Intermittent retinal artery occlusions as the first clinical manifestation of polycythemia vera: a case report.

BACKGROUND: Polycythemia vera (PV) is a myeloproliferative neoplasm with increased hemoglobin, hematocrit, platelet count and leukocytosis, resulting in increased blood viscosity. PV which is initially presenting with ocular symptoms is rare, but irreversible retinal vessel occlusions leading to the diagnosis of PV have been described in literature. CASE PRESENTATION: We describe a patient with PV, initially presenting with attacks of monocular temporary loss of vision due to intermittent retinal artery occlusions of different retinal arteries. The patient was immediately treated with phlebotomy and the impaired arterial retinal perfusion could be restored without permanent retinal ischemia. We were able to document these transient arterial occlusions with fundus photography as well as fluorescein angiography. To the best of our knowledge, a case like this has never been documented before. CONCLUSION: This report is pertinent, in order to raise awareness among clinicians for polycythemia vera, as it can in fact be used as a differential diagnosis for patients with retinal artery occlusion. We would like to stress that early therapy might reverse the vessel complications.

Maculopathies in Glaucoma. / Glaukomassoziierte Makulopathien.

In the presence of glaucoma, various changes in the macula can occur during the course of the disease itself or its treatment. Maculopathies that can be observed in glaucoma include cystoid macular edema, hypotony maculopathy, and microcystic macular edema. The following article discusses the pathophysiology, causes, course, clinical presentation, and treatment of these maculopathies.

Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration.

BACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) thickness and olfactory function are both emerging biomarkers in multiple sclerosis (MS). Impairment of odor identification and discrimination is an irreversible feature of more advanced MS suggested to be associated with neurodegeneration, while olfactory threshold is a transient feature of early, active MS possibly associated with short-term inflammatory disease activity. OBJECTIVE: The aim of this study was to validate the association of olfactory (dys)function and parameters of MS disease course in a large cohort of MS patients and to correlate olfactory function with pRNFL thickness as a surrogate biomarker of neurodegeneration. METHODS: In a cross-sectional design, olfactory function was assessed using the Sniffin' Sticks test, which quantifies three different qualities of olfactory function (threshold, discrimination, and identification). pRNFL thickness was measured by spectral-domain optical coherence tomography (OCT). Results were correlated with age, sex, disease duration, relapses, Expanded Disability Status Scale (EDSS), cognitive function, depression, smoking, and pRNFL thickness by multivariable linear regression models. RESULTS: We included 260 MS patients (mean age of 35.9 years, 68.7% female). Olfactory threshold correlated significantly with number of relapses in the year prior to assessment and shorter disease duration. Odor discrimination, identification, and their sum score were significantly correlated with longer disease duration, higher EDSS, and reduced cognitive function. pRNFL thickness was associated with identification and discrimination, but not with threshold. CONCLUSION: Olfactory threshold is a marker of short-term inflammatory relapse activity unrelated to parameters of neurodegeneration, while odor identification and discrimination are markers of neurodegeneration mostly independent of relapse activity. Assessment of olfactory function provides an opportunity to stratify MS patients with regard to inflammation and neurodegeneration.

Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis.

BACKGROUND: Serum neurofilament light chain (sNfL) levels and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in multiple sclerosis (MS). However, data on the relation between sNfL and pRNFL are scarce. OBJECTIVE: We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing-remitting (RR) MS patients. METHODS: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL levels were measured using single-molecule array (SimoaTM) assay. Annualized loss of pRNFL (aLpRNFL) was determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models. RESULTS: After correction for sex, age, and baseline sNfL, an sNfL increase of 10 pg/mL was associated with an aLpRNFL of -0.7 µm (95% confidence interval (CI): (-1.3, -0.2), p < 0.001). Patients with ⩾2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2 µm, standard deviation (SD) 0.6) compared to patients with no sNfL measure >75th percentile (0.4 µm, SD 0.2, p < 0.001). Between 15% and 20% of the aLpRNFL variance could be predicted from sNfL levels. CONCLUSION: sNfL levels contribute to the prediction of retinal thinning in patients with RRMS, strengthening its value as a biomarker of neuro-axonal damage.

Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis.

BACKGROUND: Peripapillary retinal nerve fibre layer (pRNFL) thickness is emerging as a marker of axonal degeneration in multiple sclerosis (MS). OBJECTIVE: We aimed to prospectively assess the predictive value of pRNFL for progression of physical and cognitive disability in relapsing-remitting MS (RRMS). METHODS: In this 3-year longitudinal study on 151 RRMS patients, pRNFL was measured by spectral-domain optical coherence tomography (OCT). We used proportional hazard models, correcting for age, sex, disease duration, Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) at baseline, to test a pRNFL thickness ≤88 µm at baseline for prediction of EDSS progression and cognitive decline. We also evaluated the decrease in pRNFL thickness from baseline to year 3 in a multivariate linear regression model. RESULTS: pRNFL thickness ≤88 µm was independently associated with a threefold increased risk of EDSS progression ( p < 0.001) and a 2.7-fold increased risk of cognitive decline within the subsequent 3 years ( p < 0.001). Mean pRNFL delta was -5.3 µm (SD, 4.2). It was significantly negatively impacted by EDSS progression, cognitive decline, higher age and disease duration, while positively impacted by disease-modifying therapy (DMT). CONCLUSION: Cross-sectional and longitudinal monitoring of pRNFL is useful as a biomarker for prediction of physical and cognitive disability progression in patients with RRMS in everyday clinical practice.

Susac's syndrome: clinical course and epidemiology in a Central European population.

OBJECTIVE: Susac's syndrome is characterized by inflammation and occlusion of pre-capillary arterioles with the clinical triad of branch retinal artery occlusion (BRAO), encephalopathy and hearing loss. No epidemiological data are available for the disease. METHODS: All neurology departments in Austria were addressed to report adult patients who were on immunosuppressive treatment for a diagnosis of Susac's syndrome between 1 August 2010 and 1 August 2015. Clinical course, treatment regimens, period and point prevalence rates, and annual incidence of Susac's syndrome in Austria in people over 19 years of age are reported. RESULTS: Ten patients with Susac's syndrome were identified, and eight of them were newly diagnosed within the five-year timeframe. Minimum five-year period prevalence of the disease is 0.148/100,000 (95% confidence interval (CI) 0.071-0.272), annual incidence is 0.024/100,000 (95% CI 0.010-0.047). Minimum point prevalence rates varied from 0.030/100,000 (95% CI 0.004-0.108) to 0.088/100,000 (95% CI 0.032-0.192). Of all 10 patients, 8 showed typical callosal or internal capsule magnetic resonance imaging lesions at first presentation, 7 presented with BRAO and 5 had hearing loss or tinnitus at the beginning of the disease. Four patients developed the complete clinical triad of Susac's syndrome during the observation period. CONCLUSIONS: We provide for the first time population-based data about the clinical course, prevalence and incidence of Susac's syndrome.

Severe reactive ischemic posterior segment inflammation in Acanthamoeba keratitis: Case report of a patient with Sjögren's syndrome.

PURPOSE: We report on a case of Acanthamoeba keratitis (AK)-related reactive ischemic posterior segment inflammation following intraocular surgery in a patient with primary Sjögren's syndrome (PSS). CASE REPORT: A 48-year-old female patient with severe protracted AK underwent uneventful cataract surgery upon development of a corneal scar. Four weeks postoperatively, she experienced a rapid loss of vision to no light perception. Central retinal artery occlusion and ischemic optic neuropathy could be excluded, and a diagnosis of PSS was made. The condition remained unresponsive to systemic steroid treatment and ultimately led to enucleation of the globe. Histologic work-up revealed ischemic posterior segment inflammation and Acanthamoeba cysts in the corneal stroma. CONCLUSION: Autoimmune disease may be a risk factor for AK-related severe reactive ischemic posterior segment inflammation, and intraocular surgery can be a trigger to its manifestation.

