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ZusammenfassungDie Frühgeborenenretinopathie zählt zu den häufigsten behandelbaren Erblindungsursachen bei Kindern. Es handelt sich um eine vasoproliferative Netzhauterkrankung, die nur bei Frühgeborenen auftritt. Durch ein konsequentes augenärztliches Screening können nahezu alle Augen mit behandlungsbedürftiger ROP frühzeitig identifiziert und einer Behandlung zugeführt werden, sodass das Risiko einer schweren Sehbehinderung oder Erblindung durch eine ROP erheblich gesenkt wird.

Zusammenfassung Hintergrund Die Frühgeborenenretinopathie („retinopathy of prematurity“ [ROP]) zählt in Deutschland und weltweit zu den häufigsten Erblindungsursachen im Kindesalter; ein adäquates Screening ist essenziell. Der telemedizinische Ansatz mit objektiver Dokumentation des Netzhautbefundes eröffnet die Möglichkeit, untersucherunabhängig alle ROP-Stadien sicher zu diagnostizieren, wenn die Befundung durch ein ROP-geschultes Augenärzteteam erfolgt. Ziel der Arbeit 10-Jahres-Vergleich des ROP-Screenings an 2 deutschen Level-1-Perinatalzentren: universitär und vor Ort vs. nichtuniversitär und telemedizinisch. Material und Methoden Retrospektive Analyse der Screeninguntersuchungen stratifiziert nach Gestationsalter (GA), Geburtsgewicht (GG), Geschlecht, Mehrlingsgeburten, ROP-Zeitpunkt, Behandlungsbedürftigkeit, -zeitpunkt und Untersuchungshäufigkeit. Ergebnisse Von 2009 bis 2019 wurden 1191 Frühgeborene gescreent, davon 29 Externe. Bei den verbleibenden 1162 wurden 3713 Netzhautuntersuchungen durchgeführt; 34 % hatten eine ROP, 5,4 % wurden behandelt (Gießen 3,7 %, Siegen 7,2 %). Mittleres GA war 28,9 SSW (± 2,5), mittleres GG 1155 g (± 417,5). Die Zahl der ROP-Diagnosen stieg in Gießen um 227,3 % und in Siegen um 111,1 % aufgrund zunehmender Zahlen der betreuten Kinder. Diskussion Die vergleichende Analyse bestätigte national und international steigende ROP-Screening-Untersuchungen und Kinder mit akuter ROP. Das telemedizinische Screening war dem Vor-Ort-Screening gleichwertig und sicher. Mit beiden Screeningmethoden wurden alle Behandlungsbedürftigen zeitgerecht erkannt. Kein Kind mit einem GA > 29 SSW benötigte eine Behandlung, analog zu Ergebnissen des schwedischen Registers. Im deutschen ROP-Register waren aber einzelne Frühgeborene mit einem GA ≥ 30 SSW behandlungsbedürftig.

Aims: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital. Methods: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement. Results: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59). Conclusions: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology. Precis: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways.

Introduction: To evaluate the current management of RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of Voretigene Neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-Eye) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. Methods: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. Results: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1 – 19/center, median 6), and 43 planned for treatment (range 0 – 10/center, median 6). The overall age range was 3 – 52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2 – 60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full field stimulus test (FST) improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. Discussion/Conclusion: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-Eye HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of two class 4 or 5 mutations on both alleles, or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers.

To quantify changes in ductions following nasal transposition of the split lateral rectus muscle (NTSLR) for treating third nerve palsy.Retrospective cohort study.A single eye from each patient with third nerve palsy treated with NTSLR with ocular motility measurements.Observation of changes in pre- and postoperative ductions. Outcome measures including patient demographic and surgical factors associated with the ability to adduct beyond the midline after NTSLR were evaluated using multivariable logistic regression.A total of 116 patients met the inclusion criteria for this study. The NTSLR significantly decreased abduction (median of 0 limitation [interquartile range (IQR), 0-0] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p0.001), with a corresponding improvement in adduction (median, -5 [IQR, -5 to -4] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p0.001). There was no change in median supraduction or infraduction after NRSLR (p0.05). The ability to adduct beyond the midline after NTSLR was demonstrated in 42% of patients. Although not statistically significant, a trend toward a postoperative ability to adduct beyond the midline was seen in patients who had concurrent superior oblique muscle tenotomy (odds ratio [OR] = 5.08; 95% CI, 0.91-40.9) or who were designated with partial rather than complete third nerve palsy (OR = 2.29; 95% CI, 0.82-6.70).NTSLR improves the horizontal midline positioning of eyes with third nerve palsy. Most eyes lose the ability to abduct, but some regain a modest ability to adduct while vertical ductions remain unchanged.

Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.

Zusammenfassung Hintergrund Durch Verbesserungen in der neonatologischen Versorgung von Frühgeborenen und die Entwicklung neuer Behandlungsmöglichkeiten der Frühgeborenenretinopathie („retinopathy of prematurity“ [ROP]) haben sich die Anforderungen an das ROP-Screening seit der Veröffentlichung der letzten Fassung der deutschen Leitlinie zum ROP-Screening im Jahr 2008 verändert. Auf Grundlage aktueller Studiendaten wurde die Leitlinie in 2020 grundlegend überarbeitet und in einer aktualisierten Fassung veröffentlicht. Ziel Dieser Artikel fasst die wichtigsten Änderungen in der neuen Leitlinie zusammen. Ergebnisse Die Altersgrenze für einen Screeningeinschluss wurde für Kinder ohne zusätzliche Risikofaktoren auf ein Gestationsalter von unter 31 Wochen gesenkt. Die Mindestdauer für eine Sauerstoffsupplementation, die einen Einschluss in das Screening bei Frühgeborenen erforderlich macht, wurde auf über 5 Tage angehoben. Eine Behandlung bei ROP in Zone II kann nun schon bei jedem Stadium 3 mit Plus-Symptomatik unabhängig von der Anzahl der betroffenen Uhrzeiten erfolgen. Für die Nachkontrollen nach Anti-VEGF („vascular endothelial growth factor“)-Therapie wurden Kriterien zur Frequenz und Dauer definiert. Das verbindliche Dokument für diese und weitere neue Empfehlungen ist die Leitlinie selber. Schlussfolgerungen Die Empfehlungen der Leitlinie ermöglichen eine zuverlässige Identifikation von Kindern mit ROP-Risiko für den Einschluss in das Screening und eine rechtzeitige Erkennung fortgeschrittener Krankheitsstadien für die Therapieeinleitung, um so Erblindung durch ROP zu verhindern.

While many studies have investigated links between motor and visual spatial cognitive abilities in typically developing children, only a few studies have tested this link among children with innate handicaps. Therefore, we assessed motor abilities (using the M-ABC-2) and visual spatial cognitive skills (using the Block Design subtest of the WPPSI-III and a picture mental rotation task, PRT) of 5-7 year old typically developing children (n= 17) and same-aged children with severe deficits in stereopsis due to infantile esotropia (n= 17). Compared to the typically developing children, children with esotropia showed significantly poorer motor performances, especially in manual dexterity and ball skills, and significantly poorer and slower performance on the visual spatial cognitive tasks. Especially the girls treated for infantile esotropia needed more time to mentally rotate the pictures of the PRT correctly. Overall, this study showed that perceptual, motor and cognitive processes are interconnected and that children treated for infantile esotropia had an increased risk of motor and visual spatial cognitive deficits.

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the

Purpose: The first ocular gene augmentation therapy, voretigene neparvovec (VN) (Luxturna®), has been approved for clinical use in an increasing number of countries (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Among the EVICR.net clinical centers, we conducted the first multinational survey to understand distribution, diagnostic work-up, and management of inherited retinal degeneration (IRD) cases in Europe with a special focus on RPE65 mutation-associated IRDs. Methods: An electronic survey questionnaire including 35 questions specifically addressing RPE65 mutation-associated IRDs was developed and sent to the 101 EVICR.net clinical centers. Results: The overall response rate was 49%. Forty-two centers see IRD patients, and 22/42 follow patients with confirmed biallelic RPE65 mutations. Fifteen of the 22 centers (68%) and 3/22 (14%) follow 1–5 and 6–10 patients with homozygous RPE65 mutations, respectively. Additionally, 15/22 (68%) and 3/22 (14%) follow 1–5 and >20 patients with compound heterozygous RPE65 mutations, respectively. Fifty-nine percent of mutations were ACMG Class 4 and 5 (at least 1 allele), 82.8% reported previously and 17.2% novel. Referral diagnoses (the mean per center) were Leber congenital amaurosis (38.2%), early-onset severe retinal degeneration (16.8%), rod-cone-dystrophy/retinitis pigmentosa (RP) (28.1%), and unclassified visual impairment (17.0%). Twenty-five percent of the centers changed the referral diagnosis in >47.5% of cases; 32% follow a specific referral process for RPE65 mutation-associated IRD patients. Annual follow-up visits are done in 55% of the centers and biannual visits in 23%. In 32%, other centers also follow the patients. Kinetic perimetry is done in 82%, static perimetry in 45%, and microperimetry in 18% of the centers. Full-field light stimulus threshold testing with blue and red stimuli to quantify the rod and cone function is used in 6/22 centers (27%). A mobility course is available in one center (5%). Conclusion: This first multinational survey on management of patients with RPE65 mutation-associated IRDs in Europe shows that about half of the responding EVICR.net centers have such patients under care. There is heterogeneity in diagnoses and management practices. At the start of clinical practice experience with VN, these data provide a useful baseline and highlight the need for consensus/guidelines to inform standard of care in this new era of gene therapy.

