Retinal thickness in Parkinson's disease

BACKGROUND: Visual symptoms are common in Parkinson's disease with studies consistently demonstrating reductions in visual acuity, contrast sensitivity, colour and motion perception as well as alterations in electroretinogram latencies and amplitudes. Optical coherence tomography can examine retinal structure non-invasively and retinal thinning has been suggested as a potential biomarker for neurodegeneration in Parkinson's disease. Our aim was to examine the retinal thickness of a cohort of Parkinson's disease subjects (and age-matched controls) to establish the practical utility of optical coherence tomography in a representative older Parkinson's disease group. METHODS: Fifty-one established Parkinson's disease subjects and 25 healthy controls were subjected to ophthalmological assessment and optical coherence tomography (Zeiss Stratus 3000™) of macular thickness and volume and retinal nerve fibre thickness around the optic nerve head. Twenty four percent of control and 20% of Parkinson's disease subjects were excluded from final analysis due to co-morbid ocular pathology. Further data was excluded either due to poor tolerability of optical coherence tomography or poor quality scans. RESULTS: Despite a reduction in both visual acuity and contrast sensitivity in the residual evaluable Parkinson's disease cohort, we did not detect any differences between the two study groups for any measures of retinal thickness, in contrast to previously published work. CONCLUSIONS: In addition to technical problems inherent in the evaluation, the lack of difference between Parkinson's disease and healthy control subjects suggests longitudinal studies, employing newer techniques, will be required to define the role of optical coherence tomography as a potential diagnostic biomarker.

Inter-observer agreement for spectral- and time-domain optical coherence tomography image grading: a prospective study

The purpose of this study was to compare inter-observer agreement of Stratus™ OCT versus Spectralis™ OCT image grading in patients with neovascular age-related macular degeneration (AMD). Thirty eyes with neovascular AMD were examined with Stratus™ OCT and Spectralis™ OCT. Four different scan protocols were used for imaging. Three observers graded the images for the presence of various pathologies. Inter-observer agreement between OCT models was assessed by calculating intra-class correlation coefficients (ICC). In Stratus™ OCT highest interobserver agreement was found for subretinal fluid (ICC: 0.79), and in Spectralis™ OCT for intraretinal cysts (IRC) (ICC: 0.93). Spectralis™ OCT showed superior interobserver agreement for IRC and epiretinal membranes (ERM) (ICC(Stratus™): for IRC 0.61; for ERM 0.56; ICC(Spectralis™): for IRC 0.93; for ERM 0.84). Increased image resolution of Spectralis™ OCT did improve the inter-observer agreement for grading intraretinal cysts and epiretinal membranes but not for other retinal changes.

Pathology hinting as the combination of automatic segmentation with a statistical shape model

With improvements in acquisition speed and quality, the amount of medical image data to be screened by clinicians is starting to become challenging in the daily clinical practice. To quickly visualize and find abnormalities in medical images, we propose a new method combining segmentation algorithms with statistical shape models. A statistical shape model built from a healthy population will have a close fit in healthy regions. The model will however not fit to morphological abnormalities often present in the areas of pathologies. Using the residual fitting error of the statistical shape model, pathologies can be visualized very quickly. This idea is applied to finding drusen in the retinal pigment epithelium (RPE) of optical coherence tomography (OCT) volumes. A segmentation technique able to accurately segment drusen in patients with age-related macular degeneration (AMD) is applied. The segmentation is then analyzed with a statistical shape model to visualize potentially pathological areas. An extensive evaluation is performed to validate the segmentation algorithm, as well as the quality and sensitivity of the hinting system. Most of the drusen with a height of 85.5 microm were detected, and all drusen at least 93.6 microm high were detected.

