Retinal Capillary Hemangioblastoma Research Articles

Ocular Manifestations of von Hippel-Lindau Disease.

In this review article, we aimed to analyze the available data on the ocular manifestations of von Hippel-Lindau (VHL) disease. In this disease, the VHL protein becomes inactivated by germline mutations of the VHL tumor suppressor gene on chromosome 3p25-26, resulting in an overproduction of VEGF in non-hypoxic conditions. Ocular manifestations are expected in roughly half of VHL patients. Retinal capillary hemangioblastomas (RCHs) are the most commonly observed tumors in VHL and are often the initial manifestation of the disease. Ablative therapy, surgical resection, and pharmacotherapy have been implemented to control tumors. Left untreated, RCHs will often enlarge, emphasizing the importance of early diagnosis and treatment to preserve vision. Complications of enlarging peripheral or optic nerve tumors may be severe. Large RCHs may disrupt normal retinal architecture, eventually leading to exudative retinal detachment. Rarely, non-retinal manifestations, such as neovascularization of the iris or cornea, may progress to neovascular glaucoma and vision loss. Ablative therapy of larger tumors carries increasing risks and offers limited success, often necessitating surgical resection. Because this life-threatening disease is not routinely encountered in clinical practice, clinicians will benefit from our review which brings awareness to the ocular presentation of VHL and lifelong screening recommendations for diagnosed patients.

Endoresection utilizing pars plana vitrectomy for benign and malignant intraocular tumors.

Endoresection of intraocular tumors is a complicated procedure utilizing pars plana vitrectomy techniques. Though it has potential downsides and complications, there is potential for this technique in the treatment of malignant and benign intraocular tumors. Endoresection has been utilized in some form for the last three decades, but recent advances in vitreoretinal surgery have improved the technique. Endoresection is used most commonly to treat posterior uveal melanoma, but success in treating benign tumors, such as astrocytoma or retinal capillary hemangioblastoma has emboldened surgeons to expand its indications. It appears that removal of a malignant tumor, such as uveal melanoma may spare the eye some damaging effects of radiation retinopathy and radiation optic neuropathy. These benefits may occur even when the tumor is treated concurrently with plaque brachytherapy, proton beam irradiation, or stereotactic radiotherapy. The benefits of the technique are tempered, however, by the inherent difficulties associated with performing the surgery. These include potentially severe intraoperative bleeding, recurrent rhegmatogenous retinal detachment with proliferative vitreoretinopathy, air embolism, and recurrence of the tumor at the edge of the resection. Nonetheless, endoresection has recently been used for retinoblastoma in refractory cases in order to spare the globe. Endoresection is an advanced vitreoretinal surgical technique that has potential advantages in the treatment of malignant and benign intraocular tumors.

Spontaneous Hyaloidal Contraction and Complex Retinal Detachment in a Patient With Von Hippel-Lindau Syndrome

The authors present an interventional case report of a patient with von Hippel-Lindau (VHL) syndrome who developed simultaneous exudative and combined tractional, rhegmatogenous, and exudative retinal detachment (RD) in the right and left eyes, respectively, following uneventful cryotherapy application of retinal capillary hemangioblastoma (RCH). After pars plana vitrectomy combined with encircling scleral buckling with radial element placement and silicone oil injection, complete retinal reattachment was achieved. The exudative RD of the fellow eye was managed initially with intense topical corticosteroid treatment and subsequent placement of a radial scleral buckle due to the presence of clinically apparent traction. Both eyes remained stable after successful surgical interventions, and long-term follow-up revealed no evidence of recurrent disease. The authors conclude that rapid worsening of vitreoretinal traction and exudation are complications that can occur after treatment of RCH in patients with VHL syndrome leading to complex retinal detachments. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:238-241.].