Three-year clinical outcome of XEN45 Gel Stent implantation versus trabeculectomy in patients with open angle glaucoma.

OBJECTIVE: To reliably compare the three-year clinical outcome and safety of XEN45 Gel Stent implantation (XEN) vs. trabeculectomy (TRAB) in patients with glaucoma. SUBJECT/METHODS: We conducted a retrospective cohort study with patients with primary open angle or pseudoexfoliation glaucoma with uncontrolled intraocular pressure (IOP) undergoing XEN or TRAB at the Innsbruck University Clinic of Ophthalmology and Optometry, Austria and analysed changes in IOP, numbers of IOP-lowering medications, and complete surgical success (i.e., IOP ≤ 18 mmHg, ≥20% IOP reduction and not requiring IOP-lowering medication) up to 36 months postoperatively. RESULTS: Between 2013 and 2019, we performed XEN Gel Stent implantation in 58 eyes and trabeculectomy in 84 eyes. From baseline to 36 months, mean IOP decreased from 23.4 to 13.8 mmHg (mean reduction 35%, 95% confidence interval 23-48%, p < 0.001) in the XEN group and from 25.1 to 11.2 mmHg (mean reduction 50%, 41-60%, p < 0.001) in the TRAB group. TRAB provided higher IOP reduction than XEN Gel Stent implantation at 12, 24, and 36 months (all p < 0.05). In XEN versus TRAB, IOP-lowering medication was required by 98.3% vs. 97.6% before surgery (p = 0.781), differed significantly at month 12 (43.2% vs. 2.0%, p < 0.001)but not at month 24 or 36. Complete surgical success was achieved in 40.0% vs. 62.8% at month 24 (adjusted odds ratio 2.70; 1.04-7.00, p = 0.040) and 27.3% vs. 56.8% at month 36 (4.36; 1.25-15.18, p = 0.021). CONCLUSION: Compared to XEN, TRAB was associated with lower intraocular pressure, less IOP-lowering medication, and higher probability of achieving complete surgical success over a 36-month follow-up period.

Emergency Care for High-Altitude Trekking and Climbing.

Introduction: High altitude regions are characterized by harsh conditions (environmental, rough terrain, natural hazards, and limited hygiene and health care), which all may contribute to the risk of accidents/emergencies when trekking or climbing. Exposure to hypoxia, cold, wind, and solar radiation are typical features of the high altitude environment. Emergencies in these remote areas place high demands on the diagnostic and treatment skills of doctors and first-aiders. The aim of this review is to give insights on providing the best possible care for victims of emergencies at high altitude. Methods: Authors provide clinical recommendations based on their real-world experience, complemented by appropriate recent studies and internationally reputable guidelines. Results and Discussion: This review covers most of the emergencies/health issues that can occur when trekking or during high altitude climbing, that is, high altitude illnesses and hypothermia, freezing cold injuries, accidents, for example, with severe injuries due to falling, cardiovascular and respiratory illnesses, abdominal, musculoskeletal, eye, dental, and skin issues. We give a summary of current recommendations for emergency care and pain relief in case of these various incidents.

Eye Disease in Patients with Rheumatic Diseases: A Retrospective Observational Cohort Study.

Data on eye diseases in rheumatic patients are limited. The aim of this study was to retrospectively assess the prevalence of ophthalmologic diseases in patients at a rheumatology outpatient clinic who also visited the ophthalmologic clinic. For this retrospective observational cohort study, a chart review was performed according to the STROBE guidelines. In this cohort, an ophthalmologic diagnosis was made in 26.9% of the 1529 rheumatic outpatients, whereas from a rheumatologic perspective, inflammatory non-infectious diagnoses dominated, at 71.7%. From an ophthalmologic perspective, diagnoses without inflammatory pathophysiologic backgrounds dominated, at 54.9%. Inflammatory non-infectious ophthalmologic disease was diagnosed in 24.2% of patients with rheumatoid arthritis and 29.3% of patients with peripheral spondyloarthritis. Not a single rheumatoid arthritis patient was diagnosed with anterior uveitis; however, 16.5% of spondyloarthritis patients were diagnosed with anterior uveitis (p < 0.001). The prevalence of uveitis was 16.3% in axial and 20.1% in peripheral spondyloarthritis. In conclusion, an interdisciplinary rheumatologic-ophthalmologic setting appears justified to further improve the management of patients with rheumatic diseases.

