Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT1/MT2 agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.

Excessive scleral shrinkage, rather than choroidal thickening, is a major contributor to the development of hypotony maculopathy after trabeculectomy.

PURPOSE: We previously reported that eyes with hypotony maculopathy (HM) after trabeculectomy (TLE) exhibited more reduction of axial length (AL) than those without HM, suggesting that inward collapse of the scleral wall may contribute to the development of HM after TLE. However, we did not evaluate change in choroidal thickness (CT), which could influence AL measures. We compared the magnitude and rate of AL and CT changes in eyes with and without HM by simultaneously measuring these parameters before and after TLE. METHODS: We enrolled 77 eyes of 77consecutive patients with glaucoma, who underwent TLE between March 2014 and March 2016. Intraocular pressure (IOP), central corneal thickness, keratometry, AL, and CT were measured pre- and postoperatively, up to 6 months. These biometrics were compared in eyes with and without HM. RESULTS: The 14 patients who developed HM were significantly younger than those who did not. The eyes with HM exhibited significantly reduced AL (2.8%) compared to those without HM (0.7%). There was no significant difference in CT change between the two groups. The rate of AL reduction was significantly correlated with age, postoperative IOP, and preoperative AL. Post-adjustment logistic regression analysis revealed that eyes with AL reduction rate ≥ 2% had 11.67 higher risk for developing HM (95% confidence interval, 1.28-106.6; P = 0.03). CONCLUSIONS: AL reduction rates ≥ 2% were significantly associated with HM. Excessive reduction in AL, which was seen in eyes with HM, was not an artificial measure resulting from choroidal thickening but rather reflected reductions in the anterior-posterior diameter of the eyeball. Inward collapse of the scleral wall leads to redundancy of the chorioretinal tissue, contributing to the development of HM after TLE.

Intraocular silicone implant to treat chronic ocular hypotony: an in vivo trial.

PURPOSE: The management of chronic ocular hypotony and complicated proliferative vitreoretinopathy-related retinal detachment represents a challenge. Being non-absorbable and non-biodegradable, a silicone oil implant is expected to restore the volume and the intraocular pressure of the globe, as well as to approximate the detached retina. Further advantages could be a long-term tamponade potential, absence of toxicity, and prevention of silicone oil emulsification or anterior chamber oil-prolapse. The aim of this study was to assess the histological tolerance of the silicone oil implant in a pig model. METHODS: A seamless silicone balloon implant with optional surface modifications was developed. Mini pigs were used as experimental animals, and three variants of silicone implants with different surfaces were tested: uncoated, NCO-sP(EO-stat-PO) coated, and heparin-NCO-sP(EO-stat-PO) coated silicone implants. An extracapsular lens extraction was achieved via a standard phacoemulsification followed by a standard three-port vitrectomy. The implant was then placed in the posterior segment and filled with 5000 centistoke silicone oil. One month later, the pigs were euthanized, the eyes were enucleated, and histological specimens were prepared for microscopy. RESULTS: The analysis of the histology revealed that adverse histological changes in conjunctiva, cornea, iris, and ciliary body could be excluded in all eyes operated on regardless of which variant of implant had been employed. The retina as the implant-contacting ocular tissue showed overall good tolerance, although some inflammatory reaction and fibrous proliferation was evident in some cases. CONCLUSIONS: The silicone oil implant is a promising candidate and has the potential to fulfill clinical requirements to act as a long-term intraocular tamponade agent. The heparin-NCO-sP(EO-stat-PO) coating approach could lead to a novel bioactive surface for intraocular devices with excellent properties to hinder cell adhesion and protein adsorption, although further studies will be necessary to evaluate long-term biocompatibility and long-term resistance to biological attacks.

Microarchitecture of Schlemm Canal Before and After Selective Laser Trabeculoplasty in Enhanced Depth Imaging Optical Coherence Tomography.

