Progressive Retinopathy Research Articles

Serous retinal detachment after panretinal photocoagulation for proliferative diabetic retinopathy: a case report

BackgroundProliferative diabetic retinopathy is a major cause of visual impairment in working-age adults worldwide. Panretinal photocoagulation is a cornerstone in its management; however, it may include a range of side effects and complications, one of these being serous retinal detachment. To the best of our knowledge, this is the first report of the use of intravitreal injection of bevacizumab for serous retinal detachment after panretinal photocoagulation.Case presentationA 24-year-old Saudi man with poorly controlled type 1 diabetes presented with bilateral progressive proliferative retinopathy in spite of several sessions of panretinal photocoagulation. After one additional such session, he developed bilateral serous retinal detachment and vision loss, which was managed with a single bilateral intravitreal bevacizumab injection. The serous retinal detachment subsided with partial recovery of vision.ConclusionsSerous retinal detachment after panretinal photocoagulation for proliferative diabetic retinopathy is a rare complication nowadays. In this case, it seems that excessive photocoagulation exceeded the energy-absorbing capacity of the retinal pigment epithelium, leading to a disruption of the blood–retinal barrier. A single injection of bilateral intravitreal bevacizumab was sufficient to control the serous retinal detachment. This effect may have been due to a reduction of vascular leakage resulting from the mechanism of action of this drug. No complications were noted from the injection. Caution should be exerted when attempting bilateral panretinal photocoagulation.

C2orf71 Mutations as a Frequent Cause of Autosomal-Recessive Retinitis Pigmentosa: Clinical Analysis and Presentation of 8 Novel Mutations.

To define the phenotype of C2orf71 associated retinopathy and to present novel mutations in this gene. A retrospective multicenter study of patients with retinopathy and identified C2orf71 mutations was performed. Ocular function (visual acuity, visual fields, electroretinogram [ERG] responses); retinal morphology (fundus, optical coherence tomography); and underlying mutations were analyzed. Thirteen patients from 11 families, who were aged 7 to 63 years (mean: 32.1 years) at their first examination with presumed compound heterozygous (6/13 patients) or homozygous (7/13 patients) C2orf71 mutations were identified. Eight of the mutations were novel. Truncation mutations were responsible in all cases. Nyctalopia was observed in less than 50% of patients. Visual acuity ranged from 20/20 to light perception. Severe visual loss was associated with atrophic maculopathy. Full-field ERG responses showed severe progressive cone-rod or rod-cone dysfunction. Typical fundus changes were progressive symmetrical retinopathy with an early mild maculopathy and patchy circular midperipheral RPE atrophy. Normal retinal lamination was preserved despite early disruption of the ellipsoid zone and RPE irregularities. Outer retinal tubulations were associated with better-preserved visual acuity. On the basis of our multicenter analysis, C2orf71 might represent a more frequently mutated gene in autosomal recessive retinitis pigmentosa in some populations. The phenotype analysis over a wide age range showed a variable and progressive retinal degeneration with early onset maculopathy and a better visual potential before the age of 30 years.

TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of Nε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum Nε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between Nε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the Nε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.

Impact of intravitreal pharmacotherapies including antivascular endothelial growth factor and corticosteroid agents on diabetic retinopathy.

Diabetic retinopathy is common and increasing in prevalence. Pharmacologic management of diabetic macular edema (DME) has improved tremendously over the last decade with the use of two families of intravitreally administered medications: antivascular endothelial growth factor-specific agents and corticosteroids. Clinical evaluation of these pharmaceuticals has demonstrated that they can have a substantial impact on diabetic retinopathy severity levels and the underlying retinal vasculature itself. Phase 3 trials employing ranibizumab, aflibercept, and fluocinolone acetonide enrolling eyes with center-involving DME causing visual acuity loss have demonstrated impressive alteration of the natural history of progressive diabetic retinopathy worsening over time through blunted progression to proliferative diabetic retinopathy, improving diabetic retinopathy severity levels, and slowing progressive retinal nonperfusion, the underlying disease process central to diabetic retinopathy itself. Accumulating data indicate that the threshold to initiate ocular-specific pharmacologic treatment for diabetic retinopathy, previously predominately limited to eyes with visual loss because of center-involved DME or proliferative diabetic retinopathy, is being lowered to earlier stages of diabetic retinopathy. Ongoing clinical trials and secondary analyses continue to further explore the impact and durability of vascular endothelial growth factor blockade and corticosteroids on modification of diabetic retinopathy and the underlying retinal vasculature itself.

