Jesus Merayo-Lloves

Analysis of the Acute Ophthalmic Manifestations of the Erythema Multiforme/Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Disease Spectrum

PURPOSE To evaluate the epidemiology, possible etiologic factors, complications encountered, and treatment administered to a group of patients with ocular involvement in the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum who were seen at two large tertiary referral centers over a 34-year period. METHODS Hospital records from 1960 to 1994 at the Massachusetts General Hospital and Shriners Hospital for Crippled Children were reviewed for patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Only patients fulfilling specific clinical diagnostic criteria and those who received a diagnosis by a dermatologist were included in the review. RESULTS A total of 366 patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis were identified. Drugs were the most commonly identified etiologic factor in all three conditions: sulfonamides were the most frequently identified agents. Eighty-nine patients (24%) had ocular manifestations at the time of their acute hospital stay. Ocular involvement was seen in 9% of patients with erythema multiforme, in 69% with Stevens-Johnson syndrome, and in 50% with toxic epidermal necrolysis. The ocular problems were more severe in patients with both Stevens-Johnson syndrome and toxic epidermal necrolysis. There was no significant difference between the number of patients who were treated with systemic steroids and those who were not (P = 0.42). CONCLUSIONS The erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum remains an important cause of severe visual loss in a significant number of patients. Systemic steroids used during the acute phase of the disease appear to have no effect on the development of ocular manifestations. Studies on the acute immunopathogenic mechanisms occurring in these disease are warranted if more effective therapies are to be found.

Visual Outcomes Prognosticators in Juvenile Rheumatoid Arthritis-associated Uveitis

PURPOSE The purpose of the study is to delineate the visual prognosticators in juvenile rheumatoid arthritis-associated uveitis. METHODS The records of 43 patients with juvenile rheumatoid arthritis-associated uveitis who were observed for at least 6 months were studied retrospectively. Bivariate and multivariate statistical models were applied to more than 40 parameters to determine the relative odds of visual rehabilitation among patients with each characteristic. RESULTS Thirty-seven (86%) patients were females and 6 (14%) males. The mean known age of uveitis onset was 13 years, with females having, on average, 4 years earlier onset of disease compared to males (P = 0.04). Ninety-three percent had chronic, 5% had recurrent, and 2% had an acute monophasic disease course. Of the 76 affected eyes, 93% were nongranulomatous and 97% had iridocyclitis. The mean overall duration of uveitis was 146 months, with females suffering from a significantly longer duration of active disease than did males (P < 0.001). Nineteen (44%) patients underwent cataract extraction, and 16 (37%) underwent vitrectomy. Thirty (70%) of the patients experienced visual improvement with their therapy. When controlling for potential confounders, male sex (P = 0.006), shorter duration of uveitis (P = 0.007), older age at disease onset (P = 0.02), and a shorter delay in presentation to a subspecialist (P = 0.02) were associated significantly with visual acuity improvement. Visual acuity at presentation (P = 0.001), use of systemic nonsteroidal anti-inflammatory drugs (P = 0.01), older age at disease onset (P = 0.02), absence of glaucomatous neuropathy (P = 0.02), and male sex (P = 0.03) were correlated strongly with a final visual acuity outcome of 20/40 or better. CONCLUSION Juvenile rheumatoid arthritis-associated uveitis is a serious disease with a guarded visual prognosis. It is hoped that increased awareness of its prognosticators will lead to treatment and referral patterns that have the best chance of minimizing the likelihood of visual impairment in patients with juvenile rheumatoid arthritis.

Secondary Glaucoma in Patients with Uveitis

Purpose: To evaluate the prevalence of secondary glaucoma (SG), clinical forms of uveitis more frequently associated with glaucoma, and describe the treatment and complications encountered in a cohort of patients with glaucoma and uveitis during a 10-year period. Methods: The hospital records of patients with uveitis referred to the Immunology Service of the Massachusetts Eye and Ear Infirmary for a decade were reviewed for cases of SG. Results: One hundred and twenty of the 1,254 patients (9.6%) with uveitis developed SG. SG was more frequent in anterior uveitis (67%) but was also associated with posterior uveitis (13%) and pars planitis (4%). Herpetic keratouveitis (22%), Fuchs’ iridocyclitis (19%), juvenile rheumatoid arthritis-associated iridocyclitis (16%), syphilis (14%), and sarcoidosis (12%) were the leading types of uveitis associated with SG. Despite aggressive medical and surgical therapy, SG was associated with progressive visual field loss and optic nerve damage in 39 patients (33%). Conclusion: SG is an underappreciated, vision-threatening complication in patients with uveitis. Increased vigilance for emergence of this complicating problem during the care of patients with uveitis is warranted, and medical and surgical treatment for reducing IOP should be especially aggressive in these patients. We hypothesize that earlier, more aggressive treatment of uveitis will reduce the presence of glaucoma as an additional vision-robbing complication of uveitis.