PURPOSE: To characterize the in vivo effect of selective laser trabeculoplasty (SLT) on the Schlemm canal (SC) in eyes with primary open-angle glaucoma (POAG). MATERIALS AND METHODS: Eighty-one serial horizontal enhanced depth imaging optical coherence tomograph B-scans (interval between B-scans, ∼35 µm) of the nasal corneoscleral limbus were obtained before and 4 weeks after SLT. Fifty B-scans in the overlapping regions before and after SLT were selected for analysis based on the structures of aqueous and blood vessels as landmarks. The SC cross-sectional area (CSA) was measured in each selected B-scan and averaged to generate the mean SC CSA of the eye. SC volume in the overlapping region was calculated using commercially available 3-dimensional reconstruction software. The mean SC CSA and SC volume were compared between pre-SLT and post-SLT B-scans. Correlation analysis was performed between SC CSA changes and intraocular pressure (IOP) changes. RESULTS: Thirteen POAG eyes (13 patients) were included for analysis (mean age, 68.2±9.2 y). After SLT, the mean IOP was reduced from 19.8±7.6 to 14.4±3.8 mm Hg (P=0.003); the mean SC CSA increased by 8%, from 2478±550 to 2682±598 µm (P=0.029); and the mean SC volume increased from 4,304,592±954,777 to 4,658,250±1,039,956 µm (P=0.029). Increase in SC CSA had a significant positive correlation with IOP reduction after SLT (P=0.023, R=0.622). CONCLUSIONS: SLT expands SC in POAG patients and even more so with greater IOP reduction after SLT. Post-SLT expansion of SC may be due to increased trabecular aqueous outflow, IOP decrease, or structural changes in trabecular meshwork resulting from SLT.

Progressive hemifacial atrophy with ciliary body atrophy and ocular hypotony.

Progressive hemifacial atrophy (PHA) is a disease of unknown etiology affecting one-half of the face. Ocular involvement is uncommon. Atrophy of iris is rare, with only a few cases of partial atrophy being reported in the literature. We report a case of total atrophy of iris and ciliary body with associated ocular hypotony in a 16-year-old girl with PHA. We believe this is the first reported case of complete atrophy of iris and ciliary body in PHA. Ocular hypotony in PHA was thought to be due to intra-ocular inflammation. However in our case it appears to be secondary to severe atrophy of the ciliary body.

Previous cyclodestruction is a risk factor for late-onset hypotony and suprachoroidal haemorrhage after glaucoma drainage device surgery.

AIM: To investigate whether previous cyclodestructive (eg, cyclophotocoagulation and cyclocryodestruction) procedures have any influence on the general outcome and pressure level after glaucoma drainage device (GDD) surgery. METHODS: Retrospective analysis of 110 consecutive patients who had undergone GDD (Baerveldt 250 mm(2) and 350 mm(2) implant, AMO, USA) surgery with a minimum follow-up of 3 months. The patients were divided into patients with previous cyclodestructive surgery before GDD surgery (I; 47 patients) and patients without previous cyclodestructive surgery (II; 63 patients). Intraocular pressure (IOP), medication score, best-corrected visual acuity and surgical treatments were recorded before and after drainage device implantation. RESULTS: Patients of group I had a mean preoperative IOP of 32.1 mm Hg and a mean medication score of 4.8; patients of group II had a mean preoperative IOP of 29.2 mm Hg (p=0.18) and a mean medication score of 4.9 (p=0.84). All patients who developed suprachoroidal haemorrhage (six cases) belonged to group I (6/47=12.8%), no patient of group II (0/63=0%) developed suprachoroidal haemorrhage (Fisher's test: p=0.01). Twelve patients developed late-onset (>6 weeks after GDD surgery) hypotony, nine of them belonging to group I (9/47=19.1%) and three of them to group II (3/63=4.8%) (Fisher's test: p=0.03). CONCLUSIONS: While taking potential bias arising from the retrospective nature of the study into consideration, a history of previous cyclodestructive procedures before GDD surgery seems to be a major risk factor for suprachoroidal haemorrhage and for late-onset postoperative hypotony.

Ocular hypotony after the use of indocyanine green for epiretinal membrane surgery.

