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Under-recognition of polypoidal choroidal vasculopathy could result in suboptimal treatment
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An accurate diagnosis and the correct identification of the polypoidal choroidal vasculopathy subtype of wet macular degeneration are necessary to determine the proper and most effective treatment route for patients.
However, the gold standard of diagnostic tools for the disease is underused in America, and polypoidal choroidal vasculopathy (PCV) is often misdiagnosed in patients as typical wet age-related macular degeneration, Raymond Wee, MD, of Retina Consultants of Hawaii, said.
“The biggest point I have is that PCV is an under-recognized disease in the United States because ICG (indocyanine green) angiography is underutilized. Recognition of PCV is extremely important because the treatment algorithm is different from wet AMD. If you are not recognizing the disease, you could be treating it like run-of-the-mill wet AMD, which is primarily a pharmacological treatment,” Wee said.
PCV can result in an abnormal subretinal vascular network with polyp formation, Wee said. Treatment routes depend on several factors, but diagnosing the disease can be difficult if ICG angiography is not used.
The diagnosis of PCV typically requires a combination of history, clinical examination and multimodal imaging, Kapil Kapoor, MD, of Wagner Macula & Retina Center in Virginia, said.
Image: Kokame GT, Wee R
A patient’s history will usually reveal painless vision loss in Asian or African women, often slightly younger than the typical age for AMD, he said.
“Given that [PCV] is not as common in the United States, its decreased prevalence often allows the cases that do present to go unrecognized. Fundus exam will sometimes reveal subtle orange-reddish bulbous lesions in the setting of exudates, hemorrhages and subretinal fluid and the absence of significant drusen. Ultimately, a panel of multimodality imaging is helpful to clinch the diagnosis. Optical coherence tomography with enhanced depth imaging is helpful to document the presence of subretinal fluid and exudates and may identify a pachychoroid,” Kapoor said.
Symptoms are similar
Because the clinical findings of PCV and wet AMD are almost identical, ICG angiography with a scanning laser ophthalmoscope video angiography is a necessity for diagnosing the disease, Gregg T. Kokame, MD, MMM, of Retina Consultants of Hawaii, said.
“Scanning laser ophthalmoscopic video angiography is more sensitive at diagnosing PCV than ICG angiography obtained on a fundus camera. A newer technique that is useful for practices is to utilize en face OCT imaging, which can show the very characteristic polypoidal dilations and subretinal vessels well, and since the data is often available on most OCT machines in use, it can be utilized on previous OCT studies, even prior to treatment was started. Polyps may regress after treatment, especially with prior photodynamic therapy,” Kokame said.
However, ICG angiography is not readily used in the U.S. to diagnose PCV. In addition, ICG angiography is expensive to perform if the scanning laser ophthalmoscope will be utilized, which is best for PCV, he noted.
“The dye is also expensive, and having diagnostician staff trained to do ICG angiography is often lacking. Retina specialists also have not been trained on how to read ICG angiograms well during their training,” Kokame said.
Observation of polyps
Kokame said that a successful confirmation of PCV hinges on the ophthalmologist’s use of ICG angiography and observation of the presence of polyps, which are often hyperfluorescent with a hypofluorescent border but not always with a branching network.
“En face OCT is also a promising way to make the diagnosis. A B-scan OCT shows the polyps as inverted U-shaped lesions under the retina and between the [retinal pigment epithelium] and Bruch’s membrane, and the branching vascular network as a double line sign with slight elevation of the RPE above Bruch’s membrane,” he said.
The diagnosis of PCV absolutely requires the use of ICG angiography, but not every hyperfluorescent spot on the ICG angiography is a polyp, Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth), of the National Healthcare Group Eye Institute of Singapore, said.
It is important to use a set of diagnostic criteria to confirm PCV in a patient. The presence of an early hyperfluorescent nodule on ICG angiography can be the first step to diagnosing PCV, Tan said.
“The criteria which we use is the presence of an early hyperfluorescent nodule on ICG angiography, together with at least one of the following six criteria: nodular appearance of the polyp on stereoscopic examination, a hyperfluorescent halo around the nodule, the presence of a branching vascular network, pulsation of the polyp, orange-red subretinal nodules, which correspond to the location of the ICG angiography hyperfluorescence, or a massive submacular hemorrhage, defined as an area of four disc areas or larger,” Tan said.
Subtypes affect outcomes
Once a diagnosis of PCV is confirmed, Tan noted the disease should be classified into one of three subtypes he and colleagues defined in a 2014 study published in British Journal of Ophthalmology.
