Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Von Hippel-Lindau Syndrome Phenotype With Prominent Vitreoretinal Neovascularization Treated With Early PPV: A Case Series and Literature Review

Talhah Zubair, AB; Natalia F. Callaway, MD, MS; Cassie Ann Ludwig, MD; Peter H. Tang, MD, PhD; Ryan A. Shields, MD; Marco H. Ji, MD; Daniel Vail, BA; Matthew A. Powers, MD, MBA; Darius M. Moshfeghi, MD

Abstract

BACKGROUND AND OBJECTIVE:

To describe a case series of three patients in one family with Von Hippel-Lindau (VHL) disease who presented with vitreoretinal neovascularization and resulting tractional retinal detachments (TRDs). This vitreoretinal phenotype of VHL may benefit from early surgical intervention.

PATIENTS AND METHODS:

Descriptive case series of three patients in one family with VHL disease. A review of the literature regarding surgical intervention for VHL was performed.

RESULTS:

All three patients developed prominent intravitreal neovascularization with fibrovascular growth within the vitreous secondary to a retinal capillary hemangioma. Two subjects with intravitreal neovascularization were treated with laser and cryotherapy but eventually developed a TRD. The final vision in these two patients was light perception and 20/300. The eye that was preemptively treated with vitrectomy to remove the vitreous sustaining the neovascularization had visual acuity of 20/50 after surgery.

CONCLUSION:

Intravitreal neovascularization with fibrovascular proliferation may be an indication for vitrectomy prior to the development of retinal detachment.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:109–115.]

Abstract

BACKGROUND AND OBJECTIVE:

To describe a case series of three patients in one family with Von Hippel-Lindau (VHL) disease who presented with vitreoretinal neovascularization and resulting tractional retinal detachments (TRDs). This vitreoretinal phenotype of VHL may benefit from early surgical intervention.

PATIENTS AND METHODS:

Descriptive case series of three patients in one family with VHL disease. A review of the literature regarding surgical intervention for VHL was performed.

RESULTS:

All three patients developed prominent intravitreal neovascularization with fibrovascular growth within the vitreous secondary to a retinal capillary hemangioma. Two subjects with intravitreal neovascularization were treated with laser and cryotherapy but eventually developed a TRD. The final vision in these two patients was light perception and 20/300. The eye that was preemptively treated with vitrectomy to remove the vitreous sustaining the neovascularization had visual acuity of 20/50 after surgery.

CONCLUSION:

Intravitreal neovascularization with fibrovascular proliferation may be an indication for vitrectomy prior to the development of retinal detachment.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:109–115.]

Introduction

Retinal capillary hemangiomas (RCHs) are the earliest and most common presenting manifestation of Von Hippel-Lindau (VHL) disease.1,2 Although small RCHs can remain asymptomatic for years or even regress, most continue to progress.3 Left untreated, these benign tumors often cause secondary effects including subretinal exudates, fibrovascular proliferation, and serous and tractional retinal detachment (RD), and this can ultimately result in permanent vision loss.4

Various interventions have been attempted to treat large RCHs, defined as greater than 2 disc diameters (DD) in size.7–13 Anti-vascular endothelial growth factor (VEGF) agents have failed to show stable regression of large RCHs.7 Brachytherapy, external beam therapy, transpupillary thermotherapy, and photodynamic therapy (PDT) have all been used to treat large RCHs with marginal success.8–13 Traditionally, the final resort for large treatment-resistant RCHs or those evolving to RD is surgical intervention. Outcomes are often poor, and the timing of surgery is often at the discretion of the treatment physician.

Here we describe a series of three VHL patients within a single family with a unique clinical phenotype of VHL demonstrating as significant intravitreal neovascularization and fibrovascular proliferation. Two of these patients elected to be observed until they developed RDs, with poor visual outcomes. One patient underwent early pars plana vitrectomy (PPV) and was able to maintain moderate visual acuity (VA) until she declined further treatment. We review the literature for the timing of surgical intervention for VHL-associated RCH and further describe this unique phenotype of VHL.

Patients and Methods

Herein we present one family with genetically confirmed VHL with four members treated at Byers Eye Institute. Two of the patients are sisters (II-2 and II-3) and the third (III-1) is the daughter of the older sister (II-2) (Figure 1). The maternal grandmother (I-2) has a lesion on the right optic nerve with lipid maculopathy but no vitreous involvement. Patients were treated to our management for VHL-associated RCHs. Informed consent was obtained from all patients. All work was conducted in compliance with Health Insurance Portability and Accountability Act regulations and human rights research in accordance with the tenets of the Declaration of Helsinki.

