Daniela Lazzarini

Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study

Background/aims The aim of this study was to evaluate the long-term corneal toxicity of topical chemotherapy with 1% 5-fluorouracil (5-FU) as a sole or adjuvant treatment of ocular surface squamous neoplasia (OSSN). Methods Forty-one consecutive cases of OSSN were included in this prospective study. Patients underwent topical chemotherapy with 1% 5-FU four times/day for 4 weeks (one course). Adjunctive courses were repeated until clinical and cytological tumour regression. Clinical confocal microscopy was used to check for 5-FU long-term corneal toxicity. Results Mean follow-up was 89.7±14.4 months (range 63–122 months). Twenty-two patients (53.7%) underwent topical 5-FU as a sole treatment, and 19 patients (46.3%) as adjuvant and/or debulking therapy. The mean number of 5-FU cycles was 1.9 (range 1–5 cycles). Three tumours (7.3%) treated with 5-FU alone recurred during follow-up. Recurrences were successfully treated with additional 5-FU courses. Clinical confocal microscopy showed no long-term difference between the treated eye and fellow (control) eye in: endothelial cells count, pleomorphism and polymegatism, anterior stromal keratocyte density, sub-basal nerve plexus fibre number, density, and beadings and central cornea epithelium thickness (p=NS). Conclusion Topical 5-FU, as a sole or combined therapy, must be considered a long-term safe and effective treatment for patients affected by OSSN.

Corneal Confocal Microscopy in Patients with Vernal Keratoconjunctivitis

PURPOSE To compare corneal morphologic features using in vivo confocal microscopy in vernal keratoconjunctivitis (VKC) patients compared with normal subjects. DESIGN Prospective, comparative study. PARTICIPANTS Thirty-two VKC patients (26 males, 6 females; mean age, 17.1 years) and 40 normal subjects (20 males, 20 females; mean age, 19.3 years) were included. METHODS All subjects underwent a full ophthalmologic examination. Confoscan CS4 (Nidek, Gamagori, Japan) images of the central cornea were obtained with a ×40 noncontact lens and Z-ring device. MAIN OUTCOME MEASURES The superficial and basal epithelium, subbasal nerve plexus, anterior stroma, stromal nerves, and endothelium of the central cornea were studied. RESULTS The VKC patients had increased diameter, reflectivity, and presence of nuclear activation of superficial epithelial cells; reduced density of the basal membrane; lower density of keratocytes, increased presence of activated keratocytes, and inflammatory cells in the anterior stroma; and lower density and number of fibers, lower number of beadings, and higher grade of tortuosity of fibers in the subbasal nerve plexus. Increased alterations in thickness, deflections, and tortuosity were observed in stromal corneal nerves. An increased number of inflammatory cells in close proximity to the subbasal and stromal nerve fibers also was observed in VKC subjects. CONCLUSIONS Corneal involvement in VKC is associated with alterations of the epithelium and subbasal and stromal corneal nerves. These changes may relate to the tear dysfunction and nonspecific hyperreactivity typical of these patients. Corneal confocal microscopy is a useful tool for studying in vivo pathologic corneal changes in VKC.

Mitomycin C-assisted photorefractive keratectomy in high myopia: a long-term safety study.

Purpose: To evaluate the long-term corneal safety of topical mitomycin C (MMC) used during photorefractive keratectomy to prevent haze formation in highly myopic eyes. Methods: Twenty-eight patients with bilateral high myopia underwent photorefractive keratectomy. One eye was randomly assigned to intraoperative 0.02% MMC and the fellow eye to conventional treatment. Each eye was checked at baseline and at 5 years after surgery using in vivo corneal confocal microscopy. Results: At baseline, the endothelial cell density was 2970 ± 295 cells per square millimeter in the MMC-treated eyes and 2839 ± 323 cells per square millimeter in the control eyes. At 5 years, it was 2803 ± 307 and 2780 ± 264 cells per square millimeter, respectively (P = 0.27). The number of corneal nerve fibers was 3.9 ± 1.6 in the MMC-treated eyes and 4.4 ± 1.3 in the control eyes. At 5 years, it was 3.0 ± 1.6 and 2.7 ± 1.3, respectively (P = 0.15). The density of corneal nerves was 9600 ± 2915 μm/mm2 in the MMC-treated eyes and 11,352 ± 3898 μm/mm2 in the control eyes. At 5 years, the density was higher in the MMC-treated eyes (6790 ± 2447 μm/mm2) than in the control eyes (6024 ± 2977 μm/mm2) (P = 0.003). The number of nerve beadings at baseline was 12.9 ± 1.7/100 μm in the MMC-treated eyes and 12.3 ± 2.0/100 μm in the control eyes. At 5 years, it was 9.9 ± 2.6/100 and 9.4 ± 2.9/100 μm, respectively (P = 1.00). At 5 years, corneal nerve branching and tortuosity were similar in the 2 groups (P = 0.88 and 0.54, respectively). Epithelium thickness remained statistically unchanged (P = 0.69). Conclusions: Intraoperative use of topical 0.02% MMC compared with standard treatment does not induce significant long-term corneal changes, as assessed by in vivo corneal confocal microscopy.

