Emerging drugs for the treatment of glaucoma: a review of phase II & III trials.

INTRODUCTION: Glaucoma is a progressive optic neuropathy and the leading cause of irreversible vision loss. By 2040, the number of individuals with glaucoma is expected to nearly double. The only known modifiable risk factor for glaucoma is intraocular pressure. Topical medications are often used as first-line therapies. Although there are numerous available treatments, there continues to be a need for the development of new medical therapies due to variable response, intolerable side-effect profiles in some patients, and elevated intraocular pressure refractory to other treatments. AREAS COVERED: This review will cover glaucoma medications currently undergoing phase II and III of drug development. EXPERT OPINION: There are numerous drugs currently in development that have demonstrated significant and clinically relevant reduction of intraocular pressure. Differentiating factors include improved tolerability, novel mechanisms of action, multiple mechanisms of action, or superior IOP reduction. However, the availability of generic prostaglandin analogs may limit adoption of these novel compounds as first-line agents, except for certain subgroups of glaucoma patients. Use as adjuvant or second-line therapy appears more likely for the majority of glaucoma patients.

Episcleral venous pressure response to brain stem stimulation: Effect of topical lidocaine.

Episcleral venous pressure (EVP) is important for steady state intraocular pressure (IOP), as it has to be overcome by aqueous humor in order to leave the eye. Recent evidence suggests a neuronal tone being present, as topical anesthesia lowered EVP. The superior salivatory nucleus in the brainstem could be identified to elicit increases in EVP during electrical stimulation. In the present study the effect of topical anesthesia on the stimulation effect was investigated. 8 Spraque Dawley rats were anesthetized, artificially ventilated with CO2 monitoring and continuous blood pressure monitoring. Intraocular pressure was measured continuously through a cannula in the vitreous body. Episcleral venous pressure was measured by direct cannulation of an episcleral vein via a custom made glass pipette connected to a servonull micropressure system. Electrical stimulation of the superior salivatory nucleus (9 µA, 200 pulses of 1 ms duration) increased EVP from 8.51 ± 1.82 mmHg to 10.97 ± 1.93 mmHg (p = 0.004). After application of topical lidocaine EVP increased from 7.42 ± 1.59 mmHg to 9.77 ± 1.65 mmHg (p = 0.007). The EVP response to stimulation before and after lidocaine application was not statistically significantly different (2.45 ± 0.5 vs 2.35 ± 0.49 mmHg, p = 0.69), while the decrease in baseline EVP was (8.51 vs. 7.42 mmHg, p = 0.045). The present data suggest that distinct neuronal mechanisms controlling the episcleral circulation of rats exist. This is in keeping with previous reports of two distinct arterio-venous anastomoses, one in the limbal circulation and one in the conjunctival/episcleral circulation.

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

OBJECTIVE: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs. METHODS: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 µg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 µg (n = 8) in one eye; IOP was evaluated through day 66. RESULTS: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes. CONCLUSIONS: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.

Evaluation of the effect of daily activities on intraocular pressure in healthy people: is the 20 mmHg border safe?

PURPOSE: The aim of this prospective study was to evaluate the intraocular pressure (IOP) variations during daily activities such as reading, speaking and carrying in regard to investigating whether an elevation or decrease exists. SUBJECTS AND METHODS: Forty-four eyes of 44 healthy subjects were evaluated. The IOP was measured in relaxation and after reading, speaking and carrying a shopping bag for 5 min on different days, respectively. The subjects rested for 15 min between the activities. Mean initial IOP levels were compared with mean IOP levels after reading, speaking and carrying a shopping bag with paired t test. A p value of 0.05 was considered as statistically significant. RESULTS: We observed no changes in mean IOP after reading (p = 0.188). Mean IOP was increased after speaking and carrying compared with mean basic IOP (p = 0.001 and p = 0.001, very significant, respectively). The mean IOP began to decrease 15 min after speaking and carrying and came back to the baseline values one hour later. CONCLUSIONS: The IOP is not stable during daily activities. Simple actions such as carrying or speaking have an increasing effect on IOP. This should be taken into consideration in glaucoma patients during control measurements, especially in patients in whom the IOP was near to the 20 mmHg border.

Radius-Maumenee syndrome-associated glaucoma, a therapeutic challenge: A case report.

