Photodynamic Therapy (PDT)
Photodynamic therapy (PDT) is the use of a photosensitive dye to transform light into chemical energy; the process releases free radicals thereby causing site-specific vascular occlusion with cellular destruction and minimal injury to nearby tissues. PDT, using a variety of photosensitizers, is currently used to treat a host of medical conditions from acne vulgaris to cancer. PDT was introduced to ophthalmology in the 1990s , using intravenously administered verteporfin, as the photosensitive dye, followed by the application of low power and long duration infrared laser. In the eye, it is used to induce occlusion of abnormal microvasculature in both choroidal neovascular membranes and choroidal tumors . The initial indication for PDT was choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), however, it is now second-line to anti-VEGF therapy. Nevertheless, the initial success of PDT has spurred the exploration of its role in treating various posterior pathologies.
Drug/Laser Mechanism of Action
Verteporfin Drug Information
Verteporfin (Visudyne, Bausch & Lomb), is a benzoporphyrin derivative with a molar mass of 718.794 g and a half-life of about 5 hours. It is a second generation photosensitizer, approved in 2000 by the FDA, clinically indicated for the treatment of CNV in classic subfoveal neovascular AMD, pathologic myopia, and ocular histoplasmosis. There is insufficient evidence regarding the treatment of predominantly occult subfoveal CNV . Verteporfin is designed to have an intensified, longer wavelength absorption of 690 nm compared to first generation Photofrin at only 630nm. This advantage allows for a 50% increase in tissue penetration by light. In addition, Verteporfin’s relatively quick half-life allows it to be rapidly cleared from the body, minimizing a patient’s photosensitivity to typically 1-2 days post-PDT treatment.
Verteporfin Mechanism of Action
Photodynamic therapy uses laser energy to activate the photosensitizing agent, verteporfin, forming singlet oxygen and free radicals that interact with endothelial cell membranes on choroidal blood vessels . The reaction increases local immune modulating factors like histamines, thromboxane and TNF-α. The response leads to a series of events including vasoconstriction, thrombosis, increased vascular permeability, blood stasis and hypoxia promoting vasoocclusion of pathologic blood vessels . In the case of CNV, this process serves to induce regression due to their thin and fragile nature.
Standard Laser Settings and Protocol at 689 nm light
Dose: 6 mg/m2 body surface area www.bauschretinarx.com/visudyne/ecp/dosingcalculator
Fluence (full): 50 J/cm2
Irradiance: 600 mW/cm2
Time: 83 seconds
1. Verteporfin is administered via intravenous infusion of 30ml over 10 minutes
2. 15 minutes after the initiation of the infusion, laser light is delivered over 83 seconds using a laser contact lens on the treatment eye under topical anesthesia
3. Treatment spot size should be 1000 microns larger than the greatest linear dimension of the lesion (ensuring full coverage of the lesion with a 500-micron border)
Total treatment time is typically 20 minutes for the patient and 5 minutes for the physician.
Note: In order to avoid damage to the optic nerve, it is recommended that the PDT laser spot does not extend within 200 microns of the optic nerve head border. Maximum spot size depends on the magnification of the contact lens used; ~ 7500 microns when using a Volk SuperQuad lens with a 2.0x laser spot magnification factor.
Safety Enhanced” Settings
Verteporfin has a proven long-term safety profile, however, there remains a concern for post-procedure scarring and choroidal hypoperfusion, especially in eyes with multiple treatment requiring lesions. For this reason, several “safety enhanced” protocols were designed and studied using various modifications of the PDT regime including half (3mg/m2) and one-third (2mg/m2) verteporfin dose, half (25J/cm2) and quarter (12J/cm2) fluence laser, and half time at 43 seconds.  The literature is still evolving regarding the best PDT parameters to use and optimum efficacy pertaining to specific chorioretinal pathology.
Patients are typically followed every 4-12 weeks. After the initial treatment period, patients may be tested with fluorescence and/or indocyanine green angiography (FA/ICG) angiography to investigate the efficacy of treatment and guide additional treatment sessions.
The most common side effect of PDT is verteporfin induced photosensitivity . To reduce the risk of sunburn, it is recommended that patients wear sunglasses, a wide-brimmed hat, and clothes with complete skin coverage, as well as to avoid swimming outdoors for 2-3 days following treatment.
