Andreas K. Lauer

Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye

Significance Retinal vascular diseases are a leading cause of blindness. Optical coherence tomography (OCT) has become the standard imaging modality for evaluating fluid accumulation in these diseases and for guiding treatment. However, fluorescein angiography (FA) is still required for initial evaluation of retinal ischemia and choroidal neovascularization, which are not visible in conventional structural OCT. The limitations of FA include poor penetration of fluorescence through blood and pigment, inability to determine the depth of the pathology due to its two-dimensional nature, and some uncommon but potentially severe complications. As a noninvasive three-dimensional alternative, OCT angiography may be used in routine screening and monitoring to provide new information for clinical diagnosis and management. Retinal vascular diseases are important causes of vision loss. A detailed evaluation of the vascular abnormalities facilitates diagnosis and treatment in these diseases. Optical coherence tomography (OCT) angiography using the highly efficient split-spectrum amplitude decorrelation angiography algorithm offers an alternative to conventional dye-based retinal angiography. OCT angiography has several advantages, including 3D visualization of retinal and choroidal circulations (including the choriocapillaris) and avoidance of dye injection-related complications. Results from six illustrative cases are reported. In diabetic retinopathy, OCT angiography can detect neovascularization and quantify ischemia. In age-related macular degeneration, choroidal neovascularization can be observed without the obscuration of details caused by dye leakage in conventional angiography. Choriocapillaris dysfunction can be detected in the nonneovascular form of the disease, furthering our understanding of pathogenesis. In choroideremia, OCTs ability to show choroidal and retinal vascular dysfunction separately may be valuable in predicting progression and assessing treatment response. OCT angiography shows promise as a noninvasive alternative to dye-based angiography for highly detailed, in vivo, 3D, quantitative evaluation of retinal vascular abnormalities.

Intravitreal bevacizumab (Avastin) treatment of neovascular age-related macular degeneration.

Purpose: To report the change in visual acuity and central retinal thickness by optical coherence tomography (OCT) after intravitreal injections of bevacizumab for the treatment of neovascular age-related macular degeneration (AMD). Methods: A retrospective case series in a university-based practice evaluated patients with subfoveal choroidal neovascularization (CNV) due to AMD. Patients received intravitreal injections (1.25 mg) of bevacizumab and were monitored monthly with determination of best-corrected ETDRS visual acuity and OCT for persistence of retinal thickening. Eyes were retreated on an “as needed” basis, defined by presence of intraretinal or subretinal fluid. Patients were monitored every 2 months to 3 months for persistence of angiographic leakage. Results: Seventy-nine eyes of 74 consecutive patients received the initial injection of bevacizumab between August 1, 2005, and January 30, 2006. Sixty-eight eyes (86%) of 64 patients had at least 3 months of follow-up. Mean central retinal thickness ± SD decreased from 304 ± 83 &mgr;m at baseline to 237 ± 105 &mgr;m at 3 months (P = 0.00002). Mean ETDRS visual acuity gained 4 letters from 20/100 at baseline to 20/80-1 at 3 months (P = 0.040). Twenty eyes (25%) appeared to have a sustained response to a single injection and did not require further injections through 3 months. Two patients had a potentially drug-related adverse event (ischemic stroke and myocardial infarction). No serious injection-related adverse events occurred. Conclusions: Intravitreal bevacizumab injection affects a rapid decrease in retinal thickness to normal or near-normal levels and improvement in visual acuity in eyes with CNV due to AMD. The sustainability of changes in retinal thickness and visual acuity in response to bevacizumab treatment warrant further investigation and long-term follow-up.

Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy

IMPORTANCE Macular ischemia is a key feature of diabetic retinopathy (DR). Quantification of macular ischemia has potential as a biomarker for DR. OBJECTIVE To assess the feasibility of automated quantification of capillary nonperfusion as a potential sign of macular ischemia using optical coherence tomography (OCT) angiography. DESIGN, SETTING, AND PARTICIPANTS An observational study conducted in a tertiary, subspecialty, academic practice evaluated macular nonperfusion with 6 × 6-mm OCT angiography obtained with commercially available 70-kHz OCT and fluorescein angiography (FA). The study was conducted from January 22 to September 18, 2014. Data analysis was performed from October 1, 2014, to April 7, 2015. Participants included 12 individuals with normal vision serving as controls and 12 patients with various levels of DR. MAIN OUTCOMES AND MEASURES Preplanned primary measures were parafoveal and perifoveal vessel density, total avascular area, and foveal avascular zone as detected with 6 × 6-mm OCT angiography and analyzed using an automated algorithm. Secondary measures included the agreement of the avascular area between the OCT angiogram and FA. RESULTS Compared with the 12 healthy controls (11 women; mean [SD] age, 54.2 [14.2] years), the 12 participants with DR (4 women; mean [SD] age, 55.1 [12.1] years) had reduced parafoveal and perifoveal vessel density by 12.6% (95% CI, 7.7%-17.5%; P < .001) and 10.4% (95% CI, 6.8%-14.1%; P < .001), respectively. Total avascular area and foveal avascular zone area were greater in eyes with DR by 0.82 mm2 (95% CI, 0.65-0.99 mm2; P = .02) and 0.16 mm2 (95% CI, 0.05-0.28 mm2; P < .001). The agreement between the vascular areas in the OCT angiogram and FA had a κ value of 0.45 (95% CI, 0.21-0.70; P < .001). Total avascular area in the central 5.5-mm-diameter area distinguished eyes with DR from control eyes with 100% sensitivity and specificity. CONCLUSIONS AND RELEVANCE Avascular area analysis with an automated algorithm using OCT angiography, although not equivalent to FA, detected DR reliably in this small pilot study. Further study is necessary to determine the usefulness of the automated quantification in clinical practice.