INTRODUCTION: Radius-Maumenee syndrome is a rare cause of open-angle glaucoma, secondary to elevated episcleral venous pressure (EVP) without any orbital or systemic abnormalities. CASE PRESENTATION: We present a case of a male patient in his mid-sixties, who presented with bilateral dilated episcleral vessels, bilateral glaucoma, chorioretinal folds in both maculae and choroidal effusion in his left eye. Our case highlights the differentials that should be considered and the systematic investigations that should be performed. We describe the clinical, optical coherence tomography and angiography findings of this patient and propose a potential pathophysiological mechanism leading to the propensity for perioperative complications. CONCLUSION: Radius-Maumenee syndrome should be a diagnosis of exclusion. Secondary glaucoma can remain refractory to medical treatment and filtering surgery carries the risk intra-operative or post-operative uveal effusions.

Topical netarsudil for treatment of glaucoma with elevated episcleral venous pressure: A pilot investigation in sturge-weber syndrome.

PURPOSE: Topical netarsudil 0.02% may reduce intraocular pressure (IOP) by decreasing episcleral venous pressure (EVP), which carries theoretical utility for glaucoma associated with elevated EVP. A role for netarsudil in patients with elevated EVP is evaluated in a pilot investigation using a cohort of individuals with Sturge-Weber syndrome (SWS). METHODS: Retrospective study of patients with SWS and glaucoma who were treated with netarsudil. Five patients (six eyes) were identified. Data collected included demographics, visual acuity, IOP, glaucoma medical and surgical treatments, and adverse effects of netarsudil. RESULTS: Mean age was 13.6 ± 8.5 years. EVP elevation was presumed based on clinical stigmata and/or historical features. Mean number of baseline glaucoma medications was 3.3 ± 1.2. There was a significant reduction in the IOP at netarsudil initiation (mean 26.2 ± 4.5 mmHg) to 1 month of netarsudil therapy (mean 20.2 ± 3.8 mmHg, p = 0.0283) and latest IOP on netarsudil (mean 17.6 ± 1.4 mmHg, p = 0.0034). Mean duration of netarsudil therapy was 18.7 ± 11.8 months. Three patients required additional glaucoma procedures; one patient required an additional glaucoma medication. Three eyes (50%) developed conjunctival hyperemia. One patient discontinued netarsudil at 29 months, to reduce drop burden. CONCLUSIONS: Netarsudil can effectively reduce IOP in patients with SWS, even when used as a fourth or fifth glaucoma medication. A possible role for netarsudil in the management of patients with elevated EVP is suggested pending further future investigations.

Radius-Maumenee syndrome: A case series with a long-term follow-up.

The aim of the case series is to highlight the surgical challenges experienced like failed intervention, choroidal effusion, a postoperative cystoid macular oedema, and describe treatment options for Radius-Maumenee syndrome. Authors reported on 3 bilateral cases of Radius-Maumenee syndrome which underwent medical treatment, trabeculectomy with Mitomycin C, implantation with XEN45, Ahmed glaucoma valve, Baerveldt glaucoma implant, and cyclophotocoagulation.

Bilateral Episcleral Corkscrew Vessels: Expedition into the Unknown - Case Report.

We aim to report a case of a middle-aged woman with bilateral idiopathic elevated episcleral venous pressure (IEEVP) and its difficulties in the diagnostic approach. Particularly in this case, the atypical feature of ocular hypertension without glaucomatous optic nerve damage may be misleading. We present a 66-year-old woman with longstanding bilateral "red eyes." Clinical findings included bilateral episcleral vessel engorgement and tortuosity and raised intraocular pressure with open iridocorneal angles. Despite ocular hypertension, glaucomatous neuropathy was absent and confirmed by normal structural (optical coherence tomography) and functional (standard automated perimetry) tests. The systemic workup was unremarkable. Magnetic resonance angiography showed bilateral dilated superior ophthalmic veins. Cerebral digital subtraction angiography was requested, and no carotid-cavernous fistula (or other significant vascular findings) was identified. The diagnosis of IEEVP was assumed. In conclusion, our case highlights the systematic investigation necessary in cases of bilateral episcleral vessel engorgement and tortuosity and the possible differential diagnosis to be considered to rule out life-threatening causes of elevated episcleral venous pressure. It is important for clinicians to be aware of IEEVP even in patients with atypical features that despite significative ocular hypertension had no glaucomatous damage.

Outcomes of medical and surgical management in eyes with idiopathic elevated episcleral venous pressure.

