Inflammation and the Nervous System: The Connection in the Cornea in Patients with Infectious Keratitis

Purpose. To study the density and morphologic characteristics of epithelial dendritic cells, as correlated to subbasal corneal nerve alterations in acute infectious keratitis (IK) by in vivo confocal microscopy (IVCM). Methods. IVCM of the central cornea was performed prospectively in 53 eyes with acute bacterial (n = 23), fungal (n = 13), and Acanthamoeba (n = 17) keratitis, and in 20 normal eyes, by using laser in vivo confocal microscopy. Density and morphology of dendritic-shaped cells (DCs) of the central cornea, corneal nerve density, nerve numbers, branching, and tortuosity were assessed and correlated. It should be noted that due to the “in vivo” nature of the study, the exact identity of these DCs cannot be specified, as they could be monocytes or tissue macrophages, but most likely dendritic cells. Results. IVCM revealed the presence of central corneal DCs in all patients and controls. The mean DC density was significantly higher in patients with bacterial (441.1 ± 320.5 cells/mm2; P < 0.0001), fungal (608.9 ± 812.5 cells/mm2; P < 0.0001), and Acanthamoeba keratitis (1000.2 ± 1090.3 cells/mm2; P < 0.0001) compared with controls (49.3 ± 39.6 cells/mm2). DCs had an increased size and dendrites in patients with IK. Corneal nerves were significantly reduced in eyes with IK compared with controls across all subgroups, including nerve density (674.2 ± 976.1 vs. 3913.9 ± 507.4 μm/frame), total nerve numbers (2.7 ± 3.9 vs. 20.2 ± 3.3), main trunks (1.5 ± 2.2 vs. 6.9 ± 1.1), and branching (1.2 ± 2.0 vs. 13.5 ± 3.1; P < 0.0001). A strong association between the diminishment of corneal nerves and the increase of DC density was observed (r = −0.44; P < 0.0005). Conclusions. IVCM reveals an increased density and morphologic changes of central epithelial DCs in infectious keratitis. There is a strong and significant correlation between the increase in DC numbers and the decreased subbasal corneal nerves, suggesting a potential interaction between the immune and nervous system in the cornea

Corneal Sensation and Subbasal Nerve Alterations in Patients with Herpes Simplex Keratitis

Purpose To study and correlate corneal sensation in patients with herpes simplex keratitis (HSK) with density and morphology of subbasal corneal nerves by in vivo confocal microscopy (IVCM). Design Prospective, cross-sectional, controlled, single-center study. Participants Thirty-one eyes with the diagnosis of acute (n=7) or chronic (n=24) HSK and the contralateral clinically unaffected eyes were studied and compared to normal controls (n=15). Methods IVCM (Confoscan 4, Nidek) and corneal esthesiometry (Cochet-Bonnet) of the central cornea were performed bilaterally in all patients and controls. Patients were grouped into normal (>5.5 cm), mild (>2.5 to 5.5cm) and severe (≤2.5 cm) loss of sensation. Main Outcome Measures Changes in corneal nerve density, total nerve number, main nerve trunks, branching and tortuosity were evaluated after IVCM and correlated to corneal sensation, disease duration, and number of recurrences. Results HSK eyes, as compared to controls, demonstrated significant (p<0.001) decrease in mean nerve density (448.9±409.3 vs. 2,258.4±989.0 μm/frame), total nerve number (5.2±4.5 vs. 13.1±3.8), main nerve trunks (2.3±1.6 vs. 4.7±1.2) and nerve branches (3.2 ± 4.3 vs. 9.8±3.3). In contralateral unaffected eyes, mean nerve density (992.7±465.0 μm/frame), total nerve number (7.8±3.3), and branches (4.5±2.3) were significantly decreased as compared to controls (p<0.002). Reduced nerve density, total nerve count and main trunks in HSK eyes were significantly correlated with corneal sensation across all subgroups (p<0.001). Nerve density decreased within days of infection and was correlated to frequency of episodes in patients with HSK (p<0.02). Conclusions In vivo confocal microscopy reveals that the loss of corneal sensation in HSK correlates strongly with profound diminishment of the subbasal nerve plexus after herpes simplex virus (HSV) infection. Surprisingly, the contralateral clinically unaffected eyes also demonstrated a diminishment of the subbasal nerve plexus, as compared to normal subjects, revealing bilateral nerve alteration in an apparently unilateral disease

