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Ophthalmic Pearls

Photodynamic Therapy for Neovascular AMD
By Sunil K. Srivastava, MD, and Jonathan Etter
Edited by Sharon Fekrat, MD, and Ingrid U. Scott, MD, MPH
 
 

Age-related macular degeneration remains the leading cause of irreversible central visual loss among the elderly in the United States with a prevalence of 11 percent in Americans between the ages of 65 and 74 and 28 percent in those 75 and older.1 AMD warrants special attention especially given that the Census Bureau predicts that those aged 85 and over will comprise 4.6 percent of the U.S. population by 2050.2

Despite the fact that non-neovascular macular degeneration is more common, it is the neovascular variant, characterized by CNV, that most often causes acute severe loss of vision. Use of fluorescein angiography has helped further characterize neovascular AMD into classic and occult forms.

  • Classic CNV demonstrates a lacy hyperfluorescence in the early phase of the angiogram with leakage in later phases.
  • Occult CNV demonstrates either late-phase leakage from an undetermined source or the presence of a fibrovascular pigment epithelial detachment.

The Macular Photocoagulation Study (MPS) showed benefit in using argon laser photocoagulation for the treatment of well-demarcated subfoveal, juxtafoveal and extrafoveal CNV lesions. Although rates of severe vision loss were decreased in treated groups compared with untreated groups at later points in time, MPS laser photocoagulation has several drawbacks. For instance, immediate vision loss commonly occurs in patients with subfoveal lesions treated with laser, and scotomas are a common complication in patients with juxtafoveal and extrafoveal lesions treated with laser. In addition, recurrence rates are high.

There has been increasing use of photodynamic therapy (PDT) to treat neovascular AMD since FDA approval in 2000. Two large clinical trials—Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) and Verteporfin in Photodynamic Therapy (VIP)—have shown the treatment to be effective in slowing the visual deterioration associated with some types of CNV. In addition, PDT was found to be well tolerated without significant systemic adverse events.

Preferred Patients
PDT is not appropriate for all cases of neovascular AMD. Factors such as visual acuity and lesion location, composition and size must be considered. Initially, PDT was indicated only for predominantly classic (> 50 percent classic) subfoveal lesions with a greatest linear dimension of 5,400 micrometers. More recently, small (< four MPS disc areas) subfoveal occult CNV without any classic component or minimally classic lesions have also been found to benefit from PDT.3

How It Works
PDT relies on the tissue presence of a photosensitizing agent that is subsequently activated by a specific wavelength of light. The only such agent currently approved is verteporfin (Visudyne).

Following infusion of the photosensitizing agent, verteporfin accumulates preferentially in areas of CNV because low-density lipoprotein receptors are preferentially expressed on neovascular endothelial cells. This is crucial to PDT’s ability to initiate vascular destruction in areas of CNV while sparing normal vasculature.

Upon interaction with the light, the agent is transformed into an activated state that reacts with oxygen to yield cytotoxic singlet oxygen. Cell damage results in endothelial destruction, which serves to sclerose CNV.

Implementing PDT
Someone skilled in intravenous infusion is required for administering verteporfin.

The patient’s height and weight are measured and used to calculate the patient’s body surface area. Verteporfin dosage is 6 milligrams per meter squared of body surface area; slide rules provided by the agent’s manufacturer permit the calculations to be made quickly.

Prior to mixing and delivering the infusion, all calculations should be rechecked to ensure correct dosage.

The drug is infused intravenously over 10 minutes. Fifteen minutes after the start of the infusion, a 689 nanometer laser light delivering 50 Joules per centimeter2 at an intensity of 600 milliwatts/cm2 over 83 seconds is administered. The treatment spot size is calculated from the fluorescein angiogram. The greatest linear dimension is determined and 1,000 µm is added to this measurement. A fundus contact lens of known magnification is placed onto the eye and the lesion is centered within the treatment spot area.

The half-life of verteporfin is between five and six hours; therefore, most has been cleared from the body after 24 hours. It is important that patients avoid direct sunlight for five days following verteporfin therapy to avoid photosensitivity reactions.

Patients should be instructed to remain indoors for this time as well and to limit skin exposure with the use of protective clothing. The use of sunscreen as a substitute during this period does not prevent damage to skin and is therefore contraindicated.

Follow-Up
Patients are commonly seen between six weeks to three months following treatment. At that point, a repeat fluorescein angiogram is generally performed to evaluate for any further leakage. If leakage is present, PDT is often repeated. If leakage is absent, PDT is not indicated at that visit.

For at least the first two years following PDT, frequent follow-up is encouraged (specific time intervals vary depending upon individual practice).4

Adverse Effects
Overall, PDT is well tolerated. However, patients should be informed about the possibility of the following side effects:5

  • Visual disturbances. Both the VIP and TAP trials found an increased incidence of visual disturbances in those receiving PDT compared with placebo. The term “visual disturbance” is broad and includes abnormalities of vision (blurriness, flashes, floaters), decreased vision and visual field defects. Most visual disturbances reported after PDT are mild and temporary. About 5 percent of patients experience a significant decrease in visual acuity.
  • Back pain. Following the infusion of verteporfin, 2.2 percent of patients will experience back pain. The pain usually occurs only during the infusion period, and its mechanism is unknown. If the patient experiences back pain, it is recommended that the infusion be halted. If 50 percent or more of the verteporfin has been administered, PDT may be completed.
  • Photosensitivity. Because verteporfin is a photosensitizing agent, it can cause skin damage if the patient is exposed to sunlight following infusion. Most adverse events in this category occur in the form of moderate sunburn. Photosensitivity can be prevented if dosing is appropriate and if the patient remains out of direct sunlight for five days postinfusion.
  • Injection site reactions. Appropriate venipuncture technique diminishes the risk of this event.
  • Severe allergic reactions. These are extremely rare; nevertheless, as with any infusion, the patient should be monitored. 

Future Developments
PDT reduces the amount of vision loss in patients with subfoveal CNV. Nevertheless, some degree of vision loss usually still occurs despite successful treatment. Additional treatment modalities are currently under investigation. In the future, these therapies may be used in conjunction with, or as a replacement for, PDT.

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1 Martidis, A. and M. Tennant. “Age-Related Macular Degeneration,” in Ophthalmology, ed. M. Yanoff et al. (St. Louis: Mosby, 2004), 925–933.
2 U.S. Administration on Aging; www.aoa.gov.
3 Blinder, K. J. et al. Am J Ophthalmol 2003; 136:407–418.
4 Verteporfin Roundtable 2001 and 2001 Participants. Retina 2002:22(1):6–18.
5 Azab, M. et al. Retina 2004:24(1):1–12.

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Dr. Srivastava is a retina fellow at Duke University and Mr. Etter is a fourth-year medical student at Jefferson Medical College in Philadelphia

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