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Purpose To describe the size and appearance of the foveal avascular zone (FAZ) in the superficial and deep plexus in young children with treated or spontaneously regressed retinopathy of prematurity (ROP), in comparison with age-matched controls and young adults, as seen with OCT angiography (OCTA), and to compare these parameters with foveal classic OCT images and visual function. Design Prospective, cross-sectional study. Participants Twenty-five children with treated or spontaneously regressed ROP (mean 5.0±0.8 years) compared with 15 healthy term-born age-matched children and 20 healthy adults. Methods OCTA was performed using a DRI OCT Triton (Swept Source OCT, Topcon, Oakland, NJ). The best-quality images of 1 eye per patient were analyzed. Superficial FAZ and deep FAZ were analyzed separately. Single-scan OCTs were performed using a Spectralis SD-OCT (HRA+OCT, Heidelberg Engineering, Heidelberg, Germany). The foveal pit characteristics and the degree of macular developmental arrest (MDA), defined as the ratio of the outer nuclear layer + external limiting membrane (ONL+) and the inner retinal layers in the fovea (ONL+/IRL-ratio), were analyzed with a custom-made automated layer segmentation tool (DiOCTA, copyright by Justus-Liebig-University, Giessen, Germany). Visual acuity (VA) was tested with Early Treatment of Diabetic Retinopathy Study letter charts. Main Outcome Measures The ONL+/IRL-ratio, superficial FAZ area, deep FAZ area, foveal parameters, and VA. Results Foveal pit depth and area were significantly reduced in both treated and spontaneously regressed ROP, whereas the foveal diameter was comparable in all groups. OCTA showed a significantly narrowed superficial FAZ in eyes with treated and spontaneously regressed ROP. In contrast, the deep FAZ was of comparable size in all groups. A reduced superficial FAZ significantly correlated with reduced ONL+/IRL-ratio, and thus the degree of MDA. In treated and spontaneously regressed ROP, reduced superficial FAZ and MDA correlated significantly with diminished VA. Conclusions OCTA is feasible in young children with a history of ROP and without neurodevelopmental delay. It allows detecting a decreased superficial FAZ size noninvasively. A small superficial FAZ, reduced ONL+/IRL-ratio as a measure of MDA, and reduced VA are concurrent factors in preterm children who are otherwise neurologically normal.

Disorders of visual perception often lead to impairments relevant to daily living within the framework of conspicuous ophthalmological symptoms and of central lesions or developmental problems. The aim of the presented Sk2 guidelines according to the regulations of the Association of the Scientific Medical Societies in Germany is to discuss the terminology, including the associated concepts, to name etiologies of the disorder and the resulting risk groups for which a systematic investigation should be included. Finally, to give an orientation on the necessary ophthalmological, pediatric neurological and neurophysiological diagnostics and to present the therapeutic and special pedagogic options and requirements.

Zusammenfassung Hintergrund Die Neurofibromatose Typ 2 (NF2) ist eine autosomal-dominant vererbliche Erkrankung mit unvollständiger Penetranz, die durch das Vorkommen von gutartigen Tumoren des zentralen und peripheren Nervensystems charakterisiert ist. Zu diesen zählen Astrozytome, Ependymome, Meningeome und Schwannome, bei denen beidseitige Vestibularisschwannome typisch sind. Okulär manifestiert sich die NF2 durch juvenile subkapsuläre Katarakte, epiretinale Membranen sowie kombinierte Hamartome der Retina und des retinalen Pigmentepithels. Material und Methoden Bei einer Patientin mit retinalem Hamartom bei NF2 wurde eine multimodale Bilddokumentation durchgeführt und mit einer Metaanalyse publizierter Fälle retinaler Hamartome bei NF2 verglichen. Ergebnisse Berichtet wird über den Fall eines 14-jährigen Mädchens mit molekulargenetisch gesicherter Neurofibromatose Typ 2. In der Spectral-Domain-optischen Kohärenztomografie (SD-OCT) fielen beidseitige, asymptomatische, retinale astrozytäre Hamartome im Bereich der retinalen Ganglienzell- und Nervenfaserschicht auf. Eine Metaanalyse der 25 publizierten Fälle ergab, dass die häufigste Form von Tumoren der Retina das kombinierte Hamartom der Retina und des retinalen Pigmentepithels (CHRRPE, 16 Fälle) war, gefolgt von den retinalen astrozytären Hamartomen (RAH, 7 Fälle). Dabei wurden die retinalen Hamartome meistens beidseitig beschrieben. Es wurden 11 Fälle beschrieben, bei denen retinale Hamartome vor der klinischen Diagnose der NF2 festgestellt wurden. Es konnte keine Geschlechtsprävalenz festgestellt werden. Die 3 häufigsten okulären Befunde bei NF2 waren Sehminderung, Katarakt und epiretinale Membranen. Schlussfolgerung Das Spektrum der spezifisch okulären Befunde bei NF2 ist sehr groß. Deren Feststellung kann gerade im jungen Alter diagnoseweisend für die Erstdiagnose der NF2 sein und somit eine frühzeitige Erkennung und gegebenenfalls eine rechtzeitige und erfolgreichere Therapie weiterer Tumormanifestationen ermöglichen. Retinale astrozytäre Hamartome können sehr dezent ausgeprägt sein und bei einer Routineuntersuchung nicht auffallen. Eine Fundusinfrarotaufnahme ist bei der ophthalmologischen Untersuchung insbesondere von kleinen Kindern ein nützliches Werkzeug und kann in manchen Fällen funduskopisch kaum erkennbare Befunde aufdecken, die dann gezielt mit SD-OCT untersucht werden können.

International audience; Kongenitale stationäre Nachtblindheit (Englisch: congenital stationary night blindness, CSNB) bezeichnet eine klinisch und genetisch unterscheidbare Gruppe von nicht progressiven Netzhauterkrankungen, die kaum Fundusauffälligkeiten zeigt. Die Vererbung kann autosomal-dominant (adCSNB), autosomal-rezessiv (arCSNB) oder X-chromosomal (XLCSNB) sein. Weitere klinische Merkmale können Myopie, Hyperopie, Strabismus, Nystagmus und reduzierter Visus sein. Mittels Elektroretinografie kann eine Riggs- und eine Schubert-Bornschein-Form unterschieden werden. Während die Riggs-Form eine Fehlfunktion der Stäbchen selbst aufweist, zeigen Patienten mit der weitaus häufigeren Schubert-Bornschein-Form eine Signalübertragungsstörung zwischen den Photorezeptoren und nachgeschalteten Bipolarzellen. Die Schubert-Bornschein-Form der CSNB lässt sich anhand des Elektroretinogramms (ERG) noch weiter in eine inkomplette (Englisch: incomplete, icCSNB) und komplette Form (Englisch: complete, cCSNB) einteilen. Während es sich bei der cCSNB um eine Fehlfunktion des ON-Signalwegs handelt, sind bei der icCSNB sowohl der ON- als auch der OFF-Signalweg und damit meist auch die Sehschärfe betroffen. Mittels klassischer Kopplungsanalyse, Kandidatengenanalyse und seit Neuerem Hochdurchsatzsequenzierung konnten bisher Mutationen in 13 verschiedenen Genen mit dieser Erkrankung assoziiert werden. Durch Studien an Zelllinien oder Tiermodellen konnte gezeigt werden, dass der Phänotyp der Patienten mit der Expression, Proteinlokalisation und Funktion der entsprechenden Moleküle korreliert: Gene, die bei Patienten mit der Riggs-Form der CSNB mutiert sind, haben eine bedeutende Rolle in der Phototransduktionskaskade der Stäbchen. Gene, die bei Patienten mit der icCSNB mutiert sind, kodieren für Proteine, die für die Freisetzung des Neurotransmitters Glutamat am synaptischen Spalt der Photorezeptoren verantwortlich sind. Gene, die bei Patienten mit der cCSNB mutiert sind, kodieren für Proteine, die für die Aufnahme des Glutamats und Weiterleitung des Signals an den ON-Bipolarzellen verantwortlich sind. Erste Therapieversuche im Tiermodell zeigen, dass die CSNB mittels eines gentherapeutischen Ansatzes geheilt werden könnte. Die CSNB betreffende Studien sind einerseits wichtig für eine genaue Diagnose für den Patienten, andererseits helfen sie bei der Entschlüsselung der Moleküle, die für die Signalübertragung zwischen Photorezeptoren und Bipolarzellen eine Rolle spielen, ein bislang wenig erforschtes Gebiet.; Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next-generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field.

