Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Volume:
66
Journal Article
Peer reviewed
Open access
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Purpose
To investigate the long‐term outcomes of patients who underwent vitrectomy for proliferative diabetic retinopathy.
Methods
Cumulative incidences were calculated for low vision (<0.3), ...re‐vitrectomy in the study eye and fellow eye vitrectomy. To identify potential prognostic factors that associate with these outcomes, we used multivariable Cox regression models.
Results
In a total of 217 patients, we found 1‐, 5‐ and 10‐year cumulative incidences of low vision in the study eye of 24%, 31% and 39%, respectively. For both eyes, these rates were, respectively, 10%, 14% and 14%. Low vision in both eyes was associated with higher age and worse contralateral visual acuity. The 1‐, 5‐ and 10‐year cumulative incidences for re‐vitrectomy in the study eye were 16%, 27% and 27%, respectively, and for a vitrectomy in the fellow eye 24%, 40% and 54%, respectively. Re‐vitrectomy of the study eye was associated with worse contralateral visual acuity, while vitrectomy of the fellow eye was associated with shorter diabetes duration, worse contralateral visual acuity, higher HbA1c level and worse diabetic retinopathy severity stage of the fellow eye.
Conclusion
Functional visual acuity in at least one eye was achieved or preserved in most patients. After 10 years, about a quarter of all patients underwent a re‐vitrectomy, while more than half of the patients needed a vitrectomy of the fellow eye. Knowledge of these long‐term outcomes is essential when counselling patients for a vitrectomy.
Purpose
To describe clinical characteristics and management in a large cohort of patients with retinal detachment due to a giant retinal tear (GRT).
Methods
We performed a retrospective cohort study ...with 222 eyes of 206 patients with a primary and non‐traumatic GRTs between 2005 and 2022. We analysed the relevant clinical and surgical data from these patients.
Results
Eighty‐six per cent (n = 177) of patients were male. We observed no relation between refractive error and GRT size (Spearman's rho: r = −0.018, p = 0.83). We achieved a primary and final treatment success in 77%, respectively 92%, of eyes. The final visual outcome was 20/40 or better in 65% and 36% of eyes in fovea‐on and fovea‐off GRTs respectively. Thirty‐five per cent (n = 73) of patients developed a retinal detachment in the fellow eye. The median time until a retinal detachment in the fellow eye occurred after GRT was 20 months, and 10% developed within 1 month. A prediction model for the development of retinal detachment in the fellow eye resulted in a receiver operating characteristics curve with an area under the curve of 0.68 (95% CI: 0.57–0.78, p = 0.001).
Conclusion
We observed a highly significant gender imbalance in patients with a non‐traumatic GRT. One third of patients developed a retinal detachment bilaterally. Ten per cent of fellow eye's retinal detachment that develop after GRT, occur within 1 month. Clinical parameters showed limited predictive value for a retinal detachment in the fellow eye. These findings suggest an underlying genetic factor.
IMPORTANCE: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. OBJECTIVE: To identify the genes and pathways associated with ...idiopathic MFC. DESIGN, SETTING, AND PARTICIPANTS: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. MAIN OUTCOMES AND MEASURES: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. RESULTS: This study included a total of 4437 participants in cohort 1 (170 3.8% Dutch patients with idiopathic MFC and 4267 96.2% controls; mean SD age, 55 18 years; 2443 female 55%) and 1344 participants in cohort 2 (52 3.9% patients with MFC and 1292 96.1% controls; 737 male 55%). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio OR, 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10−9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10−8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H–related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10−3) and proteins involved in platelet activation and the complement cascade. CONCLUSIONS AND RELEVANCE: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.
Purpose
To evaluate the clinical course of idiopathic multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC) and the efficacy and safety of treatment options during pregnancy.
Methods
...Patients with MFC or PIC and a pregnancy in 2011–2019 from two academic centres were enrolled. For the most recent pregnancy, data on best‐corrected visual acuity (BCVA) before and after pregnancy, relapse rate in pregnancy and postpartum period and obstetric, maternal and neonatal outcomes were collected. Treatment regimens consisted of a wait‐and‐see regime and an immunosuppressive treatment regime with systemic corticosteroids and/or azathioprine, both combined with intravitreal antivascular endothelial growth factor injections when indicated.