No difference in genotype frequencies of polymorphisms of the nitric oxide pathway between Caucasian normal and high tension glaucoma patients.

PURPOSE: Substantial evidence suggests that ocular perfusion is regulated by nitric oxide (NO), and polymorphisms in genes encoding for enzymes involved in NO formation and degradation (endothelial nitric oxide synthase [NOS3] and cytochrome b-235 alpha polypeptide gene [CYBA]) might contribute to vascular dysregulation observed in glaucoma. We therefore assessed the association of glaucoma with polymorphisms of NOS3 and CYBA previously associated with cardiovascular disease. We also compared the distribution of these polymorphisms in patients with high tension glaucoma (HTG) and normal tension glaucoma (NTG) and evaluated its association with vascular dysregulation in a subset of glaucoma patients. METHODS: Three hundred Caucasian patients with HTG and 127 with NTG were enrolled in the study and genotyped for G894T (rs1799983) and T-786C (rs2070744) in NOS3 and C242T (rs4673) in CYBA. RESULTS: None of these polymorphisms had a different allele or genotype distribution between HTG and NTG patients nor had the presence of vasospasms any impact. CONCLUSIONS: We studied the frequencies of a set of relevant polymorphisms of the NO system in a large cohort of glaucoma patients and found no association. These results therefore suggest the absence of a relevant relationship with different glaucoma forms in Caucasians.

Effects of glaucoma surgery on visual field progression in open-angle glaucoma considering the floor effect.

PURPOSE: The aim of this retrospective analysis was to investigate whether trabeculectomy (TRAB) and XEN® Gel Stent implantation (XEN) - both filtrating surgery techniques - can slow down the deterioration of visual field (VF) parameters considering the floor effect, which could lead to a misestimation of pre- and postoperative VF rate of progression (ROP). METHODS: Included in this study were patients with open-angle glaucoma, who underwent either TRAB or XEN® gel stent implantation and who had at least three VF tests before and after surgery, over an observation period of 13 years. The annual ROP of the mean defect (MD) and the square root of loss variance (sLV) were calculated with two different censoring thresholds: by censored regression and by ordinary least squares regression (OLSR). In addition, the diagnostic range of sLV was calculated. RESULTS: 48 eyes of 39 glaucoma patients were included in the study. The annual rate of MD progression was significantly reduced by filtering surgery when calculating the yearly ROP using OLSR (p = 0.006) and by censoring values exceeding a precalculated cut-off of 14.20 dB (p = 0.041) and a cut-off from the literature of 15.00 dB (p = 0.028). On average, the MD was impacted by a significant floor effect of 14.20 dB (95% CI: 12.83-15.56), corresponding to 17.7/59 absolute defects or 29.9% of the whole VF. When applying both OLSR and censored regression, the annual rate of sLV progression did not show a significant difference. The sLV showed a diagnostic boundary at a MD of 15.78 dB. CONCLUSION: This study shows that filtering surgery can reduce the progression of VF in patients with open-angle glaucoma, especially those whose disease develops aggressively. This is valid even if the floor effect in advanced cases is compensated by censored regression. On average, the ROP of MD is affected by a significant floor effect at about 29.9% absolute loss of the whole VF.

Symptomatic idiopathic bilateral multifocal retinal pigment epithelial detachments.