Interferon γ-Dependent Migration of Microglial Cells in the Retina after Systemic Cytomegalovirus Infection

Microglial cells are the resident macrophages of the central nervous system and participate in both innate and adaptive immune responses but can also lead to exacerbation of neurodegenerative pathologies after viral infections. Microglia in the outer layers of the retina and the subretinal space are thought to be involved in retinal diseases where low-grade chronic inflammation and oxidative stress play a role. This study investigated the effect of systemic infection with murine cytomegalovirus on the distribution and dynamics of retinal microglia cells. Systemic infection with murine cytomegalovirus elicited a significant increase in the number of microglia in the subretinal space and an accumulation of iris macrophages, along with morphological signs of activation. Interferon γ (IFN-γ)-deficient mice failed to induce changes in microglia distribution. Bone marrow chimera experiments confirmed that microglial cells in the subretinal space were not recruited from the circulating monocyte pool, but rather represented an accumulation of resident microglial cells from within the retina. Our results demonstrate that a systemic viral infection can lead to IFN-γ-mediated accumulation of microglia into the outer retinal layers and offer proof of concept that systemic viral infections alter the ocular microenvironment and therefore, may influence the course of diseases such as macular degeneration, diabetic retinopathy, or autoimmune uveitis, where low-grade inflammation is implicated.

PVR recurrence and the timing of silicon oil removal

BACKGROUND: Following vitrectomy for PVR-associated retinal detachment, placement of an encircling band, filling with silicone oil (SO) and successful retinal reattachment, a recurrence of PVR can develop. Retinal redetachment after SO removal is usually due to secondary or residual PVR. We wanted to ascertain whether the anatomical and functional outcomes of surgery in patients with a reattached retina and recurrent PVR can be improved by delaying the removal of SO. PATIENTS AND METHODS: 112 consecutive patients with PVR-associated retinal detachment who had undergone vitrectomy with SO filling, were monitored for at least 6 months after SO removal. Prior to SO removal, the retina posterior to the encircling band had to be completely reattached. Patients who developed PVR after SO filling were divided into two groups according to the duration of SO retention: 12 - 18 months (group 2: n = 48); > 18 months (group 3: n = 21). Individuals without PVR recurrence after SO filling and in whom the SO was consequently removed within 4 - 12 months served as control (group 1: n = 43). Anatomical success, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) served as the primary clinical outcome parameters. RESULTS: Six months after SO removal, the anatomical success rates (86.3 %, 88.8 % and 84.6 %, in groups 1, 2 and 3, respectively; log rank = 0.794) and the BCVAs (p = 0.861) were comparable in the three groups. Mean IOP (p = 0.766), and the frequency of complications such as PVR recurrence (p = 0.936), bullous keratopathy (p = 0.981) and macular pucker (p = 0.943) were likewise similar. Patients in whom SO was retained for more than 18 months had the highest IOPs and required the heaviest dosage with anti-glaucoma drugs. CONCLUSIONS: In patients who develop a recurrence of PVR after vitrectomy and SO filling the surgeon can observe and treat retinal changes for up to 18 months without impairing the anatomical and functional outcomes. The retention of SO for more than 18 months does not improve the anatomical outcome. However, it can impair the functional outcome by precipitating the development of a persisting secondary glaucoma.

Ocular manifestations in congenital toxoplasmosis

BACKGROUND: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function. METHODS: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed. RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis. CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.

Vitrectomy for juvenile uveitis: prognostic factors for the long-term functional outcome

