Henry L. Hudson

A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration.

PURPOSE To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with neovascular age-related macular degeneration (AMD). DESIGN Dose-escalation, multicenter, interventional clinical trial. PARTICIPANTS Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions <or=12 disc areas in size and >or=50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA) <or=20/40 received a single intraocular injection of 0.05 mg (n = 3), 0.15 mg (n = 3), 0.5 mg (n = 3), 1 mg (n = 6), 2 mg (n = 3), or 4 mg (n = 3) of VEGF Trap-Eye. METHODS Safety assessments included eye examinations, vital signs, and laboratory tests. Measures of bioactivity included changes from baseline in BCVA, optical coherence tomography (OCT), and fluorescein angiography. The primary end point was 6 weeks and patients were followed up for 12 weeks. MAIN OUTCOME MEASURE Safety assessments. RESULTS There were no serious adverse events and no identifiable intraocular inflammation. The mean decrease in excess foveal thickness for all patients was 104.5 mum at 6 weeks, and the mean increase in visual acuity was 4.43 letters. In the 2 highest dose groups combined (2 and 4 mg), the mean increase in BCVA was 13.5 letters, with 3 of 6 patients demonstrating improvement of >or=3 lines and 3 patients requiring no adjunctive treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of CNV. CONCLUSIONS Intravitreal injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small, there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.

Relation of the functional and structural fundus changes after submacular surgery for neovascular age-related macular degeneration.

AIMS--This study was carried out to investigate the precise pattern of visual loss associated with subfoveal choroidal neovascular membranes and the mechanism by which vision is stabilised or improved after submacular surgery. METHODS--Preoperative and postoperative quantitative microperimetry using the scanning laser ophthalmoscope was performed on six eyes of five patients with age-related macular degeneration who underwent subfoveal choroidal neovascular membrane excision. The relation of the microperimetry findings to the preoperative and postoperative fluorescein angiographic features was also assessed. RESULTS--Four of the six eyes had visual improvement by the 6 month postoperative visit; the other two had stabilisation of vision at the preoperative level. Despite these beneficial visual effects, none of the patients fixated within the bed of the excised choroidal neovascular membrane. Subfoveal choroidal membrane excision was associated with a 36% average increase in the absolute scotoma at the 1 month postoperative visit, compared with the preoperative size. The postoperative scotoma appeared to remain stable or decreased slightly in size between the 6 month and 1 year postoperative visits. Recovery of vision was associated with the development of a more stable preferred eccentric fixation locus, of which the distance from the centre of the foveal avascular zone was related to final postoperative vision. Most of the eccentric fixation loci were inferotemporal to the bed of the excised choroidal neovascular membrane. The surgical retinotomy site was associated with persistent postoperative relative scotoma in five of the six cases, but resolved in one patient after 1 year. CONCLUSION--These findings indicate that quantitative scanning laser ophthalmoscope microperimetry may aid in the surgical planning of subfoveal choroidal neovascular membrane excision.

Graves Exophthalmos Unrelated to Extraocular Muscle Enlargement: Superior Rectus Muscle Inflammation May Induce Venous Obstruction

Exophthalmos is the most commonly measured sign of Graves ophthalmopathy, whereas enlargement of the extraocular muscles is the principal pathologic abnormality. The purpose of this article is to explore possible etiologies of increased volume of orbital fat and of proptosis in patients with no substantially increased total extraocular muscle volume. Computed tomographic scans of the 13 orbits reviewed in this study had the following characteristics in common: a fine, reticular pattern within the orbital fat, a prominent superior ophthalmic vein, and an enlarged superior rectus muscle. Quantitative analysis revealed that superior rectus muscle volume showed a statistically significant correlation with proptosis, whereas medial, lateral, and inferior rectus muscle volumes did not correlate with proptosis. Based on anatomic considerations, the authors postulate that superior rectus muscle enlargement alone may produce reduced venous outflow from the orbit, thereby expanding the apparent orbital fat volume and producing proptosis.

