PURPOSE

To investigate the longitudinal progression, risk factors, and complications associated with retinal hemangioblastomas (RHs) in nonadvanced stages of von Hippel-Lindau (VHL) syndrome using ultra-widefield (UWF) imaging.

DESIGN

Single-center longitudinal cohort study.

SUBJECTS

Caucasian patients with genetically confirmed VHL syndrome.

METHODS

Annual evaluations included dilated fundus examinations, UWF pseudocolor fundus retinal images, UWF fluorescein angiography, and OCT. Genetic analysis classified VHL mutations. Baseline RH counts and anatomical distributions were recorded as central (juxtapapillary, macular), peripheral, or both. Longitudinal follow-up tracked new RH formation and visual acuity (VA) values.

MAIN OUTCOME MEASURES

Cumulative incidence, incidence rate ratios (IRRs), and risk factors of new RHs assessed using mixed-effects negative binomial regression models. Hazard of recurrent RHs evaluated through Cox frailty models and longitudinal changes in VA.

RESULTS

Among 78 eyes of 43 patients (mean age: 47.8 ± 13.6 years), 110 RHs were documented at baseline, with 3 (3%) centrally located, 35 (32%) peripherally, and 72 (65%) spanning both zones. von Hippel-Lindau variants were investigated in 37 patients: 19 had missense variants (51%), and 18 had presumed null alleles (49%), including nonsense (10 of 37; 27%), frameshift (1 of 37; 3%), splice site (1 of 37; 3%), and exon deletion mutations (6 of 37; 16%). Over a median follow-up of 31 months (interquartile range: 27-109), 35 (43%) eyes developed new RHs, with an incidence rate of 0.22 RHs per eye-year (95% confidence interval: 0.17-0.27). By the last available examination, 26 eyes (34%) remained disease-free, whereas17 (23%) showed no progression of existing RHs. Age reduced the IRR of new RHs by 4.2% annually ( = 0.003), whereas higher baseline tumor burden and vascular leakage increased the IRR significantly ( < 0.001 and = 0.03, respectively). Peripheral RHs were the strongest predictor of recurrence (hazard ratio = 16.4, < 0.001), whereas older age remained protective (hazard ratio = 0.96, = 0.04). Visual acuity (logarithm of the minimum angle of resolution) worsened from 0.05 ± 0.2 (Snellen equivalent: 20/22) at baseline to 0.11 ± 0.3 (Snellen equivalent: 20/25) at the final visit.

CONCLUSIONS

Peripheral RHs and vascular leakage are significant risk factors for RH progression and recurrence in VHL syndrome. Although older age provides a protective effect, close monitoring of high-risk eyes is essential to enable timely intervention and preserve vision.

FINANCIAL DISCLOSURES

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.