Purpose: To correlate visual field assessment with saccadic vector optokinetic perimetry (SVOP) in children with ganglion cell loss due to anterior pathway pathologies resulting in hemianopic visual field defects measured with optical coherence tomography (OCT). Methods: 5 young (aged 3-6 years) and 5 adult patients with hemianopia, 10 healthy preschoolers (mean age 4.4 years), and 10 healthy adults (mean age 25.3 years) were tested with SVOP and OCT (focusing on the ganglion cell layer, GCL+). In adults, visual field testing was also performed with static and fundus-controlled perimetry. Results: OCT allowed precise structure analysis and showed a vertical border with GCL+ loss on the hemianopic side in children and adults compared to controls. SVOP showed visual field defects on the hemianopic side in peripheral regions and inadequate results at the parafoveal positions in both groups. In contrast, static and fundus-controlled perimetry showed a clear border in foveal and parafoveal regions. Conclusions: All children underwent SVOP with minimal restrictions, allowing functional evaluation of peripheral visual field positions. Parafoveal positions showed multiple false-positive results. The function-structure relationship is measurable even in young children by using the GCL+ analysis. This combination of novel child-friendly techniques allows collecting objectively measured values and simplifies diagnosis and follow-up in treatment.

Purpose: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle–dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. Methods: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. Results: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. Conclusion: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

Zusammenfassung Einleitung Die Entwicklung und Reifung der Netzhaut ist ein komplexer Prozess, der sich bis in das Kleinkindesalter und darüber hinaus erstrecken kann. Die zentrale Netzhaut frühgeborener Kinder kann durch eine Reifungsstörung betroffen sein, die durch eine abgeflachte, dickere Fovea mit überlagernden Schichten innerer Netzhaut und einem gestörten Verhältnis der äußeren Photorezeptorschicht zu den inneren Netzhautschichten („macular developmental arrest“: MDA) gekennzeichnet ist und zu funktionellen Nachteilen führen kann (Bowl et al. 2016 18). In dieser Studie untersuchten wir ehemalige Extremfrühgeborene mit spontan zurückgebildeter Frühgeborenenretinopathie (ROP) und ohne ROP sowie gleichaltrige Termingeborene elektrophysiologisch und betrachteten die Ergebnisse in Bezug zur Makulareifung. Methoden Im Rahmen einer umfangreichen prospektiven Kohortenstudie untersuchten wir n = 60 frühgeborene Kinder mit spontan rückgebildeter ROP (srROP, n = 15), ohne ROP (noROP, n = 45) in der Anamnese sowie n = 10 termingeborene altersentsprechende Kinder (Term). Bei jedem Kind wurden zur funktionellen Analyse jeweils ein Ganzfeldelektroretinogramm (ffERG: a- und b-Welle), multifokales ERG (mfERG: P1) nach ISCEV-Standard sowie eine optische Kohärenztomografie (SD-OCT, Spectralis, Heidelberg Engineering, Deutschland) der Fovea zur morphologischen Einordnung durchgeführt. Ergebnisse Im skotopischen ffERG zeigten Kinder mit srROP und noROP vor allem dann signifikant reduzierte b-Wellen-Antworten, wenn ein MDA im OCT nachweisbar war. Im mfERG war die P1-Komponente des zentralen Hexagons und des 2. konzentrischen Ringes bei Kindern mit MDA signifikant reduziert. Alle anderen Parameter zeigten keinen signifikanten Unterschied zwischen den Gruppen. Schlussfolgerung Elektrophysiologische Veränderungen finden sich bei ehemaligen extrem frühgeborenen Kindern vor allem bei im SD-OCT nachweisbarer Makulareifungsstörung (MDA), und zwar sowohl bei Kindern ohne akute ROP als auch bei Kindern mit spontan zurückgebildeter ROP: Die reduzierte b-Welle im skotopischen ffERG und die reduzierte P1-Komponente im mfERG deuten auf eine Beteiligung der Bipolarzellen bei MDA hin. Insbesondere die Korrelation von MDA mit Auffälligkeiten im ffERG könnte ein Zeichen dafür sein, dass MDA mit einer globaleren Reifungsstörung der Netzhaut einhergeht und diese bei Extremfrühgeborenen mit und ohne ROP auftreten kann.

Aufgrund der demografischen und gesellschaftlichen Entwicklung ist die Anzahl der Menschen hoheren Lebensalters gestiegen, die in Seniorenheimen vollstationar gepflegt werden. Mit dem Wechsel in ein Heim wird die arztliche Versorgung komplizierter; verschiedene regionale Studien weisen insbesondere auf eine ambulante facharztliche Unterversorgung hin. Vor diesem Hintergrund wurde in dieser Studie die aktuelle ophthalmologische Versorgung in Seniorenheimen in Deutschland untersucht. Diese prospektive, multizentrische Querschnittstudie wurde durch 14 Studienzentren in Deutschland im Zeitraum von 2014 bis 2016 durchgefuhrt. Insgesamt wurden Bewohner von 32 Einrichtungen nach Genehmigungen durch die zustandigen Ethikkommissionen untersucht. Die standardisierte augenarztliche Untersuchung beinhaltete Anamnese, Refraktion, Visusbestimmung, Tonometrie, Spaltlampenuntersuchung und Funduskopie in Mydriasis. Alle Untersuchungen fanden jeweils vor Ort in den Heimen statt. Der augenarztliche Behandlungsbedarf wurde charakterisiert, und die Daten wurden deskriptiv und mittels logistischer Regression ausgewertet. Insgesamt wurden 600 Bewohner (434 Frauen und 166 Manner) zwischen 50 und 104 Jahren untersucht. Fur 368 Personen (61%) ergab sich ein ophthalmologischer Befund, der eine weitere Behandlung erforderte. Zu den haufigsten Diagnosen des Vorderabschnitts zahlten eine visusrelevante Katarakt (315; 53%), Veranderungen der Augenlider (127; 21%), Benetzungsstorungen (57; 10%) und Nachstar (43; 7%). Bei 63 (11%) Bewohnern zeigte sich ein Glaukomverdacht, und bei 55 (9%) bestatigte sich die Diagnose eines vorbekannten Glaukoms, welches jedoch bei einem Drittel unzureichend oder gar nicht therapiert wurde. Funduskopisch zeigten sich bei 236 Bewohnern (39%) Zeichen einer altersabhangigen Makuladegeneration (AMD). Lediglich 52% der Senioren waren innerhalb der letzten 5 Jahre augenarztlich untersucht worden. 39% der Bewohner gaben an, dass sie sich aktuell nicht in der Lage sehen wurden, einen Augenarzt zu konsultieren. Insgesamt wurden 3,7% der untersuchten Bewohner von den Studienarzten als bettlagerig eingestuft. Berichtete Hurden waren vorwiegend Transport und fehlende Unterstutzung/Begleitung. Die vorliegende Erhebung zeigt ein erhebliches ophthalmologisches Versorgungsdefizit in deutschen Seniorenheimen. Neue bzw. eine Erweiterung derzeitiger Versorgungsmodelle sind dringend notwendig.