Purpose: Idiopathic elevated episcleral venous pressure (IEEVP) is a rare cause of secondary glaucoma and is a diagnosis of exclusion. The aim of this study was to describe the clinical presentation and analyze the outcomes of medical and surgical management in eyes diagnosed with idiopathic elevated episcleral venous pressure. Methods: A retrospective analysis of eyes diagnosed with IEEVP over a 5-year period between April 2012 and March 2016 was performed. The demographic details, medical history, and clinical course of the cases were obtained from the medical records. Data pertaining to the severity of glaucomatous damage, response to medical management, need for surgical intervention, and their outcomes were analyzed. Results: Fifteen eyes of 13 patients were included. Thirteen eyes (86.6%) had open angle configuration. Among the 13 eyes that had glaucoma, eight eyes (61.5%) had severe glaucoma, four eyes (30.7%) had moderate glaucoma, and one eye (7.6%) had mild glaucoma. The median follow-up was 210 days. Seven of the 15 eyes (46.6%) required a glaucoma filtration procedure, and three underwent prophylactic sclerotomies. 71.4% of these eyes had complete success. One out of the seven operated eyes required choroidal drainage post-operatively. Conclusion: IEEVP is an extremely rare condition and presents with raised intra-ocular pressure and tortuous episcleral vessels. The management of IEEVP is similar to that of primary open angle glaucoma. Uveal effusion is to be anticipated, and hence, combining trabeculectomy with prophylactic sclerotomies is advisable.

The Effects of Acute Intracranial Pressure Changes on the Episcleral Venous Pressure, Retinal Vein Diameter and Intraocular Pressure in a Pig Model.

PURPOSE: Orbital veins such as the retinal veins and episcleral veins drain into the cavernous sinus, an intracranial venous structure. We studied the effects of acute intracranial pressure (ICP) elevation on episcleral venous pressure, intraocular pressure and retinal vein diameter in an established non-survival pig model. METHODS: In six adult female domestic pigs, we increased ICP in 5 mm Hg increments using saline infusion through a lumbar drain. We measured ICP (using parenchymal pressure monitor), intraocular pressure (using pneumatonometer), episcleral venous pressure (using venomanometer), retinal vein diameter (using OCT images) and arterial blood pressure at each stable ICP increment. The average baseline ICP was 5.4 mm Hg (range 1.5-9 mm Hg) and the maximum stable ICP ranged from 18 to 40 mm Hg. Linear mixed models with random intercepts were used to evaluate the effect of acute ICP increase on outcome variables. RESULTS: With acute ICP elevation, we found loss of retinal venous pulsation and increased episcleral venous pressure, intraocular pressure and retinal vein pressure in all animals. Specifically, acute ICP increase was significantly associated with episcleral venous pressure (ß = 0.31; 95% CI 0.14-0.48, p < .001), intraocular pressure (ß = 0.37, 95%CI 0.24-0.50; p < .001) and retinal vein diameter (ß = 11.29, 95%CI 1.57-21.00; p = .03) after controlling for the effects of arterial blood pressure. CONCLUSION: We believe that the ophthalmic effects of acute ICP elevation are mediated by increased intracranial venous pressure producing upstream pressure changes within the orbital and retinal veins. These results offer exciting possibilities for the development of non-invasive ophthalmic biomarkers to estimate acute ICP elevations following significant neuro-trauma.

Successful Reduction of Intraocular Pressure in a Patient with Glaucoma Secondary to Sturge-Weber Syndrome Using a Suprachoroidal Shunt.

AIM: We present a case of successful reduction of intraocular pressure (IOP) in a patient with Sturge-Weber syndrome (SWS) and moderate open angle glaucoma using a suprachoroidal shunt. BACKGROUND: Patients with SWS glaucoma often have elevated episcleral venous pressure resulting in elevated IOP. This makes the conventional pathway for aqueous humor outflow a poor target for IOP reduction, yielding it difficult to treat. Medication and procedures that facilitate uveoscleral outflow have been more successful. CASE DESCRIPTION: We present a case where a suprachoroidal shunt device (CyPass®) was used to reduce IOP in a patient with SWS. The IOP reduction has persisted for 12 months without complication or the requirement for topical prostaglandin analog use. CONCLUSION: The uveoscleral pathway is a preferred target for IOP reduction in patients with elevated episcleral venous pressure. The CyPass device offers a promising ab interno minimally invasive glaucoma surgery (MIGS) approach to reduce IOP in cases where a pathologic pressure gradient exists in the trabecular meshwork. CLINICAL SIGNIFICANCE: Glaucoma in patients with SWS has been historically difficult to treat. Previous surgical procedures that have been successful are more invasive and have required the creation of alternative drainage routes of aqueous humor. The CyPass device offers a promising less invasive option to reduce IOP in these patients. HOW TO CITE THIS ARTICLE: Junttila TL, Alberto N, Winkels M, et al. Successful Reduction of Intraocular Pressure in a Patient with Glaucoma Secondary to Sturge-Weber Syndrome Using a Suprachoroidal Shunt. J Curr Glaucoma Pract 2020;14(1):43-46.

