Aflibercept: an update on recent milestones achieved.

In the last decade, intravitreal medications targeted to vascular endothelial growth factor (VEGF) such as pegaptanib, ranibizumab and bevacizumab have revolutionized the treatment and significantly improved visual acuity outcomes in patients with retinal vascular diseases such as age-related macular degeneration (AMD), diabetic macula edema (DME) and retinal vein occlusion (RVO). In recent years, aflibercept, an anti-VEGF drug that targets all isoforms of VEGF as well as placenta growth factor, has shown similar effectiveness in recent clinical trials. Aflibercept has firmly joined ranibizumab and bevacizu-mab as an important therapeutic option in the management of neovascular AMD. More recently, aflibercept appears to be contending with ranibizumab and bevacizumab as an important therapeutic option in the management of DME and RVO.

Aflibercept for the treatment of neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) can have devastating effects on vision, especially in its neovascular form. In the last decade, the use of intravitreal pharmacotherapy targeted to vascular endothelial growth factor (VEGF) has significantly improved the visual outcomes in patients with neovascular AMD. Although we have become accustomed to these unprecedented improvement outcomes, maintaining good visual results with anti-VEGF therapy requires tremendous effort, time and cost, typically involving monthly clinic visits and intravitreal injections. The introduction of aflibercept, an anti-VEGF drug that targets all isoforms of VEGF as well as placenta growth factor, has shown promise throughout recent clinical trials as an equally effective treatment for neovascular AMD that requires less frequent dosing than either ranibizumab or bevacizumab. Based on clinical trial results, the U.S. Food and Drug Administration approved aflibercept in November 2011 for use in neovascular AMD, giving patients the hope of alleviating some of the burden associated with treatment.

Iris nodules associated with infectious uveitis.

BACKGROUND/AIM: Iris nodules are an uncommon clinical sign in uveitis. The diseases most commonly associated with iris nodules and uveitis include sarcoidosis, Vogt-Koyanagi-Harada syndrome, multiple sclerosis, Fuchs' heterochromic iridocyclitis, and metastatic infection. While many of these diseases may be appropriately treated with immunosuppressive medication, the management of infectious uveitis is antimicrobial therapy. Inappropriate immunosuppressive therapy may result in a poor outcome for the patient with an infection. Consequently, cases of uveitis with iris nodules were reviewed to identify clinical features that may help differentiate infection from non-infectious inflammation. METHODS: The clinical database of 1353 consecutive patients evaluated at a tertiary care referral based North American uveitis clinic were retrospectively reviewed to identify cases of infectious uveitis with iris nodules. A Medline search was performed to identify additional cases. From these cases information regarding clinical presentation, diagnosis, treatment, and outcome were collected. RESULTS: Three cases (three eyes) were identified from the authors' own records of infectious uveitis with iris nodules. An additional 25 cases of infectious uveitis with iris nodules were identified in 22 published reports. Analysis of the authors' cases and these reports showed that infectious uveitis with iris nodules was specifically characterised by some or all of the following: (1) creamy, soft appearance to the nodule(s), (2) unilateral disease, (3) persistence or growth of the nodule(s) despite corticosteroid therapy, (4) marked inflammatory response in the anterior chamber and/or vitreous humour, and/or (5) history suggesting a potential source of septic emboli. CONCLUSION: Certain features of the clinical history and examination are useful in the diagnosis of metastatic infection in patients presenting with uveitis and iris nodules.

Clinicopathologic correlation of fluorescein and indocyanine green angiography in exudative age-related macular degeneration.

PURPOSE: To correlate the clinical and histopathologic features of an eye with age-related macular degeneration studied with fluorescein (FA) and indocyanine green (ICG) angiography 4.5 months before the patient's death. METHODS: Histopathologic features from serial sections through the macula of a 76-year-old man with occult choroidal neovascularization (CNV) were reconstructed in a scaled two-dimensional map and compared with FA and ICG angiogram images obtained 4.5 months before his death. RESULTS: The region of prior laser photocoagulation was identified as a well-demarcated hypofluorescent region in the early frames of the FA and the early and late phases of the ICG angiogram. This corresponded histopathologically to a well-circumscribed area of absence of the choriocapillaris, loss of the outer retina and retinal pigment epithelium, and scarring of the choroid. Occult CNV characterized by elevated late hyperfluorescence on the FA and intense well-defined hyperfluorescence on the ICG angiogram corresponded to a thick fibrovascular membrane in the subretinal space and within Bruch's membrane. Thin extensions of both the subretinal and intra-Bruch's membrane fibrovascular membrane components corresponded to nonelevated stippled late hyperfluorescence on the FA and mild late hyperfluorescence on the ICG angiogram. CONCLUSION: Histopathologic mapping revealed a large fibrovascular complex located subretinally and within Bruch's membrane with thin and thick components that correlate well with findings of occult CNV on FA and ICG angiography.

