Roberto Ratiglia

Corneal Involvement in Rheumatoid Arthritis: An In Vivo Confocal Study

PURPOSE To analyze the in vivo morphology of corneal cells and nerves in patients with rheumatoid arthritis (RA), with or without secondary Sjögrens syndrome (SSII), and to investigate the correlations between corneal alterations and RA activity. METHODS Fifty patients with RA and 30 age- and gender-matched control subjects were studied. SSII was diagnosed according to the American-European Consensus Group criteria, and RA activity was evaluated by the Lansbury index (LI). Confocal microscopy was used to investigate corneal thickness, the number of epithelial and stromal cells, and keratocyte hyperreflectivity. In addition, the sub-basal plexus was assessed for the number, tortuosity, and reflectivity of the nerve fibers and the presence of beadlike formations. RESULTS Sixteen percent of patients with RA also had SSII. Between the SSII and non-SSII groups, no significant differences were found in the LI or in the clinical and confocal variables. Significant differences were present between patients with RA and control subjects for all the variables studied except nerve reflectivity. In patients with RA with and without SSII, LI correlated significantly with the number of beadlike formations and the number of hyperreflective, activated keratocytes. CONCLUSIONS Confocal microscopy of patients with RA showed several changes in corneal cells and nerves. The number of beadlike formations and the number of activated keratocytes could be interpreted as confocal signs of ocular surface disease activity. These correlations with the index of systemic disease activity, LI, may provide insight regarding the pathogenic mechanisms of dry eye in patients with RA.

Retinal angiomatous proliferation: natural history and progression of visual loss.

Purpose: To investigate the natural history and visual outcome in eyes with untreated retinal angiomatous proliferation, a neovascular form of age-related macular degeneration. Methods: Fourteen consecutive white patients (11 women, 78%; mean age, 74 years) with 16 eyes affected by retinal angiomatous proliferation were prospectively followed-up without treatment by means of complete ophthalmologic examinations at regular intervals, including best-corrected visual acuity and dynamic fluorescein and indocyanine green angiography using a scanning laser ophthalmoscope. Results: The patients were observed for a mean of 20 months (range, 6–44 months). Mean visual acuity in the eyes with retinal angiomatous proliferation was 0.48 at the initial examination, decreased to 0.23 after 6 months, and was 0.19 at the final examination, with a mean decrease of 6 lines from baseline. In 13 eyes (81%), visual acuity deteriorated by 2 Early Treatment Diabetic Retinopathy Study lines or worse by the time of the 6-month examination, and 31% of the patients had experienced severe loss of vision; the remaining 3 eyes (19%) showed a relatively stable clinical course and visual acuity. By the time of the final examination, visual acuity had decreased to 0.1 or worse in 11 eyes (69%), and 5 of the 14 patients (36%) were legally blind. At the final examination, 10 eyes (62%) showed a subretinal fibrosis and 9 (56%) showed a retinal choroidal anastomosis. Conclusion: Retinal angiomatous proliferation is a distinct form of neovascular age-related macular degeneration with high vasogenic potential, having its own clinical course and visual prognosis. The poor visual outcome is because of the exudative nature of the retinal angiomatous proliferation, and progression to poor vision is common and rapid (within 3 months in faster cases, and within 1 year in slower cases). The treatment options for this type of neovascular lesion should be planned bearing in mind its unfavorable natural history.

In Vivo Confocal Evaluation of the Ocular Surface Morpho-Functional Unit in Dry Eye