Die okulare Rosazea im Kindesalter ist eine seltene, aber oft unterdiagnostizierte Erkrankung. Chronische Blepharokonjunktivitis, Chalazien, Hornhauttrubungen und -neovaskularisationen sind typische Befunde. Die empfohlene Therapie besteht aus topischen (Lidhygiene, Steroide, Ciclosporin, Benetzungsmittel) und systemischen (Antibiotika, z. B. Erythromycin) Masnahmen. Unsere Fallserie von 8 Kindern belegt die Wirksamkeit der lokalen 1,5 % Azithromycin-Therapie kombiniert mit Lidhygiene bei kindlicher okularer Rosazea. Ein weiterer Vorteil dieser topischen Therapie ist, dass sie nur 2‑mal taglich uber 3 Tage mit anschliesender Pause von 7 Tagen angewendet werden muss. Dies verbessert auch die Therapietreue.

Der zerebrale Folatmangel (CFD) fuhrt unbehandelt neben neurologischen Veranderungen zu einer massiven Degeneration der Aderhaut/Netzhaut, die das Gesichtsfeld und die Sehscharfe zunehmend einschranken. Im Folgenden stellen wir den Fall einer Patientin mit einem CFD vor, die bereits im Vorschulalter durch autistische Personlichkeitszuge auffiel und erst im Alter von 3 Jahren zu sprechen begann. Im Alter von 6 Jahren wurde sie wegen einer unklaren Visusminderung am rechten Auge vorgestellt. Die bei Erstvorstellung noch milden Aderhaut‑/Netzhautveranderungen beidseits in der Peripherie wurden in den Folgejahren deutlicher, und es trat eine zentral betonte chorioretinale Atrophie hinzu. Im Verlauf kam es zu einer weiteren beidseitigen Visusminderung, welche ab dem 14. Lebensjahr bei 0,1 stagnierte. Die kausale Zuordnung der Befunde der Patientin war uber Jahre hinweg nicht moglich: Eine Chorioideremie wurde molekulargenetisch ausgeschlossen (CHM-Gen ohne auffallige Mutation), gegen eine Atrophia gyrata sprach der normale Ornithin-Spiegel. Eine Mitochondriopathie wurde, soweit moglich, mittels Exomsequenzierung ausgeschlossen. Mit Hinzutreten weiterer nichtokularer Symptome (neuromuskulare Storungen, EEG-Veranderungen, autistische Storung) erfolgte eine nochmalige intensivierte Labordiagnostik durch die behandelnde Kinderklinik. Schlieslich gelang mit dem Nachweis einer auserst niedrigen Konzentration des Folsauremetaboliten 5‑Methyltetrahydrofolat im Liquor cerebrospinalis die Diagnose eines CFD. Daraufhin wurde eine hoch dosierte Substitutionstherapie mit Folsaure eingeleitet. Nach Ausschluss pathogener Mutationen im FOLR1-Gen fur den zerebralen Folatrezeptor 1 wurden als Ursache hochtitrige blockierende Autoantikorper gegen den zerebralen Folatrezeptor 1 nachgewiesen.