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 Lebers 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.

Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular edema.

Diabetic macular edema (DME) and choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) are the leading causes of vision loss in the industrialized world. The mainstay of treatment for both conditions has been thermal laser photocoagulation, while there have been recent advances in the treatment of CNV using photodynamic therapy with verteporfin. While both of these treatments have prevented further vision loss in a subset of patients, vision improvement is rare. Anti-vascular endothelial growth factor(VEGF)-A therapy has revolutionized the treatment of both conditions. Pegaptanib, an anti-VEGF aptamer, prevents vision loss in CNV, although the performance is similar to that of photodynamic therapy. Ranibizumab, an antibody fragment, and bevacizumab, a full-length humanized monoclonal antibody against VEGF, have both shown promising results, with improvements in visual acuity in the treatment of both diseases. VEGF trap, a modified soluble VEGF receptor analog, binds VEGF more tightly than all other anti-VEGF therapies, and has also shown promising results in early trials. Other treatment strategies to decrease the effect of VEGF have used small interfering RNA to inhibit VEGF production and VEGF receptor production. Corticosteroids have shown efficacy in controlled trials, including an acortave acetate in the treatment and prevention of CNV, and intravitreal triamcinolone acetonide and the fluocinolone acetonide implant in the treatment of DME. Receptor tyrosine kinase inhibitors, such as vatalanib, inhibit downstream effects of VEGF, and have been effective in thetreatment of CNV in early studies. Squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF, and has shown promising results with systemic administration. Initial results are also encouraging for other growth factors, including pigment epithelium-derived factor administered via an adenoviral vector. Ruboxistaurin, which decreases protein kinase C activity, has shown positive results in the prevention of diabetic retinopathy progression, and the resolution of DME. Combination therapy has been investigated, and may prove to be quite effective in the management of both DME and AMD-associated CNV, although ongoing and future studies will be crucial to treatment optimization for each condition.

Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial

Objective Tumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial to assess the effectiveness and safety of adalimumab, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. Methods Subjects with non-infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled. Treatment outcome was ascertained by a composite endpoint comprised of visual acuity, intraocular inflammation, ability to taper immunosuppressives, and posterior segment imaging. Clinical response was defined by improvement in at least one parameter, worsening in none, and well controlled intraocular inflammation. Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks. Results Twenty-one of 31 patients (68%) were characterised as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. The most common reason for study termination was primary or secondary inefficacy. No patients experienced treatment-limiting toxicity clearly related to study therapy. Conclusions Adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after study enrolment, and maintained in 39% after 1 year. Ongoing study is required to determine the place of adalimumab and other TNF blockers in the treatment of uveitis.

DETECTION OF NONEXUDATIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY

Purpose: To evaluate eyes with age-related macular degeneration and high-risk characteristics for choroidal neovascularization (CNV) with optical coherence tomographic (OCT) angiography to determine whether earlier detection of CNV is possible. Methods: Eyes with drusen, pigmentary changes, and with CNV in the fellow eye were scanned with a 70-kHz spectral domain OCT system (Optovue RTVue-XR Avanti). The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was used to distinguish blood flow from static tissue. Two masked graders reviewed scans for CNV, defined as flow in the outer retinal/sub-RPE slab. Choroidal neovascularization flow area repeatability and between-grader reproducibility were calculated. Results: Of 32 eyes, 2 (6%) were found to have Type 1 CNV with OCT angiography. The lesions were not associated with leakage on fluorescein angiography or fluid on OCT. One case was followed for 8 months without treatment, and the CNV flow area enlarged slightly without fluid buildup on OCT or vision loss. Between-grader reproducibility of the CNV flow area was 9.4% (coefficient of variation) and within-visit repeatability was 5.2% (pooled coefficient of variation). Conclusion: Optical coherence tomographic angiography can detect the presence of nonexudative CNV, lesions difficult to identify with fluorescein angiography and OCT. Further study is needed to understand the significance and natural history of these lesions.

RPE tears after pegaptanib treatment in age-related macular degeneration.

