Nancy M. Holekamp

Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration

PURPOSE Pigment epithelium-derived growth factor (PEDF) is a potent inhibitor of angiogenesis that is found in the normal eye. The purpose of this study is to report decreased levels of PEDF in the vitreous of eyes with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). DESIGN Prospective case-control study. METHODS In a prospective case-control study, undiluted vitreous was collected from nine eyes of nine patients with CNV due to AMD and from an age-matched control group of 12 eyes of 12 patients with retinal disorders not involving neovascularization. Vitreous PEDF and vascular endothelial growth factor (VEGF) concentrations were determined by Western blot analyses and enzyme-linked immunosorbent assay (ELISA), respectively. Angiogenic activities of the vitreous samples were assessed in vitro using an endothelial cell chemotaxis assay. RESULTS In vitreous samples from nine eyes with CNV due to AMD the mean +/- SD PEDF level was 2.8 ng/microl +/- 1.3 ng/microl. In vitreous samples from 12 age-matched control eyes the mean +/- SD PEDF level was 16.4 ng/microl +/- 7.1 ng/microl. The difference between the two groups was statistically significant (P =.00003). No significant difference in vitreous VEGF concentration was seen between CNV/AMD samples and control samples (P =.23). All CNV/AMD vitreous samples induced endothelial cell migration in vitro. No sample from age-matched non-age-related macular degeneration controls could induce endothelial cell migration, and 11 of 12 were able to block VEGF-induced migration in vitro. This inhibitory activity required active PEDF. CONCLUSION The vitreous of patients with CNV due to AMD contained lower levels of PEDF and lacked the antiangiogenic activity of vitreous from age-matched controls. This suggests that loss of PEDF creates a permissive environment for CNV patients with AMD.

Case-control study of endophthalmitis after cataract surgery comparing scleral tunnel and clear corneal wounds.

PURPOSE To study the possible association between clear corneal incision with or without placement of a suture during cataract extraction and postoperative endophthalmitis. DESIGN Retrospective, comparative, case-controlled study. METHODS Thirty-eight patients treated for culture-positive, acute post-cataract surgery endophthalmitis, and 371 randomly selected control patients who underwent uncomplicated cataract surgery in the referring community were studied. Incision type and use of suture during cataract surgery of endophthalmitis patients were compared with the controls. The data were analyzed using logistic regression methods. RESULTS Of the 38 patients with endophthalmitis, 17 patients (45%) had clear corneal incisions and 21 patients (55%) had a scleral tunnel incision. In 371 controls, 76 patients (20%) had clear corneal incisions and 295 patients (80%) had scleral tunnel incisions. Clear corneal incision was associated with a threefold greater risk of endophthalmitis than was scleral tunnel incision (Odds Ratio, 3.36, 95% Confidence Interval = 1.67 to 6.78). The type of incision was significant (chi(2) = 11.53, P =.0007); a clear corneal incision was more frequently associated with endophthalmitis. A subgroup analysis revealed that the presence or absence of a suture was not significant (chi(2) = 1.31, P =.2524). CONCLUSIONS In this retrospective, case-controlled study, clear corneal incisions were found to be a statistically significant risk factor for acute post-cataract surgery endophthalmitis when compared with scleral tunnel incisions.

Outcome results in macular hole surgery: An evaluation of internal limiting membrane peeling with and without indocyanine green

