Addressing the Difficult AMD Cases

When it comes to AMD treatment, an open mind is essential.

STUART MICHAELSON

Like pitchers who must constantly adjust to tough, young, ever-improving batters, retina specialists can never afford to stop learning and changing tactics as they tackle the challenges difficult cases of AMD can present.

That fact was in great evidence when five doctors recently shared challenging patient histories that forced them to make mid-game alterations to solve crucial quality-of-life problems a wide array of AMD sufferers face.

The answers varied: In some cases, doctors changed the choice of drug or frequency of doses; in others, they used photodynamic therapy, now rarely applied in AMD. In another case, genetic testing led to successful treatment, and in still another, steroid treatment made a difference. In another, an examination of AMD issues related to ethnic background proved key to making the right medical call.

TWO PATIENTS, TWO SECOND LOOKS

Ravi D. Patel, MD, director of clinical research at Retinal Vitreal Consultants in Chicago, remembers two AMD patients whose treatments benefited from second looks of their cases.

In July 2012, Dr. Patel started treating a 61-year-old woman who winters in Florida and lives the rest of the year in Chicago. Upon presentation, the woman suffered from acute blurred and distorted vision in her right eye. Her vision in that eye was 20/60, and her left eye was 20/40. She was diagnosed with wet AMD in the right eye, and dry AMD in the left.

OCT and fluorescein angiography found a choroidal neovascular membrane in the right eye, as well as subretinal and intraretinal fluid. Dr. Patel initiated treatment with three monthly intravitreal injections of ranibizumab (Lucentis, Genentech, South San Francisco, CA). At month four, the fluid had resolved, with visual improvement to 20/30 in the right eye.

For her third through sixth visits, at six-week intervals, she received ranibizumab injections. But on the sixth visit, she had intraretinal fluid accumulation and decreased visual acuity. The treatment had reached a crossroads.

At that point, she received a seventh ranibizumab injection and was told to return in a month. At that juncture, she continued to have persistent intraretinal fluid, and her vision was now 20/70.

More Imaging, New Drug

Given the unresponsive nature of the wet AMD after seven injections of ranibizumab, she underwent another fluorescein angiogram and additional OCT imaging. Dr. Patel changed her treatment to aflibercept (Eylea, Regeneron, Tarrytown, NY) for three monthly intravitreal injections, leading to mild improvement in the intraretinal fluid, although not as much as from the first three ranibizumab intravitreal injections.

Figure. In this patient, VA of 5/200 when first treated improved to 20/70 (top), then 20/60 (center), and then 20/30 (bottom).

Further OCT imaging detected outer retinal tubulation, which is commonly under-diagnosed. Dr. Patel then performed PDT, and upon a follow-up visit a month later, he found her intraretinal fluid had significantly decreased, with retinal contour improvement and visual acuity improvement to 20/40.

At that point, Dr. Patel resumed monthly ranibizumab intravitreal injections with an effective treatment response. “This,” he says, is a “great example of not being single-minded” and the importance of “thinking outside of the box.”

The Second Case

In a second case, also in 2012, Dr. Patel treated a 73-year-old woman with a history of dry AMD in both eyes. Her vision was 20/40 in the right eye and 20/80 in the left. She had drusen in both eyes, and in her left eye, she had a very small retinal hemorrhage and intraretinal fluid, signifying conversion from dry to wet AMD.

A fluorescein angiogram revealed an occult neovascular membrane in her left eye, as well as vitreomacular traction. The VMT was causing mild disruption of the foveal contour.

After four monthly intravitreal ranibizumab injections, some mild anatomical and visual improvement occurred. After considering vitrectomy to remove the vitreous and to relieve the traction, Dr. Patel turned to ocriplasmin (Jetrea, Thrombogenics, Iselin, NJ), which the FDA approved in 2012.

After relieving the traction with an intravitreal injection of ocriplasmin, Dr. Patel resumed monthly ranibizumab injections, with treatment success and VA of 20/40 in the left eye.