Topical Bevacizumab in the Treatment of Corneal Neovascularization

Objectives To study the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization (NV). Design In a prospective, open-label, non-comparative study, 10 eyes from 10 patients with stable corneal NV were treated with topical bevacizumab 1.0% for 3 weeks and followed up to 24 weeks. Main Outcome Measures The primary safety variables were the occurrence of ocular and systemic adverse events throughout the course of the study. The primary efficacy variables were neovascular area (NA), measuring the area of the corneal vessels themselves; vessel caliber (VC), measuring the mean diameter of the corneal vessels; and invasion area (IA), measuring the fraction of the total corneal area covered by the vessels. Results From baseline visit to the last follow-up visit, the mean reduction was 47.1% ± 36.7% for NA, 54.1% ± 28.1 for VC, and 12.2% ± 42.0% for IA. The decreases in NA and VC were statistically significant (p = 0.0014 and p = 0.00009, respectively). However, changes in IA did not achieve statistical significance (p = 0.19). Visual acuity and central corneal thickness showed no significant changes. Topical bevacizumab was well-tolerated with no adverse events. Conclusions Short-term topical bevacizumab therapy reduces the severity of corneal NV without local or systemic side-effects. Application to Clinical Practice Topical bevacizumab provides an alternative therapy in the treatment of stable corneal neovascularization

Unilateral Herpes Zoster Ophthalmicus Results in Bilateral Corneal Nerve Alteration

Purpose Herpes zoster ophthalmicus (HZO), thought to be a unilateral disease, results in loss of corneal sensation, leading to neurotrophic keratopathy. This study aimed to analyze bilateral corneal nerve changes in patients with HZO by in vivo confocal microscopy (IVCM) and their correlation with corneal sensation as a measure of nerve function. Design Prospective, cross-sectional, controlled, single-center study. Participants Twenty-seven eyes with the diagnosis of HZO and their contralateral clinically unaffected eyes were studied and compared with normal controls (n = 15). Methods In vivo confocal microscopy (Confoscan 4; Nidek Technologies, Gamagori, Japan) and corneal esthesiometry (Cochet-Bonnet; Luneau Ophthalmologie, Chartres, France) of the central cornea were performed bilaterally in all patients and controls. Patients were grouped into normal (>5.5 cm), mild (>2.5–5.5 cm), and severe (<2.5 cm) loss of sensation. Main Outcome Measures Changes in corneal nerve density, total nerve number, main nerve trunks, branching, and tortuosity were evaluated after IVCM and were correlated to corneal sensation, disease duration, and number of recurrences. Results Eyes with herpes zoster ophthalmicus had a significant (P<0.001) decrease in total nerve length (595.8±358.1 vs. 2258.4±989.0 μm/frame), total number of nerves (5.4±2.8 vs. 13.1±3.8), number of main nerve trunks (2.3±1.1 vs. 4.7±1.2), and number of nerve branches (3.2±2.3 vs. 8.4±3.7) as compared with controls. In the contralateral clinically unaffected eyes, total nerve length (1053.1±441.4 μm/frame), total number of nerves (8.3±2.9), and main nerve trunks (3.1±1.0) also were decreased significantly as compared with controls (P<0.01). Reduced nerve density, total nerve count, main trunks, and tortuosity was correlated significantly with corneal sensation across all subgroups (P<0.001). Conclusions Patients with unilateral HZO demonstrated a profound and significant bilateral loss of the corneal nerve plexus as compared with controls, demonstrating bilateral changes in a clinically unilateral disease. Loss of corneal sensation strongly correlated with subbasal nerve plexus alterations as shown by IVCM

HERPETIC-KERATITIS - PERSISTENCE OF VIRAL PARTICLES DESPITE TOPICAL AND SYSTEMIC ANTIVIRAL THERAPY - REPORT OF 2 CASES AND REVIEW OF THE LITERATURE

Objective.-First, to characterize the histologic features of corneal buttons taken from two patients with chronic active herpetic stromal keratitis. Both eyes had suffered frequent and prolonged viral epithelial recurrences despite topical and systemic antiviral therapy and developed uniquely rapid deposition of chalklike stromal deposits. Second, to determine the clinical outcome of surgical intervention in eyes with such a pattern of herpetic disease.Design.Patients received topical antiviral medication and 200 to 400 mg of acyclovir five times daily for 2 or 5 months until penetrating keratoplasty. They received tapered doses of acyclovir after surgery. Corneal buttons were evaluated with light microscopy and electron microscopy.Results.-Light microscopy of the specimens revealed calcium in the area of the chalklike deposits and a few cocci in the deep stroma. Electron microscopy showed numerous herpetic viral particles at various stages of maturity, including completely enveloped organisms, in the basal cells and keratocytes, and a few cocci in basal cells. Apart from one minor recurrence of a dendritic ulcer, both patients were free of herpetic disease at 13 and 22 months, required little to no medication, and had clear grafts.Conclusions.-Rapid calcium deposition in herpetic corneas may indicate disease of sufficient severity to warrant surgical intervention for removal of a stromal viral reservoir. Such intervention can stop further recurrences of keratitis that is poorly controlled by antiviral therapy. Such chronically diseased eyes may also harbor unsuspected bacterial infection.SCHEPENS EYE RES INST,20 STANIFORD ST,BOSTON,MA 02114HARVARD UNIV,SCH MED,DEPT OPHTHALMOL,BOSTON,MA 02115ESCOLA PAULISTA MED SCH,BR-04023 SAO PAULO,BRAZILESCOLA PAULISTA MED SCH,BR-04023 SAO PAULO,BRAZILWeb of Scienc