This pedigree shows the family reported in this case series. At the time of publication, patient II-2 is 40 years old, patient II-3 is 36 years old, and patient III-1 is 19 years old. The mother (I-2) of patients II-2 and II-3 is known to have Von Hippel-Lindau but was never treated in our clinic.

Figure 1.

This pedigree shows the family reported in this case series. At the time of publication, patient II-2 is 40 years old, patient II-3 is 36 years old, and patient III-1 is 19 years old. The mother (I-2) of patients II-2 and II-3 is known to have Von Hippel-Lindau but was never treated in our clinic.

Clinical management was complicated by the family's decision to involve the senior author (DMM) as the lead physician, with one local vitreoretinal surgeon in constant consultation and numerous non-local academic vitreoretinal surgeons opining and consulting on the cases. Our senior author counseled early and aggressive intervention at the first sign of intravitreal neovascularization, whereas others were urging observation despite continued vitreous involvement.

Case 1 (Patient II-3)

Patient II-3 was diagnosed with VHL disease at age 18 after her mother and sister were both diagnosed. A screening MRI showed evidence of multiple small hemangioblastomas in her cerebellum, pituitary, and cervical spinal cord. At that time, a complete ophthalmologic examination was negative. In subsequent years, she received numerous treatments for complications from VHL disease but did not develop any ocular manifestations of VHL until age 29.

Left Eye: From ages 29 to 33, patient II-3 developed recurring and persistent bilateral RCHs that were initially managed with laser photocoagulation and PDT. Due to the histories of tractional RDs in her sister (II-2) and niece (III-1) following the development of intravitreal neovascularization (Figure 2C), patient II-3 underwent PPV with membrane peel and silicone oil infusion. The surgery was uncomplicated; however, the vitreous overlying the tumor was fibrotic and strongly adherent.

Patient II-3 (Case 1). (A, B) Earliest and latest available Optos fundus photography of right eye, spanning 3 years. (C) Preoperative photo taken when intravitreal neovascularization was first noted in left eye. (D) One month after a preemptive pars plana vitrectomy and membrane peel.

Figure 2.

Patient II-3 (Case 1). (A, B) Earliest and latest available Optos fundus photography of right eye, spanning 3 years. (C) Preoperative photo taken when intravitreal neovascularization was first noted in left eye. (D) One month after a preemptive pars plana vitrectomy and membrane peel.

Our patient underwent a second procedure approximately 6 weeks later to remove the silicone oil from her left eye, which had a best-corrected visual acuity (BCVA) of 20/50 at the time (Figure 2D). After silicone oil removal, she slowly developed subretinal proliferative vitreoretinopathy (PVR) in the papillomacular bundle with secondary macular edema and a decline of her BCVA to 20/150 as measured by Snellen. After refusing further surgical intervention, she developed a macula-off tractional RD with anterior PVR associated with her previously regressed RCH. During the course of the subsequent year, our patient underwent six more surgeries to repair the RD with BCVA, initially improving to 20/50 but ultimately worsening to hand motion due to recurrent PVR-associated retinal redetachments and macular edema.

Right Eye: Patient II-3 continues to demonstrate BCVA of 20/20 in her right eye 3 years after her last intervention in the left eye (Figure 2A–B). Her recurrent small RCHs in the right eye have been effectively managed with laser photocoagulation and PDT.

Case 2 (Patient II-2)

Patient II-2 developed symptoms of VHL at age of 16 when she presented with vertigo caused by a cerebellar hemangioblastoma. Afterwards, she underwent several surgeries including craniotomy and stereotactic radiosurgery for numerous cerebellar and spinal cord lesions. At age 23, her BCVA was 20/20 in both eyes when she began to develop recurrent bilateral RCHs that were stabilized with laser photocoagulation and PDT for 8 years.

Left eye: At age 31, her vision slowly worsened over the course of several months when she developed posterior vitreous detachment followed by both serous and tractional RDs, as well as vitreous hemorrhage after laser photocoagulation (Figure 3D). She elected for surgical intervention when her vision worsened to counting fingers and she demonstrated substantial vitreous traction. She underwent PPV with the insertion of a scleral buckle along with membrane peeling and silicone oil infusion. BCVA of this eye improved to 20/300 over many years (Figure 3E).

Patient II-2 (Case 2). (A) Right eye Optos fundus photography demonstrating vitreal neovascularization and traction over the fovea 2 days before pars plana vitrectomy (PPV). (B) Right eye when neovascularization was first noted a year earlier. (C) Right eye 4 months after PPV. (D, E) Earliest and latest available photos of left eye, spanning 5 years.

