neuropathological process of the transmission mechanism of neurodegenerative lesions. Giorgio et al. found that compared with the healthy control group, patients with NTG and POAG had significantly more gray matter atrophy in their visual system and non-visual brain areas, and significantly more changes in DTI-derived anatomical connections. 

The diffuse structural and functional abnormalities of the brain of a patient with glaucoma may, at least in part, be unrelated to the increase of IOP and subsequent retinal degeneration. 

Murai et al. have used DTI to report a significant correlation between optic radiation axon injury and decreased cerebral glucose metabolism in the striate cortex of POAG patients.

The DTI method has been widely used to evaluate microstructural abnormalities of white matter in the brain; however, it has some limitations. For example, due to the existence of organelles, cell membranes, and other barriers, water molecules often show non-Gaussian diffusion in biological tissues. Therefore, the practicability and sensitivity of the DTI model may not be completely optimal. In addition, DTI studies have shown damage to the integrity of the overall microstructure in the visual pathway of patients with glaucoma. 

The mechanism behind the difference of directional diffusion rate in glaucoma DTI research is not clear, and the pathophysiology of glaucoma may be more complex than the deterioration of the axon and myelin sheath.

MRI IN GLAUCOMA (PART 1)

 

Magnetic resonance imaging (MRI) is currently not a standard investigation in most glaucoma patients. However, a number of studies have shown striking central nervous system (CNS) changes in MRI studies in such patients.

The advanced MRI used in glaucoma brain detection mainly involves the following 7 types of methods: 

1. MRI quantitative morphometry; 

2. Blood oxygenation level dependent functional MRI (BOLD-fMRI); 

3. Diffusion-weighted imaging (DWI); 

4. Magnetic resonance spectroscopy (MRS); 

5. Diffusion tensor imaging (DTI); 

6. Diffusion kurtosis imaging (DKI); and 

7. Magnetization transfer imaging (MTI).

MRI quantitative morphometry:

It is now possible to image brain structure, volume, and microstructural damage.

The techniques for quantitative evaluation of brain morphology can be divided into 2 types: voxel-based morphometry (VBM), and surface-based morphometry (SBM).

The VBM technique uses a statistical method to allocate the probability that a voxel is occupied by gray matter, whereas SBM determines the vertices defining the interface surface of gray matter cerebrospinal fluid (CSF) and gray and white matter, and uses these vertices to estimate the thickness of the cerebral cortex with submillimeter accuracy.

Using MRI VBM, Hernowo et al. found that the volume of all structures of the visual pathway in glaucoma patients was significantly reduced, including the optic nerve, optic chiasm, optic tract, LGN, and optic radiation. The volumetric MRI techniques have observed a decrease in occipital surface area or visual cortex volume in both hemispheres of glaucoma patients.

In terms of the severity of glaucoma, Wang et al. used T1 weighted MRI images to conduct VBM and SBM analysis on the whole brain. They found that in patients with glaucoma, the left LGN volume was negatively correlated with the bilateral optic cup disk ratio, the right LGN volume was positively correlated with the average deviation of the right VF, and the right V1 cortical thickness was negatively correlated with the right optic cup disk ratio. In patients with primary open angle glaucoma (POAG), these changes in brain visual structure can reflect the clinical severity of glaucoma.

Blood oxygenation level-dependent functional MRI (BOLD-fMRI):

The BOLD effect is the most commonly used method to obtain information related to brain function. It is an indirect measurement of cortical activity. The BOLD-fMRI is a non-invasive imaging method that uses deoxyhemoglobin as the natural contrast agent in vivo to monitor blood oxygen levels of the brain in real-time.

Different Rs-fMRI studies of glaucoma have shown decreased connectivity in regions associated with vision. 

POAG results in decreased cortical activity in the visual cortex, including the central region. Primary angle closure glaucoma (PACG) showed decreased activity in the bilateral secondary visual cortex (BA18). 

Reduction of BOLD activity may also involve many areas of non-visual pathways.

PACG is mainly related to frontal lobe dysfunction. Chen et al. used the ReHo method and found that PACG was involved in abnormal spontaneous brain activities in multiple brain regions, such as the left fusiform gyrus, left anterior cerebellar lobe, right frontotemporal space and right insula, bilateral middle occipital gyrus, and the right paracentral lobule. 