PURPOSE To evaluate the anatomic closure rate and visual outcome in patients undergoing pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling with and without indocyanine green (ICG) enhancement. DESIGN Retrospective, noncomparative interventional case series. PARTICIPANTS One hundred ninety-three consecutive patients (204 eyes) seen at the Barnes Retina Institute with the clinical diagnosis of macular hole who underwent PPV between January 1998 and December 2000. INTERVENTION A consecutive series of 97 patients undergoing PPV with or without unilateral epiretinal membrane removal without ILM peeling (group 1), 44 patients with PPV and ILM peeling without ICG (group 2), and 35 patients with ICG-assisted ILM peeling (group 3). RESULTS Overall, 86.4% of the holes closed with one operation, with 75 of 97 (77.3%) eyes in group 1, 43 of 44 (97.7%) eyes in group 2, and 34 of 35 (97.1%) eyes in group 3 (chi(2)= 10.51, P = 0.007). Of the eyes that did not close, 18 patients in group 1 underwent repeat surgery, with 90 of 97 (92.8%) eyes ultimately achieving closure. Visual acuity after surgery was 20/50 or better in 55 of 97 (56.7%) patients, 31 of 44 (70.4%) patients, and 18 of 35 (51.4%) patients in groups 1, 2, and 3, respectively (chi(2) = 3.43, P = 0.18) and increased by 2 or more lines from their preoperative status in 63 of 97 (64.9%) patients, 34 of 44 (77.3%) patients, and 25 of 35 (71.4%) patients, respectively (chi(2)= 2.25, P = 0.32). Multivariate logistic regression demonstrated that use of ILM peeling during vitrectomy increases the chances of developing 20/50 vision or better (odds ratio [OR], 2.4; 95% confidence interval, 1.06-5.45; P = 0.04). No eyes received concurrent cataract extraction with macular hole surgery, but 75 of 166 (45.2%) required cataract extraction postoperatively. Complications included 20 retinal tears, 4 retinal detachments, and 34 patients with postoperative elevations in intraocular pressure (IOP; defined as IOP greater than 30 mmHg). CONCLUSIONS Although this study is limited by the shorter follow-up in patients undergoing ILM peeling with or without ICG relative to the control group, our experience indicates that the use of ILM peeling is associated with a statistically significant improvement in the rate of primary macular hole closure with a single operation.

The gel state of the vitreous and ascorbate-dependent oxygen consumption: relationship to the etiology of nuclear cataracts.

OBJECTIVE To investigate the rate and mechanism of oxygen consumption by the vitreous. METHODS Oxygen consumption was measured with a microrespirometer. Vitreous ascorbate was measured spectrophotometrically and by gas chromatography-mass spectrometry. Vitreous degeneration was related to the rate of oxygen consumption and ascorbate concentration in samples obtained during vitrectomy. RESULTS Prolonged exposure to oxygen or treatment with ascorbate oxidase eliminated oxygen consumption by the vitreous. Adding ascorbate restored oxygen consumption. Oxygen consumption persisted after boiling or treating the vitreous with the chelating agents EDTA and deferoxamine. In patients undergoing retinal surgery, liquefaction of the vitreous and previous vitrectomy were associated with decreased ascorbate concentration and lower oxygen consumption. CONCLUSIONS Ascorbate in the vitreous decreases exposure of the lens to oxygen. The catalyst for this reaction is not known, although free iron may contribute. The gel state of the vitreous preserves ascorbate levels, thereby sustaining oxygen consumption. Vitrectomy or advanced vitreous degeneration may increase exposure of the lens to oxygen, promoting the progression of nuclear cataracts. CLINICAL RELEVANCE Determining how the eye is protected from nuclear cataracts should suggest treatments to reduce their incidence.

Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes. Submacular Surgery Trials Pilot Study report number 1

