To evaluate radiographic lacrimal gland (LG) volume and dimensions in Ahmed glaucoma valve (AGV)- versus trabeculectomy-treated eyes and contralateral non-treated eyes.

In this retrospective cohort study, 1616 medical records acquired between 2010 and 2020 were examined. In AGV-treated (group 1) eyes, there were 19 patients with records sufficient for radiological LG evaluation, and in trabeculectomy-treated (group 2) eyes, there were 18. The hospital workstation software was used to assess high-resolution computed tomography (HRCT) scans conducted under standard protocol using a 128 SL Optima CT 660 scanner. The software (Vitrea™) was used to perform semi-quantitative volumetric measurements. LG dimensions were obtained in the axial and reformatted coronal planes on each side, and four measures were generated using the widest LG tip-to-tip diameters in two planes: coronal length, coronal width (CW), axial length (AL), and axial width.

The time interval between surgery and HRCT imaging was 50.97 ± 26.25 months. Group 1 had significantly lower LG volume than group 2 (594.11 ± 259.45 vs. 933.67 ± 294.09 mm3, P = 0.001). When compared to non-treated eyes, AGV-treated eyes had lower LG volume (P = 0.065) while trabeculectomy-treated eyes had higher LG volume (P = 0.031). Further, group 1 had decreased length and width in both the axial and coronal planes as compared to group 2, with AL and CW being significantly different (P < 0.05).

AGV and trabeculectomy had varied impacts on LG volume and dimensions despite being conducted in the same quadrant. HRCT appears to be effective in analysing AGV position, which may be related to LG volumetric and dimensional issues.

A detailed understanding of the immunopathogenesis of mucous membrane pemphigoid (MMP) is of particular importance in view of the mostly difficult diagnostics and treatment of this blistering autoimmune dermatosis. A still unknown disturbance of the body's own immune tolerance leads to the formation of autoreactive cells. As the disease progresses these produce autoantibodies which are directed against structural proteins in the basement membrane zone (BMZ). After they bind to the target antigen, complement factors are deposited along the BMZ and inflammatory cells invade the underlying tissue and produce the characteristic subepithelial blistering. This inflammatory response is associated with fibrosis and scarring in many affected tissues. Most phases of MMP pathogenesis are poorly understood; however, the last few years have shed more light on this processes. These advances are mostly the result of animal and cell culture models. Typical clinical and immunopathological characteristics of MMP, such as oral, conjunctival and skin lesions, are reflected, for example, in an antibody transfer-induced mouse model for anti-laminin 332 MMP in adult mice. Dapsone, as first-line treatment for MMP patients, significantly reduced the severity of these symptoms, and fibrosis in the skin and mucous membranes was also found histologically, which makes the model well-suited for testing new therapeutic approaches for MMP patients and might be of help for further elucidation of the immunopathogenesis of MMP.

Assessment of ocular surface in patients using anti-glaucoma medications (AGM) is rarely a priority for clinicians since glaucoma management targets intraocular pressure and preserves vision. This review summarizes the various adverse effects of topical AGM on the ocular surface and highlights the importance of ocular surface assessment in these patients.

A literature search of articles (English only) on the subject matter was conducted focusing on recent articles published in the past 5 years.

The use of multiple anti-glaucoma medications in glaucoma patients increases patients' exposure to the drug and the preservatives present in these medications. Long-term use of these medications has deleterious effects on the conjunctiva, cornea, eyelids, and periocular tissues like trichiasis, entropion, symblepharon, forniceal shortening, punctate keratopathy, non-healing epithelial defects, and pannus. Treatment requires drug withdrawal or substitution by oral or topical non-preserved and less toxic preparations of AGMs. The ocular surface and symptoms can improve if the condition is diagnosed early and after drug withdrawal in over 90% of eyes. However, stopping or changing AGMs can often present with its own unique set of challenges in intra-ocular pressure control which may often need glaucoma surgery in close to 20% of eyes for IOP control.

Topical antiglaucoma medications (with their preservatives) can induce severe ocular surface and periorbital changes. Early identification and withdrawal of the offending drug/preservative can help to reverse the changes except in eyes with extensive cicatrization.

Drug induced cicatrizing conjunctivitis (DICC) is defined as a disease in which conjunctival cicatrization develops as a response to the chronic use of inciting topical and, rarely, systemic medications. DICC accounts for up to one third of cases of pseudopemphigoid, a large group of cicatrizing conjunctival diseases sharing similar clinical features to those of mucous membrane pemphigoid (MMP) but generally without the morbidity of progressive scarring or the need for systemic immunosuppression. The preservatives in topical anti-glaucoma medications (AGM) are the most frequently implicated inciting causes of DICC although topical antivirals, vasoconstrictors and mydriatics and some systemic drugs have been implicated. The literature review summarizes the classification, epidemiology, etiopathogenesis, histopathology, clinical presentation, diagnosis, management, and treatment outcomes of DICC in the context of a case series of 23 patients (42 eyes) with AGM induced DICC, from India and the UK. In this series all subjects reacted to preserved AGM with one exception, who also reacted to non-preserved AGM. At diagnosis >70% of eyes showed punctal scarring, inflammation, and forniceal shortening. Pemphigoid studies were negative in the 19/23 patients in whom they were carried out. DICC can be classified as non-progressive, progressive with positive pemphigoid immunopathology or progressive with negative pemphigoid immunopathology. It is unclear whether progressive DICC is a stand-alone disease, or concurrent (or drug induced) ocular MMP. Progressive cases should currently be treated as ocular MMP. The diagnosis can be made clinically when there is rapid resolution of symptoms and inflammation, usually within 1-16 weeks, after withdrawal of suspected inciting medications, ideally by temporary substitution of oral carbonic anhydrase inhibitors. If the response to withdrawal is uncertain, or the progression of inflammation and scarring continues then patients must be evaluated to exclude concurrent (or drug induced) MMP, and other potential causes of CC, for which the treatment and prognosis is different. Management, in addition to withdrawing inciting medications, may require short-term treatment of conjunctival inflammation with steroids, treatment of associated corneal disease with contact lenses or surface reconstructive surgery, control of intra-ocular pressure with non-preserved AGM and, in some, surgery for glaucoma or for trichiasis and entropion.

