Glaucoma: Current Concepts

Educational Objectives

The goal of this program is to improve the management of glaucoma via the use of pharmaceuticals and changes in lifestyle. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the mechanisms through which bevacizumab can reverse neovascularization and prevent glaucoma in some patients.

2.   Identify lifestyle choices that can influence intraocular pressure in glaucoma patients.

3.   Discuss results of research on the relationship between diet and nutritional supplements and glaucoma risk.

4.   Recommend appropriate levels of exercise and physical activity to patients with advanced glaucoma.

5.   Explain the role of inflammation in the development of ocular surface disease and the contribution of benzal­konium chloride to that process.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and the planning committee re­ported nothing to disclose. In his lecture, Dr. Eisengart discusses the off-label use of bevacizumab intravitreal injection.

Acknowledgements

Drs. Eisengart and Callender spoke at the 27th Annual Meeting: Update for the Comprehensive Ophthalmologist 2009, held April 24, 2009, in Cleveland, OH, and sponsored by Case Western Reserve University. Dr. Khan was re­corded at Advances in Ophthalmology, held December 5-6, 2008, in Toronto, ON, and sponsored by the University of Toronto. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Bevacizumab in Glaucoma Surgery

Jonathan A. Eisengart, MD, Senior Clinical Instructor, Case Western Reserve University, University Hospitals Case Medical Center, Department of Ophthalmology and Visual Sciences, Cleveland, OH

Background: vascular endothelial growth factor (VEGF)  —stimulates growth of vascular endothelial cells; enhances growth of new vessels and increases permeability of existing vessels; promotes survival of neovascular networks; some evidence suggests VEGF also involved in cascade leading to fibroblast proliferation; produced in response to hypoxia, oncogenes, and various growth factors and cytokines

Bevacizumab (Avastin): recombinant monoclonal IgG antibody; has human and murine regions; binds to VEGF; prevents it from interacting with cell surface receptors; currently approved for treating metastatic colon and breast cancer and non–small-cell lung cancer; risks  —  intestinal perforation, bleeding, thrombotic events (stroke and heart attack), hypertension, renal problems, heart failure, and impaired wound healing

Risks associated with ophthalmic use: intravitreal injection  —low risk for endophthalmitis, retinal detachment, hemorrhage, and uveitis; systemic risks low; standard ophthalmic injection 1.25 mg; cancer chemotherapy dose 5 to 15 mg/kg (300-900 mg) every 2 to 3 wk; hypertension most commonly reported systemic side effect associ­ated with ophthalmic use; others include headache, nausea, and vomiting; ophthalmic use growing, despite lack of Food and Drug Administration  approval

Use in glaucoma surgery: particularly helpful for neovascular glaucoma; open-angle  —  could rescue eye from chronic glaucoma; closed-angle  —  can improve surgical outcomes; antifibrotic properties can help rescue failing bleb and reduce need for antimetabolites (mitomycin C)

Rescue therapy for neovascular glaucoma: given early enough, bevacizumab can reverse neovascularization and prevent glaucoma and angle closure, sometimes within 24 hr; most published data suggest  »60% of patients can avoid glaucoma surgery if angle still open; bevacizumab cannot open closed angle; results at different institutions vary; patients still require close follow-up

Bevacizumab as adjuvant to surgery: speaker treated 43-yr-old woman with diabetes, corneal edema, florid iris vascularization, pain, closed angle, decreased vision, and intraocular pressure (IOP) of 71 mm Hg; panretinal photocoagulation (PRP) contraindicated due to corneal edema; neovascularization resolved after intravitreal in­jection of bevacizumab; Ahmed tube then placed successfully; cornea cleared within 3 wk; patient underwent PRP and had 20/30 vision within 1 mo