Background Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). Methods Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. Results A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. Conclusion Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

Zusammenfassung Hintergrund Mutationen im CRB1-Gen wurden bei frühkindlicher schwerer Netzhautdegeneration (EOSRD, early-onset severe retinal dystrophy) und Stäbchen-Zapfen-Degeneration des Kindesalters identifiziert. Diese Studie beschreibt das phänotypische Spektrum bei krankheitsverursachenden CRB1-Mutationen in den ersten beiden Lebensdekaden. Material und Methoden Acht Patienten im Alter von 3 Monaten bis 20 Jahren wurden einer ophthalmologischen Untersuchung mit Prüfung des bestkorrigierten Visus (BCVA), Farbsehprüfung, Funduskopie, optischer Kohärenztomografie (SD-OCT) und Fundusautofluoreszenz (FAF) unterzogen. Die SD-OCTs wurden mit der DIOCTA-Auswertesoftware sowie manuell einer Schichtanalyse unterzogen. In Abhängigkeit von der Kooperationsfähigkeit der Patienten wurden eine Ganzfeldelektroretinografie (ffERG, ISCEV-Standard) sowie eine Goldmann-Perimetrie durchgeführt. Ergebnisse Fünf der Patienten trugen Mutationen, die zu einem Verlust des Genproduktes führten (Spleißmutationen, Nonsense-Mutationen, Leserasterverschiebungen) und zeigten bereits in den ersten Lebensmonaten ein massiv reduziertes Sehvermögen (BCVAmax: 0,04). Der 6. Patient trug eine homozygote Missense-Mutation und zeigte im Alter von 6 Jahren einen BCVAmax von 0,05. Zwei weitere Patienten mit einer hypomorphen Missense-Mutation auf mindestens einem Allel zeigten einen besseren Visuserhalt mit BCVA bis zu 0,5 im Alter von 20 Jahren. Das ffERG lag bei allen Patienten unter der Norm und war bei der Mehrheit nicht mehr ableitbar. Das Gesichtsfeld war stark eingeschränkt. Die Photorezeptorschichten waren im SD-OCT, soweit überhaupt abgrenzbar, deutlich reduziert. Die Schichtdicke der inneren Körnerschicht nahm mit zunehmender Degeneration zu. Die Analyse der A-Scans zwischen Nervenfaserschicht (RNFL) und Bruch-Membran zeigte eine besser erhaltene Netzhautschichtung bei den Patienten mit Missense-Mutationen. Schlussfolgerung Patienten mit CRB1-Mutationen zeigen in erster Linie einen schweren Phänotyp mit stark reduziertem Sehvermögen von Geburt an. Missense-Mutationen mit einer möglichen Restfunktion des Genprodukts sind mit leichteren Phänotypen assoziiert. Eine schwere und progrediente Gesichtsfeldeinschränkung war allgemein in der 1. Lebensdekade vorhanden. Die reduzierte Abgrenzbarkeit der retinalen Schichtung im SD-OCT deutet auf einen Verlust der strukturellen Integrität aller Netzhautschichten hin.

The RPE represents one of the two major cell types in the retina that have been targeted by gene therapy, next to the photoreceptors. Following subretinal delivery, viral vectors, such as adeno-associated virus (AAV), lentivirus or adenovirus based vectors, or nanoparticles deliver genetic material into this cell type, allowing robust and long term transgene expression as the basis for the gene addition therapy approach. Due to this characteristic of the RPE cell layer, several RPE based inherited retinal dystrophies, such as RPE65 or MERTK deficiency and choroideremia, have been addressed by gene therapeutic approaches that have reached clinical stage with more than 100 patients treated cumulatively around the world. Usually, RPE defects result in loss of photoreceptor function, and the clinical benefit is mainly measured at the photoreceptor level, with varying degree of improvement. Treatment approaches for other disorders are at the preclinical level, including gene addition as well as the newly developed genome editing approach, which relies on the cell’s own capacity to repair an artificially induced DNA double strand break near the target site. Gene therapeutic approaches have also been developed for age-related acquired retinal disorders, in which the disease-causing factors that are often associated with neovascular changes to the retina or chronic stimulation of the immune system, are targeted either by gene addition or genome editing.

Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a new retinal optical coherence tomography (OCT) finding. The Optic Disc Drusen Studies Consortium had made recommendations to distinguish PHOMS from true optic disc drusen (ODD) in 2018. While publications on PHOMS have increased since then, the accuracy of the definition of PHOMS and reliability of detection is unknown. In this multi-rater study, we demonstrate that the 2018 definition of PHOMS resulted in a poor multi-rater kappa of 0.356. We performed a Delphi consensus process to develop a consistent and refined definition of PHOMS with clear principles around the nature of PHOMS and how they differ from normal anatomy. Fifty explanatory teaching slides, provided as supplementary material, allowed our expert group of raters to achieve a good level of agreement (kappa 0.701, 50 OCT scans, 21 raters). We recommend adopting the refined definition for PHOMS.