Late Overcorrection of Hypotropia in Graves Ophthalmopathy: Predictive Factors

The authors have occasionally noted Graves ophthalmopathy patients with stable, restrictive hypotropia who demonstrate excellent initial postoperative realignment, only to develop marked overcorrection within weeks to months after surgery. The charts of 12 consecutive patients who underwent a first operation for single, uncomplicated vertical muscle imbalance were evaluated. Five patients were identified who developed an overcorrection 2 to 5 months after surgery (overcorrected group). A stable comparison group of seven patients retained stable orthotropia after surgery. In cases of patients with late overcorrection, proptosis and superior rectus muscle volume, as measured preoperatively, were significantly greater than in the stable comparison group. There also was postoperative limitation of infraduction in most instances.

Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis?

PURPOSE To describe the ocular presentation of disseminated mycobacterial disease occurring during immune-recovery in a patient with acquired immune deficiency syndrome (AIDS). STUDY DESIGN Case report and literature review. PARTICIPANTS A 41-year-old AIDS patient with a prior diagnosis of cytomegalovirus retinitis. METHODS The patient developed progressive, bilateral multifocal choroiditis with panuveitis 2 months after beginning and responding to highly active antiretroviral therapy. His left eye became blind and painful and was enucleated. Pathologic examination revealed massive choroiditis with well-formed, discrete granulomas and multiple intracellular and extracellular acid-fast organisms within the choroidal granulomas. Culture and polymerase chain reaction of vitreous specimens revealed Mycobacterium avium complex (MAC). RESULTS Empiric, and later sensitivity-guided, local and systemic antibiotic therapy was used to treat the remaining right eye, but it continued to deteriorate. Despite medical therapy, three vitrectomies and repeated intravitreal injections of amikacin, a total retinal detachment ensued. One week after the third vitrectomy, the patient died from mesenteric artery thrombosis in the setting of disseminated mycobacterial disease. CONCLUSIONS This is the first report of ocular inflammation as the presenting finding in the recently recognized syndrome of immune-recovery MAC disease. Pathogenesis of this entity is related to an enhanced immune response to a prior, subclinical, disseminated infection. The formation of discrete granulomas, normally absent in MAC infections in AIDS, reflects this mechanism.

Implantable Telescope for End-Stage Age-related Macular Degeneration: Long-term Visual Acuity and Safety Outcomes

PURPOSE To evaluate long-term safety and best-corrected visual acuity (BCVA) results of a telescope prosthesis in patients with end-stage age-related macular degeneration (AMD). DESIGN Prospective, open-label clinical trial with fellow-eye controls. METHODS Patients with end-stage AMD (bilateral geographic atrophy or disciform scars; BCVA, 20/80 to 20/800) received the telescope prosthesis at 28 centers. Methods were similar to those described in the one-year results, with follow-up visits continuing at 18 and 24 months. Main outcome measures included BCVA change from baseline, endothelial cell density (ECD) and morphometry, and incidence of complications. RESULTS At two years, data from 174 (92.6%) of 188 available patients were analyzed. Overall, 103 (59.5%) of 173 telescope-implanted eyes gained three lines or more (doubling of visual angle) of BCVA compared with 18 (10.3%) of 174 fellow control eyes (P < .0001). Mean BCVA improved 3.6 lines (standard deviation [SD], 1.9 lines) and 2.8 lines (SD, 2.3 lines) from baseline in eyes with the 3X and 2.2X device models, respectively. Mean ECD stabilized through two years, with 2.4% mean cell loss occurring from one to two years. There was no significant change in coefficient of variation or percentage of hexagonal endothelial cells from within six months to two years after surgery. The most common complication was inflammatory deposits. CONCLUSIONS Long-term results of this telescope prosthesis show the substantial BCVA improvement at one year is maintained at two years. Key indicators of corneal health demonstrate ECD change that reflects remodeling of the endothelium associated with the implantation procedure. ECD stabilizes over time, and there is no evidence of any ongoing endothelial trauma.