Pharmacological restoration of visual function in a zebrafish model of von-Hippel Lindau disease

Von Hippel-Lindau (VHL) syndrome is a rare, autosomal dominant disorder, characterised by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality of Vhl−/− mice in utero restricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in the vhl gene represent a viable, alternative vertebrate model to investigate associated ocular loss-of-function phenotypes. Previous studies reported neovascularisation of the brain, eye and trunk together with oedema in the vhl−/− zebrafish eye. In this study, we demonstrate vhl−/− zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in the vhl−/− eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib malate, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed in vhl−/− zebrafish. We conclude that the zebrafish vhl gene contributes to an endogenous molecular barrier that prevents development of intraretinal vasculature, and that pharmacological intervention with sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal vessels in vhl−/− zebrafish.

Submacular sclerosing capillary hemangioblastoma

PurposeTo report a case of submacular cystic lesion that turned out to be a sclerosing capillary hemangioblastoma. The retinal capillary hemangioblastoma may arise as a part of von Hippel-Lindau syndrome 1 however, they may occur as an isolated entity 2, but submacular capillary hemangioblastoma has never been reported. ObservationsA case of a 56-year-old female who presented with a right yellow submacular lesion. The mass was excised via pars-plana vitrectomy and histopathological assessment revealed a submacular sclerosing capillary hemangioblastoma. Conclusionand importance: The capillary hemangioblastoma is a benign vascular tumor that may arise submacularly and is not necessarily associated with von Hippel-Lindau disease. It is difficult to be differentiated clinically from other submacular lesions but the possibility should be considered.

EARLY DETECTION OF RETINAL HEMANGIOBLASTOMAS IN VON HIPPEL-LINDAU DISEASE USING ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY.

To study the use of ultra-widefield fluorescein angiography (UWF FA) in the detection and management of retinal capillary hemangioblastomas in patients with von Hippel-Lindau disease. This is a retrospective study of patients with von Hippel-Lindau disease who underwent UWF FA using the Optos camera at a single center from June 2009 to May 2015. The clinical use of UWF FA was reviewed, and the number of hemangioblastomas identified on UWF FA was compared with ophthalmoscopy and a simulated seven standard field (7SF) FA montage. Twenty eyes of 10 patients were identified. Only 33% of lesions seen on UWF FA were also found on ophthalmoscopy, and 88% of lesions visualized on UWF FA were located outside the 7SF overlay. In 5 eyes that had gaze steering, 18% of lesions could be visualized only on gaze-steered images. For the 14 eyes with data available, 6 had procedures recommended and 8 eyes observed based on data from UWF FA. One of 20 eyes had a lesion on ophthalmoscopy that was missed by imaging. Ultra-widefield FA using the Optos camera is helpful for the evaluation and management of patients with von Hippel-Lindau disease. The UWF FA with gaze steering appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography.

THERAPEUTIC OUTCOMES AFTER ENDORESECTION OF COMPLEX RETINAL CAPILLARY HEMANGIOBLASTOMA.

To evaluate the anatomical and functional outcomes after endoresection of complex retinal capillary hemangioblastoma (RCH). Retrospective case series of 12 patients (13 eyes), all treated with pars plana vitrectomy, endodiathermy of feeding and draining vessels, endoresection of RCH and silicone oil injection. The mean age at the time of surgery was 32.5 ± 15.9 years. The mean follow-up duration after initial surgery was 50.5 ± 49.4 months. Indications for surgery included RCH with associated complications such as tractional retinal detachment in five eyes (38%), exudative retinal detachment in four eyes (31%), and combination of tractional retinal detachment and exudative retinal detachment in four eyes (31%). The dimensions of the resected RCHs were as follows: >3.0 mm in seven eyes (54%), >3.5 mm in three eyes (23%), and >4.0 mm in three eyes (23%). No tumor was located closer than 10 mm to the optic nerve or fovea. Anatomical success after initial surgery was 92%. One eye had a second vitreoretinal procedure owing to recurrent RD. The mean preoperative Snellen visual acuity was 20/303. The mean Snellen visual acuity at the final visit was 20/73. At the final visit, visual acuity had improved in seven eyes (54%), and six eyes (46%) were stable. Short-term complications included recurrent proliferative vitreoretinopathy in one eye (8%), transient ocular hypertension requiring topical antiglaucoma treatment in four eyes (31%), and long-term complications included progression of cataract in seven eyes (54%). Combined pars plana vitrectomy, endodiathermy of feeding and draining vessels, endoresection of RCH, and silicone oil injection may be an effective treatment option for complex RCH, achieving high anatomical success and stable or even improved visual acuity, acceptable rates of disease- and treatment-related complications, and minimal need for retreatment.

Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina.

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl-mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266-74. ©2018 AACR.

Abstract 1851: A murine model of von Hippel-Lindau associated retinal hemangioblastoma

Abstract Purpose: von Hippel-Lindau disease (VHL) is an autosomal dominant condition that features a constellation of cysts or highly vascularized tumors due to loss of heterozygosity (LOH) of the VHL gene, resulting in deregulated hypoxia-induced factors (HIFs). Clinical manifestations of VHL include hemangioblastomas in the central nervous system and retina. To date, no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. The RCHs may arise from arrested hemangioblast progenitor cells, with VHL LOH in the tumor stroma. The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix (bHLH) transcription factor, a critical regulator of hematopoiesis and vasculogenesis. We aim to generate a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast progenitor population with the angioblast-specific Cre line, (SCL) Cre-ERt2. Methods: We established a genetic mouse model in which the inducible Vhl gene is specifically “knocked-out” in angioblast cells using the stem cell leukemia (SCL) Cre-ERt2 transgenic mice. Two-week-old SCL-CreERt2;Vhl-F/F mice were administrated tamoxifen (2mg/40g body weight) for 5 consecutive days to activate the Cre recombinase that induces Vhl deletion in angioblast-derived cells. Fundoscopy was done monthly to detect retinal lesions. Fluorescein angiography (FA) was performed on affected mice. All retinas were analyzed by histology at 4 months of age. Genome typing of the Vhl conditional KO allele was conducted in retinal lesions using microdissection, nest-PCR and Sanger sequencing. Results: About 64% (18/28) of the transgenic mice exhibited various retinal vascular defects following induction. Affected mice demonstrated retinal vascular lesions that were variably associated with prominent vessels, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. FA revealed vascular leakage from the lesions. Histological analyses showed RCH-like lesions of tortuous, dilated vessels surrounded by “tumorlet” cells, isolated foamy stromal cells, and glia, classically found in RCH. Vhl LOH was detected in the tumor-like area as verified by sequencing. Conclusion: This is the first demonstration of VHL-associated RCH in a transgenic mouse model. This model may be useful for studying RCH pathogenesis, including HIF-dependent and HIF-independent pathways, and for testing potential therapies. Citation Format: Herui Wang, Qi Zhang, Lijin Dong, Liliana Guedez, Stanley Park, Yujuan Wang, Shida Chen, Chun Gao, Wai T. Wong, Henry Wiley, Emily Chew, Chi-Chao Chan, Zhengping Zhuang. A murine model of von Hippel-Lindau associated retinal hemangioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1851. doi:10.1158/1538-7445.AM2017-1851

VITREORETINAL SURGERY FOR PATIENTS WITH SEVERE EXUDATIVE AND PROLIFERATIVE MANIFESTATIONS OF RETINAL CAPILLARY HEMANGIOBLASTOMA BECAUSE OF VON HIPPEL-LINDAU DISEASE.

