Bilateral Iris Neovascularization as the Initial Sign of Obesity-Hypoventilation (Pickwickian) Syndrome: Hypoxia/Hypercapnia as a Stimulus for Angiogenesis

Rubeosis iridis usually occurs secondary to decreased or absent retinal capillary perfusion (eg, diabetic retinopathy, central retinal vein occlusion, ocular ischemia). Clinical observations have established a relationship between retinal ischemia and ocular neovascularization, leading to the half-century-old hypothesis that factors produced by an ischemic retina stimulate local as well as distant blood vessel growth.¹ However, it is not clear which aspect of ischemia (eg, reduced nutrient delivery, hypoxia, hypercapnia, increased metabolites) might lead to the production of an angiogenesis factor. We describe a unique case in which rubeosis iridis is seen as a consequence of systemic hypoxia/hypercapnia without retinal ischemia as part of the obesity-hypoventilation (pickwickian) syndrome.

A 36-year-old man was referred for evaluation of bilateral rubeosis iridis noted shortly (4 and 6 months) after uneventful bilateral cataract surgery. There was no ocular discomfort. Visual acuity was 20/25 OU. Pupillary border rubeosis was observed (Figure 1, A) and documented by iris angiography (Figure 1, B). Fundus examination showed dilated veins and rare intraretinal hemorrhages (Figure 2, A) with prompt perfusion by fundus fluorescein angiography (Figure 2, B). Intraocular pressure was 16 mm Hg in both eyes.

The patient was not receiving any systemic medications. He had been lethargic for a few years and worked as a truck driver until 6 months prior to cataract surgery.

Medical evaluation demonstrated obesity (weight, 152 kg [338 lb]), somnolence, right ventricular failure, polycythemia, arterial blood PO₂ of 32 mm Hg (normal, 75-100 mm Hg), arterial blood PCO₂ of 69 mm Hg (normal, 35-45 mm Hg), and sleep apnea, consistent with advanced obesity-hypoventilation (pickwickian) syndrome. The patient was admitted to Johns Hopkins Hospital (Baltimore, Md) and transferred to the intensive care unit for positive pressure oxygen delivery and monitoring of respiratory and cardiac status.

With treatment of the hypoxia and a 23-kg (51-lb) weight loss, the systemic condition improved, with PO₂ increasing to 93 mm Hg. The rubeosis promptly involuted (Figure 1, C). Follow-up examination at 1, 3, and 6 months disclosed no recurrence of rubeosis.

Since there was no demonstrable retinal ischemia (decreased or absent retinal capillary blood flow) in this case, it appears that hypoxia (reduced oxygen supply to a tissue that can occur in the presence of normal perfusion of the tissue by blood) and/or hypercapnia alone may induce angiogenesis. When rubeosis iridis is secondary to ischemia, management often involves treatment of the ischemic retina with panretinal photocoagulation. It is thought that less diffusible angiogenic factor is thereby released by the retina, with regression of rubeosis iridis. In this case, however, the rubeosis iridis resolved without photocoagulation, after systemic hypoxia/hypercapnia was corrected. Cataract surgery may have removed a barrier, facilitating forward diffusion of an angiogenic substance. The etiology of bilateral presenile cataracts in this patient remains unknown.

This case demonstrates that severe systemic hypoxia/hypercapnia may be associated with iris neovascularization, with complete resolution following correction of the conditions. The possible role of hypoxia in angiogenesis is supported by studies demonstrating hypoxic stimulation of the angiogenic factor VEGF (vascular endothelial growth factor) in cultured retinal cells² and hypoxic down-regulation of PEDF (pigment epithelium–derived factor), an inhibitor of angiogenesis.³ Additionally, superoxia has been demonstrated to down-regulate VEGF levels in the ischemic primate retina.⁴ Hypercapnia, although less extensively studied, has been suggested by Holmes et al⁵ to play a direct role in neovascularization in a newborn rat model. Therapies targeted toward hypoxia/hypercapnia and their downstream mediators might therefore be effective in the treatment of neovascularization associated with ischemic ocular conditions.

Corresponding author: Elia J. Duh, MD, Maumenee 809, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: duhe@welchlink.welch.jhu.edu).