Prevalence of serologic evidence of cat scratch disease in patients with neuroretinitis.

OBJECTIVE: To determine the prevalence of Bartonella henselae seropositivity in patients with a clinical diagnosis of neuroretinitis. DESIGN: Retrospective, clinic-based, cross-sectional study. PARTICIPANTS: Eighteen consecutive patients seeking treatment at the Casey Eye Institute from November 1993 through November 1998 who had neuroretinitis. METHODS: The billing and photographic records of the Casey Eye Institute were searched for patients with a primary or secondary diagnosis of neuroretinitis or Leber's idiopathic stellate neuroretinitis. Charts were then reviewed to determine the results of B. henselae antibody titers and other pertinent clinical information. MAIN OUTCOME MEASURES: Results of B. henselae serologic testing. RESULTS: Fourteen of 18 patients with neuroretinitis had serologic studies. Nine of the 14 tested patients (64.3%) were found to have elevated IgM or IgG for B. henselae, suggesting current or past infection. Patients with positive serologic analysis results tended to have worse vision at presentation. There were no other obvious differences between seropositive and seronegative groups in this study, including duration or quality of recovery. CONCLUSIONS: At our tertiary care ophthalmology institution, most tested patients with neuroretinitis had evidence of past or present cat-scratch disease based on positive serologic analysis for B. henselae, a much greater prevalence than is expected to be found in the general population or in patients with idiopathic uveitis. Further study is indicated to clarify the prevalence of cat-scratch disease in neuroretinitis and the role and efficacy of antibiotics in treatment.

Severe ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy.

PURPOSE: To report severe ocular and orbital toxicity after administration of intracarotid etoposide phosphate and carboplatin. METHOD: Case report. RESULTS: A 52-year-old man with glioblastoma multiforme underwent left intracarotid administration of eto poside phosphate and carboplatin inferior to the ophthalmic artery. Within 7 hours, a nonpupillary block angle-closure glaucoma developed secondary to uveal effusion in the ipsilateral eye, which was relieved by cycloplegia. Four days later, severe orbital inflammation resulted in a visual acuity of counting fingers, proptosis, optic neuropathy, and total external ophthalmoplegia in the eye. The patient's condition improved after a lateral cantholysis and administration of high-dose intravenous corticosteroids. Two weeks later, an anterior uveitis occurred in the left eye, which responded to topical corticosteroids. During a 2-month period, the patient recovered to a visual acuity of 20/70, near normal motility, and normal intraocular pressure, and the ocular and orbital inflammation resolved. Preexisting ipsilateral chemotherapy-induced maculopathy became more pronounced. CONCLUSION: Ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy is infrequently reported.

Eyelid laceration in a neonate by fetal monitoring spiral electrode.

PURPOSE: To report an unusual case of birth injury caused by an internal fetal monitoring spiral electrode. METHOD: Case report. RESULTS: A neonate with eyelid lacerations was examined within the first hour of life after a fetal scalp electrode was inadvertently affixed to the left upper eyelid during labor. The superficial lacerations healed without sequelae, and there was no globe injury. CONCLUSIONS: Ocular adnexal birth injury by a fetal monitoring scalp electrode has been reported rarely. Because fetal brow malpresentation is uncommon, the occurrence of this injury is unusual. Although alarming, the periorbital edema associated with this malpresentation probably protects the eyelid from perforation and the globe from injury.

Glaucoma drops control intraocular pressure and protect optic nerves in a rat model of glaucoma.

