Reginald Birngruber

Photodynamic Therapy With Verteporfin for Choroidal Neovascularization Caused by Age-related Macular Degeneration: Results of a Single Treatment in a Phase 1 and 2 Study

OBJECTIVE To evaluate the safety and short-term visual and fluorescein angiographic effects of a single photodynamic therapy treatment with verteporfin with the use of different dosage regimens in patients with choroidal neovascularization (CNV) from age-related macular degeneration. DESIGN Nonrandomized, multicenter, open-label, clinical trial using 5 dosage regimens. SETTING Four ophthalmic centers in North America and Europe providing retinal care. PARTICIPANTS Patients with subfoveal CNV caused by age-related macular degeneration. METHODS Standardized protocol refraction, visual acuity testing, ophthalmic examination, color photographs, and fluorescein angiograms were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in 97 patients and for less than 3 months in 31 other patients. RESULTS The mean visual acuity change (and range of change) from baseline at the follow-up examination at week 12 after a single treatment with regimens 1 through 5 was -0.2 (-3 to +2), -0.9 (-9 to +5), -1.6 (-9 to +2), +0.4 (-8 to +7), and +0.1 (-8 to +9) lines, respectively. Only the highest light dose (150 J/cm2) in regimens 2 and 3, which produced angiographic nonperfusion of neurosensory retinal vessels, caused marked vision loss. Some cessation of fluorescein leakage from CNV was achieved without loss of vision when the light dose used was less than 150 J/cm2. Systemic adverse events were rare. Cessation of fluorescein leakage from CNV was noted in all regimens by 1 week after photodynamic therapy. Fluorescein leakage from at least a portion of the CNV reappeared by 4 to 12 weeks after treatment in almost all cases. Progression of classic CNV beyond the area of CNV identified before treatment was noted in 42 (51%) of the 83 eyes with classic CNV followed up for 3 months after a single treatment. Eyes in which the area of any CNV leakage at 12 weeks was less than at baseline had a significantly better visual acuity outcome (+0.8 line) than eyes in which CNV leakage progressed (-0.8 line). CONCLUSIONS Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age-related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cm2, no other adverse events were of concern. Randomized clinical trials to investigate whether this new modality can preserve vision in patients with CNV secondary to age-related macular degeneration are justified.

Optical coherence tomography of the human skin

BACKGROUND Optical coherence tomography (OCT) is a new diagnostic method for tissue characterization. OBJECTIVE We investigated normal and pathologic structures in human skin in several locations to evaluate the potential application of this technique to dermatology. METHODS Based on the principle of low-coherence interferometry, cross-sectional images of the human skin can be obtained in vivo with a high spatial resolution of about 15 microns. Within a penetration depth of 0.5 to 1.5 mm, structures of the stratum corneum, the living epidermis, and the papillary dermis can be distinguished. RESULTS Different layers could be detected that were differentiated by induction of experimental blisters and by comparison with corresponding histologic sections. Furthermore, OCT images of several skin diseases and tumors were obtained. CONCLUSION OCT is a promising new imaging method for visualization of morphologic changes of superficial layers of the human skin. It may be useful for noninvasive diagnosis of bullous skin diseases, skin tumors, and in vivo investigation of pharmacologic effects.

Vascular Targeting in Photodynamic Occlusion of Subretinal Vessels

PURPOSE To evaluate the potential of photodynamic therapy (PDT) using benzoporphyrin derivative (BPD) for occlusion of subretinal neovascular membranes, the authors studied efficiency and collateral damage of PDT-induced photothrombosis in the rabbit choriocapillary layer. METHOD Benzoporphyrin derivative, a new photosensitizer, currently in clinical trials for tumor therapy, was used. Low-density lipoprotein served as a carrier to enhance selective targeting of vascular endothelial cells. RESULTS Complete choriocapillary occlusion was achieved at a BPD dose of 2 mg/kg and a radiant exposure as low as 10 J/cm2. When PDT was performed 3 hours after BPD application, damage to the neural retina was minimal. Only inner photoreceptor segments showed mitochondrial swelling probably secondary to choroidal ischemia. Bruchs membrane remained intact. Retinal pigment epithelium was invariably damaged as seen with other photosensitizers. CONCLUSION Compared with photocoagulation BPD-PDT allows endothelial-bound intraluminal photothrombosis, sparing important structures such as neural retina and Bruchs membrane. It may thus provide a more selective treatment of juxtafoveal and subfoveal neovascular membranes.

Thermal and biomechanical parameters of porcine cornea.

Purpose. New methods in refractive surgery require a considerable understanding of the material “cornea” and are often studied by theoretical modeling in order to gain insight into the procedure and an optimized approach to the technique. The quality of these models is highly dependent on the preciseness of its input parameters. Porcine cornea often is used as a model in preclinical studies because of its similarity to man and its availability. Methods. The important physical parameters for biomechanical deformation, heat conduction, and collagen denaturation kinetics have been determined for porcine cornea. Experimental methods include densitometry, calorimetry, turbidimetry, tensile tests, stress relaxation, and hydrothermal isometric tension measurements. Results. The density of porcine cornea was measured as &rgr; = 1062 ± 5 kg/m3, the heat capacity gave c = 3.74 ± 0.05 J/gK. The stress–strain relation for corneal strips is represented by a third order approximation where the secant modulus yields about Esec ≈ 0.4 MPa for small strains less than 2%. The normalized stress relaxation is described by an exponential fit over time. The denaturation process of cornea is characterized by specific temperatures which can be related to the change of the mechanical properties. Denaturation kinetics are described according to the model of Arrhenius yielding the activation energy &Dgr;Ea = 106 kJ/mol and the phase transition entropy &Dgr;S = 39 J/(mol · K). Conclusions. The established set of parameters characterizes the porcine cornea in a reliable way that creates a basis for corneal models. It furthermore gives direct hints of how to treat cornea in certain refractive techniques.