Ocular manifestations of autoimmune polyendocrinopathy syndrome type 1.

The ocular manifestations in autoimmune polyendocrinopathy syndrome type 1 (APS1) are frequent and have a poor prognosis. The phenotype of these APS1-associated ocular features have been recently characterized in molecularly confirmed patients with APS1. Keratopathy and retinopathy can be severe manifestations of APS1. Heterogeneous corneal involvement can be observed, ranging from minimal superficial punctate staining to severe stromal scarring with deep corneal neovascularization. This phenotypic heterogeneity, observed even in patients with identical AIRE mutations, is suggestive of a poor genotype-phenotype correlation. Similarly, in patients with retinopathy, peripheral pigmentary changes are noted in all cases, yet with heterogeneous severity, ranging from isolated patchy atrophy of the retinal pigment epithelium to a retinitis pigmentosa-like fundus. Macular atrophy with vision loss is found in most cases. The severity of ophthalmic findings is uncorrelated to that of systemic manifestations. An autoimmune origin with specific autoantibodies directed against corneal and/or retinal autoantigens is the main mechanism believed to be responsible for the ocular manifestations of APS1. Progressive keratopathy and/or retinopathy can lead to severe visual loss and pain in patients with APS1. Although no treatment has shown efficacy regarding the APS1-associated ocular manifestations, ophthalmologic examinations are recommended in these patients.

Diagnosis and Management of Kearns-Sayre Syndrome Rely on Comprehensive Clinical Evaluation

We appreciate the readers’ interest and their comprehensive comments and advice about the article,[1] which mainly concerned details of the patients’ information. In this paper, we reported 19 Kearns-Sayre syndrome (KSS) patients whose diagnoses were in accordance with the current clinical diagnostic criteria of KSS, i.e., the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age, plus at least one of the followings: heart block, cerebellar symptoms, or cerebrospinal fluid protein levels above 1000 mg/L.[2] The diagnostic criteria have been widely used.[3] Apart from clinical features, muscle pathology and molecular genetic analysis can play a great role in the diagnostic workup. Muscle pathology showed ragged-red fibers (RRF), ragged-blue fibers (RBF), or cytochrome c-oxidase (COX)-negative fibers in almost all patients.[4] Southern blot or long-range polymerase chain reaction can detect single large-scale deletion in about 90% of KSS patients,[5] while mitochondrial DNA (mtDNA) point mutations or nuclear gene mutations have been reported in other KSS patients.[6] In general, single large-scale deletion can be detected only from the muscle, but not from blood cells of KSS patients.[7] Among the 19 patients reported by us, 15 patients underwent muscle biopsy in our hospital which showed RRF, RBF, and COX-negative fibers in all of them; however, mtDNA mutation detection was available in 11 of them because muscle tissue of the other four (patients 8, 10, 17, and 18) were not enough for further gene analyses; one patient (patient 12) had muscle biopsy in another hospital, and we got a little muscle tissue to do the mutation examination although RBF% cannot be counted. Three patients (patients 2, 5, and 7) refused to receive muscle biopsy, but all of them showed typical KSS features. We performed common mtDNA point mutations analysis (mtDNA A3243G, A8344G) in their blood, which were negative. Biochemical investigations, especially activity assay of respiratory chain complexes in muscle tissues, can also help provide evidence for the diagnosis of mitochondrial disease.[8] Unfortunately, such a detecting platform has not been established in our laboratory. There were several articles studying the exact nature of high signal lesions on diffusion-weighted imaging (DWI) in patients with mitochondrial diseases, especially mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. However, the results were conflicting since some reported an increase in the apparent diffusion coefficient (ADC) values suggesting vasogenic edema while others described a decrease in the ADC values reflecting cytotoxic edema.[9] In our KSS patients, we also found the same interesting phenomena that the ADC values of the regions with high signal on DWI were not consistent. Some patients showed increased ADC values while the others showed decreased ADC values. We proposed that the discrepancy might be due to the different disease stages in different individual patients although further studies are needed to elucidate the underlying pathophysiological mechanism. The results of Moraes et al.[2] showed cognitive decline in 31% of KSS patients, which was associated with the presence of disability. In our research, the present study was mainly focused on the electrocardiogram and brain magnetic resonance imaging changes of the patients. Cognitive function was only evaluated in one patient, which also showed a moderate decline of cognitive function. In our research, all the patients underwent Holter monitoring, and as we reported in the article, none of them developed ventricular arrhythmias, which was also a big difference from previous reports. Therefore, the cardiologists did not suggest implantable cardioverter defibrillator implantation in these patients. According to the height and weight standardized growth charts for Chinese children and adolescents aged 0–18 years,[10] we only found the heights of three patients more than two standard deviations below the mean for age and gender. The heights of other six patients were below the mean height for age and gender but did not reach the definition for short stature. Again, we show our greatest thanks for the comments and advices, and hope that we can learn more about the disease to bring more effective treatment for the patients in the near future, by our efforts together.

Neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are neurodegenerative conditions that associate cognitive decline, progressive cerebellar atrophy, retinopathy, and myoclonic epilepsy. NCL result from the excessive accumulation of neuronal and extraneuronal lipopigments, despite having diverse underlying biochemical aetiologies. Here we review the clinical presentation, pathophysiology and genetics of these conditions as well as the approach to diagnosis and management.

The effectiveness of continuous intravitreal adrenaline as mydriatic adjuvant on pars plana vitrectomy in diabetic patient, a randomized clinical trial

IntroductionDilated pupil is an important factor for good visualization during pars plana vitrectomy (PPV) in patients with diabetic retinopathy. Despite its side effects, intravitreal adrenaline has been used to maintain pupil dilation. ObjectiveTo assess the effect of intravitreal adrenaline infusion on pupil dilation in patients with diabetic retinopathy undergoing PPV. MethodsThis study included 30 eyes of 30 patients with progressive diabetic retinopathy underwent PPV. Pupils of all eyes were dilated by topical application of a combination of 1% tropicamide and 2.5% phenylephrine, and eyes were randomized 1:1 to continuous intravitreous infusion of adrenaline (0.5mg/500ml in balanced salt solution) or vehicle control. Surgical procedures were recorded with a high definition video recorder. Normalized pupillary area (NPA) was measured on recorded images before and at the end of surgery. ResultsPost-operative NPA differed significantly between the two groups (p=0.04). By contrast, pre-operative NPA (p=0.81) and changes in NPA (p=0.17) did not. ConclusionIntravitreal infusion of adrenaline did not have a significant effect on pupil dilation, compared with non-adrenaline, in patients with diabetic retinopathy undergoing PPV.

Bardet Biedl syndrome in South Africa: A single founder mutation.

Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA).Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA. This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered.Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.

