[Surgical management of orbital malignant melanoma: our experience and a report of three cases]. / Chirurgische Behandlung des malignen Orbita-Melanoms: unsere Erfahrung und ein Bericht über drei Fälle.

PURPOSE: The aim of this study is to illustrate our personal experience concerning the diagnostic and therapeutic management of primary and secondary orbital melanomas. PATIENTS AND METHODS: Nine patients (five men and four women) with a histological diagnosis of orbital malignant melanoma were surgically treated in our department during the last 10 years (1995 - 2005). RESULTS: All the patients had a unilateral orbital malignant melanoma. A primary tumour was diagnosed in one case. There was metastatic orbital localisation of a cutaneous malignant melanoma in two cases. In six cases, a secondary melanoma originated from the uveal tract (three cases), conjunctiva (two cases), or paranasal sinuses (one case). All the patients underwent surgical treatment of the tumour (exenteration in 5 cases; subtotal exenteration in one case; subtotal excision in two cases; and craniofacial resection in one case) combined with immunotherapy in one case. The median age at surgery was 66 years, with a mean postoperative follow-up of 17 +/- 14 months. Four patients died of widespread dissemination of the melanoma after a mean time of 13 +/- 7 months. Two more patients died of causes other than melanoma. Three patients were still living at 9, 33 and 45 months after surgery. None of the patients presented with a local relapse of the melanoma during follow-up. CONCLUSION: Although different approaches have been proposed, the prognosis of orbital melanoma remains poor. In our experience too, the patients with longest survival were those whose tumours were exenterated.

Effect of brimonidine on intraocular pressure in normal tension glaucoma: a short term clinical trial.

PURPOSE: To evaluate the efficacy and safety of 0.2% brimonidine eye drops given twice daily in normal tension glaucoma. PATIENTS AND METHODS: Sixteen consecutive patients fulfilling eligibility criteria (glaucomatous optic neuropathy associated with visual field defect in at least one eye, intraocular pressure (IOP) < or = 18 mmHg (average of the two highest readings of the round-the-clock curve, including one reading at midnight in supine position), no prior glaucoma therapy, angle wide open, visual acuity 20/40 or better) were enrolled in this prospective, randomized, placebo-controlled clinical trial with crossover design, lasting 30 days for each treatment phase plus 15-day washout in between. Main outcome was IOP (average of the two highest readings of the round-the-clock curve). RESULTS: Mean IOP was significantly reduced by brimonidine (from 17.1 +/- 0.7 mm Hg to 13.9 +/- 2.2 mmHg, p<0.001 (paired Student t-test)). At the end of the 30-day brimonidine phase, 4 of 16 subjects showed a > or = 30% IOP decrease over baseline. CONCLUSIONS: In the short term, 0.2% brimonidine eye drops can induce a significant IOP decrease in eyes with normal tension glaucoma.

Beta-adrenergic antagonists in the treatment of glaucoma.

PURPOSE: Beta-blockers have been used since the late 1970's as 'first-choice' in the treatment for glaucoma. Since the introduction of new molecules in clinical routine, the current role of beta-blockers in glaucoma therapy has been rediscussed. In particular, concerns have been raised regarding their actual safety profile. METHODS: This review will focus on the latest advances on the efficacy and safety profiles of non-selective beta-blockers. CONCLUSIONS: The data provided will help to trace a more appropriate role for beta-blockers in glaucoma therapy.

Correlation between optical coherence tomography, pattern electroretinogram, and visual evoked potentials in open-angle glaucoma patients.