Zusammenfassung Hintergrund Die Korrektur einer Kopfzwangshaltung (KZH) bei infantilem Nystagmussyndrom (INS) erfolgt mit der Kestenbaum-Operation (KO) in Form der beidseitigen Rücklagerung der in KZH aktiven Agonisten und Verkürzung ihrer Antagonisten oder mit der Anderson-Operation (AO) durch die alleinige Rücklagerung der Agonisten. Ziel der Arbeit Vergleich der Ergebnisse hoch dosierter AO und KO bei ähnlicher KZH. Patienten und Methoden In unterschiedlichen Zeiträumen (2013 bis 2019 bzw. 2003 bis 2013) kam ausschließlich die AO bzw. die KO zur Anwendung. Eine hoch dosierte AO erhielten in einer konsekutiven Fallserie 33 Orthotrope mit INS und KZH, eine KO erhielten 19 Patienten. Die Mediane und Streubreiten (min–max) in den Gruppen AO/KO betrugen: Alter bei OP 7 (4–44) Jahre/6 (4–27) Jahre; KZH 32,5°(20–45)/30°(17–40); Operationsstrecke pro Auge AO 13 (10–16) mm (Standarddosis), KO 10 (6–12) mm + 10 (6–12) mm (Mittel 0,60 mm/°KZH). Ergebnisse Die KZH betrug nach ca. 3 Monaten 10°(−3–20)/10°(−7–20), bei der Spätkontrolle (8 bis 153 Monate) 10°(0–20)/10°(−27–30). Sie war bei der letzten Kontrolle um 67 % (20–100)/64 % (14–100) verringert. Eine Restdrehung ≤15° fand sich in 79/81 % der Fälle (91 % nach AO ≥13 mm; n = 23), ein Rest ≤10° in 55/57 %, (65 % nach AO ≥13 mm). Die Ad‑/Abduktionsfähigkeit der rückgelagerten Muskeln betrug nach AO 30°/30° (10–37/15–45), nach KO 32°/30° (10–40/12–45). Eine assoziierte Kopfneigung wurde durch den Eingriff nicht verbessert. Der mittlere Anstieg des binokularen Visus betrug jeweils 6 Jahre. Schlussfolgerung AO und KO waren bei der verwendeten Dosierung wirkungsgleich. Die geringere Invasivität der AO spricht für deren Anwendung als Ersteingriff.

Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness. This proliferative retinal vascular disease affects only prematurely born infants. Major risk factors include low gestational age and prolonged postnatal oxygen supplementation. ROP screening allows for timely identification of treatment-requiring infants and thus significantly reduces the risk of severe visual impairment and blindness from ROP. Current treatment options comprise retinal laser coagulation and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. We provide a review of scientific data and current treatment recommendations, with special attention to the updated German guideline on ROP screening, the statement of the German ophthalmological societies on anti-VEGF therapy of ROP, and the new third edition of the International Classification of Retinopathy of Prematurity (ICROP3).

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Zusammenfassung Hintergrund 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. Methoden 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. Ergebnisse 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. Schlussfolgerungen 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.

We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine’s indispensability ...

To evaluate the effectiveness of a high-dose Anderson procedure (AP) to correct infantile nystagmus–related anomalous head turn (HT). Twenty-nine consecutive orthotropes with infantile nystagmus with and without associated sensory defect received high-dose AP. HT was measured while the patient tried to read letters at best-corrected visual acuity (BCVA) level at 5 m and 0.3 m. BCVA, binocular vision (BV), and alignment (prism and cover test) were measured. High-dose AP with recessions of 9–16 mm was performed. All measures were taken before and 3–6 and ≥ 8 months post surgery. Success was defined by postoperative HT ≤ 10°/HT ≤ 15°. Medians and ranges (minimum-maximum) were:. Age at surgery was 7 years (4–44). HT at 5 m and HT at 0.3 m were 35° (20–40) and 20° (0–35), respectively. After 4 months (3–6), HT was 10° (− 3–20) and 5° (− 5–20); success rates were 74%/96% and 83%/96%. After 15 months (8–45), HT was 12° (0–20) and 6° (0–15); success rates were 46%/75% and 92%/100%; residual HT > 15° occurred in 5/9 cases with recessions

The lateralis splitting technique has been an interesting option for treating large-angle exotropia due to complete 3rd nerve paralysis since its inception in the early 1990s. The purpose of this study is to report on our experience regarding the effectiveness and complications of this method. Retrospective analysis of a consecutive series of 29 patients operated by one single experienced surgeon and examined according to a specific operative and perioperative protocol. Patients were examined preoperatively, on the 2nd day and 3rd month after surgery. Outcome measures include strabismus angle, horizontal motility, head turn, binocular function, and incidence and resolution of postoperative serous retinal detachment as seen with infrared imaging and spectral domain optical coherence tomography (SD-OCT). Surgery brought about a large and stable reduction of strabismus angle and head turn. It reduced horizontal motility, but moved the range of monocular excursion much closer to center. Eighty percent of patients with constant diplopia acquired some fields of single binocular vision. A significant number of cases (33.3%) developed transitory serous retinal detachment with varying onset and extent. This is by far the largest published study regarding the outcome of lateralis splitting in NIII palsy. The procedure is difficult, yet a very useful option. Serous detachment is a serious complication, but usually transitory. Its cause and mechanisms are not fully understood and warrant further investigation.

