1. Counsel patients about complications associated with laser-assisted in situ keratomileusis (LASIK).

2. Identify patients likely to benefit from treatment for lattice degeneration before undergoing LASIK.

3. Detail the complications and risk factors for complications after intraocular procedures.

4. Compare the available approaches to inhibiting the production or activity of vascular endothelial growth factor.

5. Implement strategies to reduce the frequency of intraocular injections for the management of AMD.

Retinal Complications and Concerns with Intra- and Extraocular Refractive Surgery

Epidemiology: prevalence of myopia—≈25% in United States (varies globally); retinal detachment—lifetime risk in general population, 1 in ≈350; 67% of retinal detachments occur in myopic patients; risk increases with axial length (but decreases with extreme myopia); significant myopia associated with lifelong risk of 8% to 11%; lattice degeneration— prevalence ≈8% in general population and ≈15% among myopic patients; 40% of patients with retinal detachments have identifiable lattice degeneration at time of surgery

Macular hemorrhage: myopia increases risk for lacquer cracks, which may result in hemorrhage (generally resolve spontaneously); generally not associated with choroidal neovascularization (CNV) or poor visual outcomes; use of pressure ring—application and release causes significant fluctuations in intraocular pressure (IOP) and axial length, and may result in acute lacquer crack; laser—possibly transmits energy to vitreous cavity, resulting in macular hemorrhage

Other problems: LASIK flap may be dislodged during vitreous surgery (important to inform posterior-segment surgeon about history of LASIK); silicon oil-induced band keratopathy may develop in LASIK flap; once flap dislodged, fibrous or epithelial tissue may grow beneath

Treating lattice degeneration: no evidence of definitive benefit; lower relative risk for retinal detachment after LASIK may be related to use of preoperative prophylactic laser therapy; speaker recommends treating symptomatic patients and those with substantial lattice degeneration; funduscopy recommended before performing LASIK; study found pathology (mostly lattice degeneration) warranting laser prophylaxis in ≈1% of eyes

Anti-VEGF Therapy for Age-related Macular Degeneration: Current Update and Future Developments

Vascular endothelial growth factor (VEGF): secreted by retinal pigment epithelium (RPE) and other parts of body in response to ischemia; induces cellular signaling; VEGF family—VEGF-A (multiple isomers) primarily responsible for angiogenesis; platelet-derived growth factor also involved in angiogenesis; effects—stimulates angiogenesis; increases vascular permeability; induces inflammation

Angiogenesis: receptors on cell membrane interact with growth factors; activation induces signaling, leading to cell growth, proliferation, and migration; approaches to blocking angiogenesis—prevent growth factors from interacting with receptors; interfere with signaling; prevent proliferation; inhibit matrix metalloproteinase (MMP)

VEGF functions: general—induces vascular permeability (50,000 times more potent than histamine); recruits white blood cells; extraocular functions—involved in embryonic development, female reproductive cycle, and bone repair; important for repair after myocardial infarction; ocular functions—not well understood; probably involved in maintenance of choroid and fenestrae; implicated in CNV; results from animal studies—synthetic VEGF injected into primate eye caused capillaries to dilate and leak and microaneurysms to form; at 1 wk, presentation similar to that of diabetic retinopathy, including proliferation of endothelial cells and stimulation of angiogenesis

Targeting VEGF pathway: aptomers (eg, pegaptanib [Macugen]) selectively inhibit VEGF; anti-VEGF antibodies (eg, bevacizumab [Avastin]; ranibizumab [Lucentis]); antibodies to VEGF receptor; small interfering RNA (siRNA) interferes with production of VEGF; VEGF trap; kinase inhibitors decrease cellular signaling

Injection techniques: preparation—anesthetic choices include topical lidocaine (applied with pledget) and subconjunctival lidocaine; lidocaine gel falling out of favor (may harbor bacteria); povidone iodine important, but may cause irritation; antibiotics—optional; speaker uses fluoroquinolones; given prophylactically and/or after injection; speculum—required when applying povidone iodine; holding eyelids open with fingers acceptable (do not allow eyelids to touch); injection—superotemporal (preferred by speaker; fewer bacteria under upper eyelid) or inferotemporal; adequate anesthetic (topical plus subconjunctival) recommended

Pegaptanib: aptomer (more selective than antibodies); clinical trials—VEGF Inhibition Study In Ocular Neovascularization (VISION) compared intravitreal injections of pegaptanib (at several doses) to sham injection; concurrent photodynamic therapy (PDT) allowed (physician’s discretion); treatment effectively minimized vision loss but resulted in minimal visual improvement; in treatment and control groups, vision loss stabilized after ≈1 yr