In cases of aggressive posterior retinopathy of prematurity (APROP), recurrences can occur after intravitreal injection of bevacizumab (IVB), in spite of successful treatment of the acute stage. Therefore, long-term examinations in extremely premature patients are needed. We defined recurrences as a relapse of plus disease and leakage (with or without proliferation) at the vascularisation border, but also anterior and posterior to it.RetCam wide-field colour images and fluorescein angiography were performed before the first IVB (0.312 mg bevacizumab in 0.025 ml per eye), before each further therapy, i.e. additional intravitreal injection, laser- or cryocoagulation or pars-plana vitrectomy, and at the end of the therapy. We analysed the images of 18 eyes with APROP of 9 extreme premature patients treated between 08/2007 and 12/2017 (GA 21 - 27 weeks, BW 430 - 890 g).Long-term therapeutic success was achieved in only 4 eyes/2 children (22%) with one single injection. In 2 eyes/2 children (11%), a second and third injection was given within 2 weeks because of an insufficient therapeutic effect. Up to 3 injections together with laser coagulation were needed in 12 eyes/6 children (67%), in order to achieve complete resolution of ROP activity. In 6 eyes/2 children (33%), resolution of leakage at the original vascularisation border was achieved only with further laser coagulation. In one single eye, retinal detachment occurred after unsuccessful retinal surgery. Before IVB, fluorescein angiography disclosed leakage due to proliferation in most of the patients (12 eyes/6 children). In recurrences after IVB, a posterior shift of the leakage site was found (14 eyes/4 children), whereas after laser photocoagulation proliferative changes were also detected anterior to the vascularisation border (5 eyes/3 children). Treatment was indicated based on angiographic findings in 14 eyes/4 children where wide-field colour images did not show plus disease or proliferation.Intravitreal injection of 0.312 mg bevacizumab has been shown to be an effective therapy for the acute stage of APROP. Long-term success required consequent monitoring and treatment of APROP recurrences. Fluorescein angiography was particularly useful to detect recurrences that were not evident in wide-field colour images.Bei aggressiver posteriorer Frühgeborenenretinopathie (APROP) können Rezidive nach intravitrealer Injektion von Bevacizumab (IVB) trotz erfolgreicher Aktivitätskontrolle des Akutstadiums auftreten und erfordern daher langfristige Kontrolluntersuchungen bei Extremfrühgeborenen. Als Rezidiv wird das Wiederauftreten von Pluszeichen und Leckage (mit oder ohne Proliferation) posterior, an und anterior der Vaskularisationsgrenze definiert.RetCam-Weitwinkelfotografien und Fluoreszenzangiografien erfolgten bei Therapiebeginn mit IVB (Bevacizumab 0,312 mg in 0,025 ml pro Auge), vor jeder weiteren Therapie (IVB, Laser- oder Kryokoagulation, Pars-plana-Vitrektomie) sowie am Therapieende. Es wurde das Bildmaterial von 18 Augen/9 Extremfrühgeborenen mit APROP die zwischen 08/2008 und 12/2017 behandelt wurden (GA 21 – 27 Wochen, GG 430 – 890 g) ausgewertet.Mit einer einmaligen Injektion konnte nur bei 4 Augen/2 Kindern (22%) ein langfristiger Therapieerfolg erreicht werden. In 2 Augen/2 Kindern (11%) wurde bei nicht ausreichendem Therapieeffekt eine 2. und 3. Injektion innerhalb von 2 Wochen durchgeführt. Bis zu 3 Injektionen zusammen mit einer Laserkoagulation waren in 12 Augen/6 Kindern (67%) erforderlich, um eine vollständige Rückbildung der ROP-Aktivität zu erreichen. In 6 Augen/3 Kindern (33%) konnte erst mit der Laserkoagulation eine Rückbildung der Leckage an der ursprünglichen Vaskularisationsgrenze erreicht werden. In einem einzigen Auge kam es trotz allem zu einer Netzhautverziehung mit konsekutiver frustraner Netzhautchirurgie. Vor IVB war die Leckage in ⅔ auf Proliferationen zurückzuführen (12 Augen/6 Kinder). Bei Rezidiven nach IVB zeigte sich eine Verschiebung des Leckageortes nach posterior (14 Augen/4 Kinder), während nach Laserkoagulation Leckagen durch Proliferationen auch anterior der Vaskularisationsgrenze beobachtet wurden (5 Augen/3 Kinder). Eine Therapieindikation bei fehlenden Pluszeichen und nicht erkennbaren Proliferationen in der Weitwinkelfotografie ergab sich bei 14 Augen/4 Kindern aufgrund von angiografischen Aktivitätszeichen.Die intravitreale Injektion von 0,312 mg Bevacizumab zeigte sich als effektive Behandlungsmethode des APROP-Akutstadiums. Der langfristige Therapieerfolg erforderte die konsequente Erfassung und Behandlung von APROP-Rezidiven. Besonders hilfreich war dabei die Fluoreszenzangiografie in der Diagnostik von nicht erkennbaren Rezidiven in der Weitwinkelfotografie.

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants., SCOPUS: ar.j, info:eu-repo/semantics/published

Achromatopsia (ACHM) is a hereditary cone photoreceptor disorder characterized by the inability to discriminate colors, nystagmus, photophobia, and low-visual acuity. Six genes have been associated with this rare autosomal recessively inherited disease, including the GNAT2 gene encoding the catalytic α-subunit of the G-protein transducin which is expressed in the cone photoreceptor outer segment. Out of a cohort of 1,116 independent families diagnosed with a primary clinical diagnosis of ACHM, we identified 23 patients with ACHM from 19 independent families with likely causative mutations in GNAT2, representing 1.7% of our large ACHM cohort. In total 22 different potentially disease-causing variants, of which 12 are novel, were identified. The mutation spectrum also includes a novel copy number variation, a heterozygous duplication of exon 4, of which the breakpoint matches exactly that of the previously reported exon 4 deletion. Two patients carry just a single heterozygous variant. In addition to our previous study on GNAT2-ACHM, we also present detailed clinical data of these patients.

To correlate cone- and rod-mediated function with morphology of the macula in preterm-born children without and with spontaneously regressed retinopathy of prematurity (ROP).We performed spectral-domain optical coherence tomography (SD-OCT) single scans in the macular center of preterm-born children aged 6 to 12 years (mean ± SD, 7.4 ± 1.8) without ROP (noROP; n = 59) and with spontaneously regressed ROP (srROP; n = 34), documented with wide-angle digital imaging during routine screening for acute ROP, and compared the data from 14 age-matched term-born children. SD-OCT data were compared to functional cone- and rod-mediated results of scotopic and photopic chromatic pupillometry (cP) and two-color fundus-controlled perimetry (2C-FCP).SD-OCT showed a shallowed foveal pit with significantly reduced outer nuclear layer to inner retinal layer ratio, indicating macular developmental arrest (MDA). MDA was present in 44% of the srROP and 27% of the noROP children. Pupil reaction to photopic red stimuli on blue background showed significantly lower values in all preterm-born children with MDA. In accordance, photopic light increment sensitivity (LIS) to red stimuli in the foveal center on the 2C-FCP was also significantly reduced in children with MDA. Under scotopic conditions, no significant differences were apparent in both pupil reaction with cP and LIS with 2C-FCP.Both objective pupillary response to cone-mediated photopic red stimuli and subjective central cone-mediated results in fundus-controlled perimetry were reduced in preterm-born children with MDA. MDA was present in a significant number of patients with srROP, but also without ROP.

A 4-year-old girl was referred as an emergency case because of diplopia and intermittent exophthalmos of the left eye. Symptoms had occurred together with recurrent episodes of a common cold. The examinations revealed no conspicuous findings. Photographic and video analysis revealed hypotropia of approximately 25 ° together with protrusion of the left eye. The patient history and findings were compatible with a superior oblique click syndrome with an atypical distal distinct thickening of the superior oblique tendon. Rheumatological and otorhinolaryngological findings were inconspicuous.

PURPOSE To report the rate and management of intra- and early postoperative complications of bag-in-the-lens intraocular lens (IOL) implantation technique for cataract treatment in paediatric patients of different age groups. SETTINGS Department of Ophthalmology, Justus-Liebig-University Giessen, University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany. DESIGN Retrospective non-randomized consecutive case series. METHODS Ninety eyes of 60 paediatric cataract patients were enrolled to this retrospective non-randomized observational consecutive case series single-centre study. All patients underwent cataract surgery with bag-in-the-lens IOL implantation between January 2008 and December 2018, performed by two experienced surgeons. The entire cohort was divided into four age groups: first - 0- 36 months-17 years of age. The intra- and postoperative complications were based on the clinical records. The description of management of complications related specifically to bag-in-the-lens IOL technique was based on the 39 consecutive cases operated since 1 Jan 2016 by one single surgeon that were all video documented. The early postoperative period was defined as 12 months after surgery. RESULTS Overall, there were 27 unilateral and 33 bilateral surgical cases of 24 female and 36 male children. The mean age at surgery was 45.25 months (range 1-200 months). The most common intraoperative events were vitreous prolapse and anterior capsule rupture with 28.9% and 13.3%, respectively. Within 12 months of follow-up, five eyes (5.6%) were re-operated because of visual axis reo-pacification (VAR). Intraocular hypertension was diagnosed in seven eyes (7.8%), including two cases that required surgical treatment. In all cases with intra- and early postoperative complications related specifically to bag-in-the-lens technique, it was possible to manage them and successfully implant bag-in-the-lens IOL. CONCLUSIONS Implementation of bag-in-the-lens technique in the treatment of paediatric cataract was associated with a relatively low rate of intra- and postoperative complications, including rare cases of VAR. The correct management of complications related specifically to bag-in-the-lens IOL implantation technique shall to be considered during the learning curve.

