This article is more than 5 years old. Information may no longer be current.
Effects of abnormal ocular angiogenesis can extend beyond retinal pathologies
Treating any form of abnormal neovascularization requires addressing the underlying causes.
PITTSBURGH — Most attention in ophthalmology regarding angiogenesis has been on retinal diseases, but other neovascular pathologies can also cause ocular morbidity. Corneal neovascularization can result from a number of infectious diseases, and neovascular glaucoma can be a difficult-to-treat sequelae of retinal disease. Experts discussed the management of these conditions at the clinical course “Angiogenesis and Its Inhibition” at the University of Pittsburgh Medical Center.
Corneal neovascularization is an important cause of visual impairment and blindness worldwide. Trachoma infects more than 400 million people worldwide, of which 6 million are blind. Onchocerciasis infects more than 50 million people, with approximately 1 million blind. Herpes keratitis is the leading cause of corneal blindness, with approximately 500,000 cases annually in the United States alone, according to Francis S. Mah, MD.
|
Dr. Mah said a small epidemiological study of U.S. patients found approximately a 4% incidence of corneal neovascularization among 845 consecutive patients. Researchers hypothesized that if the results could be applied to the entire country, there would be approximately 1.4 million patients in the United States with corneal neovascularization. “That is a pretty significant number,” Dr. Mah said.
The production and release of angiogenic factors can also lead to neovascular glaucoma. Both Andrew W. Eller, MD, and Robert J. Noecker, MD, said that neovascular glaucoma is actually the end stage of underlying retinal disease, and it is one of the most difficult pathologies for glaucoma subspecialists to manage.
“When you talk about neovascular glaucoma, … the eye is often severely threatened and may be on the verge of death,” Dr. Eller said.
There are three major factors that determine the fate of the eye affected by neovascular glaucoma, according to Dr. Eller. They are the extent of the angle damage from neovascularization, the amount of optic nerve damage from elevated IOP and the extent of retinal (macular) ischemia.
“We can usually save the eye from an anatomical standpoint by controlling the IOP by medical or surgical means and resolving the neovascular process by ablating the peripheral retina with either laser or cryotherapy,” he said. “Even though we can often save the eye, it is often dead from a visual standpoint if there has been extensive damage to the optic nerve from a prolonged elevation of the IOP or if there is a loss of macular function from profound ischemia.”
Although these diseases involve different areas of the eye, they all share common causes and pathologies. Vascular endothelial growth factor (VEGF) production, inflammation, hypoxia, fibroblast growth factor and matrix metalloproteinases have all been associated with the development of both corneal neovascularization and neovascular glaucoma.
“We know that angiogenesis is the formation of new vessels from previously avascular structures … when the balance of angiogenic and antiangiogenic factors is tilted toward the angiogenic factors,” said Deepinder K. Dhaliwal, MD.
“In the cornea, these new vessels are arising from the capillaries and the venules … And it’s important to remember that while some neovascularization is related to hypoxia … other etiologies include trauma, aniridia, as well as autoimmune and degenerative disorders. There are a wide variety [of causes],” she said.
Elevated VEGF levels have also been identified in the aqueous humor of patients with neovascular glaucoma, although other factors that may be responsible for the disease have been investigated, Dr. Eller noted.
Corneal neovascularization
There are some positive effects of corneal neovascularization, according to Dr. Dhaliwal. The new blood vessels can help facilitate healing by enabling the transport of immunologic humeral and cellular elements. Such vessels can also transport raw materials for repairing ocular tissue, she said.
“In addition, antibiotics and other drugs … can be carried to the site of infection, and these vessels can eliminate toxic substances. So they do have an important purpose, initially. The problem occurs when [the vessels] persist,” she noted.
Ocular surface disorders are characterized by an abundance of limbal stem cells. Eventually, the conjunctival epithelium becomes vascularized, and the vessels migrate over the corneal surface. This leads to decreased vision, recurrent corneal erosion and an incompetent barrier function. Additionally, leaking blood vessels can deposit lipids, which can in turn become a source of recurrent inflammation.
“We know that lymphatic channels augment the immune response, and therefore the immune privilege of the cornea is disrupted. And we know having a neovascularized cornea is a high risk for corneal graft rejection. … I think we would all agree that … treatment is necessary,” Dr. Dhaliwal said.
Treatment options
In treating corneal neovascularization, it is important to address the underlying cause of the disorder. Cases of infectious keratitis require immediate use of antibiotics or antiviral drugs. Cases occurring after penetrating keratoplasty require early suture removal. Cases of ocular cicatricial pemphigoid require systemic immunosuppression, while atopic keratoconjunctivitis patients can do well with allergy avoidance, Dr. Dhaliwal said.
