Anterior chamber enhancement predicts optic nerve infiltration in retinoblastoma

Abstract

Objectives: As described recently, intravenously injected gadolinium-based contrast agent (GBCA) penetrates into the anterior eye chamber (AC) and is drained from the retina to the distal optic nerve (ON) along perivascular spaces, which serves retinal homeostasis and was termed the orbital glymphatic system (GS). Independently, AC enhancement predicted ON infiltration, a major risk factor for advanced retinoblastoma (RB), in a small RB patient cohort. We aimed to review the supposed imaging biomarker for ON infiltration in a large RB cohort and with respect to the recently described orbital GS.

Methods: This IRB-approved retrospective single-center study encompassed 539 orbital MRIs performed with an orbital coil and with the children under general anesthesia. Differences of signal intensity ratios (∆SIRs) of the AC to the lens were determined between non-contrast and GBCA-enhanced T1-weighted images and were correlated with histopathologic presence of ON infiltration.

Results: ∆SIR of the RB eye was an independent, significant predictor for ON invasion in multivariate analysis with adjustment for tumor size (p < 0.05) and increased with infiltration level.

Conclusions: GBCA enhancement of the AC predicts ON infiltration. This might be caused by impairment of the orbital glymphatic system, which is supposed to clear toxic metabolites from the retina to the postlaminar ON. In RB with ON infiltration, this efflux path is likely to be inhibited, which is supposed to result in disturbed retinal homeostasis, release of vascular endothelial growth factor, and iris neovascularization, which increases penetration of GBCA into the AC.

Key points: • Infiltration of the optic nerve can be predicted by anterior chamber enhancement after intravenous MRI contrast agent administration. • Increased anterior chamber enhancement in retinoblastoma with optic nerve infiltration might result from dysfunction of the orbital glymphatic system with disturbance of retinal homeostasis and consecutive iris neovascularization.

Keywords: Gadolinium; Glymphatic system; Magnetic resonance imaging; Optic nerve; Retinoblastoma.

Fig. 1

Flow chart with inclusion and exclusion criteria. Abbreviations: RB, retinoblastoma; GBCA, gadolinium-based contrast agent

Fig. 2

Example of orbital MRI of retinoblastoma with optic nerve infiltration. Sagittal (A, F) and axial fat-saturated (B, G) T1-weighted MRI post injection of a gadolinium-based contrast agent (GBCA). Axial T2-weighed (C, H) and axial native (D, I) as well as GBCA–enhanced (E, J) T1-weighted MRI. (A–E) Orbital MRI sequences of a right-sided retinoblastoma (RB) with prelaminar optic nerve (ON) infiltration in a 36-month-old boy. While the right anterior eye chamber (AC) shows GBCA enhancement (short arrow in B + E), the optic nerve does not show GBCA enhancement (long arrow in B + E). Subsequent enucleation and histological analysis revealed prelaminar ON infiltration. (F–J) Orbital MRI of a right-sided RB with postlaminar ON infiltration in a 40-month-old boy. Both the right AC and distal ON show pronounced GBCA enhancement (G, J, short and long arrow, respectively).

Fig. 3

A Comparison of histograms of anterior chamber (AC)-to-lens signal intensity ratios (SIRs) prior to and following gadolinium-based contrast agent (GBCA) injection in eyes harboring retinoblastoma (RB, n = 356). Mean post-injection time (± standard deviation) was 12:21 ± 2:36 min. Mean SIR post injection was significantly higher than prior to injection indicating GBCA penetration into the AC (p < 0.001). B Comparison of difference of AC-to-lens SIRs (∆SIRs) between healthy eyes (n = 183) and eyes affected by RB (n = 356). Mean ∆SIR of RB eyes was significantly higher compared to that of healthy eyes indicating increased GBCA accumulation in eyes with RB (p < 0.001)

Fig. 4

Boxplots of anterior chamber-to-lens signal intensity ratio differences (∆SIRs) depending on the optic infiltration level. The number of asterisks represent the level of significance (*p < 0.05, **p < 0.01, ***p < 0.001). A Differences of anterior chamber-to-lens signal intensity ratios (∆SIRs) were significantly higher in retinoblastoma (RB) eyes with infiltration of the optical nerve (n = 107) compared to absence of optic nerve infiltration (n = 94, p = 0.001), indicating gadolinium-based contrast agent (GBCA) enhancement in the anterior chamber (AC) dependent on optic infiltration status. B ∆SIRs increased gradually with degree of optic nerve infiltration. Even prelaminar infiltration showed a significantly greater ∆SIR compared to absence of ON infiltration (p = 0.03)

Fig. 5

Illustration of the orbital glymphatic theory. A, B Fluorescence imaging depicted orbital glymphatic flow from the retina to the postlaminar optic nerve (ON). Images were extracted from Wang et al [13] and show that intravitreally injected fluorescent-labeled human β-Amyloid (hAβ-647) is drained from the retina to the postlaminar ON via perivenous spaces (PVS) in rodents (A). Remarkably, tracer accumulated in the dural lining of the nerve as well as in cervical lymph nodes post injection (p.i.). Intraocular pressure remained constant during injection (B). C, D Schematic illustration of orbital glymphatic flow. The orbital glymphatic model comprises perivenous fluid and waste drainage (black arrows) from the retina (1) to the postlaminar ON (2) and subarachnoid space (SAS) surrounding the ON (3) driven by the intraocular-intracranial pressure difference (IOP, ICP). Drainage from the SAS is mediated by meningeal lymphatics in the dura mater (4). E, F Orbital gadolinium-based contrast agent (GBCA) distribution following intravenous injection. The here-shown images were obtained by a heavily T2-weighted fluid-attenuated inversion recovery sequence (hT2w) which is highly sensitive to GBCAs in fluids while suppressing tissue signal (E). Three hours post intravenous GBCA injection (F) enhancement of ocular structures (inter alia anterior chamber, white arrow) is accompanied by enhancement of the SAS surrounding the postlaminar ON (white arrowhead). This suggests that intravenous GBCA injection enables visualization of the orbital glymphatic flow

Fig. 6

Schematic depiction of hypothesis about correlation between anterior chamber (AC) enhancement and optic nerve (ON) infiltration in eyes affected by retinoblastoma (RB). Infiltration of the ON by RB (1) impedes perivenous glymphatic flow (black arrows) from the retina to the postlaminar ON. As the orbital glymphatic flow is supposed to serve fluid and waste clearance from the retina, its dysfunction might result in disturbance of retinal homeostasis, which triggers release of vascular endotheleal growth factor (VEGF, 2). Consecutive neovascularization of the iris (3) increases vessel permeability and penetration of gadolinium-based contrast agent into the AC (4)