46. The First Viable Mouse Model of cblC Type Combined Methylmalonic Acidemia and Homocysteinemia: AAV Gene Therapy Rescues Neonatal Lethality and Provides Insight into Disease-Associated Retinal Degeneration

Combined methylmalonic acidemia and homocysteinemia, cblC type (cblC), is the most common inborn error of cobalamin metabolism and is caused by mutations in the MMACHC gene. MMACHC transports and processes intracellular cobalamin (vitamin B12) into its two active cofactors, 5’-adenosylcobalamin and methylcobalamin, necessary for the enzymatic reactions of methylmalonyl-CoA mutase and methionine synthase, respectively. Mutations in MMACHC result in methylmalonic acidemia, hyperhomocysteinemia and hypomethioninemia. Disease manifestations include growth failure, anemia, heart defects, developmental delay and a progressive maculopathy and pigmentary retinopathy that causes blindness, usually by the end of the first decade. Despite the use of conventional therapies including cobalamin injections and other cofactors, the manifestions of cblC, in particular the eye disease, remain unresolved with treatment. In order to explore disease pathophysiology and develop AAV gene therapy for cblC deficiency, we first created a viable mouse model using TALENs to edit the murine Mmachc gene, near the location of the most common mutation in humans, c. 271dupA. Two alleles were investigated: c. 165_166delAC p. P56CfsX4 (Δ2) and c. 162_164delCAC p. S54_T55delinsR (Δ3). MmachcΔ2/Δ3 and MmachcΔ3/Δ3 homozygous mutant mice displayed reduced survival, severe growth retardation, and massive metabolic perturbations. The median survival was less than 7 days with 90% of the mutant mice perishing before 3 weeks (Δ2 n=13; Δ3 n=42). The weights of MmachcΔ3/Δ3 mice were reduced relative to heterozygote and wild type littermates (n=15, p<0.0001). MmachcΔ2/Δ2 and MmachcΔ3/Δ3 mice (n=4, n=6) recapitulated the biochemical features of cblC, with significantly elevated plasma methylmalonic acid, homocysteine, cystathionine and decreased methionine compared to littermate controls (n=7) (p<0.05 for all metabolites). To assess the potential for gene therapy as a treatment for cblC, we generated two AAV vectors: rAAVrh10-CBA-mMmachc and rAAV9-CBA-hMMACHC and compared AAV with biweekly injections of OH-cobalamin, the standard therapy. MmachcΔ3/Δ3 mice were then treated with a single vector dose (1 × 1011 GC) delivered via intrahepatic injection in the neonatal period. MmachcΔ3/Δ3 mice treated with AAV vectors (AAVrh10 n=11, AAV9 n=5) displayed dramatically improved clinical appearance with improved growth (p= 0.0568), and increased survival (p<0.0001 for both vectors), with the oldest treated mutants currently living beyond 9 months. Successful gene therapy in the MmachcΔ3/Δ3 mice also enabled us to model, for the first time, cblC associated ocular pathology: surviving MmachcΔ3/Δ3 mice displayed thinning of the outer nuclear layer and shortening of photoreceptor outer segments, consistent with the pathology described in patients. Our results demonstrate that AAV gene delivery of MMACHC represents a new therapy for cblC which can treat the systemic, and possibly ocular, manifestations of this relatively common and devastating inborn error of metabolism.

MELAS and Kearns-Sayre overlap syndrome due to the mtDNA m. A3243G mutation and large-scale mtDNA deletions.

This paper reported an unusual manifestation of a 19-year-old Chinese male patient presented with a complex phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome and Kearns–Sayre syndrome (KSS). He was admitted to our hospital with the chief complaint of “acute fever, headache and slow reaction for 21 days”. He was initially misdiagnosed as “viral encephalitis”. This Chinese man with significant past medical history of intolerating fatigue presented paroxysmal neurobehavioral attacks that started about 10 years ago. During this span, 3 or 4 attack clusters were described during which several attacks occurred over a few days. The further examination found that the hallmark signs of this patient included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy and bifascicular heart block (Wolff–Parkinson–White syndrome). By young age the disease progression is characterized by the addition of migraine, vomiting, and stroke-like episodes, symptoms of MELAS expression, which indicated completion of the MELAS/KSS overlap syndrome. The m. A3243G mitochondrial DNA mutation and single large-scale mtDNA deletions were found in this patient. This mutation has been reported with MELAS, KSS, myopathy, deafness and mental disorder with cognitive impairment. This is the first description with a MELAS/KSS syndrome in Chinese.

Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.

Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1+/Δex41mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.

Association of a Pro-Inflammatory Axis Comprised By TSP1-TGF-CTGF/CCN2 with a Decrease in Mir-19a-3p in the Pathophysiology of Diabetic Retinopathy

Diabetic retinopathy (DR) is the leading cause of legal blindness in working age adults in the United States with about 18 thousand new cases of blindness each year. Approximately 75% of patients with type-2 diabetes will develop some sign of retinopathy after 15 years. The healthcare costs associated with diabetes related vision loss has been estimated at $500 million annually and the cost rises significantly with the severity of DR. Therefore, preventing the progression of DR from mild non-progressive diabetic retinopathy (NPDR) to progressive diabetic retinopathy (PDR) could ameliorate the economic burden related to diabetes and vision loss. Our laboratory has focused on a pro-inflammatory axis comprised by thrombospondin-1 (TSP1), transforming growth factor β (TGFb) and connective tissue growth factor (CTGF/CCN2) in the pathophysiology of DR. Furthermore, the regulation of this pro-inflammatory axis during disease states in humans associated with acute and chronic inflammation such as type-2 diabetes has not been elucidated. The current prospective study documents a potential regulatory mechanism, namely a microRNA associated with the up-regulation of the pro-inflammatory axis. Patients were recruited between February 2013 to May 2014. In May of 2015 it was determined by this research team that the data was mature for final analysis and, thus the results are the topic of this abstract. The participants were patients with type-2 diabetes (n=36) with either evidence of non-proliferative diabetic retinopathy (NPDR Group, n=16), or with evidence of proliferative diabetic retinopathy (PDR Group, n=20) as well as non-diabetic human subjects (Control Group, n=21). Each patient's history and duration of diabetes was obtained from the medical electronic records.TSP1 was found significantly increased in the NPDR (502±145.03 ng/ml, p<0.05) and PDR (1033.9±136 ng/ml, p<0.001) groups when compared to control group (167±41.9 ng/ml). TGF-β was found significantly increased in the NPDR (32.0±4.49 pg/ml, p<0.001) and PDR (7.75±1.7 pg/ml, p<0.05) groups when compared to control (0.75±0.05 pg/ml). CTGF/CCN2 was found significantly increased in the NPDR and PDR groups, namely 3.69±1.52 ng/ml (p<0.001) and 1.69±0.4 ng/ml (p<0.05) respectively when compared to the control group (0.25±0.049 ng/ml). Tumor necrosis factor-α was found significantly increased (17.3±2.1 pg/ml, p<0.05) in the NPDR group but not in the PDR group (trend for higher levels) when compared to control group (9.61±0.74 pg/ml). Interleukin-4 was found decreased in both the NPDR (1.54±0.23 pg/ml, p<0.05) and the PDR (2.02±0.26, p<0.05) groups when compared with the control group (5.42±1.63 pg/ml). IL-4 recently has been documented as an important regulator of lipid metabolism.When comparing the three groups using an ANOVA, one microRNA, namely miR-19a-3p was found to be the most strongly differentially expressed using a cutoff p-value ≤ 0.05 after a Benjamini-Hochberg correction for multiple testing, recommended when doing panel or array profiling. Figure 1 panel A shows the expression level centered to assay average for miR-19a-3p detected in most samples. Panel B clearly illustrates a significant decrease in miR-19a-3p in both groups, namely NPDR (p<0.0012) and PDR (p<0.049).Interestingly down-regulation of miR-19a was found independent of progression of disease suggesting that the differential expression seen in our study in the NPDR and PDR groups is inherent to the underlying disease. These last observations including the mechanistic steps involved are currently under investigation in our laboratory, since understanding, how the down-regulation of miR-19a leads to up-regulation of TSP1-TGFb-CTGF/CCN2, might have a two-fold potential value in type-2 diabetes. First, it can be used as a biomarker for early diagnosis, prognosis and therapeutic response. Second, a therapeutic approach would be able to restore the mature miRNA levels in the proper tissue/cells. In summary our results support the role of a pro-inflammatory axis in the pathophysiology of type-2 diabetes as a result of differential expression of miR-19a. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Eye on Mitochondrial Disorders.

Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome.

The “eye of the tiger” sign

An 8-year-old boy presented with recurrent falls while walking and abnormal twisting postures of all four limbs for last 2 yr. He also had cognitive decline and decrease in speech output. His elder brother died of similar illness at the age of 11 yr. Examination revealed generalized dystonia, spasticity and dysarthria. Fundus examination showed bilateral retinal pigmentary changes and optic atrophy (Fig. 1). Magnetic resonance imaging of brain revealed hypo-intense globus pallidi with central hyperintensity, i.e. “eye of the tiger” sign on T2-weighted images (Fig. 2). These findings were consistent with the diagnosis of pantothenate kinase associated neurodegeneration (PKAN). Genetic testing could not be performed because of financial constraints. PKAN, formerly called Hallervorden-Spatz disease is a form of neurodegenerationwith brain iron accumulation, inherited in an autosomal recessive manner [1]. PKAN is characterized by progressive dystonia, rigidity, dysarthria, intellectual deterioration and pigmentary retinopathy starts before 10 yr of age. The “eye of the tiger” sign describes the central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. The hypointensity on T2-weighted image is because of

Localization of damage in progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer retina, parafovea versus peripheral fovea.

To evaluate the relative involvement of inner and outer retina in hydroxychloroquine (HCQ) retinopathy while on the drug, and after drug cessation, using data from spectral-domain optical coherence tomography (SD-OCT). A total of 102 SD-OCT scans were obtained from 11 patients (classified as having early, moderate, or severe stages of toxicity) over a period of 4 years after cessation of HCQ. The inner and outer retina boundaries were identified automatically to measure thickness and characterize progression topographically. The segmentation of retinal layers was verified in SD-OCT cross-sections for all eyes and scans included in this study (a total of 102 scans). Topographic analysis showed that inner retina was not involved in HCQ toxicity to any meaningful degree, either between stages of retinopathy or after the drug is stopped. The characteristic bull's eye pattern of outer macula thinning appears when comparing moderate retinopathy (before any RPE damage) to the early stage. Later damage, as toxicity evolved to a severe stage, was diffuse across most of the macula. If the drug was stopped at an early or moderate stage, progression was limited to the first year and occurred diffusely without parafoveal localization. Hydroxychloroquine retinopathy primarily involves outer retina (photoreceptors). Outer retinal thinning while using HCQ initially involves the parafovea, but becomes diffuse across the macula as damage progresses or after drug cessation. When HCQ is stopped at an early or moderate stage (before RPE damage), progression seems to be limited to the first year.

Pharmacologic vitreolysis with ocriplasmin: rationale for use and therapeutic potential in vitreo-retinal disorders.

With increased knowledge about the origins and pathophysiology of vitreo-retinal disorders—and, in particular, the central role of anomalous posterior vitreous detachment in vitreo-maculopathies—a paradigm shift from surgery to pharmacotherapy is taking place with the development of pharmacologic vitreolysis. The first approved agent for pharmacologic vitreolysis therapy is ocriplasmin, a truncated form of the nonspecific serine protease plasmin. Twelve studies comprise the current ocriplasmin clinical trial program, demonstrating the efficacy and safety of a single intravitreal injection of ocriplasmin for the treatment of patients with symptomatic vitreo-macular adhesion or vitreo-macular traction, including patients with macular holes. Although post-approval implementation of ocriplamsin in clinical practice has shown success rates of up to 78%, there have been recent case reports of acute, transient visual dysfunction. There are thus new initiatives to further refine clinical indications for case selection and to identify possible untoward effects. Although more studies are warranted, it appears that ocriplasmin offers a good alternative to surgery. The future lies in pharmacologic vitreolysis, and the future of pharmacologic vitreolysis lies in prevention. Thus, long-term studies are needed to define a role for pharmacologic vitreolysis, in particular with ocriplasmin, in the prevention of progressive diabetic retinopathy and age-related macular degeneration.