The evaluation of long-term results of vitreoretinal surgery and retinal capillary hemangioblastoma (RCH) resection in patients with complicated retinal detachment (RD) secondary to RCHs. Twelve eyes of 12 patients were operated on with vitreoretinal surgery, including occlusion of afferent and efferent feeder vessels with endodiathermy and endolaser photocoagulation, and subsequent resection of RCHs. The long-term anatomical and visual outcomes were retrospectively evaluated. Total exudative RD was detected in six eyes and subtotal exudative RD was found in the remaining six eyes. A tractional component was present in eight eyes, and four eyes had pure exudative RD. Laser treatment had been previously applied to four eyes but vitreoretinal surgery was the primary treatment in eight eyes. A total of 19 RCHs were resected. The quadrant location of RCHs was superior temporal in six, superior nasal in five, inferior nasal in five, and inferior temporal in three. The dimensions of the RCHs ranged between 1 and 4 disk diameters (DD) (1-DD in 1 eye, 1.5-DD in 3, 2-DD in 10, 2.5-DD in 3, 3-DD in 1, and 4-DD in 1). Preoperative mean logarithm of the minimum angle of resolution visual acuity was 1.9 ± 1.0 (3.0-0.7) (20/1,588 ± 20/200 [20/20,000-20/100]). Silicone oil and C3F8 was applied to four and eight eyes, respectively. The median postoperative follow-up was 30.5 (18-48) months. Single operation and final anatomical success was obtained in 9 and 11 eyes, respectively. Mean logarithm of the minimum angle of resolution visual acuity in the postoperative 18th month and at the final visit were 1.05 ± 0.8 (3.0-0.2) (20/224 ± 20/125 [20/20,000-20/32]) and 0.96 ± 0.8 (3.0-0.2) (20/182 ± 20/125 [20/20,000-20/32]), respectively. New RCHs occurred in eight eyes. Rubeosis iridis was not present in any of the eyes. Promising anatomical and visual outcomes were obtained after vitreoretinal surgery and resection of RCHs in eyes with complicated RD secondary to RCH. However, life-long follow-up is needed to recognize recurrent RD seen even in the early period or recurrences of RCHs seen in the long-term period.

Posterior Pole and Peripheral Retinal Fibrovascular Proliferation in von Hippel Lindau Disease.

To report the occurrence of fibrovascular proliferation (FVP) in the retina in von Hippel-lindau (VHl) patients and its association with prior treatment. A retrospective study. A retrospective study of 101 VHL patients. Fundus photos were available for 28 patients. FVP was classified into peripheral and posterior pole. All 28 patients had retinal capillary hemangioblastomas (RCH) in 1 or both eyes; 15 patients were found to have FVP (group A), whereas 13 patients did not (group B). Mean age of patients in group A was 35 ± 11.3 years and 36.6 ± 13.8 in group B (P = 0.74). In group A, 27 eyes had RCH; 21 (77.77%) had FVP. In group B, 19 eyes had RCH. The number of treated eyes was significantly higher in group A (81.48%) than group B (42.1%) (P = 0.007). In group A, FVP was noted in the posterior pole in 9 eyes, in the periphery in 5 eyes, and 7 eyes developed both posterior pole and peripheral FVP. FVP can occur in the peripheral retina and in the posterior pole. There is a significant association between prior treatment of RCH and the occurrence of FVP.

Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease

To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. Observational case review. Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. Visual acuity, size of RCH, and degree of exudation. Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH.

Laser Photocoagulation for Peripheral Retinal Capillary Hemangioblastoma in von Hippel-Lindau Disease

