Altered Blood Flow in the Ophthalmic and Internal Carotid Arteries in Patients with Age-Related Macular Degeneration Measured Using Noncontrast MR Angiography at 7T.

BACKGROUND AND PURPOSE: Age-related macular degeneration is associated with reduced perfusion of the eye; however, the role of altered blood flow in the upstream ophthalmic or internal carotid arteries is unclear. We used ultra-high-field MR imaging to investigate whether the diameter of and blood flow in the ophthalmic artery and/or the ICA are altered in age-related macular degeneration and whether any blood flow changes are associated with disease progression. MATERIALS AND METHODS: Twenty-four patients with age-related macular degeneration and 13 similarly-aged healthy controls participated. TOF and high-resolution dynamic 2D phase-contrast MRA (0.26 × 0.26 × 2mm3, 100-ms effective sampling rate) was acquired at 7T. Vessel diameters were calculated from cross-sectional areas in phase-contrast acquisitions. Blood flow time-series were measured across the cardiac cycle. RESULTS: The ophthalmic artery vessel diameter was found to be significantly smaller in patients with age-related macular degeneration than in controls. Volumetric flow through the ophthalmic artery was significantly lower in patients with late age-related macular degeneration, with a significant trend of decreasing volumetric ophthalmic artery flow rates with increasing disease severity. The resistance index was significantly greater in patients with age-related macular degeneration than in controls in the ophthalmic artery. Flow velocity through the ophthalmic artery and ICA was significantly higher in patients with age-related macular degeneration. Ophthalmic artery blood flow as a percentage of ipsilateral ICA blood flow was nearly double in controls than in patients with age-related macular degeneration. CONCLUSIONS: These findings support the hypothesis that vascular changes upstream to the eye are associated with the severity of age-related macular degeneration. Additional investigation into the potential causality of this relationship and whether treatments that improve ocular circulation slow disease progression is warranted.

Long-term outcomes of neovascular glaucoma treated with and without intravitreal bevacizumab.

AIMS: To compare the outcomes of neovascular glaucoma (NVG) treated with and without intravitreal bevacizumab in a large case comparison study. METHODS: The study is a retrospective, comparative, case series of 163 eyes of 151 patients with NVG, including 99 treated without and 64 treated with intravitreal bevacizumab. Medical and surgical treatments for NVG were assessed. The main outcome measures were visual acuity (VA) and intraocular pressure (IOP). RESULTS: At the time of NVG diagnosis, the median VA was count fingers (CF) in the non-bevacizumab group and 2/300 in the bevacizumab group. IOP (mean±SD) was 43.1±13.0 mm Hg in the non-bevacizumab group and 40.8±11.5 mm Hg in the bevacizumab group. IOP (mean±SD) decreased to 18.3±13.8 mm Hg in the non-bevacizumab group and 15.3±8.0 mm Hg in the bevacizumab group, and the median VA was CF in both treatment groups at a mean follow-up of 12 months. Panretinal photocoagulation (PRP) substantially reduced the need for glaucoma surgery (P<0.001) in bevacizumab treated NVG eyes. CONCLUSIONS: Although bevacizumab delayed the need for glaucoma surgery, PRP was the most important factor that reduced the need for surgery. Vision and IOP in eyes with NVG treated with bevacizumab showed no long-term differences when compared with eyes that were not treated with bevacizumab. Thus, intravitreal bevacizumab serves as an effective temporizing treatment, but is not a replacement for close monitoring and definitive treatment of NVG. PRP remains the treatment modality that affects the course of NVG in terms of decreasing the need for surgery to control IOP.

Outcomes of treatment of neovascular glaucoma with intravitreal bevacizumab.

