TREATMENT OPTIONS FOR PREMACULAR AND SUB-INTERNAL LIMITING MEMBRANE HEMORRHAGE.

INTRODUCTION: Premacular hemorrhage (PH) and sub-internal limiting membrane hemorrhage (sub-ILM-H) are among the causes of sudden deterioration of central visual acuity. Anatomical and functional outcomes of different therapeutic options were evaluated retrospectively. METHODS: The study included three eyes of three patients (2 females and 1 male). Location of the hemorrhage was determined by spectral domain optical coherence tomography. Subhyaloid premacular location of the hemorrhage was proven in one eye of each woman and sub-ILM location of the hemorrhage in one eye of the male. The baseline best corrected visual acuity (BCVA) was 0.63 in the eyes of the females and 0.16 in the eye of the male. Conservative treatment option was chosen in case of juxtafoveolar PH in the eye of the female patient on anticoagulant warfarin therapy. The female patient with PH secondary to proliferative diabetic retinopathy (PDR) underwent Nd: YAG laser hyaloidotomy. The male patient with unexplained cause of the sub- ILM-H underwent 25-Gauge vitrectomy with ILM peeling and subsequent ultrastructural morphometric and histopathological examination of the ILM. RESULTS: Both BCVA and retinal finding improvement were achieved in all patients. Final BCVA was 0.8 in the eye of the female patient with PDR and 1.0 in rest of the eyes of the other patients. No complications were recorded at follow-up visits. Histopathological and morphometric examination demonstrated variable ILM thickness (2.70 ±1.58 μm) and proved presence of fibroblasts and macrophages with hemosiderin deposits on the retinal side of ILM. CONCLUSION: The choice of the treatment option of PH and sub-ILM-H depends on input parameters such as the initial BCVA, the extent and the location of the hemorrhage, as well as the overall health of the patient. Nd: YAG laser hyaloidotomy is an effective method for rapid recovery of visual functions. Surgical ILM peeling and aspiration of the underlying hemorrhage result in the removal of breakdown products of hemoglobin and minimization of the risk of secondary epiretinal membranes development.

Innovative strategies for treating retinal diseases.

OBJECTIVE: The aim of this comprehensive paper is to acquaint the readers with innovative approaches in the treatment of retinal diseases, which could in the coming years to get into clinical practice. Retinal prostheses, retinal pigment epithelial (RPE) transplantation, gene therapy and optogenetics will be described in this paper. METHODOLOGY: Describing the basic characteristics and mechanisms of different types of therapy and subsequently literary minireview clarifying the current state of knowledge in the area. RESULTS: Retinal prostheses, RPE transplantation, gene therapy and optogenetics offer yet unexplored possibilities and are considered as the future of treatment of retinal diseases where classical pharmacotherapy or surgical treatment are no longer sufficient. However, all these methods challenge not only in the innovative technical implementation itself, but also for the ethical, administrative and economic demands. CONCLUSION: There will be certainly interesting development in the treatment of retinal diseases, but it is not possible to fully estimate which modality of treatment will be dominant in the future.

Review of SRD5A3 Disease-Causing Sequence Variants and Ocular Findings in Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation, and a Detailed New Case.

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.

Molecular genetic cause of achromatopsia in two patients of Czech origin.

INTRODUCTION: Achromatopsia is an autosomal recessive retinal disorder with an estimated prevalence ranging from 1 in 30.000 to 50.000. The disease is caused by mutations in six different genes. The aim of the study was to perform molecular genetic analysis in 11 unrelated probands with a clinical diagnosis of achromatopsia and to describe clinical findings in those that were found to carry biallelic pathogenic mutations. METHODS: All probands and their parents underwent ophthalmic examination. Mutation detection was performed using Sanger sequencing of CNGB3 exons 6, 7, 9-13, which have been found to harbour most disease-causing mutations in patients with achromatopsia of European origin. RESULTS: Three known pathogenic variants in CNGB3 were identified in 2 probands. Proband 1 was a compound heterozygote for the c.819_826del; p.(Arg274Valfs*13) and c.1006G>T; p.(Glu336*). Proband 2 carried the c.1148del; p.(Thr383Ilefs*13) in a homozygous state. The best corrected visual acuity in proband 1 (aged 19 years) was 0.1 in both eyes, in proband 2 (aged 8 years) 0.05 in the right eye and 0.1 in the left eye. Both individuals had nystagmus, photophobia, and absence of colour discrimination. Fundus examination appeared normal however spectral-domain optical coherence tomography revealed subtle bilaterally symmetrical structural changes in the fovea. CONCLUSION: Molecular genetic analysis of Czech patients with achromatopsia was performed for the first time. Identification of disease-causing mutations in achromatopsia is important for establishing an early diagnosis, participation in clinical trials assessing gene therapies and may be also used for preimplantation genetic diagnosis.