Patients with PACG show abnormal spontaneous neural activity in the visual cortex, sensorimotor cortex, frontal lobe, frontal parietal lobe network, and the DMN. This indicates that the visual, cognitive, and emotional functions of individuals with PACG may be impaired.

Zhang et al. used Rs-fMRI to analyze the brains of patients with NVG and revealed dysfunction in the brain regions of the right romantic operculum, left antagonist cingulate and paracingulate gyri, left precuneus, and the right caudate. Peng et al. observed abnormal spontaneous activity in NVG patients in the right cuneus, right middle occipital gyrus, left cingulate gyrus, right precuneus, left medial frontal gyrus, right superior frontal gyrus, and left middle frontal gyrus. These abnormal changes in specific brain regions can be considered possible clinical indicators of NVG.

In terms of the severity of glaucoma, some researchers have observed that in mild and moderate cases of glaucoma, the primary visual cortex seems to be more affected than other advanced visual areas. For example, abnormal spontaneous neural activity in the left wedge, bilateral middle temporal gyrus, and the right prefrontal cortex have been shown to be associated with the severity of POAG.

At present, fMRI is a very interesting clinical research tool for understanding how glaucoma functionally affects the central nervous system; however, it still has some limitations. First, fMRI technology is based on the premise that neural networks are associated with anatomic known visual regions, but other neural network components which may be affected by glaucoma cannot be clearly defined. Second, fMRI signal has low-temporal resolution due to down-sampling and indirectly measures underlying neuronal activity.

DRIVING DIFFICULTIES IN GLAUCOMA PATIENTS

Glaucoma patients with significant visual field (VF) defects show poorer driving performance, higher collision risks, and a greater likelihood of driving cessation. They face difficulties with lane maintenance, slower hazard responses, and self-regulation while driving.

A systematic review to study the impact of glaucomatous VF loss on the driving performance of glaucoma patients, the extent of driving limitation and cessation, as well as the risk of motor vehicle collisions (MVCs) has been conducted by Toh et al.

23 studies were included for the final review. 

The study reported that moderate to severe VF defects resulted in poorer driving performance, with slower response times to road hazards, decreased ability for lane maintenance, and increased difficulty driving at night. 

Patients with more severe VF defects and with bilateral glaucoma were more likely to limit or cease driving compared with those with milder and unilateral glaucoma. 

A greater severity of VF loss was associated with a higher risk of MVCs.

The study concluded that more severe glaucomatous VF and bilateral glaucoma is associated with worse driving performances and a higher risk of MVCs, in both simulator and real-world settings.

REFERENCE:

Toh, Zhi Hong MBBS (S’pore), MMed (Ophth), FRCOphth*; Koh, Serene Yi Ning†; Yang, Wei Yun Lily MBBS (S’pore), DAvMed (Lond.)‡; Munro, Yasmin Lynda MSc (IS)§; Ang, Bryan Chin Hou MBBS (S'pore),FAMS (S'pore), FRCOphth*,†,§,∥. The Effect of Glaucomatous Visual Field Defects on Driving: A Systematic Review. Journal of Glaucoma 34(11):p 837-852, November 2025. | DOI: 10.1097/IJG.0000000000002633 

SEGMENTAL AQUEOUS HUMOUR OUTFLOW

Does aqueous humor outflow (AHO) occur uniformly from the eye?

Studies have reported wide variation in the AHO in glaucomatous and non-glaucomatous eyes. 

A study using aqueous angiography (AA) was performed by Beri et al, to evaluate AHO pathways in nonglaucomatous subjects. The study found there is a segmental pattern of outflow, with the nasal quadrant having the maximum and the temporal quadrant having the least AHO pathways.

A cross-sectional, observational, single-center study recruited 30 subjects with visually significant age-related cataract planned for phacoemulsification. AA was performed using indocyanine green (ICG) dye 0.1% just before phacoemulsification. Images were analyzed at 60 seconds from the injection of ICG dye for angiographic signal intensity in 4 quadrants and 8 sectors, circumferentially (360 degrees) along the limbus. Signal intensities were evaluated and compared between quadrants and sectors as the primary outcome measure. Signal intensities between males and females, right and left eyes were assessed as secondary outcome measures, using appropriate statistical tests.