BACKGROUND/AIMS: To evaluate the course of treatment and outcomes of neovascular glaucoma (NVG) treated with intravitreal bevacizumab. METHODS: The study is a retrospective, non-comparative, consecutive, interventional case series. Demographic data, past ocular history, cause of NVG and anterior chamber angle status were recorded. Visual acuity (VA), intraocular pressure (IOP), number of IOP-lowering medications and type of treatment administered were recorded at the time of NVG diagnosis and at follow-up intervals. Treatment-related complications and reasons for vision loss were recorded. RESULTS: The study included 56 eyes of 52 patients. At the time of NVG diagnosis, the median VA was count fingers, and the mean IOP (SD) was 40 (11) mm Hg. At 6 months after initial bevacizumab injection, the median VA was 1/200, and the mean IOP (SD) was 18 (15) mm Hg. Seventy-one per cent of eyes underwent panretinal photocoagulation after NVG diagnosis. Sixty-one per cent of eyes received a glaucoma drainage implant (GDI). The Kaplan-Meier cumulative proportion of eyes with open angles receiving a GDI after initial bevacizumab injection was not statistically significantly different from that of eyes with closed angles. Forty-six per cent of eyes received repeat bevacizumab injections. Eleven eyes had hyphaema after both bevacizumab injection and GDI surgery, while three eyes had hyphaema after GDI surgery but prior to initial bevacizumab injection. CONCLUSIONS: Intravitreal bevacizumab is now a frequently used adjunct for the treatment of NVG. Eyes must be monitored closely after initial injection of intravitreal bevacizumab, regardless of initial angle status, as many may still require surgery to lower IOP or repeat injections of intravitreal bevacizumab.

Macular spectral-domain optical coherence tomography in patients with X linked retinoschisis.

AIM: To evaluate macular anatomy in patients with X linked retinoschisis (XLRS) using spectral-domain optical coherence tomography (SD-OCT). METHODS: Consecutive observational case series. Clinical features were obtained through retrospective chart review. Only eyes without prior surgical interventions and those scanned with SD-OCT were included. The OCT images were analysed. RESULTS: Fourteen eyes of seven males with XLRS scanned with SD-OCT, age 5 to 45 years, were identified. On clinical examination, stellate spoke-like cystic maculopathy was present in nine eyes, and an atrophic foveal lesion in five eyes. SD-OCT revealed cystoid spaces accounting for retinal splitting in the inner nuclear layer in 12 eyes, and outer plexiform layer in two eyes of one patient. A few small cysts, not accounting for the foveal splitting, were seen in the outer nuclear layer in four eyes and in the ganglion cell layer and/or nerve fibre layer in six eyes. CONCLUSIONS: SD-OCT localised the foveomacular retinoschisis in XLRS to the retinal layers deeper than the nerve fibre layer. In the present study, the foveomacular schisis was seen most frequently in the inner nuclear layer.

Predicted biological activity of intravitreal VEGF Trap.

AIM: To compare the intravitreal binding activity of VEGF Trap with that of ranibizumab against vascular endothelial growth factor (VEGF) using a time-dependent and dose-dependent mathematical model. METHODS: Intravitreal half-lives and relative equimolar VEGF-binding activities of VEGF Trap and ranibizumab were incorporated into a first-order decay model. Time-dependent VEGF Trap activities (relative to ranibizumab) for different initial doses (0.5, 1.15, 2 and 4 mg) were calculated and plotted. RESULTS: Seventy-nine days after a single VEGF Trap (1.15 mg) injection, the intravitreal VEGF-binding activity would be comparable to ranibizumab at 30 days. After injection of 0.5, 2 and 4 mg VEGF Trap, the intravitreal VEGF-binding activities (comparable to ranibizumab at 30 days) would occur at 73, 83 and 87 days, respectively CONCLUSION: On the basis of this mathematical model, VEGF Trap maintains significant intravitreal VEGF-binding activity for 10-12 weeks after a single injection.

The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide.