[Gene Therapy for Inherited RETINAL AND OPTIC NERVE Disorders: Current Knowledge]. / Genová terapie dedicných onemocnení SÍTNICE A ZRAKOVÉHO NERVU: soucasný stav poznání.

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

[Clinical Tests Testing New Therapies for Stargardt Disease]. / Klinické zkousky testující nové terapie pro Stargardtovu chorobu.

PURPOSE: To provide information on currently ongoing clinical trials for Stargardt disease. METHODS: We have searched the clinical trial register (www.clinicaltrials.gov) for the keyword "Stargardt" and list active ongoing studies. RESULTS: There are currently eight registered clinical trials enrolling patients with Stargardt disease; all in phase I or II aiming at four mechanisms of action: inhibition of the production of vitamin A toxic dimers, gene therapy restoring wild type transcription of the ABCA4 gene, neuroprotection preventing retinal cells from oxidative damage, and replacement of the damaged retinal pigment epithelium using stem cell therapy. The basic prerequisite for enrolment in the vast majority of clinical trials is confirmation of the clinical diagnosis by mutational analysis. CONCLUSION: The wide variety of therapies that are registered as clinical trials for Stargardt disease significantly raises the possibility that effective treatments will be available in the near future for this currently incurable condition and that molecular genetic testing should be increasingly considered. KEY WORDS: Stargardt disease, clinical trial, ABCA4, mutation.

[Preimplantation genetic diagnosis and monogenic inherited eye diseases]. / Preimplantacní genetická diagnostika a dedicná onemocnení oka.

OBJECTIVE: Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. METHODS: The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. RESULTS: PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). CONCLUSION: In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases.Key words: preimplantation genetic diagnosis; monogenic eye diseases; in vitro fertilization.

[Dynamic vitreomacular traction]. / Dynamická vitreomakulární trakce.

PURPOSE: To describe clinical findings in patient with dynamic changes of vitreomacular interface and retina. To provide summary of findings about mechanism of accommodation and its potential impact on vitreous and retina. METHODS: In 57 year old patient we performed comprehensive ophtalmological examination including spectral domain optical coherent tomography (SD-OCT). We observed the impact of accommodative effort, head-downward position, combination of accommodative effort and head-downward position and influence of light reflex on vitreomacular interface and retina and change of minimal foveal thickness. RESULTS: On SD-OCT we could observe vitreofoveal adhesion on both eyes. During accommodative effort in combination with head-downward position we could observe symptomatic dynamic vitreomacular traction with temporary elevation of minimal foveal thickness. We could not observe impact of only head-downward posture, reading with spectacle correction of presbyopia or light reflex on change of vitreomacular interface or retina. CONCLUSION: We should suspect dynamic changes of vitreomacular interface and retina when we see fluctuating impairment of central visual acuity particularly when it is in connection with accommodation and head-downward posture.Key words: accommodation, head-downward position, vitreomacular interface, SD-OCT.

[STORY of the Papilla - a Case Report]. / Príbeh jedné papily.

