Intravitreal Triamcinolone Acetonide in Von Hippel-Lindau Patient with Novel Mutation.

von Hippel-Lindau (VHL) is a multisystemic inherited disease which most commonly affects the retina and central nervous system. The hallmark retinal manifestation of VHL in the eye is retinal capillary hemangioblastoma (RCH). Significant visual morbidity can result from exudative retinal detachments (ERDs) or tractional retinal detachments. Here, we present a 21-year-old male with long-standing poor vision in the right eye. On examination, he was found to have a massive ERD in the right eye with multiple RCH in both eyes. Genetic testing revealed a heterozygous (c.390dupT) mutation in the VHL gene. Intravitreal triamcinolone acetonide injection resulted in subretinal fluid absorption and near total resolution of ERD. Retinal flattening made RCH accessible for laser photocoagulation. Following multiple focal lasers to the RCH, the lesions were regressed with the flat retina and stable vision. Copyright:

Introduction

von Hippel–Lindau (VHL) disease is an autosomal dominant disease which was found to arise from mutations in the VHL gene. Its manifestations are multisystematic, affecting the retina and central nervous system, as well as kidneys, pancreas, liver, and adrenal glands. The hallmark lesion in the eye is the retinal capillary hemangioblastoma (RCH), which appears as a round, circumscribed, orange-red vascular lesion, found in either the peripheral retina or the juxtapapillary retina.[1] Although not present in every VHL patient, the RCH constitutes one of the diagnostic criteria of clinically defined VHL disease.[2] RCHs can cause significant visual morbidity through the development of an exudative retinal detachment (ERD) or tractional retinal detachment (TRD). The mainstay of treatment of RCH includes focal laser and cryotherapy. Other modalities of treatment include photodynamic therapy (PDT) and antivascular endothelial growth factors (anti-VEGF). Here, we report favorable outcomes of intravitreal triamcinolone acetonide (IVTA) in ERD associated with VHL disease.

Case Report

A 21-year-old male presented to vitreoretinal services at King Khaled Eye Specialist Hospital with poor vision in the right eye for 9 months. Best-corrected visual acuity (BCVA) was light perception and 20/20 in the right and left eyes, respectively. Anterior segment examination was unremarkable in both eyes. Intraocular pressure (IOP) was 12 mmHg in both eyes. Fundus examination of the right eye revealed a subtotal ERD and multiple RCH with dilated tortuous feeding arteries and draining veins [Figure 1a]. Two RCH were found in the left eye at the optic disc and inferior retina [Figure 1b]. Fundus fluorescein angiography showed staining of the RCH with fluorescein pooling inferiorly in the area of ERD in the right eye and fluorescein staining of the two RCH lesions in the left eye [Figure 1c and d]. Spectral domain optical coherence tomography (SD-OCT) showed detached macular area right eye and normal retinal architecture in the left eye [Figure 1e and f]. Magnetic resonance imaging of the brain and orbit as well as abdominal computed tomography were unremarkable. Next generation sequencing for VHL gene revealed a novel heterozygous (c.390dupT) mutation which was confirmed by polymerase chain reaction and Sanger sequencing. 2 mg/0.05 ml IVTA was given to the right eye as well as focal laser to the inferior lesion in the left eye. Four weeks later, BCVA was improved to hand movement in the right eye with 16 mmHg IOP. Fundus examination revealed incomplete absorption of subretinal fluids, confluent exudation at the upper border of the ERD, and a clearer view of RCH so focal laser was done. Two months later, vision in the right eye improved to 2/200 with 15 mmHg IOP. Fundus examination showed flat retina and dispersed exudation superiorly in the mid-periphery [Figure 2a]. SD-OCT of the right eye showed flattened macular area [Figure 2b]. More focal laser was done in the right eye, and the patient was given close follow-ups.

Figure 1

Clinical and multimodal findings of a 21-year-old male with von Hippel–Lindau disease. (a) A fundus photo of the right eye showing a subtotal exudative retinal detachment and multiple retinal capillary hemangioblastoma with dilated tortuous feeding arteries and draining veins. (b) A fundus photo of the left eye showing two Retinochoroidal hemangioma (RCH) were found in the left eye at the optic disc and inferior retina. (c) A fundus fluorescein angiography of the right eye showing staining of the retinal capillary hemangioblastoma with pooling of fluorescein at the area of exudative retinal detachment. (d) A fundus fluorescein angiography of the left eye showing fluorescein staining at the 2 retinal capillary hemangioblastoma lesions. (e) A spectral domain optical coherence tomography of the right eye showing detached macular area. (f) A spectral domain optical coherence tomography of the left eye showing the normal retinal architecture

Figure 2

The effect of intravitreal triamcinolone acetonide on exudative retinal detachment in von Hippel–Lindau. (a) Flat retina and dispersed exudation superiorly in the mid-periphery. (b) A spectral domain optical coherence tomography showing the flattened macular area

Discussion

Diagnosis of VHL is based on positive family history of VHL disease with one associated tumor. In the absence of a definite family history, at least two RCHs or central nervous system hemangiomas, or one hemangioma plus one visceral tumor, establish the diagnosis.[3] Although it is an autosomal dominant disorder, around 20% of VHL patients manifest a de novo mutation.[4] Our patient had a novel heterozygous duplication of one base pair (c. 390dupT) which leads to a frameshift resulting in a stop codon (p. Asn131*) and mRNA degradation and truncation of protein. RCH are found in 49%–85% of VHL patients.[1] ERD occurs as a result of progressive leakage and exudation from capillaries with incompetent vascular wall.[1] Gaudric et al. reported the outcomes of 23 eyes of 21 patients with ERD or TRD in VHL patients, who had undergone vitrectomy, with or without retinectomy for tumor resection.[5] In the group which had retinectomy (9 eyes), an average of 2 surgeries was needed and long-term complications included RCH reproliferation and neovascular glaucoma in 4 eyes. In the remaining 5 eyes, visual acuity ranged from 20/320 to counting fingers. In the group without retinectomy (14 eyes), an average of 1.7 operations was needed. New RCH occurred in 10 eyes and required laser treatment. In the long term, 1 eye had an RCH reproliferation and neovascular glaucoma, and 2 eyes had recurrence of ERD. In the 11 remaining eyes, visual acuity ranged from 20/320 to 20/20. Intravitreal anti-VEGF injections were used in patients with VHL for treatment of juxtapapillary RCH or macular edema in combination with PDT with reported success.[6] The effect of anti-VEGF on ERD in VHL patients is yet to be determined. IVTA was used previously in two VHL cases, one for macular edema and one for ERD in combination with scleral buckling and external drainage.[78] In Coats disease, which causes ERD in a similar pathological manner to RCH, IVTA was found to achieve absorption of subretinal fluids and macular exudates.[910] Triamcinolone acetonide is an anti-inflammatory drug that reduces local cytokines as well as chemokines. In vivo, it was shown to cause reduction in the permeability of the outer blood–retinal barrier, resorption of exudation, and downregulation of inflammatory stimuli.[9]

• In our patient, IVTA was successfully used to achieve the absorption of subretinal fluid and the resolution of ERD. This effect which might be temporary was enhanced by multiple focal lasers of the RCH to achieve long-term regression of RCH. Although this approach can spare patients the need for surgical interventions and their complications, close follow-up is recommended to re-evaluate the need for further focal laser application.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.