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

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

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

Short-Term Impact of FS-LASIK and SMILE on Dry Eye Metrics and Corneal Nerve Morphology

PURPOSE: To analyze the short-term (up to 1 month) clinical outcomes in patients undergoing corneal laser refractive surgery and the impact on dry eye disease (DED) metrics and corneal nerves using in vivo confocal microscopy (IVCM). METHODS: The unaided distance visual acuity, corrected distance visual acuity, and spherical equivalent refraction (SEQ) were determined in 16 and 13 patients undergoing FS-LASIK and SMILE, respectively. DED metrics assessed were Ocular Surface Disease Index, Dry Eye Questionnaire 5-items (DEQ-5), tear film osmolarity, tear meniscus height, noninvasive keratograph breakup time (NIKBUT), ocular staining, and meibomian gland atrophy. An automated analysis of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length (CNFL), and corneal nerve fiber fractal dimension were obtained from the IVCM scans using ACCMetrics software (University of Manchester). RESULTS: Both surgical techniques provided good refractive and visual outcomes. DED symptoms were found to be higher after FS-LASIK compared with SMILE (P < 0.05). A decrease in tear meniscus height (∼31%) and NIKBUT (∼40%) was reported after FS-LASIK (P = 0.005 and P = 0.001, respectively) but not after SMILE. Both procedures affected corneal nerve fiber density, corneal nerve branch density, CNFL, and corneal nerve fiber fractal dimension, but the impact was significantly greater with FS-LASIK (P = 0.001). Only CNFL correlated with the reported symptoms (DEQ-5) after FS-LASIK (r = -0.545, P = 0.029). CONCLUSIONS: FS-LASIK and SMILE provided good refractive and visual outcomes. There was an increased impact on DED symptoms after FS-LASIK compared with SMILE, although there were no significant differences between the procedures for most of the other ocular surface metrics assessed. The IVCM findings showed that SMILE had less impact on corneal nerves compared with FS-LASIK

The impact of herpes zoster and post-herpetic neuralgia on quality-of-life

International audienceBACKGROUND: The potentially serious nature of herpes zoster (HZ) and the long-term complication post-herpetic neuralgia (PHN) are often underestimated. One in four people will contract herpes zoster in their lifetime, with this risk rising markedly after the age of 50 years, and affecting one in two in elderly individuals. Pain is the predominant symptom in all phases of HZ disease, being reported by up to 90% of patients. In the acute phase, pain is usually moderate or severe, with patients ranking HZ pain as more intense than post-surgical or labour pains. Up to 20% of patients with HZ develop PHN, which is moderate-to-severe chronic pain persisting for months or years after the acute phase. We review the available data on the effect of HZ and PHN on patients' quality-of-life. DISCUSSION: Findings show that HZ, and particularly PHN, have a major impact on patients' lives across all four health domains--physical, psychological, functional and social. There is a clear correlation between increasing severity of pain and greater interference with daily activities. Non-pain complications such as HZ ophthalmicus can increase the risk of permanent physical impairment. Some elderly individuals may experience a permanent loss of independence after an acute episode of HZ. Current challenges in the management of HZ and PHN are highlighted, including the difficulty in administering antiviral agents before pain becomes established and the limited efficacy of pain treatments in many patients. We discuss the clinical rationale for the HZ vaccine and evidence demonstrating that the vaccine reduces the burden of the disease. The Shingles Prevention Study, conducted among >38,000 people aged >or=60 years old, showed that the HZ vaccine significantly reduces the burden of illness and the incidence of both HZ and PHN. In the entire study population, zoster vaccination reduced the severity of interference of HZ and PHN with activities of daily living by two-thirds, as measured by two questionnaires specific to HZ. SUMMARY: A vaccination scheme may positively impact the incidence and course of HZ disease, thereby improving patients' quality-of-life

Quantitative RT-PCR profiling of the Rabbit Immune Response: Assessment of Acute Shigella flexneri Infection

Quantitative reverse transcription PCR analysis is an important tool to monitor changes in gene expression in animal models. The rabbit is a widely accepted and commonly used animal model in the study of human diseases and infections by viral, fungal, bacterial and protozoan pathogens. Only a limited number of rabbit genes have, however, been analyzed by this method as the rabbit genome sequence remains unfinished. Recently, increasing coverage of the genome has permitted the prediction of a growing number of genes that are relevant in the context of the immune response. We hereby report the design of twenty-four quantitative PCR primer pairs covering common cytokines, chemoattractants, antimicrobials and enzymes for a rapid, sensitive and quantitative analysis of the rabbit immune response. Importantly, all primer pairs were designed to be used under identical experimental conditions, thereby enabling the simultaneous analysis of all genes in a high-throughput format. This tool was used to analyze the rabbit innate immune response to infection with the human gastrointestinal pathogen Shigella flexneri. Beyond the known inflammatory mediators, we identified IL-22, IL-17A and IL-17F as highly upregulated cytokines and as first responders to infection during the innate phase of the host immune response. This set of qPCR primers also provides a convenient tool for monitoring the rabbit immune response during infection with other pathogens and other inflammatory conditions