Photodynamic Therapy for the Eye

Anatomy and Physiology

Photodynamic therapy involves the application of a topical photosensitizing agent over a target area, followed by activation of the agent by light irradiation. It leads to the formation of reactive oxygen intermediates in the presence of oxygen. These intermediates act on essential cellular components leading to apoptosis and necrosis due to irreversible oxidization.When being used for ophthalmic purposes, the abnormal endothelial cells in the proliferating blood vessels selectively accumulate verteporfin.

The photochemical reaction is then initiated by irradiating verteporfin by the light of wavelength 689 nm. The light of wavelength 689 nm is chosen as it reaches the pathological endothelial cells within the choroid even with overlying blood, fibrotic tissue, and melanin. The far-red light has good penetration.[2] This irradiation excites the molecules of verteporfin, and these excited molecules react with oxygen molecules, which leads to the formation of free radicals. It is these free radicals that cause damage and death of the pathological endothelial cells. The death and damage are caused by activating a clotting cascade and platelet aggregation, which culminates in microvascular occlusion.

Indications

Photodynamic therapy is not only used in dermatology but also in the fields of general oncology, cardiovascular, and ophthalmology. The various indications in dermatology include:[3][4][5][6][7][8]

1. Approved Indications:
   • Actinic Keratoses: 
     • Aminolevulinic acid (ALA) is approved by the FDA for the treatment of hypertrophic actinic keratoses on the face and scalp only with blue light. An ALA patch and an ALA gel formulation with nanoemul­sion with red light are also approved in Europe. In the FDA-approved protocol, the photosensitizer is to be applied only to the lesions, but due to the phenomenon of field cancerization, many providers are using broad facial applications. For broad area application, incubation period should be less than an hour in order to prevent a phototoxic reaction. Methyl aminolevulinate (MAL) is approved with an incubation period of 3 hours under occlusion with 37 J/cm2 or 75 J/cm2 of red light. A single therapy session is approved in Europe, with repeated sessions after three months for non-responsive/incompletely responsive lesions. Two therapy sessions using MAL instituted seven days apart are approved by the FDA.
   • Basal Cell Carcinoma: MAL photodynamic therapy is also approved for the treatment of basal cell carcinoma in Europe.
   • Bowen disease: MAL photodynamic therapy is also approved for the treatment of Bowen disease in Europe.
2. Off-label Indications:
   • Cutaneous premalignant and malignant conditions: nevoid BCC syndrome (Gorlin syndrome), actinic cheilitis, disseminated superficial actinic porokeratosis, keratoacanthoma, Kaposi sarcoma, cutaneous T-cell lymphoma, cutaneous metastasis.
   • Inflammatory dermatological disorders: psoriasis, acne vulgaris, scleroderma, lichen sclerosis, alopecia areata.
   • Cutaneous infections: prevention of MRSA infection, leishmaniasis, tinea pedis, HPV infections/ dermatosis (verruca vulgaris, condylomata, epidermodysplasia verruciformis), molluscum contagiosum.
   • Aging and photorejuvenation: PDT has been reported to stimulate the production of type 1 and type 3 procollagen and hence augment dermal remodeling.
   • Tumor prevention[9]

Indications of photodynamic therapy in the field of ophthalmology include:

• Neovascular age-related macular degeneration: Verteporfin photodynamic therapy was developed to treat subfoveal choroidal neovascularization in wet age-related macular degeneration. TAP and VIP studies approved the use of verteporfin PDT for wet age-related macular degeneration. However, after ANCHOR and MARINA Trials, Anti-VEGF injections became the mainstay of treatment for wet AMD. Currently, the role of PDT in treating wet AMD is limited and is generally used nowadays either in cases refractory to ant-VEGF injections or as a combination therapy with anti-VEGF injections.[10][11]
• Polypoidal choroidal vasculopathy (PCV): PCV often manifests as massive sub-retinal exudation and hemorrhage. Anti-VEGF injections, laser photocoagulation, and PDT are various modalities deployed to treat PCV.[12][13] According to results derived from the EVEREST Trial, active subfoveal and juxtafoveal PCV should be treated with full fluence PDT with three loading doses of anti-VEGF injections.[14] Reduced fluence PDT should be performed when best-corrected visual acuity is more than 6/12 or when the lesion size is greater than 3 disc diameters because such lesions have a high chance of bleeding with standard fluence PDT.[15]
• Non-AMD choroidal neovascularization: In recent years, anti-VEGF therapy has become the mainstay of treatment for non-AMD choroidal neovascularization like in myopic choroidal neovascular membrane (myopic CNVM), angioid streaks, idiopathic myopic CNVM, owing to better safety profile and better visual outcomes, and thus the role of PDT is limited in such conditions.
• Central serous chorioretinopathy (CSCR): CSCR is generally a self-limiting pathology in most cases, affecting young individuals. For chronic and recalcitrant CSCR, focal laser photocoagulation has been the mainstay of treatment. But laser can potentially cause significant adverse effects like symptomatic scotomas, RPE atrophy, and secondary CNVM. To overcome these side effects, Subthreshold micropulse diode laser may be used with similar results and way less collateral damage. However, Verteporfin PDT is now generally considered to be the preferred treatment modality since it can directly target the principal abnormality of choroidal hyperpermeability.[16][17][18][19]
• Choroidal hemangioma: Various techniques have been used to treat choroidal haemangiomas in the past, including laser photocoagulation, transpupillary thermotherapy, and radiation therapy (external beam, plaque brachytherapy, or proton beam). Verteporfin PDT is now considered to be the treatment of choice for this condition.[20]