Epidemiology of allergic conjunctivitis: clinical appearance and treatment patterns in a population-based study.

Purpose of reviewTo analyse the most recently published studies on the prevalence of allergic conjunctivitis alone or in association with allergic rhinitis, and the clinical and demographic aspects of the disease. Recent findingsAllergic conjunctivitis or conjunctival symptoms are present in 30–71% of patients with allergic rhinitis. Allergic conjunctivitis alone has been estimated in 6–30% of the general population and in up to 30% in children alone or in association with allergic rhinitis. Seasonal allergic conjunctivitis is the most frequent form; however, studies from tertiary, ophthalmology referral centers report that the chronic forms, such as vernal and atopic keratoconjunctivitis, are the most frequently seen by ophthalmologists. A recent large survey performed at a national level involving 304 ophthalmologists showed that the majority of patients with allergic conjunctivitis suffer annually of few episodes of mild ,intermittent conjunctivitis. However, 30% of patients are affected by frequent episodes with intense and persistent symptoms. Treatment is frequently not appropriate. SummaryEven though allergic conjunctivitis is often associated to allergic rhinitis, epidemiology studies frequently do not include specific ophthalmological evaluations. An understanding of allergic conjunctivitis disease, its prevalence, demographics and treatment paradigms will provide important information towards understanding its pharmacoeconomics and burden on the national health systems.

Small fiber peripheral neuropathy in Wilson disease: an in vivo documentation by corneal confocal microscopy.

PURPOSE Wilson disease (WD) is a disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs, as the brain and cornea. The aim of this study was to investigate central corneal changes and in particular to assess the parameters of corneal subbasal nerve plexus (SBNP) in patients affected by WD, using corneal confocal microscopy (CCM). METHODS A total of 24 patients affected by WD and 24 healthy control subjects were included in this cross-sectional comparative study. One eye of each subject was examined to quantify different corneal parameters. Mean cell diameter and mean cell density of the epithelium; number of fibers (NF), nerve fiber length density (NFLD), number of branchings (NBr), number of beadings (NBe), and fiber tortuosity (FT) of the SBNP; mean cell density of keratocytes of the anterior, medium, and posterior stroma; and mean cell density, polimegatism, and pleomorphism of the endothelium, and central corneal sensitivity were analyzed. RESULTS Wilson disease induced significant alterations in SBNP, and corneal epithelium. The NFLD (P < 0.0001), NF (P = 0.001), NBe (P = 0.025), and NBr (P < 0.0001) were significantly lower, whereas FT (P < 0.0001) was significantly higher in WD subjects compared to controls. Moreover mean epithelial cell diameter (P < 0.0001) and mean epithelial cell density (P < 0.0001) were significantly higher and lower compared to controls, respectively. CONCLUSIONS The CCM showed significant corneal changes in SBNP, with concomitant corneal epithelium changes in WD, demonstrating the presence of small fiber peripheral neuropathy in these patients. The CCM may contribute to diagnosis and monitoring of the peripheral nervous system involvement in WD.

Vernal keratoconjunctivitis-like disease in adults.

PURPOSE To identify clinical, demographic, immunologic, and health-related quality-of-life data from a cohort of vernal keratoconjunctivitis (VKC) patients with the onset of the disease after puberty (VKC-like disease). DESIGN Retrospective, observational case series. METHODS Forty-nine patients with late-onset VKC-like disease from among 600 consecutive VKC patients. History of disease, test results for allergen sensitivity, signs and symptoms, impact of disease on work productivity, health-related quality of life, and treatment satisfaction were assessed. In addition, multiplex bead analysis for Th1/Th2 cytokines were carried out in tear samples from 20 VKC patients (10 adults and 10 children) and from 10 normal subjects. RESULTS A family history of allergy was positive in only 28% and positive prick test results were present in 55% of the 49 VKC-like adult patients. Based on typical signs and symptoms, 48% were affected by the limbal form, 33% were affected by the tarsal form, and 19% were affected by the mixed form. Corneal ulcer complicated the disease in only 2 adult patients. Although the disease was not considered a limiting factor for work, productivity was reduced by 26% and social activities were reduced by 31% during active flare-ups. No significant differences were found in tear cytokine pattern production between VKC in children and VKC in adults. CONCLUSIONS A late onset VKC-like disease can appear in young adults with signs and symptoms similar to those in pediatric disease, but with less corneal involvement.

Allergic conjunctivitis: a cross‐sectional study

Ocular allergy is a common disease in daily practice.