The most frequently reported adverse events (10-30%) were injection site reactions such as pain, edema, inflammation, rashes, hemorrhage, and discoloration; rare cases of skin necrosis have been reported. Patients may also experience visual disturbances including blurred vision, flashes of light, visual field defects and scotoma. Rarely anaphylactic reactions have been reported prompting immediate discontinuation of verteporfin .
Although rare, the most common ocular complications seen with PDT are secondary CNV and reactive hyperplasia of the RPE, mainly reported in patients undergoing multiple sessions of standard dose verteporfin and full fluence laser settings. Fortunately, secondary CNV is successfully treated with intravitreal anti-vegf agents. Although 1-4% of patients may develop a decrease in vision, this is typically transient and risks are decreased with reduced dose/fluence settings. 
Age-Related Macular Degeneration (Wet Form)
Age-Related Macular Degeneration (AMD) is one of the most common causes of irreversible central vision loss in the elderly population. There are two forms of AMD: dry and wet. Dry AMD is non-neovascular and is characterized by retinal pigment epithelium abnormalities and drusen. Wet AMD is characterized by the rapid growth of abnormal choroidal neovascular blood vessels (CNV) under the macula. These new blood vessels often lack integrity and leak blood and fluid that harm the central retina leading to fibrosis and drastic vision loss over time. 
Photodynamic therapy was used as a first line treatment in 1999 after the release of the Treatment of AMD with Photodynamic Therapy (TAP) study. The TAP randomized, multi-center, double-masked, placebo-controlled trials, conducted in Europe and the US, enrolled 402 patients with predominantly classic choroidal neovascularization (CNV). Patients treated with PDT had a higher percentage of eyes retaining baseline vision than placebo (12 months: 61% treated, 46% placebo; 24 months: 53% treated, 37% placebo) (p< 0.001) . Of note, patients with minimally classic subfoveal CNV lesions (lesions where classic CNV makes up only 0-50% of the area of the entire lesion) treated with PDT had no statistically significant difference in final VA in comparison to the placebo group. In the 3-year TAP extension study, those treated with PDT exhibited stable vision and no significant systemic safety problems over a 5 year period .
The Verteporfin in Photodynamic (VIP) therapy study of subfoveal minimally classic choroidal neovascularization revealed that reduced fluence (300 mW/cm2 for 83 seconds at 25 J/cm3) PDT was a safe and more efficacious option for the treatment of AMD in comparison to standard fluence. At 12 months, a loss of at least 3 lines of visual acuity was observed in 14% in the reduced fluence group compared to 28% in the standard fluence group and 47% in the placebo group. Results were similar in the 2 year follow-up. Progression to classic CNV was seen in 28% of the placebo group and 5% of the reduced fluence (p=0.007) and 3% of the standard fluence group (p=0.002). 
Shortly after these initial studies, in 2009, the ANCHOR study which enrolled 423 patients in a multicenter, international, double-masked, randomized control trial revealed anti-VEGF therapy as more efficacious in the treatment of wet AMD in comparison to PDT. At 24 months, 90.0% of patients who were treated with monthly ranibizumab lost less than 15 letters of visual acuity in comparison to 65.7% of patients treated with PDT (p<0.0001). Currently, PDT is recommended for CNV in AMD either refractory to anti-VEGF therapy or as monotherapy in patients with contraindications to anti-VEGF. 
Recent studies have looked into the efficacy of combination PDT and anti-VEGF therapy vs anti-VEGF monotherapy in the treatment of neovascular AMD. The MONT BLANC study enrolled 255 patients in a prospective, multicenter, double-masked, randomized trial and showed that at 12 months, the combination group of ranibizumab and verteporfin PDT was non-inferior to ranibizumab monotherapy .
Central Serous Chorioretinopathy
Central serous chorioretinopathy (CSCR) is characterized by metamorphopsia and loss of central vision due to accumulation of subretinal fluid in the macula and distorting central vision secondary to hyperpermeability and thickening of the choroid and impairment of RPE function. Although the exact pathophysiology of the disease is not known, it is associated with middle aged males,typically with type A personality, corticosteroid use, and stress.  The most commonly used treatments for CSCR at this time are PDT, High Density Subthreshold Micropulse Laser (HSML), mineralocorticoid antagonist including eplerenone or spirinolactone, and argon laser photocoagulation.