AIM: Off-label intravitreal injections of bevacizumab (Avastin) have been given for the treatment of neovascular and exudative ocular diseases since May 2005. Since then, the use of intravitreal bevacizumab has spread worldwide, but the drug-related adverse events associated with its use have been reported only in a few retrospective reviews. The International Intravitreal Bevacizumab Safety Survey was initiated to gather timely information regarding adverse events from doctors around the world via the internet. METHODS: An internet-based survey was designed to identify adverse events associated with intravitreal bevacizumab treatment. The survey web address was disseminated to the international vitreoretinal community via email. Rates of adverse events were calculated from participant responses. RESULTS: 70 centres from 12 countries reported on 7113 injections given to 5228 patients. Doctor-reported adverse events included corneal abrasion, lens injury, endophthalmitis, retinal detachment, inflammation or uveitis, cataract progression, acute vision loss, central retinal artery occlusion, subretinal haemorrhage, retinal pigment epithelium tears, blood pressure elevation, transient ischaemic attack, cerebrovascular accident and death. None of the adverse event rates exceeded 0.21%. CONCLUSION: Intravitreal bevacizumab is being used globally for ocular diseases. Self-reporting of adverse events after intravitreal bevacizumab injections did not show an increased rate of potential drug-related ocular or systemic events. These short-term results suggest that intravitreal bevacizumab seems to be safe.

[Treatment of neovascular age-related macular degeneration with Ranibizumab/Lucentis]. / Therapie der neovaskulären altersbedingten Makuladegeneration mit Ranibizumab/Lucentis.

Vascular endothelial growth factor (VEGF) is considered to play an essential role in the pathogenesis of age-related macular degeneration due to its vascular permeability-inducing and angiogenic properties. Ranibizumab, a small antibody fragment designed to competitively bind all VEGF isoforms, passes after intravitreal injection all retinal layers reaching the retinal pigment epithelium-choroid complex. Experimental animal models showed the drug to be safe and effective. Subsequently, Phase I/II clinical trials conducted in patients with neovascular AMD demonstrated a good safety profile, and a significant functional benefit. Ranibizumab therapy repeated every four weeks for the treatment of neovascular AMD is currently in Phase III clinical trials. Combination therapy trials aiming for improved treatment durability and effectiveness are currently ongoing as well as new treatment strategies using intermittent, optical coherence tomography (OCT) guided therapy. Anti-VEGF therapy using Ranibizumab is a promising new treatment option for neovascular AMD.

Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions.

PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (S(all) statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or S(all) scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.

PURPOSE: To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone-rod degeneration (CRD). METHODS: One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified. RESULTS: The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes. CONCLUSIONS: This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

Persistent indocyanine green angiographic findings in multiple evanescent white dot syndrome.

This report describes unique findings of persistent peripapillary and posterior pole hypofluorescence on indocyanine green angiography (ICGA) in multiple evanescent white dot syndrome (MEWDS). A 38-year-old woman experienced a sudden decrease of visual acuity in the left eye. Multiple white lesions were seen on fundus examination. Fluorescein angiography, indocyanine green angiography, and automated perimetry were performed. Fundus appearance and fluorescein angiography were consistent with the diagnosis of MEWDS. Automated perimetry revealed an enlarged blind spot. ICGA revealed a zone of hypofluorescence surrounding the optic disc and throughout the posterior pole. The enlarged blind spot resolved after seven weeks along with the signs and symptoms of MEWDS. Nine months after initial presentation, ICGA revealed persistent peripapillary and posterior pole hypofluorescence. Resolution of the enlarged blind spot and return of vision does not completely correlate with the disappearance of hypofluorescent areas on ICGA. These findings suggest that MEWDS may result in persistent abnormalities in choroidal circulation even after clinical symptoms resolve.

Purtscher-like retinopathy associated with pancreatic adenocarcinoma.

PURPOSE: To investigate a case of Purtscher-like retinopathy that occurred in association with pancreatic adenocarcinoma. METHOD: Case report. RESULTS: A 63-year-old woman presented with multiple gray patches in the central vision of both eyes. Visual acuity was 20/20 in both eyes. Funduscopy showed large peripapillary yellow-white patches within the superficial retina and small superficial retinal hemorrhages in both eyes. The patient subsequently had abdominal pain. Computed tomography of the abdomen demonstrated a large pancreatic mass with extension into the liver. Histologic examination of a percutaneous needle biopsy specimen showed mucinous pancreatic adenocarcinoma. CONCLUSION: Pancreatic adenocarcinoma should be added to the list of systemic diseases that can be associated with Purtscher-like retinopathy.

