Mark B. Abelson

Conjunctivitis of allergic origin: Immunologic mechanisms and current approaches to therapy

The pathogenesis of ocular allergy involves multiple mechanisms, which lead to mast cell degranulation and the release of chemical mediators. Mast cell mediators that have been implicated in allergic ocular disease include histamine, eosinophil chemotactic factors, eosinophil granule major basic protein, platelet-activating factor, prostaglandin D2, and several other less well-defined preformed or newly synthesized mediators. The release of these chemical mediators ultimately results in conjunctival vasodilation, increased vascular permeability, leukocyte chemotaxis, and, rarely, ocular surface destruction. Current therapy of ocular allergy involves elimination of the offending allergen, modulation of the immune system, and pharmacologic inhibition of the chemical mediators. The purpose of this article is to provide a better understanding of the pathogenesis and current therapy of ocular allergic disorders and to review the central role of the mast cell and chemical mediators involved in ocular allergy.

Vigabatrin: 2008 update.

Vigabatrin (VGB) is a structural analogue of γ‐aminobutyric acid (GABA) that irreversibly inhibits GABA‐transaminase (GABA‐T), increasing brain levels of GABA. VGB is under assessment for treatment of infantile spasms (IS) and refractory complex partial seizures (CPS). Response can be rapid with spasm cessation following approximately 2 weeks of therapy. Patients with symptomatic tuberous sclerosis (TS) and other patients have achieved spasm cessation. Comparison with ACTH has been performed. Patients with refractory CPS have responded as well. Adverse effects and structural findings on imaging occur with VGB treatment. T2 hyperintensities within brain have been observed. Psychotic disorders or hallucinations have occurred rarely. A specific adverse effects is associated VGB, with a peripheral visual field defect (VFD) detected in some patients. Prevalence and incidence of the VGB‐induced peripheral VFD varied depending on the age of the patient and the extent of exposure to VGB, with 25% to 50% prevalence in adults; the prevalence in children was 15% and retinal defect in infants ranged from 15% to 31%. A bilateral nasal defect may be the first clinical indication and may progress to a concentric, bilateral field defect observed in many affected patients; central visual acuity is almost always preserved. The earliest finding of the first abnormal field examination in adults was after 9 months of treatment; with a mean duration of VGB exposure of 4.8 years. In children, the earliest onset of a first abnormal field examination was after 11 months, with a mean time to onset of 5.5 years. The earliest sustained onset of the VGB‐induced retinal defect in infants was 3.1 months.

Alternative reference values for tear film break up time in normal and dry eye populations.

In several tissues and cell lines, including epithelial cells of the prostate, breast and seminal vesicles, and in acinar cells of the meibomian and other sebaceous glands, androgens have a major stimulatory effect on the production, accumulation and/or secretion of lipids.1–11 In most of these tissues and cell lines, the composition of these lipids is complex. Accumulating lipids include cholesterol esters, diacylglycerides, triglycerides and wax esters. Depending on the tissue type, these lipids may have different physiological functions and dysregulation of their production is related to pathological conditions as diverse as acne, dry eye syndromes and cancer. In acne and dry eye syndromes local modulation of androgen action may provide an effective therapy.7,12

Factors influencing predilection and outcome in bacterial keratitis.

Complete records from 175 patients with 176 episodes of culture-proven bacterial keratitis treated over a 4-year period at the Massachusetts Eye and Ear Infirmary in Boston were analyzed. Sixty-three percent of the infections involved gram-positive organisms, and 40% involved gram-negative organisms; 15% were polymicrobial. There was a high incidence of infection with Staphylococcus aureus (28%), coagulase-negative staphylococci (14%), diphtheroids (14%), Pseudomonas aeruginosa (14%), and Streptococcus pneumoniae (12%). Gram stain correlation was achieved in 55%. Potential predisposing factors, usually multiple, were identified in 97% of the patients. Fifty percent of the ulcers were associated with such iatrogenic factors as prior topical corticosteroid therapy, penetrating keratoplasty, and contact lens use. Trauma occurred in only 16%. Several statistically significant associations of epidemiologic factors and outcome variables were revealed. Ninety-five percent of the ulcers resolved with therapy, but only 44% of the patients had visual acuity better than the level at admission, and 13% developed major complications.

Eosinophil Granule Major Basic Protein and Charcot-Leyden Crystal Protein in Human Tears

We measured the levels of major basic protein and Charcot-Leyden crystal protein in tears from patients with ventral keratoconjunctivitis or miscellaneous inflammatory or noninflammatory ocular conditions, and from normal subjects. Patients with vernal keratoconjunctivitis had significantly increased levels of both proteins in their tears compared with the other subjects tested; levels of major basic protein seemed to correlate with the severity of the disease. The levels of Charcot-Leyden crystal protein paralleled those of major basic proteins.

Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity

PURPOSE To evaluate the effectiveness and safety of olopatadine hydrochloride and to determine its optimal concentration and the onset and duration of action for treating allergic conjunctivitis. Olopatadine is a new topical ophthalmic antiallergic agent that demonstrates activity as both an antihistamine and a mast cell stabilizer. Two double-masked, randomized, placebo-controlled, contralateral eye comparison studies were conducted using the conjunctival allergen challenge model. METHODS A total of 169 subjects received 0.05% or 0.1% olopatadine. Study subjects were healthy adult men and women with a history of active allergic conjunctivitis within the previous two seasons but not receiving current treatment. With an allergen dose that produced signs and symptoms of allergic conjunctivitis at visits 1 and 2, the conjunctival allergen challenge was performed 27 minutes after study drug administration at the third visit (onset-of-action challenge) and at 8 hours after study drug administration at the fourth visit (duration-of-action challenge). Olopatadine was administered in one eye and placebo in the opposite eye. Itching and redness were scored for both eyes at 3, 10, and 20 minutes after the conjunctival allergen challenge. RESULTS Both 0.05% and 0.1% concentrations of olopatadine were significantly (P < .05) more effective than placebo in inhibiting itching and redness at all evaluations when administered 27 minutes or 8 hours before the conjunctival allergen challenge. There were no serious or drug-related ocular or nonocular adverse events in either study. CONCLUSION These findings demonstrate the rapid and prolonged (at least 8 hours) ocular antiallergic action of olopatadine.

The Level of Tryptase in Human Tears: An Indicator of Activation of Conjunctival Mast Cells

Tryptase, a neutral endoprotease, is secreted by activated mast cells in human tissues. Tryptase levels in various body fluids have been used as an indicator of mast cell activation. The authors determined tryptase levels in unstimulated tears collected from the following groups of patients: (1) normal control, (2) nonallergic ocular inflammation, (3) asymptomatic seasonal allergic conjunctivitis, (4) symptomatic seasonal allergic conjunctivitis, (5) vernal conjunctivitis, and (6) contact lens-associated giant papillary conjunctivitis. They also assessed the release of tryptase into the tear fluid after provoking the conjunctiva with (7) allergens, (8) compound 48/80, and (9) rubbing. Tryptase levels were elevated in tears of patients with active ocular allergy and also increased after provoking the conjunctiva with allergens in atopic subjects and with compound 48/80 and rubbing in nonatopic subjects. Tryptase levels in tear fluid may prove useful as a clinical indicator of mast cell involvement in ocular allergic disorders. In provocation experiments, tryptase levels may be used to evaluate and compare different mast cell stabilizing agents.

Tear Histamine Levels in Vernal Conjunctivitis and Other Ocular Inflammations

Histamine levels were measured in tears from normal volunteers (geometric mean, 5 ng/ml), patients with vernal conjunctivitis (16 ng/ml), and patients with a wide variety of external ocular inflammatory disease (3 ng/ml). Histamine levels were significantly higher in patients with vernal conjunctivitis than in normal subjects (P < 0.01) or patients with other types of ocular inflammation (P < 0.001). We postulate that histamine is an important mediator in the expression of the inflammatory response in vernal conjunctivitis, and that its elevation may be caused by abnormalities in the number of mast cells, the stability of the mast cells or in the system that regulates histamine.

Evaluation of Olopatadine, a New Ophthalmic Antiallergic Agent with Dual Activity, Using the Conjunctival Allergen Challenge Model

BACKGROUND An ophthalmic antiallergic agent with selective H1 antihistaminic and mast cell stabilizing properties has been developed. OBJECTIVES To evaluate efficacy and safety, determine optimal concentration, and demonstrate onset and duration of action of this new drug, olopatadine. METHODS This was a placebo-controlled, randomized, double-masked, parallel-group, single-center study with five outpatient visits at least 7 days apart. Ninety-eight healthy, allergy-positive, subjects with a recent history of active allergic conjunctivitis not receiving current treatment participated. Conjunctival allergen challenge (CAC) tests were performed on visits 1 and 2 to identify an allergen and concentration that consistently elicited signs and symptoms of allergic conjunctivitis. On visits 3, 4, and 5, CAC was performed 27 minutes, 8 hours, and 6 hours, respectively, after instillation of one drop of olopatadine (0.01%, 0.05%, 0.1%, or 0.15%) in one eye and placebo in the other. Both eyes were scored for the intensity of itching and redness at 3, 10, and 20 minutes after the CAC. RESULTS All four concentrations of olopatadine were clinically and statistically superior to placebo in preventing ocular itching at all evaluations and preventing redness at most evaluations from immediately and 8 hours after drug administration. No drug-related adverse events were reported. The 0.1% concentration was found to be most effective. CONCLUSIONS The results indicate that olopatadine ophthalmic solution is safe and effective in the treatment of allergic conjunctivitis, with the 0.1% concentration of olopatadine being optimal. The rapid onset and at least 8 hour duration of action of olopatadine indicates that the drug can be used twice daily.

The Ocular Protection Index.

The interaction of the time between blinks, or the interblink interval (IBI), and tear film breakup time (TFBUT) helps to regulate the integrity of the ocular surface. A protected surface exists when the TFBUT matches or exceeds the IBI. In contrast, an unprotected surface exists when TFBUT is less than the IBI. This is clinically relevant because repeated intermittent exposure of a tear film-deficient cornea can lead to ocular discomfort and the development of clinical signs, such as keratitis and redness. The relationship between TFBUT and IBI has been quantified by the Ocular Protection Index (OPI), which is calculated by dividing TFBUT by IBI. If the OPI is <1.0, the patient has an exposed ocular surface, putting them at risk for the development of the signs and symptoms of dry eye, whereas if the OPI is ≥1.0, the patients ocular surface is tear film protected. The OPI has proven to be useful in assessing the factors that may cause or exacerbate dry eye. This review discusses the development and use of the OPI model, its relationship to dry eye, and factors that are known to alter blink rate and tear film integrity.