When it comes to treating retinal disease, Dr. Patel stresses, “Many things are not what they initially seem.”

PDT PROVES KEY

Sunir J. Garg, MD, FACS, of the Retina Service of Wills Eye Hospital in Philadelphia, recalls the case of a man he started treating in 2009, when the man was in his 80s.

Referred to Dr. Garg by an area ophthalmologist, the patient had blurred vision and distortion in the left eye; the right eye was 20/20 with dry AMD. The left eye had 20/60 vision and wet AMD. Dr. Garg treated him with intravitreal bevacizumab (Avastin, Genentech) for two visits.

Because those treatments yielded no real change, Dr. Garg switched to monthly ranibizumab injections for more than a year. The result was that while the man’s condition did not worsen, it did not improve either.

Dr. Garg then performed PDT with verteporfin (Visudyne, Valeant Pharmaceuticals, Bridgewater, NJ) in the left eye, and after one treatment, all of the fluid was gone. For the next two-and-a-half years, the man came in for checkups every two or three months, and he required no treatments during that time.

Unexpected Relapse

However, when the man came in for a checkup in November 2012, he had blurred vision. Dr. Garg found recurrent fluid in the left eye upon examination that OCT imaging had confirmed.

At that point, Dr. Garg treated his patient with four monthly ranibizumab injections, which stabilized his condition but did not result in resolution of the fluid. Dr. Garg then performed another PDT treatment in early 2013. When the man returned one month after PDT, the fluid had resolved. A more recent visit in July was also encouraging. The fluid was still resolved, achieved without further injections.

The patient “was really very happy” with his progress, Dr. Garg says, noting that the man’s vision was 20/60 when he first presented in 2009, at which it remained until 2010, when it worsened to 20/400.

But with the PDT and ranibizumab treatments, his vision slowly improved, and now it is 20/40 — “the best it has ever been.”

GENETIC TESTING MAKES A CRUCIAL DIFFERENCE

Veeral Sheth, MD, director of scientific affairs at University Retina and Macula Associates in Oak Forest, IL, recalls a patient who came to him in the summer of 2011.

Dr. Sheth says the patient, a man then 66 years old, had pigmentary changes in his right eye and that his left eye, with 20/70 vision, had a large area of intraretinal fluid associated with pigment epithelial detachment. A general ophthalmologist referred the man to Dr. Sheth for AMD evaluation.

Through an angiogram, Dr. Sheth confirmed the diagnosis of wet AMD in the man’s left eye and treated him with ranibizumab. After six injections, Dr. Sheth saw only minimal change in the appearance of the retina, and vision remained at 20/70, with persistent fluid.

The patient, feeling that “things weren’t getting better,” was concerned. The injections of ranibizumab increased in frequency: After returning for a seventh injection, the man received an eighth two weeks later.

A Turning Point

During this time, Dr. Sheth turned to genetic testing for the man, who had received a second opinion. The testing offered a diagnosis of possible central serous chorioretinopathy.

The genetic test, which examined multiple genes to compute a clinical score to assess risk, from high to low, of AMD, demonstrated that the man was at high risk for AMD-related CNV despite his relatively young age.

Because of the persistent PED after seven ranibizumab injections, Dr. Sheth switched the man’s treatments from ranibizumab to aflibercept. Soon after the change, “quick and robust improvement” occurred.

The PED improved after the first injection, with vision improving to 20/60. After the second injection, the fluid was gone, and the vision was 20/50, where it has remained as of June 2013.

IMPROVEMENT AFTER STEROID TREATMENT

Timothy G. Murray, MD, MBA, founding director and CEO of Ocular Oncology and Retina of Miami, remembers the case of a 76-year-old woman who lived alone. She was “terrified that she couldn’t take care of herself” after experiencing vision problems, Dr. Murray says. After combination therapy involving steroids, she was able not only to continue caring for herself but also to drive her car.