In all cases, contact lenses should be discontinued because the lenses can induce hypoxia, she noted.
“The mainstay of medical therapy has been topical corticosteroids. They have wonderful anti-inflammatory properties, including the inhibition of inflammatory cells and chemotaxis, as well as the inhibition of pro-inflammatory cytokines. They also inhibit vascular endothelial cell proliferation and regeneration,” Dr. Dhaliwal said.
One novel approach to treating corneal neovascularization has been the topical application of dietary isoflavonoids and flavonoids. “As we know, these are antioxidants … and they had a nice antiangiogenic effect in mice when applied topically” in a preclinical study, she said.
Possible surgical options
There are several surgical options for treating corneal neovascularization, which mainly involve occlusion of the irregular blood vessels, according to Dr. Dhaliwal.
One approach to laser therapy, called photothrombosis, involves low power light activation of fluorescein dye to produce a localized photochemical thrombosis. Fluorescein allows more localized delivery of laser energy to blood vessel walls.
Patients receive topical anesthesia and antibiotics or antiviral prophylaxis preoperatively if necessary. After fluorescein is administered intravenously, a blue-green argon laser is applied for 10 to 20 seconds around the entire vascular bed using a 150- to 200-µm spot size for 0.5 seconds with 200 mW of power, she said.
Researchers at the University of Pittsburgh evaluated this procedure in a pilot study of 14 patients. Patients typically needed three to five treatment sessions over 9 to 15 weeks for complete resolution of corneal edema. Patients noted a significant improvement in the cornea’s cosmetic appearance. The researchers noted that signs of corneal edema, neovascularization and lipid keratopathy receded, and there was a decrease in generalized corneal damage, she said.
Fine needle diathermy
Fine needle diathermy is another technique for treating corneal neovascularization without specialized equipment, Dr. Dhaliwal said. “The key is that it is very low cost and is accessible to all ophthalmologists,” she said.
In fine needle diathermy, a fine cutting needle attached to a 10-0 nylon suture is inserted close to the limbus at the same depth as the neovascularization. An electrode from a unipolar diathermy unit, set to its lowest setting, is connected to the patient and the diathermy probe is then placed in contact with the needle. This contact is maintained until mild blanching of the corneal stroma occurs, which usually requires no more than 1 second. The procedure is then repeated to cover the entire area of neovascularization, Dr. Dhaliwal said.
In a study by researchers in England, patients who had active graft rejection due to neovascularization improved after the vessels were exposed to treatment.
“These patients had actually failed previous treatment with high-dose corticosteroids,” she said.
Neovascular glaucoma
Corneal neovascularization is responsible for many cases of visual impairment and blindness worldwide, but neovascular glaucoma may be more difficult for ophthalmologists to treat.
The pathogenesis of neovascular glaucoma is most often related to underlying retinal disease such as diabetic retinopathy, leading to the production and expression of VEGF. Generally, neovascular glaucoma develops after an eye has developed extensive retinal ischemia with areas of nonperfusion, according to Dr. Eller.
Elevated VEGF levels have been identified in the aqueous humor of neovascular glaucoma patients, although other factors may also be responsible for the disease.
The damage from neovascular glaucoma is related to iris neovascularization. Blood vessels grow on the surface of the iris and form a matrix containing myofibroblasts and contractile tissue. These pull on the iris, causing it to contract and appose the angle, which leads to elevated IOP.
“Clinically we have an ischemic retina that is producing VEGF, which is coming around into the anterior chamber,” Dr. Eller said.
Diabetic patients who have had complicated anterior segment surgery, such as cataract surgery with posterior capsule rupture and vitreous loss, are at greater risk of iris and angle neovascularization and, ultimately, glaucoma, he said. Additionally, 95% of patients with rubeosis iridis also have retinal or disc neovascularization, he noted.
In addition, patients with central retinal vein occlusion (CRVO) and ocular ischemic syndrome preferentially develop neovascular glaucoma or iris neovascularization rather than disc or retinal new vessels. And patients with retinal detachment can develop retinal neovascularization and rubeosis iridis.
“I think CRVO is far and away one of the most common causes of iris neovascularization,” Dr. Eller said, noting that such patients should be seen monthly after initial diagnosis and treatment.
Approaches to treatment
“There really isn’t any difference between the articles [about neovascular glaucoma] in 1980, 1990 and 2000 when it comes to treatment of glaucoma. And pertinently, this is one of the things we do not do all that well,” Dr. Noecker said, noting there is a lack of good clinical evidence to guide treatment decisions.
Regarding treatments for neovascular glaucoma, “once again, we want to eliminate the underlying problem,” Dr. Noecker said.