Use in trabeculectomy: bevacizumab may modulate wound healing; used postoperatively, may rescue failing bleb; used intraoperatively, may improve surgical success rates; may supplement or replace antimetabolites; kills or suppresses murine fibroblasts in vitro in dose-dependent manner; in rabbit study, prolonged bleb survival and re­duced histologic evidence of fibrosis, compared to 5-fluorouracil; pilot study  —1.25 mg bevacizumab adminis­tered subconjunctivally to 12 patients immediately after trabeculectomy; no antimetabolites used; 11 successful cases, with good bleb morphology; speaker also uses bevacizumab to help rescue failing blebs; signs of impend­ing bleb failure  —  abundant vascularity, and increased thickness; low placement; rising IOP; injected near or into bleb, bevacizumab decreases vascularity, and may modulate wound healing and reduce scarring

Remaining issues: effectiveness not yet proven in controlled clinical trials; best route of administration still uncer­tain; unclear whether bevacizumab can replace or just augment antimetabolites; short-term and long-term safety problems, if any

Glaucoma: More Than Meets the Eye

Odette V. Callender, MD, Chief of Ophthalmology, Veterans Affairs Medical Center, Wilmington, DE

Complementary and alternative medicine (CAM): in one survey, 5.4% of glaucoma patients using CAM, mostly megavitamins and herbal therapy, followed by exercise and diet modification; of those patients, 70% got infor­mation from sources other than health care provider (eg, friends, internet); another study showed that internet sites often presented information without supporting facts or sources

Vitamins and herbs: Nurses’ Health Study and Health Professionals’ Follow-Up Study found no association be­tween antioxidant consumption and risk for primary open-angle glaucoma; unrelated literature review showed no beneficial effects on glaucoma from megavitamin consumption; Beaver Dam Study also showed no protective ef­fect of vitamin or mineral supplements; ginkgo  —  associated with temporary decrease in mean deviation and cor­rected pattern standard deviation (MD/CPSD), suggesting temporary improvement of visual field (VF); mechanism unknown; warn patients that ginkgo inhibits platelet aggregation, thus possibly contraindicated in pa­tients taking aspirin or warfarin

Diet: findings conflict; to date, insufficient information to recommend for or against any particular food or food group; eating more fruits and vegetables promotes health, “so it’s probably good for your eyes”

Marijuana: several studies have shown that marijuana decreases IOP in 60% to 65% of users, whether they have glaucoma or not; average drop 25%; lasts only 3 to 4 hr; not associated with any improvement in VF or optic nerve appearance; potency of plant sources varies widely; synthetic forms developed for cancer patients associ­ated with only small decrease in IOP (average of 1.5 mm Hg); mechanism of action  —  acts on central cannabi­noid receptor (CB1); CB1 found on ciliary body, so marijuana may decrease production of aqueous; effect dose-dependent; side effects  —  increased appetite, orthostatic hypotension, euphoria, and ocular effects; long-term ef­fects include hormonal and emphysema-like changes (concentration of tars and other carcinogens in marijuana exceeds that in tobacco cigarettes); may also increase cerebrovascular resistance, with consequent increased risk for stroke, seizure, and long-term cognitive defects; conclusion  —  risks outweigh potential benefits

Acupuncture: associated with possible mild short-term effect (15 min to 24 hr); no studies have measured effect be­yond 24 hr

Yoga: as relaxation technique, no discernible effect on IOP; sirsasana (headstand posture) for 5 min associated with immediate doubling of baseline IOP; pressure drops as soon as normal posture resumed, but remains elevated over baseline by 2 to 3 mm Hg; conclusion  —  headstand associated with significant increase in IOP that returns nearly to normal as soon as patient resumes normal posture; possibly detrimental for people with advanced glau­coma; might also explain why some patients worsen despite apparently normal IOP readings

