Melanie Hingorani

T-cell cytokines in chronic allergic eye disease

BACKGROUND The pathophysiology of chronic allergic eye disease cannot be explained by type I hypersensitivity alone, and T cell-mediated inflammation has been strongly implicated as a possible additional mechanism. Previous studies suggested that T(H2)-like T cells play an important role in one form of chronic allergic eye disease. OBJECTIVES This study examined the cytokine profile of T cells in different clinical groups of subjects with chronic allergic eye disease (i.e., vernal keratoconjunctivitis [VKC], atopic keratoconjunctivitis [AKC], and giant papillary conjunctivitis [GPC]) and normal control subjects. METHODS In situ hybridization was used to identify cytokine messenger RNA (mRNA), and two-color immunohistochemical analysis was used to demonstrate cytokine immunoreactivity localizing to T cells in the conjunctiva. RESULTS Allergic tissue expressed increased levels of mRNA for IL-3, IL-4, and IL-5 when compared with normal tissue. There was significantly greater IL-2 mRNA expression in subjects with AKC than in those with VKC (p = 0.004) and those with GPC (p = 0.02). Immunoreactivity for T-cell IL-5 was present more frequently in subjects with VKC (p = 0.004), GPC (p = 0.02), and AKC (p = 0.04) than in normal control subjects. However, T-cell IFN-gamma protein expression was greater in subjects with AKC than in subjects with VKC (p = 0.01), GPC (p = 0.01), and control subjects (p = 0.005). CONCLUSIONS These results show a T(H2)-like T-cell cytokine array in subjects with VKC and GPC but a shift in cytokine profile toward a T(H1)-like pattern, potentially because of differences in chronicity of the disorders, in subjects with AKC. These important functional T-cell variations in chronic allergic eye conditions are likely to be important in understanding differences in clinical characteristics and therapeutic responses.

Cytokine production and mRNA expression by conjunctival T-cell lines in chronic allergic eye disease.

Activated CD4+ T cells, mast cells and eosinophils are the main cytokine‐producing cell‐types infiltrating the conjunctiva during chronic allergic eye diseases. Interactions between these cells are thought to play an important immunopathogenic role in these disorders (giant papillary conjunctivitis; vernal keratoconjunctivitis; atopic keratoconjunctivitis).

A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis

OBJECTIVE This study aimed to investigate the therapeutic effect of topical cyclosporin A (CsA) 2% in maize oil as a steroid-sparing agent in steroid-dependent atopic keratoconjunctivitis. DESIGN Prospective, randomized, double-masked, placebo-controlled trial. PARTICIPANTS Twenty-one patients with steroid-dependent atopic keratoconjunctivitis were studied. INTERVENTION Patients used either topical CsA or vehicle four times daily for 3 months in addition to their usual therapy, and the clinical response was used to taper or stop topical steroids when possible. MAIN OUTCOME MEASURES Steroid drop usage per week, ability to cease steroid use, scores for symptoms and clinical signs, drop side effects, and overall subjective rating of trial drop by patients and clinician were measured. RESULTS Cyclosporin A had a greater steroid-sparing effect than did placebo. Nine of 12 CsA patients ceased steroids compared to 1 of 9 placebo patients (P = 0.01), the final steroid use was lower in the CsA group (2.6 +/- 1.4 vs. 27.7 +/- 17.7, P = 0.005), and the mean reduction in steroid use was greater for CsA (85.5 +/- 14.7 vs. 13.9 +/- 16.0, P = 0.005). Clinical signs and symptom scores were reduced to a greater level for CsA. Serious side effects were lid skin maceration in one patient using CsA and an allergic reaction in one placebo patient. Marked blurring of vision after drop instillation was common in both groups, but intense stinging was more common in CsA patients (9/12 vs. 1/9, P = 0.01), limiting frequency of drop use. The clinician rated the trial drops as good or excellent more frequently for CsA (11/12 vs. 0/9, P < 0.0001). CONCLUSIONS Topical CsA is an effective and safe steroid-sparing agent in atopic keratoconjunctivitis and, despite difficulties in patient tolerance, also improves symptoms and signs.