“When we go through stages where we want to intervene, where we have a window of opportunity … the earlier stages are the ones where we can get the most benefit,” he said.
In the early stages of neovascular glaucoma, patients have normal IOP. However, patients begin developing tiny neovascular vessels around the pupillary margins, which can be seen using a high-magnification slit lamp and gonioscopy, Dr. Noecker said.
“We are looking for irregular nonradial vessels not in the substance of the iris stroma,” he said.
Patients are not typically seen until the second stage of neovascular glaucoma. At this point, IOP begins increasing, there is continuous neovascularization around the iris, and the angle disappears, Dr. Noecker said. There is also proliferation of neovascular tissue around the angle along with the development of fibrovascular membranes, which block the trabecular meshwork, he said.
In advanced neovascular glaucoma, patients have highly elevated IOP, photophobia and reduced visual acuity. IOP can frequently reach 50 to 60 mm Hg or more, and patients’ corneas begin to decompensate.
“The advanced stage … is the stage we would prefer not to see patients,” he said. “These are extremely inflamed eyes, and there is a limit to what we can do to correct this. … It may be the case that we are preserving the anatomy rather than the function of the eye.”
Treatment options
Dr. Noecker said that treatments for neovascular glaucoma involve first identifying the underlying problem, which is typically a retinal vascular problem such as vein occlusion or diabetic retinopathy.
“We want to stop them from developing neovascularization and neovascular glaucoma if possible. And in these cases, we are once again taking care of a retinal disease. We are catching it early before it becomes a problem, and typically we treat these with panretinal photocoagulation,” Dr. Noecker said.
“We also often institute medical therapy if the neovascularization of the iris is not complete or advanced to stop the condition from advancing,” he said. “Controlling the inflammation is important in this process just as in other neovascular processes.”
Topical atropine can help reduce blood flow through the iris. But topical steroids are the mainstay of treatment as well as medications to reduce IOP, he said.
For advanced cases, surgical intervention is frequently required, although primarily for patients who have useful vision at the time of diagnosis. Medications can also be used as a temporizing measure.
“We want to avoid a miotic agent because it would exacerbate the inflammation and also decrease the uveoscleral outflow, therefore increasing IOP. You may be forced to use oral or systemic medication,” Dr. Noecker said.
“Typically we use [medications] that reduce aqueous production; the prostaglandins, prostamides, the jury is out,” he said. “Certainly you can try them if other therapies have failed. But [they are] probably not first-line therapy in contrast to what we use for primary open-angle glaucoma.”
“You want to decrease the inflammation [first]. And if we have the option we prefer to wait; surgery is often less complicated and patients do better if we allow the eye to quiet down before we have to intervene,” Dr. Noecker said.
Trabeculectomy has a high rate of failure in neovascular glaucoma patients, he said. Ciliary body destruction and cryotherapy can be beneficial, although cryotherapy can be painful. Transscleral photocoagulation may be a less painful option, but it can lead to continued vision loss from such conditions as cataract formation and macular edema.
Newer treatment approaches
Newer approaches to treating neovascular glaucoma include the use of intravitreal triamcinolone, photodynamic therapy and selective laser trabeculoplasty.
In a small study of five patients in the early stages of neovascular glaucoma, monotherapy with intravitreal triamcinolone resulted in an IOP decrease from 32 mm Hg to 25 mm Hg. There was also a significant drop in rubeosis iridis among the patients treated, according to Dr. Noecker.
“Even if there is neovascularization of the iris, if you intervene quick enough, you see regression and a positive effect on IOP,” he said. “Triamcinolone appears to have an antiangiogenic effect on the iris and angle neovascularization. It may just be removing those vessels from the iris or the angle, making them go away is responsible for the decrease in pressure.”
PDT has also been shown to have some efficacy in a small case series involving patients with IOP greater than 40 mm Hg, he said.
In addition, there are anecdotal reports that SLT can induce a decrease in IOP in neovascular glaucoma patients with active angle neovascularization.
“Its mechanism is unclear. We really don’t really understand how SLT works in open-angle glaucoma. But it appears to be influencing the up-regulation of cytokines and macrophages. There is no thermal effect, unlike most laser treatments where you have coagulation of vessels. But it may be a potential therapy once we understand it better,” Dr. Noecker said.
For Your Information:
- Deepinder K. Dhaliwal, MD, Andrew W. Eller, MD, Francis S. Mah, MD, and Robert J. Noecker, MD, can be reached at the University of Pittsburgh Medical Center, Eye and Ear Institute, 203 Lothrop St., 8th Floor, Pittsburgh, PA 15213; 412-647-2200; fax: 412-647-5119.
- Michael Piechocki is an OSN Correspondent who writes primarily for OSN’s sister publication Orthopedics Today.