More Number of Blood-brain barrier disruption sessions for CNS tumors tied to maculopathy: JAMA
Osmotic blood-brain barrier disruption (BBBD) therapy was first introduced in the early 1980s as a method to increase the penetration of chemotherapeutics into the central nervous system (CNS). The procedure involves intra-arterial injection of a warmed, hypertonic mannitol solution to disrupt the tight junctions of vascular endothelial cells that form the blood-brain barrier followed by intra-arterial or intravenous chemotherapy. Pigmentary maculopathy was first described in patients with primary CNS lymphoma treated with BBBD and chemotherapy in 1986.
The current study done by Simonett et al evaluated the rate of and potential risk factors for maculopathy development in patients with a variety of malignant CNS tumors treated with BBBD therapy. In addition, the study evaluated functional and structural changes in eyes with BBBD-associated maculopathy after the completion of systemic therapy.
In this retrospective case series, data from February 1, 2006, through December 31, 2019, were collected from patients treated with osmotic BBBD at a single tertiary referral center who had subsequent ophthalmic evaluation. Exposure included treatment with BBBD therapy for any malignant CNS tumor.
The BBBD procedure varied based on CNS tumor category and selected chemotherapeutics but followed a previously described general protocol. Briefly, patients received an intraarterial hypertonic mannitol infusion followed by systemic chemotherapy. Duration and number of treatments were variable and dependent on relevant study protocol, adverse effects, disease response, and tumor recurrences.
Electronic medical records of 283 patients treated with osmotic BBBD and chemotherapy for a CNS tumor were identified and reviewed. Of these patients, 68 had a documented ophthalmoscopic examination and/or retinal imaging after their BBBD therapy start date. Three patients were excluded because the presence of maculopathy was unable to be determined.
Diagnoses of CNS tumors included primary CNS lymphoma; glioma; pineal tumor; and others including primitive neuroectodermal tumors and metastatic tumors. Macular pigmentary changes or RPE atrophy were present in 32 patients (49.2%) and occurred in all CNS tumor categories. Of these 32 patients, 19 (59.4%) had at least 1 retinal imaging modality, 16 (50.0%) had color fundus photographs, 15 (46.9%) had OCT, and 4 (13%) had fluorescein angiography.
Maculopathy appearance was variable but predominantly involved the foveal and parafoveal regions. Morphologic patterns included (1) central RPE stippling, (2) reticular pigmentary changes, (3) parafoveal bull's-eye, and (4) parafoveal or subfoveal geographic atrophy. Fourteen of the 15 patients (93.3%) with maculopathy and OCT imaging had evidence of focal ellipsoid zone (EZ) disruption.
Geographic atrophy was observed in 8 eyes of 5 patients. These patients had a mean (SD) age of 59.3 (4.4 years) at first BBBD treatment and a mean (SD) of 36.6 (13.2) BBBD treatment sessions. Four had primary CNS lymphoma and 1 had a glioma. The median time from first BBBD treatment to first identification of geographic atrophy was 90.9months (range, 44.2- 131.8 months). Four of the 5 patients had OCT, which showed complete RPE and outer retinal atrophy (cRORA) in all cases and outer retinal tubulations along the edge of RPE atrophy in 3 cases.
Because systemic methotrexate was used ubiquitously and exclusively in patients with primary CNS lymphoma, high multicollinearity was found between systemic chemotherapy agent and CNS tumor diagnosis.The 2 most common systemic chemotherapy agents, methotrexate and carboplatin, were included.
The number of BBBD treatment sessions, but not age, sex, presence of intraocular lymphoma (all patients with intraocular lymphoma received some degree of intraocular chemotherapy), systemic chemotherapy agent, or CNS tumor category, was associated with maculopathy development (P = .001).
After completion of BBBD therapy, progressive enlargement of geographic atrophy occurred in 5 eyes of 3 patients, and choroidal neovascularization developed in 1 eye.
These results suggest that BBBD can be associated with late-onset and progressive RPE and outer retinal atrophy. Osmotic disruption of the blood-brain barrier, in combination with chemotherapy, has long been known to be associated with a pigmentary maculopathy in patients with primary CNS lymphoma.
In this series, 49.2% of patients who underwent BBBD therapy and ophthalmoscopic examination were found to have macular RPE changes.
A few findings suggest that direct disruption of the blood retinal barrier likely plays a key role in the origin of this maculopathy. First, there are many similarities in the development and function of the blood-brain and blood-retinal barriers, and hypertonic mannitol may disrupt the cellular tight junctions of both in similar ways. Second, episodes of subretinal fluid observed shortly after BBBD therapy suggest that there is transient disruption of RPE tight junctions. Third, the predominant clinical findings in these patients, including pigmentary changes and geographic atrophy, localize to the RPE, which is the cell layer responsible for the outer blood-retinal barrier.
On logistic regression analysis, the number of BBBD treatment sessions was the only statistically significant factor associated with maculopathy development. Although treatment plans varied by patient factors and CNS diagnosis, a common protocol included 2 BBBD treatment sessions per month for 12 months. Patients who underwent a higher number of treatment sessions typically have BBBD treatment restarted because of CNS malignant tumor recurrence. Overall, this finding suggests a dose-dependent association or toxicity threshold in regard to maculopathy development.
This study suggested that BBBD-associated maculopathy is not unique to primary CNS lymphoma; rather, it can be found in patients with a number of different malignant CNS tumors treated with BBBD therapy and chemotherapy.
The number of BBBD treatment sessions was associated with maculopathy development, whereas age, systemic chemotherapy agent, and CNS tumor type were not. Evolution of macular changes after completion of BBBD therapy was common.
Notably, geographic RPE atrophy was observed years after BBBD, which the present investigation suggests may progress after completion of systemic therapy. Of importance, BBBD can be a life and function-saving therapy. Rather, these findings may have implications for patient education and ophthalmic monitoring. Patients should undergo a baseline ophthalmic examination before the start of BBBD therapy, as well as yearly ophthalmic examinations during and after systemic treatment with retinal imaging if a pigmentary maculopathy or RPE atrophy is detected.
Source: Simonett et al; JAMA Ophthalmol. 2021;139(2):143-149
doi: 10.1001/jamaophthalmol.2020.5329