PDT was first used to treat CSCR in 2003 by Yannuzzi et al. The study consisted of 20 eyes with chronic CSCR and revealed stable or improved vision at 6 weeks post PDT treatment. Mean visual acuity improved by an average of 0.55 lines and aided in the resolution of subretinal fluid.
In 2014, a large meta-analysis by Erikitola et. al of 117 citations and 31 studies, describing 787 eyes with CSCR treated with photodynamic therapy, concluded that despite small sample sizes, different methodologies, and the lack of matched controls, each study exhibited successful resolution of SRF and improved BCVA to varying degrees. They also found that treatment of both acute and chronic CSCR showed improved BCVA at 3 and 6 months. Additionally in these studies all eyes treated with half-dose verteporfin PDT led to a reduction in CSCR with a lower rate of side effects. Furthermore 3 out of 7 of the half-dose verteporfin studies showed a complete resolution of SRF without recurrence. In contrast, all studies with variable modifications of laser fluence had a recurrence of CSCR post PDT treatment within 1 year. 
Newer studies have divided the recommendations for treatment between acute and chronic CSCR. A recent meta-analysis conducted by van Rijssen et. al showed that acute CSCR can be managed with close observation due to the high rate of SRF resolution in the first 3-4 months . Due to the possibility of damage to the outer segment photoreceptors in CSCR treatment is warranted in some acute cases. Current evidence suggests that early treatment with half-dose PDT can be considered in patients with active acute CSCR who have had previous or bilateral disease, or patients who want quicker improvements of their vision.  In a randomized control trial conducted by Chan et. al, at 12 month follow up, 37/39 patients with acute CSCR had resolution of subretinal fluid with half-dose verteporfin PDT in comparison to 11/19 having resolution in the observation-only group. In addition, OCT measuring central foveal thickness was significantly lower in the half-dose verteporfin PDT group.
For chronic CSCR, the literature has shown that half-dose verteporfin PDT is the most effective treatment. The PLACE and SPECTRA trials heavily support this claim. The PLACE trial investigated the efficacy of half-dose verteporfin PDT vs HSML in the treatment of chronic CSCR. In patients treated with PDT, 67.2% had resolution of SRF compared to 28.8% in patients treated with HSML (p <0.001). In addition, the PDT group had a 4.60 EDTRS letter improvement in BCVA in comparison to a 1.39 letter improvement in the HSML group (P = 0.011).
Lastly, the SPECTRA trial concluded that half-dose PDT was more efficacious than eplerenone in the treatment of chronic CSCR. They showed that at 3 month follow-up, 78% of patients in the PDT group had complete resolution of SRF in comparison to 17% in the eplerenone group (p <0.01). Of note, they did not find a significant difference in BCVA between the two groups. Lastly, they did report that only 6% of patients experienced complications in the PDT group in contrast to 33% in the eplerenone, suggesting that PDT is also safer.
Pathologic Myopia with CNV
Pathologic Myopia is described as myopia associated with degenerative changes to the sclera, RPE, and choroid leading to decreased visual function. Elongation of the globe with posterior staphyloma are believed to contribute to the pathologic changes responsible for compromising vision.
PDT treatment for CNV secondary to pathologic myopia was shown to have improvement in BCVA at least five ETDRS letters when compared to placebo (40% vs 13%) at 24 months . The RADIANCE study, a double-blind, randomized control trial, compared PDT to ranibizumab for the treatment of CNV secondary to pathologic myopia. Patients treated with ranibizumab had an average BCVA gain of more than 10 ETDRS letters in comparison to only 2 ETDRS letter gain in the PDT group. At this time, treatment with anti-VEGF injections is established as first line treatment and PDT is recommended for use in myopic CNV in cases where anti-VEGF is ineffective or contraindicated.
