Massimo G. Bucci

Vernal keratoconjunctivitis revisited: A case series of 195 patients with long-term followup

OBJECTIVE This study aimed at revisiting vernal keratoconjunctivitis (VKC) on the basis of anamnestic, clinical, immunologic, histopathologic, and followup data of 195 patients. DESIGN Retrospective noncomparative case series. PARTICIPANTS One hundred and ninety-five patients with VKC. METHODS Clinical evaluation and outcome in 151 of 195 patients with a median followup of 47 months. Evaluation was by telephone survey in 69 patients. MAIN OUTCOME MEASURES (1) Demographic, clinical, and immunologic features of VKC and their influence on the course of the disease; (2) conjunctival and corneal complications and efficacy of treatment observed during the followup period. RESULTS VKC is a chronic disease. More than 60% of patients had repeated recurrences all year round. Males had an earlier presentation of symptoms than females and the male/female ratio decreased with age. Major (greater than 80%) and minor (up to 80%) diagnostic criteria were defined for clinical signs and symptoms of the disease. Negative skin test or radioallergosorbent test was present in approximately 50% of patients, whereas eosinophil infiltration was a constant histopathologic finding. A marked conjunctival sensitivity to nonspecific stimuli was noted in more than one third of patients. In 6% of cases, a reduction of visual acuity resulted from corneal scarring, and in 2% of patients, steroid-induced glaucoma was observed. The large size of giant papillae indicates poor prognosis for the persistence of the disease and its evolution into a chronic, perennial condition. CONCLUSIONS VKC is a chronic eosinophilic disease of the ocular surface involving IgE, non IgE-mediated mechanisms, and age-sex-related influences. Although the disease has a good prognosis, severe visual impairments may result from long-standing inflammation.

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 μg/mL) were tested on 24 rats, and the higher dose was found to be more effective. Glaucoma was then induced in an additional 36 rats: half untreated and half treated with 200 μg/mL NGF QID for 7 weeks. Apoptosis/survival of RGCs was evaluated by histological, biochemical, and molecular analysis. Three patients with advanced glaucoma underwent psychofunctional and electrofunctional tests at baseline, after 3 months of NGF eye drops, and after 3 months of follow-up. Seven weeks of elevated IOP caused RGC degeneration resulting in 40% cell death. Significantly less RGC loss was observed with NGF treatment (2,530 ± 121 vs. 1,850 ± 156 RGCs/mm2) associated with inhibition of cell death by apoptosis. Patients treated with NGF demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity. NGF exerted neuroprotective effects, inhibiting apoptosis of RGCs in animals with glaucoma. In 3 patients with advanced glaucoma, treatment with topical NGF improved all parameters of visual function. These results may open therapeutic perspectives for glaucoma and other neurodegenerative diseases.

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.

Allergen dose response and late symptoms in a human model of ocular allergy

Eleven ryegrass-sensitive patients were challenged weekly for 4 weeks with incremental doses of ryegrass allergen applied topically to one eye; a buffer was applied to the other eye. A clinical examination and tear-fluid cytology were performed before challenge and at 20 minutes, 1 hour, and 6 hours after challenge. A significant clinical reaction and neutrophil accumulation in the tear film occurred at 20 minutes. At 1 hour, a clinical response and tear cytologic reaction were present only at higher antigen concentrations. Six hours after antigen challenge, only the highest allergen concentration (320,000 BU/ml) produced a clinical late-phase reaction (LPR) (p less than 0.01) and tear cytologic change (presence of eosinophils and lymphocytes). Five nonryegrass-sensitive control subjects were unresponsive to a similar challenge. These results indicate that a conjunctival response to allergen challenge is dose dependent, that is, the higher the dose, the more likely an LPR will occur and that an LPR correlates with significant numbers of inflammatory cells in the tear film.

Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group.