The patient, who presented for treatment for AMD, had a disciform scar in her right eye, which left her functionally blind in that eye. Her right eye had not been previously treated.

The new concern was a vision change in her left eye, with distortion in the central macula. She was diagnosed with an AMD-associated occult subretinal neovascular complex, leaving her afraid that she would be completely blind.

Suffering persistently poor VA and with progressive intraretinal cystic development of fluid, she was treated with bevacizumab in her left eye. After a return six weeks later, when she received an additional bevacizumab injection, Dr. Murray shortened treatments to four-week intervals.

Triamcinolone to the Rescue

With increasing fluid in the retina and large cystic leakage, Dr. Murray turned to a steroid, intravitreal triamcinolone acetonide (Triescence, Alcon, Fort Worth, TX), used in a series of treatments in combination with bevacizumab.

Dr. Murray was able to extend out the treatment injections to eight-week intervals, with the eventual result that vision in the left eye, which was 5/200 when he first treated her, improved to 20/70. After the first steroid injection, vision improved to 20/60 and then, after the second, to 20/30 (Figure).

Dr. Murray’s take-home message for this woman, whom he continues to treat two years after he first took her on as a patient, was that “bevacizumab alone was not enough to address the leakage, but with a combination of bevacizumab and a steroid, fluid leakage was eliminated.”

Noting that the potential inflammatory component of AMD may be more responsive to steroid treatment than anti-VEGF, Dr. Murray adds that while steroids have drawbacks in that they can induce cataracts and glaucoma, they were the right course for this patient. The patient had already undergone cataract surgery, and she did not require glaucoma therapy.

Still, at the start, the woman “was terrified,” but Dr. Murray “reassured her that we could improve her vision.” Nevertheless, he adds, “she was disappointed when her vision didn’t improve after the first steroid treatment.”

It is common, Dr. Murray said, for vision to decrease after the first steroid treatment, but within 72 hours, significant improvement occurred, and she was “very pleased.”

ETHNIC BACKGROUND PROVIDES A CLUE

Lee M. Jampol, MD, Louis Feinberg Professor at Northwestern University, recalls a middle-aged patient he treated approximately six years ago, who was unable to work after losing sight in his left eye.

The patient, a physician of Chinese-American background, was examined by a specialist who noted hemorrhaging and fluid and diagnosed AMD. The specialist treated him with standard therapies (including anti-VEGF drugs and intravitreal steroids) with little response.

At this point, Dr. Jampol remembers, the man was “very unhappy” because he was losing his sight and, it seemed, his career. In search of a second opinion, Dr. Jampol examined the man, seeing only a few drusen in the involved eye and none in the other eye.

An Unusual Diagnosis

Dr. Jampol, aware of AMD issues associated with African-Americans, people from the Far East, including China and Japan, and natives of India, suspected idiopathic polypoidal choroidal vasculopathy, which is often associated with patients from those ethnic backgrounds. An indocyanine green angiogram confirmed the diagnosis.

Idiopathic PCV is an uncommon condition usually considered to be a variant of neovascular AMD, which is also seen in younger patients and seems to affect pigmented individuals preferentially. Patients of Asian and African-American descent are more at risk of developing the disorder.

With the diagnosis confirmed, Dr. Jampol treated his patient with PDT. Patients with idiopathic PCV often show poor responses, Dr. Jampol said, to anti-VEGF treatments, but they often respond to PDT.

The response to PDT, Dr. Jampol says, was “dramatic”; the hemorrhaging and fluid disappeared, and the patient’s vision improved. Years have now passed without a recurrence.

CONCLUSION

Clearly, anti-VEGF drugs have revolutionized the treatment of AMD, but they do not constitute a “magic bullet” for every patient. While treatment-resistance can be frustrating to both doctor and patient, patience and innovation can help even the most recalcitrant cases. RP