PURPOSE: To report a rare case of idiopathic bilateral serous retinal pigment epithelial detachments. OBSERVATIONS: We present a case of a 43-year-old female patient with metamorphopsia with the presence of innumerable bilateral serous retinal pigment epithelial detachments. Detailed ocular and systemic clinical work-up revealed no underlying disease. CONCLUSIONS: /Importance: Idiopathic multiple serous retinal pigment epithelial detachments are an extremely rare condition, that has been observed as an incidental clinical finding in asymptomatic patients. Multimodal imaging and detailed systemic work up are essential to rule out an underlying disease. Initial symptoms, as in our case, are uncommon and usually occur only in patients with complications such as choroidal neovascularization or hemorrhages. Therefore, regular follow ups are recommended to early detect and treat possible complications.

Uveitis in Tumor Patients Treated with Immunological Checkpoint- and Signal Transduction Pathway-Inhibitors.

PURPOSE: New tumor therapies like immune checkpoint inhibitors and small molecule inhibitors of MEK and BRAF have increased the patient's survival rate but can be burdened with severe side-effects including uveitis. Here, we show the spectrum, treatment, and outcome of uveitis types induced by tumor treatment. METHODS: In this retrospective study, we have included 54 patients from different centers who were developing uveitis under tumor therapy. A 16-item questionnaire was analyzed for type, treatment, and outcome of uveitis and type of tumor treatment, which we have correlated here. RESULTS: Irrespective of the tumor treatment, most patients developed anterior uveitis. All patients received corticosteroids and some additional immunosuppressive treatments. Cessation of tumor therapy was necessary only in a minority of cases. CONCLUSIONS: Ocular autoimmunity should be differentiated from toxic effects of cancer treatment and timely recognized since it can be generally well controlled by anti-inflammatory treatment, preserving the patient's vision without cessation of the tumor treatment.

Two-year outcomes of minimally invasive XEN Gel Stent implantation in primary open-angle and pseudoexfoliation glaucoma.

PURPOSE: The aim of this study was to evaluate the efficacy of XEN® Gel Stent implantation in the treatment of primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (XFG) regarding the reduction of intraocular pressure (IOP) and number of IOP-lowering medications over 2 years. METHODS: In this retrospective, observational, single-centre study, patients with POAG or XFG underwent implantation of the XEN® Gel Stent with or without combined phacoemulsification. Changes in mean IOP, mean number of IOP-lowering medications, number of postoperative interventions, complete or qualified surgical success rate (defined as IOP < 18 mmHg without or with IOP-lowering medication, respectively) and complete surgical failure rate (defined as the necessity of a glaucoma-related secondary surgical intervention or loss of light perception) were assessed 12 months (12M) and 24 months (24M) postoperatively. RESULTS: Seventy-nine eyes of 63 patients with open-angle glaucoma were included in the study (71% POAG, 29% XFG). Before surgery, mean IOP was 23.4 ± 7.9 mmHg. IOP was 14.6 ± 3.6 mmHg 12 months postoperatively (-31% from baseline, 95% CI -42% to -20%, n = 30, p < 0.001) and 14.8 ± 4.4 mmHg 24 months postoperatively (-29% from baseline, 95% CI -30% to -41%, n = 28, p < 0.001). Mean number of IOP-lowering medications was significantly reduced from 2.7 ± 1.1 before surgery to 1.0 ± 1.2 (-69%, 95% CI -89% to 46%, p < 0.001) 12 months after surgery and 1.0 ± 1.2 (-64%, 95% CI -91% to -36%, p < 0.001) at 24 months after surgery. Complete surgical success was achieved in 39% (12M) and 34% (24M) of patients and qualified success in 29% (12M) and 27% (24M). 13 (16%) eyes were classified as complete surgical failure. In 62% of the patients needling procedures had to be performed. CONCLUSION: The XEN® Gel Stent is an efficacious minimal invasive glaucoma surgery for primary open-angle and pseudoexfoliation glaucoma, resulting in significant reduction of IOP and a reduction in glaucoma medications from baseline in two-third of treated patients with 2-year follow-up. Frequent follow-up examinations were mandatory to identify early and late bleb failure and additional needling procedures were necessary to reestablish aqueous flow.

Susac syndrome (Retino-cochleo-cerebral vasculitis), the ophthalmologist in the role of the whistleblower.