Contraindications

Contraindications to photodynamic therapy include:[3][21]

• Non-responsive tumor

• Photosensitive dermatosis including porphyria, SLE and others

• Allergy to components

• The drug is categorized under pregnancy category C

Equipment

Currently, two topical photosensitizers are FDA approved for dermatology indications. These are aminolevulinic acid and methyl aminolevulinate, the methylated derivative of ALA.

ALA is an unstable molecule and has low lipid solubility. This restricts the penetration of ALA through skin or cell membranes. Hence there is a requirement of longer contact times with ALA and limitation of ALA use in superficial skin diseases. Novel preparations of ALA have been developed, which have increased penetration and better molecular stability.

MAL, on the other hand, is a more stable molecule with better lipid solubility and hence deeper penetration as compared to ALA.

Light sources: Protoporphyrin 9 can be activated by visible light in the 404 to 420 nm (Blue wavelength, Soret band) and 635 nm (red wavelength regions).

Longer wavelengths of light result in deeper penetration. Hence blue light is used in the treatment of thin actinic keratoses, and red light is required for the treatment of deeper and thicker lesions and to target deeper tissues like the sebaceous glands.

Light sources include xenon lamps, halogen lamps, lasers (PDL, LP, Argon, Diode), IPL, LED, and fluorescence diagnostic systems.[22][3][4] When being put into use for ophthalmic purposes, verteporfin is injected intravenously as an infusion lasting for about 10 minutes. It is advisable to wait for 5 minutes as it allows the molecules of verteporfin to accumulate in the diseased endothelial cells. After a waiting period of 5 minutes, the eye of the patient being treated is irradiated by PDT laser, which uses the light of wavelength 689 nm.[2] The standard protocol for full fluence PDT uses an irradiance of 600 mW/cm, a fluence of 50 J/cm, for a duration of 83 seconds.

Preparation

After cleansing the skin with a cleansing lotion and alcohol swab, the lesions should be debrided superficially, if required.[5] For ophthalmic purposes, the lesion size needs to be mapped prior to PDT. Indocyanine green (ICG) angiography helps delineate the total size of the lesion. Pupils of the patient need to be dilated with tropicamide+phenylephrine eye drop prior to the procedure. Laser spot size is decided on the basis of the greatest linear dimension (GLD) of the lesion mapped on ICG. The laser spot size is generally kept as >500 um than the GLD of the lesion.[2]

Technique or Treatment

If there is any bleeding, it should be halted prior to the application of the selected photosensitizer. The incubation time required varies as per the photosensitizer and the indication for which PDT is being used. ALA requires an incubation period of 30 mins to 18 hours with or without occlusion. For MAL-PDT, the incubation period is of 3 hours with occlusion. Physical protection against the light with aluminum foil is required to prevent any effect of natural light. After the incubation period, the topical agent is removed with either a dry gauze or saline solution. ALA-PDT employs various light sources. MAL-PDT uses a 635 nm red light. The patient is advised to use chemical and physical photoprotective measures after the procedure.[5]

Ophthalmic Procedure:

Verteporfin is injected intravenously as an infusion. The infusion is given for about 10 min. The dose used is 6 mg/m of the body surface area.[23] After injecting verteporfin, it is advised to wait for about 5 minutes as it allows the molecules of verteporfin to accumulate in the pathological endothelial cells. After the wait of 5 minutes is over, the eye to be treated is irradiated by PDT laser, which uses the light of wavelength 689 nm. The laser delivery system is mounted on a slit lamp, which is used to visualize the fundus. The size of the laser spot to be used is determined by the greatest linear dimension (GLD) of the lesion as elucidated on angiography. The size of the laser spot exceeds the size of the lesion by roughly 500 um. For a standard, full fluence PDT, the irradiance used is 600 mW/cm with a fluence of 50 J/cm for a duration of 83 seconds.[2]

To enhance the safety profile of PDT and reduce the chances of subretinal hemorrhage, reduced fluence PDT is used, which uses a laser fluence of 25 J/cm.