Purpose: To describe retinal pigment epithelial (RPE) tears in patients with age-related macular degeneration (AMD) status post pegaptanib (Macugen) injection. Methods: Six eyes from six patients who developed RPE tears while undergoing treatment with pegaptanib for AMD-related fibrovascular pigment epithelial detachment (PED) and occult choroidal neovascularization (CNV) were identified retrospectively. Diagnosis of pre-pegaptanib fibrovascular PED and post-pegaptanib RPE tears were made by clinical examination, fluorescein angiography (FA), and optical coherence tomography (OCT) imaging of the macula. Results: Four patients developed an RPE tear within 8 weeks after the first pegaptanib injection, while RPE tears were found in two patients following a second injection. Only one of the patients reported acute vision loss, although three of six eyes had a decrease in objective visual acuity in the affected eye to the count fingers level. All six cases displayed the classic clinical and angiographic appearance of RPE tears. In addition, OCT imaging showed an irregular, hyperreflective RPE layer with a focal defect. Conclusions: RPE tears are known to occur in the setting of PED spontaneously or after laser treatment, but have only recently been described in association with intravitreal pegaptanib. OCT imaging of eyes status post pegaptanib therapy may be helpful in identifying this complication. Patients with AMD, especially those with occult CNV and fibrovascular PED, receiving pegaptanib therapy should be monitored for RPE tears, which may warrant deferral of further injections.

Bartonella henselae infection associated with neuroretinitis, central retinal artery and vein occlusion, neovascular glaucoma, and severe vision loss.

PURPOSE To report a case of Bartonella henselae infection. DESIGN Observational case report. METHODS Review of the clinical, laboratory, photographic, and angiographic records of a patient with cat scratch disease associated with central retinal artery and vein occlusion, neovascular glaucoma, and severe vision loss. RESULTS A 21-year-old man had no light perception in the left eye secondary to concurrent central retinal artery and vein occlusion believed to have resulted from infection with Bartonella henselae. Forty days later, he developed neovascular glaucoma in the left eye. CONCLUSION Ocular complications associated with Bartonella henselae infection may include central retinal artery and vein occlusion, neovascular glaucoma, and severe vision loss.

Visualization of 3 Distinct Retinal Plexuses by Projection-Resolved Optical Coherence Tomography Angiography in Diabetic Retinopathy

Importance Projection artifacts in optical coherence tomography angiography (OCTA) blur the retinal vascular plexuses together and limit visualization of the individual plexuses. Objective To describe projection-resolved (PR) OCTA in eyes with diabetic retinopathy (DR) and healthy eyes. Design, Setting, and Participants In this case-control study, patients with DR and healthy controls were enrolled in this observational study from January 26, 2015, to December 4, 2015, at a tertiary academic center. Spectral-domain, 70-kHz OCT obtained 3 × 3-mm macular scans. The PR algorithm suppressed projection artifacts. A semiautomated segmentation algorithm divided PR-OCTA into superficial, intermediate, and deep retinal plexuses. Two masked graders examined 3-layer PR-OCTA and combined angiograms for nonperfusion and abnormal capillaries. Main Outcomes and Measures Retinal nonperfusion and capillary abnormalities and the diagnostic accuracy of detecting DR. Results Twenty-nine eyes of 15 healthy individuals (mean [SD] age, 36.2 [13.4] years; 11 women) and 47 eyes of 29 patients with DR (mean [SD] age, 55.5 [11.9]; 10 women) underwent imaging. PR-OCTA revealed 3 distinct retinal plexuses in their known anatomical locations in all eyes. The intermediate and deep plexuses of healthy eyes revealed capillary networks of uniform density and caliber, whereas the superficial plexus revealed vessels in the familiar centripetal branching pattern. In eyes with DR, 3-layer PR-OCTA disclosed incongruent areas of nonperfusion and varied vessel caliber and density in the deeper plexuses. Masked grading of capillary nonperfusion on 3-layer PR-OCTA detected DR with 100% sensitivity (95% CI, 90.8%-100%) and 100% specificity (95% CI, 85.4%-100%). With unsegmented retinal angiograms, the sensitivity and specificity were 78.7% (95% CI, 63.9%-88.8%) and 100% (95% CI, 85.4%-100%), respectively (P = .002 for sensitivity). On 3-layer PR-OCTA, sensitivity was 72.2% (95% CI, 54.6%-85.2%) for severe nonproliferative DR and proliferative DR eyes with generalized nonperfusion in 2 or more individual plexuses, but on combined angiogram, sensitivity was 25.0% (95% CI, 12.7%-42.5%) for generalized nonperfusion (P < .001). PR-OCTA disclosed dilated vessels in the intermediate and deep plexuses in 23 eyes (100%) with proliferative DR, 13 eyes (100%) with severe nonproliferative DR, 8 eyes (73%) with mild to moderate nonproliferative DR, and 0 control eyes. Conclusions and Relevance By presenting 3 retinal vascular plexuses distinctly, PR-OCTA reveals capillary abnormalities in deeper layers with clarity and may distinguish DR from healthy eyes and severe DR from mild DR with greater accuracy compared with conventional OCTA.