Inherited retinal diseases (IRDs) may be caused by variations in genes affecting the connecting cilium of photoreceptor cells and intraflagellar transport, manifested as ciliopathies.We performed genotype-phenotype correlations in 30 patients with biallelic mutations inThirty patients aged 1 month to 84 years (median at first visit 0.6 y) were followed between 5 months and 25.7 years (median 4.8 y). Twenty-three of these patients carried the c.2991+1655AG mutation (30/60 allele 2, 7 homozygous). The second most frequent mutation was p.K1575* (9/60 alleles). The full-field electroretinogram showed residual response in a few patients only. After progression, electrophysiological responses were below threshold in all patients. Severely reduced visual acuity persisted from birth. Eight patients had quantifiable best corrected visual acuity (BCVA, logMAR 2 - 0.3), in one case up to the age of 84 y. Absent fixation of targets was noted in 15 patients during the first months of life. Ten of these patients did not improve during follow-up past the second year of life. The other patients developed at least light perception (LP, n = 7) or hand movement (HM, n = 3). Better BCVA was not restricted to the c.2991+1655AG mutation. Fundus photography documented degenerative changes throughout the retina with macular degeneration and circular increased fundus autofluorescence signals (9/30 patients) in the perimacular ring and in the rod ring, and spotty changes in the periphery. SD-OCT (6/30 patients) disclosed reduced photoreceptor layer (OPL to OS) thickness and preserved inner retinal thickness (RNFL to INL). Better BCVA did not correlate to genotype or central photoreceptor layer thickness.As reported earlier,Eine häufige Ursache erblicher Netzhautdegenerationen sind Mutationen in Genen, die für den Aufbau des verbindenden Ziliums der Photorezeptoren und den interflagellaren Transport codieren. Diese Erkrankungen werden als Ziliopathien zusammengefasst. Eines der häufigsten Ziliopathiegene ist dasPatienten mit ursächlichen Mutationen im30 Patienten im Alter zwischen 1 Monat und 84 Jahren (Median der ersten Vorstellung 0,6 Jahre) wurden in einem Zeitraum zwischen 5 Monaten und 25,7 Jahren (Median 4,8 Jahre) erfasst. Bei 23 Patienten lag c.2991+1655AG vor (30/60 Allele, 7 homozygot). Die zweithäufigste Mutation war p.K1575* (9/60 Allele). Im Ganzfeld-Elektroretinogramm fanden sich bei wenigen Patienten initial noch Restpotenziale. Im weiteren Verlauf waren bei allen Patienten keine Potenziale mehr nachweisbar. Die Sehschärfe war seit Geburt stark reduziert. Bei 8 Patienten lag ein quantifizierbarer Visus (logMAR 2 – 0,3) vor. Eine fehlende Fixation wurde bei 15 Patienten während der ersten Lebensmonate berichtet. Für 10 dieser Patienten fand keine Verbesserung statt. Die übrigen Patienten entwickelten Lichtscheinwahrnehmung (LSP) oder Erkennen von Handbewegungen. Eine bessere Sehschärfe war nicht auf Patienten mit c.2991+1655AG-Mutation beschränkt. Der Augenhintergrund zeigte degenerative Veränderungen in der gesamten Fläche mit paramakulär ringförmig erhöhter Fundusautofluoreszenz (FAF) und punktförmig erhöhter FAF in der Peripherie (9/30 Patienten). Die Netzhautschichtung (6/30 Patienten) war im Bereich der Photorezeptoren (OPL bis OS) stark verdünnt bei erhaltener Dicke der inneren retinalen Schichten (RNFL bis INL). Die Schichtung der zentralen Netzhaut oder der Genotyp ließen keine Rückschlüsse auf die Sehschärfe zu. SCHLUSSFOLGERUNGEN

International audience; PURPOSE:To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses.DESIGN:Global, multicenter, retrospective chart review.METHODS:Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD.PROCEDURES:Data were extracted from patient charts.MEASUREMENTS:Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available).RESULTS:VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships.CONCLUSIONS:The number of clinical diagnoses and lack of a consistent RPE65 mutation-to-phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a rare condition that affects smooth muscle cells, is caused by biallelic null alleles in MYH11. We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit. Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively. Her mother carries the deletion, whereas her father is heterozygous for the c.379C>T p.(Pro127Ser) change. Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties. Thus, the unusual and complex clinical presentation of the patient results from compound heterozygosity for a 16p13.11 microdeletion including the entire MYH11 gene and a loss-of-function missense variant on the remaining MYH11 allele. In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell-associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction.

Purpose: Spatially resolved functional assessment of rods and cones under photopic and scotopic conditions is desirable to evaluate the treatment outcome of gene therapeutic applications in inherited retinal disorders, such as early- onset severe retinal dystrophy (EOSRD) or achromatopsia. Methods: A sample of 3 healthy subjects, 6 patients with RPE65 deficiency (aged 11-45 years), and 3 patients with cone dysfunction disorders underwent spectral sensitivity testing (SST) under conditions of dark and light adaptation using a Humphrey Field Analyzer modified perimeter. Results: SST in healthy subjects revealed sensitivity curves corresponding well with the CIE (International Commission on Illumination) standard fundamentals. Absence of cone function was observed in patients with cone dysfunction disorders. In patients with RPE65 mutations, SST under conditions of both dark and light adaptation revealed similar curves at typical cone sensitivities. S cone-related thresholds were diminished in young patients (11-14 years) and absent in adults (19 years and over). Conclusion: In the present study, residual vision was cone mediated both under photopic and scotopic conditions in young patients with EOSRD associated with RPE65 mutations, but S cone function was severely reduced early on. In rod monochromats, vision was rod mediated both under conditions of dark and light adaptation. These observations are important for ongoing and future clinical trials employing gene therapeutic strategies in both rod-cone dystrophies and achromatopsia.