Corneal confocal microscopy in patients with oxaliplatin‐induced peripheral neuropathy

Dear Editor, We read with great interest the paper by Smith et al. (2013) on corneal confocal microscopy (CCM) as an efficient, well-tolerated, and reproducible method for assessing corneal innervation. CCM provides information on small sensory fibers by direct observation of corneal innervation and has been proven to be useful in some ocular diseases (herpetic infections, corneal dystrophies, amyloidosis, dry eye) and after corneal surgery (Midena et al., 2009). Moreover, this procedure has been applied in the evaluation of several conditions such as diabetic neuropathy (Rosenberg et al., 2000; Tavakoli et al., 2010a), idiopathic small fiber neuropathy (Gemignani et al., 2010; Tavakoli et al., 2010b), Fabry disease (Tavakoli et al., 2009), Charcot-Marie-Tooth disease type 1A (Tavakoli et al., 2012), and in some diseases that lead to secondary small fiber damage such as hereditary sensory and autonomic neuropathy (Mimura et al., 2008), autoimmune neuropathy (Lalive et al., 2009), and chemotherapy-induced peripheral neuropathy (CIPN) (Ferrari et al., 2010). Some studies showed a correlation between corneal nerve damage assessed with CCM and the severity of intraepidermal nerve fiber loss (Quattrini et al., 2007); moreover, CCM is able to detect early small nerve fiber regeneration after pancreas and kidney transplantation in diabetic patients (Tavakoli et al., 2013). We would like to share our experience with CCM as a possible tool to investigate oxaliplatin (OXA)-induced peripheral neuropathy. OXA-induced peripheral neuropathy represents a major dose-limiting adverse effect of OXA-based chemotherapy that can lead to severe disability and therapy discontinuation. OXA chronic neurotoxicity affects up to 80% of patients (Argyriou et al., 2013) and may persist for a long time after therapy discontinuation, or appear and worsen after

Cytostatic and cytotoxic effects of 5-fluorouracil on human corneal epithelial cells and keratocytes.

Purpose: To investigate the effects of various 5-fluorouracil (5-FU) concentrations, exposure times, and application techniques on in vitro–cultured human corneal cells. Methods: Human corneal epithelial cell (HCEC) and human corneal keratocyte (HCK) cultures were exposed to different 5-FU concentrations (0.025%–1%) and incubation durations (5 minutes to 2 hours). The cytostatic effect was evaluated as the percentage of inhibition of migration relative to the control. The evaluation of cytotoxic effect included both phase contrast microscopic observations and viability measures performed using an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] colorimetric assay. The results are expressed as ratio of optical density (OD) reduction 24 hours after exposure. Results: The cytostatic effect was time and dose dependent. The 50% inhibiting dose was 0.55% after 1 hour of incubation for HCECs and was 0.5% after 2 hours of incubation for HCKs. A 100% inhibitory effect was never observed at any concentration or incubation duration. No cytotoxic changes were observed using an 5-FU concentration of <1%; 1% 5-FU showed time-dependent cytotoxic changes in HCEC cultures only. MTT analysis showed no OD reduction at 5-FU concentrations of <1%, whereas 1% 5-FU showed OD reduction <50% at any tested exposure time. HCECs showed higher reduction in OD than HCKs. Conclusions: 5-FU formulations topically used in clinical practice showed limited toxicity in normal cultured corneal epithelial cells and keratocytes.

Corneal staining patterns in vernal keratoconjunctivitis: the new VKC-CLEK scoring scale

Aim To propose a new scoring system in the assessment of ocular surface epithelial damage in vernal keratoconjunctivitis (VKC). Methods 25 consecutive patients with VKC (50 eyes) were evaluated using the Quality of Life in children with VKC (QUICK) questionnaire and objective clinical measures: fluorescein and lissamine green staining and cornea confocal microscopy (Heidelberg Retina Tomography 3). Oxford, Van Bljsterweld and a new system, the VKC-Collaborative Longitudinal Evaluation of Keratoconus study (CLEK) (VKC-CLEK) scores, were used to evaluate the epithelial damage after staining. Results Mean Oxford and VKC-CLEK scores were significantly different after fluorescein staining (P<0.001), but significantly correlated (P<0.001; r=0.649). The same data were obtained comparing Van Bljsterweld and VKC-CLEK after lissamine green staining (P<0.001; r=0.760). In patient with limbal VKC, a statistically significant difference was found comparing new VKC-CLEK scores and Oxford or Van Bljsterweld scores (P<0.001), but not in tarsal VKC. A statistically superior concordance was found between QUICK and VKC-CLEK scores compared with standard staining scores values (P<0.001). Conclusions Oxford and Van Bijsterveld scores are not adequate for the evaluation of the epithelial damage in patients with limbal VKC because the staining patterns considered for these tests do not correspond to the staining patterns in patients with VKC. We propose a new scoring system, VKC-CLEK, to better evaluate both limbal and tarsal epithelial damage in patients with VKC.