BACKGROUND/PURPOSE: Susac syndrome is a rare microangiopathy of suspected autoimmune origin affecting arteries of the retina, the cochlea and the brain. The aim of the study was to give a review of the disease entity and determine the proportion of cases and their characteristics in a uveitis referral centre. PATIENTS AND METHODS: Charts of patients with the diagnosis of Susac syndrome seen in the Uveitis Clinic of the Centre for Ophthalmic Specialised Care (COS), Lausanne, Switzerland were reviewed retrospectively to determine the frequency of such cases in a uveitis referral centre. Clinical symptoms and signs, functional data, imaging signs and evolution were analysed in the 3 COS cases and one case shared with the Uveitis Clinic of the Department of Ophthalmology, University of Innsbruck, Austria. Characteristic signs were searched possibly allowing a prompt diagnosis. RESULTS: During the period from 1994 to 2019 (24 years, 2045 patients), 3 charts with the diagnosis of Susac syndrome were found (0.15%). The whole collective, including the additional case, comprised three women aged 28, 32 and 63 at presentation and one man, aged 42. None of the 3 cases that were referred were diagnosed beforehand. The characteristic item found in all 4 cases was the abrupt arterial stop or segmental interruption of arteries and increased staining of arterial wall on angiography more clearly shown on indocyanine green angiography that can potentially be proposed as a crucial diagnostic element. All 4 cases responded to dual steroidal and non-steroidal immunosuppression. Under treatment, all four patients did not show any further evolution. CONCLUSION: Susac syndrome is a multilocation arteritis of the head that can involve the eye, ear and brain often first diagnosed by the ophthalmologist. The diagnosis is rapidly reached in uveitis referral centres but seems to be missed otherwise, A helpful angiographic sign to be searched is an abrupt or segmental arterial stop and increased staining of the arterial wall more clearly seen on indocyanine green angiography. Patients often present first to the ophthalmologist who should be acting as a whistleblower to avoid severe involvement of the brain.

N-chlorotaurine Inactivates Acanthamoeba and Candida albicans in the Porcine Ex Vivo Corneal Infection Model.

PURPOSE: N-chlorotaurine (NCT) is an anti-infective belonging to the class of chloramines and an investigative drug for the topical treatment of keratoconjunctivitis. The aim of the present study was to demonstrate its efficacy against Acanthamoeba and Candida in corneas infected ex vivo. METHODS: Corneal buttons from porcine eyes were contaminated with Acanthamoeba castellanii trophozoites or Candida albicans Centraalbureau voor Schimmelcultures 5982 and incubated for 7 and 3 days, respectively. Subsequently, they were treated with 1% NCT for 5 to 120 minutes. After further incubation for 2 days in the absence of NCT in tests with A. castellanii, the buttons were homogenized, and the amoebae grown for a further 5 days before they were counted in a light microscope. For C. albicans, quantitative cultures were performed from corneal homogenates. RESULTS: Incubation of 120 minutes in NCT completely inhibited the regrowth of A. castellanii and reduced the number of C. albicans colony-forming unit counts by 4 log10. In addition, at 60 minutes, significant reductions of both pathogens could be observed. Histology showed penetration of pathogens into the stroma of the corneal buttons. CONCLUSIONS: NCT inactivates A. castellanii and C. albicans in corneal tissue.

Substance P and secretoneurin in vitreous aspirates of patients with various vitreoretinal diseases.