To study the efficacy and limits of laser photocoagulation for retinal capillary hemangioblastoma (RCH) of various sizes in von Hippel-Lindau disease. Retrospective study. The records of 176 patients with von Hippel-Lindau were reviewed retrospectively. Seventy-four patients with 304 RCHs in 100 eyes were treated primarily with laser photocoagulation. Eyes with concomitant rhegmatogenous or tractional retinal detachment or with papillary RCH were excluded. The treatment consisted of inactivating RCH using direct green laser photocoagulation with long-duration laser burns (0.1-0.7 seconds). The number of RCH lesions per eye, RCH size in disc diameter (DD) at diagnosis, the presence of retinal lipid exudation or subretinal fluid, and visual acuity were recorded. Final outcomes included RCH inactivation, posttreatment complications, and final visual acuity. Patient mean age was 28 years (range, 8-62). Mean follow-up duration after treatment was 4.5 years (range, 0.4-17.5). Median RCH size was 0.25 DD (range, 0.25-3.00). Laser alone inactivated 97% of RCHs. A mean number of 1.6 laser sessions (range, 1-8) were needed to achieve RCH inactivation. A single laser session allowed coagulating 77% of RCHs. Their median size was 0.50 DD (range, 0.25-1.50). More than 1 laser session was needed to inactivate 23% of RCHs. Their median size was 1 DD (range, 0.25-3.00). Among them, 29 (10% of all RCHs) needed additional laser session during the first 48 hours. Their median size was 1.5 DD (range, 0.5-3). Subretinal fluid transiently increased in 7 eyes after the first laser session and was controlled promptly by additional photocoagulation. Additional cryotherapy was needed only in 7 eyes with large RCH partially inactivated by laser. In all eyes, visual acuity remained stable during the follow-up. In the absence of tractional retinal detachment, laser photocoagulation allowed inactivating most RCHs up to 3 DD, even when they were associated with subretinal fluid. Laser photocoagulation alone inactivated 100% of RCHs up to 1 DD, and 73% of larger RCHs. In such cases, additional cryotherapy increased RCH inactivation to 94% so that 99% of all treated RCHs were finally inactivated.

Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome.

BackgroundVon Hippel–Lindau (VHL) syndrome is a dominantly inherited multisystem cancer syndrome caused by a heterozygous mutation in the VHL tumor suppressor gene. Previous studies suggested that similar populations of Caucasian and Japanese patients have similar genotype or phenotype characteristics. In this comprehensive study of East Asian patients, we investigated the genetic and clinical characteristics of patients with VHL syndrome.MethodsTo create a registry of clinical characteristics and mutations reported in East Asian patients with VHL syndrome, we conducted a comprehensive review of English language and non-English language articles identified through a literature search. Publications in Japanese or Chinese language were read by native speakers of the language, who then performed the data extraction.ResultsOf 237 East Asian patients with VHL syndrome, 154 unique kindreds were identified for analysis. Analyzed by kindred, missense mutations were the most common (40.9%, 63/154), followed by large/complete deletions (32.5%, 50/154) and nonsense mutations (11.7%, 18/154). Compared with a previously reported study of both East Asian and non-East Asian patients, we found several key differences. First, missense and frameshift mutations in the VHL gene occurred less commonly in our population of East Asian patients (40.9% vs. 52.0%; P = 0.012 and 8.4% vs. 13.0%; P < 0.001, respectively). Second, large/complete deletions were more common in our population of East Asian patients (32.5% vs. 10.5%; P < 0.001). Third, phenotypically, we observed that, in our population of East Asian patients with VHL syndrome, the incidence of retinal capillary hemangioblastoma was lower, whereas the incidence of renal cell carcinoma was higher.ConclusionsEvidence suggests that the genotypic and phenotypic characteristics of East Asian patients with VHL syndrome differ from other populations. This should be considered when making screening recommendations for VHL syndrome in Asia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40880-016-0141-z) contains supplementary material, which is available to authorized users.

PARS PLANA VITRECTOMY IN ADVANCED CASES OF VON HIPPEL-LINDAU EYE DISEASE.