PURPOSE: To determine whether chronic topical glaucoma therapy can control intraocular pressure (IOP) and protect nerve fibers in a rat model of pressure-induced optic nerve damage. METHODS: Sixteen adult Brown Norway rats were-administered unilateral episcleral vein injections of hypertonic saline to produce scarring of the aqueous humor outflow pathways. Twice daily applications of either artificial tears (n = 6), 0.5% betaxolol (n = 5), or 0.5% apraclonidine (n = 5) were delivered to both eyes, and awake pressures were monitored with a TonoPen XL tonometer for 17 days before the rats were killed. RESULTS: For animals administered artificial tears, the mean IOP of the experimental eyes was 39 +/- 2 mm Hg compared with 29 +/- 1 mm Hg for the control eyes. This difference was statistically significant (P < 0.001). Mean IOPs in the experimental eyes of animals administered betaxolol and apraclonidine were 29 +/- 7 and 29 +/- 4 mm Hg, respectively, whereas the mean IOP in the control eyes was 28 +/- 1 mm Hg for both groups. There was no statistically significant difference among these values. The mean IOP for the experimental eyes in the betaxolol and apraclonidine groups was lower than that in animals administered artificial tears (P = 0.003). Quantitative histologic analysis of optic nerve damage in experimental eyes showed that four of the six animals administered artificial tears had damage involving 100% of the neural area. This degree of damage appeared in only 3 of 10 animals administered glaucoma therapy. Optic nerve protection was closely correlated with IOP history because damage was limited to less than 10% of the cross-sectional area in all animals in which the maximal IOP was less than or equal to 39 mm Hg, more than 2 SD below the mean value for eyes administered artificial tears. CONCLUSIONS: Topical glaucoma therapy in this model can prevent IOP elevation and protect optic nerve fibers.

The role of eicosanoids in the chemotactic response to Pasteurella haemolytica infection.

The chemotactic role of eicosanoids in the pathogenesis of Pasteurella haemolytica infection was studied, using a tissue chamber infection model and pharmacological inhibitors of eicosanoid synthesis. Tissue chambers were implanted subcutaneously in 12 calves allotted to three treatment groups of equal size. At 45 days after implantation, calves received saline, dexamethasone, or phenylbutazone treatments, and tissue chambers in all animals were then inoculated with P. haemolytica. Chamber fluid samples were collected before inoculation and at 2, 6, 18, 40, and 90 h after inoculation. Bacterial counts, total leukocyte counts, pH and albumin concentrations in chamber fluids were determined using standard bacteriological and clinical pathological methods. Concentrations of eicosanoids and activity of interleukin-1 (IL-1) were measured by radioimmunoassay and a helper T cell bioassay, respectively. Concentrations of leukotriene B4 (LTB4), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (PGF1 alpha) and prostaglandin E2 (PGE2) increased markedly after inoculation. An inhibitory effect of dexamethasone on both LTB4 production and neutrophil influx, together with the temporal relationship between these two events, suggested that LTB4 served as a chemo-attractant. Activity-time profiles for IL-1 in chamber fluids were similar to those of the eicosanoids. Phenylbutazone and dexamethasone reduced the severity of the inflammatory responses as measured by lower concentrations of albumin and higher pH in treated versus control chamber fluids. The results of this study suggest that eicosanoid inflammatory mediators play an important chemotactic role in the pathogenesis of P. haemolytica infection.

Distribution of intramuscularly administered erythromycin into subcutaneous tissue chambers before and after inoculation with Pasteurella haemolytica.

Distribution of erythromycin into subcutaneous tissue chambers was characterised pharmacokinetically and the effect of Pasteurella haemolytica infection on the extent of penetration was studied. Thermoplastic tissue chambers were implanted subcutaneously in the paralumbar fossae of six calves. Thirty-five days after implantation, the tissue chamber distribution of intramuscularly administered erythromycin (30 mg kg-1) was studied. Chambers were then inoculated with P haemolytica and the tissue chamber pharmacokinetics of erythromycin were again studied. Diffusion of erythromycin into tissue chambers was best described using a two-compartment model with tissue chambers representing a relatively inaccessible compartment. Despite changes in chamber fluid pH, the extent of erythromycin penetration into chambers was not affected by P haemolytica inoculation. Comparison of computer simulated concentration-time curves resulting from different routes of administration revealed that penetration of erythromycin into less accessible sites was more likely to be higher after intravenous administration than after intramuscular administration.

Pharmacokinetics of intravenously and orally administered pyrimethamine in horses.

Single-dose pharmacokinetic variables of pyrimethamine were studied in horses. Pyrimethamine (1 mg/kg of body weight) was administered IV and orally to 6 adult horses, and plasma samples were obtained at frequent intervals thereafter. Plasma pyrimethamine concentration was assayed by gas chromatography, and concentration-time data were analyzed, using a pharmacokinetic computer program. The IV and oral administration data were best described by 3-compartment and 1-compartment models, respectively. The median volume of distribution at steady state after IV administration was 1,521 ml/kg and the median elimination half-time was 12.06 hours. Mean plasma concentration after oral administration fluctuated between a maximal concentration of 0.18 microgram/ml and 0.09 microgram/ml (24 hours after dosing). Bioavailability after oral administration was 56%.