To assess the efficacy of dynamic intraoperative spectral-domain optical coherence tomography (iSD-OCT) imaging for inverted internal limiting membrane (ILM) flap technique (IILMFT) in large macular hole (MH) surgery. Prospective, non-randomized, observational study was conducted on 8 eyes of 7 patients with large, chronic and recurrent MHs, which were treated by pars plana vitrectomy (PPV) with IILMFT. All patients underwent standard pre- and postoperative examination. The iSD-OCT imaging was performed using microscope integrated systems before, during, and after ILM peeling. The iSD-OCT data were post-processed using graphic software and reviewed for tissue behavior and instruments position. The real-time iSD-OCT-assisted IILMFT allowed for real-time imaging of the entire surgery with visualization of the MH, vitreoretinal instruments, and all steps of inverted ILM flap formation. In spite of shadowing created by the steel instruments, it was possible to follow and control the distance between the instrument tips and retinal layers. Dynamic imaging of the surgical maneuvers including ILM peeling and mechanical apposition of MH edges revealed the iatrogenic impact on the retina (depression and appearance of hyporeflective zones). iSD-OCT imaging could confirm the proper position of the inverted ILM flap at the very end of the surgery after fluid-air exchange. iSD-OCT imaging is an effective tool for learning and performing a well-controlled and safe inverted ILM flap technique in patients with large MH. Clinical significance of the structural iSD-OCT findings has to be further studied.

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing (WES), we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. The aryl hydrocarbon receptor is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. It was further shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in the mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in the Ahr(-/-) mice appears early in development and presents as conjugate horizontal pendular nystagmus (Chevallier et al., 2013; Juricek et al., 2017). We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Ein 4‑jahriges Madchen wurde notfallmasig wegen Diplopie und intermittierendem Exophthalmus des linken Auges vorgestellt. Die Symptome waren parallel zu rezidivierenden grippalen Infekten aufgetreten. Unsere Untersuchungen ergaben keine Auffalligkeit. Anhand von Fotografien und Videoaufnahmen, die eine Hypotropie von ca. 25° und eine Protrusio des linken Auges zeigten, wurde die Diagnose eines Obliquus-superior-Klick-Syndroms mit einem atypisch distalen Passagehindernis gestellt. Rheumatologische und HNO-arztliche Befunde waren unauffallig.

Background/aimsTo determine success rate and complications associated with nasal transposition of the split lateral rectus muscle (NTSLR) for treating strabismus from 3rd-nerve palsy.MethodsAn international, multicentre, registry of patients with unilateral 3rd-nerve palsy treated with NTSLR was created. Patients with concurrent surgery on the contralateral eye were excluded. Primary outcome was horizontal alignment within 15 prism dioptres (PD) of orthotropia. Incidence of technical difficulties and vision-threatening complications by 6 months post-procedure were reported.ResultsNinety-eight patients met inclusion criteria. Median age was 33.5 years (IQR 10.75–46). Aetiologies included congenital (31%), neoplastic (16%) and traumatic (15%). Twenty-five per cent of patients had prior ipsilateral strabismus surgery. Median exotropia decreased from 70PD preoperatively (IQR 50–90) to 1PD postoperatively (IQR 0–15.5), with a success rate of 69%. Performing concurrent superior oblique muscle tenotomy (SOT) was independently associated with success (p=0.001). Technical challenges occurred in 30% of cases, independently associated with a history of ipsilateral strabismus surgery (p=0.01). Eleven per cent of patients had vision-threatening complications, independently associated with more posterior placement of the split lateral rectus (LR) muscle (preducedthis risk.ConclusionNTSLR significantly improved primary position alignment altered by 3rd-nerve palsy. Concurrent SOT and placement of the split LR muscle ≤4.25 mm posterior to the MR muscle insertion optimised outcomes. NTSLR proved technically challenging when prior ipsilateral strabismus surgery had been performed.