Visual acuity outcomes of patients 50 years of age and older with high myopia and untreated choroidal neovascularization.

OBJECTIVE: To evaluate visual outcomes of untreated submacular choroidal neovascularization (CNV) in patients 50 years of age and older with high myopia. DESIGN: Retrospective observational case series. PARTICIPANTS: Twenty-two eyes in 22 patients were studied. All were 50 years of age and older with myopia of 6.0 diopters (D) or greater or an axial length of 25.5 mm or greater. Patients had untreated CNV documented by clinical examination and fluorescein angiography at two medical centers between 1986 and 1997. INTERVENTION: Demographic and clinical data were abstracted from patients' medical records. MAIN OUTCOME MEASURE: Visual acuity at 1 year after CNV diagnosis. RESULTS: The study included 22 eyes of 22 patients (mean age, 63.1 years; mean refraction, -11.0 D). Baseline visual acuity (VA) in the study eye was 20/40 or greater in 2 (9%) patients, 20/50 to 20/150 in 9 (41%) patients, and 20/200 or less in 11 (50%) patients. Drusen were present in seven (32%) eyes, and lacquer cracks were noted in ten (45%) eyes. Mean refractive error was -7.0 D for patients with drusen and -12.5 D for patients without drusen. Choroidal neovascularization was less than 0.25 disc diameters (DD) in 11 (50%) eyes, 0.25 to 0.5 DD in 5 (23%) eyes, and greater than 0.5 DD in 6 (27%) eyes. Visual acuity in the study eye 1 year after CNV diagnosis was 20/40 or greater in 3 (14%) patients, 20/50 to 20/150 in 3 (14%) patients, and 20/200 or less in 16 (73%) eyes. The presence of drusen was significantly associated with older age and a lower degree of myopia but was not associated with size of the CNV or visual acuity outcome. CONCLUSION: When compared to patients younger than 50 years of age with high myopia and CNV reported in previous publications, the patients in the current series generally have poorer visual outcomes.

Limitations of the American Academy of Neurology and American Clinical Neurophysiology Society paper on QEEG.

The AAN/ACNS report is misleadingly negative regarding the current status of quantitative EEG and tends to discourage its development and use with other related clinical problems. There have been many excellent studies showing that QEEG can be useful for the evaluation and understanding of mild traumatic brain injury, learning disabilities, attention deficit disorders, alcoholism, depression, and other types of substance abuse. In fact, Hughes and John recently provided in this Journal an extensive and detailed review of the use of QEEG in psychiatric disorders. The bias of the AAN/ACNS report is also evident when contrasted to the outstanding review of the clinical utility of QEEG by the American Medical EEG Association, which clearly articulates the opposite points in many cases and concludes that QEEG has reached maturity. At present, the most one can say is that there are legitimate scientific debate and differences of opinion concerning the utility of QEEG, as there are in many other areas of medicine. The AAN/ACNS article should not be considered the definitive opinion. Too many implications for health care are at stake. The debate and research may continue without withholding valuable help from the public. We hope that revised guidelines will be drafted in such a way as to encourage the development of quantitative EEG and brain mapping rather than discourage future research support and use of QEEG with patients. Furthermore, we strongly feel that this technology should be available to, and be explored and used by, nonphysicians who are properly trained and certified.

Bestrophin gene mutations in patients with Best vitelliform macular dystrophy.

Best vitelliform macular dystrophy (VMD2) is an autosomal dominant dystrophy with a juvenile age of onset. Mutations in the Bestrophin gene were shown in patients affected with VMD2. In a mutation study, we made three new and interesting observations. First, we identified possible mutation hotspots within the gene, suggesting that particular regions of the protein have greater functional significance than others. Second, we described a 2-bp deletion in a part of the gene where mutations have not previously been reported; this mutation causes a frameshift and subsequent premature termination of the protein. Finally, we have evidence that some mutations are associated with variable expression of the disease, suggesting the involvement of other factors or genes in the disease phenotype.