PURPOSE To report complications and changes in vision during 2 years of follow-up of patients with age-related macular degeneration assigned randomly to surgical removal or to laser photocoagulation of subfoveal recurrent neovascular lesions in a pilot trial designed to test methods, to refine estimates of outcome rates, and to project patient accrual rates for a larger multicenter randomized trial to evaluate submacular surgery. PATIENTS AND METHODS Eligible patients with previous laser photocoagulation of extrafoveal or juxtafoveal choroidal neovascularization secondary to age-related macular degeneration were enrolled at 15 collaborating clinical centers. Assignments to treatment arm were made by personnel at a central coordinating center. Adherence to eligibility criteria and treatment assignment was assessed centrally at a photograph reading center. Patients were examined at 3, 6, 12, and 24 months after treatment for data collection purposes. Outcome measures reported include treatment complications, adverse events, requirements for additional treatment, and 2-year changes in visual acuity from baseline. RESULTS Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery; all were treated as assigned. One patient in each group died before the 2-year examination. Visual acuity was measured at the 2-year examination for 31 of the surviving patients (89%) in the laser arm and for 28 of the surviving patients (85%) in the surgery arm. The 2-year measurements for 36 of the 59 patients (61%) were made by an examiner masked to treatment assignment and to the identity of the study eye. Improvements and losses of visual acuity were observed in both treatment arms; 20 of 31 study eyes (65%) in the laser arm and 14 of 28 study eyes (50%) in the surgery arm had visual acuity 2 years after enrollment that was better than or no more than 1 line worse than the baseline level. Changes in visual acuity and the size of the central macular lesions from baseline to the 2-year examination were similar in the treatment arms. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser-treated eyes and 18 surgically treated eyes had additional intraocular procedures. CONCLUSIONS The data from this pilot trial suggest no reason to prefer submacular surgery over laser photocoagulation for treatment of patients with age-related macular degeneration who have lesions similar to those studied in this pilot trial. Any clinical trial designed to compare submacular surgery with laser photocoagulation in eyes with age-related macular degeneration and subfoveal recurrent neovascular lesions must enroll several hundred patients in order to reach a statistically valid conclusion regarding differences between these two methods of treatment with respect to either changes in visual acuity or complication rates.

The Vitreous Gel: More than Meets the Eye

PURPOSE To reexamine the role of the vitreous gel in ocular health and disease based on recent information in the ophthalmic literature. DESIGN Perspective. METHODS Review, analysis, and discussion of the implications of selected pertinent literature. RESULTS A new understanding of the vitreous gel is emerging, placing it central to many disease processes affecting the eye, including diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, nuclear sclerotic cataract, and primary open-angle glaucoma. The vitreous gel recently has been found to have the important function of oxygen regulation and distribution within the eye. As the gel undergoes age-related liquefaction or surgical removal this function is impaired. The resultant elevated intraocular oxygen tension likely proves beneficial for vascular endothelial growth factor-mediated retinal diseases. However, it may lead to oxidative stress within the eye and may contribute to disease states such as nuclear cataract and primary open-angle glaucoma. CONCLUSIONS An intact gel vitreous is central to a healthy human eye. We now understand that age-related liquefaction of the vitreous gel accompanies several age-related ocular diseases. The field of ophthalmology would benefit from future research to understand age-related vitreous liquefaction and to identify its cause.

Vitreoretinal influences on lens function and cataract

The lens is composed of a thin metabolically active outer layer, consisting of epithelial and superficial fibre cells. Lying within this outer shell are terminally differentiated, metabolically inactive fibre cells, which are divided into an outer cortex and central nucleus. Mature fibre cells contain a very high protein concentration, which is important for the transparency and refractive power of the lens. These proteins are protected from oxidation by reducing substances, like glutathione, and by the low-oxygen environment around the lens. Glutathione reaches the mature fibre cells by diffusing from the metabolically active cells at the lens surface. With age, the cytoplasm of the nucleus becomes stiffer, reducing the rate of diffusion and making nuclear proteins more susceptible to oxidation. Low pO2 is maintained at the posterior surface of the lens by the physical and physiological properties of the vitreous body, the gel filling the space between the lens and the retina. Destruction or degeneration of the vitreous body increases exposure of the lens to oxygen from the retina. Oxygen reaches the lens nucleus, increasing protein oxidation and aggregation and leading to nuclear cataract. We suggest that maintaining low pO2 around the lens should prevent the formation of nuclear cataracts.