PURPOSE To compare intraocular pressure (IOP) after adding either latanoprost or pilocarpine to timolol treatment or switching to latanoprost monotherapy in glaucomatous eyes in which IOP was inadequately controlled with timolol. METHODS This 6-month randomized study comprised 148 patients with primary open-angle or pseudoexfoliation glaucoma, which was inadequately controlled with topical beta-adrenergic antagonists. After a 2- to 4-week run-in period with timolol 0.5% twice daily, patients were assigned in randomized fashion to three study groups: one group received add-on therapy of latanoprost 0.005% once daily, the second group received add-on therapy of pilocarpine 2% three times daily, and the third group switched to latanoprost 0.005% once daily. Mean diurnal IOP was measured at baseline and after 3 and 6 months of treatment. RESULTS At 6 months, 128 patients had completed the study. Diurnal IOP was significantly reduced from baseline in all groups. Adding latanoprost to timolol treatment reduced diurnal IOP by 6.1+/-0.3 mmHg (-28%), adding pilocarpine to timolol treatment reduced diurnal IOP by 4.2+/-0.3 mmHg (-19%), and switching from timolol to latanoprost monotherapy reduced diurnal IOP by 5.5+/-0.3 mmHg (-25%). CONCLUSION A significantly greater reduction in diurnal IOP was achieved after addition of latanoprost than after addition of pilocarpine in patients in whom IOP was not adequately controlled with timolol alone. Further, the results of this study indicate that a switch to latanoprost monotherapy can be attempted before combination treatment is initiated.

Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension

Abstract• Background: It has been shown that intravitreal injection of NGF inhibits ganglion cell degeneration after optic nerve transection and ischemic injury. The aim of our study was to investigate the presence of NGF in aqueous humor and its involvement in retinal damage during ocular hypertension. • Methods: We used an experimental model of ocular hypertension in rabbit. Before treatment and 4, 10 and 15 days after induction of hypertension, we evaluated histological retinal damage and NGF levels in aqueous humor using an immunoenzymatic assay. Polyclonal anti-NGF antibodies were injected intravitreally into one eye of each rabbit (n = 6), and the animals were killed after 4 days of hypertension. Another group of rabbits (n =12) was injected retro-ocularly with NGF and killed after 10 or 15 days of treatment for histologic evaluation of the retina. • Results: Our data show that experimental ocular hypertension in adult rabbits induces retinal damage and enhances local NGF levels. The highest NGF value was found after 4 days of intraocular hypertension; high levels persisted, though to a lesser extent, for up to 15 days. Histological examination revealed that the number of retinal ganglion cells (RGC) remained unchanged during the first 4 days but decreased at 10 days. These studies also showed that retro-ocular administration of NGF reduced RGC loss, whereas intraocular injection of NGF antibodies, which inhibited the endogenous NGF, exacerbated the retinal insult. • Conclusion: These findings demonstrate a protective effect of NGF on RGC damaged by ocular hypertension and prompt further investigations to evaluate a possible therapeutic use of NGF to retard RGC death in humans.

Conjunctival Provocation Test as a Model for the Study of Allergy and Inflammation in Humans

The clinical response after allergen challenge and immunologic mechanisms leading to tissue inflammation have been extensively studied in the skin, nose and lung of allergic subjects. The present paper reviews personal studies aimed at evaluating clinical, cellular and humoral events after administration of specific allergen to the eye. Specific conjunctival provocation tests performed in grass-sensitive patients caused persisting inflammatory changes in conjunctival scrapings and tear fluid with a significant accumulation of different inflammatory cells depending on the time of observation (neutrophils, 20 min; eosinophils, 6 h; neutrophils, eosinophils and lymphocytes, 12-24 h after provocation). Increasing the dose of allergen resulted in a dose-dependent increase in the number of inflammatory cells recruited. When high doses of allergen were used, the challenge not only induced late-phase histological changes, but also clinical symptoms 6-10 h after provocation. Several mediators of allergic inflammation, such as histamine, C3a des-Arg, leukotrienes B4 and C4, were also present and could be measured in tears after allergen challenge. Our studies represent the first evidence in humans that a late phase of allergic reaction occurs in the eye. They also suggest that the conjunctival provocation test may represent a model for the study of cells and mediators involved in the pathophysiology of allergic inflammation as well as of its pharmacologic modulation.