By means of highly sensitive radioimmunoassays, the levels of substance P (SP) and secretoneurin (SN) were detected in vitreous aspirates of patients with macular holes which served as controls, in patients with nonproliferative diabetic retinopathy (DR), active proliferative diabetic retinopathy (active PDR), inactive PDR, rhegmatogenous retinal detachment and proliferative vitreoretinopathy (PVR). Furthermore, SN-like immunoreactivities were characterized by reversed phase-HPLC. The concentration of SN was more than 20-fold higher in macular holes when compared with SP and reversed phase HPLC revealed evidence that the vitreous levels of SN represent authentic SN. SN was significantly decreased in patients with nonproliferative DR, active PDR and inactive PDR by more than 70% which seems to result from a reduced expression and/or secretion from the cilary epithelium and a reduced release from the retina both due to diabetes mellitus. By contrast SP was increased in rhegmatogenous retinal detachment most obviously due to an enhanced outflow of the peptide through retinal breaks. Despite their proangiogenic activities, SP and SN are unlikely to be involved in the pathogenesis of neovascularizations in DR because of their unchanged and reduced levels, respectively, but the low levels of both peptides may facilitate the regression of vasoproliferations following laser photocoagulation.

Tolerability of N-chlorotaurine plus ammonium chloride in the rabbit and human eye--a phase 1 clinical study.

BACKGROUND: N-chlorotaurine (NCT), an endogenous mild antiseptic, is well-tolerated by application to the human conjunctiva and has been shown to offer beneficial effects in infectious conjunctivitis. Animal tests revealed improved efficacy of a combination of NCT with ammonium chloride in adenoviral conjunctivitis. The aim of this study was to evaluate the tolerability of NCT plus ammonium chloride in the healthy rabbit and human eye. METHODS: First, a tolerability study was performed in rabbits. In a blinded and randomized fashion, one eye was treated with the test medication, the other one with 0.9% saline. Twenty-one animals (three per concentration) were treated with one drop every 2 hours for 6 days. Second, in two volunteers one drop of a defined concentration was applied to one eye every 15 min for 1 hour, saline to the control eye. Four different concentrations were tested on different days. Third, a double-blind, randomized phase 1 study in 13 healthy volunteers was performed. One drop of 0.1% NCT plus 0.1% NH(4)Cl versus saline was applied every 15 min within the first hour, followed by four drops every 2 hours. This regimen was done daily for 5 days. RESULTS: In rabbits, no side effects were seen with 0.1% NCT plus 0.1% NH(4)Cl, while higher concentrations sometimes caused short-time and minimal conjunctival injection and secretion after dosing. By 1% NCT plus 1% NH(4)Cl, these effects were moderate, but disappeared again without any detectable residues. In the pilot study with two volunteers, treatment with 0.5% NCT plus 0.1% NH(4)Cl caused medium-scale eye burning for 30 seconds, while 0.1% NCT plus 0.1% NH(4)Cl was very well-tolerated, with no or minimal burning for a few seconds. In the subsequent phase 1 study, 0.1% NCT plus 0.1% NH(4)Cl was well-tolerated by all subjects except for minimal eye burning for a few seconds after dropping. No objective signs of eye changes could be detected in the human beings. CONCLUSION: The results of this study clearly demonstrate the good tolerability of a promising NCT formulation with improved activity.

Peptidergic nerves in the eye, their source and potential pathophysiological relevance.

Over the last five decades, several neuropeptides have been discovered which subsequently have been found to be highly conserved during evolution, to be widely distributed both in the central and peripheral nervous system and which act as neurotransmitters and/or neuromodulators. In the eye, the first peptide to be explored was substance P which was reported to be present in the retina but also in peripherally innervated tissues of the eye. Substance P is certainly the best characterized peptide which has been found in sensory neurons innervating the eye. Functionally, it has been shown to act trophically on corneal wound healing and to participate in the irritative response in lower mammals, a model for neurogenic inflammation, where it mediates the noncholinergic nonadrenergic contraction of the sphincter muscle. Over the last three decades, the interest has extended to investigate the presence and distribution of other neuropeptides including calcitonin gene-related peptide, vasoactive intestinal polypeptide, neuropeptide Y, pituitary adenylate cyclase-activating polypeptides, cholecystokinin, somatostatin, neuronal nitric oxide, galanin, neurokinin A or secretoneurin and important functional results have been obtained for these peptides. This review focuses on summarizing the current knowledge about neuropeptides in the eye excluding the retina and retinal pigment epithelium and to elucidate their potential functional significance.