S.S. Dahr

High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis.

PURPOSE This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis. METHODS Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8mg/kg at day 0 and 4mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2mg/kg every 4 weeks for 52 weeks. The primary outcome assessed was a two-step decrease in vitreous haze at day 21. Secondary outcomes evaluated included best-corrected visual acuity, retinal thickness as measured by optical coherence tomography, retinal vascular leakage assessed by fluorescein angiography, anterior chamber and vitreous cellular inflammation. RESULTS Four male patients and one female patient were enrolled. Diagnoses included birdshot retinochoroidopathy (two patients), Vogt-Koyanagi-Haradas disease, bilateral idiopathic panuveitis and bilateral idiopathic intermediate uveitis. By the 4th week, four of five patients demonstrated a two-step decrease in vitreous haze. The other participant did not meet this criterion until week 20, but all five patients maintained stability in vitreous haze grade throughout their follow-up periods. At enrollment, mean visual acuity (10 eyes in 5 patients) was 69.2 ETDRS letters and following treatment was 78.2 letters (p<0.12). Anterior chamber cell, vitreous cell, and vitreous haze also improved in the majority of eyes. Adverse events were generally mild except for one episode of left-lower lobe pneumonia requiring hospitalization and treatment. CONCLUSION This is the first demonstration that high-dose daclizumab can reduce inflammation in active uveitis. Daclizumab was well tolerated but there may be a potential increased risk of infection associated with immunosuppression. All five patients demonstrated a decrease in vitreous haze and measures of intraocular inflammation at final follow-up. The results of this small, non-randomized pilot study support the consideration of high-dose daclizumab therapy in cases of active posterior uveitis.

Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina.

Objective: This pilot study was designed to provide preliminary data concerning the safety and efficacy of pegylated anti-vascular endothelial growth factor (VEGF) therapy, pegaptanib, for patients with juxtapapillary or large peripheral angiomas secondary to von Hippel-Lindau (VHL) disease. Methods: This study was an open label, nonrandomized, prospective, pilot study of intravitreal injections of pegaptanib (3 mg/100 &mgr;L), given every 6 weeks for minimum of 6 injections. Five patients with severe ocular VHL lesions were enrolled in the study. The primary outcome of this study was a change of ≥15 letters (3 lines) in best-corrected visual acuity by 1 year. Secondary outcomes included changes in macular thickness, as determined by optical coherence tomography, and changes in fluorescein leakage. Results: Two of five patients completed the course of treatment and 1 year of follow-up. These two patients had progressive decrease in retinal hard exudate and reduction in central retinal thickness measured by optical coherence tomography. One of these two patients had improvement in visual acuity of 3 lines. No significant change in fluorescein leakage or tumor size was detected in either patient. Lesions in the other three patients continued to progress despite treatment, and these patients did not complete the entire treatment course. One patient developed a tractional retinal detachment. Additional serious adverse events included transient postinjection hypotony in two eyes. Conclusions: Intravitreal injections of anti-VEGF therapy (pegaptanib) may decrease retinal thickening minimally and reduce retinal hard exudates in some patients with advanced VHL angiomas. This finding may be related to a reduction in vasopermeability, because there was no apparent effect of treatment on the size of the primary retinal angiomas in this small pilot study.

Clinical Course of Retrobulbar Hemangioblastomas in von Hippel–Lindau Disease

OBJECTIVE To report clinical findings of rare retrobulbar optic nerve hemangioblastomas associated with von Hippel-Lindau disease (VHL). DESIGN Retrospective observational case series. PARTICIPANTS Nine patients with VHL. METHODS The clinical course and magnetic resonance imaging findings of patients with VHL and hemangioblastomas affecting the anterior visual pathway from the intraorbital optic nerve to the optic chiasm are reviewed. MAIN OUTCOME MEASURE Clinical course of retrobulbar optic nerve hemangioblastomas. RESULTS The mean age of VHL diagnosis was 24+/-14 years, and mean follow-up was 5+/-4 years. All had other CNS lesions and retinal hemangioblastomas. Approximately 50% (5/9) had a previous enucleation or had visual acuity loss (4/9), some due to other VHL ocular complications. Four patients underwent surgical resection of an intracranial hemangioblastoma. Growth patterns and pathology are similar to those of other hemangioblastomas in the CNS. CONCLUSIONS Although these lesions are rare, patients with VHL who present with signs of optic neuropathy should be evaluated for anterior visual pathway hemangioblastomas impinging on the optic nerve from the orbit to the chiasm. On neuroimaging, the hemangioblastomas may demonstrate chiasmal or optic tract edema, associated cysts, and T(2) flow voids. Lesions may remain radiologically and clinically stable, evolve radiographically with no visual or neurological progression, or progress clinically and radiographically. Patients at risk for visual loss should be considered for surgical resection. Close coordination among neuroradiology, neurosurgery, and ophthalmology patient care teams is advised for optimal management of these patients.

Vascular Endothelial Growth Factor and Retinal Diseases

In humans, the vascular endothelial growth factor (VEGF) gene resides on chromosome 6p21.3 (1). Northern blot and primer extension analysis have shown that the human VEGF gene has a single major transcription start site, 1038 bp upstream from the ATG initiation codon. This start site is located near a cluster of potential Sp1 factor binding sites, and the promoter contains potential binding sites for the transcription factors AP-1 and AP-2 (2). A hypoxia response element located upstream of the VEGF genes can bind hypoxia-inducible factor (HIF)-1 and may act as an enhancer (3,4). Hypoxia can also increase the half-life of VEGF mRNA, which is intrinsically labile. Binding of HuR, a hypoxia-induced stability factor that is a member of the Elav-like protein family, to an AU-rich element in the 3′-UTR of VEGF mRNA increases the half-life of VEGF mRNA by three- to eightfold (5).