Segmental AHO was noted in all patients. The median signal intensity was highest in the nasal quadrant [45.95(35.59–54.34)] followed by the inferior [31.56 (24.82–41.71)], superior [30.16 (28.2–37.43)], and temporal [26.66 (22.92–34.33)] quadrants, and their difference was statistically significant (P<0.0001). Median signal intensity among 8 sectors was highest in the nasosuperior sector [23.05 (17.14–29.20)] and least in the temporoinferior sector [12.98 (10.82–17.51)] (P<0.0001). 

No significant difference was observed in median signal intensities between males [132.83 (115.82–174.18)] and females [143.74 (122.43–166.00)] (P=0.771) and right eyes [143.74 (118.53–170.6)] and left eyes [133.51 (122.43–153.86)] (P=0.967). 

Such findings have been reported from glaucomatous eyes also. These reports can be used to find the optimum place for MIGS insertion and possibly for performing Trabeculectomy.

REFERENCE: 

Beri, Nitika MS*; Patil, Anuja MD†; Midha, Neha MD‡; Angmo, Dewang MD†; Bari, Aafreen MD†; Sharma, Namrata MD†; Dada, Tanuj MD†. Quantitative Assessment of Functional Aqueous Humor Outflow by Aqueous Angiography. Journal of Glaucoma 34(11):p 888-894, November 2025. | DOI: 10.1097/IJG.0000000000002617 

AI out performs humans in glaucoma screening

Artificial Intelligence (AI) utilizes the latest cutting technology to identify human diseases.

Screening for glaucoma remains challenging due to the myriad presentations of the condition. Presently, screening is regarded as economically and practically unfeasible.

However, studies are being performed to investigate the possibility of using AI to screen for glaucoma.

A study presented at the 129th annual meeting of the American Academy of Ophthalmology by Anthony Khwaja and his colleagues from the University of London, Institute of Ophthalmology and Moorefields Eye Hospital, has shown that AI can out-perform humans in screening for glaucoma.

The study used 6,304 fundus images gathered for a large, population-based cohort study (EPIC-Norfolk Eye Study) to compare the accuracy of their algorithm and a trained human grader to estimate a key measure of glaucoma, vertical cup-disc ratio. A glaucoma specialist examined the patients to confirm the diagnosis.

Results showed the algorithm correctly identified patients with glaucoma 88 to 90 percent of the time; human graders were correct 79 to 81 percent of the time. The algorithm did not differentiate between those who had glaucoma or might have glaucoma.

It remains to be seen how a single feature of glaucoma (the vertical C:D R) can be used to diagnose glaucoma patients. This feature is dependent on the ISNT rule and is often seen in only 50% of the population.

URIC ACID AND GLAUCOMA

Uric acid (UA) is a purine metabolite present intracellularly and in all body fluids. Usually high UA levels have been associated with gout and kidney stones.

However, UA has both pro-oxidant and antioxidant features in-vitro by production and scavenging of reactive oxygen species. 

The beneficial impacts of UA have been shown in certain neurodegenerative conditions, such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. However, the role of UA in the underlying mechanism of glaucoma is still unclear.

A meta-analysis was performed by Mohammadi et al, to identify case-control studies comparing the serum UA concentrations of the patients with glaucoma and controls. The mean ± standard division difference was used to assess the difference in serum UA concentrations between the glaucoma patients and controls.

The meta-analysis involved 6 studies involving 1,221 glaucoma patients and 1,342 in the control group.

The pooled analysis included all six studies, showing that serum UA level was higher in glaucoma patients than in other patients without glaucoma. In detail, the meta-analysis using a random effect model indicates that the mean UA level in glaucoma patients was 0.13 (I2 = 91.92%, 95% CI = −0.42 to 0.68) higher than the controls; however, it was not statistically significant.

Three out of six case-control studies within this meta-analysis found a significant inverse association. In comparison, three other studies have reported a positive association between high UA levels and glaucoma.

These findings provide evidence that glaucoma patients have a higher serum UA level compared to the controls, but this difference is not statistically significant. Prospective studies are needed to determine the possible association between increased UA and glaucoma pathogenesis.