The association between antiglaucoma medications and the development of ocular pseudopemphigoid (OPP) has been described; however, the independent risk of each medication has not been quantified.

Case/non-case analyses were performed in the FDA Adverse Events Reporting System (FAERS) using data from 2010-2020 to examine the reporting odds ratio (ROR) signal for OPP for all classes of antiglaucoma medications under multiple conditions: (i) comparison to all other drugs in FAERs, (ii) comparison to other antiglaucoma medications, (iii) comparison to vehicle/hydrating eye drops with cases of OPP and (iv) comparison to vehicle/hydrating eyedrops with and without cases of OPP to control for topical irritant and preservative effects.

A statistically significant ROR for OPP was found for aggregate antiglaucoma medications under the first condition but not the third or fourth (i.96.97 (95% CI 52.54-178.98). The largest signal for OPP when compared to other glaucoma drugs and eye drops was seen with unoprostone (ii.68.96 (95% CI 8.35-569.50, iii.39.85 (95% CI 4.14-383.33), iv.581.67 (95% CI 49.38-6851.57) followed by carteolol (ii.32.51(95% CI 9.02-117.67), iii.10.67 (95% CI 1.77-64.13), iv.77.84 (95% CI 12.95-467.78) and betaxolol (ii.23.38 (95% CI 7.28-74.46), iii.6.94 (95% CI 1.27-38.01), iv.50.67 (95% CI 9.26-277.25). A statistically significant ROR was noted only for the beta-blockers class aggregate under conditions ii and iv.

Our findings support an association between OPP and antiglaucoma medications; under the most stringent control for topical irritant/preservative effect by of comparison to topical eye drops, unoprostone, carteolol, betaxolol and timolol all had a significant ROR for OPP.

Many patients are treated for glaucoma. Like other drugs, anti-glaucoma eye drops may induce dermatological adverse effects. We aim to review the dermatological adverse effects secondary to the active agents in anti-glaucoma eye drops through a literature review. In January 2020, we queried PubMed using the following MeSH terms: glaucoma/drug therapy or glaucoma, open angle/drug therapy cross-referenced with parasympathomimetics/adverse effects or adrenergic agonists/adverse effects or carbonic anhydrase inhibitors/adverse effects or prostaglandins F, synthetic/adverse effects or adrenergic beta antagonists/adverse effects or ophthalmic solutions/adverse effects. The initial search identified 1128 studies, of which 49 were excluded for being in a foreign language, 15 for not involving eye drops, 968 for not focusing on adverse dermatological effects, and 11 for insufficient documentation or redundancy. After adding 38 linked studies, we finally analysed 123 studies. The ocular and periocular dermatological adverse effects of eye drops are contact dermatitis, hyperpigmentation, prostaglandin analogue periorbitopathy, mucous membrane pemphigoid, eyelash depigmentation, skin hypertrichosis, and rare cases of melanoma and skin depigmentation. The reported distant dermatological adverse effects are psoriasis, excessive sweating, lichen planus, alopecia, toxic epidermal necrolysis, erythema multiforme, erythroderma, subacute cutaneous lupus erythematosus, nail pigmentation and bullous pemphigoid. Most of the cutaneous adverse effects of anti-glaucoma eye drops are ocular and periocular and induced by prostaglandin analogues. Distant adverse effects are rare and sometimes questionable but should be kept in mind, especially mucous membrane pemphigoid, which could lead to blindness. The role of preservatives, such as benzalkonium chloride, should also be considered.

Glaucoma-related ocular surface disease (G-OSD) is a significant, yet often underdiagnosed, ocular co-morbidity affecting 40% to 59% of glaucoma patients worldwide. Although the use of topical glaucoma medications represents a proven strategy to control the untoward effects of high intraocular pressure, this treatment can profoundly disrupt the homeostasis of the tear film. The cumulative effect of medications, preservatives, and excipients alter underlying cellular structures which results in tear film abnormalities and instability of the ocular surface. Furthermore, these chronic inflammatory changes have been shown to impact efficacy of glaucoma treatment, patient compliance with therapy and overall quality of life. The pathogenesis of G-OSD is multifactorial and involves a vicious self-perpetuating cycle of inflammatory cytokines and proteins. The diagnosis of such disease is based on similar tests used in assessing traditional dry eye, taking into consideration findings specific to this patient population. The hallmark of treatment for these patients is to minimize the ocular surface inflammatory response by choosing glaucoma therapies that spare the ocular surface such as preservative free formulations and initiating dry eye treatment early in the course of care. In summary, glaucoma affects millions of patients around the world and chronic use of topical glaucoma medications may negatively impact the patient's ocular surface, symptoms, and vision. Understanding the pathogenesis of G-OSD, recognizing its risk factors and incorporating diagnostic and therapeutic strategies that restore and maintain ocular surface homeostasis will result in improved care for our patients.