PURPOSE: To present a case report with "unclear" and sudden decrease of left eye visual acuity and bilateral visual fields defects. METHODS: A case report. CASE PRESENTATION: A 66-year-old woman was referred to our Center of Neuroophthalmology and Orbitology by a neurologist for a history of sudden decrease of visual acuity of her left eye 3 years ago. From September 2009, she was examined at various and not only ophthalmology departments. One by one the optic nerve neuritis, traumatic, compressive or toxic neuropathy and also nutritive neuropathy because of vitamin B(12) deficiency were excluded. The patient underwent also a genetic examination for Lebers hereditary optic nerve neuropathy, but this diagnosis was not confirmed. On magnetic resonance imaging, an atrophy of both optic nerves was described, with no further progression found during the follow-up examination after one year. In available patients medical records we found out that on optical coherence tomography scans optic disc drusen of the both eyes are visible, but this wasnt described in the records. Also, an examination of Visual Evoked Potential was performed - this confirmed the diagnosis of optic disc drusen. However, our patient was further examined for visual lost of the left eye. At the time of presentation (January, 2014), her best-corrected visual acuity of the right eye was 0.5, and counting fingers at 50 cm distance with correct light projection in the left eye. Static perimetric examination demonstrated bilateral and concentric narrowing of visual fields. The eyes were parallel, with no limitation of their movements in any direction. The patient was without diplopia, the direct pupil reactions to the light were sluggish bilaterally, and anterior segments of both eyes were with no pathologies. Examination of the fundus revealed bilateral findings of pale optic disc with absent optic cup and indistinct "lumpy" margins. Waxy pearl-like irregularities of the papila of both eyes were visible even without pupil dilatation. Bilateral optic disc drusen were confirmed by ultrasonography, fundus autofluorescence and spectral-domain optical coherence tomography. CONCLUSION: Optic disc drusen are often asymptomatic, frequently it is an accidental finding during the biomicroscopy of fundus due to ordinary eye examination. Rarely, optic disc drusen can cause blood circulation failure on the optic disc with typical defects of the visual field. Thats why we shouldnt forget the optic disc drusen in the differential diagnosis considerations.

[The molecular genetic and clinical findings in two probands with Stargardt disease]. / Molekulárne genetická prícina a klinický nález u dvou probandu se Stargardtovou chorobou.

PURPOSE: The aim of our study was to describe the phenotype and to perform molecular genetic investigation in two probands of Czech origin diagnosed with Stargardt disease (STGD). METHODS: Both males underwent ocular examination including assessment by high-resolution spectral domain optical coherence tomography (SD-OCT). DNA was isolated from venous blood. Mutation detection was performed using the ABCA4 genotyping microarray (Asper Ophthalmics, Estonia). RESULTS: The best corrected visual acuity in proband 1 (aged 39 years) was 0.1 bilaterally, and 0.05 in proband 2 (aged 26 years). Fundus examination showed typical multiple yellow-white lesions and macular atrophy. Alterations of retinal pigment epithelium, retinal thinning and disruption of the photoreceptor inner segment ellipsoid band were detected with an SD-OCT. Two known disease-causing mutations in ABCA4 were identified in proband 1; c.4234C>T, p.(Gln1412*) in exon 28; and c.5882G>A, p.(Gly1961Glu) in exon 42. Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified. CONCLUSION: The frequency and full spectrum of ABCA4 mutations in Czech patients with inherited retinal disorders is yet to be established. The inability to detect a second pathogenic change in ABCA4 coding sequences in proband 2 warrants further investigation.

[Clinical findings in members of a Czech family with retinitis pigmentosa caused by the c.2426_2427delAG mutation in RPGR]. / Klinické nálezy u clenu ceské rodiny s retinitis pigmentosa podmínenou mutací v ORF15 genu RPGR.

PURPOSE: To describe the phenotype of members of the first Czech retinitis pigmentosa family with an identified molecular genetic cause (c.2426_2427delAG in RPGR), followed for more than 13 years. METHODS: Medical records were reviewed and a detailed ophthalmic examination including spectral-domain optical coherence tomography and full-field and multifocal electroretinography (ERG) was performed in two affected males, three female carriers and one unaffected female. RESULTS: A 22-year-old male who denied suffering from nyctalopia had a best corrected visual acuity (BCVA) of 0.63 in both eyes. Moderate myopia and myopic astigmatism were present bilaterally. Color vision and contrast sensitivity were normal. There was an eccentric constriction of the visual fields that spared the central 20 degrees in both eyes. Fundus examination revealed bilateral pigmentary changes in the mid-periphery. Full-field ERG documented a 10% rod and 20% cone response. The phenotype of his cousin, also aged 22 years, was more severe. He complained of nyctalopia since 12 years of age. His BCVA was 0.3 in the right eye and 0.5 in the left eye. Myopia and astigmatism were present bilaterally. Contrast sensitivity and color vision were severely impaired. Full field ERG was extinct, but some activity on multifocal ERG was still detectable. The constriction of the visual fields reached 5 degrees in both eyes. Fundus examination showed the typical retinitis pigmentosa appearance. All carriers denied that they suffered from nyctalopia, but two of them had decreased BCVA in at least one eye. None exhibited typical bone spicules or a tapetal-like reflex. Significant refractive errors were present in all eyes of the carriers. CONCLUSION: The finding of moderate or high myopia and astigmatism in males with retinitis pigmentosa as well as refractive errors in female relatives indicates possible X-linked inheritance, which may be especially important in pedigrees where the transmission pattern can not be clearly established. Our study highlights the inter-individual variability in phenotype observed in similar aged patients with identical ORF15 RPGR mutations.