OBJECTIVE: [corrected] To correlate the nerve fiber layer (NFL) thickness and the visual function evaluated by electrophysiologic retinal and cortical responses assessed in open-angle glaucoma (OAG) eyes. DESIGN: Prospective case-control study. PARTICIPANTS: Thirty glaucoma patients (mean age, 47.1 +/- 7.15 years; refractive error range, +/- 2 spherical equivalent) with a mean deviation of computerized static perimetry (24/2 Humphrey, Dublin, CA) from -5 to -28 dB and intraocular pressure less than 21 mmHg on pharmacologic treatment and 14 age-matched control participants. METHODS: Nerve fiber layer thickness was measured by optical coherence tomography. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli (the single check edges subtend 15 minutes of the visual arc) reversed at the rate of two reversals per second. Linear regression analyses were adopted to establish the correlation between NFL thickness and PERG and VEP parameters. MAIN OUTCOME MEASURES: Nerve fiber layer thickness measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and then averaged (12 values averaged) and identified as NFL overall, whereas the data obtained in the temporal quadrant only (three values averaged) were identified as NFL temporal. PERG P50 implicit time and P50-N95 amplitude and VEP P100 implicit time and N75-P100 amplitude were also measured. RESULTS: In OAG eyes, we found a significant (P < 0.01) reduction in NFL thickness in both NFL overall and NFL temporal evaluations with respect to the values observed in control eyes. PERG and VEP parameters showed a significant (P < 0.01) delay in implicit time and a reduction in peak-to-peak amplitude. In OAG eyes, the NFL overall and NFL temporal values were significantly correlated (P < 0.01) with the PERG P50 implicit time and P50-95 peak-to-peak amplitude. No correlations (P > 0.01) between NFL values and VEP parameters were found. CONCLUSIONS: There is a correlation between PERG changes and NFL thickness, but there is no correlation between VEP changes and NFL thickness in patients affected by OAG.

Visual function correlates with nerve fiber layer thickness in eyes affected by ocular hypertension.

PURPOSE: To test whether the high variability observed when measuring pattern electroretinogram (PERG), visual evoked potentials (VEP), and spatial contrast sensitivity (SCS) in eyes with ocular hypertension is associated with variation in nerve fiber layer thickness, as measured by optical coherence tomography (OCT). METHODS: The study involved 32 untreated eyes (32 patients; age range, 29-64 years) showing a normal whiteon-white 24/2 Humphrey (San Leandro, CA) perimetry, IOP between 23 and 28 mm Hg, best corrected acuity of 20/20 or better, and none of the following papillary signs on conventional color stereo slides: rim notch(es), peripapillary splinter hemorrhages, or increased vertical-to-horizontal cup-to-disc ratio. On recruitment, each eye underwent SCS testing, OCT, PERG, and VEP recordings. Linear regression (Pearson's test) or Spearman's rank regression was adopted for the analysis of the data. RESULTS: The 95% confidence limits of the electrophysiological data were: PERG P50 latency, 59.3 to 63 msec; PERG P50 to N95 amplitude, 0.74 to 1.15 cmV; VEP P100 latency, 113 to 118 msec; VEP N75 to P100 amplitude, 3.81 to 4.90 micromV. The 360 degrees nerve fiber layer thickness overall (NFLO) ranged between 113 and 169 microm (145+/-16 microm; mean+/-SD) and significantly correlated with PERG P50 to N95 amplitude (r: 0.518; P = 0.002), PERG P50 latency (r: -0.470; P = 0.007), VEP N75 to P100 amplitude (r: 0.460; P = 0.008), VEP P100 latency (r = -0.422; P = 0.016) and SCS at 3 cyc/deg (r: -0.358; P = 0.044). CONCLUSIONS: The variability of PERG, VEP, and SCS testing observed in eyes with ocular hypertension is associated with differences in NFL thickness (the thinner the layer, the worse the visual function).

Self-assessment of the quality of vision: association of questionnaire score with objective clinical tests.

PURPOSE: To investigate the association of a quality of life-visual function questionnaire with an objective clinical test of visual function. METHODS: We have developed a questionnaire to assess self-reported visual satisfaction in ophthalmic patients suffering from chronic eye conditions causing visual impairment. The questionnaire was administered to 120 patients suffering from age-related cataract, chronic open angle glaucoma, age-related macular degeneration, branch retinal vein occlusion, and presbyopia or minor refractive defects. All the participants also underwent determination of visual acuity, contrast sensitivity, glare, and visual field. RESULTS: The questionnaire has a good reproducibility, a high internal consistency, and is able to discriminate between the different groups of patients. The total questionnaire score is significantly associated with the results of all visual function tests with the exception of glare. When entered into a multiple linear regression model, near visual acuity and contrast sensitivity are still considerably associated with the total questionnaire score. The psychological attitude of the patient towards his/her health problem is also associated with the total average score. CONCLUSIONS: Overall, the model explains 49% of the variance in the average questionnaire score.