Polypoidal Choroidal Vasculopathy
Polypoidal choroidal vasculopathy (PCV) is a maculopathy characterized by orange-red nodular polypoid lesions within a choroidal branching vascular network. Patients usually present with recurrent episodes of hemorrhagic and serous pigment epithelial detachments. At this time there is no unanimous first-line treatment for PCV. The only randomized controlled trial to date is the EVEREST Trial which suggests that standard verteporfin PDT by itself, or in combination with 0.5mg ranibizumab is better than 0.5mg ranibizumab therapy alone.  At 6-month follow-up, polyp regression was seen in 71% of patients treated with standard verteporfin PDT alone, 78% of patients treated with both PDT and ranibizumab, and only 29% of patients treated with ranibizumab monotherapy (p< 0.01). The mean change in BCVA was an improvement of 10.9 letters in the combination group, 7.5 letters in the PDT only group, and 9.2 letters in the ranibizumab only group. As a result of this study and expert opinion, the current evidence-based guidelines for PCV is ICG guided stand protocol PDT monotherapy or a combination PDT and ranibizumab. In addition, it is recommended that PDT treatment of the entire PCV lesion is performed as opposed to only treating the actively leaking polyps. 
Peripapillary Choroidal Neovascularization
Peripapillary Choroidal Neovascularization (PP-CNV) is described as choroidal neovascularization within one disc diameter of the optic nerve head. PP-CNV is usually idiopathic but may also be a result of other chorioretinal pathologies causing inflammation. Usually, patients do not become symptomatic until there is macular involvement. Traditional laser photocoagulation was previously the first-line treatment, but due to the risk of thermal injury in such a sensitive part of the retina, PDT and anti-VEGF injections have become the primary first-line treatment. In a study conducted by Bernstein et al, 7 patients with PP-CNV treated with PDT all had improvement in BCVA and only 2 patients required 2 sessions . In a different study conducted by Figueora et. al, they concluded that anti-VEGF injections w ould require multiple injections to achieve the same result. At this time there are no studies directly comparing the efficacy of different treatments for PP-CNV. Of note, most studies have looked into PDT treatment with standard protocol, but it is hypothesized that safety-enhanced protocols would be equally as effective due to the fact that the neovascularization seen in PP-CNV is less aggressive than classic subfoveal CNV. 
Multifocal Choroiditis and Punctate Inner Choroidopathy
Multifocal choroiditis (MFC) and Punctate Inner Choroidopathy (PIC) are both inflammatory diseases that are described as “punched out” yellow-white chorioretinal lesions at the posterior pole and mid periphery. They are typically seen in myopic females in their third to the fifth decade of life. The main difference between the two pathologies is that PIC is a rather acute process absent of vitritis that usually self-resolves, while MFC is a chronic process usually with clinical vitritis that requires treatment. The most common cause of vision loss in these patients is seen secondary to complications of CNV.
Multiple studies have reported improvement or stabilization of BCVA for most patients with CNV secondary MFC and PIC using PDT treatment. A study by Parodi et al compared bevacizumab monotherapy versus PDT and found significantly better BCVA and decreased rate of recurrence of CNV in the bevacizumab group compared to PDT. Central macular thickness was significantly reduced in both groups, suggesting that anti-VEGF therapy may cause less cell damage than PDT. 
Histoplasmosis is a fungal infection by the organism Histoplasma capsulatum. This disease can affect many organs in the body, including the eyes. Ocular histoplasmosis can cause choroidal neovascularization, which leads to vision loss if located at or near the fovea . Because ocular histoplasmosis is a systemic infection, there is a 20-24% chance that the fellow eye can also develop CNV, potentially leading to significant visual impairment. Photodynamic therapy has shown to be a safe and excellent option for treating CNV secondary to histoplasmosis . Anti VEGF agents have also shown to be beneficial in the literature, as patients show regression of their CNV with an average of 4.5 intravitreal injections per year. Ramaiya et al conducted a randomized trial comparing anti-VEGf agents to PDT in the treatment of ocular histoplasmosis associated CNV and found that all patients in the PDT group required rescue ranibizumab injections to fully induce regression of the CNV . Of note, patients in the ranibizumab only group required 7.7 injections for full treatment while patients in the PDT group required only 2.5 of the rescue ranibizumab injections. Neither group had vision loss in the follow-up period but 80% of the ranibizumab-only group had vision gain of 15 letters or more in comparison to 50% in the PDT group. These studies suggest that ranibizumab alone or in combination with PDT may be an effective treatment for choroidal neovascularization secondary to ocular histoplasmosis.