PURPOSE: This study evaluated the long-term effect of pars plana vitrectomy (PPV) in children and adolescents with chronic uveitis on visual function, anatomical outcome, and the requirement of systemic treatment. Further, predictive preoperative factors associated with a beneficial visual outcome were assessed. METHODS: Retrospective review of 29 eyes of 23 consecutive paediatric and juvenile patients below 20 years of age with chronic uveitis who underwent a PPV for visually significant opacities in 25 eyes, vitreous haemorrhage in three eyes, and retinal detachment in one eye. The clinical diagnosis was chronic intermediate uveitis in 22 eyes and retinal vasculitis of different origin in seven eyes. RESULTS: LogMAR visual acuity improved from an average of 0.91 to 0.33 (P<0.001). Cystoid macular oedema (CME) was significantly reduced in eight of 10 eyes postoperatively (P=0.021). In the multiple regression analysis, a low preoperative logMAR visual acuity and the presence of a CME had a negative influence on the final logMAR visual acuity. Furthermore, the appearance of chronic uveitis relapses was significantly reduced from 15 eyes before to seven eyes after surgery (P=0.042). CONCLUSIONS: PPV has a beneficial effect on the course and the complications of chronic uveitis in paediatric and juvenile patients with respect to the anatomical and visual outcome. Preoperative logMAR visual acuity and clinically significant CME were the most accurate predictors for the functional outcome.

Systemically transferred hematopoietic stem cells home to the subretinal space and express RPE-65 in a mouse model of retinal pigment epithelium damage

Stem cell regeneration of damaged tissue has recently been reported in many different organs. Since the loss of retinal pigment epithelium (RPE) in the eye is associated with a major cause of visual loss - specifically, age-related macular degeneration - we investigated whether hematopoietic stem cells (HSC) given systemically can home to the damaged subretinal space and express markers of RPE lineage. Green fluorescent protein (GFP) cells of bone marrow origin were used in a sodium iodate (NaIO(3)) model of RPE damage in the mouse. The optimal time for adoptive transfer of bone marrow-derived stem cells relative to the time of injury and the optimal cell type [whole bone marrow, mobilized peripheral blood, HSC, facilitating cells (FC)] were determined by counting the number of GFP(+) cells in whole eye flat mounts. Immunocytochemistry was performed to identify the bone marrow origin of the cells in the RPE using antibodies for CD45, Sca-1, and c-kit, as well as the expression of the RPE-specific marker, RPE-65. The time at which bone marrow-derived cells were adoptively transferred relative to the time of NaIO(3) injection did not significantly influence the number of cells that homed to the subretinal space. At both one and two weeks after intravenous (i.v.) injection, GFP(+) cells of bone marrow origin were observed in the damaged subretinal space, at sites of RPE loss, but not in the normal subretinal space. The combined transplantation of HSC+FC cells appeared to favor the survival of the homed stem cells at two weeks, and RPE-65 was expressed by adoptively transferred HSC by four weeks. We have shown that systemically injected HSC homed to the subretinal space in the presence of RPE damage and that FC promoted survival of these cells. Furthermore, the RPE-specific marker RPE-65 was expressed on adoptively transferred HSC in the denuded areas.

Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD

PURPOSE: To test the hypothesis that the extension of areas with increased fundus autofluorescence (FAF) outside atrophic patches correlates with the rate of spread of geographic atrophy (GA) over time in eyes with age-related macular degeneration (AMD). METHODS: The database of the multicenter longitudinal natural history Fundus Autofluorescence in AMD (FAM) Study was reviewed for patients with GA recruited through the end of August 2003, with follow-up examinations within at least 1 year. Only eyes with sufficient image quality and with diffuse patterns of increased FAF surrounding atrophy were chosen. In standardized digital FAF images (excitation, 488 nm; emission, >500 nm), total size and spread of GA was measured. The convex hull (CH) of increased FAF as the minimum polygon encompassing the entire area of increased FAF surrounding the central atrophic patches was quantified at baseline. Statistical analysis was performed with the Spearman's rank correlation coefficient (rho). RESULTS: Thirty-nine eyes of 32 patients were included (median age, 75.0 years; interquartile range [IQR], 67.8-78.9); median follow-up, 1.87 years; IQR, 1.43-3.37). At baseline, the median total size of atrophy was 7.04 mm2 (IQR, 4.20-9.88). The median size of the CH was 21.47 mm2 (IQR, 15.19-28.26). The median rate of GA progression was 1.72 mm2 per year (IQR, 1.10-2.83). The area of increased FAF around the atrophy (difference between the CH and the total GA size at baseline) showed a positive correlation with GA enlargement over time (rho=0.60; P=0.0002). CONCLUSIONS: FAF characteristics that are not identified by fundus photography or fluorescein angiography may serve as a prognostic determinant in advanced atrophic AMD. As the FAF signal originates from lipofuscin (LF) in postmitotic RPE cells and since increased FAF indicates excessive LF accumulation, these findings would underscore the pathophysiological role of RPE-LF in AMD pathogenesis.