5-fluorouracil in combined trabeculectomy and clear-cornea phacoemulsification with posterior chamber intraocular lens implantation. A one-year randomized, controlled clinical trial.

PURPOSE: To test the effect of postoperative subconjunctival 5-fluorouracil (5-FU) on the pressure outcome in combined procedure (limbus-based trabeculectomy + clear-cornea phacoemulsification). METHODS: Prospective randomized, controlled clinical trial; n = 24 eyes (24 patients) with concurrent open-angle glaucoma and cataract; 12 eyes per treatment group; sample size adjusted for a minimal expected difference in the event rate between the 2 treatment groups = 50%, control rate = 20%; type I error = 0.05; power = 95%. Uncomplicated limbus-based trabeculectomy + uncomplicated clear-cornea phacoemulsification + posterior chamber intraocular lens. The 5-FU group = five subconjunctival injections of 5 mg 5-FU, starting from day 8 after surgery, one injection per week. Control group = no injections. The groups were matched for age, preoperative intraocular pressure (IOP), duration of preoperative antiglaucoma treatment, preoperative pilocarpine and adrenergics, preoperative laser trabeculoplasty, and beta-blockers in the fellow eye. The IOP less than or equal to 15 mmHg without treatment 1 year after surgery (IOP = average of the two highest values measured in the diurnal curve, 8 AM to 6 PM, one reading every 2 hours). RESULTS: Each patient completed a 1-year follow-up. Ten of 12 eyes of the 5-FU group showed an IOP less than or equal to 15 mmHg at the end of follow-up versus 1 of 12 eyes in the control group (Fisher's exact test, P = 0.00064). The IOP range was 10 to 17 mmHg in the 5-FU group and 14 to 22 mmHg in the control group. CONCLUSION: Postoperative 5-FU may improve the 1-year success rate of trabeculectomy combined with clear-cornea phacoemulsification.

Effect of a YAG laser iridotomy on intraocular pressure in pigment dispersion syndrome.

PURPOSE: To determine whether an iridotomy can prevent an increase in intraocular pressure (IOP) in patients with pigment dispersion syndrome. METHODS: Consecutive subjects (n = 21) recruited into this randomized, controlled clinical trial in a hospital-based outpatient referral center, had pigment dispersion syndrome in both eyes, and underwent a YAG laser iridotomy in one eye (randomly chosen); no intervention was performed in the fellow eye. A significant elevation of IOP was arbitrarily defined as an increase of more than 5 mmHg. RESULTS: Eleven (52.3%) untreated eyes versus 1 (4.7%) treated eye showed a significant elevation of IOP during the 2-year follow-up. The IOP difference between the untreated and the fellow treated eye at the end of the 2-year follow-up period is inversely related to the age of each patient. CONCLUSION: YAG laser iridotomy may reduce the incidence of ocular hypertension in eyes affected by pigment dispersion syndrome. This effect, being less pronounced after 40 years of age, may be of clinical relevance in young subjects.

Serial administration of adrenergic antagonist and agonist ("pulsatile therapy") reduces the incidence of long-term drift to timolol in humans.