Circumscribed choroidal hemangiomas (CCH) are benign vascular tumors in the posterior pole of the retina that appear as local dome shaped orange-red choroidal mass. CCH are usually asymptomatic and typically require treatment when vision is affected by subretinal fluid exudation. There are no guideline driven first-line treatments for CCH at this time, however options include: PDT, laser photocoagulation, transpupillary thermotherapy, external beam radiotherapy, and proton beam therapy.
PDT was first used in 2000 showing success in resolution of subretinal fluid, tumor flattening, visual acuity improvement and reduction in field loss in both acute and chronic cases of exudate retinal detachments. (37-39)
The first large study investigating PDT’s efficacy in CCH was conducted by Boixadera et al. in 2009 (40). This was a prospective, multicenter, nonrandomized trial that enrolled 31 patients and issued up to four treatment sessions at 12-week intervals over one year. Results indicated that 83% of patients required 1 session, 14% required 2 sessions, and 3% required 3 PDT treatments to eliminate associated exudative retinal detachment. In this study, visual acuity increased from a mean of 20/60 to 20/35 (P<0.001) and 69% of patients had complete visual recovery (p <0.001). Complete resolution of CME was seen in all but 2 cases and CCH tumor thickness decreased in all cases. In addition, visual field exams after treatment showed resolution of central scotomas and there were no adverse events reported.
Lee et. al compared double vs standard dose verteporfin PDT for the treatment of CCH. The results showed a significant improvement in tumor height and greatest linear regression (p=0.031) in the double dose verteporfin group. Visual outcomes were similar and no adverse effects were seen in either group. A study conducted by Papastefanou et. al compared standard (83 seconds) vs double duration PDT (166 seconds). Results showed a greater reduction in tumor thickness (p=0.04), central retinal thickness (p=0.02) and improvement of visual acuity in (0.33 vs - 0.05 letter improvement) in the double duration PDT group. These studies suggest that double dose or double duration verteporfin PDT may be as safe, and with better tumor regression compared to standard regimen.
Some preliminary studies comparing PDT to proton beam therapy (PBT), plaque radiotherapy and external beam therapy (EBT) have also been reported. A study by Papastefanou et al, compared 23 patients who received EBT, to 16 patients who received PDT, to 3 with plaque radiotherapy for CCH. The study showed no difference in tumor thickness or visual gain between the EBT and PDT groups. In all 3 cases with plaque radiotherapy, BCVA was decreased after treatment. Of note, 43% of the EBT group and 67% of the plaque radiotherapy group experienced complications suggesting that PDT is the safer of 3 treatments . Mathis et al, compared the results of 119 patients with CCH treated with PDT to 72 patients treated with PBT. The difference in BCVA was not significant (p=0.932) and final tumor thickness was significantly lower in the PBT group (p=0.001).
Retinal Capillary Hemangioblastomas
Retinal Capillary Hemangioblastomas(RCH) are benign vascular tumors characterized, usually associated with Von Hippel-Lindau (VHL) disease. These tumors are typically found in the juxtapapillary or mid periphery regions of the retina. Vision loss is caused by exudates and edema from the tumor or glial proliferation causing retinal traction. Currently, there is no single first line treatment modality for RCH; however, options include observation, PDT, laser photocoagulation, surgery, transpupillary thermotherapy, proton beam therapy, cryotherapy, intravitreal anti-VEGF agents and triamcinolone acetonide. PDT’s ability to treat RCH has been noted by several different case studies but there have been no trials comparing different treatment options.
The largest and most cited case study was conducted by Sachdeva et al, where six eyes were administered PDT 1-3 times over 32 months. All eyes demonstrated tumor regression or stabilization as well as improvement in subretinal fluid and lipid exudation; however, only 3 eyes experienced an improvement in BCVA. In addition, three eyes required further PDT treatment due to recurrent subretinal fluid. The results are limited by the small sample size but other studies have exhibited similar results, showing that RCH treated with PDT reduces subretinal fluid, induces tumor regression with variable visual outcomes.
Choroidal nevi, the most common primary intraocular tumor seen in adults, are benign in nature and most are asymptomatic requiring observation and monitoring only. Approximately 11% of choroidal nevi either subfoveal or located near the fovea become symptomatic later when complicated by CNV and/or subretinal fluid causing serous macular detachment. 