Patients with conjunctival cicatrizing disease may develop lacrimal obstruction. Little is published on lacrimal obstruction as the presenting feature of otherwise asymptomatic cicatrizing conjunctival disease. The records of all patients presenting between 1994 and 2015 with lacrimal obstruction found to have cicatrizing conjunctival disease were reviewed. Demographic details, clinical findings, disease progression and treatment were analyzed. Thirty-five patients (25 female), aged 43-91 years (median 74, mean 71.3 years) had epiphora and a mild conjunctival cicatrizing process. Nine patients had onset of epiphora after cataract surgery. All except one patient had obstruction of the proximal lacrimal system (punctum and/or canaliculus). In 14 cases, the obstruction was unilateral (both puncta or canaliculi), with one progressing to bilateral obstruction after 11 years. In 19, all 4 puncta or canaliculi were obstructed. Two patients had unilateral nasolacrimal duct obstruction; one developed contralateral canalicular obstruction 2 years later. Conjunctival biopsies were obtained in 19 of 35 cases (54%), and OCP immunohistochemistry was positive in 7/19 (37%). All other biopsies showed chronic inflammation. Two patients had lichen planus. In follow-up (range 0.1-11 years, mean 3.2 years), 2 patients' conjunctival disease progressed mildly, and 3 progressed moderately, with 2 of these 5 having positive OCP immunohistochemistry, and 1 having lichen planus. Patients with conjunctival cicatrization may present with lacrimal obstruction, usually punctal or canalicular. Conjunctival disease is usually mild and non-progressive, but patients should be monitored for disease progression.

Glaucoma is a chronic, progressive disease in which retinal ganglion cells disappear and subsequent, gradual reductions in the visual field ensues. Glaucoma eye drops have hypotensive effects and like all other medications are associated with adverse effects. Adverse reactions may either result from the main agent or from preservatives used in the drug vehicle. The preservative benzalkonium chloride, is one such compound that causes frequent adverse reactions such as superficial punctate keratitis, corneal erosion, conjunctival allergy, and conjunctival injection. Adverse reactions related to main hypotensive agents have been divided into those affecting the eye and those affecting the entire body. In particular, β-blockers frequently cause systematic adverse reactions, including bradycardia, decrease in blood pressure, irregular pulse and asthma attacks. Prostaglandin analogs have distinctive local adverse reactions, including eyelash bristling/lengthening, eyelid pigmentation, iris pigmentation, and upper eyelid deepening. No systemic adverse reactions have been linked to prostaglandin analog eye drop usage. These adverse reactions may be minimized when they are detected early and prevented by reducing the number of different eye drops used (via fixed combination eye drops), reducing the number of times eye drops are administered, using benzalkonium chloride-free eye drops, using lower concentration eye drops, and providing proper drop instillation training. Additionally, a one-time topical medication can be given to patients to allow observation of any adverse reactions, thereafter the preparation of a topical medication with the fewest known adverse reactions can be prescribed. This does require precise patient monitoring and inquiries about patient symptoms following medication use.

Pemphigus is an autoimmune bullous disease that may be influenced by genetic and exogenous factors. Drugs are a leading cause of pemphigus. There is a need for a thorough history taking so as to find the culprit medication. The diagnosis of drug-induced pemphigus is challenging. Patients have often been exposed to multiple drugs, and some drugs may have a prolonged latency period between exposure and onset of the disease. The in vitro interferon-gamma (IFN-gamma) release from lymphocytes test has been shown to be of diagnostic value in drug-induced skin reactions. Cessation of the offending drug may alleviate the clinical manifestations and reduce the need for medical treatment.

Glaucoma affects millions of people around the world. With the baby boom generation aging, the number of people affected by primary open-angle glaucoma in the US is expected to reach 3.3 million by 2020, and about half may not know they have the disease. The treatment of most forms of glaucoma includes the use of topical agents that enhance aqueous humour outflow, reduce aqueous production, or both. Topical intraocular pressure-lowering drugs must penetrate across the tissues of the eye to reach their therapeutic targets. Often, these tissues show the first signs and symptoms of drug toxicity and adverse effects. These include eyelid dermatitis, malpositions, lacrimal system scarring, ocular discomfort upon instillation, tear film instability, conjunctival inflammation, subconjunctival fibrosis, conjunctival epithelium changes, and corneal surface and endothelial impairment. For these reasons, ophthalmologists should evaluate the risks and benefits of ophthalmic medications before initiating therapy, identify the minimum dosages necessary to achieve a therapeutic benefit, and monitor patients for local and systemic adverse effects. Adverse events may be reduced by changing to a different class of topical medication, using corticosteroids, lubricating the eyes frequently, and reducing exposure to preservatives. This in turn can lead to higher levels of adherence to antiglaucoma therapy, improved outcomes and a reduction in the costs associated with long-term glaucoma complications. This article reviews the ocular adverse effects associated with the various classes of topical antiglaucoma drugs, with a particular focus on the ocular surface, eyelids and periorbital tissue.

To investigate the inhibitory effects of drugs containing timolol on the proliferation of human conjunctival cells in vitro.

