Delayed Gadolinium Leakage in Ocular Structures on Brain MR Imaging: Prevalence and Associated Factors

DISCUSSION

In our study, GLOS was demonstrated on MR imaging in 5.9% of patients imaged for a broad range of clinical indications. Its occurrence was not limited to patients with neurovascular conditions but was also seen in those with other various pathologies and even in patients without any identified abnormality of the brain and orbits on MR imaging. This expanded distribution of GLOS underscores the importance of considering it as a potential physiologic phenomenon in a diverse cohort of patients undergoing gadolinium-enhanced MR imaging.

Our findings showed that most (around 64%) GLOS occurred within 72 hours of prior IV GBCA administration, while 36% of GLOS occurred after the usual 72-hour time window. Univariable regression analysis revealed associations between GLOS and older age, lower eGFR, prior cataract surgery, and a shorter time interval from the initial gadolinium-enhanced MR imaging scan to the index brain MR imaging. In multivariable regression analysis, however, only lower eGFR levels and a shorter time interval from prior GBCA injection to the index brain MR imaging were identified as statistically significant independent predictors of GLOS, though the effect sizes were relatively small. The dose, frequency, and type of GBCAs administered had no impact on the occurrence of GLOS.

Distinct from the general diffusion of GBCAs into extravascular spaces seen commonly in patients with chronic renal disease,²² GLOS was recently recognized in a cohort of patients with stroke at the US National Institutes of Health.¹ Subsequent work on GLOS by other authors has mainly focused on strokes and TIAs, leading to the prevailing perception of GLOS as a manifestation of ischemic insult.^{1⇓⇓⇓⇓⇓-7} However, a recent study from a stroke unit showed that the occurrence of GLOS is not specific to stroke but rather possibly represents blood-retinal barrier dysfunction related to small-vessel disease.⁵ In our study, which included a heterogeneous group of different neurologic conditions not limited to patients with stroke, we observed the occurrence of GLOS in patients with other entities such as brain tumors, intracranial hemorrhage, infectious/inflammatory processes, post-intracranial aneurysm coiling, and even in those with normal brain MR imaging findings. Our findings are consistent with those in prior studies showing an association between GLOS and older age.^1,3,5 Additionally, we observed an association with lower eGFR, similar to findings of Galmiche at al,⁵ but we did not find any association with the dose of GBCA administered.

The 5.9% prevalence of GLOS in our study is much lower than the previously reported rates of 30%–76% in the setting of acute-onset permanent or reversible brain ischemia.^{1⇓-3,5⇓-7} Galmiche et al⁵ also sought to understand GLOS beyond stroke, reporting a prevalence of approximately 30% in their study subjects with proved ischemic stroke or TIA. In contrast, only 5.5% of our study subjects had ischemic stroke or TIA. Several factors may have contributed to our lower GLOS prevalence, including the extension of the time interval between the GBCA injection and the index brain MR imaging beyond 72 hours, the younger age of our patients, and fewer patients with impaired renal function. Other authors who reported a higher prevalence of GLOS reviewed MR imaging performed only within 24–72 hours after GBCA injection.^1,5 In our study, most documented GLOS (14/26, 53.8%) also manifested between 24 and 72 hours after GBCA administration. Furthermore, only 3.9% of our subjects had an eGFR between 30 and 60 mL/min/1.73 m², and none had an eGFR <30 mL/min/1.73 m², representing better renal function than found in the population included in previous studies. The interplay of a more heterogeneous, relatively younger, healthier population, at least from the renal function perspective, likely resulted in the low prevalence of GLOS in our study.