Conjunctival hyperresponsiveness to ocular histamaine challenge in patients with vernal conjunctivitis

We compared the conjunctival responsiveness to histamine diphosphate in patients with vernal conjunctivitis and in healthy control subjects. Fourteen asymptomatic patients with vernal conjunctivitis and 10 healthy volunteers were challenged in one eye with 10 microliters of increasing doses (0.01, 0.05, 0.5, and 1 mg/ml in phosphate-buffered saline) of histamine diphosphate. The contralateral eye was challenged with the diluent only. Photographs of each eye were taken for evaluation of conjunctival redness by two masked investigators. Both patients with vernal conjunctivitis and control subjects reacted to histamine with a dose-dependent conjunctival redness 2 to 5 minutes after ocular challenge. Conjunctival redness was more intense in patients with vernal conjunctivitis than in control subjects after ocular challenge with 0.01 and 0.05 mg/ml of histamine diphosphate solution (p less than 0.05). Moreover, the threshold concentration of histamine diphosphate, extrapolated from each individual dose-response curve, was significantly (p less than 0.02) lower in patients with vernal conjunctivitis than in control subjects. Our findings suggest that patients with vernal conjunctivitis demonstrate conjunctival hyperresponsiveness to a nonspecific challenging agent. Nonspecific conjunctival hyperreactivity, a novel concept in allergic eye disease, may be relevant for a better understanding of the pathogenesis and clinical variability of vernal conjunctivitis.

Do sex and hormonal status influence choroidal circulation

AIMS To investigate the relation between pulse amplitude (PA), pulsatile ocular blood flow (POBF), and sex and hormonal status. METHODS Measurements of POBF and PA were obtained by ocular blood flow tonography in 76 healthy subjects: 32 males and 44 females (age range 17–77 years). Females were divided into two age groups: group 1 (premenopausal) 17–42 years, and group 2 (post-menopausal) 55 years old and over. Two groups of age matched males served as controls. RESULTS Premenopausal females demonstrated a significantly higher rate of POBF and PA than age matched males and post-menopausal females. CONCLUSION Sex and hormonal status were shown to influence choroidal circulation.

The effect of increased intraocular pressure on pulsatile ocular blood flow in low tension glaucoma

In the present study the relationship between intraocular pressure (IOP) and pulsatile ocular blood flow (POBF) in low tension glaucoma (LTG) has been investigated. The POBF was measured using the Ocular Blood Flow system of Langham in undisturbed eyes and repeated at IOP increments of about 5 and 10 mmHg in 20 patients affected with bilateral LTG and in 25 healthy subjects matched for age, IOP, refractive error, arterial blood pressure and heart rate. The POBFs were 740.1 (SD 58.83) and 667 (SD 108) microliters/minute (microliter/min) in the control and LTG groups, respectively and statistically significantly different. The POBFs at an IOP increased by 5 mmHg were 658.1 (SD 60.2) and 457.3 (SD 74.8) microliter/min in the control and LTG groups, respectively; in the control group the mean POBF at an IOP increment of 10 mmHg was 552.1 microliters/min (SD 66.9), and in the LTG group was 317.7 microliters/min (SD 85.2). Statistical analysis of the data showed a significant difference of POBFs in the two groups either at an IOP increment of 5 or 10 mmHg (p < 0.0001). The substantial decrease of POBF with increased IOP in LTG eyes compared with normals shows an altered response of the vascular system in LTG. These findings are probably consistent with a lack of the myogenic autoregulation in reply to IOP-induced modifications of the perfusion pressure.