REFERENCE:

Mohammadi M, Yarmohammadi A, Salehi-Abargouei A, Ghasemirad H, Shirvani M, Ghoshouni H. Uric acid and glaucoma: a systematic review and meta-analysis. Front Med (Lausanne). 2023 Jul 28;10:1159316. doi: 10.3389/fmed.2023.1159316. PMID: 37575992; PMCID: PMC10422028.

CLOSED EYE IOP AND EM MONITORING

Normally, intraocular pressure (IOP) exhibits a significant circadian rhythm, typically peaking in the early morning hours before the end of sleep (3–4 mmHg higher than daytime levels), with a trough occurring at the end of the day. This phenomenon is closely associated with changes in body position (supine posture increases episcleral venous pressure by 3–6 mmHg) and fluctuations in glucocorticoid levels.

Furthermore, frequent eye movements during sleep, such as those occurring during rapid eye movement (REM) sleep, can increase resistance to aqueous humor outflow. This is particularly concerning in patients with angle-closure glaucoma, where the risk of acute attacks is 3–5 times higher at night compared to during the day.

Smart contact lenses have emerged as a promising solution for continuous, noninvasive ocular signal monitoring instead of discrete measurements.

While Goldman Appalanation Tonography (GAT) is the ideal method, it requires topical anesthesia and fluorescein instillation before measurement, and the fluorescein concentration can influence accuracy. Furthermore, GAT-like instruments often require a slit lamp examination. Corneal thickness, stiffness, and tear film characteristics can also introduce measurement errors. 

Contact lenses are a practical solution to the problems of continuous monitoring. Gan and colleagues have proposed a stretchable self-decoupled BCL comprising electromagnetic capacitive IOP (CIOP) and neodymium-iron-boron (NdFeB)-MEM components. The design features an NdFeB/polydimethylsiloxane (PDMS) interlayer film that separates double-layered serpentine-geometry spiral copper (Cu) films.

This innovation involves a stretchable bimodal contact lens (BCL) amalgamating self-decoupled electromagnetic capacitive intraocular pressure (CIOP) and magnetic eye movement (MEM) monitoring components. This integrated system offers a non-invasive and comfortable solution for real-time eye health monitoring, providing accurate measurements and continuous tracking of eye status. 

In this way, both IOP and EM can be monitored continuously through closed lids.

REFERENCE:

Gan, X., Yao, G., Li, C. et al. Closed-eye intraocular pressure and eye movement monitoring via a stretchable bimodal contact lens. Microsyst Nanoeng 11, 83 (2025). https://doi.org/10.1038/s41378-025-00946-y

ALI IBN ISA AL-KAHHAL

Absar Alam, a first year student of BUMS at Ajmal Khan Tibbiya College in Aligarh, made a presentation on Ali Ibn Isa al-Kahhal.

His presentation in Urdu is available on YouTube.

Kindly follow the link below:

https://youtu.be/NcZBZi0ildQ?si=ZulHSJSykaJcdCmF

Some more information on Kahhal can be accessed here:

https://ourgsc.blogspot.com/search?q=Kahhal

OXFORD MICROSTENT

Zhang et al, working at Oxford University, have developed a novel deployable microstent for MIGS applications, leveraging deployable structure concepts and biocompatible nitinol to mechanically separate ocular tissues in the subconjunctival space (SCS).

The microstent can be delivered minimally invasively, ab internally via a needle and subsequently expands within the SCS. 

This design incorporates structural elements to sustain conjunctival-episcleral separation without relying on anti-fibrosis treatments. It is specifically optimized to form a posterior, consistently elevated bleb while preventing migration, improving durability, and ensuring long-term efficacy.

The device is constructed from nitinol, a biocompatible metal renowned for its proven long-term ocular safety and successful use in larger filtration devices like the EX-PRESS shunt.

The enhanced flexibility allows the stent to conform to surrounding tissues, potentially reducing fibrosis and minimizing patient discomfort. 

This microstent consists of a flexible tube that connects the AC to the SCS and a self-expanding element to support a subconjunctival bleb. The expandable element is designed to triple its original size upon deployment, a transformation enabled by the superelasticity of nitinol.