The subtypes are determined by using both ICG angiography and fluorescein angiography (FA). If interconnecting channels are seen by using ICG angiography, PCV is classified as “type A.” If a branching vascular network is seen, ophthalmologists need to then further look at the FA to determine if leakage is present. If there is no significant leakage on the FA, PCV is classified as “type B,” and if there is significant leakage on FA, PCV is classified as “type C,” Tan said.
“Using our classification, we found that type A had the best outcomes, followed by type B, and type C had the worst outcomes. We believe that type C may be a more aggressive variant of the disease,” Tan said.
Treatment options
The retrospective, institution-based study included 107 patients who presented with symptomatic PCV. The researchers used photodynamic therapy with verteporfin to treat the macular PCV lesions.
In the study, Tan and colleagues found at 5-year follow-up that 80% of type A patients had best corrected visual acuity of 20/40 or greater, compared with 66.7% of type B patients and 7.7% of type C patients.
The EVEREST study found that PCV treated with PDT combined with intravitreal Lucentis (ranibizumab, Genentech) had superior polyp closure compared with ranibizumab alone.
“However, we have not studied whether different treatment regimens may be better for each of the various subtypes,” Tan said.
Ranibizumab in doses of 1 mg or 2 mg for patients with PCV led to improved visual acuity, Wee noted in a study he presented at the American Society of Retina Specialists annual meeting in August.
“We looked at vision and anatomy outcomes and found visually the results were good, but anatomically there was still persistence of the branching vascular network. There was improvement of polyp closure rates, but high-dose ranibizumab does not cure the disease. There are still persistent anatomical defects,” he said.
The study included 21 patients with confirmed PCV who were treated with monthly injections of 1 mg or 2 mg of ranibizumab. The original study design, Wee said, was for all patients to receive 2 mg of ranibizumab, but a year into the study, high-dose ranibizumab was no longer available.
Fifteen patients received 2 mg of ranibizumab for 1 year, two patients received 2 mg of ranibizumab for 6 months and then were given 1 mg for the remainder of the study, and four patients received 1 mg of ranibizumab for the entire duration of the study.
“At the 1-year time point, there was a statically significant improvement in vision. This trails off at the 2-year time point. There was stabilization of vision seen in the vast majority of patients at all time points. The central foveal thickness improved dramatically and in a statistically significant way. When we look at comparing the regular dose of ranibizumab to the higher dose, we see that visually they do very similar. Anatomically we saw a bit of a difference polyp-wise, as the higher dose had better polyp closure; there were still many polyps open [with the regular dose]. Also, the ranibizumab did not close the branching vascular network,” Wee said at the meeting.
Location of polyps
PDT to treat PCV is the gold standard of care in Asia and results in the best anatomical outcomes, such as branching vascular network regression and polyp closure rates, but it is not typically used in the United States, Wee said.
Wee and his colleagues devised their own treatment algorithm for PCV. Wee noted he does not break PCV down into specific subtypes, but first looks to see if a patient is symptomatic or asymptomatic. If asymptomatic, Wee said the patient should be monitored closely by the ophthalmologist.
“If symptomatic, you need to look at the anatomical location of the polyps and the branching vascular network complex. If it is extrafoveal, you can simply use macular laser or PDT, but if it is juxtafoveal or subfoveal, PDT has risks associated with that. The risks are low but can be catastrophic. They could experience subretinal or sub-RPE hemorrhaging or foveal atrophy,” he said.
Wee said if a juxtafoveal or subfoveal lesion is present, then visual acuity becomes an important factor in determining treatment. Patients with 20/50 vision or better can receive anti-VEGF therapy. If vision is 20/60 or worse, ophthalmologists should consider PDT with anti-VEGF therapy, with or without steroids.
“We could also consider anti-VEGF monotherapy, and if there is no good response, we could go to PDT,” Wee said.
Kokame added that if the PCV is subfoveal, he would consider antiangiogenic therapy if vision is 20/50 or better and PDT with anti-VEGF injection if vision is 20/50 or worse. The recently released results of the EVEREST II study show a better visual result and anatomic polyp closure result with PDT combined with anti-VEGF than anti-VEGF monotherapy. This result, released at the American Academy of Ophthalmology meeting, shows that patients in America are not often receiving the best option for treatment, which is combined PDT with anti-VEGF therapy, Kokame said.
