DEUBIQUITINATING ENZYME INHIBITORS AND NEUROPROTECTION

 

Deubiquitinating enzyme (DUB) inhibitors are promising pharmacological interventions for neurodegenerative disorders.

A study by Hu et al has demonstrated that the pan-DUB inhibitor PR-619 has a neuroprotective effect on retinal ganglion cells (RGCs).

PR-619 exerts various biological functions including, induction of autophagy, anti-apoptotic effects, and antitumor properties.

In the experimental glaucoma model of the study, impaired mitophagy was seen in the RGCs.

Parkin is an intricately multifunctional member of the E3 ubiquitin ligase family. It mediates the selective elimination of impaired mitochondria through mitophagy. When mitochondria lose membrane potential, indicating dysfunction or damage, parkin activation and accumulation facilitate mitophagy.

Parkin exerts its ubiquitin-tagging effect upon several proteins present within the mitochondrial outer membrane. These ubiquitinated proteins, bearing Parkin's molecular insignia, serve as beacons of recognition for a host of autophagy receptors and adaptors, among which optineurin emerges as a prominent player.

Evidence shows activated parkin-mediated mitophagy reduces neuronal apoptosis in Parkinson’s and Alzheimer’s diseases.

Dysfunctional mitophagy plays a role in glaucoma pathogenesis.

In vivo, PR-619 increased RGC survival in glaucomatous rats. In vitro, protected RGCs against excitotoxicity and reduced ubiquitin-specific protease (USP) 15 expression.

Additionally, PR-619 upregulated parkin expression, increased LC3-II/LC3-I ratios, and elevated LAMP1 levels, indicating enhanced mitophagy in vivo and in vitro.

Moreover, numbers of mitophagosomes were increased in the optic nerves of PR-619-treated ocular hypertensive rats in vivo.

Prior investigations have substantiated that PR-619 confers neuroprotection to RGCs challenged with glutamate excitotoxicity by augmenting parkin-dependent mitophagy.

Therefore, PR-619 could be a useful strategy for saving RGCs in glaucoma patients.

REFERENCE:

Hu X, Zhang J, Ma H, Lian W, Song W, Du C, Chen S, Wang D, Wei J, Lu Q. The broad-spectrum deubiquitinating enzyme inhibitor PR-619 protects retinal ganglion cell and augments parkin-mediated mitophagy in experimental glaucoma. Sci Rep. 2024;14:24654.

Sirt6; ANTI-AGING; GLAUCOMA

Glaucoma is characterized by progressive loss of retinal ganglion cells (RGCs).

The loss of RGCs also occurs as an age-dependent process.

Several regulatory factors, that could impact glaucoma and aging, have been studied in animal models.

Sirtuins (Sirts) belong to a widely preserved protein family.

They resemble the yeast Sir2 protein, which operates as a NAD-dependent histone deacetylase, prolonging the yeast’s lifespan.

The anti-aging protein, Sirt6, is highly expressed in RGCs.

It is essential in protecting RGCs from the effects of aging and glaucoma.

In mouse models of high-tension glaucoma, the Sirt6 level was decreased after IOP elevation.

Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma.

Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons.

The study shows the critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma.

Wenbo Zhang, a co-author and Professor of Ophthalmology at the University of Texas, was quoted as saying "Therapeutically targeting Sirt6 offers a promising new avenue for glaucoma treatment, especially for cases that do not respond to traditional treatments aimed at reducing eye pressure". He added, "This could be a game-changer in how we approach this disease." 

REFERENCE:

Xia F, Shi S, Palacios E, Liu W, Buscho SE, Li J, Huang S, Vizzeri G, Dong XC, Motamedi M, Zhang W, Liu H. Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma. Mol Ther. 2024 Jun 5;32(6):1760-1778. doi: 10.1016/j.ymthe.2024.04.030. Epub 2024 Apr 24. PMID: 38659223; PMCID: PMC11184404.

GLAUCOMA FOLLOWING INFANTILE CATARACT SURGERY

 

Cataract surgery, especially infantile cataract surgery, is associated with a higher incidence of glaucoma post-operatively.