[Cytomegalovirus retinitis in HIV negative patients - retrospective study]. / Cytomegalovirová retinitida u HIV negativních pacientu - retrospektivní studie.

AIM: To evaluate own experience with the diagnosis and treatment of cytomegalovirus (CMV) retinitis in HIV negative patients with immunodeficiency. METHODS: Retrospective study and case reports. RESULTS: In the Centre for diagnosis and treatment of Uveitis 1869 patients with uveitis we have examined from June 2003 to June 2012. CMV retinitis was diagnosed in 7 patients (1 woman and 6 men) according to the typical clinical findings and history of immunodeficiency. In 2 atypical findings was the diagnosis confirmed by determination of DNA pathogen in vitreous sample (a patient with non-Hodgkin lymphoma) or by positive serology (CMV in leukocytes - indolent form of CMV retinitis in a patient with systemic lupus erythematosus). In 8 cases we found fulminant form, in 1 case indolent form of CMV retinitis. The average age of patients was 39,1 years (18-51 years old), ratio of men to women 6 : 3. In 6 of 9 cases we noticed bilateral retinitis. The average period of observation in our study was 15,8 months (1-48 months). Five of our patients underwent bone marrow transplantation, 2 patients were treated with systemic immunosuppressive drugs (colitis ulcerosa, systemic lupus erythematosus) and 2 patients had chemotherapy for lymphoma. The initiation or modification of treatment (gancyklovir p.o./i.v., foscarnet i.v.) was consulted and coordinated with others specialists. After initiation of treatment we followed-up 7 patients. In 4 eyes of 3 patients (31 %) the improvement of visual acuity was documented, in 5 eyes of 5 patients (38 %) the visual acuity was stabilized. The worsening of vision in 4 eyes of 3 patients (31 %) was caused by complications without any connection to virostatic therapy. All of our patients, who underwent bone marrow transplantation, died within 12 months since the diagnosis of CMV retinitis was determined. CONCLUSION: The diagnosis of CMV retinitis only in 9 cases (0,48% of all uveitic patients) confirms the rare occurrence of this retinitis. The important tool to the diagnosis of CMV retinitis is the history of immunodeficiency. In an atypical findings, the analysis of intraocular fluids or serological tests could help to the final diagnosis. The occurrence of CMV retinitis signify a very unfavourable prognosis for patients who underwent bone marrow transplantation and these patients died within 12 months since CMV retinitis has been diagnosed. The management of the therapy requires close interdisciplinary cooperation.

[Minimal ocular findings in a patient with Best disease caused by the c.653G>A mutation in BEST1]. / Minimální nález u pacienta s Bestovou chorobou podmínenou mutací c.653G>A v genu BEST1.

PURPOSE: To describe the phenotype in an asymptomatic 64-year-old patient with family history of Best disease and to identify the disease causing variant in the BEST1 gene. METHODS: Detailed ocular examination of the proband including spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography and electrooculography was performed. Direct sequencing approach was used to screen the whole coding sequence of 11 exons of BEST1. RESULTS: An early vitelliform stage of Best disease presenting as a small yellowish spot in the macula was observed in the right eye. The fundus appearance in the left eye was normal. SD-OCT of the right macula revealed hypodense space between the retinal pigment epithelium and the neuroretinal layer. Arden ratio was bilaterally mildly reduced; 1.36 in the right and 1.3 in the left eye. Molecular genetic analysis identified a heterozygous change c.653G>A (p.Arg218His) as the disease-causing variant. CONCLUSION: Here we report for the first time a phenotype-genotype correlation in a Czech patient with Best disease. SD-OCT is a fast method that may show the presence of small pathological changes. The screening of BEST1 gene enables identification of disease-causing variants in asymptomatic individuals with normal fundus appearance and thus improves counseling to the affected families.