Ranibizumab: monoclonal antibody fragment (R-Fab) binds all isoforms of VEGF (whereas pegaptanib primarily binds VEGF 165); clinical trials—Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR; phase 3 trial) found ranibizumab superior to verteporfin PDT for improving vision and minimizing vision loss; treatment resulted in 20-letter difference in visual acuity at 1 yr; another phase 3 trial (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration [MARINA]) showed improved visual outcomes with ranibizumab treatment, compared to sham injection in patients with minimally classic lesions; third phase 3 trial (FhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety [FOCUS]) found increased incidence of uveitis when ranibizumab combined with PDT (vs PDT alone) in patients with classic CNV

Dosing frequency: phase 3b study (Phase IIIb, multicentre, randomized, double-masked, sham Injection-controlled study of Efficacy and safety of Ranibizumab [PIER]) included induction phase (patients treated monthly with ranibizumab) followed by maintenance phase (injections every 3 mo); visual gain achieved with induction therapy lost (in some patients) during maintenance therapy, but outcomes at 1 yr remained better than control; smaller study (Prospective Optical coherence tomography imaging of patients with Neovascular AMD Treated with intra-Ocular ranibizumab [PrONTO]) compared monthly injections to as needed dosing; triggers for injection in “as needed” group included presence of fluid or hemorrhage on optical coherence tomography (OCT); comparable results in both groups during 2-yr follow-up; on average, patients receiving as-needed treatments needed 5 to 6 treatments per year; approaches—“treat and observe” approach (speaker’s preference) begins with monthly induction phase, followed by monthly OCT to assess need for additional treatment; “treat and extend” approach begins with monthly injections, then extends treatment interval by 2 wk after each subsequent injection (with goal of 3-mo interval, if possible, for lifetime); speaker’s protocol—gives injections as long as vision continues to improve; gives one additional injection after vision stabilizes; performs monthly assessment using OCT or fluorescein angiography; reinitiates treatment for patients with evidence of fluid or hemorrhage on OCT; considers treating patients who report decline in vision or who say “I’m getting worse” (even if no drop in vision)

Combination therapy: adding full- or half-dose of verteporfin PDT may decrease number of injections needed; combination with dexamethasone also used; quadruple therapy for patients with age-related macular degeneration (AMD) uses bevacizumab, intraocular dexamethasone, reduced fluence PDT, and partial vitrectomy; study showed only 5% of patients required second injection

Bevacizumab: full-sized antibody used in cancer therapy; small study (Systemic Avastin for Neovascular AMD [SANA]) showed treatment (intravenous [IV] infusion) of patients with macular degeneration resulted in improvements in vision and retinal thickness; OCT showed regression of fluid; blood pressure increased transiently; although visual outcomes superior to those seen with ranibizumab, IV therapy rejected because of increased risk for stroke; intravitreal injections—study showed reduced retinal thickness, improved vision, and absence of systemic adverse effects; some patients required \>1 injection; access for off-label use—previously, readily available through compounding pharmacies; because of legal issues, manufacturer can no longer sell Avastin to compounding pharmacies, but can sell to physicians and ship to compounding pharmacies (“drop shipment”; practice illegal in some states); note—Lucentis available free of charge for any off-label indication for patients who earn <$100,000/yr; preoperative use—caliber of blood vessels decreases; capillaries begin to reperfuse

Risk for stroke: bevacizumab—5% with systemic administration (data from patients with cancer); unknown risk associated with ocular administration (IV dose 300-500 times higher than ocular dose); ranibizumab—according to Safety in Previously Treated and Newly Diagnosed Patients with Neovascular Age-related Macular Degeneration (SAILOR) study, higher dose (0.5 mg) associated with higher risk than lower dose (0.3 mg); comparative risk—unknown; differences in half-life, localization, and VEGF affinity may affect relative risk

VEGF trap: binding domain of surface receptor for VEGF combined with Fc region of antibody; effectively acts as antibody against anything that binds to receptor (eg, VEGF, other cytokines); trap functions as decoy receptor for VEGF; phase 2 trial (CLEAR-IT)—intravitreal injection well tolerated; treatment resulted in decreased central retinal thickness and increased visual acuity (similar to that reported with ranibizumab); monthly dosing best, but appears effective at intervals up to 2 mo; phase 3 trial (VIEW 1)—in progress; head-to-head comparison with ranibizumab; primary features—reduces retinal thickness; improves vision; safe and well tolerated; may allow dosing every 8 wk (vs monthly); expected to be expensive

Gene silencing: siRNA prevents gene expression by interfering with messenger RNA (mRNA); siRNA may target mRNA that encodes for, eg, VEGF or VEGF receptor; phase 3 study—in progress; induction phase with ranibizumab

Rationale for combination therapy: first inactivate existing VEGF with antibody; prevent further production of VEGF using gene silencing; goal—reduce frequency of injections

Protein kinase inhibition: mechanism of action of several drugs used to treat patients with cancer; studies looking at intraocular use in progress; agents interfere with signaling proteins; oral agent in development; concern about hypertension but not thromboembolism

Developing therapies: radiation therapy—clinical trial in progress; vitrectomy performed; β-radiation probe placed beneath retina (shielded); initial results encouraging, but enrollment slow; gene therapy—uses adenovirus vector to manipulate DNA