Intraocular Nd:YAG laser surgery: laser-tissue interaction, damage range, and reduction of collateral effects

The damage mechanisms of intraocular Nd:YAG laser surgery and their respective damage ranges were investigated in vitro using bovine cornea specimens as a model tissue. The main damage mechanisms are plasma formation and expansion, emission of acoustic transients, and cavitation with jet formation. When a sequence of laser pulses is applied, the interaction of the acoustic transients with gas bubbles remaining from preceding laser exposures is also important. To distinguish the effects caused by the different physical mechanisms, laser pulses were aimed directly onto the corneal endothelium, through the cornea, and parallel to the cornea at various distances. Simultaneously, the cavitation bubble size was determined. The damage range of the acoustic transients produced by a 4 mJ laser pulse is several millimeters, when they can interact with small gas bubbles attached to the corneal endothelium. >

Theoretical investigations of laser thermal retinal injury.

A thermal damage model including heat conduction for retinal lesions is described to explain thermal threshold damage and compare it to experimental values in the regime of 1 ms to 300 ms. With the aid of these model calculations unspecific thermal damage (denaturation of proteins) could be separated from thermally induced damage to the photoreceptors. Furthermore, the thermal model allows an extrapolation to hazards to the fundus from intense light irradiation that have not been investigated experimentally.

Origin of retinal pigment epithelium cell damage by pulsed laser irradiance in the nanosecond to microsecond time regimen

Selective photodamage of the retinal pigment epithelium (RPE) is a new technique to treat a variety of retinal diseases without causing adverse effects to surrounding tissues such as the neural retina including the photoreceptors and the choroid. In this study, the mechanism of cell damage after laser irradiation was investigated.

Low-coherence optical tomography in turbid tissue: theoretical analysis

On the basis of white-light interferometry and statistical optics, a theoretical model for low-coherence optical tomography is presented that establishes the relation of interference modulation with path-length-resolved reflectance and that can provide analytical expressions and numerical solutions by means of a Fourier transform. The Monte Carlo technique is used to simulate the path-length-resolved reflectance from different multilayer tissue phantoms. Theoretical analyses and preliminary experimental results suggest that, unlike time-resolved spectroscopy, low-coherence optical tomography detects the local relative variations of path-length-resolved reflectance from the turbid tissues.

Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples

Abstract · Background: Conventional photocoagulation of subfoveal choroidal neovascularization (CNV) is often accompanied by visual loss due to thermal damage to adjacent retinal structures. Photodynamic therapy (PDT) allows vascular occlusion by selective photochemical destruction of vascular endothelial cells only. In a pilot study we evaluated the use of PDT in CNV. · Methods: In a clinical phase I/II trial, patients with subfoveal CNV were treated with PDT. Benzoporphyrin derivative monoacid ring A (BPD) was used as sensitizer at a drug dose of 6 mg/m2 or 12 mg/m2. Irradiation was performed via a diode laser emitting at 690 nm coupled into a slit lamp. Safe and maximum tolerated light doses were defined by dose escalation from 25 to 150 J/cm2. Photodynamic effects were documented ophthalmoscopically and angiographically. · Results: Sixty-one patients received a single course of BPD-PDT. Preliminary results suggest no damage to retinal structures within the treated area clinically. Retinal perfusion was not altered, while CNV demonstrated immediate absence of fluorescein leakage in the majority of lesions subsequent to PDT. At optimized parameters (6 mg/m2 and 50 J/cm2) complete cessation of leakage from classic CNV occurred in 100% of cases at 1 week and in 50% at week 4. In 70–80% of classic CNV, leakage reappeared at week 12, but markedly less than before treatment. · Conclusion: PDT allows temporary absence of leakage from CNV with preservation of visual acuity. The long-term prognosis of CNV secondary to age-related macular degeneration treated with repeated courses of PDT is being evaluated in a phase III trial.

Photodynamic Therapy of Experimental Choroidal Melanoma Using Lipoprotein-delivered Benzoporphyrin

BACKGROUND Benzoporphyrin derivative monoacid (BPD) is a new photosensitizer currently undergoing clinical trial for cutaneous malignancies. Compared with the clinically most frequently used sensitizer, Photofrin, BPD may offer higher tumor phototoxicity, better tissue penetration, and absence of significant skin sensitization. Low-density lipoprotein (LDL) carriers heighten efficiency and selectivity of BPD because neovascular and tumor cells express an increased number of LDL receptors. Hence, in addition to the vaso-occlusive effects similar to most other photosensitizers, LDL-BPD also has been shown to cause direct tumor cell damage. METHODS Benzoporphyrin derivative monoacid was complexed with human LDL and used in photodynamic treatment of choroidal melanomas experimentally induced in eight albino rabbits. Five rabbits served as controls. Three hours after intravenous injection of 2 mg/kg body weight of LDL-BPD, eight tumors were irradiated at 692 nm and 100 J/cm2 via an argon-pumped dye laser coupled into a slit lamp. RESULTS Angiography and histologic findings showed immediate photothrombosis after disintegration of endothelial membranes. After complete necrosis of tumor cells within 24 hours, a small fibrotic scar slowly developed. No tumor regrowth was noted up to 6 weeks when animals were killed. CONCLUSION These data suggest that photodynamic treatment with LDL-BPD may be a promising modality for multiple clinical applications, including tumors and neovascularizations II.