Maria Silvana Galantuomo,1,* Maurizio Fossarello,1 Alberto Cuccu,1 Roberta Farci,1 Markus N Preising,2 Birgit Lorenz,2 Pietro Emanuele Napoli1,* 1Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy; 2Department of Ophthalmology, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany *These authors contributed equally to this work Background: Juvenile X-linked retinoschisis (RS1, OMIM: 312700) is a hereditary vitreoretinal dystrophy characterized by bilateral foveal schisis and, in half of the patients, splitting through the nerve fiber layer in the peripheral retina. In the first decade of life, patients usually develop a decrease in visual acuity. Long-term visual outcomes can be poor due to the limited number of known successful treatments. Purpose: The purposes of this study were to present, for the first time, a p.Arg197Cys missense mutation in the RS1 gene (OMIM: 300839) in a four-generation Italian family with RS1 and to examine the clinical response to the treatment with acetazolamide tablets alone or in combination with dorzolamide eye drops as assessed by spectral-domain optical coherence tomography (SD-OCT). Methods: Eleven individuals, including two brothers with RS1 (patients 1 and 2), underwent a full medical history examination and a comprehensive ocular assessment that involved SD-OCT, fluorescein angiography, electroretinography and DNA analysis. Each RS1 patient received oral acetazolamide (375 mg daily) during the first three months. Thereafter, patient 1 continued only with dorzolamide eyedrops three times a day for a period of three months, while patient 2 spontaneously stopped both medications. Results: Sequence analysis of the RS1 gene identified a hemizygous c.589C>T (p.Arg197Cys) missense mutation in exon 6, which has not been previously reported in an Italian family. A different response to the medical therapy was observed in the four eyes of the two affected brothers hemizygous for this abnormality. Of note, after acetazolamide interruption, a rebound effect on cystoid macular edema reduced the beneficial effects of the initial therapy for RS1 from p.Arg197Cys mutation. Indeed, a minimal rebound effect on cystoid macular edema, and an improvement in visual acuity, was observed in patient 1 during the six months of treatment. Conversely, in patient 2, an initial improvement in cystoid macular edema was not associated with visual acuity changes, followed by a marked rebound effect. Conclusion: This study showed that the sequential use of acetazolamide tablets and dorzolamide eye drops should be considered and studied further as a possible treatment for macular edema and visual impairment in patients with RS1 from a hemizygous p.Arg197Cys mutation. Keywords: juvenile X-linked retinoschisis, oral acetazolamide, topical dorzolamide, cystoid macular edema, macular schisis, foveal zone thickness

Einleitung: Optische Koharenztomografie ist ein wichtiges Werkzeug zur Darstellung und Analyse retinaler Ultrastrukturen. Allerdings ist die Einsatzmoglichkeit ublicher Standgerate bei Kindern begrenzt. In unserem Artikel berichten wir uber unsere Erfahrungen bei der taglichen Arbeit mit dem handgehaltenen Gerat Bioptigen zur Spectral-Domain optischen Koharenztomografie (HH-SD-OCT) bei Sauglingen und Kleinkindern der kinderophthalmologischen Ambulanz. Methoden: Zwischen Oktober 2014 und April 2016 untersuchten wir insgesamt 259 Patienten. Ausgewertet wurden Indikationen und Diagnosen. Einzelne Beispiele verschiedener Patientenfalle werden exemplarisch vorgestellt, um Vor- und Nachteile der neuartigen Technik darzustellen. Ergebnisse: Mit einer mittleren Untersuchungszeit von 18,3 Minuten (± 8,3 SD) konnten Kinder ab einem Alter von 7 Wochen nicht invasiv untersucht werden (Median: 1,59 Jahre; ± 1,32 SD). Mit 32,8 % aller Falle waren Beurteilungen im Rahmen einer Fruhgeburt die haufigste Indikation zum HH-SD-OCT. Nystagmus, Netzhautdystrophien, reduzierter Visus und Albinismus umfassten weitere 37,4 % aller Indikationen. Schlussfolgerung: Das handgehaltene OCT ist eine gewinnbringende Erganzung in der Diagnostik von Erkrankungen in der padiatrischen Ophthalmologie. Neben bereits etablierten Methoden zur Bildgebung wie dem Kontaktverfahren zur Weitwinkelfundusfotografie ermoglicht das HH-SD-OCT, neue Informationen retinaler Veranderungen objektiv zu dokumentieren und sie im Verlauf weiterzuverfolgen. Bei unruhiger Fixation ist aufgrund des fehlenden Eyetrackings eine Orientierung am hinteren Netzhautpol schwierig und Verlaufsuntersuchungen nur mit zusatzlichem Analyseaufwand moglich.

Augenmuskeloperationen bei Nystagmus werden i. d. R. durchgefuhrt, um eine kompensatorische Kopfzwangshaltung (KZH) zu korrigieren, deren Ursache eine exzentrisch gelegene Nystagmusruhezone ist. Die Verlagerung der Ruhezone in den Geradeausblick behebt die KZH. Die Kestenbaum-Operation besteht in der beidseitigen Rucklagerung der wahrend der KZH wirkenden Agonisten und der Resektion oder Faltung ihrer Antagonisten. Die Anderson-Operation ist auf die Rucklagerung der Agonisten beschrankt und damit weniger invasiv. Wir berichten uber unsere Erfahrungen mit der Anderson-Operation. Patienten und Methoden: Von September 2013 bis Juni 2015 fuhrten wir die Anderson-Operation bei 11 konsekutiven orthotropen Patienten mit einem idiopathischen infantilen Nystagmus oder mit einem sensorischen Defekt assoziierten Nystagmus durch. Patienten, die positiv auf konvergenzinduzierende Prismen reagierten, also von einer artifiziellen Divergenzoperation profitieren konnten, wurden ausgeschlossen. Ergebnisse: Mediane und Streubreiten (Minimum–Maximum): Alter: 7 Jahre (4–30); bestkorrigierte binokulare Sehscharfe 0,5 (0,05–1,0); KZH 30° Drehung (20–40); gleiche Rucklagerungsstrecken von 12 mm (10–17) an den beiden horizontalen Agonisten, in einem Fall unter Verwendung von Interponaten (bovines Perikard). Drei (3–6) Monate postoperativ war die KZH auf 7° (0–20) reduziert. Die Erfolgsraten nach den Kriterien einer restlichen KZH ≤ 10° und ≤ 15° betrugen 73 % (95 %-Konfidenzintervall [KI] 39–93 %) und 82 % (95 %-KI 48–97 %). Ubereffekte oder andere storende Nebenwirkungen traten nicht auf. In 2 Fallen erfolgte nach 8 Monaten eine Verstarkung. In einem Fall wurde nach 1 Jahr eine schon primar vorhandene, postoperativ dekompensierte Exophorie korrigiert. Schlussfolgerung: Die Anderson-Operation hat die KZH deutlich verringert oder komplett korrigiert. In allen Fallen erfolgten Rucklagerungen um mindestens 10 mm. Die Erfolgsraten waren ahnlich wie nach einer Kestenbaum-Operation. Im Vergleich zu dieser ist die Anderson-Operation weniger invasiv. Die Heilungsphase ist kurzer. Der sichere Erhalt von Ziliargefasen ist ein Vorteil im Hinblick auf eventuelle weitere Eingriffe.

From the ophthalmological view, albinism is a disorder of reduced pigmentation of the retinal and irdial pigment epithelium and the iris and choroid stroma. The reduced pigmentation is accompanied by morphological changes in the retina and the optic nerve. The functional relationship of these morphological changes is not yet well understood. This review summarises the genetic causes of reduced pigment synthesis and impaired pigment distribution, and discusses the variability of expression of albinism symptoms, in the light of other disorders affecting retinal development.