Lifestyle habits

Caffeine: among people with hypertensive or normotensive glaucoma or ocular hypertension, associated with sig­nificant elevation of IOP 30, 60, and 90 min after drinking regular coffee; no such elevation seen after drinking herbal tea or decaffeinated coffee; 30 to 50 mg caffeine sufficient to produce effect in healthy patients; Blue Mountains Eye Study  —  enrolled patients with glaucoma, ocular hypertension, and normal eyes; among glau­coma patients, regular coffee drinkers had higher mean IOP and borderline positive association with higher caf­feine consumption and higher IOP; theory  —  caffeine may inhibit aqueous drainage or formation; conclusion  —  caffeine ingestion may increase IOP within 60 to 90 min in all patients; occurs with 30 to 50 mg of caffeine; ef­fect persists for ³3 hr but wears off after 4 hr; however, regular coffee drinkers may have mean higher baseline IOP, suggesting long-term effect; effect likely dose-dependent; consider counseling patients with advanced glau­coma to limit coffee intake; caffeine present in many beverages other than coffee, as well as foods and over-the-counter drugs; tobacco accelerates caffeine metabolism

Smoking: multiple studies have looked at role of smoking in increasing glaucoma risk, with inconsistent findings reported; raises IOP more in glaucoma patients than in controls; may affect aqueous humor dynamics; reduces IOP-lowering benefits of trabeculectomy; no clear effect of smoking status on effects of medication; conclusions  —  unclear whether smokers have higher glaucoma risk than nonsmokers; may increase IOP, but not enough to produce glaucoma; duration of hypertensive effect unknown; does appear to reduce effectiveness of trabecular surgery

Alcohol: Beaver Dam study showed no association between glaucoma and drinking status; other studies have shown alcohol related to ocular hypertension but not glaucoma, possible protective effect of alcohol, and lower IOP after alcohol consumption; conclusion  —  alcohol has no association with glaucoma risk and may even lower it

Exercise: associated with lowering of IOP, especially in glaucoma patients; lesser decrease in IOP among physi­cally fit individuals; must continue exercise program for benefit to persist; mechanism unknown; one theory attri­butes to exercise-induced lactic acidosis; if patient has pigment dispersion, consider pretreatment with pilocarpine before exercise; advanced congenital glaucoma  —  in study of 3 adults, exercise associated with re­duced central visual acuity and foveal sensitivity, and decreased mean deviation in VF; possibly related to vascu­lar steal from eyes during activity; reversible; consider advising patients with advanced glaucoma to limit activity if they notice visual symptoms; water ingestion  —  in healthy subjects, associated with transient rise in IOP; conclusions  —  exercise temporarily decreases IOP; benefit fades if not continued for ³3 wk; physical fitness low­ers IOP, but decreases additional effect of acute exercise; patients with advanced glaucoma or pigment dispersion should exercise with caution (consider evaluating patient before and after activity); water consumption during ex­ercise may blunt IOP-lowering effect

Weight lifting: in study of 30 healthy men, bench pressing increased IOP; effect exacerbated by holding breath; in study of 8 glaucoma patients, bench press and seated rows associated with increased IOP; IOP also increased during isometric exercises with heavy resistance; conclusions  —  weight lifting and isometrics may significantly increase IOP in healthy people and glaucoma patients; holding breath further increases pressure

High-resistance musical instruments: oboe, bassoon, French horn, trumpet; IOP related to force of blowing and ex­piratory resistance; higher or louder notes require more force and pressure; possibly problematic for professional musicians

Diabetes: associated in one study with thinner optic nerve layers; thinning worsened by panretinal photocoagulation (PRP); as diabetes severity increased, blinded observers more likely to label optic nerve as positive or suspicious for glaucoma; possibly due to edema; conclusions  —  diabetes may affect nerve fiber layer being observed; may also affect visual field results, especially among patients with previous PRP

Seasonal variations: several studies in different countries observed higher IOP in winter; mechanism unclear; effect persists even after trabeculectomy

Cosmetics: bimatoprost ophthalmic solution (Latisse) recently approved for treating hypotrichosis; may exacerbate hypotony in patients with ciliary body dysfunction and mask high IOP, especially if patient already treating hypo­trichosis with prostaglandin analogue

Glaucoma and the Ocular Surface

Hamza Khan, MD, Clinical Assistant Professor of Ophthalomolgy, University of British Columbia, Vancouver

