Transient increased exudation after photodynamic therapy of intraocular tumors.

To report transient increased exudation after photodynamic therapy (PDT) of three different intraocular tumors (retinal hemangioblastoma, retinal astrocytoma, amelanotic choroidal melanoma). PDT with verteporfin (6 mg/m(2) body surface area) was delivered at a dose of 50 J/cm(2) and intensity of 600 mW/cm(2) over 83 s. All patients experienced decreased vision within a few days following PDT. Optical coherence tomography showed development of subfoveal fluid in all cases and noncystoid intraretinal edema in the eye with juxtapapillary retinal hemangioblastoma. There was complete absorption of retinal/subretinal fluid with improvement of visual acuity to 20/20 in all cases between 3 weeks to 4 months after PDT.

INTRODUCTION

Photodynamic therapy (PDT) is based on the interaction of light with a photosensitizer leading to release of cytotoxic singlet oxygen and resultant oxidative damage to the target tissue.1 The tumoricidal activity of PDT is caused by direct cell damage and microvascular injury.2–4 PDT has been used for the management of various intraocular tumors including circumscribed5–8 and diffuse choroidal hemangioma,5–9 choroidal melanoma,10–12 retinal hemangioblastoma,13–16 retinal vasoproliferative tumor,1718 and retinal astrocytoma.19–21 We describe the development of transient tumor vascular hyperpermeability with increased intraretinal/subretinal fluid following PDT of three different types of intraocular tumors (retinal hemangioblastoma, retinal astrocytoma, amelanotic choroidal melanoma).

Approval was obtained from institutional review board of Wills Eye Institute. Written informed consent was obtained from patients.

CASE REPORTS

Case 1

An asymptomatic 61-year-old female with a 1.5 mm juxtapapillary retinal hemangioblastoma OD showed progressive retinal edema despite three prior off-label intravitreal bevacizumab injections (1.5 mg) [Figures 1a and b]. PDT was delivered to the tumor, followed immediately by a fourth intravitreal bevacizumab injection (1.5 mg). One day after the procedure, the patient presented with a complaint of blurred vision. On examination, the best corrected visual acuity (BCVA) had decreased from 20/20 preoperatively to 20/70. Optical coherence tomography (OCT) showed extension of retinal edema into fovea [Figure 1c]. There was spontaneous recovery of BCVA to 20/25 and complete resolution of macular edema 3 weeks after PDT [Figure 1d]. Eight months after PDT BCVA was 20/20 but the patient complained of a persistent paracentral ring of haziness. The tumor remained stable with no recurrent intra- or subretinal fluid during subsequent follow-up of 3 years.

Figure 1

(a) Juxtapapillary retinal hemangioblastoma with adjacent lipid exudation. Note minimal lipid exudation in the papillomacular bundle region (b) Foveal contour is normal before photodynamic theraphy (PDT) (c) OCT performed 1 day after PDT shows retinal edema and subretinal fluid under the foveola (d) Three weeks after PDT there is complete reabsorption of intraretinal and subretinal fluid. There are a few focal intraretinal optically dense juxtafoveal deposits consistent with ophthalmoscopically visible lipid exudates

Case 2

A 17-year-old female with juxtafoveal retinal astrocytoma OD measuring 6 mm in diameter and 3 mm in thickness underwent successful standard fluence PDT with verteporfin (6 mg/m2; 689 nm diode laser; 600 mW/cm2; 83 s) for management of macular edema originating from the retinal tumor with improvement in BCVA from 20/70 to 20/30. Three years after PDT, BCVA decreased to 20/60 due to recurrent macular edema [Figures 2a and b] and she underwent a second standard fluence PDT with verteporfin. Two days after the second PDT, she noted decreased vision. On examination, the BCVA was 20/80 and OCT showed increased subretinal fluid at the fovea [Figure 2c]. Three weeks later BCVA improved to 20/60 and 4 months later best corrected visual acuity was 20/20 with complete resolution of macular edema and subfoveal fluid [Figure 2d]. The patient required two more sessions of PDT during the subsequent 3 years for management of recurrent macular edema.

Figure 2

(a) Partially pigmented retinal astrocytoma (needle biopsy proven) with lipid exudation at the superior, inferior, and nasal margins extending into the fovea, forming a foveal star (b) OCT before PDT reveals moderate intraretinal cystoid edema at the fovea (c) Three days after PDT there is increased subretinal fluid (d) Four months later, there is complete reabsorption of intraretinal and subretinal fluid leaving retinal atrophy

Case 3

A 62-year-old female with visual acuity of 20/20 and an enlarging amelanotic choroidal melanoma in her left eye (OS) measuring 7 mm in basal dimension and 2.7 mm in thickness [Figures 3a and b] was treated with PDT. Two days after PDT, the patient noted decreased vision OS and 11 days later, the best corrected visual acuity was measured at 20/200. OCT confirmed subretinal fluid extending from the treated melanoma into the foveal region [Figure 3c]. The vision improved without treatment 1 month after PDTand 3 months later there was complete resolution of subretinal fluid with visual acuity of 20/20 [Figure 3d]. Subsequent tumor growth required treatment with I-125 plaque radiation.

Figure 3

(a) Color fundus photograph showing small amelanotic choroidal melanoma with documented growth (b) OCT shows normal fovea before PDT (c) Eleven days after PDT, neurosensory retinal detachment extending under the fovea is evident (d) Three months after PDT, subretinal fluid has completely disappeared and foveal contour has returned to normal

DISCUSSION

Increased exudation has been reported following PDT of ocular conditions other than tumors, including choroidal neovascular membrane (CNVM) and polypoidal choroidal vasculopathy.22–25 Reports of increased leakage after PDT from intraocular tumors are limited to juxtapapillary retinal hemangioblastoma.1316 Possible mechanisms of post-PDT vascular hyper-permeability include direct damage to endothelial cells,26 retinal pigment epithelial damage and dysfunction,2728 or an angiogenic response induced by PDT.2930

A post-PDT increase in intraocular tumor leakage is an early phenomenon causing symptoms within a few days of PDT. In all three of our cases, the visual disturbance was transient with complete absorption of fluid and recovery of vision to pre-PDT levels within 1 month after PDT. Despite the transient nature of increased leakage post-PDT, prolonged presence of intraretinal or subretinal fluid or deposition of lipid exudate at the fovea could potentially lead to permanent structural damage and loss of vision. An example is the patient in Case 1 above who noted persistent paracentral field defects up to 8 months after complete absorption of fluid.

The use of off-label intravitreal bevacizumab injection immediately after PDT in our first case did not prevent development of increased retinal edema. It has been shown that increased vascular leakage starts as early as 5-10 min after PDT of rat cremaster muscle.3 Additionally some have proposed that application of anti-VEGF compounds before PDT may be more effective in blocking the effects of VEGF.30 Fingar and co-workers3 also found a direct relationship between dose of photosensitive material used (Photofrin; Pinnacle Biologics Inc., Bannockburn, IL, USA) and the severity of increased vascular leakage and were able to block post-PDT leakage by intra-arterial injection of indomethacin.

In summary, we report development of transient increased leakage causing increased retinal edema or subretinal fluid following PDT for different types of intraocular tumors (retinal hemangioblastoma, retinal astrocytoma, amelanotic choroidal melanoma). Further studies are needed to identify effective methods for prevention of this potentially vision-threatening complication.