Purpose To study, by a new, integrated, laser scanning confocal microscopy approach, the ocular surface morpho-functional unit in patients with primary Sjogren syndrome (SSI), non–Sjogren syndrome dry eye (non-SSDE), and meibomian gland disease (MGD). Methods Patients and age- and sex-matched control subjects (N = 60; 15 each) were consecutively enrolled in a prospective case-control study. Laser scanning confocal microscopy was used to obtain simultaneous optical sampling of the ocular surface components: cornea, bulbar and tarsal conjunctiva, MGs, and eyelid margin. Results For all superficial epithelia, except eyelid margins, there were reduced cell densities in each group compared with that in controls (p < 0.001). The lowest cell densities were in the SSI group (p < 0.001). Eyelid margin superficial cell density was decreased only in MGD (p < 0.001). Basal epithelial cell density at the corneal apex was increased in both SSI and non-SSDE compared with that in controls (p < 0.01). In the conjunctiva, it was decreased in each group compared with that in controls (p < 0.01). Subbasal dendritic cell density was significantly increased in both SSI and MGD compared with that in controls (p < 0.01). Conjunctival inflammatory cell density and MG inflammation were increased in each group compared with those in controls (p < 0.001), with the highest values in SSI. Subbasal nerve plexi had fewer fibers and higher bead density in each group compared with those in controls (p < 0.001). There was increased tortuosity in both SSI and MGD (p < 0.001). Patients with MGD had the lowest MG acinar density, the largest diameter of acini and acinar orifices, and the highest secretion reflectivity (p < 0.001). Conclusions Laser scanning confocal microscopy can provide an in vivo, noninvasive, high-resolution overview of the ocular surface morpho-funcional unit. This confocal integrated approach may be useful in both research and clinical settings.

In Vivo Confocal Microscopy of Meibomian Glands in Contact Lens Wearers

PURPOSE To evaluate by in vivo laser scanning confocal microscopy (LSCM) the morphologic changes in the meibomian glands (MGs) and the status of periglandular inflammation in contact lens wearers (CLWs) and to investigate the correlations between clinical and confocal findings. METHODS Twenty CLWs and 20 age- and sex-matched control subjects were consecutively enrolled. Each participant completed an Ocular Surface Disease Index questionnaire and underwent a full eye examination, including tear film break-up time, fluorescein and lissamine green staining, and Schirmer test. LSCM of the MGs were performed to determine the cell density of the mucocutaneous junction epithelium, acinar unit density and diameter, glandular orifice diameters, meibum secretion reflectivity, and inhomogeneous appearance of the glandular interstice and acinar wall. RESULTS All clinical parameters showed statistically significant differences between groups (P < 0.01, Mann-Whitney U test) except the Schirmer test. Confocal data (Mann-Whitney U test) showed significantly decreased basal epithelial cell density (P < 0.01), lower acinar unit diameters (P < 0.05), higher glandular orifice diameters (P < 0.05), greater secretion reflectivity (P < 0.01), and greater inhomogeneity of the periglandular interstices (P < 0.05) in CLWs compared with controls. The duration of contact lens wear was correlated with the acinar unit diameters (P < 0.05, Spearman). CONCLUSIONS Morphologic changes in the MGs shown by LSCM were interpreted as signs of MG dropout, duct obstruction, and glandular inflammation. A comprehensive LSCM evaluation of the ocular surface in CLWs could better clarify the role of MG dropout and eyelid margin inflammation on the pathogenesis of CL-induced dry eye.

Rituximab treatment in a patient with severe thyroid-associated ophthalmopathy: Effects on orbital lymphocytic infiltrates

Rituximab (RTX) has been shown in previous work to improve thyroid-associated ophthalmopathy (TAO), but very little data is available on the effects of RTX in the target tissues. We studied the effects of RTX on peripheral lymphocytes and on the intra-orbital infiltrates in one patient with severe TAO who was treated with two cycles of therapy. Intra-orbital tissues derived at decompression from 3 patients with moderate-severe and 1 with severe TAO, treated with standard immunosuppression, were studied as controls. Peripheral blood lymphocytes were analyzed throughout the study period, while intra-orbital tissue lymphocytes at decompression. In the patient treated with RTX visual field and acuity improved in response to peripheral CD 20+ cell depletion, although there was a proportion of persisting CD 19+ cells. After RTX re-treatment the patients optic nerve function improved only transiently. The number of CD 20+ cells was lower in orbital tissues (0-1%) than in the peripheral blood (3%). A greater percentage of CD 19+ was observed in the orbits compared to the periphery, most of which were CD 19+5+ (80%). By immunohistochemistry, orbital tissues from all control patients showed CD 20+ and CD 3+ cells, independently of the duration of TAO and of the treatment with either steroids or radiotherapy. This is the first report on the therapeutic effect of RTX in active, severe TAO associated to the depletion of intra-orbital CD 20+ lymphocytes. After RTX, CD 19+5+ lymphocytes were shown to be 2-3 times more prevalent in the orbital infiltrates, compared to CD 20+ cells. Persistence of autoreactive cells is believed to be related to TAO relapse.