Reduced dose PDT is also used at times, which uses half the amount of standard dose, that is, 3 mg/m of the body surface area.

Literature is limited to decide upon the adequate parameters for different chorioretinal disorders.

Complications

Adverse effects and complications of photodynamic therapy include:[3][24]

1. Short term adverse effects:
   • Pain
   • Erythema and edema
   • Pruritus
   • Urticaria
   • Contact dermatitis
   • erosive pustular dermatosis of the scalp 
   • Decreased delayed-type hypersensitivity responses
   • Extensive ALA application could lead to systemic absorption and systemic phototoxicity
2. Long term adverse effects:
   • Pigmentary changes and scarring: Hyperpigmentation/hypopigmentation
   • Bullous pemphigoid: pathogenic mechanism unknown

Carcinogenicity: keratoacanthomas, basal cell carcinoma, invasive squamous cell carcinoma, melanomas have been reported post-treatment with PDT. But as yet, the role of PDT in causing tumor has not been clearly defined and requires further elucidation.

The reason the use of PDT has declined over the years in ophthalmology is because of its complications, the most common being deterioration in vision due to subretinal hemorrhage.[25] Photosensitivity reactions after the injection of verteporfin are quite common. Therefore patients are advised not to step out into the sunlight and completely cover the skin to avoid light exposure to the skin for 48 hours after injection.

During intravenous infusion, verteporfin can extravasate into the areolar tissue surrounding the blood vessels, and it can lead to skin necrosis if not addressed promptly. Backache following verteporfin infusion is a relatively rare complication.

Clinical Significance

Approved as a therapeutic modality for actinic keratosis and some non-melanoma skin cancers, photodynamic therapy provides for a non-invasive, relatively lesser painful therapeutic modality with the advantage of excellent cosmesis and preservation of normal tissue. Photodynamic therapy is increasingly being applied to non-oncological indications in dermatology. Recent advances have provided for improved delivery systems for the photosensitizers. Also, there is ongoing research in the development of newer photosensitizers.

After exposure to light of appropriate wavelength (470-700 nm), the photosensitizing agent undergoes biochemical changes leading to the generation of reactive oxygen species, which then results in selective cytotoxic damage.

The topically applied agents are prodrugs, which, over time, are converted into protoporphyrin 9, which acts as the photosensitizer.[22][26] Mainly localized in mitochondria, protoporphyrin accumulates in the cells of premalignant and malignant lesions owing to their rapid proliferation and reduced ferrochelatase activity. It also accumulates in other structures, including blood vessels, melanin, and sebaceous glands.[21] The activation of the photosensitizer by the light of appropriate wavelength results in a series of chemical reactions, finally culminating in the formation of free oxygen radicals. These free radicals result in cytotoxicity and also vascular damage. This, in turn, activates the inflammatory response and the host immune responses. All these factors induce damage in the targeted tissue.[3]

Protoporphyrin 9 generated from the photosensitizers is metabolized fully into heme within a period of 24 to 48 hours, and hence this largely reduces prolonged cutaneous phototoxicity.[22]

The advantage of topical photosensitizers is that there is a minimal risk of generalized photosensitivity.[24]The role of PDT in present-day ophthalmology is quite limited owing to its difficult availability and high cost. Alternative therapies like anti-VEGF injections and laser photocoagulation, which have a better safety profile, have made the need for PDT to be felt a little lesser.

Enhancing Healthcare Team Outcomes

As multiple variables regulate the selectivity in photodynamic therapy, the clinical response in an individual patient is difficult to anticipate. These variables include uptake of the photosensitizer into the target tissue, metabolism of the prodrug into active photosensitizer, penetration, and selectivity of the light source. Another variable affecting PDT is the temperature of the tissue, with the warming of the tissues being reported to result in better efficacy of PDT.[21][7] 

The advent of newer drug delivery systems and newer photosensitizers has propelled the field of photodynamic therapy forward. A combination of photodynamic therapy with other treatment modality has come up as a promising approach for improving the efficacy and decreasing the adverse effects associated with photodynamic therapy. The improved clinical outcome has been reported with the use of immunomodulation therapy like imiquimod cream along with photodynamic therapy.[27] [Level 3]

A novel concept of ambulatory phototherapy has opened avenues for the delivery of photodynamic therapy with significantly less pain and more convenience to the patients as compared to the standard photodynamic therapy.[28][29] [Level 3]