Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors.

Angio-oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE-I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE-I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE-I-related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE-I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE-I treatment-related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE-I AE.

Evaluation of the integrity of human corneal epithelium maintained in organ-culture during eye banking using Corneamax®

Purpose: Mediums have been developed to conserve corneal endothelium in organ-culture during eye banking. CorneaMax® is used by 25% of Eye Bank in Europe. Only little is known about conservation of corneal epithelium with this medium during banking. Its preservation could be of interest in clinic to cure corneal disease with stem cells deficiency. Therefore, we wanted to examine the integrity of human corneal epithelium maintained in CorneaMax®. Methods: Human corneas, considered unsuitable for transplantation, were obtained from the Eye Bank in Lausanne. Average post-mortem time was 14 hours. Cornoscleral rings were maintained in organ-culture in Corneamax® at 32°C. Samples were formalin-fixed after period ranging from 0 (D0) to 35 days (D35, N=5 for each time points) and stained with H&E. Proliferation and apoptosis were evaluated by immunostaining with antibody against Ki67 and Caspase3 respectively. Results: Corneas, which were not in organ-cultured (D0), showed different morphology, including intact epithelium with 5 to 7 layers, but also completely denuded basement membrane. In two cases, at D0, the epithelium lost its adherence to the basal lamina of the cornea creating a large epithelial sheet. During the two first days, corneas and limbus area lost totally their epithelium, except for some remaining limbal basal cells. From day 2 to day 10, regeneration of the epithelium took place, starting from the limbal region in direction to the central cornea. From day 10 to day 35, corneal epithelium appeared as an atrophic epithelium, consisting of only two cell layers. Proliferation happened in the whole cornea during the 35 days of organ-culture, as shown by Ki67 positive cells. Apoptosis was rarely detected in the corneal epithelium. Conclusions: Corneas maintained in CorneaMax® showed a complete disappearance of the corneal epithelium during the two first days and a conservation of limbal basal cells in the limbal region. These remaining cells allowed a full regeneration of the tissue, leading to an atrophic epithelium, composed of only two cell layers. This atrophic epithelium could be seen in all the organ-cultured corneas during the 35 days of conservation. This study is a first step to develop medium in organ-culture in order to conserve corneal epithelial cells.

Long-Term Follow-Up of Multilayer Amniotic Membrane Transplantation (MLAMT) for Non-Traumatic Corneal Perforations or Deep Ulcers with Descemetocele.

Background: To evaluate the long-term efficacy of multilayer amniotic membrane transplantation for reconstruction of epithelium and stroma in non-traumatic corneal perforations (less than 2 mm) or deep ulcers with descemetocele.Design: Retrospective, non-comparative, interventional case series.Patients and Methods: Eleven consecutive patients with non-traumatic corneal perforations or deep corneal ulcers with descemetocele refractory to conventional treatments: herpetic or zoster keratitis (n = 4), Sjögren's syndrome (n = 2), rosacea (n = 1), hydrops (n = 1), mucous membrane pemphigoid (n = 1), bacterial keratitis (n = 1) and perforation after protontherapy for melanoma (n = 1). Intervention was: multilayer amniotic membrane transplantation with cryopreserved amniotic membrane. Complication rate and clinical outcome were evaluated in this long-term follow-up.Results: Mean follow-up was 32 months (12 to 60). Integration of the multilayer amniotic membrane was obtained in 10 cases after one year. Corneal epithelium healed above the membrane in 10 cases within 3 weeks and remained stable after 32 months in 9 cases. Thickness of the stroma was increased and remained stable during the follow-up in 9 cases. In one case herpetic keratitis recurred with a corneal perforation. The clearing of the amniotic membrane was gradually obtained over a period of 11 months. Complications occurred in 15 % of the eyes during the long-term follow-up.Conclusion: Multilayer amniotic membrane transplantation is a safe and efficient technique for a long restoration of the corneal integrity after non-traumatic corneal perforations or deep corneal ulcers with descemetocele. Long-term prognosis of these eyes depends of the gravity of the initial disease.