Timoptol, Timoptol XE, Rysmon TG, and Timabak solutions were used. These commercially available drugs were diluted to 1/30, 1/100, and 1/300, and their effects on cell morphology, cell count, and cell activity were investigated. The effects of drugs containing benzalkonium chloride (BAK) as well as those of the Rysmon TG vehicle alone were also assessed.

At 1/30 dilution, cells treated with Timoptol and Timoptol XE showed cell deformation. Timoptol and Timoptol XE also caused a significant decrease in the number of cells at 1/100 and 1/30 dilutions. Cell activity decreased in a concentration-dependent manner after the addition of either Timoptol or Timoptol XE. Rysmon TG and Timabak showed significantly higher cell activity than Timoptol or Timoptol XE at both 1/100 and 1/30 dilutions. The cell count increased in a concentration-dependent manner in the BAK-free group, while cell activity decreased in a concentration-dependent manner in the cultures in the BAK-containing group.

Compared with Timoptol and Timoptol XE, Rysmon TG and Timabak showed milder toxicity on human conjunctival cells in vitro.

To compare the anatomical pattern of lacrimal drainage system obstruction (LDSO) associated with topical anti-glaucoma medications (AGM) with a control group.

In a cross-sectional controlled study, case group included patients on topical anti-glaucoma medications and control group included patients with no history of glaucoma, free of ocular disease, and not using topical medications. Data recording, eye examination, and categorization of patients into case and control groups were performed by a senior ophthalmology resident. Diagnostic probing and irrigation test was performed by an oculoplastic surgeon who was masked to the patients' data. Chi-square (X(2)) and tests were used to assess the effect of sex and systemic diseases, as well as logistic regression analysis with intra-cluster correlation for the effect of topical anti-glaucoma medications on lacrimal drainage system, and then independent sample t-tests to compare the mean ages, plus the binary logistic regression test for the effect of increasing age on LDSO.

There were 128 eyes of 96 patients in the case and 277 eyes of 172 patients in the control group. Two groups were similar regarding to the age, sex, and associated systemic disorders (0.3<P<0.5). There was a significantly more LDSO in the case than control group (P = 0.008). Upper LDSO was observed in 76.92% (20/26) of the cases, and 37.5% (9/24) of the control group (P = 0.01). Nasolacrimal duct obstruction was also found in 19.23% of case group.

Although punctum and canaliculus are the main anatomical sites of LDSO associated with topical AGM, common canaliculus and nasolacrimal duct separately or in association with punctum and canaliculus may also be involved.

Cicatricial pemphigoid is the most common of the immunobullous disorders causing conjunctival cicatrization and is an autoimmune disease in which the ocular component of the immunopathology is directed at the conjunctival basement membrane. The disease is usually bilateral and more common in females, with most cases occurring between 30-90 years, and most often in the seventh decade. The disease occasionally occurs in children. Tear deficiency is a major cause of symptoms, although loss of vision is usually due to surface failure before the onset of aqueous tear deficiency, which occurs late in the progression of the disease. Management of the dry eye must be integrated with the management of the other components of both the ocular surface disease and inflammation. Management requires plastic surgery for the lid and lash malposition, tetracyclines and lid hygiene for the accompanying blepharitis. For the dry eye, the use of lubricants without preservatives is important, to avoid toxicity, and lubricant ointment is helpful for the relief of symptoms in terminally dry eyes without the capacity for surface wetting. Contact lenses, either large limbal diameter rigid gas permeable or gas permeable scleral lenses, are useful for treating dry eye and improving vision in some patients. Control of the conjunctival inflammation is mandatory to prevent disease progression and usually requires systemic immunosuppressive therapy.

Ocular manifestations are a comorbidity of a group of chronic autoimmune blistering diseases that includes mucous membrane pemphigoid, linear immunoglobulin A disease, epidermolysis bullosa acquisita, and ocular pemphigus vulgaris. Various diagnostic measures differentiate between the diseases and allow for appropriate treatment including a specific selection of immunomodulatory medications. New treatment modalities offer alternatives that may minimize disease severity and residual tissue damage and may reduce treatment-related complications.

Cicatricial entropion and trichiasis may be caused by a variety of diseases, of which trachomatous entropion is the commonest worldwide. The spectrum of disease in the authors' community is quite different. The purpose of this study was to establish the aetiology of entropion and trichiasis in patients referred to a Melbourne-based subspecialty oculoplastics practice, excluding epiblepharon, congenital entropion and involutional entropion, and to compare the final diagnosis with the referring diagnosis.

All records of patients with cicatricial entropion and trichiasis presenting to the practice of one of the authors over the period 1990-2000 were analysed. Demographic data, referring diagnosis and final diagnosis were tabulated.

The commonest final diagnosis was ocular cicatricial pemphigoid. In only a small proportion of cases was this diagnosis considered by the referring practitioners. In addition, two cases of undiagnosed conjunctival neoplasia presented with entropion and trichiasis.

In all patients with entropion and trichiasis, a careful history and examination should be obtained and appropriate investigations performed to try and establish a firm diagnosis.

The aim of the study was to evaluate the occurrence of ocular adverse effects observed after administration of anti-allergic eye drops with and without a preservative in patients with allergic conjunctivitis.

A total of 3090 patients with allergic conjunctivitis and treated with anti-allergic eye drops were included in an open nonrandomised prospective study by 507 general practitioners located throughout France. The symptoms of discomfort and pain experienced during instillations as well as the characteristics of the patients and of their allergic pathology were recorded.