Intraocular pressure elevation associated with blood in Schlemm's canal after strabismus surgery.

PURPOSE: To report a case of increased intraocular pressure (IOP) associated with blood in Schlemm's canal following strabismus surgery. OBSERVATIONS: A 43-year-old female presented with acquired comitant esotropia. The patient had undergone an uneventful bilateral medial rectus recession and right lateral rectus resection operation under general anesthesia. Routine post-operative follow-up at day 3 detected a marked chemosis at the temporal side of the conjunctiva, an elevated IOP of 30 mmHg, and the presence of blood in Schlemm's canal in the temporal angle of the right eye. Episcleral venous outflow impairment was hypothesized to be the cause of secondary ocular hypertension in this patient. IOP was controlled with anti-glaucoma drops. Conjunctival chemosis, IOP, and blood in Schlemm's canal gradually decreased, and all topical medications were ceased at 11 weeks after the surgery. CONCLUSION AND IMPORTANCE: An IOP elevation can be an early complication after strabismus surgery. The presence of blood in Schlemm's canal suggests that the cause is impairment of episcleral venous flow. Although the episode can be transient, this report underlines the importance of IOP examination during the early post-operative period.

Secondary open-angle glaucoma and serous macular detachment associated with pulmonary hypertension.

PURPOSE: We describe a patient with secondary open-angle glaucoma and serous macular detachment associated with pulmonary hypertension. OBSERVATIONS: A 59 year-old male with pulmonary hypertension presented with vision loss and was noted to have bilateral engorged epibulbar vessels, blood in Schlemm's canal, elevated intraocular pressure, retinal venous tortuosity and serous retinal detachments. Enhanced depth optical coherence tomography (ED-OCT) showed bilateral serous macular detachments with marked choroidal thickening. Fluorescein angiography and indocyanine green angiography revealed choroidal vascular congestion and engorgement. Improvement of subretinal fluid was achieved with systemic control of his venous hypertension, and the intraocular pressure responded to medical anti-glaucoma therapy. CONCLUSIONS: Pulmonary hypertension may be associated with secondary open-angle glaucoma, choroidal engorgement and serous macular detachment, and should be considered in the differential diagnosis of elevated episcleral venous pressure. Management of ocular complications is challenging and requires a multi-disciplinary approach.

[Radius-Maumenee syndrome: A rare cause of glaucoma]. / Syndrome de Radius-Maumenee : une cause rare de glaucome.

Radius-Maumenee syndrome is a rare cause of severe secondary open-angle glaucoma. The ocular hypertension is due to episcleral venous hypertension. This syndrome consists of open angle glaucoma and episcleral venous dilatation without orbital or systemic abnormalities. It is diagnosis of exclusion after ruling out carotid-cavernous fistula, thyroid orbitopathy and an invasive orbital process that might explain the elevated episcleral venous pressure. Treatment begins with glaucoma eyedrops and, in case of failure, filtering surgery. Uveal effusion syndrome and postoperative choroidal detachment are frequent complications of filtering surgery in patients with this syndrome. We present the case report of a 59-year-old woman with Radius-Maumenee syndrome.

Elevated episcleral venous pressure and its implications: A case of Radius-Maumenee syndrome.

We report a rare case of dilated episcleral veins with unilateral secondary open-angle glaucoma. Our case highlights the possible differentials to be considered and the systematic investigations to be done while ruling out the etiologies. Radius-Maumenee syndrome is a diagnosis of exclusion. Raised IOP can remain refractory to the medical therapy and conventional trabeculectomy carries higher risk of complications. Here, we discuss the choice of surgical treatment and its implications on management of this secondary open-angle glaucoma.

Idiopathic elevated episcleral venous pressure in a teenager.

PURPOSE: To report a case of unilateral idiopathic elevated episcleral venous pressure (IEEVP) in a 15-year-old patient. We reviewed and summarized published case reports of IEEVP to determine how to manage this challenging and rare condition. OBSERVATIONS: A 15-year-old Caucasian male presented with elevated intraocular pressures (IOP), blood in Schlemm canal in the left eye, and asymmetric cupping with corresponding glaucomatous findings on testing. We diagnosed the patient with IEEVP and describe successful surgical intervention with deep sclerectomy and viscocanalostomy. CONCLUSIONS AND IMPORTANCE: IEEVP is a diagnosis of exclusion and based on clinical findings of dilated episcleral veins, blood in Schlemm canal and glaucomatous changes. If glaucomatous progression occurs with medication, filtration surgery is usually required, and most patients have good results in the literature. Care should be taken to prevent post-operative hypotony and serous choroidal detachment.