Eosinophil surface antigen expression and cytokine production vary in different ocular allergic diseases

BACKGROUND The pathophysiology of chronic ocular allergic disease is not well understood. An eosinophil infiltrate is characteristic of such disease and eosinophil activity can be related to disease severity and to keratopathy, the most serious complication. Recently, eosinophils have been shown capable of cytokine production, particularly in allergic disease, although the disease-specific cytokine spectrum of tissue eosinophils is unknown. OBJECTIVES We sought to determine eosinophil numbers (absolute numbers and percentage of total leukocytes), cell surface antigen expression, and cytokine production in conjunctiva in chronic allergic eye disease and their relationship to corneal involvement. METHODS Ultrathin sections of conjunctiva were examined by tissue staining and by 1- and 2-color immunohistochemistry. RESULTS Eosinophil numbers were greater in giant papillary conjunctivitis (GPC) and vernal keratoconjunctivitis (VKC) and not related to corneal involvement. The eosinophil expression of the cell surface antigens intercellular adhesion molecule-1, CD4, IL-2R, and HLA-DR was greater in atopic keratoconjunctivitis (AKC) and VKC, the disorders with corneal disease, than in GPC, in which the cornea is not involved. For most cytokines, localization to eosinophils was greater for VKC and AKC than for GPC. RANTES, TGF-beta, and TNF-alpha localized to eosinophils in all disorders. Variations in the pattern of eosinophil-cytokine localization were found. In VKC IL-3, IL-5, IL-6, and GM-CSF were prominent; in GPC IL-5 was prominent; and in AKC IL-4, IL-8, and GM-CSF were prominent. CONCLUSIONS Chronic ocular allergic disorders affecting the cornea are distinguished from disorders that do not do so by greater expression of eosinophil surface antigens (which may imply greater cell activation) and differences in cytokine localization to eosinophils. These differences may be secondary to the variations in T-cell subsets or a primary phenomenon. Changes in eosinophil function, rather than cell numbers, may be important in clinical variations, such as keratopathy, and may allow future therapeutic exploitation.

Therapeutic Options in Ocular Allergic Disease

SummaryThe term ocular allergy encompasses a group of diseases in which there is a high frequency of atopy, ocular itching, stringy discharge and a papillary conjunctival reaction. Conditions confined to the lids and conjunctiva (e.g. seasonal allergic conjunctivitis) have a good prognosis but those involving the cornea may result in visual impairment (e.g. atopic keratoconjunctivitis). Mast cell and eosinophil mechanisms are important in all the ocular allergies, but T cell inflammation is prominent only in vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis.Therapy involves the use of antigen avoidance (where possible), nonspecific medical therapy (e.g. cold compresses, artificial tears), specific medical therapy and, in certain situations, immunotherapy and surgery.Topical antihistamines (often in combination with a vasoconstrictor) and oral antihistamines are widely used in perennial and seasonal conjunctivitis. Levocabastine is a new preparation which is more rapid and potent. Mast cell inhibitors [e.g. sodium cromoglycate (cromolyn sodium)] have a proven track record as safe and effective therapy for all ocular allergic diseases and the newer, more potent nedocromil and lodoxamide are now available. Topical steroids are only indicated in sight-threatening disease due to their serious adverse effects and other therapy should be continued to minimise the dose required.There is a lack of intermediate potency and high potency but safe topical preparations. A number of future possibilities exist, some of which have been partially explored. Cyclo-oxygenase inhibitors have proved of limited use, but inhibitors of lipoxygenase and kinin pathways are awaited. Although results with HEPP have been disappointing, other modulators of mast cell function (e.g. picumast, β-agonists and phosphodiesterase inhibitors) may prove useful in the future. So far, results with topical cyclosporin in serious disease are very encouraging. Future developments in the manipulation of eosinophilic products, cytokines and adhesion molecules may also be relevant. However, the current situation for those with serious ocular allergy remains a disturbing dependence upon topical steroids, with all the attendant risks.

Phacoemulsification time and power requirements in phaco chop and divide and conquer nucleofractis techniques.