PURPOSE: To test whether the incidence of long-term drift to timolol can be reduced by a "pulsatile" treatment (6 months timolol-2 months dipivefrin). METHODS: In a randomized clinical trial, 100 consecutive subjects with ocular hypertension or high-tension primary open-angle glaucoma in at least one eye were randomly assigned to either group A, which was administered timolol 0.5% twice a day (b.i.d.), or to group B, which was administered timolol 0.5% b.i.d. (6 months) alternated with 0.1% dipivefrin b.i.d. (2 months). Diurnal intraocular pressure (IOP) was measured at recruitment, 1 month later during timolol administration ("reference value"), and every 6 months in group A or at the end of each pulse in group B. In bilateral cases, the right eye only was considered for the analysis. Length of follow-up was 54 months. Long-term drift was diagnosed if the IOP on timolol increased by at least 5 mm Hg over the reference value and was followed by a 5 mm Hg in the study eye without detectable drift to the beta-blocker. The actual 54-month incidence of long-term drift was 45% (21/46) in group A versus 7% (3/43) in group B (P<0.01). In group B, IOP was always higher during dipivefrin pulse than on timolol (paired samples t-test, P<0.01). However, dipivefrin proved more effective through follow-up; IOP was 21.1+/-1.2 mm Hg at month 8 (first "pulse") and 18.6+/-0.95 mm Hg at month 48 (last "pulse") (paired samples t-test, P<0.01). CONCLUSIONS: Serial administration of adrenergic antagonist and agonist can reduce the incidence of long-term drift to the beta-blockade in ocular hypertension and primary open angle glaucoma.

Decrease of intraocular pressure after subconjunctival injection of mitomycin in human glaucoma.

OBJECTIVE: To investigate the effects of a subconjunctival injection of mitomycin on the intraocular pressure in human eyes affected by glaucoma. DESIGN: Consecutive case series, prospective study, intraocular pairwise comparison (paired samples Student's t test adopted). SETTING: Hospital-based glaucoma clinic. PATIENTS: Twelve consecutive patients with bilateral glaucoma and monolateral blindness, intraocular pressure greater than 30 mm Hg in the blind eye (mean of the two highest values of the diurnal curve, confirmed at 96-hour interval), and no previous bulbar surgery. INTERVENTION: Subconjunctival injection of 0.5 mL of 0.2% mitomycin in the upper temporal quadrant, preceded and followed by treatment with topical indomethacin. MAIN OUTCOME MEASURE: Analysis of the variance of the mean intraocular pressure before and after the injection of mitomycin in each eligible eye. RESULTS: An intraocular pressure decrease was observed in each eligible eye the day after the treatment (mean [+/- SD] decrease, 7.15 +/- 1.46 mm Hg). The effect was still detectable at the end of the 60 days of follow-up (mean [+/- SD] decrease, 5.67 +/- 1.61 mm Hg). No change of intraocular pressure, in the meantime, was observed in the fellow eye. CONCLUSIONS: Topically applied mitomycin induces a decrease of intraocular pressure in human glaucomatous eyes. Our data confirm previous results obtained in albino rabbits and support the hypothesis that mitomycin exerts a still unknown direct effect on aqueous humor dynamics in the eye.

Improvement of visual field indices after surgical reduction of intraocular pressure.

In a prospective case series (consecutive patients) of 30 eyes from 30 subjects with medically uncontrolled glaucoma being treated at a hospital-based, referral glaucoma service, we sought to ascertain if a surgically obtained reduction of intraocular pressure (IOP) in human glaucomatous eyes is paralleled by an improvement of the visual field. Uncomplicated limbus-based trabeculectomy was performed in 13 men and 17 women familiar with computerized perimetry testing, with a pupil diameter of at least 4 mm (measured at the Goldmann perimeter bowl), a best-corrected visual acuity of 20/20 in both eyes, and a Mean Sensitivity (MS) index greater than 10 dB. The main outcomes measured were: visual field data (Octopus, program G1) and IOP (mean of the two highest values during the diurnal curve) obtained 3 days before and 3 months after surgery in both the operated and the fellow eyes. In the operated eyes, an increase of MS (from 17.2 +/- 2.4 to 18.9 +/- 2.8, P < .000001, paired samples two-tailed t test) was observed. Meanwhile, the Corrected Loss Variance (CLV) remained substantially the same (46.8 +/- 12.2 before, vs 47.3 +/- 13.4 after; P = .87, paired samples two-tailed t test). The increase in MS was positively correlated with the amount of IOP reduction (linear regression: r = 0.901, P < .00001). No statistically significant change of either MS or CLV values occurred in the fellow eyes. The correlation between the amount of IOP reduction and the increased MS suggests that, in the short term, reducing the IOP may improve visual function to some extent. The apparent lack of correlation between the amount of IOP reduction and the CLV may indicate that the depth of the preexistent glaucomatous scotomas remains unchanged.

