Selective RPE Laser Treatment (SRT) for Various Macular Diseases

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Brief Title

Selective RPE Laser Treatment (SRT) for Various Macular Diseases

Official Title

Selective RPE Laser Treatment (SRT) for Various Macular Diseases

Brief Summary

      In this prospective clinical study SRT is performed with various pulse durations at 1.7µs and
      additionally 200ns to evaluate the different clinical effects of both laser regimens. The
      macular diseases to be treated are drusen maculopathy and geographic atrophy due to
      age-related macular degeneration as well as diabetic macular edema and central serous
      chorioretinopathy.

      The beneficial effect in laser treatment is thought to be associated with the restoration of
      a new barrier of retinal pigment epithelium cells. If this theory is true, the destruction of
      the photoreceptors causing visual field defects would be only an unwanted and unnecessary
      side effect. Thus, SRT is able to avoid these unintentional side effects and to achieve the
      benefit by just treating the RPE.

      In this study the clinical effect of SRT for these diseases is evaluated on a long-term
      basis.
    

Detailed Description

      Conventional laser photocoagulation has been shown to be beneficial in a variety of retinal
      diseases like age related macular degeneration (AMD), diabetic maculopathy (DMP), diabetic
      retinopathy (DRP) or central serous retinopathy (CSR). There are several hints that the
      positive effect is mediated by the RPE. The RPE is the main target of laser energy due to its
      high amount of melanosomes and absorbs about 50 to 60 % of the energy applied to the retina.
      Today conventional retinal laser treatment is performed using the continuous-wave argon laser
      (514 nm). Generally the exposure times are longer than 50 ms, typically 100 to 200ms. After
      application of the laser energy onto the retina usually an ophthalmoscopically visible
      grayish-white lesion results from thermal heat conduction. Histologically a destruction of
      the RPE, which is the primary absorption site, occurs, leading to an irreversible destruction
      of the outer and inner segments of the neuroretina due to thermal denaturation.

      The effect of laser treatment to the fundus was studied by several groups. In vivo it could
      be observed that argon laser photocoagulation of the monkey- and human fundus causes necrosis
      of the RPE and a detachment of the RPE from Bruch´s membrane, budding of individual RPE cells
      and a multilayered RPE formation in the area of laser irradiation by seven days after
      treatment. Histologic sections revealed that by irradiating the RPE with a conventional argon
      laser the whole area of the cells is destroyed and the choriocapillaris as well as the
      vessels of the choroid are damaged. After laser photocoagulation RPE cells migrate and
      proliferate to cover the defect. In vivo after mild coagulations as usually performed in
      macular coagulation the RPE barrier gets intact again.

      Several macular diseases are thought to be caused only by a reduced function of the RPE
      cells. Therefore a method for the selective destruction of the RPE cells without causing
      adverse effects to choroid and neuroretina, especially to the photoreceptors, seems to be an
      appropriate treatment (SRT). The selective effect on RPE cells, which absorb about 50% of the
      incident light due to their high melanosome content has been demonstrated using 5 µs argon
      laser pulses at 514nm with a repetition rate of 500 Hz. By irradiating the fundus with a
      train of µs laser pulses it was possible to achieve high peak temperatures around the
      melanosomes. This led to a destruction of the RPE, but only a low sublethal temperature
      increase in adjacent tissue structures. This selective destruction of the RPE cells sparing
      the photoreceptors without causing laser scotoma has been proven by histologic examinations
      at different times after treatment. The first clinical trial using a Nd:YLF laser system with
      a pulse duration of 1,7µs (100 pulses, 100 and 500 Hz) also proved the concept of selective
      RPE destruction and demonstrated the clinical potential of this technique. However, one of
      the problems concerning selective RPE laser destruction is the inability to visualize the
      laser lesions. Therefore it is necessary to perform fluorescein angiography after treatment
      to confirm the laser success and to make sure that sufficient energy was used. Since
      dosimetry of such laser lesions is not known, test lesions with various energy and numbers of
      pulses in non-significant areas of the macula - usually at the lower vessel arcade - have to
      be applied to elucidate the energy levels required for treatment. If the RPE is damaged, or
      the tight junctions of the RPE barrier are broken, fluorescein from angiography can pool from
      the choriocapillaris into the subretinal space. Thus fluorescein angiography has been used to
      detect a break of the RPE barrier. However, fluorescein angiography is an invasive method and
      has as already described a potential risk for allergic reactions because of the intravenous
      injection of the fluorescein dye.