It features four slender struts asymmetrically arranged along the central axis of the flexible tube. After deployment, these struts self-expand to lift the conjunctiva and Tenon’s layer from the sclera, creating a bleb.

Results showed that a 1 mm expandable element can create a spindle-shaped bleb approximately 0.7 mm in radius and 6 mm in length without permanent deformation.

REFERENCE:

A novel deployable microstent for the treatment of glaucoma. Zhang, Yunlan et al. The Innovation, Volume 6, Issue 8, 100935

PROSTAGLANDIN ASSOCIATED ORBITOPATHY (PAP)

Introduction:

Prostaglandin Associated Periorbitopathy (PAP) is the constellation of eyelid and orbital changes that accompany the administration of topical prostaglandin analogue (PG-A) eye drops.

PAP is a common occurrence following PG-A treatment. It has been claimed that once the clinician is looking for it, it can be noticed nearly 100 percent of the time.

PAP has been reported with the use of most PG-As, including bimatoprost, travoprost, tafluprost, and latanoprost.

Older patients (>60 years) are at a greater risk of developing this condition. 

This entity was first described by Peplinski and Smith in 2004. However, the specific term Prostaglandin Associated Periorbitopathy (PAP) was coined by glaucoma specialists Dr. Louis Pasquale and Dr. Stanley Berke. Other terms previously used in the literature included Deep Superior Sulcus Syndrome and DUES (Deepening of Upper Eyelid Sulcus).

The clinical features of PAP are upper lid ptosis, deepening of the upper lid sulcus, involution of dermatochalasis, periorbital fat atrophy, mild enophthalmos, inferior scleral show, increased prominence of lid vessels, and tight eyelids. 

Other known side effects of PG-As such as lengthening of lashes and increased pigmentation of the iris and periorbital skin, can possibly fit under the term PAP as well.

PAP can appear as early as a month after the use of bimatoprost and is caused by fat atrophy, inhibition of adipocyte production, and differentiation of orbital fat due to PGF receptor stimulation by PG analogs.

Severe orbital fat atrophy in a patient with prolonged bilateral PGA use. Very deep superior sulcus and "sunken" eye appearance.

Deep sulcus, loss of orbital crease and lengthening of eyelashes on the left side.

Histopathology:

In PAP, there is significantly reduced size of individual adipocytes, suggesting overall fat atrophy rather than adipocyte death. 

Some cases demonstrate a statistically significant increase in mean adipocyte density of treated eyes, suggesting that in a given area there was a higher total number of adipocytes and thus a smaller size of each individual adipocyte. Clumped nuclei suggesting adipocyte atrophy are also seen in some cases. 

Reports suggest that those treated with bimatoprost were most affected by PAP, followed by those treated with travoprost. Those treated with latanoprost showed an increased mean adipocyte density as well however this change was not found to be statistically significant.

Pathophysiology:

The proposed mechanisms for PAP include mitochondrial apoptosis pathway of adipocytes, inflammatory fibrotic changes to the eyelid or to Mueller's muscle, atrophy of existing adipocytes, and inhibition of adipogenesis. Currently, it is most widely thought that preaponeurotic and deep orbital fat atrophy are likely the main contributors responsible for the majority of PAP changes. 

Pharmacokinetic studies of a single topical administration of 0.1% bimatoprost in male cynomolgus monkeys indicate that eyelid specimens contain more than 2,000 times higher concentrations of bimatoprost compared with aqueous and more than 16 times higher concentrations compared with iris and ciliary body. Thus, there is significant periorbital absorption of PG-A  medication.

Diagnosis:

Some patients may complain of the onset of a droopy lid or their eyelid starting to get in the way of their vision when this was previously never an issue. Performing Goldman applanation becomes increasingly difficult on patients with PAP as their orbits seem increasingly sunken in. Rarely, patients may complain of diplopia. Most commonly, patients refer to such changes as "tired-appearing eyes".

On examination, MRD1 can be decreased as compared to measurements prior to the initiation of therapy. Hertel's exophthalmometry can reveal a mild degree of enophthalmos or at least a relative decrease in values as compared to baseline. MRD2 or a measurement of inferior scleral show may be increased as compared to baseline as well. Finally, prism alternate cover test or Maddox rod testing can reveal a relative muscle deficit, most commonly a slight limitation in abduction.