Figure 3.

Patient II-2 (Case 2). (A) Right eye Optos fundus photography demonstrating vitreal neovascularization and traction over the fovea 2 days before pars plana vitrectomy (PPV). (B) Right eye when neovascularization was first noted a year earlier. (C) Right eye 4 months after PPV. (D, E) Earliest and latest available photos of left eye, spanning 5 years.

Right eye: Our patient's right eye remained 20/20 and continued to have active RCHs, which were managed with laser photocoagulation and PDT. Eventually, she developed a 2 × 3 DD area of localized retinal traction supranasally that was associated with focal vitreous traction on an RCH, which extended into the vitreous cavity (Figure 3B). The patient elected to continue with nonsurgical interventions. Her vision remained 20/20 over the next 4 years but then gradually began to worsen. She continued to demonstrate neovascular invasion of the vitreous, and intravitreal VEGF inhibitor therapy was thought to be a poor option due to the possibility of exacerbating the vitreous traction. During the next few months, her BCVA worsened to 20/50 with increased traction over her optic nerve and subretinal fluid (SRF) under the fovea. When the tractional RD eventually grew to involve the macula, the patient underwent PPV with insertion of a scleral buckle (Figures 3A and 3C). Postoperatively, her vision improved to 20/300, but after cataract surgery and subsequent repeat PPV for persistent tractional and serous RDs, her vision worsened to hand motion. She subsequently developed neovascular glaucoma and concomitant epithelial fibrous downgrowth into the anterior chamber.

Case 3 (Patient III-1)

Patient III-1 had BCVA of 20/20 bilaterally when she was first seen at the age of 11 for a screening examination. The screening found small RCHs in the right eye. From age 11 to 13, she developed recurrent RCHs bilaterally, which were effectively treated with cryotherapy and laser photocoagulation.

Right Eye: At age 13, the patient developed neovascularization from a persistent RCH in the right eye (Figure 4B). Similar to her mother, neovascular infiltration of the vitreous was prominent and led to tractional detachment of the overlying retina. After a thorough discussion of the treatment options, her mother elected observation. During the next 2 years, the patient became symptomatic with BCVA of her right eye decreasing to 20/30. At age 15, her BCVA worsened to 20/70 when she developed tractional and exudative RD with SRF encroaching on the fovea (Figure 4A). The patient immediately underwent scleral buckling with PPV, peeling of the tractional membranes, endolaser retinopexy, and placement of silicone oil without complications (Figure 4C). Three months afterward, her BCVA measured to counting fingers due to the persistence of a tractional retinal fold within the macula along with serous RD adjacent to the RCH extending into the fovea. The patient underwent three additional surgical revisions; however, her vision declined to light perception.

Patient III-1 (Case 3). (A) Right eye preoperative Optos fundus photography showing neovascularization causing tractional and serous retinal detachments with fluid encroaching the fovea. (B) Right eye 2 years earlier when patient first developed neovascularization causing vitreal traction. (C) Right eye 2 weeks after pars plana vitrectomy, membrane peel, scleral buckle placement, endolaser, and silicone oil placement. (D, E) Earliest and latest available photos of the left eye, spanning 5 years.

Figure 4.

Patient III-1 (Case 3). (A) Right eye preoperative Optos fundus photography showing neovascularization causing tractional and serous retinal detachments with fluid encroaching the fovea. (B) Right eye 2 years earlier when patient first developed neovascularization causing vitreal traction. (C) Right eye 2 weeks after pars plana vitrectomy, membrane peel, scleral buckle placement, endolaser, and silicone oil placement. (D, E) Earliest and latest available photos of the left eye, spanning 5 years.

Left Eye: The BCVA of the left eye in Patient III-1 continues to measure 20/20 (Figure 4D–E). Her recurrent small RCHs have been effectively managed with laser photocoagulation and PDT.

Discussion

Here we present the surgical management of three patients with VHL disease who exhibit a clinical phenotype of prominent vitreoretinal neovascularization, fibrovascular vitreous proliferation, and vitreoretinal traction that ultimately result in RDs and poor visual outcomes. We propose these cases represent an ocular phenotype of VHL that may benefit from early surgical intervention.

Treatment strategies for RCHs vary depending on size, location, and presence of secondary lesions such as exudative and/or tractional RD, lipid deposits, vitreous hemorrhage, and epiretinal membranes.5 Small RCHs (< 0.5 DD) respond well to laser photocoagulation,14 whereas medium sized RCHs (1 to 2 DD) require multiple sessions of cryoretinopexy or a combination of both modalities.6 Unfortunately, these treatments are often ineffective for large (> 2 DD) or multiple clustered RCHs, and these patients often develop massive exudates and tractional RDs as a consequence.