Two groups of patients (eyedrops without preservative [n = 2712] and with preservative [n = 121]) were identified. Sixty percent and 15% of the cases of allergic conjunctivitis were associated with rhinitis and asthma, respectively, and for 70% of the occurrences, an identifiable factor (pollen, dusts, animals etc.) was responsible for the appearance of the symptoms. Compliance was significantly higher for anti-allergic eye drops without preservative than for those with a preservative (average number of instillations 3.5 vs 2.9/day, p < 0.001; number of instillations omitted 3.6 vs 4.2, p = 0.01). The proportion of patients experiencing at least one adverse drug reaction was 24% for eye drops with no preservative and 89% for eye drops with a preservative (p < 0.001). The most frequently notified symptom was a sensation of prickling and burning (10% and 47%, respectively, for eye drops with no preservative and eye drops with a preservative; p < 0.001).

The prescription of eye drops with no preservative allows a significant decrease in ocular adverse drug reactions and a greater acceptance by the patient regarding his/her anti-allergic treatment.

Corneal toxicity is caused by chemical trauma and by iatrogenic and factitious disease, which are often overlooked, and which are reviewed here. The clinical signs of iatrogenic disease are usually nonspecific and identical to those resulting from other causes of surface disease. Factitious disease is either the result of mechanical trauma or the abuse of toxic eye drops. One epidemiological study, in a tertiary setting, identified 13% of keratoconjunctivitis cases as iatrogenic. Healing was prolonged taking 7-93 (median 28.5) days. Pathogenic mechanisms vary widely with different drugs and include subclinical scarring, pseudopemphigoid, drug-induced ocular cicatricial pemphigoid, and toxic follicular reactions. There is little readily available data either on the probability of the development of adverse reactions or for the comparison of different drugs. The assessment of the toxicity of topical drugs is currently by the Draize test in rabbits. New in vitro tests on human corneal epithelial cell cultures include ATP assays for cell viability, scanning EM of epithelial microvilli, and vital staining to assess cell membrane permeability and intracellular esterase. Despite their simplicity, these test systems can correlate well with clinical toxicity and provide a toxicity index for drug comparisons. Treatment requires drug withdrawal or substitution by non-preserved and less toxic preparations. Factitious injury is rare, difficult to diagnose, and should only be considered when all other diagnoses have been excluded. Prevention requires a high level of awareness of the potential for iatrogenic disease, particularly in the high-risk setting of chronic ocular surface disease.

We present 13 cases of oral mucous membrane pemphigoid (MMP) and review the literature. The cases were retrieved from the archives of Ondokuz Mayis University and Gülhane Military Medical Academy, Turkey, between 1997 and 2002. Inclusion criteria were clinical findings of oral MMP verified by histological and immunofluorescent examination. Thirteen patients (two males and 11 females), aged 16-72 years, were identified. Involvement was confined to the mouth in all cases except one, in which the conjunctiva was also affected. Two individuals in the study were < 20 years old, an age group rarely affected. The oral mucosa is often the initial site of MMP lesions, so it is important that dentists as well as physicians are aware of the symptoms and signs. A swift diagnosis, made in consultation with other specialists such as ophthalmologists and dermatologists, is needed in order to prevent a delay in treatment.

Glaucoma, a leading cause of blindness worldwide, is a chronic neurodegenerative disorder. Patients with glaucoma may require long-term administration of intraocular pressure (IOP)-lowering medications. These medications belong to several classes of molecules including beta-adrenergic blockers, cholinergic agents, alpha-adrenergic agonists, carbonic anhydrase inhibitors and ocular hypotensive lipids. Most adverse effects associated with IOP-lowering medications are mild and ocular in nature; however, several of them are associated with systemic risks as well as serious ocular effects, especially following chronic use. The following review discusses the acute and long-term effects of commonly used IOP-lowering medications.

To determine the incidence of ocular toxicity of preservatives with glaucoma medications.

A prospective epidemiological survey was carried out in 1999 by 249 ophthalmologists on 4107 patients. Ocular symptoms, conjunctiva, cornea, and eyelids were assessed. A chi(2) test was used for differences between preserved eye drops (P) and preservative free eye drops (PF).

84% patients used P, 13% received PF, and 3% a combination of P and PF eye drops. All symptoms were more prevalent with P than with PF drops (p<0.001): discomfort upon instillation (43% versus 17%), and symptoms between instillations such as burning-stinging (40% versus 22%), foreign body sensation (31% versus 14%), dry eye sensation (23% versus 14%), tearing (21% versus 14%), and eyelid itching (18% versus 10%). An increased incidence (>2 times) of ocular signs was seen with P eye drops. The prevalence of signs and symptoms was dose dependent, increasing with the number of P drops. A reduction in the symptoms and signs was observed when patients changed from P to PF eye drops (p<0.001).

Symptoms and signs are less prevalent when PF drops are used. Moreover, most of the adverse reactions induced by P glaucoma medication are reversible after removing preservatives.

To present a new indicator that measures the sulci of the lacrimal lake of the eye according to the degrees of ocular abduction at which they vanish. This new approach will help determine the severity and progression of mucosal retraction in ocular surface diseases.

A total of 181 eyes of 94 healthy persons, 130 eyes of 65 patients with Sjogren's syndrome, and 30 eyes of 15 patients with ocular pemphigoid were examined using the slit lamp. We recorded the vanishing point of the three main lacunar sulci (plico-bulbar, plicocaruncular and dermo-caruncular) while abducting.