First clinical experience with anecortave acetate (Retaane)

BACKGROUND: Anecortave acetate is an angiostatic cortisene which is injected as a posterior juxtascleral depot and has been shown to be effective in the treatment of exudative age-related macular degeneration (AMD). The compound is not yet approved in Switzerland but can be used as "compassionate use" in individual cases. PATIENTS AND METHODS: An uncontrolled case series with standardised documentation of ETDRS visual acuity, near acuity, need for magnification and fluorescein angiography was performed. RESULTS: 22 eyes of 19 patients (8 male, 11 female, average age 78.8 years) were treated with a posterior juxtascleral depot injection (PJD) of 15 mg anecortave acetate. The mean change in visual acuity after 3 months in eyes treated with anecortave acetate was -2.6 ETDRS letters corresponding to 0.52 Snellen lines. 3/20 eyes gained more than 1 line. 11/20 eyes showed stable visual acuity (+/- 1 Snellen line, +/- 5 ETDRS letters). 5/20 eyes developed moderate vision loss (one to two Snellen lines, 6-10 ETDRS letters). 1/20 lost 18 ETDRS letters (> 3 Snellen lines). There were no moderate or severe adverse events. CONCLUSIONS: A PJD of 15 mg anecortave acetate is safe and well tolerated. In eyes with occult CNV without recent progression or with residual neovascular activity after photodynamic therapy anecortave acetate may be an alternative therapeutic option before considering intravitreal anti-VEGF agents due to the much less invasive character and lower risk profile.

Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration

PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy.

Differential optical densities of intraretinal spaces

PURPOSE: To test the hypothesis that hyporeflective spaces in the neuroretina found on optical coherence tomography (OCT) examination have different optical reflectivities according to whether they are associated with exudation or degeneration. METHODS: Retrospective analysis of eyes with idiopathic perifoveal telangiectasia (IPT), diabetic macular edema (DME), idiopathic central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), or cone dystrophy (CD) and eyes of healthy control subjects. OCT scans were performed. Raw scan data were exported and used to calculate light reflectivity profiles. Reflectivity data were acquired by projecting three rectangular boxes, each 50 pixels long and 5 pixels wide, into the intraretinal cystoid spaces, centrally onto unaffected peripheral RPE, and onto the prefoveolar vitreous. Light reflectivity in the retinal pigment epithelium (RPE), vitreous, and intraretinal spaces for the different retinal conditions and control subjects were compared. RESULTS: Reflectivities of the vitreous and the RPE were similar among the groups. Hyporeflective spaces in eyes with exudation (DME, RP, and CSC) had higher reflectivity compared with the mean reflectivity of the vitreous, whereas the cystoid spaces in the maculae of the eyes without exudation (CD and IPT) had a lower reflectivity than did the normal vitreous. CONCLUSIONS: Analysis of the light reflectivity profiles may be a tool to determine whether the density of hyporeflective spaces in the macula is greater or less than that of the vitreous, and may be a way to differentiate degenerative from exudative macular disease.