Radius-Maumenee syndrome: Beyond a diagnostic and therapeutic challenge. / Síndrome de Radius-Maumenee: más allá de un reto diagnóstico y terapéutico.

Radius-Maumenee syndrome (SRM) or idiopathic episcleral venous hypertension (HVEI) is an uncommon disorder that occurs with a dilation of the episcleral vessels and an increase in intraocular pressure (IOP). It is a syndrome that constitutes a diagnostic and therapeutic challenge for the ophthalmologist. A case is presented in which, despite making an early diagnosis and trying to plan a treatment aimed at avoiding choroidal effusion, its appearance was unavoidable, having to treat it twice with good functional results so far.

Intraocular Pressure Effects and Mechanism of Action of Topical Versus Sustained-Release Bimatoprost.

PURPOSE: To assess the intraocular pressure (IOP)-lowering effects of bimatoprost sustained-release implant (BimSR) in normotensive monkeys receiving topical bimatoprost. METHODS: Six eyes from six female, normotensive, cynomolgus monkeys were treated with once-daily topical latanoprost 0.005% plus twice-daily fixed-combination dorzolamide 2%/timolol 0.5%. At week 5, topical latanoprost was switched to once-daily topical bimatoprost 0.03% and twice-daily dorzolamide 2%/timolol 0.5% was continued. At week 8, BimSR 20 µg was administered intracamerally to three eyes and topical therapy was continued in all eyes. At week 12, all topical therapy was discontinued and animals were monitored for another 4 weeks. IOP was measured with a TonoVet rebound tonometer in nonsedated animals weekly for 16 weeks. RESULTS: Average mean (standard deviation) IOP was 19.8 (1.6) mm Hg at baseline, 15.7 (0.9) mm Hg during treatment with topical latanoprost/dorzolamide/timolol from weeks 1 to 5, and 14.2 (0.5) mm Hg during weeks 6 to 8 after topical latanoprost was switched to topical bimatoprost. After BimSR was added, average mean IOP during weeks 9 to 12 was 10.8 (1.3) mm Hg, a decrease of 3.9 mm Hg compared with the topical-only arm. When topical therapy was discontinued, IOP in BimSR-treated eyes remained below that in unmedicated eyes (15.8 [0.9] vs. 20.2 [0.2] mm Hg at weeks 14-16). CONCLUSIONS: Intracameral BimSR has IOP-lowering effects additive to those of topical bimatoprost, suggesting an additional mechanism of action with intracameral drug delivery. TRANSLATIONAL RELEVANCE: Compared with topical bimatoprost, intracameral BimSR may have an additional mechanism of action of IOP lowering.

Assessment of Aqueous Humor Dynamics in the Rodent by Constant Flow Infusion.

Mice and rats are being increasingly used in glaucoma research and much useful data have been generated from them. One aspect of using these animals for this purpose involves assessment of aqueous humor dynamics. Several techniques have been described in the literature for the determination of one or more of these parameters in rodents, in both living animals and eyes perfused ex vivo. Here, we describe the practical details for a technique for the determination of all principal parameters of aqueous humor dynamics (intraocular pressure (IOP), aqueous humor formation rate (Fin), uveoscleral outflow rate (Fu), aqueous outflow facility (C), and episcleral venous pressure (Pe)) in the living rat and mouse eye, in a single experimental session.

Acute Onset Ocular Hypotony after Coronary Artery Bypass Surgery.

IMPORTANCE: The purpose of this case report is to evaluate risk factors associated with post-coronary artery bypass graft (CABG) ocular hypotony compared to post-CABG ischemic optic neuropathy. OBSERVATIONS: The patient described here is a single case at the University of California, Irvine Medical Center, from July 2016. This case demonstrates the rare incidence of acute post-CABG ocular hypotony and vision loss in a patient with prior history of optic atrophy. Both vision loss and hypotony resolved completely to baseline without intervention within 3 days postoperatively. CONCLUSIONS AND RELEVANCE: Severe anemia and large fluctuations in central venous pressure and blood pressure can occur in any patient undergoing CABG surgery. These hemodynamic shifts can cause transient ischemia to pressure controlling systems such as the ciliary body and reduce episcleral venous pressure. Other risk factors for acute hypotony in the setting of CABG surgery also include the use of hypertonic agents, cardiopulmonary bypass, and intravenous anesthesia.