In healthy persons, the average vanishing points for the first and second lacunar sulci were respectively, 53.20 +/- 12.3 and 54.50 +/- 9.8. In patients with Sjogren's syndrome, 49.53 degrees +/- 10.81 and 53.17 degrees +/- 7.28 and in patients with incipient ocular cicatricial pemphigoid, 42.69 degrees +/- 14.33 and 44.46 degrees +/- 16.85. Statistical significance was p < 0.005.

The lacunar sulci are shallower and vanish sooner in ocular cicatricial pemphigoid and Sjogren syndrome than in normals. Investigating the vanishing point of the lacunar sulci while abducting is useful for grading the shrinkage of the conjunctiva, caruncle and medial canthus.

Cicatricial pemphigoid (CP) is a heterogeneous group of rare, chronic, subepithelial blistering disorders of the mucous membranes and, occasionally, the skin, which can have serious and rarely fatal consequences. The most common clinical features are desquamative gingivitis, oral erosions, and conjunctival fibrosis. Skin lesions occur less frequently and may present as widespread vesicles and bullae, as in bullous pemphigoid (BP). In some patients, the scarring can be a source of significant morbidity because it can result in odynophagia, strictures of the upper aerodigestive tract, or corneal opacities leading to eventual blindness. This article is a comprehensive review and discusses clinical, pathologic, and pathophysiologic aspects of this group of disorders collectively known as CP. (J Am Acad Dermatol 2000;43:571-91.)

At the conclusion of this learning activity, participants should be familiar with the clinical spectrum of CP, the histopathologic and immunopathologic characteristics, the differential diagnosis, the treatment, and the natural history of the disease. Furthermore, this learning activity should facilitate early diagnosis of CP and should promote the idea that the involvement of other specialists, including ophthalmologists, otolaryngologists, gastroenterologists, and oral medicine specialists, as appropriate, will aid in providing these patients with the highest quality of care.

Several ocular side effects including uveitis, have been reported following topical beta blocker treatment for glaucoma and ocular hypertension. The incidence of these side effects was investigated in the Netherlands.

A prospective observational design was used whereby monthly questionnaires were sent to all practising ophthalmologists in the Netherlands during 3 consecutive months. Questionnaires were returned at the end of each month. Any patient whose topical beta blocker therapy was altered because of an ocular reaction was noted on this questionnaire. Ophthalmologists who did not return their questionnaires were interviewed by telephone at the end of the study period. The number of patients using topical beta blockers was derived from drug sales figures.

70% (328/467) of the ophthalmologists in the Netherlands participated in the study. During the 3 month study period 34 cases were reported: 15 patients had periorbital dermatitis, in eight patients eyelids and conjunctiva were affected, in seven patients the conjunctiva was affected, and four patients had punctate keratitis. The calculated incidence of ocular side effects during topical beta blocker therapy was 1.51 cases/1000 patient years.

Topical beta blocker therapy is associated with few clinically important ocular side effects. No cases of uveitis were reported.

Much experience has been gained with the use of older classes of antiglaucoma agents--topical beta-adrenergic-receptor antagonists, nonselective adrenergic-receptor agonists, oral carbonic anhydrase inhibitors, and cholinergic agents. In the past decade, new drugs and classes of drugs used to treat glaucoma have become available, including topical carbonic anhydrase inhibitors, prostaglandin analogues, and alpha2-adrenergic-receptor agonists. Extensive community-based use of antiglaucoma medications has led to an increased understanding of the acute and long-term safety and tolerability issues associated with their use.

This paper reviews the side effects associated with the various classes of topical antiglaucoma drugs, with a particular focus on long-term safety issues.

To describe the association between the use of various types of topical ocular medications and acquired lacrimal canalicular obstruction in 14 patients.

The records of all patients in the author's practice with either lacrimal canalicular or punctal occlusion associated with the use of topical ocular medication were reviewed.

Fourteen cases were identified. The obstructions occurred at any point from the punctum to the common canaliculus, but most commonly occurred 2-5 mm from the lacrimal punctum. There was an association with various degrees of clinically apparent subconjunctival scarring maximal at the inner canthus, rarely to a severe degree, with symblepharon, medial canthal keratinization and cicatricial medial entropion. In some cases, no subconjunctival scarring could be clinically detected. Topical medications used were often multiple and included prednisolone acetate/phenylephrine hydrochloride (n = 5), timolol maleate (n = 5), pilocarpine (n = 3), dipivefrine hydrochloride or adrenaline (n = 3), chloramphenicol (n = 3), tobramycin (n = 3), indomethacin (n = 2), ecothiopate iodide (n = 1), betaxolol (n = 1), dexamethasone (n = 1), tropicamide (n = 1) and the long-term use of naphazoline and various artificial tear preparations (n = 1). The duration of exposure ranged from 3 weeks to 20 years, with seven patients having used drops for 3-6 weeks. Seven patients had surgical repair, three by dacryocystorhinostomy (DCR) and glass by-pass tube (all successful), three by canalicular repairs (one failed) and one by DCR and canalicular repair that restenosed at the puncta, who then had successful punctoplasty and silicone intubation.

Lacrimal canalicular obstruction may occur after relatively short-term exposure to topical ocular medications or as part of a more widespread cicatricial reaction in patients on long-term medication. While a direct causal relationship cannot be confirmed, there appears to be a strong association and the site of the obstructions makes other causes unlikely.

