In this pilot study, we determined associations between VEGF or IGF-1 levels at the time of surgery with macular thickening measured as central subfield thickness (CSF) by OCT at one month following uncomplicated phacoemulsification. We found that aqueous VEGF correlated positively with a clinically meaningful change in CSF (>11% of preoperative value), suggesting it may have predictive value in determining diabetic patients at risk for macular edema following cataract surgery. We included diabetic patients with and without CSME because both CME and CSME can lead to vision loss following cataract surgery, and there are common factors in the pathogenesis (for example, inflammatory cytokines). However, we also divided out patients with CSME in some of our analyses. In patients with retinopathy, we found greater mean aqueous VEGF levels at progressively more severe levels of retinopathy in accordance with other investigators27
. Patients with CSME had the highest mean aqueous VEGF levels, but these patients also all had severe NPDR or worse retinopathy. There were too few events in which a change in CSF >11% from baseline occurred in this pilot study to distinguish the influence of CSME or severity of retinopathy on the positive association with mean aqueous VEGF or other factors.
We chose to measure CSF at one month since previous investigators found CSF following cataract surgery to be greater at one month than at later time points7
, but we also evaluated those patients who were available for examination at 6 months. In a study from the Diabetic Retinopathy Clinical Research Network, baseline or preoperative CSF values were found to be important when analyzing postoperative values, specifically that a change in CSF of >11% of the preoperative measurement was clinically significant and outside the error of measurement present when using the Stratus OCT-325
. This study also found that there was better reproducibility in CSF than in foveal center point thickness measurements. In our study, no growth factor measurement (serum VEGF, aqueous VEGF, or IGF-1) was strongly correlated with mean postoperative CSF at 1 month. However, even though only 6 patients had a > 11% change from preoperative CSF at one month, aqueous VEGF was strongly associated with a change in CSF >11% from the preoperative value at one month.
A previous study found no correlation in aqueous VEGF and CSF at the time of cataract surgery in 17 patients with diabetes16
. This study also found no correlation in CSF and aqueous VEGF, both measured postoperatively, in 8 patients who had had an intravitreous injection of anti-VEGF antibody, bevacizumab, 2 months prior to cataract surgery to treat CSME. In these patients, aqueous VEGF was lower than in the 9 who had not had previous treatment with intravitreous bevacizumab. The study differed from ours in that we determined associations between preoperative aqueous VEGF levels and postoperative CSF at one and 6 months and analyzed clinically meaningful measurements of > 11% change in CSF25
. Few patients in our study had increases in CSF that were >11% of preoperative values. This finding may be because patients in our study had good glycemic control, and most had no or mild NPDR. Few had CSME and of those who did, all had had preoperative laser treatment. Also, no patients developed new onset CSME during the follow up period, and all cataract surgery was uncomplicated.
High inter-patient variability in growth factor measurements has been reported in other studies28,29,27,15
. To minimize variability in growth factor measurements, we strove to keep the time between collection of the sample and processing and storage at −80°C to within 2 hours of surgery. The mean serum VEGF in our study (283 pg/mL) was similar to studies in the oncology (mean values ranging from 240 to 327 pg/mL) and ophthalmology literature (mean 305 pg/mL). There is debate about whether serum or plasma samples should be obtained to measure circulating VEGF levels. Many studies in the oncology literature report serum VEGF values, because obtaining VEGF from the serum, rather than the plasma, includes that bound to platelets, whereas platelet-bound VEGF is underrepresented in plasma samples30,31,32
. Several of these studies concluded that serum provided more useful data after direct comparison with plasma measurements32,33
, whereas others disagreed and favored plasma measurements34
. In addition, in the ophthalmology literature, there is disagreement, but several studies35,36
reported serum measurements of VEGF as valuable in the management of diabetic retinopathy. Therefore, we chose to measure serum VEGF in order to capture both bound and unbound VEGF. We used commercially available ELISA kits with standard curves to determine VEGF and IGF-1 protein in serum or aqueous and these analyses were completed by the same masked laboratory technician. In future studies, it may be helpful to measure both plasma and serum levels. However, we found that aqueous VEGF measurements appeared to be of greater benefit than serum VEGF or IGF-1 measurements in our analyses.
In summary, our study found that aqueous VEGF was positively correlated with a clinically meaningful percent change in CSF (>11% from the preoperative measurement25
) at one month following cataract surgery in diabetic patients. Our study suggests that aqueous VEGF may lend predictive value when determining postoperative macular thickening in diabetic patients undergoing cataract surgery and may be a useful measure in future trials. Larger studies are recommended, particularly to dissect the potential value of aqueous VEGF and severity in retinopathy as predictors.