Background: proposed mechanisms behind ocular surface changes associated with cytotoxic agents include neuro­trophic and inflammatory effects; drugs and preservatives both implicated; pathway considered immunomodula­tory, as with ocular surface diseases; also classified as drug-induced pemphigoid; laboratory and clinical data show increased expression of cellular markers for precursors to apoptosis; preservatives destabilize tear film; patients on glaucoma therapies have higher dry-eye scores; mechanical effects  —  dell formation next to filtering bleb or tube shunt

Role of inflammation in ocular surface disease: dry eye “vicious cycle”; starts with increased tear evaporation or decreased production, leading to hyperosmolarity of tear film and epithelial damage; results in inflammation and goblet cell loss, followed by poor tear film distribution, more inflammation, and perpetuation of cycle (“toxic tears”); membrane matrix phospholipid bilayer has positive feedback loop such that damage to conjunctival gob­let cells or accessory lachrymal glands leads to further damage

Role of glaucoma: medications possibly inflammatory; conjunctival specimens from glaucoma patients show in­creased expression of inflammatory markers when exposed long-term to benzalkonium chloride (BAK); b-block­ers and prostaglandins associated with higher level of C-C chemokine receptor positivity in patients with glaucoma, compared to healthy people; conjunctival cell cultures from glaucoma patients exposed to BAK sus­tain more damage to cell matrix than normal tissues; contributes to positive feedback; correlates with increased vascularity and neutrophil margination of conjunctival samples; in one study, patients using preserved drops ex­perienced ocular surface changes twice as often as patients using unpreserved drops; frequency of signs and symptoms dose-related; symptoms  —red, burning, itching eyes; vital dye staining; decreased tear film stability

Management options: use of unpreserved tears standard; reduce environmental contributors through better air flow and humidity; treat associated eyelid disease; use punctal occlusion with caution; consider supplements of omega-3-polyunsaturated fatty acids (have negative feedback on arachidonic acid pathway); reduce BAK exposure by re­ducing polypharmacy through use of combination drugs and drugs without BAK; surgical management  —  findings of Collaborative Initial Glaucoma Treatment Study show no difference, compared to medical treatment, 4 to 5 yr after surgery, but longer follow-up necessary; surgical methods have improved since then; patients in surgical arm of study did well after cataract removal; treatment of inflammation  —  insufficient evidence to recommend

Suggested Reading

Beutel J et al: Bevacizumab as adjuvant for neovascular glaucoma. Acta Ophthalmol Sept 20, 2008 [Epub ahead of print]; Bono­vas S et al: Epidemiological association between cigarette smoking and primary open-angle glaucoma: a meta-analysis. Public Health 118:256, 2004; Chandrasekaran S et al: Effects of caffeine on intraocular pressure: the Blue Mountains Eye Study. J Glaucoma 14:504, 2005; Coleman AL et al: Glaucoma risk and the consumption of fruits and vegetables among older women in the study of osteoporotic fractures. Am J Ophthalmol 145:1081, 2008; Grover S et al: Intracameral bevacizumab effectively re­duces aqueous vascular endothelial growth factor concentrations in neovascular glaucoma. Br J Ophthalmol 93:273, 2009; Jue A: Angiogenesis: trabeculectomy and bevacizumab. Semin Ophthalmol 24:122, 2009; Leske MC et al: Open-angle glaucoma and ocular hypertension: the Long Island Glaucoma Case-control Study. Ophthalmic Epidemiol 3:85, 1996; Musch DC et al: Factors associated with intraocular pressure before and during 9 years of treatment in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology 115:927, 2008; Noecker RJ et al:Corneal and conjunctival changes caused by commonly used glaucoma medi­cations. Cornea 23:490, 2004; Parrish RK 2nd et al: Five-year follow-up optic disc findings of the Collaborative Initial Glau­coma Treatment Study. Am J Ophthalmol 147:717, 2009; Pasquale LR: Optimizing therapy for newly diagnosed open-angle glaucoma: lessons learned from the Collaborative Initial Glaucoma Treatment Study. Arch Ophthalmol 126:125, 2008; Porcella A et al: The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur J Neurosci 13:409, 2001.