Article for CME creditMassive mycobacterial choroiditis during highly active antiretroviral therapy: Another immune-recovery uveitis?☆

PURPOSE To describe the ocular presentation of disseminated mycobacterial disease occurring during immune-recovery in a patient with acquired immune deficiency syndrome (AIDS). STUDY DESIGN Case report and literature review. PARTICIPANTS A 41-year-old AIDS patient with a prior diagnosis of cytomegalovirus retinitis. METHODS The patient developed progressive, bilateral multifocal choroiditis with panuveitis 2 months after beginning and responding to highly active antiretroviral therapy. His left eye became blind and painful and was enucleated. Pathologic examination revealed massive choroiditis with well-formed, discrete granulomas and multiple intracellular and extracellular acid-fast organisms within the choroidal granulomas. Culture and polymerase chain reaction of vitreous specimens revealed Mycobacterium avium complex (MAC). RESULTS Empiric, and later sensitivity-guided, local and systemic antibiotic therapy was used to treat the remaining right eye, but it continued to deteriorate. Despite medical therapy, three vitrectomies and repeated intravitreal injections of amikacin, a total retinal detachment ensued. One week after the third vitrectomy, the patient died from mesenteric artery thrombosis in the setting of disseminated mycobacterial disease. CONCLUSIONS This is the first report of ocular inflammation as the presenting finding in the recently recognized syndrome of immune-recovery MAC disease. Pathogenesis of this entity is related to an enhanced immune response to a prior, subclinical, disseminated infection. The formation of discrete granulomas, normally absent in MAC infections in AIDS, reflects this mechanism.

Choroidal Melanomas in Hispanic Patients

The initial clinical manifestation and subsequent pathologic characteristics of choroidal melanomas were reviewed in 20 enucleated eyes of Hispanic patients identified between 1974 and 1992. We compared them to 125 choroidal melanomas of randomly selected white patients identified over the same time period. At the time of diagnosis and at subsequent enucleation, the Hispanic patients were younger (P = .002) than the white patients. Eye pain (P = .016), red eye (P = .0002), and tearing (P = .012) were reported more commonly by the Hispanic patients, and on clinical examination the intraocular pressure was higher (P = .001) and more rubeosis iridis was noted (P < .0001) in the Hispanic patients than in the white patients. The tumors of the Hispanic patients were larger in their greatest base dimension (P = .003), and were heavily pigmented compared with those of the white patients (P = .0001). A trend toward less inflammation within the tumor and toward more epithelioid cell type was noted in the Hispanic patients.

Retinal manifestations of acute murine typhus

Purpose: To report the ocular manifestations of acute serologically confirmed murine typhus. Methods: A retrospective analysis of the clinical history, photography and fluorescein angiography of two patients with acute murine typhus with ocular involvement was conducted. Results: A 38 year old male and a 49 year old female were included in the study. Both complained of fever, headache, rash, night sweats and pulmonary symptoms. They had noted the recent onset of diminished visual acuity and floaters. Examination of the posterior pole revealed mild optic nerve head edema (in one patient), intraretinal hemorrhages and small localized areas of retinal whitening. The history confirmed that both patients had been exposed to fleas and the serologic testing was positive for Rickettsia typhi. The systemic and ocular findings resolved after the use of systemic antibiotics. Conclusion: Rickettsial diseases such as murine typhus should be included in the differential diagnosis of otherwise healthy individuals who present with an acute systemic febrile illness and retinitis or neuroretinitis. Summary Statement: The clinical features of two patients with serologically proven acute murine typhus with ocular involvement are presented. Both patients presented with a retinal whitening that resolved after treatment.

Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

PURPOSE To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). METHODS In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. RESULTS Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. CONCLUSIONS Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients.