VASOPROLIFERATIVE TUMORS IN INTERMEDIATE UVEITIS

Abstract

Purpose

To describe patients with intermediate uveitis complicated by vasoproliferative tumors (VPT).

Methods

Data were collected at seven Uveitis/Ocular Oncology centers on demographic, ophthalmic findings at baseline and at follow-up, and on imaging. The therapeutic intervention, final visual acuity, and duration of follow-up were recorded.

Results

A total of 36 eyes from 34 patients (12 males, 22 female; mean age 35.3 ± 14.2 years) were included in this study. Visual acuity at presentation ranged from 20/40 to counting fingers. At the time of VPT diagnosis, intermediate uveitis was active in all eyes. The mean VPT thickness was 3.06 ± 0.86 mm. Local treatment to the VPT was provide in 22 eyes (61.1%) and no local treatment to the VPT in 14 eyes (38.9%). After the VPT was detected systemic or local treatment for the inflammation was initiated and on follow-up FAs 94.4% of the eyes showed resolution of the vascular leakage. During follow-up of 35.8 months, the 22 VPTs treated locally had a reduction in the tumor thickness to 1.25 mm, while the 14 VPTs untreated remained stable (final mean tumor thickness 2.65 mm).

Conclusions

The presence of active intermediate uveitis accompanied by VPTs suggests the need for an aggressive uveitis treatment.

Summary statement

Control of inflammation is paramount in treatment of vasoproliferative tumors secondary to intermediate uveitis, associated or not with local tumor treatment.

INTRODUCTION

Intermediate uveitis is an idiopathic, insidious auto-inflammatory syndrome involving the pars plana, peripheral retina, underlying choroid, and anterior vitreous that usually affects children and young adults.¹ The clinical picture consists of vitritis with a relatively quiet anterior segment, pars plana inflammatory debris termed “snow-banking,” retinal periphlebitis, cystoid macular edema, and optic nerve edema.²

Retinal vasoproliferative tumors (VPT) have been reported as uncommon complications of intermediate uveitis.³ The histopathological description of intermediate uveitis-related VPT was first provided by Henkind and Morgan in 1966⁴, based on findings that they quoted as “Coat’s like” appearance in enucleated eyes with malignant glaucoma. In 1982 Baines et al⁴ reported a series of seven eyes with peripheral telangiectatic nodules, associated with posterior fibrocellular epiretinal membranes (7 eyes), complicated by bilateral uveitis (n=2). Similar lesions associated with other conditions including retinitis pigmentosa, Coats disease, previous retinal detachment repair, familial exudative vitreoretinopathy and retinopathy of prematurity have been reported.³

In 1983, Shields and coworkers⁵ described an unusual retinal vascular tumor in 12 eyes that produced exudative retinopathy and this tumor was termed “presumed acquired nonfamilial retinal hemangioma”.

In 1995 Shields et al⁵ reported on a larger cohort of 129 vascular tumors and coined the term “vasoproliferative tumor”. In that analysis, there were 29 VPTs classified as secondary to underlying disease, 8 of which were secondary to pars planitis. Suh et al⁶ documented an exudative “Coats-like” vascular response complicated by subretinal exudate in pars planitis.

Despite these early descriptive reports, the causative process underlying the development of VPT in eyes with pars planitis remains unknown primarily due to the lack of studies investigating a large population with detailed imaging of the involved eyes. Herein, we explore a series of 34 patients from 7 international centers with detailed imaging of VPTs and we speculate a pathogenic relationship of this long-standing inflammation to the vascular tumor.

METHODS

This was an IRB approved retrospective review of patients with intermediate uveitis. This study was approved by the Cleveland Clinic Abu Dhabi Institutional Review Board, complied with the Health Insurance Portability and Accountability Act of 1996, and followed the tenets of the Declaration of Helsinki. Diagnosis of intermediate uveitis was based on the characteristic clinical findings—namely a quiet or minimally reactive anterior chamber, cells in the anterior vitreous, and snowball opacities in the inferior vitreous. Patients with intermediate uveitis referred to 6 Uveitis Clinic and 1 Ocular Oncology Clinic over the 7-year period 2010 to 2017 were identified from each clinic’s electronic database, and those with VPT were included in this study. Clinical charts were reviewed and analyzed to identify the clinical characteristics and nature of the VPT, associated risk factors, and the course of the lesions. Demographic information including age and sex was collected. Ophthalmic findings, including best-corrected visual acuity (BCVA) at diagnosis and last follow-up, slit-lamp and dilated retinal examination findings, degree of vitritis, extent and location of snow-banking, presence of hard exudates, neovascularization, vitreous hemorrhage, and extent and nature of the VPT were recorded. The diagnosis of VPT was made upon clinical appearance by 90-diopters non-contact lens with slit-lamp microscopic examination and by indirect ophthalmoscopy with 20-diopters lens. When available, the findings of follow-up examinations were recorded to determine the natural course of VPT or their response to treatment.

Color fundus photography was obtained with a conventional 9-field fundus photography (Carl Zeiss Meditec, Dublin, CA) camera or with a wide-field fundus photography system (Optos Panoramic 200MA; Optos PLC, Dunfermline, Scotland, United Kingdom). Fluorescein angiography (FA) was performed with either a 9-field FA (Carl Zeiss Meditec, Dublin, CA; Spectralis HRA+OCT; Heidelberg Engineering) or with a wide-field system (Optos Panoramic 200MA; Optos PLC, Dunfermline, Scotland, United Kingdom). The SD-OCT acquisition protocol (Spectralis HRA OCT; Heidelberg Engineering, Heidelberg, Germany) varied according to the size and location of the VPT. Thirty-degree single-line scans (100 Automatic Real-time Tracking frames/B-scan), with and without enhanced depth imaging (EDI) function, encompassing the lesions were obtained in all the patients. In cases where the affected area was located at the posterior pole, 20° × 20° dense volume scans (25 ART frames/B-scan) were also obtained. Single 50° scans (100 ART frames/B-scan) were obtained when available.

B-scan ultrasonography was performed as an ancillary study, when appropriate, to to assess the internal echogenicity of the peripheral retinal elevations. The clinical course, therapeutic intervention, if necessary, final visual acuity, and duration of follow-up were recorded.

Statistical Analysis

When the data were normally distributed, independent t-test was used to compare groups. When the data were not normally distributed, the Mann–Whitney U test was used to compare the three groups. In cases of correlated data, paired t-test or Wilcoxon test was used depending on distribution of data. A P value of <0.01 was considered statistically significant. All the statistical analyses were performed using GraphPad InStat version 3.05 for Windows (GraphPad Software, San Diego, California, USA).

RESULTS

A total of 36 eyes from 34 patients were included in this study. Twelve patients were male and 22 were female. Mean age at onset was 35.3 ± 14.2 years (range 6 – 52 years). Three patients had tuberculosis with secondary intermediate uveitis, 1 had multiple sclerosis–associated intermediate uveitis, and the remaining 29 had idiopathic pars planitis. Visual acuity at presentation ranged from 20/40 to counting fingers (median, 20/80) in the affected eye, with a median of 20/80 if both eyes are affected. The mean follow-up interval was 35.8 months range (4-138 months) (Table 1).

Table 1.

Demographic information, ophthalmic findings, clinical characteristics and nature of the intermediate uveitis and the vasoproliferative tumors in our cohort.

						BASELINE				FINAL
	AGE	SEX	RACE	IU DIAGNOSIS	IU DURATION (months)	BCVA	VITRITIS	FA	VPT THICKNESS	FOLLOW UP	BCVA	FA	VPT TREATMENT	VPT THICKNESS
TREATED VPT
1	14	F	White	Idiopathic	6	20/60	3+	Leakage	3.00	6	20/30	Quiet	Laser, radio
2	25	M	White	Idiopathic	138	20/30	Trace	Leakage	3.30	138	20/25	Quiet	Cryo, radio	2.00
3	“	“	“	Idiopathic	138	20/25	Trace	Leakage	6.20	138	20/25	Quiet	Cryo, radio	1.90
4	39	M	White	Idiopathic	24	20/40	1+	Leakage	2.60	24	20/25	Quiet	Cryo	2.10
5	39	M	White	Idiopathic	4	20/40	1+	Leakage	3.40	4	20/25	Quiet	Cryo	3.20
6	“	“	“	Idiopathic	4	20/50	1+	Leakage	3.60	4	20/20	Quiet	Cryo	3.10
7	44	F	White	Idiopathic	36	20/80	2+	Leakage	1.80	36	20/40	Quiet	Cryo	1.20
8	17	F	Arab	Idiopathic	107	20/30	1+	Leakage	NA	48	20/25	Quiet	Laser	NA
9	52	F	Arab	Idiopathic	73	20/40	1+	Leakage	1.26	36	20/20	Quiet	Laser	NA
10	6	M	Indian	TB	28	20/30	2+	Leakage	NA	28	20/60	Quiet	Laser	NA
11	42	F	Indian	Idiopathic	84	CF	3+	Leakage	NA	84	20/30	Quiet	Laser	NA
12	46	F	White	Idiopathic	33	20/60	trace	Leakage	NA	13	20/20	Quiet	Cryo	NA
13	6	F	White	Idiopathic	36	20/80	0	Leakage	NA	36	20/400	Quiet	Laser	NA
14	49	F	White	Idiopathic	36	20/80	2+	Leakage	NA	8		Quiet	Laser	NA
15	37	M	White	Idiopathic	25	20/40	1+	Leakage	2.70	25	20/25	Quiet	Laser	1.80
16	25	F	Arab	Idiopathic	32	20/320	3+	Leakage	1.60	32	20/80	Quiet	Laser	0.90
17	44	F	Arab	Idiopathic	84	20/60	2+	Leakage	2.80	18	20/20	Quiet	Cryo	1.20
18	32	F	A.A.	Idiopathic	44	20/25	Trace	Leakage	4.10	44	20/25	Quiet	Cryo	2.30
19	19	M	White	Idiopathic	95	20/30	2+	Leakage	2.90	23	20/20	Quiet	Laser	1.80
20	21	F	White	Idiopathic	38	20/40	3+	Leakage	3.20	16	20/25	Quiet	Laser	1.70
21	49	M	Arab	Idiopathic	39	20/150	4+	Leakage	2.50	39	20/60	Quiet	Cryo	1.30
22	51	F	White	Idiopathic	24	20/100	3+	Leakage	3.30	24	20/30	Quiet	Cryo	1.80
UNTREATED VPT
1	25	F	White	Idiopathic	29	20/60	3+	Leakage	2.30	29	20/25	Quiet	None	1.70
2	42	F	Indian	TB	84	20/125	3+	Leakage	NA	84		Quiet	None	NA
3	32	M	White	Idiopathic	75	20/40	2+	Leakage	3.60	17	20/20	Quiet	None	3.10
4	28	F	Arab	Idiopathic	81	20/80	1+	Leakage	3.10	45	20/25	Quiet	None	2.90
5	23	F	Arab	MS	29	20/30	1+	Leakage	2.70	29	20/20	Quiet	None	2.80
6	40	M	White	Idiopathic	31	20/100	1+	Leakage	3.5	16	20/40	Quiet	None	2.70
7	32	M	Indian	Idiopathic	42	20/80	2+	Leakage	NA	25	20/50	Quiet	None	NA
8	62	F	White	Idiopathic	18	20/50	Trace	Leakage	NA	0			None	NA
9	28	F	Arab	Idiopathic	39	20/100	3+	Leakage	2.8	39	20/30	Quiet	None	2.50
10	48	F	White	Idiopathic	26	20/60	2+	Leakage	3.00	26	20/40	Quiet	None	2.90
11	51	M	A.A.	Idiopathic	53	20/50	1+	Leakage	2.70	18	20/25	Quiet	None	2.70
12	29	F	White	TB	21	20/60	2+	Leakage	2.40	21	20/20	Quiet	None	2.20
13	37	F	Arab	Idiopathic	28	20/80	3+	Leakage	3.30	28	20/25	Quiet	None	3.00
14	53	M	White	Idiopathic	29	20/200	1+	Leakage	NA	14	20/20	Quiet	None	NA

The VPTs were unilateral in 32/34 (93.7%) cases. On fundus photography and on indirect ophthalmoscopy the VPTs were located in the inferotemporal quadrant in 24 (66.6%), post-equatorially in 23 (63.9%) and between the equator and ora serrata in 13 (36.1%). Eight eyes had an isolated VPT (22.2%) without any structural complications, and 32 (88.9%) had a VPT complicated by a serous retinal detachment (Figure 1A and 1B), extensive inferior pars plana exudates with snowbanking in 16 eyes (44.4%) adjacent to the VPT, whereas 31 eyes (86.1%) had inferior snowballs over the tumor. Neovascularization of the vitreous base accompanied by vitreous hemorrhage occurred in one eye (Figure 2A). SD-OCT was available for 36 patients at baseline. There was no coexisting macular pathology in 14 eyes (38.8%) while 14 (38.8%) had cystoid macular edema, 4 (11.1%) had an epiretinal membrane and 4 (11.1%) had a combination of both.

Figure 1.

Panel A shows a color composite of the right eye of a patient with intermediate uveitis secondary to sarcoidosis, complicated by a VPT. The tumor is visible as a yellow mass with tangled vessels and is further complicated by an exudative retinal detachment, that on SD-OCT wide field is threatening the fovea (B). On fundus autofluorescence (C) the subretinal fluid is clearly visible along the inferior arcade as an area of faint hyperAF. Fluorescein angiography (D) of the mid-phases highlight the vascular nature of the tumor and shows a diffuse pattern of perivascular leakage in the mid to far periphery.

Figure 2.

A dense, recurrent vitreous hemorrhage, confirmed on ultrasound (A), precluded the retinal examination of a 26-year-old patient. She underwent pars plana vitrectomy, during which a VPT was identified as the source of the bleeding (B) and was treated with direct laser. At the 1-month follow-up appointment, retina examination revealed fibrotic vessels in the inferior periphery (C) and a fluorescein angiography confirmed diffuse vascular leakage (D). A comprehensive uveitis work-up showed a reactive QuantiferonTB GOLD: the patient was initiated on quadruple therapy for tuberculosis and mycophenolate mofetil to control the inflammation. At 4-months follow-up FA no leakage was detected (E).

At the time of VPT diagnosis, 8 patients (23.5%) had been treated with topical steroids only, 8 (23.5%) with a combination of topical/intravitreal/oral corticosteroids and 4 (11.8%) were on immunosuppressive therapy (2 mycophenolate mofetil and 2 methotrexate).

The intermediate uveitis was considered active in all eyes at the time of diagnosis of VPT, with active uveitis being defined as presence of vitritis and/or leakage on FA. Fluorescein angiography was available in all patients: 22 eyes had baseline 9-field FA (10 Carl Zeiss Meditec, Dublin, CA; 12 Spectralis HRA+OCT; Heidelberg Engineering), whereas 14 had wide-field FA at baseline, 2 with a contact wide-field lens (Spectralis HRA+OCT; Heidelberg Engineering) and 12 with Optos (Optos Panoramic 200MA or California; Optos PLC, Dunfermline, Scotland, United Kingdom). At baseline, 8 eyes (22.2%) had localized perivascular leakage in the inferotemporal periphery where the VPT was located and 28 eyes (77.8%) had diffuse perivascular leakage in a fern-like pattern on the 4 peripheral quadrants (Figure 3). The VPTs appeared hyperfluorescent in arterial (33 eyes, 92%), venous (34 eyes, 96%), and late (20 eyes, 56%) phases of the FA.

Figure 3.

Two peripheral retinal vasoproliferative tumors (A, C) in 2 patients with vascular leakage on fluorescein angiography (B, D). Patient A did not receive any direct treatment for the VPT, while the intermediate uveitis was controlled with mycophenolate mofetil 2g. Patient C received cryotherapy on the VPT along with subcutaneous adalimumab every 2 weeks to control the inflammation.

Ultrasound was available at baseline for 26 eyes (72.2%). The VPTs appeared ultrasonographically hyperechogenic in 100% of the cases with a mean tumor basal diameter of 5.71 ± 3.16 mm and mean tumor thickness of 3.06 ± 0.86 mm.

After the detection of the peripheral VPT, 22 eyes (61.1%; mean tumor thickness 3.13 ± 1.06 mm) received local treatment for the tumor, consisting of cryotherapy (8/22 eyes [36.4%], 2 of those progressing to plaque radiotherapy [9.1%]), argon laser photocoagulation (10 eyes [45.4%], 2/10 necessitating multiple sessions [9.1%]), intravitreal anti-VEGF (2/22 eyes [9.1%]) or a combination of cryotherapy and anti-VEGF (2/22 eyes [9.1%]). Fourteen eyes (38.9%; mean tumor thickness 2.94 ± 0.44 mm) did not receive any treatment directly for the VPT and the uveitis specialist concentrated on treating the underlying intermediate uveitis. Mean final BCVA for the 22 eyes that received direct VPT treatment was 20/50, while for the 14 eyes with untreated VPT was 20/30 (P = 0.1).

After the VPT was detected, 31 patients (91.2%) were treated with immunosuppressants (methotrexate 6, mycophenolate 9, azathioprine 6, cyclosporine A 4, adalimumab 6), 2 patient (5.9%) underwent multiple intravitreal steroid injections and a pars plana vitrectomy, 1 patient (2.9%) was treated with topical steroids alone. Systemic treatment for 3 patients with TB-associated intermediate uveitis consisted of isoniazid, rifampin, pyrazinamide, and ethambutol for a 2-month initiation phase followed by a 4-month consolidation phase with isoniazid and rifampin. One patient with intermediate uveitis secondary to MS was under taking systemic treatment as established by her neurologist.

All patients were followed with wide-field FA (4 with a contact lens on a spectralis device, 19 with Optos) or conventional 9-fields FA (13). On follow-up FAs, none of the eyes had an extension of the leakage area. In particular, 28 eyes (77.78%) showed a complete resolution of the perivascular leakage after the detection of the VPT and the initiation of an immunosuppressive therapy; 4 eyes (11.12%) had a regression of the diffuse leakage to a focal inflammation at a mean of 5 months from baseline; 2 (5.56%) eyes had a stable leakage pattern on follow-up FAs.

Thirty-six of 36 eyes (100%) with VPT had stable course without progression during follow-up. In particular, the 22 VPTs treated locally had an overall reduction in the mean tumor thickness of 1.25 mm, while the 14 VPTs untreated remained stable (final mean tumor thickness 2.65 mm). However, there was no statistically significant difference between the final follow-up size of tumors treated with direct targeting treatment and untreated tumors (P = 0.1).

At the last follow-up visit, the best-corrected visual acuity of our cohort varied from 20/20 to 20/200 (median, 20/40).

Case Examples

Case 1

A 38 year-old female patient was referred to the ocular immunology service of the Eye Clinic, Ospedali Riuniti of Ancona, Italy, for a chronic intermediate uveitis that was associated with a peripheral mass inferotemporally near the pars plana in her right eye. The vitreous showed a binocular indirect ophthalmoscopy (BIO) score of 1+ haze, while the periphery showed a yellowish mass raising from a snow bank surrounded by vitreous inflammatory snow balls. Tortuous fine retinal vessels were observed within the lesion with evident afferent and efferent vessels (Figure 4A). The FA demonstrated both blood retinal barrier impairment and signs of vasculitis associated with an hyperfluorescent mass with confirmed afferent and efferent vessels at the infero-temporal periphery of the retina (Figure 4B). A diagnosis of retinal vasoproliferative tumor secondary to a chronic intermediate uveitis was made. The patient was treated with an intravenous pulse of methylprednisolone at the dose of 1 g a day for 3 days, followed by 1 mg/Kg of oral prednisone in combination with oral mycophenolate mofetil (MMF) at the dose of 1 g twice a day. Oral corticosteroids were gradually tapered to a dose of less than 7.5 mg within 5 months. The patient also received four intravitreal injection of anti-vascular endothelial factor (VEGF) agent (Bevacizumab, AVASTIN^®, Genentech, Inc.) in her right eye monthly. At 6 months follow up the retinal tumor showed evident reduction of the vascular leakage without any sign of further growth in size. The lesion remained stable until the last follow up at 22 months (Figure 4C). The patient at that point was on systemic MMF at the dose of 1 g twice a day and 5 mg a day of oral prednisone.

Figure 4.

A yellowish mass (A) rising from a snow bank surrounded by snowballs (white arrows) was noted in a patient with chronic idiopathic intermediate uveitis. The VPT has fine, evident afferent and efferent vessels (black arrow head). Baseline fluorescein angiography (B) shows leakage from the VPT afferent (white arrow) and efferent (white arrow head). Late phase of the fluorescein angiography at 22 months of follow-up shows a reduction in the leakage from the VPT, with a vascular network that can be appreciated in the late phases.

Case 2

A 26-years-old Filipino woman presented with CF vision in her left eye due to recurrent vitreous hemorrhages from a horse-shoe tear with a bridging vessel (Figure 2A). She underwent 23-gauge pars plana vitrectomy to clear the posterior cavity and direct visualization of the retina revealed a temporal VPT with diffuse attenuation of the vessels in the inferior retina (Figure 2B). The VPT was treated with endolaser and the laser treatment was extended to the ischemic inferior periphery (Figure 2C). One month after the surgery the patient presented with a decrease in vision in the left eye to 20/80, 3+ cells in the anterior chamber and 2+ vitreous cells. Fluorescein angiography revealed diffuse vascular leakage in a fern-like patter (Figure 2D). An extensive laboratory work-up revealed a positive Quantiferon GOLD without lung involvement on chest CT. Despite clear evidence of active TB she was started on four drug anti-tuberculous treatment (ATT) (isoniazid, rifampicin, ethambutol and pyrazinamide) followed by anti-inflammatory treatment using oral prednisone 1 mg/kg and mycophenolate mofetil (1000mg bid). Three months later her BCVA in the left eye had improved to 20/15, anterior chamber and posterior cavity were completely cleared, and fluorescein angiography did not reveal any leakage. The VPT in the right eye continued to be inactive after the endolaser treatment.

DISCUSSION

Intermediate uveitis is an inflammatory syndrome predominantly affecting children and young adults.⁷ It can occur in otherwise healthy individuals or be secondary to systemic diseases such as TB or MS, and it affects both sexes typically with bilateral involvement. This clinical syndrome⁸ consists of vitritis with a relatively quiet anterior segment, pars plana inflammatory debris termed “snowbanking,” retinal periphlebitis, cystoid macular edema, and optic nerve edema. A number of complications have been described in chronic cases of intermediate uveitis⁹, including retinal detachment¹⁰, neovascularization, vitreous hemorrhage, and retinoschisis.¹¹ The presence of VPT, a vascularized mass of the neurosensory retina, has been documented in eyes with pars planitis.^3,6,10 The VPTs associated with pars planitis can be unilateral or bilateral, they develop in young adults who have a history of intermediate uveitis during their childhood, and are apparently related to the severity of the primary disease.

Suh et al⁶ documented an exudative “Coats-like” vascular response complicated by subretinal exudate in pars planitis. Felder and Brockhurst subsequently described five cases of peripheral retinal angioma in patients with pars planitis.¹²

Histological studies of VPTs showed a mix of vascular and glial proliferation, thus suggesting a reactive process of the retina, the retinal pigment epithelium, and the choroid in response to an intraocular insult, rather than neoplastic nature. ¹³ In VPTs secondary to intermediate uveitis, inflammation may represent the trigger ultimately resulting in complex cellular reactions involving a variety of cytokine- and angiogenesis-mediated retinal vascular changes secondary to the breakdown of the blood-retinal barrier, ultimately leading to an uncontrolled proliferation of fibrous tissue and angiogenesis.

