Ronald L. Gross

Intraocular Pressure Elevation Associated with Inhalation and Nasal Corticosteroids

BACKGROUND The ocular hypertensive response to corticosteroids is well established. Elevated intraocular pressure (IOP) secondary to corticosteroids by nasal spray or inhalation has rarely been reported. RESULTS Three patients showed a possible ocular hypertensive response to beclomethasone dipropionate by nasal spray or inhalation. In two patients, the IOP returned to pretreatment levels after discontinuing nasal corticosteroid spray. One patient required medication to control IOP with continued inhaled corticosteroid. One patient later demonstrated an ocular hypertensive response to oral steroids. CONCLUSION Corticosteroids by nasal spray or inhalation may cause ocular hypertension in susceptible patients. The authors recommend surveillance of IOP in patients using these medications.

Effects of elevated intraocular pressure on mouse retinal ganglion cells

We developed and characterized a mouse model of elevated intraocular pressure (IOP) to investigate the underlying cellular and genetic mechanisms of retinal ganglion cell (RGC) death. IOP was unilaterally increased in C57BL/6J mice by photocoagulation of the episcleral and limbal veins. IOP was measured using an indentation tonometer. RGC survival was measured by retrograde labeling using DiI applied to the superior colliculous. The mechanism of RGC death was investigated using TUNEL staining, immunostaining for cleaved caspase-3, and Western blot for Bcl-2 and Bax expression. RT-PCR was used to measure changes in Bcl-2, Bax, Bad, Bak, P53, ICE and Fas. Mean IOP was increased in the treated eyes from 13+/-1.8 to 20.0+/-2.8 mmHg at four weeks and 17+/-2.2 mmHg at eight weeks. RGC loss was 15.6+/-3.4% at two weeks and 27.3+/-4.5% at four weeks after laser photocoagulation. TUNEL staining and caspase-3 positive cells were increased in the ganglion cell layer (GCL) in the treated eyes and seldom found in the control eyes. Bcl-2 expression in control group was higher than in the experimental group, while Bax expression in the control group was less than in experimental group. This mouse model resulted in a consistent, sustained increase in IOP with a reduction in the number of RGCs in the treated eye. The RGCs in eyes with elevated IOP were TUNEL-positive, with increased caspase-3 and decreased Bcl-2, consistent with apoptosis as the mechanism of neuronal cell death.

Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential neuroprotective effects of beta-blockers.

The objective of this study was to examine the effects of hypoxia, glutamate, and beta-blockers on the electrical activities of retinal ganglion cells. Single-unit extracellular and whole-cell voltage clamp recording techniques were used to record electrical activities from ganglion cells in the tiger salamander retina. This was performed under physiologic conditions, hypoxia, or elevated exogenous or endogenous glutamate levels. Light-evoked spike activities, glutamate-induced currents, and voltage-gated sodium and calcium currents were measured in the presence of the beta-1 selective antagonist betaxolol or the nonselective antagonist timolol. Hypoxia resulted in suppressing or blocking the OFF responses in the majority of ON-OFF ganglion cells tested, whereas the ON responses were only slightly affected. The presence of increased glutamate had similar findings and demonstrated an increase in the spontaneous firing rate of retinal ganglion cells. Betaxolol (2-50 microM) reduced the rate of spontaneous firing of retinal ganglion cells induced by glutamate. At 2 to 50 microM, betaxolol reversibly reduced the voltage-gated sodium currents and calcium currents in retinal ganglion cells. Timolol (up to 100 microM) did not demonstrate any detectable action on these currents. The physiologic responses of retinal ganglion cells to hypoxia or elevated glutamate levels in this animal model appear to be very similar. Although short-term exposure to hypoxia and glutamate used in this study exerts reversible actions on ganglion cells and does not induce permanent cell damage, such initial physiologic actions are likely to be precursors of permanent cell damage. Thus, hypoxia and elevated glutamate levels in the retina may represent a final pathway in diseases affecting retinal ganglion cells, such as glaucoma. Similar damage could result from different factors, such as decreased perfusion-induced ischemia or anomalous neuronal processing of glutamate. Betaxolol exerts its primary neuronal actions on retinal ganglion cells. It reversibly blocked voltage-gated calcium current and reduced the spontaneous firing rate by suppressing glutamate-gated currents and sodium currents in ganglion cells. These actions may protect ganglion cells from damage caused by ischemia or elevated glutamate levels.