On the basis of our observations, we hypothesize that GLOS might represent the physiologic excretion of GBCAs into the ocular globes via the blood-aqueous barrier, with accumulation in the vitreous chamber, which was captured at a specific time delay after GBCA injection. A recent study using delayed heavily T2-weighted and fat-suppressed FLAIR at 3 and 24 hours post-GBCA injection demonstrated physiologic excretion of GBCA into the aqueous chamber of the eye via the ciliary body even in patients without blood-brain barrier disruption or renal impairment. Excreted GBCA was observed to migrate from the aqueous chambers and accumulate in the vitreous chambers.¹⁴ Similar increased signal intensity in the aqueous chamber after GBCA administration with subsequent migration to the vitreous chamber has also been shown in healthy infantile eyes and healthy controls.^10,13 Most interesting, in previous studies evaluating GLOS in patients with stroke, isolated aqueous chamber involvement was more commonly seen on scans with shorter time intervals between the initial and follow-up MR imaging,^1,2 possibly, to some extent, also related to this physiologic pathway. We found evidence of GLOS in 4/26 (15.4%) patients with normal MR imaging findings of the brain and orbits, only one of whom had impaired renal function. In addition, while GLOS was significantly associated with a lower eGFR in our study, many patients positive for GLOS on MR imaging did not have marked renal impairment. These findings indicate that GLOS may be a form of physiologic distribution or excretion of GBCA in the eye, particularly in the absence of any identifiable medical cause to explain its occurrences.

Although prior cataract surgery and age were found to be statistically associated with the presence of GLOS on univariable regression analysis, no statistical significance was noted when controlling for eGFR levels. While ocular enhancement on the postcontrast FLAIR sequence after ocular surgery has been previously demonstrated²³ and it is known that blood-ocular barrier dysregulation may persist even several years after cataract surgery,^24,25 there has been no previous study showing a direct association of prior cataract surgery with GLOS, to the best of our knowledge. In addition, several studies have also demonstrated GLOS in various ophthalmologic pathologies involving the anterior and posterior eye compartments, including optic neuritis.^{9⇓⇓-12,23} Therefore, locoregional alterations in the structural and functional integrity of the blood-aqueous and blood-retinal barriers from ocular diseases and postsurgical causes should be considered in the differential diagnosis and overall assessment of GLOS.

Our study has 3 main areas of strength. First, our retrospective study is one of the largest clinical investigations on GLOS and is also among the few conducted on a heterogeneous group of patients not limited to those having neurovascular conditions, representing a real-world clinical setting. Second, we also report 2 potential independent predictors of GLOS (lower renal functional status and short time interval from GBCA injection to index brain MR imaging). Last, we report the occurrence of GLOS beyond the previously reported usual 72-hour time window post-GBCA administration.^1,5 Delayed physiologic excretion might account for the occurrence of GLOS later during the first week in more than one-third of the patients who were positive for GLOS.

Our study has some limitations as well. First, this study is a single-center retrospective observational study in a heterogeneous population with a relatively small number of patients with GLOS. Larger prospective studies are needed to validate our findings and gain a more comprehensive understanding of the GLOS incidence and risk factors and to evaluate the impact of ophthalmologic disease on GLOS. On the basis of our study, the association between ocular diseases and the occurrence of GLOS also cannot be determined. Next, exclusion of patients with an eGFR of <30 mL/min/1.73m² as per our institutional protocol during the period of data collection precludes evaluation of this cohort. Regarding our available index MR imaging studies, when performed with gadolinium, they included a 2D FLAIR sequence acquired concurrently with GBCA injection, which could potentially affect our results. While GLOS has been found to occur as early as 12–20 minutes post-GBCA injection, however, this occurrence was documented in infantile eyes with immature blood-aqueous barriers or with a heavily T2-weighted FLAIR sequence, which is more sensitive to GBCA compared with a routine 2D FLAIR sequence.¹⁰ In addition, our imaging studies were performed at 1.5T, did not have fat suppression on FLAIR imaging, and used 2D FLAIR sequences with 5-mm section thicknesses, which could limit our ability to detect GLOS. Finally, our retrospective data derived from a routine MR imaging database precludes direct comparison with prospective data obtained with dedicated orbit surface coils and/or a heavily T2-weighted FLAIR sequence, and our rate of subjects positive for GLOS might have been understated. Despite these limitations, our study contributes data regarding the prevalence, predictors, and distribution of GLOS in patients undergoing brain MR imaging for various clinical indications.