RCHs are commonly treated nonsurgically in VHL patients until the development of a RD or other significant vision-threatening consequences occur; however, there may be benefit to early PPV in the vitreoretinal phenotype described in this paper. First, it appears that the vitreous plays a sustaining role in the maintenance of the neovascularization by providing a scaffold for growth; PPV directly relieves the traction and secondarily removes the scaffold. Second, proinflammatory growth factors are more likely to be cleared from a vitrectomized eye as opposed to being sequestered within the vitreous matrix. Third, removal of the vitreous allows for greater use of anti-VEGF and steroid therapy without concern for the development of a vitreous “crunch” syndrome.15 Retinopexy (laser or cryotherapy) is often associated with development of exudates (lipid and fluid, often massive), and these can be either blunted or treated with pre-procedural intravitreal injections of anti-VEGF or steroids agents.

More than 80 cases have been published regarding PPV in eyes with VHL-associated RCHs (Table 1), and the consensus is that, although PPV can often preserve or improve visual function, it can also accelerate the rate of RCH development.14,16–23 Thus, discretion must be exercised in determining which patients are surgical candidates. The counterpoint to performing PPV in VHL patients with RCHs is that often these young patients present unique factors such as robust attachment of the hyaloid to the retina that can lead to iatrogenic retinal tears during surgery.

Review of Published Cases of Surgery in VHL Patients With RCHs

Table 1:

Review of Published Cases of Surgery in VHL Patients With RCHs

Two of the patients did not undergo PPV until they developed RD, as a result of their preference to avoid surgery even after repeated recommendations for surgical intervention. These patients developed devastating tractional RDs, PVR, and very limited postoperative BCVA. In light of the family history and the prominent vitreoretinal neovascular phenotype, preemptive surgical treatment was offered to patient II-3 for the left eye prior to the development of a RD. Postoperatively, she maintained a BCVA of 20/50. However, she later declined further surgical intervention and ultimately developed poor visual outcomes in line with the natural history of the untreated disease.

In conclusion, VHL-associated RCHs present a challenge for treatment and require close surveillance. We describe three members of a family with a unique phenotype of prominent neovascular infiltration of the vitreous leading to tractional RDs. Early intervention with PPV should be considered prior to the progression of RD into the macula. There are limited data on the long-term outcomes of surgical intervention and timing for VHL-associated RCHs and RDs, but we know from natural history studies that, without treatment, the final visual outcome is very poor. Further research evaluating the timing, method, and genetic variants of VHL is necessary to best understand and manage this challenging disease.

References

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Review of Published Cases of Surgery in VHL Patients With RCHs

YearAuthorsPatientsEyesSizeNotes
1983Peyman et al.14223 DDExcision of RCH reported
1996Mulholland et al.1611Successful treatment with PPV, excision, and endolaser
1996McDonald et al.1766Found vitreous surgery effective for ERM or traction retinal detachment
2001Farah et al.1811Defined transretinal feeder vessel ligature technique
2007Schlesinger et al.19337–9 mmCases of tying feeder artery followed by excision
2007Liang et al.2033Excision after ablation of feeder artery with laser and diathermy
2008Wong et al.2155Concluded that vision-threatening cases may besuccessfully managed by PPV and excision
2011Gaudric et al.222123Long-term outcomes of: 9 retinectomies; 14 laser endophotocoagulation alone or combined with trans-scleral cryotherapy
2016Krzystolik et al.232324PPV can improve or preserve visual function butretinotomy can accelerate ocular VHL disease
2017Avci et al.241212Good outcomes for PPV in cases of complex retinal detachment
Total7780
Authors

From Stanford University Byers Eye Institute, Department of Ophthalmology, Palo Alto, California (TZ, NFC, CAL, PHT, RAS, MHJ, DV, DMM); and the Department of Ophthalmology, University of Colorado, Denver, Colorado (MAP).

Supported by the Heed Ophthalmic Foundation Award (NFC) and the Stanford University Medical Scholars Research Program (TZ).

The authors report no relevant financial disclosures.

Dr. Moshfeghi did not participate in the editorial review of this manuscript.

Address correspondence to Darius M. Moshfeghi, MD, Horngren Family Vitreoretinal Center, Byers Eye Institute, Department of Ophthalmology, Stanford University School of Medicine, 2452 Watson Court, Room 2277, Palo Alto, CA 94303; email: dariusm@stanford.edu.

Received: June 25, 2019
Accepted: August 27, 2019

10.3928/23258160-20200129-07

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