Due to improvements in neonatal care of premature infants and the development of novel treatment options for retinopathy of prematurity (ROP), the requirements for screening for ROP have changed since publication of the last version of the German ROP screening guideline in 2008. Based on results of recent studies, the guideline has been extensively revised in 2020 and published in an updated version.This article summarizes the most important changes in the new guideline.The age limit for screening inclusion was lowered to a gestational age of below 31 weeks for infants without additional risk factors. The minimum duration of oxygen supplementation necessitating screening inclusion in preterm infants was increased to more than 5 days. Treatment for ROP in zone II can now be given at any stage 3 with plus disease, regardless of the number of clock hours affected. Criteria for the frequency and duration have been defined for follow-up examinations after anti-vascular endothelial growth factor (VEGF) treatment. The binding document for these and other new recommendations is the guideline itself.The guideline recommendations enable a reliable identification of infants at risk for ROP for screening inclusion and a timely detection of advanced disease stages for treatment initiation, thus preventing blindness from ROP.HINTERGRUND: Durch Verbesserungen in der neonatologischen Versorgung von Frühgeborenen und die Entwicklung neuer Behandlungsmöglichkeiten der Frühgeborenenretinopathie („retinopathy of prematurity“ [ROP]) haben sich die Anforderungen an das ROP-Screening seit der Veröffentlichung der letzten Fassung der deutschen Leitlinie zum ROP-Screening im Jahr 2008 verändert. Auf Grundlage aktueller Studiendaten wurde die Leitlinie in 2020 grundlegend überarbeitet und in einer aktualisierten Fassung veröffentlicht. ZIEL: Dieser Artikel fasst die wichtigsten Änderungen in der neuen Leitlinie zusammen.Die Altersgrenze für einen Screeningeinschluss wurde für Kinder ohne zusätzliche Risikofaktoren auf ein Gestationsalter von unter 31 Wochen gesenkt. Die Mindestdauer für eine Sauerstoffsupplementation, die einen Einschluss in das Screening bei Frühgeborenen erforderlich macht, wurde auf über 5 Tage angehoben. Eine Behandlung bei ROP in Zone II kann nun schon bei jedem Stadium 3 mit Plus-Symptomatik unabhängig von der Anzahl der betroffenen Uhrzeiten erfolgen. Für die Nachkontrollen nach Anti-VEGF („vascular endothelial growth factor“)-Therapie wurden Kriterien zur Frequenz und Dauer definiert. Das verbindliche Dokument für diese und weitere neue Empfehlungen ist die Leitlinie selber.Die Empfehlungen der Leitlinie ermöglichen eine zuverlässige Identifikation von Kindern mit ROP-Risiko für den Einschluss in das Screening und eine rechtzeitige Erkennung fortgeschrittener Krankheitsstadien für die Therapieeinleitung, um so Erblindung durch ROP zu verhindern.

Purpose High myopic patients may develop strabismus due to globe dislocation out of the normal extraocular muscle cone. Surgical correction of this strabismus type is possible by joining the superior and lateral rectus muscles without the need for a scleral suture called the Yokoyama procedure. Data from large patient samples and the evaluation of a potential effect of an additional medial rectus recession (MRR) have been lacking so far. Methods We pooled retrospective patient data of 14 departments of ophthalmology in Germany and Switzerland and analysed determinants of postoperative results using multivariable regression models. Results We included 133 patients (mean age: 59.7 ± 13.4 years, surgery between 2008 and 2017) with a mean preoperative esotropia (both Yokoyama with and without MRR) of 23.8°±4.6°. The angle of preoperative esotropia increased with age. The postoperative esotropia was 8.7° ± 9.9°, and six patients were overcorrected. While preoperative esotropia was highly associated with postoperative results, we found no association of additional MRR with any of our postoperative outcome measures. The Yokoyama procedure had a higher absolute effect in patients with higher preoperative esotropia. Conclusion Our study confirms the positive effect of the Yokoyama procedure on strabismus due to high myopia in large-scale real-world data. In some cases, MRR may be needed because of muscle contracture, although additional MRR statistically did not affect the postoperative outcome. In patients with bilateral high myopic strabismus, correction of both eyes seems beneficial. The effect size of the Yokoyama procedure appears to be mainly driven by preoperative esotropia.

Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C A (p.Tyr292*) and c.1407G A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.

Inherited retinal degenerations (IRDs) are usually progressive disorders that may be difficult to diagnose in early childhood and look different from more advanced stages. This chapter focusses on early phenotypes visible with currently available imaging techniques and describes the clinical course during the first two decades. It also emphasizes the importance of recognizing carrier signs in X-linked disease.

Ocular rosacea in children is a rare but often underdiagnosed condition. It is typically associated with chronic blepharoconjunctivitis, chalazia, corneal opacity and corneal neovascularization. The recommended treatment consists of topical (eyelid hygiene, steroids, cyclosporin, lubricants) and systemic (antibiotics e.g. erythromycin) measures. This case series of 8 children demonstrates the efficacy of local 1.5% azithromycin treatment together with eyelid hygiene in pediatric ocular rosacea. A further advantage of this topical treatment is that the required application of only twice daily for 3 days followed by 7 days without treatment is convenient and improves adherence to treatment.Die okuläre Rosazea im Kindesalter ist eine seltene, aber oft unterdiagnostizierte Erkrankung. Chronische Blepharokonjunktivitis, Chalazien, Hornhauttrübungen und -neovaskularisationen sind typische Befunde. Die empfohlene Therapie besteht aus topischen (Lidhygiene, Steroide, Ciclosporin, Benetzungsmittel) und systemischen (Antibiotika, z. B. Erythromycin) Maßnahmen. Unsere Fallserie von 8 Kindern belegt die Wirksamkeit der lokalen 1,5 % Azithromycin-Therapie kombiniert mit Lidhygiene bei kindlicher okulärer Rosazea. Ein weiterer Vorteil dieser topischen Therapie ist, dass sie nur 2‑mal täglich über 3 Tage mit anschließender Pause von 7 Tagen angewendet werden muss. Dies verbessert auch die Therapietreue.

The first ocular gene augmentation therapy, voretigene neparvovec (VN) (Luxturna®), has been approved for clinical use in an increasing number of countries (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Among the EVICR.net clinical centers, we conducted the first multinational survey to understand distribution, diagnostic work-up, and management of inherited retinal degeneration (IRD) cases in Europe with a special focus on RPE65 mutation-associated IRDs.An electronic survey questionnaire including 35 questions specifically addressing RPE65 mutation-associated IRDs was developed and sent to the 101 EVICR.net clinical centers.The overall response rate was 49%. Forty-two centers see IRD patients, and 22/42 follow patients with confirmed biallelic RPE65 mutations. Fifteen of the 22 centers (68%) and 3/22 (14%) follow 1-5 and 6-10 patients with homozygous RPE65 mutations, respectively. Additionally, 15/22 (68%) and 3/22 (14%) follow 1-5 and20 patients with compound heterozygous RPE65 mutations, respectively. Fifty-nine percent of mutations were ACMG Class 4 and 5 (at least 1 allele), 82.8% reported previously and 17.2% novel. Referral diagnoses (the mean per center) were Leber congenital amaurosis (38.2%), early-onset severe retinal degeneration (16.8%), rod-cone-dystrophy/retinitis pigmentosa (RP) (28.1%), and unclassified visual impairment (17.0%). Twenty-five percent of the centers changed the referral diagnosis in47.5% of cases; 32% follow a specific referral process for RPE65 mutation-associated IRD patients. Annual follow-up visits are done in 55% of the centers and biannual visits in 23%. In 32%, other centers also follow the patients. Kinetic perimetry is done in 82%, static perimetry in 45%, and microperimetry in 18% of the centers. Full-field light stimulus threshold testing with blue and red stimuli to quantify the rod and cone function is used in 6/22 centers (27%). A mobility course is available in one center (5%).This first multinational survey on management of patients with RPE65 mutation-associated IRDs in Europe shows that about half of the responding EVICR.net centers have such patients under care. There is heterogeneity in diagnoses and management practices. At the start of clinical practice experience with VN, these data provide a useful baseline and highlight the need for consensus/guidelines to inform standard of care in this new era of gene therapy.