Calmodulin antagonists induce changes in lens permeability and transparency.

Calmodulin has been shown to perform several important functions in the lens including regulation of the plasma membrane Ca(2+)-ATPase. This study investigated the effects of a variety of different CaM antagonists on rat lens membrane potential, membrane resistance, intracellular Na+ and Ca2+ content and transparency, in order to examine the role of CaM in control of lens membrane permeability. W7, calmidazolium and trifluoperazine caused biphasic changes in lens membrane electrical characteristics. Phase 1 consisted of a depolarization of the membrane potential and an increase in resistance, indicating that K+ channels were being blocked. This was confirmed by application of the K+ channel antagonist, quinine, which inhibited Phase 1 changes. Phase 2 was a further depolarization coupled with a decrease in resistance, indicating the activation of a cation conductance. Application of W7 in low Na+ medium slowed the Phase 2 depolarization and decrease in resistance indicating that Na+ is the main charge carrier through the activated conductance. The CaM inhibitors also led to a large increase in the Na+ and Ca2+ contents of the lens. W5, a less potent analogue of W7, caused a depolarization and increase in membrane resistance, but no Phase 2 changes were observed. Na+ and Ca2+ contents were similar to control lenses after 4 hours incubation in 200 microM W5. In addition, exposure to W7, TFP and calmidazolium resulted in a loss of transparency, while W5 treated lenses remained clear. It appears, therefore, that CaM is involved in control of lens membrane permeability. Loss of control of these channels leads to catastrophic changes in the intracellular ionic environment and hence opacification of the lens.

Lens sodium channels are inactivated by anti-MIP26 antibodies.

Sodium-specific channels can be functionally identified in phosphatidylcholine liposomes incorporating detergent-solubilized membrane proteins from pig lens epithelium and outer cortex. The transport of sodium is saturable, specific and protease-sensitive. MIP26 was identified in the solubilized membrane fraction and in the liposomes by means of Western blot analysis. Pre-treatment of liposomes with anti-MIP26 antiserum abolished the transport of sodium. These data indicate that MIP26 is associated to a sodium selective transport activity.

Evidence for a Na(+)-Cl(-)-H(+)-HCO3- exchange system in the mammalian lens.

36Cl- efflux was studied in the isolated rat lens under two conditions that are known to decrease internal pH. The first follows exposure to a pulse of ammonium chloride (50 mM) and the second accompanies exposure to an acidified propionate (20 mM) solution. Under acidifying conditions, a stimulation in 36Cl- efflux was observed, that was abolished on removing external Na+ and also on removing external Cl- and HCO3-. In the absence of external Cl-, the presence of HCO3- (16 mM) resulted in an increase in 36Cl- efflux during internal acidification. In the absence of internal acidification, the addition of 0.1 mM dibutyrylcAMP or 0.5 mM IBMX to the external medium produced a rapid increase in 36Cl- efflux. This stimulation was reduced by 0.2 mM SITS. Neither cAMP or IBMX had any significant effect on the electrical resistance of the lens membranes. It is suggested that a coupled SITS-sensitive, Na(+)-Cl(-)-H(+)-HCO3- exchange mechanism is activated when the lens internal pH falls and further that cAMP may play a role in regulating this mechanism.

Low-molecular-weight sodium hyaluronate in the treatment of bacterial corneal ulcers.