PURPOSE: To report the occurrence of transient ocular hypotony after indocyanine green (ICG)-assisted macular surgery for removal of the epiretinal membrane (ERM). MATERIALS AND METHODS: This was a retrospective review of 122 eyes of 118 patients who underwent vitrectomy for idiopathic ERM. The ICG staining technique was used in 71 eyes without fluid-air exchange (FAX) and in 15 eyes with FAX. Detailed eye examinations, including intraocular pressure (IOP) measurement, were performed before and after surgery. RESULTS: We observed postoperative transient ocular hypotony with choroidal detachment in 8 of 71 eyes (11%) in the ICG (+)/FAX (-) group, and no ocular hypotony was seen in the ICG (+)/FAX (+) group (15 eyes) or in the ICG (-) group (36 eyes). The median best corrected visual acuity (BCVA) in the ICG(-)group was only significantly better than in the ICG (+)/FAX (-) with hypotony at 1 week after surgery (p = 0.046). However, there was no statistically significant difference in BCVA at 3 and 6 months after surgery among the groups (p > 0.05). CONCLUSION: ICG staining of the internal limiting membrane (ILM) supports complete ERM removal because of enhanced visualization of the border between the ILM and the ERM. However, it should be cautioned that postoperative ocular hypotony may occur in some cases of ICG-assisted macular surgery. Therefore, informed consent with careful follow-up is required when ICG-assisted surgery is performed.

Prolonged ocular hypotension: would ciliary tissue transplantation help.

AIMS: Ocular hypotony and phthisis bulbi from persistent fistulae, ciliochoridal detachments, or inflammation, that cannot be treated currently. However, complete shutdown of the ciliary epithelium is rare. Secreting, transplanted ciliary tissue could restore the IOP to a level where further visual damage would not occur or even be reversed. METHODS: Allografts of ciliary epithelium and its substrate were placed on to the surface of the iris of normal albino rabbits. The progress of the transplanted tissue was followed in the untreated animals, those who had been immunosuppressed and those who had been immunosuppresed together with cold whole body perfusion for up to 55 days. Changes were assessed by slit-lamp observation, luconyl blue staining, fluoresceine angiography, and these were compared with the histology and electron microscopic appearances. RESULTS: Transplants survived the period of ischaemia in the anterior chamber. They started to be revascularised within 4 days and were completely revascularised in 12 days. Untreated animals showed classical rejection phenomena. However, the ciliary epithelial tissue in those animals who were immunosuppressed and had been subjected to whole body perfusion remained normal and were secreting aqueous, as judged by the histological and electron microscopic appearances. CONCLUSIONS: Perfused allografts of ciliary tissue will survive in the normal anterior chamber of the immunosuppressed rabbit, and the electron microscopic evidence indicates that the tissue is producing aqueous. If this can be shown to be adequate in the damaged eye, then ciliary transplantation could be a valuable tool in the management of severe intractable hypotony.

Intraocular pressure and foveal thickness after phacoemulsification.

PURPOSE: To evaluate the natural course of intraocular pressure (IOP) and foveal thickness during the postoperative period, and the correlation between them. DESIGN: Prospective observational case series. METHODS: This institutional study comprised 30 eyes of 30 cataract patients scheduled for phacoemulsification. IOP and foveal thickness by optical coherence tomography (OCT) were measured preoperatively and three, six, nine, 12, 15, 18, 21, 24 hours, five days, one month, and two months postoperatively. RESULTS: The IOP was 4.7 +/- 2.4 mm Hg at three hours postoperatively. The IOP increased to 23.4 +/- 8.1 mm Hg at six hours and 23.5 +/- 7.3 mm Hg at nine hours postoperatively. The IOP was 1.9 mm Hg lower at one month or two months postoperatively than preoperatively. The foveal thickness was 202.1 +/- 19.2 microm and significantly higher at three hours postoperatively, and was 182.3 +/- 20.5 microm, 183.2 +/- 22.3 microm, and significantly lower at nine and 12 hours postoperatively than preoperatively. The correlation between mean IOP and mean foveal thickness is statistically significant. Fovea thickness (microns) = 207.0476 - 1.019759 x IOP (mm Hg), P value < .0001, adjusted R(2) = .8699. CONCLUSIONS: We found initial hypotony, an IOP spike during six to nine hours, and a decrease of IOP at one month and two months postoperatively. An initial increase of the foveal thickness, a significant reduction at nine hours and 12 hours, and an equivocal increase at one month or two months postoperatively were also noted. A significant negative correlation between IOP and foveal thickness was shown.

Serous retinal detachment and cystoid macular edema in hypotony maculopathy.

PURPOSE: To report the foveal structural findings of hypotony maculopathy imaged with optical coherence tomography. METHODS: Case report of a 39-year-old white woman with a 20 year history of uveitis, who underwent pars plana vitrectomy and pars plana Baerveldt implant for intractable glaucoma. Four months postoperatively, decreased vision and hypotony maculopathy ensued. Optical coherence tomographic (OCT) images were taken horizontally through the macula. RESULTS: OCT demonstrated large intraretinal cysts, serous macular detachment, and choroidal folds, which resolved upon resolution of hypotony. CONCLUSION: Cystic macular changes and serous macular detachment can be prominent features of hypotony maculopathy.