Systemic adalimumab induces peripheral corneal infiltrates: a case report.

BACKGROUND: Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. CASE PRESENTATION: A 34 year-old Caucasian woman with Crohn's disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. CONCLUSION: Paradoxical immune reactions associated with tumor necrosis factor-alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy.

Posterior Sub-Tenon Triamcinolone Injection for Chronic Macular Oedema Associated With Non-Ischemic Branch or Central Retinal Vein Occlusion

Aims: To evaluate the effectiveness and safety of Posterior Sub-Tenon (PST) Triamcinolone Acetonide (TA) injection for persistent macular oedema associated with non-ischemic Central Retinal Vein Occlusion (CRVO) or Branch Retinal Vein Occlusion (BRVO) in non-vitrectomized eye. Methods: Fourteen consecutive eyes of 14 patients characterized by macular oedema lasting more than 3 months and with a visual acuity of less than 20/40 were enrolled. Six eyes presented with BRVO, 8 eyes with CRVO. PST injection of 40 mg TA was performed in topical anaesthesia. All patients were phakic, and followed for at least 6 months. Snellen visual acuity converted to LogMAR units and anatomic responses were evaluated before, and at 1, 3, 6, and 12 (if required) months after injections and re-injection considered. Results: In the BRVO group, mean foveal thickness was 548.2±49.50 μm preoperatively, and 452.8±56.2 μm and 280.8±62.5 μm at 1 and 12 month follow-up, respectively. Statistical analysis showed significant differences between preoperative and postoperative measurements (P<.05, paired t test) 3 months after injections. Improvement of visual acuity by at least 0.2 LogMAR was seen in 3(50%) of the 6 eyes. No re-injection was needed. In the CRVO group, mean foveal thickness was 543.7±34.4 μm preoperatively, and 283.0±29.0 μm and 234.8±23.6 μm at 1 and 12 month follow-up, respectively. Statistical analysis showed significant differences between preoperative and postoperative measurements (P<.05, paired t test). Improvement of visual acuity by at least 0.2 LogMAR was seen in 7 eyes (88%). Mean number of re-injection was of 2.1±0.3. Intraocular pressure elevation of 22 mm Hg or higher was found in 2/14 eyes (14%). Cataract progression was noted in 5/14 eyes (36%). Conclusions: PST injection of TA appears to be as safe and effective treatment for chronic macular oedema associated due to both non-ischemic BRVO or CRVO, with a better efficacy in BRVO.

Corneal Dystrophies: Overview and Summary.

In this chapter, I shall discuss the genetics, mode of inheritance and molecular origin of several corneal dystrophies.

Effects of topical 0.2% Cyclosporine A on corneal neovascularization induced by xenologous amniotic membrane implantation into a corneal stroma micropocket of rats

The objective of the study was to evaluate the topical effects of 0.2% Cyclosporine A (CsA) on corneal neovascularization of rats following surgical implantation of equine amniotic membrane into a corneal stroma micropocket. The implantation of xenologous amniotic membrane was performed bilaterally in 90 rats. In the same day of the surgery each right eye started receiving topical CsA twice a day. The left eye received no medication and served as a control. The evaluation of corneal neovascularization was performed by computerized image analysis and histopathological evaluation at 1, 3, 7, 15, 30 and 60 days postoperatively. For the image analysis 10 animals were used per time period, and for the histopathological examination, five animals were used per time period. Image analysis found that corneal neovascularization began on the 3rd postoperative day, reached its peak on the 7th day, and then progressively and rapidly decreased. Statistic analysis indicated that neovascularization of the CsA treated eye on the 7th day was significantly higher than that observed in untreated eyes. On the 30th day, however, this pattern was reversed with the neovascularization observed in the CsA treated eyes declining to the low levels observed on the 3rd day. The degree of neovascularization in the untreated eyes on the 30th day declined to the baseline levels found on day 3 at the 60th day. Histopathological analysis indicated that deposition of collagen in the implanted tissue was completed by the 15th day. Therefore, we concluded that (1) equine amniotic membrane in rat corneal stroma produced an intense neovascularization until the 15th day postoperatively and then regressed, (2) deposition of collagen of the implanted tissue was completed on the 15th day postoperatively, and (3) use of CsA was associated with increase in the corneal neovascularization initially, followed by a quick and intense regression.