Previously published methods of treatment for choroidal nevus with symptomatic secondary CNV, subretinal fluid and/or macular edema have included laser photocoagulation, intravitreal anti-VEGF agents, transpupillary therapy or photodynamic therapy. At this time there are no protocols that outline a first-line treatment for symptomatic choroidal nevi. PDT has been reported as showing resolution of subfoveal fluid in 87% of cases and with BCVA either improving or remaining stable.
Risk factors for growth and conversion from choroidal nevus to melanoma including orange pigment, symptoms, peripapillary location, subretinal fluid, and thickness greater than 2 mm. In patients with 2 or more risk factors, a study by Garcia et al showed growth in tumor thickness in 18% of cases after PDT concerning for malignant transformation. This suggests that although PDT may reduce SRF in symptomatic choroidal nevus with serous macular detachment, it may not provide good tumor control in nevi with multiple risk factors for progression and that regular fundus exams are necessary.
Choroidal melanoma is the most common primary malignant intraocular tumor. Management of primary choroidal melanoma is guided by the size and location of the tumor, presence of extraocular extension, visual potential, patient age and preference, and presence or absence of metastases. Radiotherapy, administered as plaque brachytherapy, external beam or stereotactic radiotherapy is currently the most frequently used treatment for small- and medium-size melanoma. Enucleation is typically recommended for large uveal melanoma or if there is invasion of the optic nerve, extrascleral extension, neovascular glaucoma, or poor visual potential.
Currently PDT is considered to be an effective primary treatment in select cases of small non-pigmented choroidal melanoma. Although generally not used as ablative primary treatment, it may help improve subretinal fluid in symptomatic macular tumors. One series evaluating small and medium sized choroidal melanoma, reported a local control rate of 80- 89% with PDT compared with 95–97% with proton beam and stereotactic radiotherapy. 
The presence of pigmentation is now considered an exclusion criteria due to concerns regarding efficacy of treatment, as pigmentation is thought to prevent the penetration of light into the tumor. In a study conducted by Canal, eyes with pigmented choroidal melanoma that were treated with PDT alone had an increase in tumor growth over time, resulting later in enucleation. However, PDT in combination with bevacizumab has shown to aid in the regression of the superficial vasculature of pigmented choroidal melanoma, suggesting PDT may help minimize bleeding during tumor biopsy.
A recent 2021 systematic meta-analytic review showed 81% of choroidal melanoma that failed to respond to PDT were pigmented tumors. In comparison, 92% of lighter, amelanotic tumors show complete regression with PDT.  Thus the literature has suggested that lighter amelanotic tumors respond better than pigmented tumors to PDT in inducing tumor regression without compromise to vision. Moreover, PDT has been studied as neo-adjuvant treatment for amelanotic choroidal melanoma both pre and post brachytherapy. Different studies have shown reduction in tumor size and thickness with hypothesized increased sensitivity to radiotherapy.
Treatment for choroidal metastasis depends on tumor activity and extent of metastasis. Local therapies include PDT, plaque therapy, external and proton beam therapy. In 2004, Harbour was the first to report the effect of photodynamic therapy (PDT) as treatment for choroidal metastasis in a patient with primary carcinoid tumor that failed to regress with chemotherapy and radiation. Following 2 months of PDT treatment, tumor size decreased by 50% and visual acuity improved from 20/50 to baseline 20/40.
In a retrospective case series conducted by Shields et. al,40 eyes with choroidal metastasis were reviewed. Sites of the primary tumors of metastasis to the choroid were lung (39%) and breast (37%) followed by kidney (8%), thyroid (6%) and other sites (10%) including esophagus, colon, uterus, parotid, and muscle. Of the 40 eyes, 71% achieved regression after 1 session of PDT, 7% regression after 2 sessions and 22% failed to achieve any regression. Visual acuity improved in 70% of patients (p =0.02). Kaliki et al. reported a small case series of PDT treatment on eight patients with choroidal metastases with a good response in 82% of cases. Management however is usually palliative as treatment is limited to the primary tumor and due to the low life expectancy in patients with intraocular metastasis.
Images: Ophthalmic Atlas Images by EyeRounds.org, The University of Iowa are licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.
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