Balamurali K. Ambati

Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies.

Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have refined our understanding of the pathobiology of drusen, geographic atrophy, and retinal pigment epithelial detachments. Epidemiological identification of risk factors has facilitated an intelligent search for underlying mechanisms and fueled clinical investigation of behavior modification. Gene searches have not only brought us to the cusp of identifying the culpable gene loci in age-related macular degeneration, but also localized genes responsible for other macular dystrophies. Recent and ongoing investigations, often cued by tumor biology, have revealed an important role for various growth factors, particularly in the neovascular form of the condition. Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration. This in turn has culminated in preclinical and clinical trials of directed molecular interventions.

An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice

The study and treatment of age-related macular degeneration (AMD), a leading cause of blindness, has been hampered by a lack of animal models. Here we report that mice deficient either in monocyte chemoattractant protein-1 (Ccl-2; also known as MCP-1) or its cognate C-C chemokine receptor-2 (Ccr-2) develop cardinal features of AMD, including accumulation of lipofuscin in and drusen beneath the retinal pigmented epithelium (RPE), photoreceptor atrophy and choroidal neovascularization (CNV). Complement and IgG deposition in RPE and choroid accompanies senescence in this model, as in human AMD. RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. Wild-type choroidal macrophages degrade C5 and IgG in eye sections of Ccl2−/− or Ccr2−/− mice. Impaired macrophage recruitment may allow accumulation of C5a and IgG, which induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of CNV. These models implicate macrophage dysfunction in AMD pathogenesis and may be useful as a platform for validating therapies.

Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A

VEGF-A promotes angiogenesis in many tissues. Here we report that choroidal neovascularization (CNV) incited by injury was increased by excess VEGF-A before injury but was suppressed by VEGF-A after injury. This unorthodox antiangiogenic effect was mediated via VEGFR-1 activation and VEGFR-2 deactivation, the latter via Src homology domain 2-containing (SH2-containing) tyrosine phosphatase-1 (SHP-1). The VEGFR-1-specific ligand placental growth factor-1 (PlGF-1), but not VEGF-E, which selectively binds VEGFR-2, mimicked these responses. Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC). The transient decline of SPARC after injury revealed a temporal window in which VEGF-A signaling was routed principally through VEGFR-1. These observations indicate that therapeutic design of VEGF-A inhibition should include consideration of the level and activity of SPARC.

Periorbital and orbital cellulitis before and after the advent of Haemophilus influenzae type B vaccination

OBJECTIVE To evaluate the effect of the introduction of the Haemophilus influenzae B (Hib) vaccine (introduced first in 1985, then extended in 1990 to children at least 2 months of age) on the epidemiologic features of periorbital and orbital cellulitis. DESIGN Retrospective, comparative case series. PARTICIPANTS Three hundred fifteen pediatric inpatients. METHODS Children at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary with discharge diagnosis of periorbital or orbital cellulitis from 1980 through 1998 were reviewed. MAIN OUTCOME MEASURES Case rate, culture-positive isolates, and associated conditions. RESULTS A total of 297 cases of periorbital cellulitis and 18 cases of orbital cellulitis were reviewed. Before 1990, there were 27 cases of Hib-related cellulitis (11.7% of total in that period), whereas after 1990, there were only three (3.5% of total; P = 0.028). The number of cases per year was significantly lower after 1990 (21.2 +/- 10.4 vs. 8.7 +/- 3.9; P = 0.008), as were the number of positive culture isolates (for any organism) after 1990 (76 [33. 0%] vs. 9 [10.6%]; P < 0.001). The medical conditions most commonly associated with periorbital cellulitis were sinusitis (44 [14.5%]) and upper respiratory infections (73 [26.6%]). All cases of orbital cellulitis were associated with sinusitis. CONCLUSIONS The introduction of the Hib vaccine coincided with a sharp decline not only in the number of periorbital and orbital cellulitis cases related to H. influenzae, but also in the annual case rate. These data are consistent with a facilitative role for H. influenzae in the development of cellulitis secondary to other pathogens. They also may support restriction of the spectrum of antibiotics used to manage these conditions.

Quality of vision and patient satisfaction after LASIK.