Management of hypotony maculopathy and a large filtering bleb after trabeculectomy with mitomycin C: success with argon laser therapy.

We report a patient with postkeratoplasty glaucoma that developed a large, filtering bleb following trabeculectomy with intraoperative antimetabolite treatment. The hypotony and the bleb were managed using argon laser photocoagulation. A 26-year-old female patient underwent penetrating keratoplasty in the left eye for keratoconus. Postoperatively, her elevated intraocular pressure could not be controlled medically, and the patient underwent a trabeculectomy with intraoperative antimetabolite application. Two months later, hypotony maculopathy, optic disc edema, and choroidal folds developed, and her vision dropped. Steroid treatment and soft contact lenses did not help. Photocoagulation was applied twice to the surface of the bleb and the surrounding area. After the photocoagulation therapy, the patient's vision improved, intraocular pressure increased, and the optic disc edema and macular folds had resolved. Argon laser photocoagulation applied to a large filtering bleb associated with hypotony maculopathy is a useful treatment for bleb remodeling and elevating intraocular pressure.

Conjunctival dysfunction and mitomycin C-induced hypotony.

PURPOSE: To determine the role of a physically intact conjunctiva in the development of chronic hypotony after mitomycin C-enhanced trabeculectomy. METHOD: Three patients with mitomycin C-related hypotonic maculopathy, but without a leak on Siedel test, had a thorough evaluation of the bleb area and an anterior segment fluorescein angiography. The bleb was excised and a pedicle flap, rotated from the temporal conjunctiva, was sutured to cover the defect superiorly. The scleral flap and its sutures were not disturbed. The excised bleb was subjected to light and electron microscopy. RESULTS: The Seidel test result was negative in all patients, but late phases of the anterior segment angiography showed a generalized seepage of aqueous from the bleb. After revision of the bleb, there was a gradual increase in the intraocular pressure, a reversal of the hypotonic maculopathy, and consequent improvement in visual acuity in all three patients, stable up to a minimum follow-up of 18 months. On histopathologic examination, the basement membrane was thickest under thin areas of the epithelium and thinnest below thicker epithelial layers. CONCLUSION: A dysfunctional conjunctival barrier, as evidenced by the "sweating" of the bleb and histopathologic alterations in the epithelial barrier, could be responsible for the hypotonic maculopathy in these patients. Excision of the conjunctiva alone and replacement by a pedicle conjunctival graft offers a safe and effective method of treating chronic hypotony after mitomycin C-augmented trabeculectomy in such patients.

[Early and late findings with optical coherence tomography (OCT) in patients with postoperative hypotonia]. / Frühe und späte Befunde der optischen Kohärenztomographie (OCT) bei Patienten mit postoperativer Hypotonie.

PURPOSE: To study early and late findings of macular retinal thickness in patients with hypotony following filtering procedures. PATIENTS AND METHODS: 13 patients who had undergone trabeculectomy (9 with antimetabolites) developed ocular hypotony. The macular region appeared normal during biomicroscopy in 8 patients. In the hypotensive phase, macular thickness was measured using optical coherence tomography (OCT). Directly after attempted and successful normalization of intraocular pressure (7 spontaneous, 5 operative, 1 failure) as well as 6 months later, OCT measurements were repeated. Foveal thickness in the hypotonous eye was correlated with visual acuity and foveal thickness in the fellow eye. RESULTS: Intraocular pressure could be raised from a mean of 2.5 +/- 1.3 mmHg to 11.5 +/- 5.5 mmHg and later on to 13 +/- 3.7 mmHg (follow-up). Mean foveal thickness was reduced from 211 +/- 73 microns during hypotony to 170 +/- 44 microns after normalization of intraocular pressure and to 171 +/- 38 microns at late follow-up. Mean visual acuity improved from 0.17 to 0.33 and finally to 0.6. CONCLUSIONS: Despite normal appearance of the macula (8 patients) using biomicroscopy in patients with hypotony, retinal thickness in the fovea is increased. Apart from refractive changes, this retinal thickening can be held responsible for the deterioration of visual acuity in eyes with hypotony. OCT analysis and measurements may be useful to distinguish between retinal thickening that is reversible after normalization of intraocular pressure and cystoid macular edema that leads to permanent visual impairment.