      The damage mechanism in SRT is more a thermo-mechanical one than a purely thermal one as in
      conventional laser treatment due to the short-duration laser pulses in the
      microsecond-regime. Thus, microbubble formation around the melanosomes inside the RPE cell
      occurs during treatment, probably leading to disruption of the cell; this is in contrast to
      thermal denaturation in conventional laser photocoagulation. The formation of microbubbles
      around the strong absorbing melanosomes inside the RPE has been proofed as damage mechanism
      during irradiation of the RPE with µs laser pulses. If energy is absorbed and converted to
      heat the thermoelastic expansion of the absorbing medium will generate an opto-acoustic (OA)
      transient. During irradiation of RPE with µs laser pulses a classical thermoelastic transient
      will be emitted. Due to the formation and collapse of microbubbles around the melanosomes
      during a successful SRT treatment, additional OA bubble transients will be emitted. This is
      analogous to the emission of acoustic transients during formation and collapse of cavitation
      bubbles. An OA based on-line dosimetry system can differentiate between a pure thermoelastic
      transient in a subthreshold irradiation and OA bubble transients superimposed to the pure
      thermoelastic transients in case of a successful treatment irradiation. Thus, SRT can
      clinically be guided by this specific OA detection system.

      In this prospective clinical study SRT is performed with various pulse durations at 1.7µs and
      additionally 200ns to evaluate the different clinical effects of both laser regimens, which
      were already determined to be safe in animal experiments. The macular diseases to be treated
      are drusen maculopathy and geographic atrophy due to age-related macular degeneration as well
      as diabetic macular edema and central serous chorioretinopathy.

      The beneficial effect in laser treatment of diabetic macular edema is thought to be
      associated with the restoration of a new barrier of retinal pigment epithelium cells. A
      similar effect is postulated in the treatment of drusen, central serous retinopathy and
      macular edema after vein occlusion. If these latter theories are true, the destruction of the
      photoreceptors causing visual field defects would be only an unwanted and unnecessary side
      effect. Thus, SRT is able to avoid these unintentional side effects and to achieve the
      benefit by just treating the RPE.

      In this study the clinical effect of SRT for these diseases is evaluated on a long-term
      basis. For diabetic macular edema previously non-treated eyes with focal or diffuse macular
      edema are randomized to SRT or conventional treatment. Best corrected visual acuity has to be
      at least 0.1 and no central ischemia must be present. The endpoint is visual acuity and
      reduction of edema as determined by fundus photography, angiography and optical coherence
      tomography. Regarding central serous chorioretinopathy visual acuity decay should last longer
      than 2 months with angiographically seen leakage outside the fovea. Endpoint is visual acuity
      and reduction of subretinal edema as determined by optical coherence tomography. Regarding
      AMD drusen maculopathy has to show soft confluent drusen and hyperpigmented spots.
      Angiographically a choroidal neovascularization has to be ruled out. Both eyes of the patient
      must have symmetric patterns since one eye is treated and the other one observed. End point
      would be a visual acuity and reduction of drusen as determined by fundus photography. For
      geographic atrophy due to age-related macular degeneration both eyes of the patient should
      present symmetric areas of atrophy. Laser treatment takes place at the rim of the atrophy
      zone in one eye whereas the other eye is observed. Due to RPE proliferation induced by SRT
      the major endpoint for this entity will be the stop or reduction of geographic atrophy
      enlargement in the treated eye compared with the fellow eye. Visual acuity should be at least
      0.1.

      All patients will be followed at various times after treatment as derived from a strict
      inclusion and follow-up protocol. The study is approved by the institutional study board and
      ethical committee; patients safety is covered by a private insurance company.
    


Study Type

Interventional


Primary Outcome

Visual acuity

Secondary Outcome

 drusen reduction

Condition

Age-Related Macular Degeneration

Intervention

Selective RPE laser treatment


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

60

Start Date

October 2004

Completion Date

August 2010

Primary Completion Date

December 2009

Eligibility Criteria

        Inclusion Criteria:

          -  symmetric drusen maculopathy with soft drusen both eyes

          -  symmetric geographic atrophy both eyes

          -  diabetic macular edema single eye

          -  acute or chronic central serous chorioretinopathy

        Exclusion Criteria:

          -  previous laser treatment

          -  previous intravitreal injections

          -  choroidal neovascularization

          -  visual acuity > 0.1
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Carsten Framme, MD, , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT00403884

Organization ID

University Eye Hospital SRT



Study Sponsor

University of Regensburg

Collaborators

 Dr. Werner Jackstaedt Foundation

Study Sponsor

Carsten Framme, MD, Principal Investigator, University Eye Hospital Regensburg


Verification Date

November 2006