Prognosticators for visual outcome in sarcoid uveitis

PURPOSE The purpose of the study is to delineate the visual prognosticators in sarcoid-associated uveitis given the current standards of care. METHODS The records of 60 patients with sarcoid-associated uveitis who were observed for at least 6 months were studied retrospectively. Multivariate regression models using the generalized estimating equations approach to adjust for the correlation between fellow eyes were applied to determine disease, patient, and treatment characteristics that altered the odds of visual rehabilitation. RESULTS One hundred twelve eyes of 43 women and 17 men who met the inclusion criteria were identified. Seventy-seven percent of patients were white, 15% black, and 8% of Hispanic origin. Uveitis developed in the patients at a mean age of 42 (range, 4-82) years. Of the 112 affected eyes, 81% had granulomatous and 15% nongranulomatous uveitis. Most patients (66%) had anterior or intermediate uveitis alone. Ninety-one percent had chronically smoldering disease; another 7% had recurrent flares, and only 1 patient had a monophasic acute course to her uveitis. Vision-threatening complications developed in many patients, including 58% in whom cystoid macular edema developed and 25% in whom media opacities developed, requiring cataract surgery or vitrectomy or both. Overall, 34% of treated eyes and 51% of patients had final visual acuities that were superior to their acuities at presentation. The factors most significantly associated with a final visual acuity of worse than 20/40 after controlling for potential confounders were as follows: delay in presentation to a subspecialist (odds ratio [OR] = 2.94, P = 0.05), total duration of uveitis (OR = 1.04, P = 0.09), development of cystoid macular edema (OR = 0.37, P = 0.07) or glaucoma (OR = 4.54, P = 0.02), presence of intermediate (OR = 5.00, P = 0.01) or posterior uveitis (OR = 8.33, P = 0.04), and systemic steroid use (OR = 0.30, P = 0.03) were the parameters most strongly correlated with a lack of visual acuity improvement. Delay in presentation to a subspecialist (OR = 20.00, P = 0.01), development of glaucoma (OR = 50.00, P = 0.005), presence of intermediate (OR = 25.00, P = 0.02) or posterior uveitis (OR = 50.00, P = 0.02), black race (OR = 11.11, P = 0.02), (log) visual acuity at presentation (OR = 0.05, P = 0.0001), and use of systemic steroids (OR = 0.07, P = 0.02). CONCLUSION Multivariate outcomes analysis, particularly after correcting for the correlation between fellow eyes, is a useful analytic tool for optimization of standards of care and for disease risk stratification to aid both physicians and patients.

Nerve Growth Factor Promotes Corneal Epithelial Migration by Enhancing Expression of Matrix Metalloprotease-9

PURPOSE Nerve growth factor (NGF) is a neuropeptide essential for the development, survival, growth, and differentiation of corneal cells. Its effects are mediated by both TrkA and p75 receptors. Clinically relevant use of NGF was introduced to treat neurotrophic ulcerations in patients. Herein, we examine the mechanisms by which NGF enhances epithelial wound healing both in vivo and in vitro. METHODS An animal model using adult hens was implemented for the in vivo experiments. Laser ablation keratectomy was performed and animals were observed for up to 7 days. Epithelial healing was measured with fluorescein. In addition, proliferation was measured using BrdU incorporation and both TrkA and matrix metalloprotease-9 (MMP-9) expression were measured by immunohistochemistry (IHC) and Western blot (WB). In vitro experiments were carried out with telomerase-immortalized human corneal epithelial cells (HCLE). The rate of proliferation was measured using a colorimetric assay and BrdU incorporation. Real-time migration was evaluated with an inverted microscope. MMP-9 expression was evaluated by immunocytochemistry (ICC), WB, zymography, and RT-PCR. Finally, beta-4 integrin (β4) expression was assessed by ICC and WB. RESULTS Faster epithelial healing was observed in NGF-treated corneas compared with controls (P < 0.01). These corneas showed increased proliferation, TrkA upregulation, and enhanced MMP-9 presence (P < 0.01). In vitro, faster spreading and migration were observed in response to NGF (P < 0.01). Enhanced proliferation, as well as enhanced TrkA and MMP-9 expression, and decreased β4 levels were observed after adding NGF (P < 0.01). CONCLUSIONS NGF plays a major role during the epithelial healing process by promoting migration, a process that is accelerated by cell spreading. This effect is mediated by both the upregulation of MMP-9 and cleavage of β4 integrin.

Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction

Meibomian gland dysfunction (MGD) is the most frequent cause of dry eye disease (DED). Eyelid inflammation, microbial growth, associated skin disorders as well as potentially severe corneal complications culminate to make MGD a complex multifactorial disorder. It is probable that MGD is a heterogeneous condition arising from any combination of the following five separate pathophysiological mechanisms: eyelid inflammation, conjunctival inflammation, corneal damage, microbiological changes and DED resulting from tear film instability. The pathogenesis of both MGD and DED can be described in terms of a ‘vicious circle’: the underlying pathophysiological mechanisms of DED and MGD interact, resulting in a double vicious circle. The MGD vicious circle is self-stimulated by microbiological changes, which results in increased melting temperature of meibum and subsequent meibomian gland blockage, reinforcing the vicious circle of MGD. Meibomian gland blockage, dropout and inflammation directly link the two vicious circles. MGD-associated tear film instability provides an entry point into the vicious circle of DED and leads to hyperosmolarity and inflammation, which are both a cause and consequence of DED. Here we propose a new pathophysiological scheme for MGD in order to better identify the pathological mechanisms involved and to allow more efficient targeting of therapeutics. Through better understanding of this scheme, MGD may gain true disease status rather than being viewed as a mere dysfunction.

Expression of collagens I, III, IV and V mRNA in excimer wounded rat cornea: analysis by semi-quantitative PCR.

A semi-quantitative polymerase chain reaction (PCR) methodology was used to evaluate the kinetic changes occurring in collagens I, III, IV and V mRNA in rat cornea following excimer laser keratectomy. cDNA was synthesized from RNA extracted from rat cornea at various times following excimer laser photoablative keratectomy. Collagen cDNA sequences were subsequently amplified using specific sets of oligonucleotide primers. Competitive PCR amplification was carried out using an internal standard so that a semi-quantitative analysis of message for synthesis of collagen types I, III, IV and V could be performed and time course dynamics of message for these collagens studied. There was a biphasic increase in the levels of collagens III, IV and V mRNA following excimer laser keratectomy. Collagen I mRNA levels demonstrated a more sustained increase and were still elevated at 6 weeks following wounding. Collagens IV and V mRNA showed the largest increase with an approximate three fold increase over controls between 4 days and 1 week. Our results demonstrate that upregulation of stromal collagens I, III, and V mRNA and basement membrane collagen IV mRNA occurs in rat cornea following excimer laser keratectomy.

Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies.

The use of blood derivatives represents an alternative therapeutic approach that is gaining interest in regenerative medicine due to its potential to stimulate and accelerate tissue healing. Autologous serum eye drops and platelet‐enriched plasma eye drops are being used in the treatment of different ophthalmological disorders. In this review, we summarize the different blood‐derived formulations used in the treatment and care of ocular surface disorders. The biological basis and use of autologous serum and plasma rich in growth factors are deeply evaluated as well as the challenges to be addressed in the future in this new generation of blood‐derived therapies.

Experimental model of allergic conjunctivitis to ragweed in guinea pig

An experimental model of ocular allergy was developed in the guinea pig by exposing these animals to ragweed through topical contact on nasal and conjunctival mucosae, followed by subsequent challenge with ragweed contact on the conjunctiva. Animals developed clinical and histological signs of allergy with and without the use of interleukin 4 as adjuvant. This model mimics human hay fever conjunctivitis more naturally than do animal models previously reported, and it may be subsequently more valuable in the study of the response of allergic conjunctivitis to different therapeutic approaches.

A new murine model of allergic conjunctivitis and effectiveness of nedocromil sodium

BACKGROUND Allergic conjunctivitis is the most common atopic disease affecting the eye. To study the pathophysiology and effectiveness of antiallergic drugs, it is necessary to develop animal models that closely mimic human allergic conjunctivitis. OBJECTIVE The study was performed to develop an experimental murine model of ocular allergic conjunctivitis to an airborne allergen. METHODS SWR/J mice were divided into the following groups: group 1, untreated, experimental; group 2, phosphate-buffered saline-treated; group 3, nedocromil sodium-treated; and group 4, unmanipulated controls. Groups 1, 2, and 3 were exposed to ragweed by topical contact with the nasal and conjunctival mucosae. Allergic conjunctivitis was evaluated by scoring of clinical signs, serum IgE levels, and histologic findings. RESULTS Mice exposed to ragweed had clinicopathologic signs of allergic conjunctivitis and specific anti-ragweed IgE. Allergic conjunctivitis was modulated by nedocromil sodium. Treated mice had fewer clinical signs of allergy, lower levels of ragweed-specific IgE, reduction of conjunctival eosinophil infiltration, decrease in the number of intact and degranulating mast cells, and reduction of cytokine release. CONCLUSION This is the first report of a murine model of allergic conjunctivitis to an airborne allergen that can be used to study the disease pathophysiology and its response to treatment.