Purpose: An increasing number of gene therapies are developed for Inherited Retinal Degenerations (IRD). To date, 1 treatment has been approved for clinical use (FDA USA 2017, EMA Europe 2018, MoHAP UAE 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, and BFR Brazil 2020). While such therapies do not provide complete cure, they may halt degeneration or partially restore function. Identification of well-characterized patients is an emerging need. We conducted the first multinational survey to understand the management of IRDs in Europe. Methods: An electronic survey questionnaire containing 112 questions was developed and sent to the 101 EVICR.net clinical centers (14 European countries and Israel). Results: The overall response rate was 49%. Only 14% of responding centers do not see IRD patients; 52% that manage IRD patients follow ≥200 patients, 16% > 1,000. Databases exist in 86% of the centers; of these, 75% are local files, 28% local Web-based database, and 19% national Web-based. IRD patients are referred to EVICR.net centers mainly by general ophthalmologists, patient self-referrals, and medical retina specialists. Most IRD patients are first seen in adulthood. Most prominent signs and symptoms depend on the age of onset, for example, nystagmus in infancy, or night blindness, and reduced visual acuity at older age. The time from inquiring for first appointment and clinical diagnosis varies among countries: in 29% of centers, the mean time is Conclusion: At the start of this era of ocular gene therapy for IRD patients, this first international survey on management of IRDs in Europe highlights significant heterogeneity between centers and across countries and provides important baseline data for researchers, clinicians, pharmaceutical companies, and investors.

Purpose Voretigene Neparvovec-rzyl (VN) is the first available treatment for biallelic RPE65 mutation-associated inherited retinal degeneration, which is usually associated with infancy-onset severe visual impairment and complete blindness during the third life decade. We aim to estimate the cost effectiveness of VN in Germany considering medication costs of €410,550 per eye and potential indirect cost offsets by higher labor force participation. Methods We developed an individual patient sampling model to simulate patients over their lifetime. In a Monte Carlo analysis, 1000 simulations are performed. Cycle length of the two-state Markov model is 1 year. For each cycle, visual field and best-corrected visual acuity are tracked, compared with natural progression and converted to quality of life. Direct and indirect costs are recorded and the incremental cost-utility ratio is calculated. Results In the base case scenario, VN provides 4.82 additional quality-adjusted life-years over a patient's lifetime at an incremental cost-utility ratio of €156,853 per additional quality-adjusted life-year gained. Sensitivity analyses show the robustness of the results when altering treatment effect duration, discounting of quality-adjusted life-years and costs, direct costs, and natural progression. Conclusions Under a lifetime perspective, VN proves to be cost effective for the German statutory health insurance system despite high initial treatment costs. Because VN has important implications for future gene therapies, cost-utility analyses have high economic relevance from a societal perspective. Translational Relevance Our research analyzes the value of a gene augmentation therapy in clinical care in terms of quality of life gains for patients with blindness from retinal degeneration.

The correction of anomalous head posture associated with infantile nystagmus syndrome (INS) is carried out by the Kestenbaum procedure (KP) combining bilateral horizontal yoke muscle recession with resection of their antagonists or by the Anderson procedure (AP) which is confined to yoke muscle recession alone.To compare the results of highly dosed AP and KP for anomalous head turn (HT).The AP (2013-2019) and KP (2003-2013) were used as the exclusive procedures during the respective time periods. A highly dosed AP was performed in a case series of 33 consecutive orthotropic patients with INS and KP in 19 orthotropic patients with INS. Medians and ranges (min-max) in groups AP/KP were: age at surgery 7 years (4-44 years)/6 years (4-27 years), HT 32.5° (20-45°)/30° (17-40°) and surgery on each eye AP 13 mm (10-16 mm) (standard dose), KP 10 mm (6-12 mm) + 10 mm (6-12 mm) (mean 0.6 mm/°HT).The HT was diminished to 10° (-3-20°)/10° (-7-20°) ca. 3 months after surgery. At the late visit (8-153 months), the residual HT was 10° (0-20°)/10° (-27-30°). The HT was reduced by 67% (20-100%)/64% (14-100%) at the last control. A residual HT ≤15° was present in 79%/81% of cases (91% after AP ≥13 mm; n = 23) and HT ≤10° in 55%/57%, (65% after AP ≥13 mm). The maximum adduction/abduction towards the recessed muscles was 30°/30° (10-37°/15-45°) after AP and 32°/30° (10-40°/12-45°) after KP. An associated head tilt was not improved by the intervention. Mean binocular visual acuity increased by1 line in both procedures. After AP the mean increase was 1 line in children ≤6 years old and there was no increase in patients6 years of age.The effectiveness and success rates of AP and KP were similar with the dosing used. Less invasive surgery is an advantage in favor of AP as the primary procedure.