Purpose: To evaluate the differences in phaco time and power required between the divide and conquer and phaco chop nucleofractis techniques. Setting: Department of Ophthalmology, Central Middlesex Hospital, London, United Kingdom. Methods: A retrospective pilot study of 125 patients was followed by a prospective randomized study of 117 patients comparing the phaco chop with divide and conquer techniques in terms of phaco time (minutes), phaco power (%), equivalent phaco time (calculated time required if 100% power had been used throughout), intraoperative and postoperative complications, and postoperative visual acuity. Results: In the pilot study, mean phaco time in the phaco chop group was 1.4 minutes ± 0.09 (SD) and in the divide and conquer group, 3.4 ± 0.1 minutes (P < .0001). Mean equivalent phaco time was also less in the phaco chop group (0.39 ± 0.03 minutes) than in the divide and conquer group (0.98 ± 0.08 minutes) (P < .0001). In the prospective study, phaco chop required significantly less phaco time (1.2 ± 0.1 minutes) than divide and conquer (2.4 ± 0.1 minutes) (P < .0001), less phaco power (25.3% ± 1.2% versus 35.1% ± 1.2%) (P < .0001), and less equivalent phaco time (0.29 ± 0.02 minutes versus 0.84 ± 0.05 minutes) (P < .0001). The operating time was shorter in the phaco chop group. There were no differences in complications and postoperative visual acuity. Conclusions: This study showed a significant advantage of the phaco chop over the divide and conquer technique in phaco power and duration. Phaco chop also required less operative time and intraocular manipulation without an apparent increase in intraoperative or postoperative complications.

Clinical Negligence in Ophthalmology: Fifteen Years of National Health Service Litigation Authority Data

OBJECTIVE To categorize and understand the reasons behind ophthalmic clinical negligence claims in the National Health Service and how such claims can be avoided. DESIGN Retrospective analyses of all ophthalmic clinical negligence claims between 1995 and 2009 were carried out. Data were obtained from the National Health Service Litigation Authority through the Freedom of Information Act. Claims were classified according to ophthalmic subspecialty, mean payment per subspecialty, severity, paid-to-closed ratio, and cost. PARTICIPANTS One thousand two hundred fifty-three ophthalmology-related claims occurring from 1995 through 2009. Of these, 963 claims were closed over the 15-year period. Eighty-four were excluded because of insufficient case data. INTERVENTION Retrospective analysis of all public sector ophthalmology litigation claims over a 15-year period in England. MAIN OUTCOME MEASURES Subspecialty pertaining to claim, mean payment per claim, and severity of outcome of clinical incident. RESULTS Nine hundred sixty-three claims were closed over a 15-year period, of which 67% resulted in payment. The total cost of claims was £32.1 million (

Ocular cicatricial pemphigoid

50.3 million), with a mean payment per claim of £33 300 (

Clinical utility gene card for: WAGR syndrome

52 300). The specialties with the highest mean payment per claim were neuro-ophthalmology and pediatric ophthalmology. Cataract subspecialty had the highest number of claims, accounting for 34% of all claims. CONCLUSIONS Overall, the number of litigation claims in ophthalmology is low, relative to the high volume of outpatient and surgical workload.

Clinical utility gene card for: Aniridia

Purpose of review To review the content and importance of articles on ocular cicatricial pemphigoid (OCP), or mucous membrane pemphigoid (MMP) with relevance to ocular involvement, published from 2005 to 2006. Recent findings There is wide antigenic heterogeneity in MMP and OCP and attempts are being made to link this with clinical variations with varying degrees of success. A larger study demonstrates a link between multiple autoantibody reactivity and disease severity. Details of epitope specificity are emerging. A highly sensitive ELISA for laminin 5 has been developed which may provide prognostic information. Clinically, younger OCP patients show more severe ocular disease and are less well controlled by medication. A systematic review shows good evidence only for steroids and cyclophosphamide in OCP. Continued small trials suggest some role for the expensive intravenous immunoglobulin therapy in OCP where conventional treatment fails. Ocular reconstruction surgery has made some progression, and is enhanced by adjunctive medical therapy; osteo-odonto-keratoprosthesis offers some hope of prolonged retention of limited vision in end-stage disease. Summary OCP remains a difficult disease to manage well and the progress being made in understanding disease mechanisms is whence true disease-modifying, safe therapy is likely to emerge in the future.