Choe et al have identified the risk factors for incisional glaucoma surgery following infantile cataract (IC) surgery.

The population-based cohort study was conducted using the Korean National Health claims database, among Korean children born between 2002 and 2018.

650 patients had undergone IC surgery with a mean (standard deviation [SD]) follow-up period of 6.2 (3.2) years.

92 (14.2%) were diagnosed with glaucoma following infantile cataract surgery (GFICS).

Among them, 21 patients (22.8%) underwent incisional glaucoma surgery after a mean (SD) follow-up duration of 5.4 (2.8) years from the diagnosis of GFICS.

Of the 21 GFICS patients who underwent incisional glaucoma surgery, the median (IQR) age at incisional glaucoma surgery was 4 years. Among them, 10 patients underwent trabeculectomy (TLE), 10 underwent glaucoma drainage implant (GDI) surgery, and one underwent both TLE and GDI surgery.

The risk factors for developing GFICS include young age at IC surgery, microphthalmia, aphakia, and usage of trypan blue during surgery.

However, the Infant Aphakia Treatment Study (IATS) randomized clinical trial (RCT) identified similar risks of GFICS in both aphakia and pseudophakia groups.

In the multivariable analysis, genetic, metabolic, infectious comorbidities, and ophthalmic anomalies were not associated with the risk of undergoing incisional glaucoma surgery.

Likewise, factors associated with IC (i.e., age at IC diagnosis, age at IC surgery, type of IC surgery, and location of IC surgery institution) also were not associated with the risk of incisional glaucoma surgery.

However, younger age at diagnosis of GFICS was the only risk factor associated with subsequent incisional glaucoma surgery (P = 0.03).

REFERENCE:

Choe, S., Kim, Y.K. & Ha, A. Nationwide incidence of and risk factors for undergoing incisional glaucoma surgery following infantile cataract surgery. Sci Rep 14, 16286 (2024).

 

RISK FACTORS FOR UNDIAGNOSED GLAUCOMA

 

Undiagnosed glaucoma is a hidden, significant public health problem. Surveys have shown that almost 50%-90% of glaucoma cases are undiagnosed in a population.

Some risk factors associated with undiagnosed glaucomas include:

• Lower education levels
• Not consulting an ophthalmologist in the year prior to the diagnosis
• Being seen by an optometrist rather than an ophthalmologist

Features associated with undiagnosed glaucoma are:

• A smaller vertical cup-to-disc ratio (CDR)
• Negative family history of glaucoma
• Lower mean baseline intraocular pressure (IOP)
• Baseline hyperopia

In a study by Wong, the odds of having visual field defects among those with diagnosed glaucoma were lower than those with undiagnosed glaucoma (odds ratio [OR], 0.06; 95% confidence interval [95% CI], 0.01–0.69; P=0.02). In addition, the odds of undiagnosed glaucoma were 14 times higher (OR, 14.10; 95% CI, 2.83–7.08; P<0.0001) in participants with visual field defects compared with those without glaucoma. [1]

A study was performed by Chan et al, to examine the associations with previously undiagnosed primary open-angle glaucoma (POAG) in the European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study. [2]

30445 men and women aged 40–79 years were recruited in the baseline survey from the databases of 35 general practices. The predominant ethnicity of the cohort was white. Among the 314 POAG subjects, 160 of them had HTG and 154 had NTG; 207 (65.9%) were known cases, diagnosed before the start of the study and 107 (34.1%) were previously undiagnosed.

The study reported two factors associated with undiagnosed POAG:

• Lower IOP levels (OR 0.71/mm Hg, 95%CI 0.63 to 0.80, p<0.0001)
• Participants not reporting vision problems (OR 0.03, 95%CI 0.01 to 0.69, p<0.0001)

The first points to an over-reliance on the IOP level to exclude glaucoma in the community, leading to patients with lower IOP being missed.

This study demonstrates that it is easy for eye care providers to be reassured by an IOP level <24mmHg while other features of glaucoma are missed. It must be stressed therefore that among patients with non-elevated IOP, care should be taken to examine the optic disc carefully and with supportive disc imaging and visual field testing to improve the chances of identifying suspicious disc features.