A double-blind clinical trial was performed on 26 patients suffering from corneal ulcers of proven (i.e., culture-positive) bacterial etiology. After their recruitment, the subjects were randomly assigned to one of the following treatment protocols: (1) tobramycin (15 mg/ml) in saline applied at 1 drop/h or (2) tobramycin (15 mg/ml) in low-molecular-weight hyaluronic acid applied at 1 drop/h. The sample size was adjusted according to a type I error of 0.01 and type a II error of 0.05 for a minimal expected difference of 35%. The healing time was calculated from the beginning of treatment to the day on which a follow-up fluorescein test proved to be negative. The mean healing time (+/- SD) was 3.5 +/- 0.9 days in the sodium hyaluronate group and 5.9 +/- 1.5 days in the saline group (P less than 0.001). These results suggest that treatment with an antibiotic dissolved in low-molecular-weight sodium hyaluronate can further shorten the clinical course of a bacterial corneal ulcer.

Increased ion traffic through non-specific cation pathways in the ageing human lens. Evidence from radiotracer fluxes studies.

86Rb efflux studies were carried out on normal human lenses in vitro. The data confirmed previous studies showing that 86Rb efflux increases with age. Removal of Ca2+ from the lens perifusate increased 86Rb efflux at all ages. The fractional increase above baseline was highest in the younger lenses, while the net increase of the 86Rb efflux induced by a Ca(2+)-free medium increased with age. This study supports the idea that Ca(2+)-sensitive, non-specific cation channels are present in the human lens and that their contribution to membrane permeability increases as the lens ages.

Mammalian lens inter-fiber resistance is modulated by calcium and calmodulin.

The relationship between Ca2+ and lens fiber cell communication was investigated in the isolated intact rat lens by using radiotracer and electrophysiological techniques. The lens internal calcium was increased by adding the SH oxidant diamide (1 mM), by incubating in a sodium-free (n-methylglucamine) solution or by increasing external calcium from 1 to 10 mM. A 12 hours incubation in diamide produced a ten-fold increase in 45Ca uptake into the lens which was accompanied by a ten-fold increase in internal resistance. Incubation in Na-free solution or in 10 mM Ca2+ both produced a 5-fold increase in 45Ca content, while the increase in internal resistance was five and six fold respectively. This uncoupling was prevented in the diamide and Na-free treated lenses by omitting Ca2+ from the incubation medium. Fiber cell uncoupling was noticed in each of these experimental conditions after approximately 5 hours incubation, and good recovery was obtained in the high calcium solution if the stress was removed. The calmodulin antagonists calmidazolium (3 microM) and W7 (100 microM) both prevented uncoupling in the high calcium solution, provided there was a 2 hours preincubation period in calcium-free solution containing antagonist before the stress was applied. These data indicate that lens fiber cell communication is required by Ca2+ and calmodulin.

Restoring sensitivity to timolol after long-term drift in primary open-angle glaucoma.

In a prospective randomized single-masked study lasting 6 months, 39 eyes with primary open-angle glaucoma showing a long-term drift with 0.5% timolol were put on a "timolol holiday" lasting 30 or 60 days. Twenty-three of them were enrolled with dipivefrin 0.1% twice daily during the holiday. When timolol therapy was restored, the dipivefrin-treated group showed a more pronounced decrease of intraocular pressure (IOP) (8.2 +/- 1.5), whereas the IOP decrease in the nondipivefrin-treated group was lower (3.9 +/- 1.2) and of shorter duration (less than 60 days). Among the dipivefrin-treated group, the response to timolol was more prolonged in the eyes treated for 60 days: the IOP of these eyes was less than 23 mmHg throughout the follow-up.

Human lens membrane cation permeability increases with age.

Parallel studies of the ionic balance and membrane permeability characteristics of normal human lenses were carried out in three countries (USA, England and Italy). Similar age-related changes were found in each laboratory. The lens membrane potential and resistance declined markedly with age while internal Na+ and free Ca2+ increased. There was a concomitant stimulation of Na+ and K+ transmembrane fluxes. These data indicate that in the ageing process there is an increasing contribution to membrane ion traffic from a channel, or channels, that permit Na+, K+ and Ca2+ to pass. The increase in permeability coincides exactly with the increase in optical density that occurs in the ageing human lens.