To investigate spectrum of patients with Von Hippel-Lindau disease (VHL) that required pars plana vitrectomy and evaluate anatomical and functional outcomes of surgery. Twenty-three patients who underwent surgery for advanced VHL eye disease were assessed by genetic tests, diagnostic tests for systemic lesions, and clinical eye examination. The vitrectomized eyes were divided into two groups: with or without retinotomy (group R vs. NR). Functional and anatomical outcome was analyzed and compared between the groups. All patients had central nervous system hemangioblastomas and 57% had other systemic tumors. Point germline mutations, large partial deletions, and complete vhl gene deletions were found in 64%, 27%, and 9% of patients, accordingly. Destruction of hemangioblastomas by retinotomy, laser, or cryotherapy and anatomical attachment of the retina were achieved in all eyes. Preoperative mean distance best-corrected visual acuity was logarithm of the minimum angle of resolution 2.66 (20/9,140) in group R and 1.76 (20/1,150) in group NR (P < 0.05). At 6 months postoperatively, distance best-corrected visual acuity improved in 20 eyes (83%). After over 24 months postoperatively, distance best-corrected visual acuity remained better than preoperatively in 36% in the R group and in 70% in the NR group of eyes. During 24 months postoperatively in 17 eyes, new retinal capillary hemangiomas developed. The mean number of new retinal capillary hemangiomas per eye was higher in group R than in group NR (3.14 vs. 0.70; P < 0.01). In group R, number of new retinal capillary hemangioblastoma was higher in retinal segments where retinotomy was performed (n = 29) than in other areas (n = 13) (P < 0.01). Advanced VHL eye disease correlates with occurrence of central nervous system and systemic lesions. Spectrum of vhl gene mutation in the patients corresponds to that of the general VHL population. Pars plana vitrectomy in advanced VHL eye disease can improve or preserve visual function, but postoperative progression of ocular VHL disease can be accelerated in cases where retinotomy is performed.

Intravitreal bevacizumab for retinal capillary hemangioblastoma: A case series and literature review

ObjectiveTo evaluate the long-term outcomes of intravitreal bevacizumab for peripheral and juxtapapillary retinal capillary hemangioblastoma (RCH). DesignWe conducted a retrospective noncomparative interventional case series. ParticipantsThere were 4 patients (5 eyes) presenting with RCH. MethodsFive eyes with RCH presented with exudative changes and visual loss. Three eyes of 2 patients with peripheral RCH were treated with cryotherapy and 2 intravitreal injections of bevacizumab (0.5 mg). Two eyes with juxtapapillary RCH were treated with 3 intravitreal injections of bevacizumab. The main outcome measures were changes in best-corrected visual acuity (BCVA), lesion size, exudation, and retinal thickness. ResultsIn peripheral RCH, improvement of BCVA from counting fingers to 20/400 was obtained in 1 eye. One patient with bilateral RCH maintained a vision of 20/20 in 1 eye with complete anatomic regression of the 3 small peripheral RCH lesions. The fellow eye with fibrotic bands from the RCH to the optic nerve head developed a tractional retinal detachment after the first injection and was treated with pars plana vitrectomy. In patients with juxtapapillary RCH, bevacizumab injections resulted in an improvement of BCVA from 20/80 to 20/20 in 1 eye, whereas the second eye did not show an improvement of BCVA despite a regression of the tumour. ConclusionsIntravitreal anti–vascular endothelial growth factor agents, alone or in combination with other treatment modalities, may improve visual acuity. Further trials evaluating the dose, the number of injections, and the route of administration will be important in advancing antiangiogenic therapies for RCH.

Bilateral papillopathy as a presenting sign of pheochromocytoma associated with von Hippel&amp;ndash;Lindau disease

A 7-year-old girl presented with decreased vision in both eyes for 1 month. Examination showed visual acuity of 20/50 and 20/60, no afferent pupillary defect, cecocentral scotomas, and bilateral optic disc edema with extensive peripapillary and macular exudates. Magnetic resonance imaging showed multiple cortical and subcortical white matter lesions. Both the laboratory workup and the systemic examination were unrevealing. However, on follow-up, the patient showed episodic elevations of blood pressure as high as 240/160. Further workup revealed elevated urine catecholamines and a right supra-adrenal mass proven to be a pheochromocytoma by histopathologic analysis. The paroxysmal hypertension resolved, and the visual acuity, visual fields, fundus exam, and neuroimaging improved. The patient was lost to follow-up until age 18 when she developed shortness of breath and was found to have multiple pulmonary metastases identified as pheochromocytoma by biopsy. Genetic testing identified a 3p25-26 (c.482 G>A) VHL gene chromosomal mutation consistent with von Hippel–Lindau disease genotype. Multiple peripheral retinal vascular dilations and small retinal capillary hemangioblastomas were also found. This case highlights the importance of recognizing the lability of blood pressure often seen with pheochromocytomas, which may mask the underlying cause of hypertensive papillopathy and retinopathy, a diagnosis of low clinical suspicion in the pediatric population. The case also underscores the importance of thorough systemic workup, including genotyping to detect conditions where pheochromocytoma may be the presenting sign of the disease, such as multiple endocrine neoplasia 2A and 2B, von Hippel–Lindau disease, von Recklinghausen disease, tuberous sclerosis, and Sturge–Weber syndrome.