Although VPT is a benign tumor, it can produce profound visual loss related to remote effects of the tumor, including macular exudation, cystoid macular edema, vitreous hemorrhage and epiretinal membrane.^14,16 Macular edema was found in 38.8% and epiretinal membrane, in 11.1%. Subretinal, intraretinal, and preretinal hemorrhages¹⁵ may also be observed in association with VPT.¹⁷ These are thought to occur due to the rupture of one of the neoplastic vessels, or due to alterations of the retinal vessels adjacent to the tumor. The hemorrhages can vary in severity from minor punctate intraretinal bleeding to severe vitreous haemorrhages, causing a significant reduction in visual acuity. In our series, severe vitreous hemorrhage requiring vitrectomy was seen in one eye.

In chronic intermediate uveitis, retinal vascular inflammation leads to retinal vascular incompetence, resulting in fluorescein leakage and vascular wall staining.¹⁸ The differentiation between active vascular leakage and persistent vascular leakage resulting from chronic damage to the inner blood–retinal barrier can be difficult in those with chronic inflammation. Furthermore, mild leakage could persist in a quite eye as a damaged blood vessel could leak for a long time after the active inflammation has resolved. Our results suggest that the presence of disease activity in the periphery demonstrated by wide-field angiography accompanied by a VPT should guide management decisions of patients with intermediate uveitis to prevent further progression of these complications.^19,20 The detection of a VPT in an intermediate uveitis patient with active FA leakage must suggest the need for a more aggressive form of treatment which, in our series, consisted of immunosuppressive agents.²¹ Approximately, all the patients achieving treatment success in our series after detection of the VPT had corticosteroid-sparing control of inflammation at final follow-up, regardless of treatment assignment.

The relative rarity of retinal VPT secondary to intermediate uveitis has resulted in a lack of an evidence-based consensus agreement on how best to treat these lesions. In our series, the 14 cases that did not received any specific treatment for the VPT did not show any progression over a mean of 30.6 months. This may suggest that the cessation of vascular leakage and of the angiogenic stimulus obtained through immunosuppression blocked the growth of the tumor without requiring any direct treatment. At the same time, none of those 14 untreated VPTs regressed simply with inflammation control.

Twenty-two cases of VPT were treated locally along with treatment for intermediate uveitis. The choice of tumor treatment depended on the entire clinical situation and included cryotherapy²²; laser photocoagulation²³; and intravitreal injection of agents that inhibit vascular endothelial growth factor^24,25 and irradiation.

When the VPT is primary and associated with a significant amount of exudate or detachment, then treatment is warranted. In secondary VPTs, such as in our series, direct treatment of the leaking telangiectatic retinal vessels resulted in cessation of the leakage and resorption of the associated detachment in 22 eyes. Surprisingly, even in eyes where the VPTs were not directly treated, control of the peripheral vascular leakage and inflammation contributed to a resolution of the exudative detachment.

At final follow-up visit, 61.1% cases demonstrated regression. In 16/22 (72.7%) eyes with intermediate uveitis and treated VPT, the regression was documented through serial ultrasonography, while in the remaining 6 eyes ultrasonography was not available (27.2%) and clinical features suggestive of tumor regression included reduction of tumor size and fibrotic changes, reduction/resolution of retinal exudation and subretinal fluid. The untreated VPTs (38.8%) did not show demonstrable regression at final follow-up but remained unchanged, not displaying any sign of growth.

The present study is limited by its retrospective and uncontrolled methodology and by the relatively small sample size. A referral bias likely exists in this study because patients seen in our tertiary care center are followed more closely than the general population of those intermediate uveitis, and the severity of the underlying disease process is likely to be associated with a higher frequency and severity of side effects from the disease and its treatment. The results reported might have been less strong had a general population sample been available, but it is not very likely that the pattern of response to treatment would have been qualitatively different. Strengths of the study are the large amount of follow-up time and the standardized methods of chart review at each clinical visit.

In conclusion, we report a series of 36 eyes of 32 patients, in whom intermediate uveitis was associated with VPTs, probably caused by uncontrolled proliferation of fibrous tissue and angiogenesis in the retina. Inflammation seems to play a significant role in the etiology of the glial proliferation of the tumors in eyes with intermediate uveitis.