To establish a method that allows for the reliable assessment of vascular endothelial growth factor (VEGF-A) concentrations in very small blood samples of preterm infants. Systemic VEGF measurements are important in view of the most appropriate Anti-VEGF drug to be used for the treatment of acute retinopathy of prematurity (ROP). Cord blood samples from preterm (n = 6) infants, blood samples from preterm infants with treatment requiring ROP (n = 12), and blood samples from healthy adults (n = 10) were collected. Serum, citrate plasma, and serum from recalcified citrate blood were obtained. Levels of VEGF-A and platelet factor-4 (PF-4) were quantified by ELISA or AlphaLISA immunoassay. VEGF-A levels could be detected by both assays, with the AlphaLISA generating slightly lower levels in healthy adults, but not in cord blood of preterm infants. In plasma samples, VEGF levels ranged from non detectable to 181 pg/ml. PF-4 concentrations were between 0.16–3.88 µg/ml. Values of VEGF-A and PF-4 in serum and recalcified serum were significantly higher compared to plasma through the release of these cytokines after platelet activation. In plasma samples of infants with ROP, VEGF-A could always be detected and its values ranged from 19.50 to 245.91 pg/ml and PF-4 concentrations were between 0.1 and 3.3 µg/ml. Using the AlphaLISA kit, we were able to detect VEGF in small sample volumes (5 µl plasma or serum/well) in premature infants with treatment requiring ROP and to monitor platelet activation by PF-4 detection. Minimal blood probe volumes reduce phlebotomy losses avoiding the risk of iatrogenic anemia, thus allowing close monitoring of the cytokine levels in these very fragile infants.

Purpose To evaluate the precision of bag-in-the-lens intraocular lens (BIL IOL) power calculation in different age groups of pediatric cataract patients. Settings Department of Ophthalmology, Justus-Liebig-University Giessen, University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany. Design Retrospective nonrandomized consecutive case series. Methods Pediatric patients diagnosed with cataract and operated with BIL IOL implantation were divided into 4 age groups: Group 1 (0 to 3 months), Group 2 (>3 months, 36 months to 17 years). BIL IOL power was calculated with the SRK/T formula. The prediction error (PE) was defined as the absolute difference between the preoperative selected target and postoperative achieved refraction. The impact of age at the time of surgery, axial length (AL), keratometry, and corneal astigmatism on PE was analyzed. Results The study comprised 87 eyes of 56 pediatric patients. The mean and median PEs for the entire group were 1.79 diopters (D) and 1.23 D, respectively. The mean PE in each age group was: 3.43 D in Group 1, 2.14 D in Group 2, 1.60 D in Group 3, and 1.33 D in Group 4. The mean PE in eyes with ALs shorter than 20 mm was 2.67 D, and 1.44 D in eyes with an AL of 20 mm or longer. The mean PE in eyes with corneal radii less than 7.3 mm was 2.45 D, and 1.66 D in eyes with corneal radii of 7.3 mm or more. In the age and AL subgroups, the PE differences were statistically significant (P Conclusions The PE was larger in the youngest study group, and it decreased gradually with age and in eyes with ALs shorter than 20 mm. The PE has to be considered during BIL IOL power calculation in children.

Purpose To report the efficacy of the use of a new scleral depressor marker during scleral buckling surgery for retinal detachment. Design Noncomparative, consecutive case series study. Participants Eleven patients (11 eyes) with rhegmatogenous retinal detachment who underwent scleral buckling surgery performed by 2 experienced vitreoretinal surgeons. Methods The prototype of a new indenter marker was used during scleral buckling surgery. Main Outcome Measures The possibility of performing simultaneous indentation and selected marking of the desired area was assessed. Additionally, the precision of the fiber light–assisted indentation as well as force of indentation were evaluated. Results The use of a new depressor marker facilitated a quick and effective flow of the standard surgery for retinal detachment. It was possible to perform indentation and marking as separate steps of 1 session. Only desired areas of the sclera were marked during the same indentation session. The indentation required less force. When combined with chandelier light, the precision of the marking was improved as demonstrated by a light from the chandelier indicating the highest point of the indentation area. There were no complications related to the use of the new instrument. Conclusions The newly developed scleral depressor marker facilitated simultaneous indentation and marking on the sclera. The new instrument allowed for the selective marking of the desired areas during the same session of indentation. Additionally, it can be combined with chandelier fiber light, which improves the precision of the marking.

Neurofibromatosis type 2 (NF2) is a genetic condition with an autosomal dominant pattern of inheritance and incomplete penetrance. It is characterized by multiple benign tumors of the central and peripheral nervous system including astrocytomas, ependymomas, meningeomas, and schwannomas, among which bilateral vestibular schwannomas are the most frequent. Among ocular manifestations of NF2, juvenile subcapsular cataract is the most common followed by epiretinal membranes and combined hamartomas of the retina and retinal pigment epithelium.Multimodal imaging was performed in a female patient and her data were compared to an overview of published cases with retinal hamartoma in NF2.We report on a case of a 14-year-old girl with genetically confirmed NF2 who presented with bilateral, asymptomatic hyperplasia of glia cells within the ganglion cell and the nerve fibre layer by spectral domain optical coherence tomography (SD-OCT). A metaanalysis of 25 published cases revealed combined hamartomas of the retina and retinal pigment epithelium (CHRRPE) as the most common (16 cases) retinal tumors followed by retinal astrocytic hamartomas (RAH, 7 cases). Retinal hamartomas were most often reported bilaterally and observed prior to the clinical diagnosis of NF2 in 11 of 25 cases. No correlation to sex was observed. Reduced visual acuity, cataracts and epiretinal membranes were the leading ocular manifestations.There is a large spectrum of ocular-specific findings in NF2. These are seminal, especially at an early age, enabling an early diagnosis and timely therapy of further tumor manifestations. Retinal astrocytic hamartomas may be very discreet and easily missed on routine examination. Fundus infrared imaging is a useful tool allowing to detect even discreet changes rarely seen by ophthalmoscopy in young children. This allows for a more extensive evaluation by SD-OCT.Die Neurofibromatose Typ 2 (NF2) ist eine autosomal-dominant vererbliche Erkrankung mit unvollständiger Penetranz, die durch das Vorkommen von gutartigen Tumoren des zentralen und peripheren Nervensystems charakterisiert ist. Zu diesen zählen Astrozytome, Ependymome, Meningeome und Schwannome, bei denen beidseitige Vestibularisschwannome typisch sind. Okulär manifestiert sich die NF2 durch juvenile subkapsuläre Katarakte, epiretinale Membranen sowie kombinierte Hamartome der Retina und des retinalen Pigmentepithels.Bei einer Patientin mit retinalem Hamartom bei NF2 wurde eine multimodale Bilddokumentation durchgeführt und mit einer Metaanalyse publizierter Fälle retinaler Hamartome bei NF2 verglichen.Berichtet wird über den Fall eines 14-jährigen Mädchens mit molekulargenetisch gesicherter Neurofibromatose Typ 2. In der Spectral-Domain-optischen Kohärenztomografie (SD-OCT) fielen beidseitige, asymptomatische, retinale astrozytäre Hamartome im Bereich der retinalen Ganglienzell- und Nervenfaserschicht auf. Eine Metaanalyse der 25 publizierten Fälle ergab, dass die häufigste Form von Tumoren der Retina das kombinierte Hamartom der Retina und des retinalen Pigmentepithels (CHRRPE, 16 Fälle) war, gefolgt von den retinalen astrozytären Hamartomen (RAH, 7 Fälle). Dabei wurden die retinalen Hamartome meistens beidseitig beschrieben. Es wurden 11 Fälle beschrieben, bei denen retinale Hamartome vor der klinischen Diagnose der NF2 festgestellt wurden. Es konnte keine Geschlechtsprävalenz festgestellt werden. Die 3 häufigsten okulären Befunde bei NF2 waren Sehminderung, Katarakt und epiretinale Membranen.Das Spektrum der spezifisch okulären Befunde bei NF2 ist sehr groß. Deren Feststellung kann gerade im jungen Alter diagnoseweisend für die Erstdiagnose der NF2 sein und somit eine frühzeitige Erkennung und gegebenenfalls eine rechtzeitige und erfolgreichere Therapie weiterer Tumormanifestationen ermöglichen. Retinale astrozytäre Hamartome können sehr dezent ausgeprägt sein und bei einer Routineuntersuchung nicht auffallen. Eine Fundusinfrarotaufnahme ist bei der ophthalmologischen Untersuchung insbesondere von kleinen Kindern ein nützliches Werkzeug und kann in manchen Fällen funduskopisch kaum erkennbare Befunde aufdecken, die dann gezielt mit SD-OCT untersucht werden können.