Outcomes of vitreoretinal surgery in patients with X-linked retinoschisis.

BACKGROUND AND OBJECTIVE: To assess the outcomes of vitreoretinal surgery in the treatment of vision-threatening posterior segment complications of X-linked retinoschisis. PATIENTS AND METHODS: The authors performed a retrospective analysis of 16 eyes from 11 patients who underwent vitreoretinal surgery. All the patients had a documented positive family history of X-linked retinoschisis, and all patients had bilateral macular disease. RESULTS: The ages of the patients ranged from 14 months to 37 years (mean age 15.1 years; median age 11.5 years), and postoperative follow-up ranged from 3 months to 10 years (mean 2.8 years; median 1 year). The indications for surgical intervention included rhegmatogenous retinal detachment (12 eyes), vitreous hemorrhage (2 eyes), progression of the schisis cavity through the fovea (2 eyes), cataract associated with a persistent hyperplastic primary vitreous-like condition (2 eyes), and exudative maculopathy (1 eye). The primary surgical intervention included pars plana vitrectomy alone (7 eyes), pars plana vitrectomy and pars plana lensectomy (4 eyes), and a scleral buckle procedure alone (5 eyes). Surgical success (defined as reattachment of the retina, removal of media opacities, or arrest of schisis progression) was achieved in 14 of 16 eyes, after an average of 1.2 procedures per eye. The major reason for reoperations was recurrent retinal detachment due to proliferative vitreoretinopathy. Two eyes were eventually enucleated due to pain associated with neovascular glaucoma resulting from recurrent retinal detachment. Of the remaining 14 eyes, visual acuity improved in 8 eyes and remained unchanged in 6 eyes. CONCLUSION: Vitreoretinal surgery is often helpful in stabilizing or improving visual function in patients with posterior segment complications from X-linked retinoschisis.

Low incidence of retinitis pigmentosa among heterozygous carriers of a specific rhodopsin splice site mutation.

PURPOSE: To determine whether a rhodopsin splice donor site mutation at the 5' end of intron 4 is a cause of autosomal dominant retinitis pigmentosa. METHODS: Heterozygous carriers of the same rhodopsin splice site mutation in two pedigrees were identified using single-strand conformation polymorphism analysis. Twelve heterozygous carriers were evaluated by ophthalmoscopy. Goldmann kinetic visual fields, dark adaptation thresholds, and full-field electroretinograms including rod intensity-response functions. Clinical findings from the heterozygous carriers of the splice site mutation were compared with those from heterozygous carriers from a separate family with a known recessive rhodopsin null mutation, Glu249X. RESULTS: Analysis of DNA from 48 members of two pedigrees revealed 25 heterozygous carriers of the splice site mutation, ranging in age from 14 to 82 years. There were no homozygotes with the rhodopsin splice site mutation. Of the 25 heterozygous carriers, 24 were asymptomatic. Eleven asymptomatic heterozygotes were examined, including four older than 65 years of age. They were found to have normal fundi, full visual fields, and slightly elevated final rod dark adaptation thresholds. Their rod electroretinographic b-wave amplitudes were slightly diminished over the full range of blue light intensities. Rod a-wave implicit times were slightly but significantly prolonged in response to the brightest blue flash of light. These subtle abnormalities in rod function were similar to those found in asymptomatic heterozygous carriers of the recessive Glu249X mutation. Only one of the 25 heterozygous carriers of the splice site mutation had symptoms and signs of retinitis pigmentosa. CONCLUSIONS: Because 96% of these heterozygous carriers do not have retinitis pigmentosa, it is unlikely that this mutation in intron 4 is a dominant allele. The subtle abnormalities of rod function found in asymptomatic carriers are similar to those found in heterozygous carriers of a recessive rhodopsin allele. The one heterozygous carrier with retinitis pigmentosa probably has a second mutation in the rhodopsin gene or has a defect or defects in another gene that causes his disease.