In this study, other features of the severity of glaucoma such as vertical CDR and visual field mean deviation were not associated with missed OAG cases. It could be because CDR does not adequately capture features of a glaucomatous disc, and visual fields may not be done routinely at the optician. Even with advanced field defects, many patients with glaucoma are asymptomatic, so field defects will not necessarily provide a reason to visit the optician.

In conclusion, the most important healthcare implication from this analysis is to avoid being falsely reassured by a lower level of IOP in glaucoma case finding.

REFERENCES:

Wong EY, Keeffe JE, Rait JL, Vu HT, Le A, McCarty PhD C, Taylor HR. Detection of undiagnosed glaucoma by eye health professionals. Ophthalmology. 2004 Aug;111(8):1508-14. doi: 10.1016/j.ophtha.2004.01.029. PMID: 15288980.

Chan MPY, Khawaja AP, Broadway DC, Yip J, Luben R, Hayat S, Peto T, Khaw KT, Foster PJ. Risk factors for previously undiagnosed primary open-angle glaucoma: the EPIC-Norfolk Eye Study. Br J Ophthalmol. 2022 Dec;106(12):1684-1688. doi: 10.1136/bjophthalmol-2020-317718. Epub 2021 Jun 25. PMID: 34172506; PMCID: PMC9685696.

COMPLICATIONS OF GLAUCOMA DRAINAGE DEVICES (GDDs)

 

EARLY COMPLICATIONS

• EXCESSIVE HYPOTONIA
•  Induced by over-drainage of aqueous humor.
• Can lead to anterior chamber (AC) flattening with possible contact between endothelium and the silicone tube, choroidal effusion with detachment, hypotonic maculopathy, or supra-choroidal hemorrhage.
• Valved devices have less frequent early postop hypotonia.

• CHOROIDAL EFFUSION SYNDROME
• Choroidal detachment occurs in 10% to 20% of cases with classic GDDs.
• This can be avoided by implanting the GDD in the eye without inserting the tube in the AC. This allows a connective tissue capsule to develop around the plate in 6-8 weeks. In the second step, the tube is inserted into the AC.
• Alternatively, the tube is blocked by a non-absorbable or absorbable suture.
• However, slits in the silicone tube must be made to achieve some immediate filtration.
• In the case of pars plana implants temporary occlusion of the tube can be done by gas tamponade in the vitreous.

• SUPRA-CHOROIDAL HEMORRHAGE
• Incidence of supra-choroidal hemorrhage after GDD implantation varies from 0 % to 6 %.
• Implants with an IOP-regulation mechanism or a drainage tube ligature have a better prognosis.
• Predisposing factors are hypotony, angle closure glaucoma, and multiple previous surgical events.
• Choroidal hemorrhage represents the greatest risk of reduced vision postoperatively.

• ENDOTHELIUM AND LENS
• Early postop-hypotonia causes shallowing/flattening of AC with a risk of the iris/lens touching the corneal endothelium.
• Consequently, the tube can touch the cornea or iris and get obstructed.

• MOTILITY DISORDERS
• Large implants and a large filtration bleb can affect the motility of the adjacent extraocular muscles.
• Adhesions between the capsule and muscle probably play a role.
• Diplopia can occur.
• In a prospective study, motility disturbances were noticed in 46% of patients after implantation of a double-plate Molteno GDD.
• The study also reported restriction of the superior rectus, Pseudo-Brown syndrome, and paralysis of the superior oblique. However, the diplopia usually regressed within one year.
• With 350-mm² and 500-mm² Baerveldt implants, 7 to 27% of patients had motility disorders, especially with the larger size implants.
• For smaller implants, such as the Ahmed Valve, the incidence is lesser, in the range of 2-3%.

• TRANSIENT HYPERTENSION
• Temporary hypertensive phase can occur in 80% of patients in the first three postop months.
• Occurs from an inflammatory response and fibrovascular scarring surrounding the GDD plate.
• This is a critical phase with the need for inflammatory agents and reduction in IOP since this stage is critical in long-term results.
• GDD implantation can be performed with Mitomycin-C to achieve better long-term results. However, some authors found higher rates of post-op hypotonia with it.