Ocular cicatricial pemphigoid is a slowly progressive disease of mucous membranes and skin of unknown but presumed autoimmune aetiology. We describe eight cases of presumed drug-induced cicatrising conjunctival changes simulating ocular cicatricial pemphigoid, following the chronic use of topical glaucoma medication. In three of four patients who underwent conjunctival biopsy of the inferior fornix, this revealed histopathological changes similar to ocular cicatricial pemphigoid.

Physical or chemical injuries, infections, immunologic oculocutaneous disorders, drugs, and various systemic disorders may cause scarring of the conjunctiva and disturbances of the ocular surface. Trichiasis, lid margin malposition, and dry eye may result in persistent ocular irritation. The cornea may be primarily or secondarily involved. If severe, disturbances of the ocular surface may lead to significant visual impairment. Thorough evaluation of patients and of the underlying disease process is required for optimal management. Treatment may be challenging and should be comprehensive, combining medical measures and surgical correction of structural changes. Suppression of exogenous irritants, treatment of dry eye, antiinflammatory therapy, and immunosuppressants are paramount to control the underlying disease and allow optimal surgical results. Surgical correction of trichiasis and lid margin malposition, conjunctival grafting, mucous membrane transplantation, limbal stem cell transplantation, amniotic membrane transplantation, and penetrating keratoplasty help reestablish a physiologic ocular surface. Severe cases may require keratoprosthetics for visual rehabilitation. Corneal ulceration or perforation requires prompt attention to maintain ocular integrity. Special measures should be considered for patients who require cataract or glaucoma surgery.

Long-term use of topical drugs can induce changes in the conjunctiva and ocular surface. To determine the conjunctival changes resulting from topical glaucoma medication, patients with glaucoma were selected and classified into seven groups, according to the medication received: 24 eyes were treated with betaxolol, 20 eyes with levobunolol, 32 eyes with timolol maleate, 22 eyes with pilocarpine, 52 eyes with beta-blocker and pilocarpine, 34 eyes with beta-blocker and dipivefrin, and 32 eyes with maximum therapy. Patients who were under 18 were excluded, as were those with any history of ocular surgery and other interventions, long-term use of any topically administered medication except glaucoma drugs, and any history or slit-lamp examination evidence of ocular surface disorders. The changes in the conjunctiva of 216 eyes were evaluated by means of ocular surface impression cytology. The medication group showed statistically significant degrees of conjunctival metaplasia when compared to the control group (p < 0.01). The cytological grading was not correlated with age, sex, type of medication, duration of topical treatment or the number of drugs (p > 0.05). Duration of treatment exceeding three months was not correlated with cytological grading. Thus, as far as surgical treatment was concerned, it was concluded that intervention within the first three months after the diagnosis would be most beneficial in the management of glaucoma. The fact that the presence of the preservative benzalkonium chloride was the same in all preparations suggests that it may be the major factor in conjunctival metaplasia.

Ocular cicatricial pemphigoid (OCP) is a chronic autoimmune cicatrizing disease which affects the conjunctiva and other squamous epithelium, resulting in a scarring process. A similar process, limited only to the conjunctiva, observed in some patients using eye drops for the treatment of glaucoma, is called pseudo-ocular cicatricial pemphigoid (P-OCP). Immunofluorescence studies demonstrate deposition of immunoglobulins and complement components in the basement membrane zone (BMZ) of the conjunctiva and an anti-basement membrane zone antibody in the serum of patients. A striking association between OCP and MHC class II gene DQB1*0301 has been observed. The purpose of this study was to determine some of the differences in the binding of OCP and P-OCP sera to different lysate in an immunoblot assay, in an attempt to partially characterize the OCP and P-OCP antigens. Furthermore, we wanted to determine if the MHC class II gene association of P-OCP is similar to that of OCP.

We studied sera from 11 patients with active ocular cicatricial pemphigoid and seven patients with pseudo-ocular cicatricial pemphigoid and controls. Indirect immunofluorescence (IIF) studies were done using monkey esophagus and salt split normal human skin as substrate. A sensitive immunoblot assay (IBA) was developed using normal human epidermis, dermis and conjunctiva as substrate. Typing for MHC class II genes was performed on eight pseudo-ocular cicatricial pemphigoid patients by dot-blot analysis and compared to 38 matched controls.

Weak staining of the basement membrane zone was observed in nine of ten ocular cicatricial pemphigoid sera and five of seven pseudo-ocular cicatricial pemphigoid sera in the IIF assay using monkey esophagus. Using salt split human skin as substrate, ten of eleven ocular cicatricial pemphigoid sera demonstrated low titer weak binding to the epidermal side of the split. No consistent pattern of staining was seen with pseudo-ocular cicatricial pemphigoid sera. Ten of the 11 ocular cicatricial pemphigoid sera demonstrated binding to 230, 205, 160 and 85 kDa proteins in the IBA using normal human epidermis and conjunctiva lysates. When the lysates were first reacted with BP sera and then immunoblotted with ocular cicatricial pemphigoid sera, the 230, 160, and 86 kDa bands disappeared, and only the 205 kDa band persisted. The sera of five of seven pseudo-ocular cicatricial pemphigoid patients bound to 290, 230, 205, 180, 97, and 85 kDa proteins in the epidermis and conjunctiva. However, the 230, 205, 180, and 85 kDa proteins are depleted when the lysates are first reacted with BP and ocular cicatricial pemphigoid sera. In the dermal lysate, the pseudo-ocular cicatricial pemphigoid sera recognize 400, 290, 150 and 45 kDa proteins. None of these are absorbed by BP, ocular cicatricial pemphigoid or pemphigus vulgaris or epidermolysis bullosa acquisita sera. The 290 kDa proteins identified in the dermis and epidermis are distinct from each other. No binding was seen with control sera with the 3 lysates. Statistically, dot-blot analysis did not demonstrate a significant increase in the frequency of the MHC DQB1*0301 gene.