The Use of Dorzolamide and Pilocarpine as Adjunctive Therapy to Timolol in Patients with Elevated Intraocular Pressure

PURPOSE To report the results of two studies on the use of dorzolamide as adjunctive therapy to timolol in patients with elevated intraocular pressure (IOP). In the larger study, the additive effect of dorzolamide administered twice daily also was compared with 2% pilocarpine. METHODS Both studies were parallel, randomized, double-masked, placebo-controlled comparisons. In the pilot study, 32 patients received 0.5% timolol twice daily plus either 2% dorzolamide twice daily or placebo twice daily for 8 days. In the Pilocarpine Comparison Study, 261 patients received 0.5% timolol twice daily plus 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, 2% pilocarpine four times daily, or placebo (twice daily or 4 times daily) for 2 weeks. Patients then entered a 6-month extension period and received 0.5% timolol twice daily plus either 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, or 2% pilocarpine four times daily. RESULTS In the pilot study, after 8 days, additional mean percent reductions in IOP for 2% dorzolamide and placebo were 17% and 3% at morning trough and 19% and 2% at peak, respectively. In the Pilocarpine Comparison Study, after 6 months, additional mean percent reductions in IOP (morning trough) were 9%, 13%, and 10% for 0.7% dorzolamide, 2% dorzolamide, and 2% pilocarpine, respectively. Patients receiving 2% pilocarpine had the highest rate of discontinuation due to a clinical adverse experience, and the use of dorzolamide was not associated with systemic side effects commonly observed with the use of oral carbonic anhydrase inhibitors. CONCLUSION Dorzolamide twice daily was effective and well tolerated by the patients in these studies as adjunctive therapy to timolol. The larger study demonstrated that both concentrations of dorzolamide produce similar IOP-lowering effects to 2% pilocarpine.

Contralateral effect of topical β-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study

PURPOSE To evaluate the magnitude of the contralateral effect of topically administered beta-blockers on intraocular pressure. METHODS The Ocular Hypertension Treatment Study enrolled 1,636 subjects. Of these, 817 subjects were randomized to receive topical ocular hypotensive medication and 819 subjects were randomized to close observation (i.e., no topical medication). We compared the intraocular pressure of the contralateral eye of subjects at the baseline visit and after an initial one-eyed therapeutic trial of topical beta-blockers. We examined differences between baseline and follow-up intraocular pressure in untreated eyes of subjects randomized to close observation. RESULTS The mean reduction in intraocular pressure in the beta-blocker-treated eyes was -5.9 +/- 3. 4 mm Hg (-22% +/- 12%; Student t test, P <.0001). In the contralateral eyes, mean intraocular pressure reduction was -1.5 +/- 3.0 mm Hg (-5.8% +/- 12%; P <.0001). Of the contralateral eyes, 35% showed a reduction of 3 mm Hg or more, and 10% showed a reduction of 6 mm Hg or more. The contralateral effect of the relatively selective beta-blocker betaxolol did not differ from that of any of the nonselective beta-blockers. Factors associated with the magnitude of the contralateral effect were the degree of intraocular pressure reduction in the treated eye and baseline intraocular pressure of the contralateral eye. In the close observation group, no significant reduction in intraocular pressure was noted between the baseline and follow-up visit. CONCLUSIONS The contralateral effect is important in clinical practice and in clinical trials when the hypotensive effect of a topical beta-blocker is evaluated by means of a one-eyed therapeutic trial.

Risk factors for the development of Tenon's capsule cysts after trabeculectomy

Tenons capsule cysts (TCCs) are a complication of glaucoma filtering surgery. They are frequently associated with substantial elevations in intraocular pressure (IOP) beginning 2 to 8 weeks postoperatively. To determine the incidence and possible risk factors for the development of TCCs, case records of all patients who received trabeculectomy over a 4-year period at the Wills Eye Hospital were reviewed. The incidence of TCCs was 28% in those who underwent trabeculectomy. Characteristics of patients after trabeculectomy in whom TCCs developed were compared with patients after trabeculectomy in whom TCCs did not develop. Both univariate and multivariate techniques were used to assess the association of characteristics associated with the development of TCCs. Factors associated with increased risk (P less than 0.05) were: history of prior TCCs, argon laser trabeculoplasty, male gender, and the use of preoperative sympathomimetics. The use of a compression shell was associated with decreased risk (P less than 0.05).