Purpose The purpose of this article is to review the literature and find characteristics that lead to improved patient satisfaction and better quality of vision. Recent findings Flatter preoperative corneal curvature is a risk factor for starbursts after laser-assisted in situ keratomileusis (LASIK). Pupil size has not been found to be correlated with night vision symptoms. Wavefront-guided ablations reduce higher-order aberrations in comparison with traditional LASIK. Night vision symptoms are correlated with younger age, greater correction/increased ablation depth, enhancement, and decreased ablation diameter. Contrast sensitivity has been found to initially decrease after LASIK, returning to baseline 6 to 12 months postoperatively. Summary LASIK has quickly become the refractive procedure of choice around the world. Quality of vision and patient satisfaction after LASIK can be difficult to assess because of the many variables that must be considered to accurately measure these endpoints. Preoperative characteristics such as: increased patient age, decreased corneal toricity, or increased pupil size reduce patient satisfaction. Intraoperative factors like decentration, ablation-zone size, active eye tracking, and wavefront guided ablations affect quality of vision. Finally, postoperative factors such as night vision symptoms, reduced contrast sensitivity, and re-treatment can lead to a decline in patient satisfaction. Eliminating or limiting these variables may lead to increased patient satisfaction and higher quality of vision after LASIK.

Mechanism of age related macular degeneration

AMD is a poorly understood disease at this time. Since it is the leading cause of blindness in the elderly in the developed world, there is a pressing need for better treatment. Therefore, there is extensive ongoing research in both pathogenesis and therapy of AMD. Epidemiological studies have shown significant risk associated with increasing age and cigarette smoking, future studies may identify environmental risk factors though at present studies have been inconclusive. Genetic studies may identify subgroups of disease and thus help provide a selective approach to treatment. The vascular model of AMD may provide better understanding of the blood flow and post capillary resistance and help in early and newer intervention in the disease. Vascular endothelial growth factor has been extensively studied in choroidal neovascularization. It has been demonstrated in human and animal models of CNV and VEGF antagonists are currently in clinical trial. Extensive work is ongoing to prevent and treat CNV with antiangiogenic agents.

Photodynamic therapy for corneal neovascularisation and lipid degeneration

Corneal neovascularisation, and subsequent lipid keratopathy is a potential complication of penetrating keratoplasty, corneal trauma, and corneal ulceration. Corneal neovascularisation increases the risk of corneal opacification and graft rejection. Photodynamic therapy (PDT) using systemically or topically administered photosensitisers to occlude corneal vessels has successfully produced microvascular thrombosis without causing overt damage to surrounding tissues in animal models.1,2 The efficacy of PDT is achieved through the generation of reactive oxygen species from the interaction of light, oxygen, and photosensitisers such as verteporfin,3 commonly used to treat choroidal neovascularisation. Although …

Inhibition of corneal neovascularization by genetic ablation of CCR2.

Purpose. To determine if genetic ablation of the chemokine receptor CCR2 (involved in leukocyte and endothelial chemotaxis) inhibits the development of corneal neovascularization. Methods. Wild-type C57BL/6J mice, as well as species-specific counterparts with targeted homozygous disruption of the CCR2, underwent chemical and mechanical denudation of corneal and limbal epithelium. Corneas were harvested 2 weeks after injury. Neovascularization was quantified by CD31 immunostaining. Results. The mean percentages of neovascularized corneal area in control mice and CCR2-deficient mice 2 weeks after denudation were 58.3% and 38.8% (P = 0.047), respectively. Conclusions. Development of corneal neovascularization is inhibited in CCR2-deficient mice.

Nonglaucomatous cupping of the optic disc.

Optic disc cupping is a consequence of myriad disorders. The anatomy and vasculature of the disc provide great insight into why, how, and when ODC occurs in various conditions. Approaches to distinguish glaucomatous from nonglaucomatous causes of ODC should rely on patient history, visual fields assessment, and funduscopic findings, as described. Cupping can be seen with neurological processes, including benign tumors, that are treatable. The clinician must remain vigilant to detect uncommon but potentially threatening forms of nonglaucomatous optic disc cupping.

Drusen complement components C3a and C5a promote choroidal neovascularization

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.