Double-Fluence Photodynamic Therapy for Juxtapapillary Retinal Capillary Hemangioblastoma in a Pediatric Patient

An 8-year-old girl with visual loss due to non-hereditary juxtapapillary retinal capillary hemangioblastoma and associated cystoid macular edema underwent doublefluence verteporfin photodynamic therapy. Tumor regression was observed after one session, although functional visual acuity was limited by residual fibrosis and hemangioblastoma-induced amblyopia. No complications were observed.

Longitudinal Analysis of Retinal Hemangioblastomatosis and Visual Function in Ocular von Hippel-Lindau Disease

Characterization of the structural and functional progression of ocular von Hippel-Lindau (VHL) disease and analysis of patient factors influencing disease progression. Retrospective analysis of a case series from a longitudinal, observational study. Two hundred forty-nine participants with clinically defined systemic VHL disease and more than 2 years of ophthalmic follow-up. Standardized scoring of ocular phenotype and systemic characteristics was performed at each study visit and was analyzed longitudinally to determine progression of ocular VHL disease. Measures evaluated include: visual acuity, features of ocular VHL disease (presence, location, number, and extent of retinal capillary hemangioblastomas [RCHs]), germline mutation in the VHL gene, demographics (age, gender, age at onset of ocular disease), and patient characteristics (smoking status, body mass index). Most participants demonstrated relative anatomic and functional stability in ocular VHL disease status over a mean follow-up of 8.2 ± 4.0 years. Approximately three quarters (73%) of participants without ocular VHL disease at baseline remained disease free at the end of follow-up. Among eyes with ocular VHL disease at baseline, 88% did not demonstrate RCHs in a new retinal location, 70% remained stable in RCH number, and 79% remained stable in the extent of RCH involvement. Mean visual acuity for all study eyes (n = 498) decreased by 5.1 ± 0.6 letters across follow-up, with 16.1% of study eyes decreasing by more than 10 letters in visual acuity. Among eyes affected at baseline, greater vision loss was associated with the presence of juxtapapillary RCHs, development of RCH in a new location, and increase in peripheral RCH number and extent. Younger baseline age, younger age at onset of ocular VHL disease, involvement of the fellow eye with ocular VHL disease, and missense or protein-truncating germline mutations were associated significantly with increased anatomic involvement and functional deterioration. Patients with ocular VHL disease maintain relative anatomic and functional stability, with only a minority demonstrating marked anatomic progression and vision loss. Systemic and ocular risk factors for anatomic progression and vision loss can help practitioners identify patients with a higher risk profile for counseling, closer follow-up, and proactive treatment. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinoschisis detected by spectral-domain optical coherence tomography in von hippel-lindau disease.

To report the presence of retinoschises in a case of von Hippel-Lindau disease detected by spectral-domain optical coherence tomography. Case report of a 23-year-old man with von Hippel-Lindau disease who was seen for a regular follow-up examination. Ophthalmoscopy showed several retinal capillary hemangioblastomas in both eyes. Spectral-domain optical coherence tomography showed retinoschises around the retinal capillary hemangioblastoma and also around the feeder and draining vessels of the peripheral larger hemangioblastoma. The retinoschises were found under the internal limiting membrane and also in the inner and outer retinal layers. Intraretinal columns were observed in the retinoschises. Our observations show that retinoschises can develop in eyes with von Hippel-Lindau disease. The extensiveness of the retinoschises suggests that the retina is fragile in von Hippel-Lindau disease.