Morphological analysis of the corneal endothelium in eyes of dogs using specular microscopy

Both healthy eyes of 10 six-year-old male and female mongrel dogs were studied. With a contact specular microscope the corneal endothelium was examined. Endothelial cells were analyzed in the central and peripheral cornea. Morphological analysis with regard to polymegathism and pleomorphism was performed. Three images of each region with at least 100 cells were obtained. The analysis showed that polygonal cells formed a mosaic-like pattern uniform in size and shape. The predominant number of cells was hexagonal. The polymegathism index was 0.22. The study demonstrates that the morphology of the normal corneal endothelial cells of dogs is similar to that found in the human cornea.

Collagens and proteoglycans of the corneal extracellular matrix

The cornea is a curved and transparent structure that provides the initial focusing of a light image into the eye. It consists of a central stroma that constitutes 90% of the corneal depth, covered anteriorly with epithelium and posteriorly with endothelium. Its transparency is the result of the regular spacing of collagen fibers with remarkably uniform diameter and interfibrillar space. Corneal collagen is composed of heterotypic fibrils consisting of type I and type V collagen molecules. The cornea also contains unusually high amounts of type VI collagen, which form microfibrillar structures, FACIT collagens (XII and XIV), and other nonfibrillar collagens (XIII and XVIII). FACIT collagens and other molecules, such as leucine-rich repeat proteoglycans, play important roles in modifying the structure and function of collagen fibrils.Proteoglycans are macromolecules composed of a protein core with covalently linked glycosaminoglycan side chains. Four leucine-rich repeat proteoglycans are present in the extracellular matrix of corneal stroma: decorin, lumican, mimecan and keratocan. The first is a dermatan sulfate proteoglycan, and the other three are keratan sulfate proteoglycans. Experimental evidence indicates that the keratan sulfate proteoglycans are involved in the regulation of collagen fibril diameter, and dermatan sulfate proteoglycan participates in the control of interfibrillar spacing and in the lamellar adhesion properties of corneal collagens. Heparan sulfate proteoglycans are minor components of the cornea, and are synthesized mainly by epithelial cells. The effect of injuries on proteoglycan synthesis is discussed.

An experimental model of mycobacterial infection under corneal flaps

In order to develop a new experimental animal model of infection with Mycobacterium chelonae in keratomileusis, we conducted a double-blind prospective study on 24 adult male New Zealand rabbits. One eye of each rabbit was submitted to automatic lamellar keratotomy with the automatic corneal shaper under general anesthesia. Eyes were immunosuppressed by a single local injection of methyl prednisolone. Twelve animals were inoculated into the keratomileusis interface with 1 µl of 10(6) heat-inactivated bacteria (heat-inactivated inoculum controls) and 12 with 1 µl of 10(6) live bacteria. Trimethoprim drops (0.1%, w/v) were used as prophylaxis for the surgical procedure every 4 h (50 µl, qid). Animals were examined by 2 observers under a slit lamp on the 1st, 3rd, 5th, 7th, 11th, 16th, and 23rd postoperative days. Slit lamp photographs were taken to document clinical signs. Animals were sacrificed when corneal disease was detected and corneal samples were taken for microbiological analysis. Eleven of 12 experimental rabbits developed corneal disease, and M. chelonae could be isolated from nine rabbits. Eleven of the 12 controls receiving a heat-inactivated inoculum did not develop corneal disease. M. chelonae was not isolated from any of the control rabbits receiving a heat-inactivated inoculum, or from the healthy cornea of control rabbits. Corneal infection by M. chelonae was successfully induced in rabbits submitted to keratomileusis. To our knowledge, this is the first animal model of M. chelonae infection following corneal flaps for refractive surgery to be described in the literature and can be used for the analysis of therapeutic responses.