“This is because of the rare case of choroidal ischemia or sudden vision loss in eyes with good visual acuity,” Kokame said.
Combination of therapies
The combination of PDT and anti-VEGF therapy may offer the best treatment course for patients with PCV. Additionally, a patient’s subretinal fluid may also show improvement with oral eplerenone, Kapoor said.
“We have learned from clinical experience and clinical trials that PCV best responds to the combination of photodynamic therapy and intravitreal anti-VEGF rather than either of the treatments alone. In a case report we published recently, we saw a patient have clinical improvement of her subretinal fluid with oral eplerenone treatment. This patient is a 72-year-old female who presented with a pachychoroid and significant subretinal fluid and no intraretinal fluid, masquerading as central serous chorioretinopathy, and was started on oral eplerenone treatment. While she was responding to the treatment well, it was evident that as the subretinal fluid regressed some exudates were present, and knowing this is not typically consistent with CSCR, an ICG was done which revealed a peripapillary network of polyps consistent with PCV,” he said.
The case report suggested eplerenone may be a therapeutic overlap in aiding in fluid regression for these patients. The pathogenesis of PCV is elusive, but the choroidal vasculature is implicated and eplerenone has shown success in “modulating mineralocorticoid receptors in the choroidal vasculature in CSCR,” he said.
Literature supports evidence
Kokame and colleagues published a 6-month trial in BMC Ophthalmology on intravitreal Eylea (aflibercept, Regeneron) treatment for PCV. The prospective clinical trial included 21 eyes that underwent monthly intravitreal aflibercept treatment for three initial treatments and then every other month.
The eyes were evaluated for mean change in best corrected visual acuity and adverse events. At 6-month follow-up, Kokame and colleagues found the treatments resulted in stabilization of vision and regression of polyps, but the branching vascular networks remained stable in all but one eye.
“What we saw there were good visual results and better anatomical results, but still a persistent branching vascular network. PDT still results in better anatomical outcomes,” Wee, a co-author of the study, said.
Tan said the current evidence in the literature supports PDT, in addition to anti-VEGF therapy, for the treatment of PCV. The disease is an important condition that needs to be distinguished clearly from typical AMD, he said.
“It is important to diagnose PCV accurately — hence, the use of a standardized diagnostic criteria, which is very helpful and can help address the equivocal cases,” Tan said. – by Robert Linnehan
- References:
- Kapoor K, et al. Case Rep Ophthalmol. 2015;doi:10.1159/000442661.
- Kapoor K, et al. Ophthalmic Res. 2016;doi:10.1159/000444058.
- Koh A, et al. Retina. 2012;doi:10.1097/IAE.0b013e31824f91e8.
- Kokame GT. Trans Am Ophthalmol Soc. 2014;112:74-93.
- Kokame GT, et al. BMC Ophthalmol. 2016;doi:10.1186/s12886-016-0305-2.
- Kokame GT, et al. Ophthalmic Surg Lasers Imaging Retina. 2016;doi:10.3928/23258160-20160808-07.
- Tan CS, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305059.
- Tan CS, et al. Br J Ophthalmol. 2015;doi:10.1136/bjophthalmol-2014-305674.
- Tan CS. Comparison of treatment outcomes among subtypes of polypoidal choroidal vasculopathy in a multicenter randomized controlled study (EVEREST Study). Presented at: American Society of Retina Specialists meeting; Aug. 10-14, 2016; San Francisco.
- Wee R. High-dose ranibizumab treatment in polypoidal choroidal vasculopathy: PEARL 2 trial (polypoidal choroidal vasculopathy with intravitreal ranibizumab). Presented at: American Society of Retina Specialists; Aug. 10-14, 2016; San Francisco.
- For more information:
- Kapil Kapoor, MD, can be reached at Wagner Macula & Retina Center, 5520 Greenwich Road, Suite 204, Virginia Beach, VA 23462; email: kaps2003@gmail.com.
- Gregg T. Kokame, MD, MMM, can be reached at Retina Consultants of Hawaii, 98-1079 Moanalua Road, Suite 470, Aiea, HI 96701; email: retinahi@aol.com.
- Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth), can be reached at Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433; email: colintan_eye@yahoo.com.sg.
- Raymond Wee, MD, can be reached at Retina Consultants of Hawaii, 98-1079 Moanalua Road, Suite 470, Aiea, HI 96701; email: raymond_wee@hotmail.com.
Disclosures: Kapoor, Kokame, Tan and Wee report no relevant financial disclosures.
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