Paradoxical hypotony after laser in situ keratomileusis.

We present a case of paradoxically low (0 to 2 mm Hg) intraocular pressure (IOP) measured by Goldmann applanation and Tono-Pen tonometry in an eye with corticosteroid-induced high IOP after laser in situ keratomileusis. The patient complained of blurred vision and ocular pain in both eyes. The eyes were firm by palpation, and the IOP measured by Schiotz indentation tonometry was 38 mm Hg. An interface fluid pocket was identified by slitlamp examination, and the corneal surface became steeper. These findings resolved after flap relifting, interface irrigation, and addition of antiglaucoma medications. We postulate that the paradoxically low reading by applanation tonometry was due to fluid accumulation within the flap-bed interface. The applanation tonometry reflected the interface fluid pocket pressure rather than the real high IOP. An exceedingly low IOP should be verified by palpation or by Shiotz indentation tonometry, and interface fluid should be identified.

Combination of autologous blood injection and bleb compression sutures to treat hypotony maculopathy.

PURPOSE: To report successful use of a combination of autologous blood injection and bleb compression sutures to treat overfiltration with hypotony maculopathy after trabeculectomy with mitomycin C. METHODS: Two patients underwent the combined procedure and were followed until visual acuity and intraocular pressure (IOP) were stable over three consecutive visits (4 to 9 months). RESULTS: Both patients experienced improvement in visual acuity both subjectively and objectively, and both patients had an elevation in IOP that persisted over three consecutive visits. CONCLUSIONS: Combination autologous blood injection and bleb compression suture placement may be an effective means of treating hypotony maculopathy after trabeculectomy with mitomycin C.

Elastic cord-induced cyclodialysis cleft and hypotony maculopathy.

We describe a case of hypotony maculopathy in which hypotony was due to a cyclodialysis cleft produced by an elastic cord injury. Sixteen months after being hit with an elastic cord, a 43-year-old white male presented with progressive loss of vision in the right eye. The visual acuity in the right eye was 1/200 due, in part, to a subluxated and cataractous lens. The intraocular pressure (IOP) was 4 mm Hg. Gonioscopy revealed a cyclodialysis cleft at the 2 o'clock position, and fundus examination showed hypotony maculopathy. The patient underwent pars plana vitrectomy, pars plana lensectomy, repair of the cyclodialysis cleft, placement of an anterior chamber intraocular lens, and tightly sutured trabeculectomy without antimetabolite. Sixteen months following surgery, visual acuity was stable at 20/60 and IOP was 11 mm Hg but the chorioretinal folds persisted.

Anterior uveitis and hypotony after intravenous cidofovir for the treatment of cytomegalovirus retinitis.

OBJECTIVE: This study aimed to describe the incidence and risk factors for the development of anterior uveitis in patients receiving intravenous cidofovir for the treatment of longstanding cytomegalovirus retinitis. DESIGN: The study design was a retrospective cohort. PARTICIPANTS: Eighteen patients (30 eyes) receiving parenteral cidofovir for the treatment of complicated cytomegalovirus retinitis participated. MAIN OUTCOME MEASURES: The clinical response to parenteral cidofovir; the occurrence of anterior uveitis, and the management and outcome of patients with this complication; and the effect of cidofovir on intraocular pressure measurements were measured. RESULTS: There was no progression or relapse of retinitis in patients receiving intravenous cidofovir. Eight (44%) of the 18 patients developed anterior uveitis, which occurred after a median of 4 doses of intravenous cidofovir. The median CD4+ cell count at the time of development of iritis was 101/mm3. Patients who developed uveitis had a mean increase in serum creatinine over baseline measurements (P = 0.05). The use of human immunodeficiency virus type-1 (HIV-1) protease inhibitors was not different between both groups of patients (P = 1.0). The development of anterior uveitis and visually significant hypotony necessitated withdrawal of cidofovir in only one patient. CONCLUSIONS: Anterior uveitis was a common complication after intravenous cidofovir therapy. Despite the frequency of this complication, continued treatment with intravenous cidofovir was possible in the majority of patients. Patients with anterior uveitis after intravenous cidofovir may be treated successfully with topical corticosteroid therapy and cycloplegic agents.