Using a large cohort of patients with VHL disease, the present study provides a comprehensive longitudinal characterization of the ocular phenotype, visual function, and patient factors affecting disease progression. Here, the diagnosis of VHL disease in study participants was rigorously ascertained using multi-systemic clinical examination in all cases and confirmed by genetic analysis in nearly all cases. After diagnosis, participants were followed longitudinally with multi-systemic evaluations that were performed in a single research medical center, and the phenotype of ocular VHL disease was systematically collected and scored using a standardized grading system. To our knowledge, this is the largest longitudinally-followed cohort of patients with VHL disease to be described in the ophthalmic literature. The study data may be limited by the comparatively short duration of follow-up (8 years) relative to the expected lifespan of participants, and a potential bias towards an over-representation of participants with ocular symptoms during follow-up, despite the institution of regular ophthalmic examinations for all participants. Also, the total length of follow-up in individual patients was variable in this retrospective study and therefore entailed disadvantages of analysis compared to a prospective cohort study with uniform follow-up time. To provide additional time-specific progression data, we performed parallel analyses utilizing visit data at the 3- and 8-year time points following baseline. The rates for anatomical progression in these subsets demonstrated a similar stability for the majority of participants examined, corroborating the analyzed results for overall study follow-up.
In a smaller longitudinal study of 57 patients with ocular VHL disease by Kreusel et al.,20
seven of 33 participants (21.2%) progressed from unilateral to bilateral ocular involvement of VHL disease over a mean of 7.3 years of follow-up. Similarly, in another study of 103 participants by Dollfus et al.,14
approximately 28% of patients with unilateral disease at initial visit progressed to bilateral involvement by final visit over a mean of 8.4 years of follow-up. In the current study of 249 patients, we found a somewhat higher but comparable 33% rate of progression over a mean follow-up of 8.2 years. To our knowledge, no previous longitudinal study has commented on the de novo
development of ocular VHL disease in individual patients over follow-up.
Our results indicate that in general, eyes with ocular VHL disease and receiving regular treatment and follow-up are likely to remain phenotypically stable over the time scale of study follow-up. Despite this, anatomical progression in a small minority of eyes in this study was found to be marked, resulting in the overall disruption of the globe and vision loss. The data in the current study also provide a general profile for how visual function changes in a population of patients with VHL disease. A large proportion of the study population maintained its baseline level of visual acuity over study follow-up. While previous studies have also described decreases in visual acuity during follow-up in eyes with pre-existing ocular VHL disease,20
we had additionally compared this decrease relative to eyes without baseline ocular involvement, underscoring that despite general stability of ocular VHL disease, the impact of long-term ocular involvement is appreciable and likely cumulative. .
The data here revealed that the nature of anatomical progression during study follow-up can significantly influence visual function outcomes. The findings of this study indicate that eyes which either (1) develop new juxtapapillary RCHs, (2) develop RCHs in a new retinal location, or (3) increase in peripheral RCH number (from <3 to ≥3 peripheral RCHs) may be expected to be at greater risk of vision loss. This suggests that patients who undergo these patterns of anatomical progression may benefit from closer clinical follow-up and be counseled on the poorer visual prognosis associated with these anatomical progressions.
It is interesting that among the eyes progressing to new ocular involvement, those developing only new peripheral involvement maintained relatively stable mean visual acuity, and were comparable to eyes free of ocular VHL disease, in this regard. This likely indicates that peripheral RCHs which are newly emerging in the early course of disease, because of their distance from the macula, amenability to ablative treatment, and frequently non-exudative nature, may have a smaller impact on central vision compared to emerging juxtapapillary RCHs, which are more central and less amenable to treatment. Our results also indicate, however, that when RCH “load” increases in an affected eye, such as when peripheral RCH involvement increase in number or when peripheral RCHs emerge in combination with juxtapapillary tumors, affected eyes can progress more readily to vision loss.
The analysis was also able to highlight the contribution of patient factors (younger age of onset, younger baseline age, and presence of fellow eye involvement) to overall anatomical and functional progression. The age-dependent associations here indicate that pre-existing ocular VHL disease is more likely to progress during follow-up in a younger patient compared to an older one, resulting in a larger deterioration of visual acuity. Kreusel et al
had previously reported that a younger age of ocular disease onset was associated with poor vision (defined as Snellen VA ≤ 20/1000 / ETDRS 0.05). Dollfus et al
also reported that younger patients, aged 15–25 years, are in a critical age group for the development of hemangioblastomas. However, these associations were not apparent in a cross-sectional analysis performed by Webster et al.,23
in which the prevalence of ocular hemangioblastomatosis was not found to increase with age. Future investigations into age-dependent interactions with VHL gene function may further illuminate these observations, but no mechanisms are currently known.
Fellow-eye involvement as a risk factor for ocular VHL disease progression posits that particular systemic factors may play a role. In our analyses, factors such as smoking status, BMI, or sex did not significantly contribute. Involvement of VHL disease in other organ systems, which was not analyzed in this study, has been inconsistently associated with ocular disease severity; Allen et al
., found a correlation between the presence of VHL renal involvement and the severity of CNS involvement,24
while Dollfus et al
., were unable to detect a significant relation between ocular VHL involvement and the presence of other systemic VHL manifestations, including renal involvement.14
As previously described, the genotype of the germline VHL mutation to disease phenotype can be a contributory systemic factor.15, 16, 24–27
While logistic regression analyses in our dataset did not discover significant correlations between mutation genotype and progression rates in this study, Kaplan-Meier analyses, which estimate lifetime risk, associated deletion mutations in the VHL gene with a lower lifetime risk for ocular VHL disease. The mechanisms underlying these genotype-phenotype correlations remain an area of active investigation.28
In summary, these findings provide a longitudinal, comprehensive, and quantitative description of the natural history of ocular involvement of VHL disease. These findings provide data that can be helpful to practitioners to prognosticate the course of ocular VHL disease, to clinically manage affected patients, and to counsel patients and their families of the general functional impact of VHL disease. Associations between ocular and systemic factors and the risk of ocular VHL disease and progression may assist in segmenting patients into different risk categories for closer follow-up or aggressive management and may inform future investigations into the biology of ocular VHL disease.