Elevated Intraocular Pressure Causes Inner Retinal Dysfunction Before Cell Loss in a Mouse Model of Experimental Glaucoma

PURPOSE We assessed the relationship among intraocular pressure (IOP), histology, and retinal function changes in a mouse model of induced, chronic, mild ocular hypertension. METHODS IOP was elevated experimentally via anterior chamber injection of polystyrene beads and measured twice weekly with a rebound tonometer. Histology was assessed with a combination of neurobiotin (NB) retrograde labeling of retinal ganglion cells (RGCs) and TO-PRO3 staining. Retinal function was assessed with serial dark-adapted electroretinograms (ERGs) optimized for detection of the a-wave, b-wave, and positive and negative scotopic threshold responses (pSTR, nSTR). Comparisons between bead-injected and saline-injected (control) eyes were conducted. RESULTS IOP remained elevated for at least 3 months following a single injection of polystyrene beads. Elevated IOP resulted in a mild, progressive reduction of RGCs, and a mild increase in axial length at 6 and 12 weeks after bead injection. The raw b-wave amplitude was increased shortly after IOP elevation, but the raw a-wave, pSTR, and nSTR amplitudes were unchanged. pSTR and nSTR amplitudes were normalized to the increased b-wave. With this normalization, the pSTR amplitude was decreased shortly after IOP elevation. CONCLUSIONS Polystyrene bead injection results in a mild, chronic elevation of IOP that recapitulates several critical aspects of human ocular hypertension and glaucoma, and results in early changes in retinal electrical function that precede histologic changes. It is possible that glaucoma associated with elevated IOP involves the early disruption of a complex combination of retinal synapses.

Duration of IOP reduction with travoprost BAK-free solution.

PurposeTo compare the duration of action of travoprost ophthalmic solution 0.004% (Travatan® Z)™ formulated without benzalkonium chloride (BAK) to travoprost ophthalmic solution 0.004% formulated with BAK (Travatan®). MethodsThis was a prospective, randomized, double-masked study. Patients with open-angle glaucoma or ocular hypertension were randomized to receive 2 weeks of once-daily therapy with travoprost BAK-free or travoprost with BAK. Patients received the last dose of medication on day 13 and then intraocular pressure (IOP) was assessed every 12 hours for 60 hours. Statistical analysis included change in IOP from baseline for each group and comparison of mean IOP between groups. ResultsOf the 109 patients enrolled, 106 patients completed the study. Untreated mean baseline IOP at 8 AM was 26.9 mm Hg in the travoprost BAK-free group and 27.1 mm Hg in the travoprost with BAK group. At 12, 24, 36, 48, and 60 hours after the last dose, mean IOP in the travoprost BAK-free group was 18.7, 17.2, 19.5, 18.7, and 20.8 mm Hg, respectively; whereas mean IOP in the travoprost with BAK group was 18.5, 16.8, 19.7, 18.0, and 20.8 mm Hg, respectively. Mean IOP at all time points after the last dose of medication was >6 mm Hg lower than the 8 AM baseline in both groups. Between-group differences were within ±0.6 mm Hg at all postdose time points. There were no statistically significant differences between the 2 treatment groups at baseline or at any postdose time point. Drug-related side effects were uncommon, mild in intensity, and comparable between groups. ConclusionsTravoprost without BAK has similar IOP-lowering efficacy and safety compared with travoprost preserved with BAK. Both formulations of travoprost have a prolonged duration of action, with statistically and clinically significant reductions from baseline persisting up to 60 hours after the last dose.

Surgical Therapy of Chronic Glaucoma in Aphakia and Pseudophakia

Most glaucoma surgical procedures are less successful in aphakic or pseudophakic eyes. The authors reviewed 91 consecutive initial glaucoma procedures in aphakic patients from 1979 to 1986 to determine successful outcomes and complications. Success was defined as an intraocular pressure (IOP) of at least 30% below the preoperative value and less than 21 mmHg, less than 2 lines of Snellen acuity loss, and no further surgical intervention. At 9 months, success rates were: trabeculectomy, 4 of 15 patients; cyclodialysis, 3 of 20 patients; neodymium:YAG (Nd:YAG) cyclophotocoagulation, 1 of 8 patients; cyclocryotherapy, 9 of 22 patients; anterior chamber tube shunt (Schocket procedure), 3 of 6 patients; and argon laser trabeculoplasty, 2 of 20 patients. Severe complications included phthisis bulbi in 11% of cyclocryotherapy and severe visual loss in 20% with cyclodialysis and 14% with cyclocryotherapy. Results confirm the difficulty of surgical therapy in these patients.

Intraoperative application of 5-fluorouracil during trabeculectomy.

We report the preliminary results of the first 20 consecutive cases in which the antimetabolite 5-fluorouracil (5-FU) was applied directly beneath the conjunctival flap during trabeculectomy in high-risk patients. Seventeen were considered early successes, with 3-month postoperative intraocular pressures less than 21 mmHg, representing at least a 20% decrease from preoperative values. Successful blebs were pale, with conjunctival microcysts and without significant vascularization over the trabeculectomy site, similar to the appearance of blebs in eyes administered postoperative subconjunctival injections of 5-FU. There were no cases of corneal epithelial defects, and no eyes had lost more than one line of preoperative vision at the time of last follow up. Although the longer term efficacy of this method is unknown, these results suggest that it may represent a safe and effective alternative for administering 5-FU.