Results
Sixteen women (26 affected eyes) were included. Median Snellen BCVA was 20/19 before pregnancy and 20/18 after delivery. In seven pregnancies a wait‐and‐see regime and in nine pregnancies an immunosuppressive treatment regime was carried out. Fourteen intravitreal anti‐VEGF injections were given in six pregnancies. The relapse rate during pregnancy was 44% and in the postpartum period 31%. Maternal/obstetrical and fetal complications occurred in 31% and 13% of the pregnancies, respectively. Fifteen healthy children were born and one pregnancy ended in a stillbirth in a patient with a complicated obstetrical history. One patient treated with azathioprine developed intrahepatic cholestasis of pregnancy (ICP).
Conclusions
Among women with MFC and PIC BCVA remained stable during pregnancy despite a relapse rate of 44% in pregnancy. No major maternal, obstetric and fetal complications occurred in pregnant patients treated with systemic corticosteroids, azathioprine or intravitreal anti‐VEGF injections, though one patient developed ICP while treated with azathioprine.
Purpose To investigate whether long-term protection from light exposure affects the rate of disease progression in patients with autosomal recessive Stargardt disease (STGD1), measured using fundus ...autofluorescence imaging. Design Longitudinal, retrospective, interventional case series. Methods Five patients with Stargardt disease protected 1 eye from light exposure by applying a black contact lens during waking hours for ≥12 months. Disease progression was followed by performing autofluorescence imaging at semi-regular intervals. Longitudinal changes in autofluorescence were studied by evaluating areas of decreased autofluorescence and areas of increased autofluorescence as a measure of retinal pigment epithelium damage and lipofuscin accumulation, respectively. Results We observed less progression of decreased autofluorescence in 4 out of 5 light-protected eyes relative to their respective nonprotected eyes. The progression of increased autofluorescence, on the other hand, was highly variable and did not respond consistently to treatment. Conclusions Areas of decreased autofluorescence may serve as a useful biomarker for measuring the progression of Stargardt disease. The reduced progression of decreased autofluorescence in the light-protected eyes suggests that light deprivation might be beneficial in patients with Stargardt disease.
To describe the phenotype and genotype of patients with early-onset Stargardt disease.
Retrospective cohort study.
Fifty-one Stargardt patients with age at onset ≤10 years.
We reviewed patient ...medical records for age at onset, medical history, initial symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ffERG). The ABCA4 gene was screened for mutations.
Age at onset, BCVA, fundus appearance, FAF, FA, SD-OCT, ffERG, and presence of ABCA4 mutations.
The mean age at onset was 7.2 years (range, 1-10). The median times to develop BCVA of 20/32, 20/80, 20/200, and 20/500 were 3, 5, 12, and 23 years, respectively. Initial ophthalmoscopy in 41 patients revealed either no abnormalities or foveal retinal pigment epithelium (RPE) changes in 10 and 9 patients, respectively; the other 22 patients had foveal atrophy, atrophic RPE lesions, and/or irregular yellow-white fundus flecks. On FA, there was a "dark choroid" in 21 out of 29 patients. In 14 out of 50 patients, foveal atrophy occurred before flecks developed. On FAF, there was centrifugal expansion of disseminated atrophic spots, which progressed to the eventual profound chorioretinal atrophy. Spectral-domain OCT revealed early photoreceptor damage followed by atrophy of the outer retina, RPE, and choroid. On ffERG in 26 patients, 15 had normal amplitudes, and 11 had reduced photopic and/or scotopic amplitudes at their first visit. We found no correlation between ffERG abnormalities and the rate of vision loss. Thirteen out of 25 patients had progressive ffERG abnormalities. Finally, genetic screening of 44 patients revealed ≥2 ABCA4 mutations in 37 patients and single heterozygous mutations in 7.
In early-onset Stargardt, initial ophthalmoscopy can reveal no abnormalities or minor retinal abnormalities. Yellow-white flecks can be preceded by foveal atrophy and may be visible only on FAF. Although ffERG is insufficient for predicting the rate of vision loss, abnormalities can develop. Over time, visual acuity declines rapidly in parallel with progressive retinal degeneration, resulting in profound chorioretinal atrophy. Thus, early-onset Stargardt lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.
Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. ...In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.
Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a ...pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression.
The Netherlands National Trial Register NTR2605.
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