Basal cell carcinoma is the most common skin cancer of the eyelid. It most frequently occurs on the lower eyelid and the medial canthus. Although metastases appear only very rarely, basal cell carcinoma is locally destructive if left untreated. Nowadays several surgical and nonsurgical treatments can be used to remove or destroy basal cell carcinomas. The selection of optimal treatment depends on the initial individual situation as well as the age and the general condition of the patient. The "gold standard" method for the treatment of basal cell carcinomas is surgical removal with subsequent histological examination. Because of the complex anatomical characteristics of the medial canthus and the lateral nasal root region, basal cell carcinomas of this area present great challenges for any treatment method. These characteristics also explain the higher rates of incomplete removal and greater risk of recurrence, with in depth extension of the tumor. Additionally, surgical removal of the tumor from the medial canthus area often results in extended tissue defects. The plastic covering of these defects can be achieved by various reconstruction procedures.

Item does not contain fulltext Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in ~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

Zielsetzung: Uber die Ursache und Entstehung des primaren Strabismus ist wenig bekannt. Auf genetischer Ebene wird eine multifaktorielle Vererbung vermutet. Die Kopplungsanalyse war dabei bislang die hauptsachlich eingesetzte Methode. Ziel dieser Studie war die Zusammenstellung und statistische Auswertung eines fur Kopplungsanalysen bei Strabismus geeigneten Patientenkollektivs. Methode: Aus dem Archiv der Klinik und Poliklinik fur Augenheilkunde der Justus-Liebig-Universitat wurden die Krankenblatter der Jahre 2001 bis Juli 2008 ausgewertet und nach Indexfamilien gesucht, in welchen mindestens 2 Mitglieder Formen des primaren Strabismus aufwiesen. Besonders fur Kopplungsanalysen geeignet erscheinende Familien wurden kontaktiert, um mittels eines fur diese Studie entwickelten Fragebogens den Datensatz zu erganzen. Ergebnisse: Im Untersuchungszeitraum 2001 bis Juli 2008 wurden 20 813 Patienten mit primarem Strabismus erfasst. Aus dem Datensatz wurden 2380 Patienten (11 %) mit einer positiven Familienanamnese extrahiert. Mehrheitlich zeigten sich Esotropien (67 %) gefolgt von Exotropien (21 %). In den meisten Fallen (80 %) waren 2 Familienmitglieder betroffen, wobei die Kind-Eltern-Kombination mit 948 Fallen (40 %) die groste Gruppe darstellte. Eine positive Geschwisteranamnese ergab sich in 397 Fallen (17 %). 432 Familien (18 %) wiesen 3 Betroffene auf, wobei die Kombination Kind-Eltern-Geschwister mit 143 Fallen (6 %) am haufigsten auftrat. Eine positive Familienanamnese mit 4 und mehr Betroffenen zeigte sich in 46 Fallen (2 %). 42 der Indexfamilien waren aufgrund ihrer Struktur besonders fur Kopplungsanalysen geeignet. Von den genannten 42 Indexfamilien beantworteten 17 einen Fragebogen zur Vervollstandigung der Familienstammbaume. Drei dieser Familien nahmen schlieslich an einer augenarztlichen Untersuchung teil und stimmten einer Blutentnahme zur Durchfuhrung von Kopplungsanalysen zu. Schlussfolgerung: Der Anteil von Familien mit Schielpatienten in mehr als 2 konsekutiven Generationen ist sehr klein. Eine Rekrutierung solcher Familien muss daher behandlungsnah erfolgen, da dies die Kooperation der Probanden fordert.

Background Esotropia due to high myopia can be caused by inferior shift of the lateral rectus muscle (LRM). Innovative surgical methods have been developed to elevate the muscle and, thus, augment its abducting force. However, their efficacy is not yet proven to exceed that of recess–resect surgery (RR). Methods Data on high myopic esotropia were evaluated who received RR together with elevation of the LRM in the horizontal meridian by equatorial myopexy. Age, gender, axial length, amount of surgery, preoperative and 3 months postoperative strabismus angles and efficacy (mm/°) were analysed. Medians and ranges (minimum–maximum) are given. Results The age of the 46 patients (37 females, 9 males) was 57 years (36–76). Axial length was 31.5 mm (26.0–35.6), total amount of RR 10.0 mm (5–24). Esotropia 16° (4–60) was reduced to 2° (−22 to 34), hypotropia from 3° (−3 to 30) to 0° (−8 to 18). Efficacy (eyes without prior surgery only) was 1.33°/mm (0.20–3.55). Conclusions Geometrical considerations rather than empirical data yield some evidence of an augmenting effect of equatorial myopexy on RR. Efficacy of RR with LRM myopexy was higher in unilateral than bilateral high myopia. Strict indication for myopexy appears appropriate.

Vorgestellt wird die Kasuistik eines bilateralen chorioidalen Osteoms bei einem bei Erstvorstellung 6 Jahre alten Jungen. Uber den Beobachtungszeitraum von 6 Jahren zeigte sich beidseits ein deutliches Tumorwachstum. An einem Auge entwickelte sich eine staphylomartige Ausdehnung im Bereich des hinteren Augenpoles, die zu einer progressiven myopen Anisometropie fuhrte. Als eine seltene Komplikation sollte somit an die Entwicklung einer Refraktionsanomalie gedacht werden. Dies ist fur den Erhalt der monokularen und binokularen Funktion bedeutsam.

Retinopathy of prematurity (ROP) is a potentially blinding disorder of extremely premature infants caused by un-physiologic oxygen supply within the first weeks of life. The disease is characterized by uncontrolled vessel growth at the border of the vascularized zone, in severe cases leading to vitreoretinal tractions and retinal detachment. About 3–5% of all ROP cases need treatment at some point. The use of digital wide-field fundus photography, fluorescein angiography and optical coherence tomography as diagnostic tools generated a wealth of information about early disease features and treatment effects. Currently, intravitreal anti-VEGF injections are considered by many to be the optimal treatment approach for the most severe forms of Type 1 ROP, even though the pharmacological risks in terms of organ development and mortality rate have not yet been fully addressed.

Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI. Presence of the genomic modifications was verified at the RNA and protein levels. The mutant protein was observed at low levels. Optical coherence tomography studies revealed a slowly progressive retinal degeneration with photoreceptor loss starting at 9 months of age, paralleling the onset of functional deficits as seen in the electroretinogram. Early changes to the outer retinal bands can be used as biomarker during treatment applications. We further show for the first time efficient targeting using the I-SceI enzyme at the genomic locus in a proof of concept in photoreceptors following adeno-associated virus mediated gene transfer in vivo. Taken together, our studies not only provide a human-XLRP disease model but also act as a platform to design genome editing technology for retinal degenerative diseases using the currently available endonucleases.