Effect of topical dorzolamide on rabbit central corneal thickness

Our objective was to study the effect of dorzolamide on corneal hydration in an 18-week controlled experiment using ultrasonic pachymetry. Twenty-eight male rabbits were divided randomly into four groups. The 7 rabbits in each group received eye drops containing either 2% (w/v) dorzolamide or placebo in their right eye, or in their left eye. The 2% dorzolamide rabbits were treated every 8 h. Fellow eyes are defined as eyes which did not receive either dorzolamide or placebo. The study was blind for both the person who applied the drug and the one who performed the pachymetry. The effect of treatments is reported on the basis of the percentage of pachymetric variation compared to the measurement made before drug application. There was no significant difference (P = 0.061) in pachymetric variation between dorzolamide (-4.42 ± 11.71%) and placebo (2.48 ± 9.63%). However, there was a significant difference (P = 0.0034) in pachymetric variation between the dorzolamide fellow eyes (-7.56 ± 10.50%) and the placebo (-4.42 ± 11.71%). In conclusion, dorzolamide did not increase the corneal thickness in rabbits.

Dose-dependent in vitro inhibition of rabbit corneal matrix metalloproteinases by an extract of Pothomorphe umbellata after alkali injury

The in vitro ability of Pothomorphe umbellata ethanolic crude extract to inhibit matrix metalloproteinase (MMP) in normal cornea and in cornea after alkali injury was demonstrated. Corneas of albino rabbits were injured with 1 N NaOH for 20 s. After 48 h the corneas were excised, homogenized and analyzed for MMP-9 (92 kDa), pro-MMP-2 (72 kDa) and MMP-2 (67 kDa) activity by gelatin zymography. The activity was also measured in untreated corneas. After electrophoresis of 20 µg protein, gels were incubated with 50, 100, or 250 µg/mL lyophilized hydroethanolic (1:1) root crude extract of P. umbellata standardized for 4-nerolidylcatechol (7.09%). The activity of the enzymes was compared with that of untreated gel. At 48 h after injury, the activity of all MMPs was increased compared with untreated eyes. When the gels were incubated with P. umbellata extract the activity of MMP-2, pro-MMP-2 and MMP-9 decreased in a dose-dependent manner. MMP-9 activity decreased by approximately 50% after incubation with 50 µg/mL and was completely abolished at 100 and 250 µg/mL of the extract. After incubation with 50 µg/mL the activity of pro-MMP-2 and MMP-2 also decreased by 50%. The activity of pro-MMP-2 was almost completely abolished after incubation with 250 µg/mL of the extract. For MMP-2 the incubation with 100 or 250 µg/mL of the extract of P. umbellata promoted a 10-fold decrease in activity. In conclusion, P. umbellata root crude extract can be useful as an alternative therapy to control MMP activity after corneal injury.

Restoration of the rabbit corneal surface after total epithelial debridement and complete limbal excision

How is the corneal epithelium restored when all of it plus the limbus have been eliminated? This investigation explored the possibility that this may be achieved through the conjunctival epithelium. The corneal epithelium of the right eye of 12 rabbits (Oryctolagus cuniculus) was totally scraped followed by surgical excision of the limbus plus 1.0-1.5 mm of the adjacent conjunctiva. Antibiotics and corticosteroids were applied for 1 week after surgery. Histological and immunohistochemical techniques were used to monitor the events taking place on the eye surface 2 weeks and 1, 3 and 6 months thereafter. Initially, the corneal surface was covered by conjunctival-like epithelium. After 1 month and more prominently at 3 and 6 months an epithelium displaying the morphological features of the cornea and reacting with the AE5 antibody was covering the central region. It is likely that the corneal epithelium originated from undifferentiated cells of the conjunctiva interacting with the corneal stroma.