Small Dose of Rituximab for Graves Orbitopathy: New Insights Into the Mechanism of Action

citing role as increased levels of dopamine have been shown to cause choroidal vasodilation. The time course of effusion development in this case is similar to that with topiramate. This suggests that if bupropion use were causative, one of its major active metabolites, hydroxybupropion or theobupropion (both with half-lives similar to that of topiramate), may be responsible. Both metabolites inhibit dopamine and norepinephrine reuptake; thus, norepinephrine could also have a role. Bilateral effusions have been reported with venlafaxine hydrochloride, a norepinephrine and serotonin reuptake inhibitor. Bupropion is a common medication, and it is unclear why other cases have not been reported. If bupropion use were causative in this case, the absence of other similar reports may reflect underreporting; alternatively, this patient may harbor a rare, private polymorphism that causes bupropion or one of its metabolites to become a particularly potent choroidal vasodilator.

Choroidal granulomas visualized by enhanced depth imaging optical coherence tomography.

Purpose: To assess the visualization of choroidal granulomas (CG) by enhanced depth imaging optical coherence tomography (EDI-OCT) and to describe their EDI-OCT characteristics. Methods: Combined indocyanine green (ICG) angiography and EDI-OCT images of 44 CG (sarcoid, tubercular, or Vogt–Koyanagi–Harada related) were reviewed. By ICG angiography, CG were classified as full thickness or partial thickness and as small or large. Two independent operators evaluated EDI-OCT scans over granulomas to record their characteristics (full thickness/partial thickness, shape, reflectivity, internal pattern, margins, and shadowing/increased transmission effect). The agreement between ICG angiography and EDI-OCT, the interobserver agreement, and the correlations between EDI-OCT features and lesion size or disease were studied. Results: Enhanced depth imaging optical coherence tomography could visualize 100% of CG detected on ICG. Lesions resulted full thickness in 90.9% and 77.3% of the cases on ICG angiography and EDI-OCT, respectively (K = 0.5). All CG were more homogeneous and showed increased transmission of the optical coherence tomography signal as compared with the surrounding choroid. Choroidal granulomas angiographic size influenced lesions characteristics on EDI-OCT. Large granulomas were more likely to be full thickness, round shaped, with defined margins, lower reflective than the surrounding structures, and with internal homogenous pattern. The type of disease significantly influenced CG shape and pattern. Most of tubercular-related lesions showed lobulated shape and nonhomogeneous internal pattern. Conclusion: Enhanced depth imaging optical coherence tomography is suitable to visualize CG and to describe their characteristics. Choroidal granulomas size and disease influence lesions appearance on EDI-OCT. Increased transmission effect could be helpful for CG identification.

The Aging Meibomian Gland: An In Vivo Confocal Study

PURPOSE To evaluate age-related Meibomian gland (MG) changes by in vivo laser scanning confocal microscopy (LSCM). METHODS Asymptomatic healthy subjects (n=100, age range 20-83 years) with an Ocular Surface Disease Index score of less than 13 were consecutively enrolled. Two additional groups, one composed of subjects under 40 years of age (n=12) and one composed of subjects over 65 years (n=12), were included without inclusion or exclusion criteria. All subjects underwent a full ocular surface evaluation, and one eye of each subject was examined by LSCM to quantify the lower lid MG acinar unit diameters and densities, orifice diameters, secretion reflectivity, interstices inhomogeneity, and acinar wall inhomogeneity. RESULTS In the asymptomatic population, MG density and diameter decreased with age (P<0.001 and P<0.01, respectively), and secretion reflectivity and inhomogeneity of acinar walls increased (P<0.001). For the under 40-year-old subjects and the over 65-year-old subjects included without any inclusion or exclusion criteria, acinar unit density decreased with age, and secretion reflectivity, and wall inhomogeneity increased (P<0.01). There was no significant difference between the mean acinar diameters of these two groups. CONCLUSIONS In vivo LSCM imaging of age-related MG changes showed the histologic features underlying the clinically observed MG dropout. Asymptomatic older subjects mainly showed signs of atrophic, nonobstructive, age-related MG dysfunction. Comparing volunteers with and without ocular surface symptoms, LSCM can provide important information regarding the boundary between physiologic and pathologic MG aging.