Current status of anti-vascular endothelial growth factor therapy in Europe

Vascular endothelial growth factor (VEGF) is an important modulator of angiogenesis, and has been implicated in the pathology of a number of conditions, including age-related macular degeneration (AMD), diabetic retinopathy, and cancer. AMD is a progressive disease of the macula and the third major cause of blindness worldwide. If not treated appropriately, AMD can progress rapidly, causing legal blindness within months of the second eye becoming affected. Until recently, the treatment options for AMD have been limited, with photodynamic therapy (PDT) the mainstay treatment. Although PDT is effective at slowing disease progression, it rarely results in improved vision. Pegaptanib and ranibizumab are both anti-VEGF therapies licensed for the treatment of neovascular AMD in Europe; however, these drugs are not yet available in Japan. This article reviews the available clinical data on anti-VEGF therapies for the treatment of neovascular AMD in Europe, and considers the future of this exciting therapy.

Verteporfin therapy in occult with no classic CNV due to AMD: results of the Photodynamic Therapy in Occult-Only Lesions study

PURPOSE: To provide further information on verteporfin photodynamic therapy in occult with no classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Verteporfin therapy was administered at baseline and then at months 3, 6, and 9, if fluorescein leakage from CNV was evident on angiography. RESULTS: Of 202 patients enrolled, 184 completed 12 months. Each patient was treated in one eye only. All study eyes received verteporfin therapy at baseline, with a progressive decrease in the number treated at subsequent visits (mean 2.5 treatments during 12 months). The mean change in visual acuity letter score from baseline to month 12 was -11.9. At month 12, 164 eyes (82.4%) had lost <30 letters of visual acuity, 123 eyes (61.8%) had lost <15 letters, 78 eyes (39.2%) had lost <5 letters, 31 (15.6%) had >5-letter increase, and 7 (3.5%) had >15-letter improvement. The percentage of eyes with fluorescein leakage from CNV decreased from 75.5% at month 3 to 25.1% at month 12. Adverse events were documented for 54% patients. Few patients had treatment-associated adverse events (7%). Acute severe visual acuity decrease occurred in two eyes (1%), one of which had visual acuity that returned to baseline by the next follow-up visit. CONCLUSIONS: This study provides additional evidence that over 12 months, verteporfin is generally well tolerated and maintains or improves visual acuity in over one-third of eyes containing occult-only CNV. Verteporfin also improved anatomical outcomes by reducing leakage from CNV in at least two-thirds of eyes.

Secondary intraocular lenses in eyes with aphakia or dislocated IOL: impact of suture fixation on early and late complications

BACKGROUND: Secondary intraocular lens (IOL) implantation is exposed to an increased risk of complications, including endophthalmitis and retinal detachment. The present analysis compares the outcomes and complications experienced in our own series of patients. PATIENTS AND METHODS: We retrospectively reviewed a consecutive series of secondary posterior chamber IOL implantations performed in a single centre, two surgeon setting over a period of 8 years and with a follow up-time of at least 4 months. RESULTS: Between 1997 and 2005, 75 patients received a sulcus-supported secondary IOL without suture fixation, whereas suture fixation was required in 137 instances. Visual acuity improved in both groups (group 1: from 0.36 +/- 0.39 (0.01-1.2) to 0.73 +/- 0.33 (0.02-1.0; p = 0.18); group 2: from 0.33 +/- 0.34 (0.02-1.0) to 0.46 +/- 0.33 (0.01-1.0; p = 0.006), but more pronounced in eyes not requiring suture fixation (p = 0.012). IOL placement was more likely to be combined with endophacoemulsification in the not suture-fixed IOLs (12.7 vs. 5.3 %). In contrast, retinal tears (10.6 vs. 8.6 %, respectively) and retinal detachment (5.3 vs. 2.2 %, respectively) were equally distributed. In the early postoperative phase, IOP was lower in suture-fixed eyes, which showed a higher incidence of minor intraocular haemorrhages and cystoid macular edema (5.3 vs. 8.0 %); late complications up to 5 years postoperatively were equally distributed. CONCLUSION: A preoperatively less complicated anterior segment situation and a lower incidence of postoperative macular edema may account for a better visual outcome after placement of a sulcus supported IOLs without suturing. If required, suture fixation may be performed without exposing the eye to an increased risk of late postoperative complications.