LATE COMPLICATIONS

• ENDOTHELIUM/CATARACT
• Iris, lens or the tube touching the corneal endothelium can cause endothelial loss. Therefore, there is a risk of corneal decompensation.
• Tube implantation through pars plana into the vitreous can be beneficial in post-keratoplasty patients, those with iridial angle anomalies or neovascularization of the iris, and phakic patients with shallow AC.
• Pars plana implantation requires total vitrectomy to prevent vitreous blocking the tube.
• Disadvantages of this method are the risk of retinal complications, the impossibility of visual examination of the tube in case of an apparent obstruction, and a higher risk of hypotonia.
• Induction or progression of cataracts is reported in 8% to 34% of phakic patients. However, the rates are comparable for trabeculectomy and classical glaucoma surgeries.

• EROSION OF THE CONJUNCTIVA
• The conjunctiva at the site of entrance of the tube into the AC, near the limbus is occasionally eroded, causing exposure of the tube.
• The tube should be covered with pericardium, scleral patch, dura, fascia lata, or implanted through a scleral tunnel.
• The risk of exposure of the tube or plate is reported to be between 1%-3%.
• This is a risk factor for endophthalmitis.

• DISLOCATION OF THE TUBE
• In 2-3% of patients tube may displace, causing insufficient filtration.
• Usually occurs from incorrect tube implantation.
• The end of the tube in the AC should be cut diagonally with the bevel facing the endothelium to prevent occlusion by the iris and subsequent displacement.

REFERENCE:

Hille K, Moustafa B, Hille A, Ruprecht KW. Drainage devices in glaucoma surgery. Klin Oczna. 2004;106(4-5):670-81. PMID: 15646493.

HISTORY OF MEDIEVAL OPHTHALMOLOGY

CREDIT TO THE ORIGINAL AUTHORS

 

AURICULAR ACUPRESSURE IN GLAUCOMA

 

Is auricular pressure, an acupressure technique, useful in glaucoma?

In a study performed by Her et al, at the China Medical University & Hospital, Taiwan, auricular acupoint stimulator tapping and massage were performed on a group of glaucoma patients. The auricular acupoint corresponds to the kidneys, liver, and eyes.

The study involved a total of 33 glaucoma patients. In 16 patients, involving 28 eyes, auricular acupressure was done twice daily for four weeks. In the control group (17 patients, 32 eyes), tapping without massage was done at sham auricular acupoints (for wrist, shoulder, and jaw).

Intraocular pressure (IOP) and visual acuity were checked before the procedure and followed up for eight weeks.

There was significant (p <0.05) improvement in the IOP and visual acuity in the treatment group.

The most significant IOP-lowering effect was noted at about 3-4 weeks after auricular acupressure. The IOP returned to pre-treatment levels after the acupressure was discontinued for four weeks.

The most significant improvement in visual acuity was seen at 2-4 weeks and occurred in both groups.

Although the mechanism of auricular acupressure/ acupuncture remains undetermined, biological responses, such as the stimulation and activation of endocrine or autonomic nerve systems, and psychological aspects, appear to be involved. Acupressure also corrects the balance of Qi at different points in the body.

REFERENCES:

Her JS, Liu PL, Cheng NC, Hung HC, Huang PH, Chen YL, Lin CP, Lee CH, Chiu CC, Yu JS, Wang HS, Lee YJ, Shen JL, Chen WC, Chen YH. Intraocular pressure-lowering effect of auricular acupressure in patients with glaucoma: a prospective, single-blinded, randomized controlled trial. J Altern Complement Med. 2010 Nov;16(11):1177-84. doi: 10.1089/acm.2010.0020. PMID: 21058884.

Mehta P, Dhapte V, Kadam S, Dhapte V. Contemporary acupressure therapy: Adroit cure for painless recovery of therapeutic ailments. J Tradit Complement Med. 2016 Jul 22;7(2):251-263. doi: 10.1016/j.jtcme.2016.06.004. PMID: 28417094; PMCID: PMC5388088.