Imaging is not commonly done and is not usually indicated in patients suspected to have PAP.

Management:

Typically, discontinuation of the medication results in partial to complete reversal of PAP characteristics. This change has been noted to occur as quickly as 4-6 weeks.

Switching from bimatoprost to latanoprost has been somewhat effective in reversing signs of PAP. In a prospective study of 13 patients who experienced PAP on bimatoprost, 11 of them had either a decrease or disappearance of their symptoms after switching to latanoprost in only 2 months. This change was reported to have maintained over a 6 month follow up.

CURCUMIN AND EYE DISEASE

Curcumin has been used in traditional medicine for many years. It's role in ophthalmic diseases has been reviewed in an article recently published by my colleagues and myself.

It is known that reactive oxygen species (ROS) play a role in the development and progression of glaucoma. Yue and colleagues have studied the effect of curcumin as an antioxidant in glaucoma patients. 

On the other hand, Lin and colleagues have shown that trabecular meshwork (TM) cells are damaged in glaucoma. Pre-treatment with curcumin protects the TM cells against oxidative stress-induced cell death. 

Cheng and colleagues developed a thermosensitive chitosan-gelatin-based hydrogel that contains 20 μm curcumin-loaded nanoparticles and latanoprost. This dual-drug delivery system acts as a sustained-release agent. Curcumin decreases the oxidative stress-mediated damage to the TM cells by reducing inflammation-related gene expression, mitochondrial ROS production, and apoptosis.

Please access the complete article at the following link:

https://www.florajournal.com/archives/

https://www.florajournal.com/archives/2025/vol13issue4/PartC/13-1-32-664.pdf

Also see: https://ourgsc.blogspot.com/search?q=CURCUMIN

COLLOIDAL DRUG AGGREGATES IN GLAUCOMA

Hollow nanoparticle and core-shell nanoparticle eye drops improve ocular retention and sustain release of drugs for up to 7 days. These strategies use either non-biodegradable materials, which can accumulate, or degradable materials with acidic degradation products that can trigger an inflammatory response.

Colloidal drug aggregates (CDAs) are self-assembled, amorphous, drug-rich nanoparticles.

CDAs can achieve high-loading (typically >70%) drug formulations by stabilizing them with small amounts of excipients, such as polymers, proteins, lipids,indocyanine dyes or other small-molecule aggregators. This contrasts with the typical <10% drug loading in nanoparticle formulations. Although CDAs have been studied for oral and intravenous administration, their use in local delivery had not been investigated until this study.

Incorporating timolol CDAs into a new hyaluronan (HA)-oxime hydrogel prior to ocular injection achieves adequate local delivery and mitigates the leakage and rapid drug release seen with nanoparticles.

Since topical application of timolol maleate reduces intraocular pressure (IOP) in healthy rodents, this model was used to test the IOP-lowering effects of the slow release timolol palmitate CDAs in rats over 56 days following a single subconjunctival injection versus those of free timolol.

Timolol palmitate CDAs have a critical aggregate concentration of 2.72µM and sustained in vitro release over 28 days. Timolol palmitate CDAs are dispersed throughout in situ gelling hyaluronan-oxime hydrogel and injected into the subconjunctival space of rat eyes. The IOP is significantly reduced for at least 49 days with a single subconjunctival injection of timolol-palmitate CDAs compared to 6 hours for conventional timolol maleate. 

The systemic blood concentrations of timolol are significantly lower, even after 6 hours, for timolol palmitate CDA-loaded hydrogel versus free timolol maleate, thereby potentially reducing the risk of systemic side effects. This innovative approach redefines the role of CDAs and provides a framework for long-acting ocular therapeutics, shifting their perception from a drug screening challenge to a powerful tool for sustained local drug delivery.

REFERENCE:

Dang M, Slaughter KV, Cui H, Jiang C, Zhou L, Matthew DJ, Sivak JM, Shoichet MS. Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection. Adv Mater. 2025 Feb;37(8):e2419306. 

doi: 10.1002/adma.202419306.