Phenotype variations of retinal dystrophies caused by mutations in the RLBP1 gene.

Mutations in the RLBP1 gene encoding the cellular retinaldehyde-binding protein (CRALBP) cause autosomal recessive progressive retinopathy, such as retinitis punctata albescens (RPA), Bothnia-type dystrophy (BD), Newfoundland rod-cone dystrophy (NFRCD), retinitis pigmentosa (RP) and fundus albipunctatus (FA). We present the clinical heterogeneity and genetic findings of seven patients from five families with RLBP1 mutations, including three novel mutations. Seven patients underwent complete ophthalmological examination including psychophysical tests (visual acuity, colour vision, visual field, dark adaptation) and electrophysiology (Ganzfeld and multifocal ERG). Additionally, fundus photography, autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) recordings were performed. Genomic DNA was analysed by high-throughput sequencing for all RP-related genes in a diagnostic set-up. The patients presented with variable phenotypes, including RPA, BD, RP and a mild form of NFRCD. No detectable or severely depressed responses in electrophysiological examinations were seen in all cases. Visual field constriction was variable among individuals. Severely reduced visual acuity was only observed in the patient presenting with BD. The other patients retained mild to moderate reduction of visual function. Despite the morphological differences, central retinal thinning - as a common feature - could be observed. The fact that different mutations in RLBP1 are correlated with quite different morphological and functional characteristics outlines the complexity of the protein. Identifying new mutations and comparing the different phenotypes may help to better understand the function of the protein and the consequences in pathological changes that involve RPE and choroid.

Síndrome de Kearns-Sayre: manifestaciones oftalmológicas

The clinical case and genetic diagnosis of Kearns-Sayre syndrome (KSS) is described in a young patient. The findings included: ptosis, ocular motility disturbances, pigmentary retinopathy, as well as mitral insufficiency. A muscle biopsy revealed mitochondrial cytopathyand heteroplasmic mitochondrial DNA deletions.KSS is a rare neuromuscular disorder defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy and atrioventricular block. Early detection is essential to avoid potential cardiac complications.

Quantification of the changes in the openness of the major temporal arcade in retinal fundus images of preterm infants with plus disease.

We tested the hypothesis that the openness of the major temporal arcade (MTA) changes in the presence of plus disease, by quantification via parabolic modeling of the MTA, as well as measurement of an arcade angle for comparative analysis. Such analysis could assist in the detection and treatment of progressive retinopathy of prematurity. Digital image processing techniques were applied for the detection and modeling of the MTA via a graphical user interface (GUI) to quantify the openness of the MTA. An arcade angle measure, based on a previously proposed method, also was obtained via the GUI for comparative analysis. The statistical significance of the differences between the plus and no-plus cases for each parameter was analyzed using the P value. The area (Az) under the receiver operating characteristic curve was used to assess the diagnostic performance of each feature. The temporal arcade angle measure and the openness parameter of the parabolic model were used to perform discrimination of plus versus no-plus cases. Using a set of 19 cases with plus and 91 with no plus disease, Az=0.70 was obtained using the results of dual-parabolic modeling in screening for plus disease. The arcade angle measure provided comparable results with Az=0.73. Using our proposed image analysis techniques and software, this study demonstrates, for the first time to our knowledge, that the openness of the MTA decreases in the presence of plus disease.