Patients with ocular cicatricial pemphigoid and pseudo-ocular cicatricial pemphigoid produce several autoantibodies. However, there are similarities and differences between them. The MHC class II genes associated with pseudo-ocular cicatricial pemphigoid are different from those with ocular cicatricial pemphigoid. This provides a new model system to study the immune abnormalities in idiopathic and drug-related organ specific autoimmunity.

Pyogenic granulomas are vascular inflammatory lesions that represent an aberrant wound healing response. They typically arise from mucous membranes or skin. Pyogenic granulomas primarily involving the cornea have been rarely reported.

Between January 1983 and July 1994, 14 patients with histologically proven pyogenic granulomas of the cornea were treated.

The precipitating event was a persistent epithelial defect in nine patients. Ocular surface disease was present in all patients. Predisposing conditions included indolent corneal ulceration, cry eye syndrome, trachoma, trichiasis, alkali burn, multiple topical drug use, previous orbital irradiation, and ocular cicatricial pemphigoid.

Ophthalmologists should be aware that pyogenic granulomas may involve the cornea and include this entry in the differential diagnosis of tumors involving the limbus or cornea. The typical clinical appearance, rapid growth, minimal staining with rose bengal dye, response to topical steroids, and associated ocular surface disease help to distinguish this lesion from a neoplastic epithelial tumor of the conjunctiva or cornea.

Recent publications have suggested that the long term use of topical antiglaucoma medications may be detrimental to the outcome of trabeculectomy. In order to investigate this further, the effect of several adrenergic agents and a preservative on the proliferation and viability of human Tenon's capsule fibroblasts in tissue culture were examined. The following compounds were tested: adrenaline (Eppy 1% and pure adrenaline base 1%, Smith & Nephew Pharmaceuticals Ltd); dipivefrine hydrochloride (Propine 0.1% and pure dipivefrine hydrochloride 0.1% Allergan Ltd and Allergan Pharmaceuticals (Ireland) Ltd); benzalkonium chloride (pure benzalkonium chloride 0.01%, Sigma Chemical Company Ltd); the two adrenaline based preparations were also tested in the presence of an antioxidant. None of the tested compounds stimulated the proliferation of fibroblasts. The commercial products tested, their pure compounds, and the preservative all inhibited proliferation and had toxic effects on the cells. In the presence of antioxidant, commercial Eppy and pure adrenaline base appeared to have less effect on proliferation and toxicity. These findings are discussed with reference to the outcome of trabeculectomy.

The surgical treatment of lower lid entropion in ocular cicatricial pemphigoid has previously met with limited success and conventional techniques have in some cases caused disease progression. We have treated lower lid entropion in this condition with retractor plication, avoiding surgery to the conjunctiva in five patients (seven eyelids) over the past five years with successful correction of the condition and symptomatic improvement in all patients. It has not led to an acute exacerbation of the condition in any patient and we recommend it as the procedure of choice in the surgical management of entropion in this disorder.

The aim of this review is to demonstrate the spectrum of conditions encompassed by the term 'chronic progressive cicatrising conjunctivitis', to discuss mechanisms of conjunctival scar tissue formation and to describe the sequelae and therapeutic options in this potentially blinding condition. Chronic progressive cicatrising conjunctivitis is found in association with some mucocutaneous disorders (cicatricial pemphigoid, linear IgA disease), as part of paraneoplastic syndromes and after long-term treatment with certain systemic and topical medications (pseudo-pemphigoid). Recent studies on the conjunctiva of pemphigoid patients indicate that macrophages may play a pivotal role in chronic progressive conjunctival cicatrisation. They mediate the transition from inflammation to scar tissue by secretion of fibrogenic cytokines. There is evidence that similar mechanisms are involved in the other fibrosing conjunctival disorders. Sequelae of chronic conjunctival cicatrisation include the obstruction of lacrimal and meibomian glands, tear film alterations, trichiasis, keratopathy and blindness. Present possibilities and future options for the treatment of this condition are discussed.

Increasing evidence indicates that long-term use of topically administered medications can induce changes in the conjunctiva and ocular surface. We used the technique of conjunctival impression cytology to evaluate the conjunctival changes that develop with long-term use of topically administered antiglaucoma medications. Patients with glaucoma who were on a stable regimen of one, two, or three topically administered medications were recruited for study; glaucoma suspects who were not using topically administered medications served as controls. Eyes with clinical or historical evidence of external eye disease or conjunctival surgery were excluded. Impression cytology specimens, collected from the bulbar and palpebral conjunctiva, were coded and subsequently graded by a masked observer. We examined specimens from 72 eyes by using this technique. Aggregate scores for the bulbar conjunctiva were compiled, using a previously described grading system with a range of 0 (normal) to 3 (diffuse, severe metaplasia). The results show statistically significant degrees of conjunctival metaplasia associated with the number of glaucoma medications used. These results suggest that the long-term use of antiglaucoma medications induces changes in the conjunctival surface. These changes may be related to the medications themselves, the preservatives in the commercial preparations, or the duration of topical treatment. The clinical relevance of these changes remains unknown.