Retinal hamartomas respond to everolimus treatment for tuberous sclerosis: A photo essay

Abstract

Background: Tuberous sclerosis is characterized by hamartomas in multiple organs including retinal hamartomas. Everolimus is a novel treatment for tuberous sclerosis-related lesions. We present a case where everolimus led to lesion shrinkage, the skin tuberomas, as well as the retinal hamartomas, indicating that its effect can be detected, measured, and monitored with an ocular examination.

Case Report: We describe a 24-year-old female diagnosed with tuberous sclerosis since birth, with multiorgan involvement. The patients had multiorgan involvement, with angiolipomas of the kidney resistant to treatment. She also underwent subependymal giant cell astrocytoma brain tumor resection. The patient was treated with everolimus after recurrent embolization failed to shrink the renal angiolipomas. The tumors responded well to treatment.

Conclusions: Skin lesions disappeared, and fundus photos and repeat retinal optical coherence tomography measurements documented shrinkage of the retinal hamartomas during the 24 months of treatment. We conclude that a simple eye examination can monitor treatment effectiveness.

Background

Tuberous sclerosis is a systemic disorder characterized by hamartomas in multiple organs.^[1] Retinal hamartomas are one of its manifestations. Everolimus (mammalian target of rapamycin [mTOR] inhibitor) is a new treatment modality for tuberous sclerosis-related lesions, indicated for the treatment of subependymal giant cell astrocytomas (SEGA) or renal angiomyolipomas.^[2] The mutations underlying tuberous sclerosis are TSC1 or TSC2, resulting in activation of mTOR which promotes cell proliferation.^[1] Therefore, mTOR inhibition, as everolimus, is the rationale for treating these patients.

Although retinal hamartomas in patients with tuberous sclerosis are usually stable and are not vision threatening, some hamartomas may progress. In the past, laser treatment was presented as a treatment option, with limited success.

Treatment with sirolimus was shown to reduce retinal hamartomas in a series of seven patients,^[3] and a recent publication also showed retinal astrocytoma regression in response to everolimus.^[4]

The aim of this report is to show an easy non-interventional method of monitoring response to treatment, using repeated eye examinations and optical coherence tomography (OCT) measurements of retinal hamartomas.

Case Report

We describe a 24-year-old female diagnosed with tuberous sclerosis since birth, with multiorgan involvement, including rhabdomyoma of the heart, SEGA that was successfully resected, and angiolipomas of the kidney. Ocular history included hyperopic anisometropia amblyopia, operated residual esotropia, and retinal hamartomas [Figure 1].

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Genetic analysis revealed a mutation p.ARG759 c.2275A-Twhich was absent in both parents. The patient was treated witheverolimus after recurrent embolization failed to shrink therenal angiolipomas (lesion size over 3 cm is an indication fortreatment). The dosage was started at 2.5 mg and was graduallyincreased to 12 mg. Repeat ophthalmological examinationshowed stable visual acuity of 20/30 and 20/40 with normaloptic nerve function.

Fundus photos and repeat retinal OCT measurementsdocumented shrinkage of the hamartomas during the 24 monthsof treatment [Figure 2].

Discussion and Conclusions

Herein, we describe the response to the treatment of retinalhamartomas in a patient diagnosed with tuberous sclerosis,showing multiorgan involvement.

The novelty of our observation is that although treatment wastargeted at the renal angiomyolipoma, everolimus also led to asignificant shrinkage of face tuberomas and the retinal astrocyticlesions shown clearly on OCT. We hypothesize that there maybe a correlation between the regression of these lesions and theregression of lesions in other organs such as brain or kidney.

Furthermore, the visual fundus examination, which is knownfor detecting retinal hamartomas since 2006, and relativelyavailable measurements using OCT may be valuable tools formonitoring treatment efficacy. We encourage the collaborationof multidisciplinary clinicians to monitor Tuberous sclerosis(TS) patients with internal organs involvement, using funduseye examination and OCT.

References

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis.Lancet 2008;372:657-68.

Sasongko TH, Ismail NF, Zabidi-Hussin Z. Rapamycin andrapalogs for tuberous sclerosis complex. Cochrane DatabaseSyst Rev 2016;7:CD011272.

Zhang ZQ, Shen C, Long Q, Yang ZK, Dai RP, Wang J, et al.Sirolimus for retinal astrocytic hamartoma associated withtuberous sclerosis complex. Ophthalmology 2015;122:1947-9.

Zipori AB, Tehrani NN, Ali A. Retinal astrocytoma regressionin tuberous sclerosis patients treated with everolimus. J AAPOS2018;22:76-9.