Choroidal Findings in Dome-Shaped Macula in Highly Myopic Eyes: A Longitudinal Study

PURPOSE To describe choroidal findings in dome-shaped macula associated with high myopia using fluorescein angiography (FA), indocyanine green angiography (ICGA), and spectral-domain optical coherence tomography (SD OCT), and to elucidate the mechanism and natural course of serous retinal detachment (RD) associated with dome-shaped macula. DESIGN Retrospective, observational case series. METHODS We reviewed longitudinal imaging results of 52 highly myopic eyes with dome-shaped macula. Changes on FA and ICGA were assessed. Retinal, choroidal, and scleral thicknesses and bulge height were measured on SD OCT. RESULTS Serous RD was the most common abnormality associated with dome-shaped macula, detected by SD OCT in 44% of the cases with no associated choroidal neovascularization. Significant differences in the proportion of eyes with pinpoint leakage on FA (P < .001), punctate hypercyanescence on ICGA (P < .001), and pigment epithelium detachment on SD OCT (P < .001) were noted inside the inward bulge of the staphyloma between eyes with and without serous RD. Serous RD was not associated with hyperpermeability areas on ICGA. Eyes with serous RD had thicker choroid (P = .004) and tended to have thicker sclera (P = .067) and greater bulge height (P = .079). Choroidal thickness, scleral thickness, and bulge height were positively correlated (P < .01). All eyes presented a fluctuating course of serous RD during follow-up. Worsening of serous RD was associated with appearance of new punctate hypercyanescent spots on ICGA and leaking points on FA (P < .001 and P = .016, respectively). CONCLUSION Serous RD in dome-shaped macula was likely caused by choroidal vascular changes, similar to central serous chorioretinopathy, but specifically confined in the inward bulge of the staphyloma and secondary to excessive scleral thickening. Serous retinal detachment showed fluctuating changes over time, with alternating active and inactive stages. Angiographic findings in dome-shaped macula suggest the choroid as a target for possible treatment strategies.

In Vivo Confocal Microscopy of Conjunctival Roundish Bright Objects: Young, Older, and Sjögren Subjects

PURPOSE To investigate by laser scanning confocal microscopy (LSCM) the density of presumed epithelial, presumed goblet, and presumed inflammatory cells in the tarsal conjunctiva of healthy young and older subjects and in patients with Sjögrens syndrome (SS). To evaluate the interobserver variability and to compare the measured densities with known age-related and SS-related changes. METHODS The authors studied 24 eyes of 12 healthy young subjects (8 women, 4 men; average age, 26 years; age range, 21-30 years), 24 eyes of 12 healthy older subjects (10 women, 2 men; average age, 68 years; age range, 67-74 years), and 24 eyes of 12 patients with SS (10 women, 2 men; average age, 62 years; age range, 49-72 years). The inferior tarsal conjunctiva of each patient was examined in vivo by LSCM. The density of the three cell types was independently analyzed by two masked investigators. RESULTS The density of presumed epithelial, presumed goblet, and presumed inflammatory cells was significantly higher in SS patients than in both control groups (P < 0.001; Mann-Whitney U test). The densities for presumed goblet cells calculated by the two investigators were significantly different from one another (P < 0.01, Mann-Whitney U test) and were not correlated. CONCLUSIONS LSCM is a promising tool that should profoundly change the study of the ocular surface, but it requires accurate standardization before it is used in clinical practice.