Surgical Removal of Subfoveal Choroidal Neovascularization in Presumed Ocular Histoplasmosis: Stability of Early Visual Results

PURPOSE The authors assess the stability of visual acuity outcomes after the surgical removal of subfoveal choroidal neovascularization in a large series of patients with presumed ocular histoplasmosis syndrome (POHS). METHODS A retrospective study of 117 consecutive patients undergoing vitrectomy between February 1990 and December 1994 was performed. All patients underwent the surgical removal of subfoveal choroidal neovascularization due to POHS and had at least 3 months of follow-up. Postoperative Snellen visual acuity was the primary study endpoint. RESULTS With a median follow-up of 13 months (range, 3-46 months), 35% of patients had postoperative visual acuity of 20/40 or better, and 40% had improvement of three or more Snellen lines after surgery. In a subset of 54 eyes followed for at least 1 year, 91% showed stable or improved vision between the 3- and 12-month time points, and 85% showed stable or improved vision between 3 months and final visit. CONCLUSION Follow-up of a large number of patients appears to confirm initially encouraging results and to suggest stability of beneficial effect after the surgical removal of subfoveal choroidal neovascularization in POHS.

Intravitreal Bevacizumab for Choroidal Neovascularization in Ocular Histoplasmosis

PURPOSE To define the role of intravitreal bevacizumab in individuals with choroidal neovascularization (CNV) resulting from Ocular Histoplasmosis syndrome (OHS). DESIGN Retrospective chart review of a surgical therapy. METHODS We reviewed the course of 28 eyes of 28 patients who underwent intravitreal injection of bevacizumab for treatment of CNV secondary to OHS. Outcome was measured by pretreatment and posttreatment visual acuity (VA). RESULTS The average pretreatment logarithm of the minimum angle of resolution (logMAR) VA was 0.65 (Snellen equivalent of 20/88). Mean follow-up was 22.43 weeks with an average of 1.8 intravitreal injections. Average final logMAR VA was 0.43 (Snellen equivalent of 20/54). Twenty eyes (71%) experienced an increase in central VA, whereas four eyes (14%) were unchanged and four eyes (14%) experienced a decrease in vision. CONCLUSIONS Intravitreal bevacizumab may improve or stabilize VA in a significant majority of patients with neovascular complications of OHS (24 eyes [85.7%] in our study population).

Ischemic Diabetic Retinopathy May Protect against Nuclear Sclerotic Cataract

PURPOSE To determine whether diabetes mellitus is protective for nuclear sclerotic cataract at baseline and 6 and 12 months after vitrectomy surgery. DESIGN Prospective, interventional cohort study. METHODS Phakic diabetic and nondiabetic patients undergoing vitrectomy surgery for a variety of retinal conditions underwent Scheimpflug lens photography in the operated and fellow eye at baseline and at 6 and 12 months after vitrectomy surgery. RESULTS Of 52 eyes included in the analysis, 23 eyes were from diabetic patients, 14 of which had surgery for ischemic retinopathy. At baseline, eyes with ischemic diabetic retinopathy had less nuclear sclerotic cataract than nonischemic diabetic and nondiabetic eyes. This was true for eyes undergoing vitrectomy surgery (P = .0001) and for fellow eyes (P = .003). Nuclear sclerotic cataract developed after vitrectomy surgery in nonischemic diabetic eyes and nondiabetic eyes at the same rate. Diabetic eyes with ischemic retinopathy showed no significant progression of nuclear opacification, and therefore had significantly less postvitrectomy nuclear cataract at 6 months (P < 1 × 10(-6)) and at 12 months (P < .001) than nondiabetic or nonischemic diabetic eyes. Normalizing to baseline opacity and adjusting for age and other comorbidities did not alter this result. CONCLUSIONS Ischemic diabetic retinopathy, not just systemic diabetes mellitus, protected against nuclear sclerotic cataract at baseline and after vitrectomy surgery. These findings are consistent with the hypothesis that increased exposure to oxygen is responsible for nuclear cataract formation.